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TENORMIN®
(atenolol)
TABLETS
DESCRIPTION
TENORMIN®
(atenolol),
a
synthetic,
beta1-selective
(cardioselective) adrenoreceptor blocking agent, may be
chemically described as benzeneacetamide, 4 -[2'-hydroxy
3'-[(1- methylethyl) amino] propoxy]-. The molecular and
structural formulas are: structural formula
C14H22N2O3
Atenolol (free base) has a molecular weight of 266. It is a
relatively polar hydrophilic compound with a water solubility
of 26.5 mg/mL at 37°C and a log partition coefficient
(octanol/water) of 0.23. It is freely soluble in 1N HCl (300
mg/mL at 25°C) and less soluble in chloroform (3 mg/mL at
25°C).
TENORMIN is available as 25, 50 and 100 mg tablets for oral
administration.
Inactive Ingredients: Magnesium stearate, microcrystalline
cellulose, povidone, sodium starch glycolate.
CLINICAL PHARMACOLOGY
TENORMIN
is
a
beta1-selective
(cardioselective)
beta-adrenergic receptor blocking agent without membrane
stabilizing or intrinsic sympathomimetic (partial agonist)
activities. This preferential effect is not absolute, however,
and
at
higher
doses,
TENORMIN
inhibits
beta2-adrenoreceptors, chiefly located in the bronchial and
vascular musculature.
1
Reference ID: 3001231
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pharmacokinetics and Metabolism
In man, absorption of an oral dose is rapid and consistent but
incomplete. Approximately 50% of an oral dose is absorbed
from the gastrointestinal tract, the remainder being excreted
unchanged in the feces.
Peak blood levels are reached
between two (2) and four (4) hours after ingestion. Unlike
propranolol or metoprolol, but like nadolol, TENORMIN
undergoes little or no metabolism by the liver, and the
absorbed portion is eliminated primarily by renal excretion.
Over 85% of an intravenous dose is excreted in urine within
24 hours compared with approximately 50% for an oral dose.
TENORMIN also differs from propranolol in that only a small
amount (6%-16%) is bound to proteins in the plasma. This
kinetic profile results in relatively consistent plasma drug
levels with about a fourfold interpatient variation.
The
elimination
half-life
of
oral
TENORMIN
is
approximately 6 to 7 hours, and there is no alteration of the
kinetic profile of the drug by chronic administration.
Following intravenous administration, peak plasma levels are
reached within 5 minutes. Declines from peak levels are rapid
(5- to 10-fold) during the first 7 hours; thereafter, plasma
levels decay with a half-life similar to that of orally
administered drug. Following oral doses of 50 mg or 100 mg,
both beta-blocking and antihypertensive effects persist for at
least 24 hours. When renal function is impaired, elimination of
TENORMIN is closely related to the glomerular filtration
rate; significant accumulation occurs when the creatinine
clearance falls below 35 mL/min/1.73m2. (See Dosage and
administration.)
Pharmacodynamics
In standard animal or human pharmacological tests,
beta-adrenoreceptor blocking activity of TENORMIN has
been demonstrated by: (1) reduction in resting and exercise
heart rate and cardiac output, (2) reduction of systolic and
diastolic blood pressure at rest and on exercise, (3) inhibition
of isoproterenol induced tachycardia, and (4) reduction in
reflex orthostatic tachycardia.
2
Reference ID: 3001231
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A significant beta-blocking effect of TENORMIN, as
measured by reduction of exercise tachycardia, is apparent
within one hour following oral administration of a single dose.
This effect is maximal at about 2 to 4 hours, and persists for at
least 24 hours. Maximum reduction in exercise tachycardia
occurs within 5 minutes of an intravenous dose. For both
orally and intravenously administered drug, the duration of
action is dose related and also bears a linear relationship to the
logarithm of plasma TENORMIN concentration. The effect on
exercise tachycardia of a single 10 mg intravenous dose is
largely dissipated by 12 hours, whereas beta-blocking activity
of single oral doses of 50 mg and 100 mg is still evident
beyond 24 hours following administration. However, as has
been shown for all beta-blocking agents, the antihypertensive
effect does not appear to be related to plasma level.
In normal subjects, the beta1 selectivity of TENORMIN has
been shown by its reduced ability to reverse the
beta2-mediated vasodilating effect of isoproterenol as
compared to equivalent beta-blocking doses of propranolol. In
asthmatic patients, a dose of TENORMIN producing a greater
effect on resting heart rate than propranolol resulted in much
less increase in airway resistance. In a placebo controlled
comparison of approximately equipotent oral doses of several
beta blockers, TENORMIN produced a significantly smaller
decrease of FEV1 than nonselective beta blockers such as
propranolol and, unlike those agents, did not inhibit
bronchodilation in response to isoproterenol.
Consistent with its negative chronotropic effect due to beta
blockade of the SA node, TENORMIN increases sinus cycle
length and sinus node recovery time. Conduction in the AV
node is also prolonged. TENORMIN is devoid of membrane
stabilizing activity, and increasing the dose well beyond that
producing beta blockade does not further depress myocardial
contractility. Several studies have demonstrated a moderate
(approximately 10%) increase in stroke volume at rest and
during exercise.
3
Reference ID: 3001231
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In controlled clinical trials, TENORMIN, given as a single
daily oral dose, was an effective antihypertensive agent
providing 24-hour reduction of blood pressure. TENORMIN
has been studied in combination with thiazide type diuretics,
and the blood pressure effects of the combination are
approximately additive. TENORMIN is also compatible with
methyldopa, hydralazine, and prazosin, each combination
resulting in a larger fall in blood pressure than with the single
agents.
The dose range of TENORMIN is narrow and
increasing the dose beyond 100 mg once daily is not
associated with increased antihypertensive effect. The
mechanisms of the antihypertensive effects of beta-blocking
agents have not been established.
Several possible
mechanisms have been proposed and include: (1) competitive
antagonism of catecholamines at peripheral (especially
cardiac) adrenergic neuron sites, leading to decreased cardiac
output, (2) a central effect leading to reduced sympathetic
outflow to the periphery, and (3) suppression of renin activity.
The results from long-term studies have not shown any
diminution of the antihypertensive efficacy of TENORMIN
with prolonged use.
By blocking the positive chronotropic and inotropic effects of
catecholamines and by decreasing blood pressure, atenolol
generally reduces the oxygen requirements of the heart at any
given level of effort, making it useful for many patients in the
long-term management of angina pectoris. On the other hand,
atenolol can increase oxygen requirements by increasing left
ventricular fiber length and end diastolic pressure, particularly
in patients with heart failure.
4
Reference ID: 3001231
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In a multicenter clinical trial (ISIS-1) conducted in 16,027
patients with suspected myocardial infarction, patients
presenting within 12 hours (mean = 5 hours) after the onset of
pain were randomized to either conventional therapy plus
TENORMIN (n = 8,037), or conventional therapy alone (n =
7,990). Patients with a heart rate of < 50 bpm or systolic
blood pressure < 100 mm Hg, or with other contraindications
to beta blockade were excluded. Thirty-eight percent of each
group were treated within 4 hours of onset of pain. The mean
time from onset of pain to entry was 5.0 ± 2.7 hours in both
groups. Patients in the TENORMIN group were to receive
TENORMIN I.V. Injection 5-10 mg given over 5 minutes plus
TENORMIN Tablets 50 mg every 12 hours orally on the first
study day (the first oral dose administered about 15 minutes
after the IV dose) followed by either TENORMIN Tablets 100
mg once daily or TENORMIN Tablets 50 mg twice daily on
days 2-7.
The groups were similar in demographic and
medical history characteristics and in electrocardiographic
evidence of myocardial infarction, bundle branch block, and
first degree atrioventricular block at entry.
During the treatment period (days 0-7), the vascular mortality
rates were 3.89% in the TENORMIN group (313 deaths) and
4.57% in the control group (365 deaths). This absolute
difference in rates, 0.68%, is statistically significant at the P <
0.05 level.
The absolute difference translates into a
proportional reduction of 15% (3.89-4.57/4.57 = -0.15). The
95% confidence limits are 1%-27%. Most of the difference
was attributed to mortality in days 0-1 (TENORMIN - 121
deaths; control - 171 deaths).
Despite the large size of the ISIS-1 trial, it is not possible to
identify clearly subgroups of patients most likely or least
likely to benefit from early treatment with atenolol. Good
clinical judgment suggests, however, that patients who are
dependent on sympathetic stimulation for maintenance of
adequate cardiac output and blood pressure are not good
candidates for beta blockade.
Indeed, the trial protocol
reflected that judgment by excluding patients with blood
pressure consistently below 100 mm Hg systolic. The overall
results of the study are compatible with the possibility that
patients with borderline blood pressure (less than 120 mm Hg
systolic), especially if over 60 years of age, are less likely to
benefit.
5
Reference ID: 3001231
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The mechanism through which atenolol improves survival in
patients with definite or suspected acute myocardial infarction
is unknown, as is the case for other beta blockers in the
postinfarction setting. Atenolol, in addition to its effects on
survival, has shown other clinical benefits including reduced
frequency of ventricular premature beats, reduced chest pain,
and reduced enzyme elevation.
Atenolol Geriatric Pharmacology:
In general, elderly patients present higher atenolol plasma
levels with total clearance values about 50% lower than
younger subjects. The half-life is markedly longer in the
elderly compared to younger subjects. The reduction in
atenolol clearance follows the general trend that the
elimination of renally excreted drugs is decreased with
increasing age.
INDICATIONS AND USAGE
Hypertension
TENORMIN is indicated in the management of hypertension.
It may be used alone or concomitantly with other
antihypertensive agents, particularly with a thiazide-type
diuretic.
Angina Pectoris Due to Coronary Atherosclerosis
TENORMIN is indicated for the long-term management of
patients with angina pectoris.
Acute Myocardial Infarction
TENORMIN
is
indicated
in
the
management
of
hemodynamically stable patients with definite or suspected
acute
myocardial
infarction
to
reduce
cardiovascular
mortality. Treatment can be initiated as soon as the patient's
clinical
condition
allows.
(See
DOSAGE
AND
ADMINISTRATION,
CONTRAINDICATIONS,
and
WARNINGS.) In general, there is no basis for treating
patients like those who were excluded from the ISIS-1 trial
(blood pressure less than 100 mm Hg systolic, heart rate less
than 50 bpm) or have other reasons to avoid beta blockade.
As noted above, some subgroups (eg, elderly patients with
systolic blood pressure below 120 mm Hg) seemed less likely
to benefit.
6
Reference ID: 3001231
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CONTRAINDICATIONS
TENORMIN is contraindicated in sinus bradycardia, heart
block greater than first degree, cardiogenic shock, and overt
cardiac failure. (See WARNINGS.)
TENORMIN is contraindicated in those patients with a history
of hypersensitivity to the atenolol or any of the drug product’s
components.
WARNINGS
Cardiac Failure
Sympathetic stimulation is necessary in supporting circulatory
function in congestive heart failure, and beta blockade carries
the potential hazard of further depressing myocardial
contractility and precipitating more severe failure.
In patients with acute myocardial infarction, cardiac failure
which is not promptly and effectively controlled by 80 mg of
intravenous
furosemide
or
equivalent
therapy
is
a
contraindication to beta-blocker treatment.
In Patients Without a History of Cardiac Failure
Continued depression of the myocardium with beta-blocking
agents over a period of time can, in some cases, lead to
cardiac failure. At the first sign or symptom of impending
cardiac failure, patients should be treated appropriately
according to currently recommended guidelines, and the
response observed closely. If cardiac failure continues despite
adequate treatment, TENORMIN should be withdrawn. (See
Dosage and administration)
7
Reference ID: 3001231
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Cessation of Therapy with TENORMIN
Patients with coronary artery disease, who are being treated
with TENORMIN, should be advised
against
abrupt
discontinuation of therapy. Severe exacerbation of angina
and the
occurrence of myocardial infarction and ventricular
arrhythmias have been reported in angina patients following
the abrupt discontinuation of therapy with beta blockers. The
last two complications may occur with or without preceding
exacerbation of the angina pectoris. As with other beta
blockers,
when discontinuation of TENORMIN is planned,
the patients should be carefully observed and advised to limit
physical activity to a minimum. If the angina worsens or
acute coronary insufficiency develops, it is recommended that
TENORMIN be promptly reinstituted, at least temporarily.
Because coronary artery disease is common and may be
unrecognized, it may be prudent not to discontinue
TENORMIN therapy abruptly even in patients treated only
for hypertension. (See Dosage and administration.)
Concomitant Use of Calcium Channel Blockers
Bradycardia and heart block can occur and the left ventricular
end diastolic pressure can rise when beta-blockers are
administered with verapamil or diltiazem. Patients with pre
existing
conduction
abnormalities
or
left
ventricular
dysfunction
are
particularly
susceptible.
(See
PRECAUTIONS.)
Bronchospastic Diseases
PATIENTS WITH BRONCHOSPASTIC
DISEASE
SHOULD, IN GENERAL, NOT RECEIVE BETA
BLOCKERS.
Because of its relative beta1 selectivity,
however, TENORMIN may be used with caution in
patients with bronchospastic disease who do not respond
to, or cannot tolerate, other antihypertensive treatment.
Since beta1 selectivity is not absolute, the lowest possible
dose of TENORMIN should be used with therapy initiated
at 50 mg and a beta2-stimulating agent (bronchodilator)
should be made available. If dosage must be increased,
dividing the dose should be considered in order to achieve
lower peak blood levels.
8
Reference ID: 3001231
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Major Surgery
Chronically administered beta-blocking therapy should not be
routinely withdrawn prior to major surgery; however, the
impaired ability of the heart to respond to reflex adrenergic
stimuli may augment the risks of general anesthesia and
surgical procedures.
Diabetes and Hypoglycemia
TENORMIN should be used with caution in diabetic patients
if a beta-blocking agent is required. Beta blockers may mask
tachycardia
occurring
with
hypoglycemia,
but
other
manifestations such as dizziness and sweating may not be
significantly affected. At recommended doses TENORMIN
does not potentiate insulin-induced hypoglycemia and, unlike
nonselective beta blockers, does not delay recovery of blood
glucose to normal levels.
Thyrotoxicosis
Beta-adrenergic blockade may mask certain clinical signs (eg,
tachycardia) of hyperthyroidism. Abrupt withdrawal of beta
blockade might precipitate a thyroid storm; therefore, patients
suspected
of
developing
thyrotoxicosis
from
whom
TENORMIN therapy is to be withdrawn should be monitored
closely. (See Dosage and administration.)
Untreated Pheochromocytoma
TENORMIN should not be given to patients with untreated
pheochromocytoma.
Pregnancy and Fetal Injury
Atenolol can cause fetal harm when administered to a
pregnant woman. Atenolol crosses the placental barrier and
appears in cord blood. Administration of atenolol, starting in
the second trimester of pregnancy, has been associated with
the birth of infants that are small for gestational age. No
studies have been performed on the use of atenolol in the first
trimester and the possibility of fetal injury cannot be excluded.
If this drug is used during pregnancy, or if the patient becomes
pregnant while taking this drug, the patient should be apprised
of the potential hazard to the fetus.
9
Reference ID: 3001231
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Neonates born to mothers who are receiving TENORMIN at
parturition or breast-feeding may be at risk for hypoglycemia
and bradycardia. Caution should be exercised when
TENORMIN is administered during pregnancy or to a woman
who is breast-feeding. (See PRECAUTIONS, Nursing
Mothers.)
Atenolol has been shown to produce a dose-related increase in
embryo/fetal resorptions in rats at doses equal to or greater
than 50 mg/kg/day or 25 or more times the maximum
recommended human antihypertensive dose.* Although
similar effects were not seen in rabbits, the compound was not
evaluated in rabbits at doses above 25 mg/kg/day or 12.5
times the maximum recommended human antihypertensive
dose.*
PRECAUTIONS
General
Patients already on a beta blocker must be evaluated carefully
before TENORMIN is administered. Initial and subsequent
TENORMIN dosages can be adjusted downward depending
on clinical observations including pulse and blood pressure.
TENORMIN may aggravate peripheral arterial circulatory
disorders.
Impaired Renal Function
The drug should be used with caution in patients with
impaired renal function. (See Dosage and administration.)
*Based on the maximum dose of 100 mg/day in a 50 kg
patient.
Drug Interactions
Catecholamine-depleting drugs (eg, reserpine) may have an
additive effect when given with beta-blocking agents. Patients
treated with TENORMIN plus a catecholamine depletor
should therefore be closely observed for evidence of
hypotension and/or marked bradycardia which may produce
vertigo, syncope, or postural hypotension.
Calcium channel blockers may also have an additive effect
when given with TENORMIN (See WARNINGS).
10
Reference ID: 3001231
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Disopyramide is a Type I antiarrhythmic drug with potent
negative inotropic and chronotropic effects. Disopyramide has
been associated with severe bradycardia, asystole and heart
failure when administered with beta blockers.
Amiodarone is an antiarrhythmic agent with negative
chronotropic properties that may be additive to those seen
with beta blockers.
Beta blockers may exacerbate the rebound hypertension which
can follow the withdrawal of clonidine. If the two drugs are
coadministered, the beta blocker should be withdrawn several
days before the gradual withdrawal of clonidine. If replacing
clonidine by beta-blocker therapy, the introduction of beta
blockers should be delayed for several days after clonidine
administration has stopped.
Concomitant use of prostaglandin synthase inhibiting drugs,
eg, indomethacin, may decrease the hypotensive effects of
beta blockers.
Information on concurrent usage of atenolol and aspirin is
limited. Data from several studies, ie, TIMI-II, ISIS-2,
currently do not suggest any clinical interaction between
aspirin and beta blockers in the acute myocardial infarction
setting.
While taking beta blockers, patients with a history of
anaphylactic reaction to a variety of allergens may have a
more severe reaction on repeated challenge, either accidental,
diagnostic or therapeutic. Such patients may be unresponsive
to the usual doses of epinephrine used to treat the allergic
reaction.
Both
digitalis
glycosides
and
beta-blockers
slow
atrioventricular
conduction
and
decrease
heart
rate.
Concomitant use can increase the risk of bradycardia.
11
Reference ID: 3001231
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Carcinogenesis, Mutagenesis, Impairment of Fertility
Two long-term (maximum dosing duration of 18 or
24 months) rat studies and one long-term (maximum dosing
duration of 18 months) mouse study, each employing dose
levels as high as 300 mg/kg/day or 150 times the maximum
recommended human antihypertensive dose,* did not indicate
a carcinogenic potential of atenolol. A third (24 month) rat
study, employing doses of 500 and 1,500 mg/kg/day (250 and
750
times
the
maximum
recommended
human
antihypertensive dose*) resulted in increased incidences of
benign adrenal medullary tumors in males and females,
mammary fibroadenomas in females, and anterior pituitary
adenomas and thyroid parafollicular cell carcinomas in males.
No evidence of a mutagenic potential of atenolol was
uncovered in the dominant lethal test (mouse), in vivo
cytogenetics test (Chinese hamster) or Ames test (S
typhimurium).
Fertility of male or female rats (evaluated at dose levels as
high as 200 mg/kg/day or 100 times the maximum
recommended human dose*) was unaffected by atenolol
administration.
Animal Toxicology
Chronic studies employing oral atenolol performed in animals
have revealed the occurrence of vacuolation of epithelial cells
of Brunner's glands in the duodenum of both male and female
dogs at all tested dose levels of atenolol (starting at 15
mg/kg/day or 7.5 times the maximum recommended human
antihypertensive dose*) and increased incidence of atrial
degeneration of hearts of male rats at 300 but not 150 mg
atenolol/kg/day
(150
and
75 times
the
maximum
recommended human antihypertensive dose,* respectively).
Usage in Pregnancy
Pregnancy Category D
See WARNINGS - Pregnancy and Fetal Injury.
*Based on the maximum dose of 100 mg/day in a 50 kg
patient.
12
Reference ID: 3001231
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Nursing Mothers
Atenolol is excreted in human breast milk at a ratio of 1.5 to
6.8 when compared to the concentration in plasma. Caution
should be exercised when TENORMIN is administered to a
nursing woman. Clinically significant bradycardia has been
reported in breast-fed infants. Premature infants, or infants
with impaired renal function, may be more likely to develop
adverse effects.
Neonates born to mothers who are receiving TENORMIN at
parturition or breast-feeding may be at risk for hypoglycemia
and bradycardia. Caution should be exercised when
TENORMIN is administered during pregnancy or to a woman
who is breast-feeding (See WARNINGS, Pregnancy and Fetal
Injury).
Pediatric Use
Safety and effectiveness in pediatric patients have not been
established.
Geriatric Use
Hypertension and Angina Pectoris Due to Coronary
Atherosclerosis:
Clinical studies of TENORMIN did not include sufficient
number of patients aged 65 and over to determine whether
they respond differently from younger subjects. Other
reported clinical experience has not identified differences in
responses between the elderly and younger patients.
In
general, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or
cardiac function, and of concomitant disease or other drug
therapy.
Acute Myocardial Infarction:
Of the 8,037 patients with suspected acute myocardial
infarction randomized to TENORMIN in the ISIS-1 trial (See
CLINICAL PHARMACOLOGY), 33% (2,644) were 65 years
of age and older. It was not possible to identify significant
differences in efficacy and safety between older and younger
patients; however, elderly patients with systolic blood
pressure < 120 mmHg seemed less likely to benefit (See
INDICATIONS AND USAGE).
Reference ID: 3001231
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In general, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range,
reflecting greater frequency of decreased hepatic, renal, or
cardiac function, and of concomitant disease or other drug
therapy.
Evaluation of patients with hypertension or
myocardial infarction should always include assessment of
renal function.
ADVERSE REACTIONS
Most adverse effects have been mild and transient.
The frequency estimates in the following table were derived
from controlled studies in hypertensive patients in which
adverse reactions were either volunteered by the patient (US
studies) or elicited, eg, by checklist (foreign studies). The
reported frequency of elicited adverse effects was higher for
both TENORMIN and placebo-treated patients than when
these reactions were volunteered. Where frequency of adverse
effects of TENORMIN and placebo is similar, causal
relationship to TENORMIN is uncertain.
Total - Volunteered
Volunteered
and Elicited
(US Studies)
(Foreign+US Studies)
Atenolol
Placebo
Atenolol
Placebo
(n=164)
(n=206)
(n=399)
(n=407)
%
%
%
%
CARDIOVASCULAR
Bradycardia
3
0
3
0
Cold Extremities
0
0.5
12
5
Postural Hypotension
2
1
4
5
Leg Pain
0
0.5
3
1
CENTRAL NERVOUS SYSTEM/
NEUROMUSCULAR
Dizziness
4
1
13
6
Vertigo
2
0.5
2
0.2
Light-headedness
1
0
3
0.7
Tiredness
0.6
0.5
26
13
Fatigue
3
1
6
5
Lethargy
1
0
3
0.7
Drowsiness
0.6
0
2
0.5
Depression
0.6
0.5
12
9
Dreaming
0
0
3
1
GASTROINTESTINAL
Diarrhea
2
0
3
2
Nausea
4
1
3
1
14
Reference ID: 3001231
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RESPIRATORY (see WARNINGS)
Wheeziness
0
0
3
3
Dyspnea
0.6
1
6
4
Acute Myocardial Infarction
In a series of investigations in the treatment of acute
myocardial infarction, bradycardia and hypotension occurred
more commonly, as expected for any beta blocker, in atenolol
treated patients than in control patients. However, these
usually responded to atropine and/or to withholding further
dosage of atenolol. The incidence of heart failure was not
increased by atenolol. Inotropic agents were infrequently used.
The reported frequency of these and other events occurring
during these investigations is given in the following table.
In a study of 477 patients, the following adverse events were
reported during either intravenous and/or oral atenolol
administration:
Conventional Therapy
Conventional
Plus Atenolol
Therapy Alone
(n=244)
(n=233)
Bradycardia
43
(18%)
24
(10%)
Hypotension
60
(25%)
34
(15%)
Bronchospasm
3
(1.2%)
2
(0.9%)
Heart Failure
46
(19%)
56
(24%)
Heart Block
11
(4.5%)
10
(4.3%)
BBB + Major
Axis Deviation
16
(6.6%)
28
(12%)
Supraventricular Tachycardia
28
(11.5%)
45
(19%)
Atrial Fibrillation
12
(5%)
29
(11%)
Atrial Flutter
4
(1.6%)
7
(3%)
Ventricular Tachycardia
39
(16%)
52
(22%)
Cardiac Reinfarction
0
(0%)
6
(2.6%)
Total Cardiac Arrests
4
(1.6%)
16
(6.9%)
Nonfatal Cardiac Arrests
4
(1.6%)
12
(5.1%)
Deaths
7
(2.9%)
16
(6.9%)
Cardiogenic Shock
1
(0.4%)
4
(1.7%)
Development of Ventricular
Septal Defect
0
(0%)
2
(0.9%)
Development of Mitral
Regurgitation
0
(0%)
2
(0.9%)
Renal Failure
1
(0.4%)
0
(0%)
Pulmonary Emboli
3
(1.2%)
0
(0%)
15
Reference ID: 3001231
This label may not be the latest approved by FDA.
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In the subsequent International Study of Infarct Survival
(ISIS-1) including over 16,000 patients of whom 8,037 were
randomized to receive TENORMIN treatment, the dosage of
intravenous and subsequent oral TENORMIN was either
discontinued or reduced for the following reasons:
Reasons for Reduced Dosage
IV Atenolol
Reduced Dose
Oral Partial
(< 5 mg)*
Dose
Hypotension/Bradycardia
105
(1.3%)
1168
(14.5%)
Cardiogenic Shock
4
(.04%)
35
(.44%)
Reinfarction
0
(0%)
5
(.06%)
Cardiac Arrest
5
(.06%)
28
(.34%)
Heart Block (> first degree)
5
(.06%)
143
(1.7%)
Cardiac Failure
1
(.01%)
233
(2.9%)
Arrhythmias
3
(.04%)
22
(.27%)
Bronchospasm
1
(.01%)
50
(.62%)
*Full dosage was 10 mg and some patients received less than
10 mg but more than 5 mg.
During postmarketing experience with TENORMIN, the
following have been reported in temporal relationship to the
use of the drug:
elevated liver enzymes and/or bilirubin,
hallucinations, headache, impotence, Peyronie's disease,
postural hypotension which may be associated with syncope,
psoriasiform rash or exacerbation of psoriasis, psychoses,
purpura,
reversible
alopecia,
thrombocytopenia,
visual
disturbance,
sick
sinus
syndrome,
and
dry
mouth.
TENORMIN, like other beta blockers, has been associated
with the development of antinuclear antibodies (ANA), lupus
syndrome, and Raynaud’s phenomenon.
POTENTIAL ADVERSE EFFECTS
In addition, a variety of adverse effects have been reported
with other beta-adrenergic blocking agents, and may be
considered potential adverse effects of TENORMIN.
Hematologic: Agranulocytosis.
Allergic: Fever, combined with aching and sore throat,
laryngospasm, and respiratory distress.
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Reference ID: 3001231
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Central Nervous System: Reversible mental depression
progressing to catatonia; an acute reversible syndrome
characterized by disorientation of time and place; short-term
memory loss; emotional lability with slightly clouded
sensorium;
and,
decreased
performance
on
neuropsychometrics.
Gastrointestinal: Mesenteric arterial thrombosis, ischemic
colitis.
Other: Erythematous rash.
Miscellaneous: There have been reports of skin rashes and/or
dry eyes associated with the use of beta-adrenergic blocking
drugs. The reported incidence is small, and in most cases, the
symptoms have cleared when treatment was withdrawn.
Discontinuance of the drug should be considered if any such
reaction is not otherwise explicable. Patients should be
closely monitored following cessation of therapy. (See
DOSAGE AND ADMINISTRATION).
The oculomucocutaneous syndrome associated with the beta
blocker practolol has not been reported with TENORMIN.
Furthermore, a number of patients who had previously
demonstrated established practolol reactions were transferred
to TENORMIN therapy with subsequent resolution or
quiescence of the reaction.
OVERDOSAGE
Overdosage with TENORMIN has been reported with patients
surviving acute doses as high as 5 g. One death was reported
in a man who may have taken as much as 10 g acutely.
The predominant symptoms reported following TENORMIN
overdose are lethargy, disorder of respiratory drive, wheezing,
sinus pause and bradycardia. Additionally, common effects
associated with overdosage of any beta-adrenergic blocking
agent and which might also be expected in TENORMIN
overdose
are
congestive
heart
failure,
hypotension,
bronchospasm and/or hypoglycemia.
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Reference ID: 3001231
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Treatment of overdose should be directed to the removal of
any unabsorbed drug by induced emesis, gastric lavage, or
administration of activated charcoal. TENORMIN can be
removed from the general circulation by hemodialysis. Other
treatment modalities should be employed at the physician's
discretion and may include:
BRADYCARDIA: Atropine intravenously. If there is no
response to vagal blockade, give isoproterenol cautiously. In
refractory cases, a transvenous cardiac pacemaker may be
indicated.
HEART BLOCK (SECOND OR THIRD DEGREE):
Isoproterenol or transvenous cardiac pacemaker.
CARDIAC FAILURE: Digitalize the patient and administer a
diuretic. Glucagon has been reported to be useful.
HYPOTENSION: Vasopressors such as dopamine or
norepinephrine
(levarterenol).
Monitor
blood
pressure
continuously.
BRONCHOSPASM: A beta2 stimulant such as isoproterenol
or terbutaline and/or aminophylline.
HYPOGLYCEMIA: Intravenous glucose.
Based on the severity of symptoms, management may require
intensive support care and facilities for applying cardiac and
respiratory support.
DOSAGE AND ADMINISTRATION
Hypertension
The initial dose of TENORMIN is 50 mg given as one tablet a
day either alone or added to diuretic therapy. The full effect
of this dose will usually be seen within one to two weeks. If
an optimal response is not achieved, the dosage should be
increased to TENORMIN 100 mg given as one tablet a day.
Increasing the dosage beyond 100 mg a day is unlikely to
produce any further benefit.
TENORMIN may be used alone or concomitantly with other
antihypertensive agents including thiazide-type diuretics,
hydralazine, prazosin, and alpha-methyldopa.
Reference ID: 3001231
18
This label may not be the latest approved by FDA.
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Angina Pectoris
The initial dose of TENORMIN is 50 mg given as one tablet a
day. If an optimal response is not achieved within one week,
the dosage should be increased to TENORMIN 100 mg given
as one tablet a day. Some patients may require a dosage of
200 mg once a day for optimal effect.
Twenty-four hour control with once daily dosing is achieved
by giving doses larger than necessary to achieve an immediate
maximum effect. The maximum early effect on exercise
tolerance occurs with doses of 50 to 100 mg, but at these
doses the effect at 24 hours is attenuated, averaging about
50% to 75% of that observed with once a day oral doses of
200 mg.
Acute Myocardial Infarction
In patients with definite or suspected acute myocardial
infarction, treatment with TENORMIN I.V. Injection should
be initiated as soon as possible after the patient's arrival in the
hospital and after eligibility is established. Such treatment
should be initiated in a coronary care or similar unit
immediately after the patient's hemodynamic condition has
stabilized.
Treatment should begin with the intravenous
administration of 5 mg TENORMIN over 5 minutes followed
by another 5 mg intravenous injection 10 minutes later.
TENORMIN I.V. Injection should be administered under
carefully controlled conditions including monitoring of blood
pressure, heart rate, and electrocardiogram. Dilutions of
TENORMIN I.V. Injection in Dextrose Injection USP,
Sodium Chloride Injection USP, or Sodium Chloride and
Dextrose Injection may be used. These admixtures are stable
for 48 hours if they are not used immediately.
In patients who tolerate the full intravenous dose (10 mg),
TENORMIN Tablets 50 mg should be initiated 10 minutes
after the last intravenous dose followed by another 50 mg oral
dose 12 hours later. Thereafter, TENORMIN can be given
orally either 100 mg once daily or 50 mg twice a day for a
further 6-9 days or until discharge from the hospital. If
bradycardia or hypotension requiring treatment or any other
untoward effects occur, TENORMIN should be discontinued.
(See full prescribing information prior to initiating therapy
with TENORMIN Tablets.)
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Reference ID: 3001231
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Data from other beta blocker trials suggest that if there is any
question concerning the use of IV beta blocker or clinical
estimate that there is a contraindication, the IV beta blocker
may be eliminated and patients fulfilling the safety criteria
may be given TENORMIN Tablets 50 mg twice daily or 100
mg once a day for at least seven days (if the IV dosing is
excluded).
Although the demonstration of efficacy of TENORMIN is
based entirely on data from the first seven postinfarction days,
data from other beta blocker trials suggest that treatment with
beta blockers that are effective in the postinfarction setting
may be continued for one to three years if there are no
contraindications.
TENORMIN is an additional treatment to standard coronary
care unit therapy.
Elderly Patients or Patients with Renal Impairment
TENORMIN is excreted by the kidneys; consequently dosage
should be adjusted in cases of severe impairment of renal
function.
In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the
dosing range, reflecting greater frequency of decreased
hepatic, renal, or cardiac function, and of concomitant disease
or other drug therapy.
Evaluation of patients with
hypertension or myocardial infarction should always include
assessment of renal function. Atenolol excretion would be
expected to decrease with advancing age.
No significant accumulation of TENORMIN occurs until
creatinine
clearance
falls
below
35 mL/min/1.73m2.
Accumulation of atenolol and prolongation of its half-life
were studied in subjects with creatinine clearance between 5
and 105 mL/min. Peak plasma levels were significantly
increased in subjects with creatinine clearances below
30 mL/min.
The following maximum oral dosages are recommended for
elderly, renally-impaired patients and for patients with renal
impairment due to other causes:
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Reference ID: 3001231
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Atenolol
Creatinine Clearance
Elimination Half-Life
(mL/min/1.73m2)
(h)
Maximum Dosage
15-35
16-27
50 mg daily
<15
>27
25 mg daily
Some renally-impaired or elderly patients being treated for
hypertension may require a lower starting dose of
TENORMIN: 25 mg given as one tablet a day. If this 25 mg
dose is used, assessment of efficacy must be made carefully.
This should include measurement of blood pressure just prior
to the next dose ("trough" blood pressure) to ensure that the
treatment effect is present for a full 24 hours.
Although a similar dosage reduction may be considered for
elderly and/or renally-impaired patients being treated for
indications other than hypertension, data are not available for
these patient populations.
Patients on hemodialysis should be given 25 mg or 50 mg
after each dialysis; this should be done under hospital
supervision as marked falls in blood pressure can occur.
Cessation of Therapy in Patients with Angina
Pectoris
If withdrawal of TENORMIN therapy is planned, it should be
achieved gradually and patients should be carefully observed
and advised to limit physical activity to a minimum.
HOW SUPPLIED
TENORMIN Tablets
Tablets of 25 mg atenolol, NDC 0310-0107 (round, flat,
uncoated white tablets identified with "T" debossed on one
side and 107 debossed on the other side) are supplied in
bottles of 100 tablets.
Tablets of 50 mg atenolol, NDC 0310-0105 (round, flat,
uncoated white tablets identified with "TENORMIN"
debossed on one side and 105 debossed on the other side,
bisected) are supplied in bottles of 100 tablets.
21
Reference ID: 3001231
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Tablets of 100 mg atenolol, NDC 0310-0101 (round, flat,
uncoated white tablets identified with "TENORMIN"
debossed on one side and 101 debossed on the other side) are
supplied in bottles of 100 tablets.
Store at controlled room temperature, 20-25°C (68-77°F) [see
USP]. Dispense in well-closed, light-resistant containers.
TENORMIN is a trademark of the Astrazeneca group of
companies
©AstraZeneca 2002, 2003, 2004, 2008
Manufactured for:
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
By: IPR Pharmaceuticals, Inc.
Conóvanas, PR 00729
AstraZeneca
July 2011
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Reference ID: 3001231
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|
custom-source
|
2025-02-12T13:44:39.958713
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018240s031lbl.pdf', 'application_number': 18240, 'submission_type': 'SUPPL ', 'submission_number': 31}
|
11,189
|
XANAX®
alprazolam tablets, USP
CIV
DESCRIPTION
XANAX Tablets contain alprazolam which is a triazolo analog of the 1,4 benzodiazepine
class of central nervous system-active compounds.
The chemical name of alprazolam is 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-α] [1,4]
benzodiazepine.
The structural formula is represented to the right: structural formula
Alprazolam is a white crystalline powder, which is soluble in methanol or ethanol but which
has no appreciable solubility in water at physiological pH.
Each XANAX Tablet, for oral administration, contains 0.25, 0.5, 1 or 2 mg of alprazolam.
XANAX Tablets, 2 mg, are multi-scored and may be divided as shown below: usage illustration
Inactive ingredients: Cellulose, corn starch, docusate sodium, lactose, magnesium stearate,
silicon dioxide and sodium benzoate. In addition, the 0.5 mg tablet contains FD&C Yellow
No. 6 and the 1 mg tablet contains FD&C Blue No. 2.
1
Reference ID: 3004871
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CLINICAL PHARMACOLOGY
Pharmacodynamics
CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereo
specific receptors at several sites within the central nervous system. Their exact mechanism of
action is unknown. Clinically, all benzodiazepines cause a dose-related central nervous
system depressant activity varying from mild impairment of task performance to hypnosis.
Pharmacokinetics
Absorption
Following oral administration, alprazolam is readily absorbed. Peak concentrations in the
plasma occur in 1 to 2 hours following administration. Plasma levels are proportionate to the
dose given; over the dose range of 0.5 to 3.0 mg, peak levels of 8.0 to 37 ng/mL were
observed. Using a specific assay methodology, the mean plasma elimination half-life of
alprazolam has been found to be about 11.2 hours (range: 6.3-26.9 hours) in healthy adults.
Distribution
In vitro, alprazolam is bound (80 percent) to human serum protein. Serum albumin accounts
for the majority of the binding.
Metabolism/Elimination
Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4
(CYP3A4), to two major metabolites in the plasma: 4-hydroxyalprazolam and α
hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans.
Their half-lives appear to be similar to that of alprazolam. The plasma concentrations of 4
hydroxyalprazolam and α-hydroxyalprazolam relative to unchanged alprazolam concentration
were always less than 4%. The reported relative potencies in benzodiazepine receptor binding
experiments and in animal models of induced seizure inhibition are 0.20 and 0.66,
respectively, for 4-hydroxyalprazolam and α-hydroxyalprazolam. Such low concentrations
and the lesser potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam suggest that they
are unlikely to contribute much to the pharmacological effects of alprazolam. The
benzophenone metabolite is essentially inactive.
Alprazolam and its metabolites are excreted primarily in the urine.
Special Populations
Changes in the absorption, distribution, metabolism and excretion of benzodiazepines have
been reported in a variety of disease states including alcoholism, impaired hepatic function
and impaired renal function. Changes have also been demonstrated in geriatric patients. A
mean half-life of alprazolam of 16.3 hours has been observed in healthy elderly subjects
(range: 9.0-26.9 hours, n=16) compared to 11.0 hours (range: 6.3-15.8 hours, n=16) in healthy
adult subjects. In patients with alcoholic liver disease the half-life of alprazolam ranged
between 5.8 and 65.3 hours (mean: 19.7 hours, n=17) as compared to between 6.3 and 26.9
hours (mean=11.4 hours, n=17) in healthy subjects. In an obese group of subjects the half-life
2
Reference ID: 3004871
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of alprazolam ranged between 9.9 and 40.4 hours (mean=21.8 hours, n=12) as compared to
between 6.3 and 15.8 hours (mean=10.6 hours, n=12) in healthy subjects.
Because of its similarity to other benzodiazepines, it is assumed that alprazolam undergoes
transplacental passage and that it is excreted in human milk.
Race — Maximal concentrations and half-life of alprazolam are approximately 15% and 25%
higher in Asians compared to Caucasians.
Pediatrics — The pharmacokinetics of alprazolam in pediatric patients have not been studied.
Gender — Gender has no effect on the pharmacokinetics of alprazolam.
Cigarette Smoking — Alprazolam concentrations may be reduced by up to 50% in smokers
compared to non-smokers.
Drug-Drug Interactions
Alprazolam is primarily eliminated by metabolism via cytochrome P450 3A (CYP3A). Most
of the interactions that have been documented with alprazolam are with drugs that inhibit or
induce CYP3A4.
Compounds that are potent inhibitors of CYP3A would be expected to increase plasma
alprazolam concentrations. Drug products that have been studied in vivo, along with their
effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itraconazole,
2.70 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold (see
CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS–Drug Interactions).
CYP3A inducers would be expected to decrease alprazolam concentrations and this has been
observed in vivo. The oral clearance of alprazolam (given in a 0.8 mg single dose) was
increased from 0.90±0.21 mL/min/kg to 2.13±0.54 mL/min/kg and the elimination t1/2 was
shortened (from 17.1±4.9 to 7.7 ±1.7 h) following administration of 300 mg/day
carbamazepine for 10 days (see PRECAUTIONS–Drug Interactions). However, the
carbamazepine dose used in this study was fairly low compared to the recommended doses
(1000-1200 mg/day); the effect at usual carbamazepine doses is unknown.
The ability of alprazolam to induce human hepatic enzyme systems has not yet been
determined. However, this is not a property of benzodiazepines in general. Further,
alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers
administered sodium warfarin orally.
CLINICAL STUDIES
Anxiety Disorders
XANAX Tablets were compared to placebo in double blind clinical studies (doses up to 4
mg/day) in patients with a diagnosis of anxiety or anxiety with associated depressive
symptomatology. XANAX was significantly better than placebo at each of the evaluation
periods of these 4-week studies as judged by the following psychometric instruments:
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Reference ID: 3004871
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Physician’s Global Impressions, Hamilton Anxiety Rating Scale, Target Symptoms, Patient’s
Global Impressions and Self-Rating Symptom Scale.
Panic Disorder
Support for the effectiveness of XANAX in the treatment of panic disorder came from three
short-term, placebo-controlled studies (up to 10 weeks) in patients with diagnoses closely
corresponding to DSM-III-R criteria for panic disorder.
The average dose of XANAX was 5-6 mg/day in two of the studies, and the doses of XANAX
were fixed at 2 and 6 mg/day in the third study. In all three studies, XANAX was superior to
placebo on a variable defined as "the number of patients with zero panic attacks" (range, 37
83% met this criterion), as well as on a global improvement score. In two of the three studies,
XANAX was superior to placebo on a variable defined as "change from baseline on the
number of panic attacks per week" (range, 3.3-5.2), and also on a phobia rating scale. A
subgroup of patients who were improved on XANAX during short-term treatment in one of
these trials was continued on an open basis up to 8 months, without apparent loss of benefit.
INDICATIONS AND USAGE
Anxiety Disorders
XANAX Tablets (alprazolam) are indicated for the management of anxiety disorder (a
condition corresponding most closely to the APA Diagnostic and Statistical Manual [DSM
III-R] diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of
anxiety. Anxiety or tension associated with the stress of everyday life usually does not require
treatment with an anxiolytic.
Generalized anxiety disorder is characterized by unrealistic or excessive anxiety and worry
(apprehensive expectation) about two or more life circumstances, for a period of 6 months or
longer, during which the person has been bothered more days than not by these concerns. At
least 6 of the following 18 symptoms are often present in these patients: Motor Tension
(trembling, twitching, or feeling shaky; muscle tension, aches, or soreness; restlessness; easy
fatigability); Autonomic Hyperactivity (shortness of breath or smothering sensations;
palpitations or accelerated heart rate; sweating, or cold clammy hands; dry mouth; dizziness
or light-headedness; nausea, diarrhea, or other abdominal distress; flushes or chills; frequent
urination; trouble swallowing or 'lump in throat’); Vigilance and Scanning (feeling keyed up
or on edge; exaggerated startle response; difficulty concentrating or 'mind going blank’
because of anxiety; trouble falling or staying asleep; irritability). These symptoms must not be
secondary to another psychiatric disorder or caused by some organic factor.
Anxiety associated with depression is responsive to XANAX.
Panic Disorder
XANAX is also indicated for the treatment of panic disorder, with or without agoraphobia.
Studies supporting this claim were conducted in patients whose diagnoses corresponded
closely to the DSM-III-R/IV criteria for panic disorder (see CLINICAL STUDIES).
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Reference ID: 3004871
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Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, ie, a discrete
period of intense fear or discomfort in which four (or more) of the following symptoms
develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or
accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of
breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or
abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization
(feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing
control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or
hot flushes.
Demonstrations of the effectiveness of XANAX by systematic clinical study are limited to 4
months duration for anxiety disorder and 4 to 10 weeks duration for panic disorder; however,
patients with panic disorder have been treated on an open basis for up to 8 months without
apparent loss of benefit. The physician should periodically reassess the usefulness of the drug
for the individual patient.
CONTRAINDICATIONS
XANAX Tablets are contraindicated in patients with known sensitivity to this drug or other
benzodiazepines. XANAX may be used in patients with open angle glaucoma who are
receiving appropriate therapy, but is contraindicated in patients with acute narrow angle
glaucoma.
XANAX is contraindicated with ketoconazole and itraconazole, since these medications
significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP3A)
(see WARNINGS and PRECAUTIONS–Drug Interactions).
WARNINGS
Dependence and Withdrawal Reactions, Including Seizures
Certain adverse clinical events, some life-threatening, are a direct consequence of physical
dependence to XANAX. These include a spectrum of withdrawal symptoms; the most
important is seizure (see DRUG ABUSE AND DEPENDENCE). Even after relatively short-
term use at the doses recommended for the treatment of transient anxiety and anxiety disorder
(ie, 0.75 to 4.0 mg per day), there is some risk of dependence. Spontaneous reporting system
data suggest that the risk of dependence and its severity appear to be greater in patients treated
with doses greater than 4 mg/day and for long periods (more than 12 weeks). However, in a
controlled postmarketing discontinuation study of panic disorder patients, the duration of
treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to
zero dose. In contrast, patients treated with doses of XANAX greater than 4 mg/day had more
difficulty tapering to zero dose than those treated with less than 4 mg/day.
The importance of dose and the risks of XANAX as a treatment for panic disorder: Because
the management of panic disorder often requires the use of average daily doses of XANAX
above 4 mg, the risk of dependence among panic disorder patients may be higher than that
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Reference ID: 3004871
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among those treated for less severe anxiety. Experience in randomized placebo-controlled
discontinuation studies of patients with panic disorder showed a high rate of rebound and
withdrawal symptoms in patients treated with XANAX compared to placebo-treated patients.
Relapse or return of illness was defined as a return of symptoms characteristic of panic
disorder (primarily panic attacks) to levels approximately equal to those seen at baseline
before active treatment was initiated. Rebound refers to a return of symptoms of panic
disorder to a level substantially greater in frequency, or more severe in intensity than seen at
baseline. Withdrawal symptoms were identified as those which were generally not
characteristic of panic disorder and which occurred for the first time more frequently during
discontinuation than at baseline.
In a controlled clinical trial in which 63 patients were randomized to XANAX and where
withdrawal symptoms were specifically sought, the following were identified as symptoms of
withdrawal: heightened sensory perception, impaired concentration, dysosmia, clouded
sensorium, paresthesias, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite
decrease, and weight loss. Other symptoms, such as anxiety and insomnia, were frequently
seen during discontinuation, but it could not be determined if they were due to return of
illness, rebound, or withdrawal.
In two controlled trials of 6 to 8 weeks duration where the ability of patients to discontinue
medication was measured, 71%-93% of patients treated with XANAX tapered completely off
therapy compared to 89%-96% of placebo-treated patients. In a controlled postmarketing
discontinuation study of panic disorder patients, the duration of treatment (3 months
compared to 6 months) had no effect on the ability of patients to taper to zero dose.
Seizures attributable to XANAX were seen after drug discontinuance or dose reduction in 8 of
1980 patients with panic disorder or in patients participating in clinical trials where doses of
XANAX greater than 4 mg/day for over 3 months were permitted. Five of these cases clearly
occurred during abrupt dose reduction, or discontinuation from daily doses of 2 to 10 mg.
Three cases occurred in situations where there was not a clear relationship to abrupt dose
reduction or discontinuation. In one instance, seizure occurred after discontinuation from a
single dose of 1 mg after tapering at a rate of 1 mg every 3 days from 6 mg daily. In two other
instances, the relationship to taper is indeterminate; in both of these cases the patients had
been receiving doses of 3 mg daily prior to seizure. The duration of use in the above 8 cases
ranged from 4 to 22 weeks. There have been occasional voluntary reports of patients
developing seizures while apparently tapering gradually from XANAX. The risk of seizure
seems to be greatest 24-72 hours after discontinuation (see DOSAGE AND
ADMINISTRATION for recommended tapering and discontinuation schedule).
Status Epilepticus and its Treatment
The medical event voluntary reporting system shows that withdrawal seizures have been
reported in association with the discontinuation of XANAX. In most cases, only a single
seizure was reported; however, multiple seizures and status epilepticus were reported as well.
Interdose Symptoms
6
Reference ID: 3004871
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Early morning anxiety and emergence of anxiety symptoms between doses of XANAX have
been reported in patients with panic disorder taking prescribed maintenance doses of
XANAX. These symptoms may reflect the development of tolerance or a time interval
between doses which is longer than the duration of clinical action of the administered dose. In
either case, it is presumed that the prescribed dose is not sufficient to maintain plasma levels
above those needed to prevent relapse, rebound or withdrawal symptoms over the entire
course of the interdosing interval. In these situations, it is recommended that the same total
daily dose be given divided as more frequent administrations (see DOSAGE AND
ADMINISTRATION).
Risk of Dose Reduction
Withdrawal reactions may occur when dosage reduction occurs for any reason. This includes
purposeful tapering, but also inadvertent reduction of dose (eg, the patient forgets, the patient
is admitted to a hospital). Therefore, the dosage of XANAX should be reduced or
discontinued gradually (see DOSAGE AND ADMINISTRATION).
CNS Depression and Impaired Performance
Because of its CNS depressant effects, patients receiving XANAX should be cautioned
against engaging in hazardous occupations or activities requiring complete mental alertness
such as operating machinery or driving a motor vehicle. For the same reason, patients should
be cautioned about the simultaneous ingestion of alcohol and other CNS depressant drugs
during treatment with XANAX.
Risk of Fetal Harm
Benzodiazepines can potentially cause fetal harm when administered to pregnant women. If
XANAX is used during pregnancy, or if the patient becomes pregnant while taking this drug,
the patient should be apprised of the potential hazard to the fetus. Because of experience with
other members of the benzodiazepine class, XANAX is assumed to be capable of causing an
increased risk of congenital abnormalities when administered to a pregnant woman during the
first trimester. Because use of these drugs is rarely a matter of urgency, their use during the
first trimester should almost always be avoided. The possibility that a woman of childbearing
potential may be pregnant at the time of institution of therapy should be considered. Patients
should be advised that if they become pregnant during therapy or intend to become pregnant
they should communicate with their physicians about the desirability of discontinuing the
drug.
Alprazolam Interaction with Drugs that Inhibit Metabolism via Cytochrome P4503A
The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A
(CYP3A). Drugs that inhibit this metabolic pathway may have a profound effect on the
clearance of alprazolam. Consequently, alprazolam should be avoided in patients receiving
very potent inhibitors of CYP3A. With drugs inhibiting CYP3A to a lesser but still significant
degree, alprazolam should be used only with caution and consideration of appropriate dosage
reduction. For some drugs, an interaction with alprazolam has been quantified with clinical
data; for other drugs, interactions are predicted from in vitro data and/or experience with
similar drugs in the same pharmacologic class.
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The following are examples of drugs known to inhibit the metabolism of alprazolam and/or
related benzodiazepines, presumably through inhibition of CYP3A.
Potent CYP3A Inhibitors
Azole antifungal agents— Ketoconazole and itraconazole are potent CYP3A inhibitors and
have been shown in vivo to increase plasma alprazolam concentrations 3.98 fold and 2.70
fold, respectively. The coadministration of alprazolam with these agents is not recommended.
Other azole-type antifungal agents should also be considered potent CYP3A inhibitors and the
coadministration of alprazolam with them is not recommended (see
CONTRAINDICATIONS).
Drugs demonstrated to be CYP 3A inhibitors on the basis of clinical studies involving
alprazolam (caution and consideration of appropriate alprazolam dose reduction are
recommended during coadministration with the following drugs)
Nefazodone—Coadministration of nefazodone increased alprazolam concentration two-fold.
Fluvoxamine—Coadministration of fluvoxamine approximately doubled the maximum
plasma concentration of alprazolam, decreased clearance by 49%, increased half-life by 71%,
and decreased measured psychomotor performance.
Cimetidine—Coadministration of cimetidine increased the maximum plasma concentration of
alprazolam by 86%, decreased clearance by 42%, and increased half-life by 16%.
Other drugs possibly affecting alprazolam metabolism
Other drugs possibly affecting alprazolam metabolism by inhibition of CYP3A are discussed
in the PRECAUTIONS section (see PRECAUTIONS–Drug Interactions).
PRECAUTIONS
General
Suicide
As with other psychotropic medications, the usual precautions with respect to administration
of the drug and size of the prescription are indicated for severely depressed patients or those
in whom there is reason to expect concealed suicidal ideation or plans. Panic disorder has
been associated with primary and secondary major depressive disorders and increased reports
of suicide among untreated patients.
Mania
Episodes of hypomania and mania have been reported in association with the use of XANAX
in patients with depression.
Uricosuric Effect
Alprazolam has a weak uricosuric effect. Although other medications with weak uricosuric
effect have been reported to cause acute renal failure, there have been no reported instances of
acute renal failure attributable to therapy with XANAX.
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Use in Patients with Concomitant Illness
It is recommended that the dosage be limited to the smallest effective dose to preclude the
development of ataxia or oversedation which may be a particular problem in elderly or
debilitated patients. (See DOSAGE AND ADMINISTRATION.) The usual precautions in
treating patients with impaired renal, hepatic or pulmonary function should be observed.
There have been rare reports of death in patients with severe pulmonary disease shortly after
the initiation of treatment with XANAX. A decreased systemic alprazolam elimination rate
(eg, increased plasma half-life) has been observed in both alcoholic liver disease patients and
obese patients receiving XANAX (see CLINICAL PHARMACOLOGY).
Information for Patients
For all users of XANAX:
To assure safe and effective use of benzodiazepines, all patients prescribed XANAX should
be provided with the following guidance.
1. Inform your physician about any alcohol consumption and medicine you are taking now,
including medication you may buy without a prescription. Alcohol should generally not be
used during treatment with benzodiazepines.
2. Not recommended for use in pregnancy. Therefore, inform your physician if you are
pregnant, if you are planning to have a child, or if you become pregnant while you are taking
this medication.
3. Inform your physician if you are nursing.
4. Until you experience how this medication affects you, do not drive a car or operate
potentially dangerous machinery, etc.
5. Do not increase the dose even if you think the medication "does not work anymore"
without consulting your physician. Benzodiazepines, even when used as recommended, may
produce emotional and/or physical dependence.
6. Do not stop taking this medication abruptly or decrease the dose without consulting your
physician, since withdrawal symptoms can occur.
Additional advice for panic disorder patients:
The use of XANAX at doses greater than 4 mg/day, often necessary to treat panic disorder, is
accompanied by risks that you need to carefully consider. When used at doses greater than 4
mg/day, which may or may not be required for your treatment, XANAX has the potential to
cause severe emotional and physical dependence in some patients and these patients may find
it exceedingly difficult to terminate treatment. In two controlled trials of 6 to 8 weeks duration
where the ability of patients to discontinue medication was measured, 7 to 29% of patients
treated with XANAX did not completely taper off therapy. In a controlled postmarketing
discontinuation study of panic disorder patients, the patients treated with doses of XANAX
greater than 4 mg/day had more difficulty tapering to zero dose than patients treated with less
than 4 mg/day. In all cases, it is important that your physician help you discontinue this
medication in a careful and safe manner to avoid overly extended use of XANAX.
In addition, the extended use at doses greater than 4 mg/day appears to increase the incidence
and severity of withdrawal reactions when XANAX is discontinued. These are generally
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minor but seizure can occur, especially if you reduce the dose too rapidly or discontinue the
medication abruptly. Seizure can be life-threatening.
Laboratory Tests
Laboratory tests are not ordinarily required in otherwise healthy patients. However, when
treatment is protracted, periodic blood counts, urinalysis, and blood chemistry analyses are
advisable in keeping with good medical practice.
Drug Interactions
Use with Other CNS Depressants
If XANAX Tablets are to be combined with other psychotropic agents or anticonvulsant
drugs, careful consideration should be given to the pharmacology of the agents to be
employed, particularly with compounds which might potentiate the action of benzodiazepines.
The benzodiazepines, including alprazolam, produce additive CNS depressant effects when
co-administered with other psychotropic medications, anticonvulsants, antihistaminics,
ethanol and other drugs which themselves produce CNS depression.
Use with Imipramine and Desipramine
The steady state plasma concentrations of imipramine and desipramine have been reported to
be increased an average of 31% and 20%, respectively, by the concomitant administration of
XANAX Tablets in doses up to 4 mg/day. The clinical significance of these changes is
unknown.
Drugs that inhibit alprazolam metabolism via cytochrome P450 3A
The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A
(CYP3A). Drugs which inhibit this metabolic pathway may have a profound effect on the
clearance of alprazolam (see CONTRAINDICATIONS and WARNINGS for additional drugs
of this type).
Drugs demonstrated to be CYP3A inhibitors of possible clinical significance on the basis of
clinical studies involving alprazolam (caution is recommended during coadministration with
alprazolam)
Fluoxetine—Coadministration of fluoxetine with alprazolam increased the maximum plasma
concentration of alprazolam by 46%, decreased clearance by 21%, increased half-life by 17%,
and decreased measured psychomotor performance.
Propoxyphene—Coadministration of propoxyphene decreased the maximum plasma
concentration of alprazolam by 6%, decreased clearance by 38%, and increased half-life by
58%.
Oral Contraceptives—Coadministration of oral contraceptives increased the maximum plasma
concentration of alprazolam by 18%, decreased clearance by 22%, and increased half-life by
29%.
Drugs and other substances demonstrated to be CYP 3A inhibitors on the basis of clinical
studies involving benzodiazepines metabolized similarly to alprazolam or on the basis of in
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vitro studies with alprazolam or other benzodiazepines (caution is recommended during
coadministration with alprazolam)
Available data from clinical studies of benzodiazepines other than alprazolam suggest a
possible drug interaction with alprazolam for the following: diltiazem, isoniazid, macrolide
antibiotics such as erythromycin and clarithromycin, and grapefruit juice. Data from in vitro
studies of alprazolam suggest a possible drug interaction with alprazolam for the following:
sertraline and paroxetine. However, data from an in vivo drug interaction study involving a
single dose of alprazolam 1 mg and steady state dose of sertraline (50 to 150 mg/day) did not
reveal any clinically significant changes in the pharmacokinetics of alprazolam. Data from in
vitro studies of benzodiazepines other than alprazolam suggest a possible drug interaction for
the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine. Caution is
recommended during the coadministration of any of these with alprazolam (see
WARNINGS).
Drugs demonstrated to be inducers of CYP3A
Carbamazepine can increase alprazolam metabolism and therefore can decrease plasma levels
of alprazolam.
Drug/Laboratory Test Interactions
Although interactions between benzodiazepines and commonly employed clinical laboratory
tests have occasionally been reported, there is no consistent pattern for a specific drug or
specific test.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenic potential was observed during 2-year bioassay studies of
alprazolam in rats at doses up to 30 mg/kg/day (150 times the maximum recommended daily
human dose of 10 mg/day) and in mice at doses up to 10 mg/kg/day (50 times the maximum
recommended daily human dose).
Alprazolam was not mutagenic in the rat micronucleus test at doses up to 100 mg/kg, which is
500 times the maximum recommended daily human dose of 10 mg/day. Alprazolam also was
not mutagenic in vitro in the DNA Damage/Alkaline Elution Assay or the Ames Assay.
Alprazolam produced no impairment of fertility in rats at doses up to 5 mg/kg/day, which is
25 times the maximum recommended daily human dose of 10 mg/day.
Pregnancy
Teratogenic Effects: Pregnancy Category D: (See WARNINGS section).
Nonteratogenic Effects: It should be considered that the child born of a mother who is
receiving benzodiazepines may be at some risk for withdrawal symptoms from the drug
during the postnatal period. Also, neonatal flaccidity and respiratory problems have been
reported in children born of mothers who have been receiving benzodiazepines.
Labor and Delivery
XANAX has no established use in labor or delivery.
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Nursing Mothers
Benzodiazepines are known to be excreted in human milk. It should be assumed that
alprazolam is as well. Chronic administration of diazepam to nursing mothers has been
reported to cause their infants to become lethargic and to lose weight. As a general rule,
nursing should not be undertaken by mothers who must use XANAX.
Pediatric Use
Safety and effectiveness of XANAX in individuals below 18 years of age have not been
established.
Geriatric Use
The elderly may be more sensitive to the effects of benzodiazepines. They exhibit higher
plasma alprazolam concentrations due to reduced clearance of the drug as compared with a
younger population receiving the same doses. The smallest effective dose of XANAX should
be used in the elderly to preclude the development of ataxia and oversedation (see CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
Side effects to XANAX Tablets, if they occur, are generally observed at the beginning of
therapy and usually disappear upon continued medication. In the usual patient, the most
frequent side effects are likely to be an extension of the pharmacological activity of
alprazolam, eg, drowsiness or light-headedness.
The data cited in the two tables below are estimates of untoward clinical event incidence
among patients who participated under the following clinical conditions: relatively short
duration (ie, four weeks) placebo-controlled clinical studies with dosages up to 4 mg/day of
XANAX (for the management of anxiety disorders or for the short-term relief of the
symptoms of anxiety) and short-term (up to ten weeks) placebo-controlled clinical studies
with dosages up to 10 mg/day of XANAX in patients with panic disorder, with or without
agoraphobia.
These data cannot be used to predict precisely the incidence of untoward events in the course
of usual medical practice where patient characteristics, and other factors often differ from
those in clinical trials. These figures cannot be compared with those obtained from other
clinical studies involving related drug products and placebo as each group of drug trials are
conducted under a different set of conditions.
Comparison of the cited figures, however, can provide the prescriber with some basis for
estimating the relative contributions of drug and non-drug factors to the untoward event
incidence in the population studied. Even this use must be approached cautiously, as a drug
may relieve a symptom in one patient but induce it in others. (For example, an anxiolytic drug
may relieve dry mouth [a symptom of anxiety] in some subjects but induce it [an untoward
event] in others.)
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Additionally, for anxiety disorders the cited figures can provide the prescriber with an
indication as to the frequency with which physician intervention (eg, increased surveillance,
decreased dosage or discontinuation of drug therapy) may be necessary because of the
untoward clinical event.
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Treatment-Emergent Adverse Events Reported in Placebo-Controlled Trials of Anxiety
Disorders
ANXIETY DISORDERS
Treatment-Emergent
Incidence of Intervention
Symptom Incidence†
Because of Symptom
XANAX
PLACEBO
XANAX
Number of Patients
565
505
565
% of Patients
Reporting:
Central Nervous System
Drowsiness
41.0
21.6
15.1
Light-headedness
20.8
19.3
1.2
Depression
13.9
18.1
2.4
Headache
12.9
19.6
1.1
Confusion
9.9
10.0
0.9
Insomnia
8.9
18.4
1.3
Nervousness
4.1
10.3
1.1
Syncope
3.1
4.0
*
Dizziness
1.8
0.8
2.5
Akathisia
1.6
1.2
*
Tiredness/Sleepiness
*
*
1.8
Gastrointestinal
Dry Mouth
14.7
13.3
0.7
Constipation
10.4
11.4
0.9
Diarrhea
10.1
10.3
1.2
Nausea/Vomiting
9.6
12.8
1.7
Increased Salivation
4.2
2.4
*
Cardiovascular
Tachycardia/Palpitations
7.7
15.6
0.4
Hypotension
4.7
2.2
*
Sensory
Blurred Vision
6.2
6.2
0.4
Musculoskeletal
Rigidity
4.2
5.3
*
Tremor
4.0
8.8
0.4
Cutaneous
Dermatitis/Allergy
3.8
3.1
0.6
Other
Nasal Congestion
7.3
9.3
*
Weight Gain
2.7
2.7
*
Weight Loss
2.3
3.0
*
*None reported
†Events reported by 1% or more of XANAX patients are included.
In addition to the relatively common (ie, greater than 1%) untoward events enumerated in the
table above, the following adverse events have been reported in association with the use of
benzodiazepines: dystonia, irritability, concentration difficulties, anorexia, transient amnesia
or memory impairment, loss of coordination, fatigue, seizures, sedation, slurred speech,
jaundice, musculoskeletal weakness, pruritus, diplopia, dysarthria, changes in libido,
menstrual irregularities, incontinence and urinary retention.
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Treatment-Emergent Adverse Events Reported in Placebo-Controlled Trials of Panic
Disorder
PANIC DISORDER
Treatment-Emergent
Symptom Incidence*
XANAX
PLACEBO
Number of Patients
1388
1231
% of Patients Reporting:
Central Nervous System
Drowsiness
76.8
42.7
Fatigue and Tiredness
48.6
42.3
Impaired Coordination
40.1
17.9
Irritability
33.1
30.1
Memory Impairment
33.1
22.1
Light-headedness/Dizziness
29.8
36.9
Insomnia
29.4
41.8
Headache
29.2
35.6
Cognitive Disorder
28.8
20.5
Dysarthria
23.3
6.3
Anxiety
16.6
24.9
Abnormal Involuntary Movement
14.8
21.0
Decreased Libido
14.4
8.0
Depression
13.8
14.0
Confusional State
10.4
8.2
Muscular Twitching
7.9
11.8
Increased Libido
7.7
4.1
Change in Libido (Not Specified)
7.1
5.6
Weakness
7.1
8.4
Muscle Tone Disorders
6.3
7.5
Syncope
3.8
4.8
Akathisia
3.0
4.3
Agitation
2.9
2.6
Disinhibition
2.7
1.5
Paresthesia
2.4
3.2
Talkativeness
2.2
1.0
Vasomotor Disturbances
2.0
2.6
Derealization
1.9
1.2
Dream Abnormalities
1.8
1.5
Fear
1.4
1.0
Feeling Warm
1.3
0.5
Gastrointestinal
Decreased Salivation
32.8
34.2
Constipation
26.2
15.4
Nausea/Vomiting
22.0
31.8
Diarrhea
20.6
22.8
Abdominal Distress
18.3
21.5
Increased Salivation
5.6
4.4
Cardio-Respiratory
Nasal Congestion
17.4
16.5
Tachycardia
15.4
26.8
Chest Pain
10.6
18.1
Hyperventilation
9.7
14.5
Upper Respiratory Infection
4.3
3.7
Sensory
Blurred Vision
21.0
21.4
Tinnitus
6.6
10.4
Musculoskeletal
Muscular Cramps
2.4
2.4
Muscle Stiffness
2.2
3.3
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Cutaneous
Sweating
15.1
23.5
Rash
10.8
8.1
Other
Increased Appetite
32.7
22.8
Decreased Appetite
27.8
24.1
Weight Gain
27.2
17.9
Weight Loss
22.6
16.5
Micturition Difficulties
12.2
8.6
Menstrual Disorders
10.4
8.7
Sexual Dysfunction
7.4
3.7
Edema
4.9
5.6
Incontinence
1.5
0.6
Infection
1.3
1.7
*Events reported by 1% or more of XANAX patients are included.
In addition to the relatively common (ie, greater than 1%) untoward events enumerated in the
table above, the following adverse events have been reported in association with the use of
XANAX: seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated
bilirubin, elevated hepatic enzymes, and jaundice.
Panic disorder has been associated with primary and secondary major depressive disorders
and increased reports of suicide among untreated patients (see PRECAUTIONS, General).
Adverse Events Reported as Reasons for Discontinuation in Treatment of Panic
Disorder in Placebo-Controlled Trials
In a larger database comprised of both controlled and uncontrolled studies in which 641
patients received XANAX, discontinuation-emergent symptoms which occurred at a rate of
over 5% in patients treated with XANAX and at a greater rate than the placebo treated group
were as follows:
DISCONTINUATION-EMERGENT SYMPTOM INCIDENCE
Percentage of 641 XANAX-Treated Panic Disorder
Patients Reporting Events
Body System/Event
Neurologic
Gastrointestinal
Insomnia
29.5
Nausea/Vomiting
16.5
Light-headedness
19.3
Diarrhea
13.6
Abnormal involuntary movement
17.3
Decreased salivation
10.6
Headache
17.0
Metabolic-Nutritional
Muscular twitching
6.9
Weight loss
13.3
Impaired coordination
6.6
Decreased appetite
12.8
Muscle tone disorders
5.9
Weakness
5.8
Dermatological
Psychiatric
Sweating
14.4
Anxiety
19.2
Fatigue and Tiredness
18.4
Cardiovascular
Irritability
10.5
Tachycardia
12.2
Cognitive disorder
10.3
Memory impairment
5.5
Special Senses
Depression
5.1
Blurred vision
10.0
Confusional state
5.0
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From the studies cited, it has not been determined whether these symptoms are clearly related
to the dose and duration of therapy with XANAX in patients with panic disorder. There have
also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of
XANAX Tablets (see WARNINGS).
To discontinue treatment in patients taking XANAX, the dosage should be reduced slowly in
keeping with good medical practice. It is suggested that the daily dosage of XANAX be
decreased by no more than 0.5 mg every three days (see DOSAGE AND
ADMINISTRATION). Some patients may benefit from an even slower dosage reduction. In a
controlled postmarketing discontinuation study of panic disorder patients which compared
this recommended taper schedule with a slower taper schedule, no difference was observed
between the groups in the proportion of patients who tapered to zero dose; however, the
slower schedule was associated with a reduction in symptoms associated with a withdrawal
syndrome.
As with all benzodiazepines, paradoxical reactions such as stimulation, increased muscle
spasticity, sleep disturbances, hallucinations and other adverse behavioral effects such as
agitation, rage, irritability, and aggressive or hostile behavior have been reported rarely. In
many of the spontaneous case reports of adverse behavioral effects, patients were receiving
other CNS drugs concomitantly and/or were described as having underlying psychiatric
conditions. Should any of the above events occur, alprazolam should be discontinued. Isolated
published reports involving small numbers of patients have suggested that patients who have
borderline personality disorder, a prior history of violent or aggressive behavior, or alcohol or
substance abuse may be at risk for such events. Instances of irritability, hostility, and intrusive
thoughts have been reported during discontinuation of alprazolam in patients with
posttraumatic stress disorder.
Post Introduction Reports: Various adverse drug reactions have been reported in association
with the use of XANAX since market introduction. The majority of these reactions were
reported through the medical event voluntary reporting system. Because of the spontaneous
nature of the reporting of medical events and the lack of controls, a causal relationship to the
use of XANAX cannot be readily determined. Reported events include: gastrointestinal
disorder, hypomania, mania, liver enzyme elevations, hepatitis, hepatic failure, Stevens-
Johnson syndrome, angioedema, peripheral edema, hyperprolactinemia, gynecomastia, and
galactorrhea (see PRECAUTIONS).
DRUG ABUSE AND DEPENDENCE
Physical and Psychological Dependence
Withdrawal symptoms similar in character to those noted with sedative/hypnotics and alcohol
have occurred following discontinuance of benzodiazepines, including XANAX. The
symptoms can range from mild dysphoria and insomnia to a major syndrome that may include
abdominal and muscle cramps, vomiting, sweating, tremors and convulsions. Distinguishing
between withdrawal emergent signs and symptoms and the recurrence of illness is often
difficult in patients undergoing dose reduction. The long term strategy for treatment of these
phenomena will vary with their cause and the therapeutic goal. When necessary, immediate
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management of withdrawal symptoms requires re-institution of treatment at doses of XANAX
sufficient to suppress symptoms. There have been reports of failure of other benzodiazepines
to fully suppress these withdrawal symptoms. These failures have been attributed to
incomplete cross-tolerance but may also reflect the use of an inadequate dosing regimen of the
substituted benzodiazepine or the effects of concomitant medications.
While it is difficult to distinguish withdrawal and recurrence for certain patients, the time
course and the nature of the symptoms may be helpful. A withdrawal syndrome typically
includes the occurrence of new symptoms, tends to appear toward the end of taper or shortly
after discontinuation, and will decrease with time. In recurring panic disorder, symptoms
similar to those observed before treatment may recur either early or late, and they will persist.
While the severity and incidence of withdrawal phenomena appear to be related to dose and
duration of treatment, withdrawal symptoms, including seizures, have been reported after only
brief therapy with XANAX at doses within the recommended range for the treatment of
anxiety (eg, 0.75 to 4 mg/day). Signs and symptoms of withdrawal are often more prominent
after rapid decrease of dosage or abrupt discontinuance. The risk of withdrawal seizures may
be increased at doses above 4 mg/day (see WARNINGS).
Patients, especially individuals with a history of seizures or epilepsy, should not be abruptly
discontinued from any CNS depressant agent, including XANAX. It is recommended that all
patients on XANAX who require a dosage reduction be gradually tapered under close
supervision (see WARNINGS and DOSAGE AND ADMINISTRATION).
Psychological dependence is a risk with all benzodiazepines, including XANAX. The risk of
psychological dependence may also be increased at doses greater than 4 mg/day and with
longer term use, and this risk is further increased in patients with a history of alcohol or drug
abuse. Some patients have experienced considerable difficulty in tapering and discontinuing
from XANAX, especially those receiving higher doses for extended periods. Addiction-prone
individuals should be under careful surveillance when receiving XANAX. As with all
anxiolytics, repeat prescriptions should be limited to those who are under medical
supervision.
Controlled Substance Class
Alprazolam is a controlled substance under the Controlled Substance Act by the Drug
Enforcement Administration and XANAX Tablets have been assigned to Schedule IV.
OVERDOSAGE
Clinical Experience
Manifestations of alprazolam overdosage include somnolence, confusion, impaired
coordination, diminished reflexes and coma. Death has been reported in association with
overdoses of alprazolam by itself, as it has with other benzodiazepines. In addition, fatalities
have been reported in patients who have overdosed with a combination of a single
benzodiazepine, including alprazolam, and alcohol; alcohol levels seen in some of these
patients have been lower than those usually associated with alcohol-induced fatality.
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The acute oral LD50 in rats is 331-2171 mg/kg. Other experiments in animals have indicated
that cardiopulmonary collapse can occur following massive intravenous doses of alprazolam
(over 195 mg/kg; 975 times the maximum recommended daily human dose of 10 mg/day).
Animals could be resuscitated with positive mechanical ventilation and the intravenous
infusion of norepinephrine bitartrate.
Animal experiments have suggested that forced diuresis or hemodialysis are probably of little
value in treating overdosage.
General Treatment of Overdose
Overdosage reports with XANAX Tablets are limited. As in all cases of drug overdosage,
respiration, pulse rate, and blood pressure should be monitored. General supportive measures
should be employed, along with immediate gastric lavage. Intravenous fluids should be
administered and an adequate airway maintained. If hypotension occurs, it may be combated
by the use of vasopressors. Dialysis is of limited value. As with the management of
intentional overdosing with any drug, it should be borne in mind that multiple agents may
have been ingested.
Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or
partial reversal of the sedative effects of benzodiazepines and may be used in situations when
an overdose with a benzodiazepine is known or suspected. Prior to the administration of
flumazenil, necessary measures should be instituted to secure airway, ventilation and
intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper
management of benzodiazepine overdose. Patients treated with flumazenil should be
monitored for re-sedation, respiratory depression, and other residual benzodiazepine effects
for an appropriate period after treatment. The prescriber should be aware of a risk of
seizure in association with flumazenil treatment, particularly in long-term
benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil
package insert including CONTRAINDICATIONS, WARNINGS and PRECAUTIONS
should be consulted prior to use.
DOSAGE AND ADMINISTRATION
Dosage should be individualized for maximum beneficial effect. While the usual daily
dosages given below will meet the needs of most patients, there will be some who require
doses greater than 4 mg/day. In such cases, dosage should be increased cautiously to avoid
adverse effects.
Anxiety Disorders and Transient Symptoms of Anxiety
Treatment for patients with anxiety should be initiated with a dose of 0.25 to 0.5 mg given
three times daily. The dose may be increased to achieve a maximum therapeutic effect, at
intervals of 3 to 4 days, to a maximum daily dose of 4 mg, given in divided doses. The lowest
possible effective dose should be employed and the need for continued treatment reassessed
frequently. The risk of dependence may increase with dose and duration of treatment.
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In all patients, dosage should be reduced gradually when discontinuing therapy or when
decreasing the daily dosage. Although there are no systematically collected data to support a
specific discontinuation schedule, it is suggested that the daily dosage be decreased by no
more than 0.5 mg every 3 days. Some patients may require an even slower dosage reduction.
Panic Disorder
The successful treatment of many panic disorder patients has required the use of XANAX at
doses greater than 4 mg daily. In controlled trials conducted to establish the efficacy of
XANAX in panic disorder, doses in the range of 1 to 10 mg daily were used. The mean
dosage employed was approximately 5 to 6 mg daily. Among the approximately 1700 patients
participating in the panic disorder development program, about 300 received XANAX in
dosages of greater than 7 mg/day, including approximately 100 patients who received
maximum dosages of greater than 9 mg/day. Occasional patients required as much as 10 mg a
day to achieve a successful response.
Dose Titration
Treatment may be initiated with a dose of 0.5 mg three times daily. Depending on the
response, the dose may be increased at intervals of 3 to 4 days in increments of no more than
1 mg per day. Slower titration to the dose levels greater than 4 mg/day may be advisable to
allow full expression of the pharmacodynamic effect of XANAX. To lessen the possibility of
interdose symptoms, the times of administration should be distributed as evenly as possible
throughout the waking hours, that is, on a three or four times per day schedule.
Generally, therapy should be initiated at a low dose to minimize the risk of adverse responses
in patients especially sensitive to the drug. Dose should be advanced until an acceptable
therapeutic response (ie, a substantial reduction in or total elimination of panic attacks) is
achieved, intolerance occurs, or the maximum recommended dose is attained.
Dose Maintenance
For patients receiving doses greater than 4 mg/day, periodic reassessment and consideration
of dosage reduction is advised. In a controlled postmarketing dose-response study, patients
treated with doses of XANAX greater than 4 mg/day for 3 months were able to taper to 50%
of their total maintenance dose without apparent loss of clinical benefit. Because of the danger
of withdrawal, abrupt discontinuation of treatment should be avoided. (See WARNINGS,
PRECAUTIONS, DRUG ABUSE AND DEPENDENCE.)
The necessary duration of treatment for panic disorder patients responding to XANAX is
unknown. After a period of extended freedom from attacks, a carefully supervised tapered
discontinuation may be attempted, but there is evidence that this may often be difficult to
accomplish without recurrence of symptoms and/or the manifestation of withdrawal
phenomena.
Dose Reduction
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Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided
(see WARNINGS, PRECAUTIONS, DRUG ABUSE AND DEPENDENCE).
In all patients, dosage should be reduced gradually when discontinuing therapy or when
decreasing the daily dosage. Although there are no systematically collected data to support a
specific discontinuation schedule, it is suggested that the daily dosage be decreased by no
more than 0.5 mg every three days. Some patients may require an even slower dosage
reduction.
In any case, reduction of dose must be undertaken under close supervision and must be
gradual. If significant withdrawal symptoms develop, the previous dosing schedule should be
reinstituted and, only after stabilization, should a less rapid schedule of discontinuation be
attempted. In a controlled postmarketing discontinuation study of panic disorder patients
which compared this recommended taper schedule with a slower taper schedule, no difference
was observed between the groups in the proportion of patients who tapered to zero dose;
however, the slower schedule was associated with a reduction in symptoms associated with a
withdrawal syndrome. It is suggested that the dose be reduced by no more than 0.5 mg every
3 days, with the understanding that some patients may benefit from an even more gradual
discontinuation. Some patients may prove resistant to all discontinuation regimens.
Dosing in Special Populations
In elderly patients, in patients with advanced liver disease or in patients with debilitating
disease, the usual starting dose is 0.25 mg, given two or three times daily. This may be
gradually increased if needed and tolerated. The elderly may be especially sensitive to the
effects of benzodiazepines. If side effects occur at the recommended starting dose, the dose
may be lowered.
HOW SUPPLIED
XANAX Tablets are available as follows:
0.25 mg (white, oval, scored, imprinted “XANAX 0.25”)
Bottles of 100
NDC 0009-0029-01
Reverse Numbered
Unit dose (100)
NDC 0009-0029-46
Bottles of 500
NDC 0009-0029-02
Bottles of 1000
NDC 0009-0029-14
0.5 mg (peach, oval, scored, imprinted “XANAX 0.5”)
Bottles of 100
NDC 0009-0055-01
Reverse Numbered
Unit Dose (100)
NDC 0009-0055-46
Bottles of 500
NDC 0009-0055-03
Bottles of 1000
NDC 0009-0055-15
1 mg (blue, oval, scored, imprinted “XANAX 1.0”)
Bottles of 100
NDC 0009-0090-01
Bottles of 500
NDC 0009-0090-04
Bottles of 1000
NDC 0009-0090-13
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2 mg (white, oblong, multi-scored, imprinted “XANAX ” on one side and “2” on the reverse
side)
Bottles of 100
NDC 0009-0094-01
Bottles of 500
NDC 0009-0094-03
Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].
Rx only
ANIMAL STUDIES
When rats were treated with alprazolam at 3, 10, and 30 mg/kg/day (15 to 150 times the
maximum recommended human dose) orally for 2 years, a tendency for a dose related
increase in the number of cataracts was observed in females and a tendency for a dose related
increase in corneal vascularization was observed in males. These lesions did not appear until
after 11 months of treatment. company logo
LAB-0004-6.0
Revised June 2011
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XANAX® XR CIV
(alprazolam) extended-release tablets
DESCRIPTION
XANAX XR Tablets contain alprazolam which is a triazolo analog of the 1,4 benzodiazepine
class of central nervous system-active compounds.
The chemical name of alprazolam is 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-α] [1,4]
benzodiazepine. The molecular formula is C17H13ClN4 which corresponds to a molecular
weight of 308.76.
The structural formula is represented below: structural formula
Alprazolam is a white crystalline powder, which is soluble in methanol or ethanol but which
has no appreciable solubility in water at physiological pH.
Each XANAX XR extended-release tablet, for oral administration, contains 0.5 mg, 1 mg, 2
mg, or 3 mg of alprazolam. The inactive ingredients are lactose, magnesium stearate,
colloidal silicon dioxide, and hypromellose. In addition, the 1 mg and 3 mg tablets contain D
& C yellow No. 10 and the 2 mg and 3 mg tablets contain FD&C blue No. 2.
CLINICAL PHARMACOLOGY
Pharmacodynamics
CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at
stereospecific receptors at several sites within the central nervous system. Their exact
mechanism of action is unknown. Clinically, all benzodiazepines cause a dose-related central
nervous system depressant activity varying from mild impairment of task performance to
hypnosis.
Pharmacokinetics
Absorption
Following oral administration of XANAX (immediate-release) Tablets, alprazolam is readily
absorbed. Peak concentrations in the plasma occur in one to two hours following
administration. Plasma levels are proportional to the dose given; over the dose range of 0.5
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to 3.0 mg, peak levels of 8.0 to 37 ng/mL were observed. Using a specific assay
methodology, the mean plasma elimination half-life of alprazolam has been found to be
about 11.2 hours (range: 6.3–26.9 hours) in healthy adults.
The mean absolute bioavailability of alprazolam from XANAX XR Tablets is approximately
90%, and the relative bioavailability compared to XANAX Tablets is 100%. The
bioavailability and pharmacokinetics of alprazolam following administration of XANAX XR
Tablets are similar to that for XANAX Tablets, with the exception of a slower rate of
absorption. The slower absorption rate results in a relatively constant concentration that is
maintained between 5 and 11 hours after the dosing. The pharmacokinetics of alprazolam
and two of its major active metabolites (4-hydroxyalprazolam and α-hydroxyalprazolam) are
linear, and concentrations are proportional up to the recommended maximum daily dose of
10 mg given once daily. Multiple dose studies indicate that the metabolism and elimination
of alprazolam are similar for the immediate-release and the extended-release products.
Food has a significant influence on the bioavailability of XANAX XR Tablets. A high-fat
meal given up to 2 hours before dosing with XANAX XR Tablets increased the mean Cmax
by about 25%. The effect of this meal on Tmax depended on the timing of the meal, with a
reduction in Tmax by about 1/3 for subjects eating immediately before dosing and an increase
in Tmax by about 1/3 for subjects eating 1 hour or more after dosing. The extent of exposure
(AUC) and elimination half-life (t1/2) were not affected by eating.
There were significant differences in absorption rate for the XANAX XR Tablet, depending
on the time of day administered, with the Cmax increased by 30% and the Tmax decreased by
an hour following dosing at night, compared to morning dosing.
Distribution
The apparent volume of distribution of alprazolam is similar for XANAX XR and XANAX
Tablets. In vitro, alprazolam is bound (80%) to human serum protein. Serum albumin
accounts for the majority of the binding.
Metabolism
Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4
(CYP3A4), to two major metabolites in the plasma: 4-hydroxyalprazolam and α
hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans.
Their half-lives appear to be similar to that of alprazolam. The pharmacokinetic parameters
at steady-state for the two hydroxylated metabolites of alprazolam (4-hydroxyalprazolam and
α-hydroxyalprazolam) were similar for XANAX and XANAX XR Tablets, indicating that
the metabolism of alprazolam is not affected by absorption rate. The plasma concentrations
of 4-hydroxyalprazolam and α-hydroxyalprazolam relative to unchanged alprazolam
concentration after both XANAX XR and XANAX Tablets were always less than 10% and
4%, respectively. The reported relative potencies in benzodiazepine receptor binding
experiments and in animal models of induced seizure inhibition are 0.20 and 0.66,
respectively, for 4-hydroxyalprazolam and α-hydroxyalprazolam. Such low concentrations
and the lesser potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam suggest that they
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are unlikely to contribute much to the pharmacological effects of alprazolam. The
benzophenone metabolite is essentially inactive.
Elimination
Alprazolam and its metabolites are excreted primarily in the urine. The mean plasma
elimination half-life of alprazolam following administration of XANAX XR Tablet ranges
from 10.7–15.8 hours in healthy adults.
Special Populations
While pharmacokinetic studies have not been performed in special populations with XANAX
XR Tablets, the factors (such as age, gender, hepatic or renal impairment) that would affect
the pharmacokinetics of alprazolam after the administration of XANAX Tablets would not
be expected to be different with the administration of XANAX XR Tablets.
Changes in the absorption, distribution, metabolism, and excretion of benzodiazepines have
been reported in a variety of disease states including alcoholism, impaired hepatic function,
and impaired renal function. Changes have also been demonstrated in geriatric patients. A
mean half-life of alprazolam of 16.3 hours has been observed in healthy elderly subjects
(range: 9.0–26.9 hours, n=16) compared to 11.0 hours (range: 6.3–15.8 hours, n=16) in
healthy adult subjects. In patients with alcoholic liver disease the half-life of alprazolam
ranged between 5.8 and 65.3 hours (mean: 19.7 hours, n=17) as compared to between 6.3 and
26.9 hours (mean=11.4 hours, n=17) in healthy subjects. In an obese group of subjects the
half-life of alprazolam ranged between 9.9 and 40.4 hours (mean=21.8 hours, n=12) as
compared to between 6.3 and 15.8 hours (mean=10.6 hours, n=12) in healthy subjects.
Because of its similarity to other benzodiazepines, it is assumed that alprazolam undergoes
transplacental passage and that it is excreted in human milk.
Race — Maximal concentrations and half-life of alprazolam are approximately 15% and
25% higher in Asians compared to Caucasians.
Pediatrics — The pharmacokinetics of alprazolam after administration of the XANAX XR
Tablet in pediatric patients have not been studied.
Gender — Gender has no effect on the pharmacokinetics of alprazolam.
Cigarette Smoking — Alprazolam concentrations may be reduced by up to 50% in smokers
compared to non-smokers.
Drug-Drug Interactions
Alprazolam is primarily eliminated by metabolism via cytochrome P450 3A (CYP3A). Most
of the interactions that have been documented with alprazolam are with drugs that inhibit or
induce CYP3A4.
Compounds that are potent inhibitors of CYP3A would be expected to increase plasma
alprazolam concentrations. Drug products that have been studied in vivo, along with their
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effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itraconazole,
2.70 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold (see
CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS–Drug Interactions).
CYP3A inducers would be expected to decrease alprazolam concentrations and this has been
observed in vivo. The oral clearance of alprazolam (given in a 0.8 mg single dose) was
increased from 0.90±0.21 mL/min/kg to 2.13±0.54 mL/min/kg and the elimination t1/2 was
shortened (from 17.1±4.9 to 7.7 ±1.7 h) following administration of 300 mg/day
carbamazepine for 10 days (see PRECAUTIONS–Drug Interactions). However, the
carbamazepine dose used in this study was fairly low compared to the recommended doses
(1000–1200 mg/day); the effect at usual carbamazepine doses is unknown.
The ability of alprazolam to induce or inhibit human hepatic enzyme systems has not been
determined. However, this is not a property of benzodiazepines in general. Further,
alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers
administered sodium warfarin orally.
CLINICAL EFFICACY TRIALS
The efficacy of XANAX XR Tablets in the treatment of panic disorder was established in
two 6-week, placebo-controlled studies of XANAX XR in patients with panic disorder.
In two 6-week, flexible-dose, placebo-controlled studies in patients meeting DSM-III criteria
for panic disorder, patients were treated with XANAX XR in a dose range of 1 to 10 mg/day,
on a once-a-day basis. The effectiveness of XANAX XR was assessed on the basis of
changes in various measures of panic attack frequency, on various measures of the Clinical
Global Impression, and on the Overall Phobia Scale. In all, there were seven primary
efficacy measures in these studies, and XANAX XR was superior to placebo on all seven
outcomes in both studies. The mean dose of XANAX XR at the last treatment visit was 4.2
mg/day in the first study and 4.6 mg/day in the second.
In addition, there were two 8-week, fixed-dose, placebo-controlled studies of XANAX XR in
patients with panic disorder, involving fixed XANAX XR doses of 4 and 6 mg/day, on a
once-a-day basis, that did not show a benefit for either dose of XANAX XR.
The longer-term efficacy of XANAX XR in panic disorder has not been systematically
evaluated.
Analyses of the relationship between treatment outcome and gender did not suggest any
differential responsiveness on the basis of gender.
INDICATIONS AND USAGE
XANAX XR Tablets are indicated for the treatment of panic disorder, with or without
agoraphobia.
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This claim is supported on the basis of two positive studies with XANAX XR conducted in
patients whose diagnoses corresponded closely to the DSM-III-R/IV criteria for panic
disorder (see CLINICAL EFFICACY TRIALS).
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, ie, a
discrete period of intense fear or discomfort in which four (or more) of the following
symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding
heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of
shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7)
nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9)
derealization (feelings of unreality) or depersonalization (being detached from oneself); (10)
fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations);
(13) chills or hot flushes.
The longer-term efficacy of XANAX XR has not been systematically evaluated. Thus, the
physician who elects to use this drug for periods longer than 8 weeks should periodically
reassess the usefulness of the drug for the individual patient.
CONTRAINDICATIONS
XANAX XR Tablets are contraindicated in patients with known sensitivity to this drug or
other benzodiazepines. XANAX XR may be used in patients with open angle glaucoma who
are receiving appropriate therapy, but is contraindicated in patients with acute narrow angle
glaucoma.
XANAX XR is contraindicated with ketoconazole and itraconazole, since these medications
significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP3A)
(see CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS–Drug
Interactions).
WARNINGS
Dependence and Withdrawal Reactions, Including Seizures
Certain adverse clinical events, some life-threatening, are a direct consequence of physical
dependence to alprazolam. These include a spectrum of withdrawal symptoms; the most
important is seizure (see DRUG ABUSE AND DEPENDENCE). Even after relatively short-
term use at doses of < 4 mg/day, there is some risk of dependence. Spontaneous reporting
system data suggest that the risk of dependence and its severity appear to be greater in
patients treated with doses greater than 4 mg/day and for long periods (more than 12 weeks).
However, in a controlled postmarketing discontinuation study of panic disorder patients who
received XANAX Tablets, the duration of treatment (3 months compared to 6 months) had
no effect on the ability of patients to taper to zero dose. In contrast, patients treated with
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doses of XANAX Tablets greater than 4 mg/day had more difficulty tapering to zero dose
than those treated with less than 4 mg/day.
Relapse or return of illness was defined as a return of symptoms characteristic of panic
disorder (primarily panic attacks) to levels approximately equal to those seen at baseline
before active treatment was initiated. Rebound refers to a return of symptoms of panic
disorder to a level substantially greater in frequency, or more severe in intensity than seen at
baseline. Withdrawal symptoms were identified as those which were generally not
characteristic of panic disorder and which occurred for the first time more frequently during
discontinuation than at baseline.
The rate of relapse, rebound, and withdrawal in patients with panic disorder who received
XANAX XR Tablets has not been systematically studied. Experience in randomized
placebo-controlled discontinuation studies of patients with panic disorder who received
XANAX Tablets showed a high rate of rebound and withdrawal symptoms compared to
placebo treated patients.
In a controlled clinical trial in which 63 patients were randomized to XANAX Tablets and
where withdrawal symptoms were specifically sought, the following were identified as
symptoms of withdrawal: heightened sensory perception, impaired concentration, dysosmia,
clouded sensorium, paresthesias, muscle cramps, muscle twitch, diarrhea, blurred vision,
appetite decrease, and weight loss. Other symptoms, such as anxiety and insomnia, were
frequently seen during discontinuation, but it could not be determined if they were due to
return of illness, rebound, or withdrawal.
In two controlled trials of 6 to 8 weeks duration where the ability of patients to discontinue
medication was measured, 71%–93% of patients treated with XANAX Tablets tapered
completely off therapy compared to 89%–96% of placebo treated patients. In a controlled
postmarketing discontinuation study of panic disorder patients treated with XANAX Tablets,
the duration of treatment (3 months compared to 6 months) had no effect on the ability of
patients to taper to zero dose.
Seizures were reported for three patients in panic disorder clinical trials with XANAX XR.
In two cases, the patients had completed 6 weeks of treatment with XANAX XR 6 mg/day
before experiencing a single seizure. In one case, the patient abruptly discontinued XANAX
XR, and in both cases, alcohol intake was implicated. The third case involved multiple
seizures after the patient completed treatment with XANAX XR 4 mg/day and missed taking
the medication on the first day of taper. All three patients recovered without sequelae.
Seizures have also been observed in association with dose reduction or discontinuation of
XANAX Tablets, the immediate release form of alprazolam. Seizures attributable to
XANAX were seen after drug discontinuance or dose reduction in 8 of 1980 patients with
panic disorder or in patients participating in clinical trials where doses of XANAX greater
than 4 mg/day for over 3 months were permitted. Five of these cases clearly occurred during
abrupt dose reduction, or discontinuation from daily doses of 2 to 10 mg. Three cases
occurred in situations where there was not a clear relationship to abrupt dose reduction or
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discontinuation. In one instance, seizure occurred after discontinuation from a single dose of
1 mg after tapering at a rate of 1 mg every three days from 6 mg daily. In two other
instances, the relationship to taper is indeterminate; in both of these cases the patients had
been receiving doses of 3 mg daily prior to seizure. The duration of use in the above 8 cases
ranged from 4 to 22 weeks. There have been occasional voluntary reports of patients
developing seizures while apparently tapering gradually from XANAX. The risk of seizure
seems to be greatest 24–72 hours after discontinuation (see DOSAGE AND
ADMINISTRATION for recommended tapering and discontinuation schedule).
Status Epilepticus
The medical event voluntary reporting system shows that withdrawal seizures have been
reported in association with the discontinuation of XANAX Tablets. In most cases, only a
single seizure was reported; however, multiple seizures and status epilepticus were reported
as well.
Interdose Symptoms
Early morning anxiety and emergence of anxiety symptoms between doses of XANAX
Tablets have been reported in patients with panic disorder taking prescribed maintenance
doses. These symptoms may reflect the development of tolerance or a time interval between
doses which is longer than the duration of clinical action of the administered dose. In either
case, it is presumed that the prescribed dose is not sufficient to maintain plasma levels above
those needed to prevent relapse, rebound, or withdrawal symptoms over the entire course of
the interdosing interval.
Risk of Dose Reduction
Withdrawal reactions may occur when dosage reduction occurs for any reason. This includes
purposeful tapering, but also inadvertent reduction of dose (eg, the patient forgets, the patient
is admitted to a hospital). Therefore, the dosage of XANAX XR should be reduced or
discontinued gradually (see DOSAGE AND ADMINISTRATION).
CNS Depression and Impaired Performance
Because of its CNS depressant effects, patients receiving XANAX XR should be cautioned
against engaging in hazardous occupations or activities requiring complete mental alertness
such as operating machinery or driving a motor vehicle. For the same reason, patients should
be cautioned about the simultaneous ingestion of alcohol and other CNS depressant drugs
during treatment with XANAX XR.
Risk of Fetal Harm
Benzodiazepines can potentially cause fetal harm when administered to pregnant women. If
alprazolam is used during pregnancy, or if the patient becomes pregnant while taking this
drug, the patient should be apprised of the potential hazard to the fetus. Because of
experience with other members of the benzodiazepine class, alprazolam is assumed to be
capable of causing an increased risk of congenital abnormalities when administered to a
pregnant woman during the first trimester. Because use of these drugs is rarely a matter of
urgency, their use during the first trimester should almost always be avoided. The possibility
that a woman of childbearing potential may be pregnant at the time of institution of therapy
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should be considered. Patients should be advised that if they become pregnant during therapy
or intend to become pregnant they should communicate with their physicians about the
desirability of discontinuing the drug.
Alprazolam Interaction With Drugs That Inhibit Metabolism Via Cytochrome
P450 3A
The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A
(CYP3A). Drugs that inhibit this metabolic pathway may have a profound effect on the
clearance of alprazolam. Consequently, alprazolam should be avoided in patients receiving
very potent inhibitors of CYP3A. With drugs inhibiting CYP3A to a lesser but still
significant degree, alprazolam should be used only with caution and consideration of
appropriate dosage reduction. For some drugs, an interaction with alprazolam has been
quantified with clinical data; for other drugs, interactions are predicted from in vitro data
and/or experience with similar drugs in the same pharmacologic class.
The following are examples of drugs known to inhibit the metabolism of alprazolam and/or
related benzodiazepines, presumably through inhibition of CYP3A.
Potent CYP3A Inhibitors
Azole antifungal agents — Ketoconazole and itraconazole are potent CYP3A inhibitors and
have been shown in vivo to increase plasma alprazolam concentrations 3.98 fold and 2.70
fold, respectively. The coadministration of alprazolam with these agents is not
recommended. Other azole-type antifungal agents should also be considered potent CYP3A
inhibitors and the coadministration of alprazolam with them is not recommended (see
CONTRAINDICATIONS).
Drugs demonstrated to be CYP3A inhibitors on the basis of clinical studies involving
alprazolam (caution and consideration of appropriate alprazolam dose reduction are
recommended during coadministration with the following drugs)
Nefazodone — Coadministration of nefazodone increased alprazolam concentration two
fold.
Fluvoxamine — Coadministration of fluvoxamine approximately doubled the maximum
plasma concentration of alprazolam, decreased clearance by 49%, increased half-life by 71%,
and decreased measured psychomotor performance.
Cimetidine — Coadministration of cimetidine increased the maximum plasma concentration
of alprazolam by 86%, decreased clearance by 42%, and increased half-life by 16%.
Other Drugs Possibly Affecting Alprazolam Metabolism
Other drugs possibly affecting alprazolam metabolism by inhibition of CYP3A are discussed
in the PRECAUTIONS section (see PRECAUTIONS–Drug Interactions).
PRECAUTIONS
General
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Suicide
As with other psychotropic medications, the usual precautions with respect to administration
of the drug and size of the prescription are indicated for severely depressed patients or those
in whom there is reason to expect concealed suicidal ideation or plans. Panic disorder has
been associated with primary and secondary major depressive disorders and increased reports
of suicide among untreated patients.
Mania
Episodes of hypomania and mania have been reported in association with the use of XANAX
Tablets in patients with depression.
Uricosuric Effect
Alprazolam has a weak uricosuric effect. Although other medications with weak uricosuric
effect have been reported to cause acute renal failure, there have been no reported instances
of acute renal failure attributable to therapy with alprazolam.
Use in Patients with Concomitant Illness
It is recommended that the dosage be limited to the smallest effective dose to preclude the
development of ataxia or oversedation which may be a particular problem in elderly or
debilitated patients (see DOSAGE AND ADMINISTRATION). The usual precautions in
treating patients with impaired renal, hepatic, or pulmonary function should be observed.
There have been rare reports of death in patients with severe pulmonary disease shortly after
the initiation of treatment with XANAX Tablets. A decreased systemic alprazolam
elimination rate (eg, increased plasma half-life) has been observed in both alcoholic liver
disease patients and obese patients receiving XANAX Tablets (see CLINICAL
PHARMACOLOGY).
Information for Patients
To assure safe and effective use of XANAX XR, the physician should provide the patient
with the following guidance.
1. Inform your physician about any alcohol consumption and medicine you are taking now,
including medication you may buy without a prescription. Alcohol should generally not
be used during treatment with benzodiazepines.
2. Not recommended for use in pregnancy. Therefore, inform your physician if you are
pregnant, if you are planning to have a child, or if you become pregnant while you are
taking this medication.
3. Inform your physician if you are nursing.
4. Until you experience how this medication affects you, do not drive a car or operate
potentially dangerous machinery, etc.
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5. Do not increase the dose even if you think the medication "does not work anymore"
without consulting your physician. Benzodiazepines, even when used as recommended,
may produce emotional and/or physical dependence.
6. Do not stop taking this medication abruptly or decrease the dose without consulting your
physician, since withdrawal symptoms can occur.
7. Some patients may find it very difficult to discontinue treatment with XANAX XR due to
severe emotional and physical dependence. Discontinuation symptoms, including
possible seizures, may occur following discontinuation from any dose, but the risk may
be increased with extended use at doses greater than 4 mg/day, especially if
discontinuation is too abrupt. It is important that you seek advice from your physician to
discontinue treatment in a careful and safe manner. Proper discontinuation will help to
decrease the possibility of withdrawal reactions that can range from mild reactions to
severe reactions such as seizure.
Laboratory Tests
Laboratory tests are not ordinarily required in otherwise healthy patients. However, when
treatment is protracted, periodic blood counts, urinalysis, and blood chemistry analyses are
advisable in keeping with good medical practice.
Drug Interactions
Use with Other CNS Depressants
If XANAX XR Tablets are to be combined with other psychotropic agents or anticonvulsant
drugs, careful consideration should be given to the pharmacology of the agents to be
employed, particularly with compounds which might potentiate the action of
benzodiazepines. The benzodiazepines, including alprazolam, produce additive CNS
depressant effects when coadministered with other psychotropic medications,
anticonvulsants, antihistaminics, ethanol and other drugs which themselves produce CNS
depression.
Use with Imipramine and Desipramine
The steady state plasma concentrations of imipramine and desipramine have been reported to
be increased an average of 31% and 20%, respectively, by the concomitant administration of
XANAX Tablets in doses up to 4 mg/day. The clinical significance of these changes is
unknown.
Drugs that inhibit alprazolam metabolism via cytochrome P450 3A
The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A
(CYP3A). Drugs which inhibit this metabolic pathway may have a profound effect on the
clearance of alprazolam (see CONTRAINDICATIONS and WARNINGS for additional
drugs of this type).
Drugs demonstrated to be CYP3A inhibitors of possible clinical significance on the
basis of clinical studies involving alprazolam (caution is recommended during
coadministration with alprazolam)
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Fluoxetine — Coadministration of fluoxetine with alprazolam increased the maximum
plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased half-life
by 17%, and decreased measured psychomotor performance.
Propoxyphene — Coadministration of propoxyphene decreased the maximum plasma
concentration of alprazolam by 6%, decreased clearance by 38%, and increased half-life by
58%.
Oral Contraceptives — Coadministration of oral contraceptives increased the maximum
plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased
half-life by 29%.
Drugs and other substances demonstrated to be CYP3A inhibitors on the basis of
clinical studies involving benzodiazepines metabolized similarly to alprazolam or on
the basis of in vitro studies with alprazolam or other benzodiazepines (caution is
recommended during coadministration with alprazolam)
Available data from clinical studies of benzodiazepines other than alprazolam suggest a
possible drug interaction with alprazolam for the following: diltiazem, isoniazid, macrolide
antibiotics such as erythromycin and clarithromycin, and grapefruit juice. Data from in vitro
studies of alprazolam suggest a possible drug interaction with alprazolam for the following:
sertraline and paroxetine. However, data from an in vivo drug interaction study involving a
single dose of alprazolam 1 mg and steady state doses of sertraline (50 to 150 mg/day) did
not reveal any clinically significant changes in the pharmacokinetics of alprazolam. Data
from in vitro studies of benzodiazepines other than alprazolam suggest a possible drug
interaction for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and
nifedipine. Caution is recommended during the coadministration of any of these with
alprazolam (see WARNINGS).
Drugs demonstrated to be inducers of CYP3A
Carbamazepine can increase alprazolam metabolism and therefore can decrease plasma
levels of alprazolam.
Drug/Laboratory Test Interactions
Although interactions between benzodiazepines and commonly employed clinical laboratory
tests have occasionally been reported, there is no consistent pattern for a specific drug or
specific test.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenic potential was observed during 2-year bioassay studies of
alprazolam in rats at doses up to 30 mg/kg/day (150 times the maximum recommended daily
human dose of 10 mg/day) and in mice at doses up to 10 mg/kg/day (50 times the maximum
recommended daily human dose).
Alprazolam was not mutagenic in the rat micronucleus test at doses up to 100 mg/kg, which
is 500 times the maximum recommended daily human dose of 10 mg/day. Alprazolam also
was not mutagenic in vitro in the DNA Damage/Alkaline Elution Assay or the Ames Assay.
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Alprazolam produced no impairment of fertility in rats at doses up to 5 mg/kg/day, which is
25 times the maximum recommended daily human dose of 10 mg/day.
Pregnancy
Teratogenic Effects: Pregnancy Category D: (see WARNINGS section).
Nonteratogenic Effects: It should be considered that the child born of a mother who is
receiving benzodiazepines may be at some risk for withdrawal symptoms from the drug
during the postnatal period. Also, neonatal flaccidity and respiratory problems have been
reported in children born of mothers who have been receiving benzodiazepines.
Labor and Delivery
Alprazolam has no established use in labor or delivery.
Nursing Mothers
Benzodiazepines are known to be excreted in human milk. It should be assumed that
alprazolam is as well. Chronic administration of diazepam to nursing mothers has been
reported to cause their infants to become lethargic and to lose weight. As a general rule,
nursing should not be undertaken by mothers who must use alprazolam.
Pediatric Use
Safety and effectiveness of alprazolam in individuals below 18 years of age have not been
established.
Geriatric Use
The elderly may be more sensitive to the effects of benzodiazepines. They exhibit higher
plasma alprazolam concentrations due to reduced clearance of the drug as compared with a
younger population receiving the same doses. The smallest effective dose of alprazolam
should be used in the elderly to preclude the development of ataxia and oversedation (see
CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
The information included in the subsection on Adverse Events Observed in Short-Term,
Placebo-Controlled Trials with XANAX XR Tablets is based on pooled data of five 6- and 8
week placebo-controlled clinical studies in panic disorder.
Adverse event reports were elicited either by general inquiry or by checklist, and were
recorded by clinical investigators using terminology of their own choosing. The stated
frequencies of adverse events represent the proportion of individuals who experienced, at
least once, a treatment-emergent adverse event of the type listed. An event was considered
treatment emergent if it occurred for the first time or worsened during therapy following
baseline evaluation. In the tables and tabulations that follow, standard MedDRA terminology
(version 4.0) was used to classify reported adverse events.
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Adverse Events Observed in Short-Term, Placebo-Controlled Trials of XANAX
XR
Adverse Events Reported as Reasons for Discontinuation of Treatment in Placebo-
Controlled Trials
Approximately 17% of the 531 patients who received XANAX XR in placebo-controlled
clinical trials for panic disorder had at least one adverse event that led to discontinuation
compared to 8% of 349 placebo-treated patients. The most common events leading to
discontinuation and considered to be drug-related (ie, leading to discontinuation in at least
1% of the patients treated with XANAX XR at a rate at least twice that of placebo) are
shown in the following table.
Common Adverse Events Leading to Discontinuation of Treatment
in Placebo-Controlled Trials
System Organ Class/Adverse Event
Percentage of Patients Discontinuing
Due to Adverse Events
XANAX XR
(n=531)
Placebo
(n=349)
Nervous system disorders
Sedation
Somnolence
Dysarthria
Coordination abnormal
Memory impairment
7.5
3.2
2.1
1.9
1.5
0.6
0.3
0
0.3
0.3
General disorders/administration site
conditions
Fatigue
1.7
0.6
Psychiatric disorders
Depression
2.5
1.2
Adverse Events Occurring at an Incidence of 1% or More Among Patients Treated
with XANAX XR
The prescriber should be aware that adverse event incidence cannot be used to predict the
incidence of adverse events in the course of usual medical practice where patient
characteristics and other factors differ from those which prevailed in the clinical trials.
Similarly, the cited frequencies cannot be compared with event incidence obtained from
other clinical investigations involving different treatments, uses, and investigators. The cited
values, however, do provide the prescribing physician with some basis for estimating the
relative contribution of drug and non-drug factors to the adverse event incidence rate in the
population studied.
The following table shows the incidence of treatment-emergent adverse events that occurred
during 6- to 8-week placebo-controlled trials in 1% or more of patients treated with XANAX
XR where the incidence in patients treated with XANAX XR was greater than the incidence
in placebo-treated patients. The most commonly observed adverse events in panic disorder
patients treated with XANAX XR (incidence of 5% or greater and at least twice the
incidence in placebo patients) were: sedation, somnolence, memory impairment, dysarthria,
coordination abnormal, ataxia, libido decreased (see table).
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Treatment-Emergent Adverse Events:
Incidence in Short-Term, Placebo-Controlled Clinical Trials with
XANAX XR
System Organ Class/Adverse Event
Percentage of Patients
Reporting Adverse Event
XANAX XR
(n=531)
Placebo
(n=349)
Nervous system disorders
Sedation
45.2
22.6
Somnolence
23.0
6.0
Memory impairment
15.4
6.9
Dysarthria
10.9
2.6
Coordination abnormal
9.4
0.9
Mental impairment
7.2
5.7
Ataxia
7.2
3.2
Disturbance in attention
3.2
0.6
Balance impaired
3.2
0.6
Paresthesia
2.4
1.7
Dyskinesia
1.7
1.4
Hypoesthesia
1.3
0.3
Hypersomnia
1.3
0
General disorders/administration site
conditions
Fatigue
13.9
9.2
Lethargy
1.7
0.6
Infections and infestations
Influenza
Upper respiratory tract infections
2.4
2.3
1.9
1.7
Psychiatric disorders
Depression
12.1
9.2
Libido decreased
6.0
2.3
Disorientation
1.5
0
Confusion
1.5
0.9
Depressed mood
1.3
0.3
Anxiety
1.1
0.6
Metabolism and nutrition disorders
Appetite decreased
7.3
7.2
Appetite increased
7.0
6.0
Anorexia
1.5
0
Gastrointestinal disorders
Dry mouth
10.2
9.7
Constipation
8.1
4.3
Nausea
6.0
3.2
Pharyngolaryngeal pain
3.2
2.6
Investigations
Weight increased
Weight decreased
5.1
4.3
4.3
3.7
Injury, poisoning, and procedural
complications
Road traffic accident
1.5
0
Reproductive system and breast
disorders
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Dysmenorrhea
Sexual dysfunction
Premenstrual syndrome
3.6
2.4
1.7
2.9
1.1
0.6
Musculoskeletal and connective tissue
disorders
Arthralgia
Myalgia
Pain in limb
2.4
1.5
1.1
0.6
1.1
0.3
Vascular disorders
Hot flushes
1.5
1.4
Respiratory, thoracic, and mediastinal
disorders
Dyspnea
Rhinitis allergic
1.5
1.1
0.3
0.6
Skin and subcutaneous tissue disorders
Pruritis
1.1
0.9
Other Adverse Events Observed During the Premarketing Evaluation of XANAX XR
Tablets
Following is a list of MedDRA terms that reflect treatment-emergent adverse events reported
by 531 patients with panic disorder treated with XANAX XR. All potentially important
reported events are included except those already listed in the above table or elsewhere in
labeling, those events for which a drug cause was remote, those event terms that were so
general as to be uninformative, and those events that occurred at rates similar to background
rates in the general population. It is important to emphasize that, although the events reported
occurred during treatment with XANAX XR, they were not necessarily caused by the drug.
Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions: frequent adverse events are those occurring on 1 or
more occasions in at least l/l00 patients; infrequent adverse events are those occurring in less
than l/100 patients but at least l/1000 patients; rare events are those occurring in fewer than
l/1000 patients.
Cardiac disorders: Frequent: palpitation; Infrequent: sinus tachycardia
Ear and Labyrinth disorders: Frequent: Vertigo; Infrequent: tinnitus, ear pain
Eye disorders: Frequent: blurred vision; Infrequent: mydriasis, photophobia
Gastrointestinal disorders: Frequent: diarrhea, vomiting, dyspepsia, abdominal pain;
Infrequent: dysphagia, salivary hypersecretion
General disorders and administration site conditions: Frequent: malaise, weakness, chest
pains; Infrequent: fall, pyrexia, thirst, feeling hot and cold, edema, feeling jittery,
sluggishness, asthenia, feeling drunk, chest tightness, increased energy, feeling of relaxation,
hangover, loss of control of legs, rigors
Musculoskeletal and connective tissue disorders: Frequent: back pain, muscle cramps,
muscle twitching
Nervous system disorders: Frequent: headache, dizziness, tremor; Infrequent: amnesia,
clumsiness, syncope, hypotonia, seizures, depressed level of consciousness, sleep apnea
syndrome, sleep talking, stupor
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Psychiatric system disorders: Frequent: irritability, insomnia, nervousness, derealization,
libido increased, restlessness, agitation, depersonalization, nightmare; Infrequent: abnormal
dreams, apathy, aggression, anger, bradyphrenia, euphoric mood, logorrhea, mood swings,
dysphonia, hallucination, homicidal ideation, mania, hypomania, impulse control,
psychomotor retardation, suicidal ideation
Renal and urinary disorders: Frequent: difficulty in micturition; Infrequent: urinary
frequency, urinary incontinence
Respiratory, thoracic, and mediastinal disorders: Frequent: nasal congestion,
hyperventilation; Infrequent: choking sensation, epistaxis, rhinorrhea
Skin and subcutaneous tissue disorders: Frequent: sweating increased; Infrequent:
clamminess, rash, urticaria
Vascular disorders: Infrequent: hypotension
The categories of adverse events reported in the clinical development program for XANAX
Tablets in the treatment of panic disorder differ somewhat from those reported for XANAX
XR Tablets because the clinical trials with XANAX Tablets and XANAX XR Tablets used
different standard medical nomenclature for reporting the adverse events. Nevertheless, the
types of adverse events reported in the clinical trials with XANAX Tablets were generally
the same as those reported in the clinical trials with XANAX XR Tablets.
Discontinuation-Emergent Adverse Events Occurring at an Incidence of 5% or More
Among Patients Treated with XANAX XR
The following table shows the incidence of discontinuation-emergent adverse events that
occurred during short-term, placebo-controlled trials in 5% or more of patients treated with
XANAX XR where the incidence in patients treated with XANAX XR was two times greater
than the incidence in placebo-treated patients.
Discontinuation-Emergent Symptoms:
Incidence in Short-Term, Placebo-Controlled Trials
with XANAX XR
System Organ Class/AdverseEvent
Percentage of Patients Reporting
Adverse Event
XANAX XR
(n=422)
Placebo
(n=261)
Nervous system disorders
Tremor
28.2
10.7
Headache
26.5
12.6
Hypoesthesia
7.8
2.3
Paraesthesia
7.1
2.7
Psychiatric disorders
Insomnia
24.2
9.6
Nervousness
21.8
8.8
Depression
10.9
5.0
Derealization
8.0
3.8
Anxiety
7.8
2.7
Depersonalization
5.7
1.9
Gastrointestinal disorders
Diarrhea
12.1
3.1
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Respiratory, thoracic and
mediastinal disorders
Hyperventilation
8.5
2.7
Metabolism and nutrition
disorders
Appetite decreased
9.5
3.8
Musculosketal and connective
tissue disorders
Muscle twitching
7.4
2.7
Vascular disorders
Hot flushes
5.9
2.7
There have also been reports of withdrawal seizures upon rapid decrease or abrupt
discontinuation of alprazolam (see WARNINGS).
To discontinue treatment in patients taking XANAX XR Tablets, the dosage should be
reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of
XANAX XR Tablets be decreased by no more than 0.5 mg every three days (see DOSAGE
AND ADMINISTRATION). Some patients may benefit from an even slower dosage
reduction. In a controlled postmarketing discontinuation study of panic disorder patients
which compared this recommended taper schedule with a slower taper schedule, no
difference was observed between the groups in the proportion of patients who tapered to zero
dose; however, the slower schedule was associated with a reduction in symptoms associated
with a withdrawal syndrome.
As with all benzodiazepines, paradoxical reactions such as stimulation, increased muscle
spasticity, sleep disturbances, hallucinations, and other adverse behavioral effects such as
agitation, rage, irritability, and aggressive or hostile behavior have been reported rarely. In
many of the spontaneous case reports of adverse behavioral effects, patients were receiving
other CNS drugs concomitantly and/or were described as having underlying psychiatric
conditions. Should any of the above events occur, alprazolam should be discontinued.
Isolated published reports involving small numbers of patients have suggested that patients
who have borderline personality disorder, a prior history of violent or aggressive behavior, or
alcohol or substance abuse may be at risk for such events. Instances of irritability, hostility,
and intrusive thoughts have been reported during discontinuation of alprazolam in patients
with posttraumatic stress disorder.
Post Introduction Reports
Various adverse drug reactions have been reported in association with the use of XANAX
Tablets since market introduction. The majority of these reactions were reported through the
medical event voluntary reporting system. Because of the spontaneous nature of the reporting
of medical events and the lack of controls, a causal relationship to the use of XANAX
Tablets cannot be readily determined. Reported events include: gastrointestinal disorder,
hypomania, mania, liver enzyme elevations, hepatitis, hepatic failure, Stevens-Johnson
syndrome, angioedema, peripheral edema, hyperprolactinemia, gynecomastia, and
galactorrhea (see PRECAUTIONS).
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DRUG ABUSE AND DEPENDENCE
Physical and Psychological Dependence
Withdrawal symptoms similar in character to those noted with sedative/hypnotics and
alcohol have occurred following discontinuance of benzodiazepines, including alprazolam.
The symptoms can range from mild dysphoria and insomnia to a major syndrome that may
include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions.
Distinguishing between withdrawal emergent signs and symptoms and the recurrence of
illness is often difficult in patients undergoing dose reduction. The long-term strategy for
treatment of these phenomena will vary with their cause and the therapeutic goal. When
necessary, immediate management of withdrawal symptoms requires re-institution of
treatment at doses of alprazolam sufficient to suppress symptoms. There have been reports of
failure of other benzodiazepines to fully suppress these withdrawal symptoms. These failures
have been attributed to incomplete cross-tolerance but may also reflect the use of an
inadequate dosing regimen of the substituted benzodiazepine or the effects of concomitant
medications.
While it is difficult to distinguish withdrawal and recurrence for certain patients, the time
course and the nature of the symptoms may be helpful. A withdrawal syndrome typically
includes the occurrence of new symptoms, tends to appear toward the end of taper or shortly
after discontinuation, and will decrease with time. In recurring panic disorder, symptoms
similar to those observed before treatment may recur either early or late, and they will
persist.
While the severity and incidence of withdrawal phenomena appear to be related to dose and
duration of treatment, withdrawal symptoms, including seizures, have been reported after
only brief therapy with alprazolam at doses within the recommended range for the treatment
of anxiety (eg, 0.75 to 4 mg/day). Signs and symptoms of withdrawal are often more
prominent after rapid decrease of dosage or abrupt discontinuance. The risk of withdrawal
seizures may be increased at doses above 4 mg/day (see WARNINGS).
Patients, especially individuals with a history of seizures or epilepsy, should not be abruptly
discontinued from any CNS depressant agent, including alprazolam. It is recommended that
all patients on alprazolam who require a dosage reduction be gradually tapered under close
supervision (see WARNINGS and DOSAGE AND ADMINISTRATION).
Psychological dependence is a risk with all benzodiazepines, including alprazolam. The risk
of psychological dependence may also be increased at doses greater than 4 mg/day and with
longer term use, and this risk is further increased in patients with a history of alcohol or drug
abuse. Some patients have experienced considerable difficulty in tapering and discontinuing
from alprazolam, especially those receiving higher doses for extended periods. Addiction-
prone individuals should be under careful surveillance when receiving alprazolam. As with
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all anxiolytics, repeat prescriptions should be limited to those who are under medical
supervision.
Controlled Substance Class
Alprazolam is a controlled substance under the Controlled Substance Act by the Drug
Enforcement Administration and XANAX XR Tablets have been assigned to Schedule IV.
OVERDOSAGE
Clinical Experience
Overdosage reports with XANAX Tablets are limited. Manifestations of alprazolam
overdosage include somnolence, confusion, impaired coordination, diminished reflexes, and
coma. Death has been reported in association with overdoses of alprazolam by itself, as it has
with other benzodiazepines. In addition, fatalities have been reported in patients who have
overdosed with a combination of a single benzodiazepine, including alprazolam, and alcohol;
alcohol levels seen in some of these patients have been lower than those usually associated
with alcohol-induced fatality.
Animal experiments have suggested that forced diuresis or hemodialysis are probably of little
value in treating overdosage.
General Treatment of Overdose
As in all cases of drug overdosage, respiration, pulse rate, and blood pressure should be
monitored. General supportive measures should be employed, along with immediate gastric
lavage. Intravenous fluids should be administered and an adequate airway maintained. If
hypotension occurs, it may be combated by the use of vasopressors. Dialysis is of limited
value. As with the management of intentional overdosing with any drug, it should be borne in
mind that multiple agents may have been ingested.
Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or
partial reversal of the sedative effects of benzodiazepines and may be used in situations when
an overdose with a benzodiazepine is known or suspected. Prior to the administration of
flumazenil, necessary measures should be instituted to secure airway, ventilation, and
intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper
management of benzodiazepine overdose. Patients treated with flumazenil should be
monitored for re-sedation, respiratory depression, and other residual benzodiazepine effects
for an appropriate period after treatment. The prescriber should be aware of a risk of
seizure in association with flumazenil treatment, particularly in long-term
benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil
package insert including CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS
should be consulted prior to use.
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DOSAGE AND ADMINISTRATION
XANAX XR Tablets may be administered once daily, preferably in the morning. The tablets
should be taken intact; they should not be chewed, crushed, or broken.
The suggested total daily dose ranges between 3 to 6 mg/day. Dosage should be
individualized for maximum beneficial effect. While the suggested total daily dosages given
will meet the needs of most patients, there will be some patients who require doses greater
than 6 mg/day. In such cases, dosage should be increased cautiously to avoid adverse effects.
Dosing in Special Populations
In elderly patients, in patients with advanced liver disease, or in patients with debilitating
disease, the usual starting dose of XANAX XR is 0.5 mg once daily. This may be gradually
increased if needed and tolerated (see Dose Titration). The elderly may be especially
sensitive to the effects of benzodiazepines.
Dose Titration
Treatment with XANAX XR may be initiated with a dose of 0.5 mg to 1 mg once daily.
Depending on the response, the dose may be increased at intervals of 3 to 4 days in
increments of no more than 1 mg/day. Slower titration to the dose levels may be advisable to
allow full expression of the pharmacodynamic effect of XANAX XR.
Generally, therapy should be initiated at a low dose to minimize the risk of adverse responses
in patients especially sensitive to the drug. Dose should be advanced until an acceptable
therapeutic response (ie, a substantial reduction in or total elimination of panic attacks) is
achieved, intolerance occurs, or the maximum recommended dose is attained.
Dose Maintenance
In controlled trials conducted to establish the efficacy of XANAX XR Tablets in panic
disorder, doses in the range of 1 to 10 mg/day were used. Most patients showed efficacy in
the dose range of 3 to 6 mg/day. Occasional patients required as much as 10 mg/day to
achieve a successful response.
The necessary duration of treatment for panic disorder patients responding to XANAX XR is
unknown. However, periodic reassessment is advised. After a period of extended freedom
from attacks, a carefully supervised tapered discontinuation may be attempted, but there is
evidence that this may often be difficult to accomplish without recurrence of symptoms
and/or the manifestation of withdrawal phenomena.
Dose Reduction
Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided
(see WARNINGS, PRECAUTIONS, DRUG ABUSE AND DEPENDENCE).
In all patients, dosage should be reduced gradually when discontinuing therapy or when
decreasing the daily dosage. Although there are no systematically collected data to support a
specific discontinuation schedule, it is suggested that the daily dosage be decreased by no
20
Reference ID: 3004871
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
more than 0.5 mg every three days. Some patients may require an even slower dosage
reduction.
In any case, reduction of dose must be undertaken under close supervision and must be
gradual. If significant withdrawal symptoms develop, the previous dosing schedule should be
reinstituted and, only after stabilization, should a less rapid schedule of discontinuation be
attempted. In a controlled postmarketing discontinuation study of panic disorder patients
which compared this recommended taper schedule with a slower taper schedule, no
difference was observed between the groups in the proportion of patients who tapered to zero
dose; however, the slower schedule was associated with a reduction in symptoms associated
with a withdrawal syndrome. It is suggested that the dose be reduced by no more than 0.5 mg
every three days, with the understanding that some patients may benefit from an even more
gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.
Switch from XANAX (immediate-release) Tablets to XANAX XR (extended
release) Tablets
Patients who are currently being treated with divided doses of XANAX (immediate-release)
Tablets, for example 3 to 4 times a day, may be switched to XANAX XR Tablets at the same
total daily dose taken once daily. If the therapeutic response after switching is inadequate,
the dosage may be titrated as outlined above.
HOW SUPPLIED
XANAX XR (extended-release) Tablets are available as follows:
0.5 mg (white, pentagonal-shaped tablets debossed with an "X" on one side and "0.5" on the
other side)
Bottles of 60
NDC 0009-0057-07
1 mg (yellow, square-shaped tablets debossed with an "X" on one side and
"1" on the other side)
Bottles of 60
NDC 0009-0059-07
2 mg (blue, round-shaped tablets debossed with an "X" on one side and
"2" on the other side)
Bottles of 60
NDC 0009-0066-07
3 mg (green, triangular-shaped tablets debossed with an "X" on one side and
"3" on the other side)
Bottles of 60
NDC 0009-0068-07
Store at 25oC (77oF); excursions permitted to 15–30oC (59–86oF) [see USP Controlled
Room Temperature].
ANIMAL STUDIES
21
Reference ID: 3004871
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For current labeling information, please visit https://www.fda.gov/drugsatfda
When rats were treated with alprazolam at 3, 10, and 30 mg/kg/day (15 to 150 times the
maximum recommended human dose) orally for 2 years, a tendency for a dose related
increase in the number of cataracts was observed in females and a tendency for a dose related
increase in corneal vascularization was observed in males. These lesions did not appear until
after 11 months of treatment.
Rx only company logo
LAB-0006-5.0
Revised June 2011
22
Reference ID: 3004871
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For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------
---------------------------------------------------------------------------------------------------------
----------------------------------------------------
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
/s/
THOMAS P LAUGHREN
08/23/2011
Reference ID: 3004871
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018276s045lbl.pdf', 'application_number': 18276, 'submission_type': 'SUPPL ', 'submission_number': 45}
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Dantrium® Intravenous
(dantrolene sodium for injection)
DESCRIPTION: Dantrium Intravenous is a sterile, non-pyrogenic, lyophilized formulation of
dantrolene sodium for injection. Dantrium Intravenous is supplied in 70 mL vials containing 20 mg
dantrolene sodium, 3000 mg mannitol, and sufficient sodium hydroxide to yield a pH of approximately
9.5 when reconstituted with 60 mL sterile water for injection USP (without a bacteriostatic agent).
Dantrium is classified as a direct-acting skeletal muscle relaxant. Chemically, Dantrium is hydrated
1-[[[5-(4-nitrophenyl)-2-furanyl]methylene]amino]-2,4-imidazolidinedione sodium salt. The structural
formula for the hydrated salt is:
O
CH = N N
NNa
O
xH O
O2 N
O
2
The hydrated salt contains approximately 15% water (3-1/2 moles) and has a molecular weight of 399.
The anhydrous salt (dantrolene) has a molecular weight of 336.
CLINICAL PHARMACOLOGY: In isolated nerve-muscle preparation, Dantrium has been shown
to produce relaxation by affecting the contractile response of the muscle at a site beyond the myoneural
junction. In skeletal muscle, Dantrium dissociates the excitation-contraction coupling, probably by
interfering with the release of Ca++ from the sarcoplasmic reticulum. The administration of
intravenous Dantrium to human volunteers is associated with loss of grip strength and weakness in the
legs, as well as subjective CNS complaints (see also PRECAUTIONS, Information for Patients).
Information concerning the passage of Dantrium across the blood-brain barrier is not available.
In the anesthetic-induced malignant hyperthermia syndrome, evidence points to an intrinsic
abnormality of skeletal muscle tissue. In affected humans, it has been postulated that “triggering
agents” (e.g., general anesthetics and depolarizing neuromuscular blocking agents) produce a change
within the cell which results in an elevated myoplasmic calcium. This elevated myoplasmic calcium
activates acute cellular catabolic processes that cascade to the malignant hyperthermia crisis.
It is hypothesized that addition of Dantrium to the “triggered” malignant hyperthermic muscle cell
reestablishes a normal level of ionized calcium in the myoplasm. Inhibition of calcium release from
the sarcoplasmic reticulum by Dantrium reestablishes the myoplasmic calcium equilibrium,
increasing the percentage of bound calcium. In this way, physiologic, metabolic, and biochemical
changes associated with the malignant hyperthermia crisis may be reversed or attenuated.
Experimental results in malignant hyperthermia susceptible swine show that prophylactic
administration of intravenous or oral dantrolene prevents or attenuates the development of vital sign
and blood gas changes characteristic of malignant hyperthermia in a dose related manner. The efficacy
of intravenous dantrolene in the treatment of human and porcine malignant hyperthermia crisis, when
considered along with prophylactic experiments in malignant hyperthermia susceptible swine, lends
support to prophylactic use of oral or intravenous dantrolene in malignant hyperthermia susceptible
humans. When prophylactic intravenous dantrolene is administered as directed, whole blood
concentrations remain at a near steady state level for 3 or more hours after the infusion is completed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-264/S-025
Page 4
Clinical experience has shown that early vital sign and/or blood gas changes characteristic of
malignant hyperthermia may appear during or after anesthesia and surgery despite the prophylactic use
of dantrolene and adherence to currently accepted patient management practices. These signs are
compatible with attenuated malignant hyperthermia and respond to the administration of additional i.v.
dantrolene (see DOSAGE AND ADMINISTRATION). The administration of the recommended
prophylactic dose of intravenous dantrolene to healthy volunteers was not associated with clinically
significant cardiorespiratory changes.
Specific metabolic pathways for the degradation and elimination of Dantrium in humans have been
established. Dantrolene is found in measurable amounts in blood and urine. Its major metabolites in
body fluids are 5-hydroxy dantrolene and an acetylamino metabolite of dantrolene. Another
metabolite with an unknown structure appears related to the latter. Dantrium may also undergo
hydrolysis and subsequent oxidation forming nitrophenylfuroic acid.
The mean biologic half-life of Dantrium after intravenous administration is variable, between 4 to 8
hours under most experimental conditions. Based on assays of whole blood and plasma, slightly
greater amounts of dantrolene are associated with red blood cells than with the plasma fraction of
blood. Significant amounts of dantrolene are bound to plasma proteins, mostly albumin, and this
binding is readily reversible.
Cardiopulmonary depression has not been observed in malignant hyperthermia susceptible swine
following the administration of up to 7.5 mg/kg i.v. dantrolene. This is twice the amount needed to
maximally diminish twitch response to single supramaximal peripheral nerve stimulation (95%
inhibition). A transient, inconsistent, depressant effect on gastrointestinal smooth muscles has been
observed at high doses.
INDICATIONS AND USAGE: Dantrium Intravenous is indicated, along with appropriate
supportive measures, for the management of the fulminant hypermetabolism of skeletal muscle
characteristic of malignant hyperthermia crises in patients of all ages. Dantrium Intravenous should
be administered by continuous rapid intravenous push as soon as the malignant hyperthermia reaction
is recognized (i.e., tachycardia, tachypnea, central venous desaturation, hypercarbia, metabolic
acidosis, skeletal muscle rigidity, increased utilization of anesthesia circuit carbon dioxide absorber,
cyanosis and mottling of the skin, and, in many cases, fever).
Dantrium Intravenous is also indicated preoperatively, and sometimes postoperatively, to prevent or
attenuate the development of clinical and laboratory signs of malignant hyperthermia in individuals
judged to be malignant hyperthermia susceptible.
CONTRAINDICATIONS: None.
WARNINGS: The use of Dantrium Intravenous in the management of malignant hyperthermia
crisis is not a substitute for previously known supportive measures. These measures must be
individualized, but it will usually be necessary to discontinue the suspect triggering agents, attend to
increased oxygen requirements, manage the metabolic acidosis, institute cooling when necessary,
monitor urinary output, and monitor for electrolyte imbalance.
Since the effect of disease state and other drugs on Dantrium related skeletal muscle weakness,
including possible respiratory depression, cannot be predicted, patients who receive i.v. Dantrium
preoperatively should have vital signs monitored.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-264/S-025
Page 5
If patients judged malignant hyperthermia susceptible are administered intravenous or oral Dantrium
preoperatively, anesthetic preparation must still follow a standard malignant hyperthermia susceptible
regimen, including the avoidance of known triggering agents. Monitoring for early clinical and
metabolic signs of malignant hyperthermia is indicated because attenuation of malignant hyperthermia,
rather than prevention, is possible. These signs usually call for the administration of additional i.v.
dantrolene.
PRECAUTIONS:
General: Care must be taken to prevent extravasation of Dantrium solution into the surrounding
tissues due to the high pH of the intravenous formulation and potential for tissue necrosis.
When mannitol is used for prevention or treatment of late renal complications of malignant
hyperthermia, the 3 g of mannitol needed to dissolve each 20 mg vial of i.v. Dantrium should be taken
into consideration.
Information for Patients: Based upon data in human volunteers, perioperatively, it is appropriate to
tell patients who receive Dantrium Intravenous that symptoms of muscle weakness should be
expected postoperatively (i.e. decrease in grip strength and weakness of leg muscles, especially
walking down stairs). In addition, symptoms such as “lightheadedness” may be noted. Since some of
these symptoms may persist for up to 48 hours, patients must not operate an automobile or engage in
other hazardous activity during this time. Caution is also indicated at meals on the day of
administration because difficulty swallowing and choking has been reported. Caution should be
exercised in the concomitant administration of tranquilizing agents.
Hepatotoxicity seen with Dantrium Capsules: Dantrium (dantrolene sodium) has a potential for
hepatotoxicity, and should not be used in conditions other than those recommended. Symptomatic
hepatitis (fatal and non-fatal) has been reported at various dose levels of the drug. The incidence
reported in patients taking up to 400 mg/day is much lower than in those taking doses of 800 mg or
more per day. Even sporadic short courses of these higher dose levels within a treatment regimen
markedly increased the risk of serious hepatic injury. Liver dysfunction as evidenced by blood
chemical abnormalities alone (liver enzyme elevations) has been observed in patients exposed to
Dantrium for varying periods of time. Overt hepatitis has occurred at varying intervals after initiation
of therapy, but has been most frequently observed between the third and twelfth month of therapy.
The risk of hepatic injury appears to be greater in females, in patients over 35 years of age, and in
patients taking other medication(s) in addition to Dantrium (dantrolene sodium). Dantrium should be
used only in conjunction with appropriate monitoring of hepatic function including frequent
determination of SGOT or SGPT.
Fatal and non-fatal liver disorders of an idiosyncratic or hypersensitivity type may occur with
Dantrium therapy.
Drug Interactions: Dantrium is metabolized by the liver, and it is theoretically possible that its
metabolism may be enhanced by drugs known to induce hepatic microsomal enzymes. However,
neither phenobarbital nor diazepam appears to affect Dantrium metabolism. Binding to plasma
protein is not significantly altered by diazepam, diphenylhydantoin, or phenylbutazone. Binding to
plasma proteins is reduced by warfarin and clofibrate and increased by tolbutamide.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-264/S-025
Page 6
Cardiovascular collapse in association with marked hyperkalemia has been reported in patients
receiving dantrolene in combination with calcium channel blockers. It is recommended that the
combination of intravenous dantrolene sodium and calcium channel blockers, such as verapamil, not
be used together during the management of malignant hyperthermia crisis.
Administration of dantrolene may potentiate vecuronium-induced neuromuscular block.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: Sprague-Dawley female rats fed
Dantrium for 18 months at dosage levels of 15, 30, and 60 mg/kg/day showed an increased incidence
of benign and malignant mammary tumors compared with concurrent controls. At the highest dose
level (approximately the same as the maximum recommended daily dose on a mg/m2 basis), there was
an increase in the incidence of benign hepatic lymphatic neoplasms. In a 30-month study in Sprague-
Dawley rats fed dantrolene sodium, the highest dose level (approximately the same as the maximum
recommended daily dose on a mg/m2 basis) produced a decrease in the time of onset of mammary
neoplasms. Female rats at the highest dose level showed an increased incidence of hepatic
lymphangiomas and hepatic angiosarcomas.
The only drug-related effect seen in a 30-month study in Fischer-344 rats was a dose-related reduction
in the time of onset of mammary and testicular tumors. A 24-month study in HaM/ICR mice revealed
no evidence of carcinogenic activity.
The significance of carcinogenicity data relative to use of Dantrium in humans is unknown.
Dantrolene sodium has produced positive results in the Ames S. Typhimurium bacterial mutagenesis
assay in the presence and absence of a liver activating system.
Dantrolene sodium administered to male and female rats at dose levels up to 45 mg/kg/day
(approximately 1.4 times the maximum recommended daily dose on a mg/m2 basis) showed no
adverse effects on fertility or general reproductive performance.
Pregnancy: Pregnancy Category C: Dantrium has been shown to be embryocidal in the rabbit and
has been shown to decrease pup survival in the rat when given at doses seven times the human oral
dose. There are no adequate and well-controlled studies in pregnant women. Dantrium Intravenous
should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery: In one uncontrolled study, 100 mg per day of prophylactic oral Dantrium was
administered to term pregnant patients awaiting labor and delivery. Dantrolene readily crossed the
placenta, with maternal and fetal whole blood levels approximately equal at delivery; neonatal levels
then fell approximately 50% per day for 2 days before declining sharply. No neonatal respiratory and
neuromuscular side effects were detected at low dose. More data, at higher doses, are needed before
more definitive conclusions can be made.
LactationNursing Mothers: Dantrolene has been detected in human milk at low concentrations (less
than 2 micrograms per milliliter) during repeat intravenous administration over 3 days. Dantrium
Intravenous should be used by nursing mothers only if the potential benefit justifies the potential risk
to the infant. Because of the potential for serious adverse reactions in nursing infants from dantrolene,
a decision should be made whether to discontinue nursing or to discontinue the drug, taking into
account the importance of the drug to the mother.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-264/S-025
Page 7
Geriatric Use: Clinical studies of Dantrium Intravenous did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in responses between the elderly and
younger patients. In general, dose selection for an elderly patient should be cautious reflecting the
greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other
drug therapy.
ADVERSE REACTIONS: There have been occasional reports of death following malignant
hyperthermia crisis even when treated with intravenous dantrolene; incidence figures are not available
(the pre-dantrolene mortality of malignant hyperthermia crisis was approximately 50%). Most of these
deaths can be accounted for by late recognition, delayed treatment, inadequate dosage, lack of
supportive therapy, intercurrent disease and/or the development of delayed complications such as renal
failure or disseminated intravascular coagulopathy. In some cases there are insufficient data to
completely rule out therapeutic failure of dantrolene.
There are rare reports of fatality in malignant hyperthermia crisis, despite initial satisfactory response
to i.v. dantrolene, which involve patients who could not be weaned from dantrolene after initial
treatment.
The administration of intravenous Dantrium to human volunteers is associated with loss of grip
strength and weakness in the legs, as well as drowsiness and dizziness.
The following adverse reactions are in approximate order of severity:
There are rare reports of pulmonary edema developing during the treatment of malignant
hyperthermia crisis in which the diluent volume and mannitol needed to deliver i.v. dantrolene
possibly contributed.
There have been reports of thrombophlebitis following administration of intravenous
dantrolene; actual incidence figures are not available. Tissue necrosis secondary to
extravasation has been reported rarely.
There have been rare reports of urticaria and erythema possibly associated with the
administration of i.v. Dantrium. There has been one case of anaphylaxis.
Injection site reactions (pain, erythema, swelling), commonly due to extravasation, have been
reported.
None of the serious reactions occasionally reported with long-term oral Dantrium use, such as
hepatitis, seizures, and pleural effusion with pericarditis, have been reasonably associated with short-
term Dantrium Intravenous therapy.
The following events have been reported in patients receiving oral dantrolene: aplastic anemia,
leukopenia, lymphocytic lymphoma, and heart failure. (See package insert for Dantrium (dantrolene
sodium) Capsules for a complete listing of adverse reactions.)
The published literature has included some reports of Dantrium use in patients with Neuroleptic
Malignant Syndrome (NMS). Dantrium Intravenous is not indicated for the treatment of NMS and
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-264/S-025
Page 8
patients may expire despite treatment with Dantrium Intravenous.
OVERDOSAGE: Because Dantrium Intravenous must be administered at a low concentration in a
large volume of fluid, acute toxicity of Dantrium could not be assessed in animals. In 14-day
(subacute) studies, the intravenous formulation of Dantrium was relatively non-toxic to rats at doses
of 10 mg/kg/day and 20 mg/kg/day. While 10 mg/kg/day in dogs for 14 days evoked little toxicity, 20
mg/kg/day for 14 days caused hepatic changes of questionable biologic significance.
Symptoms which may occur in case of overdose include, but are not limited to, muscular weakness and
alterations in the state of consciousness (e.g., lethargy, coma), vomiting, diarrhea, and crystalluria.
For acute overdosage, general supportive measures should be employed.
Intravenous fluids should be administered in fairly large quantities to avert the possibility of
crystalluria. An adequate airway should be maintained and artificial resuscitation equipment should be
at hand. Electrocardiographic monitoring should be instituted, and the patient carefully observed. The
value of dialysis in Dantrium overdose is not known.
DOSAGE AND ADMINISTRATION: As soon as the malignant hyperthermia reaction is
recognized, all anesthetic agents should be discontinued; the administration of 100% oxygen is
recommended. Dantrium Intravenous should be administered by continuous rapid intravenous push
beginning at a minimum dose of 1 mg/kg, and continuing until symptoms subside or the maximum
cumulative dose of 10 mg/kg has been reached.
If the physiologic and metabolic abnormalities reappear, the regimen may be repeated. It is important
to note that administration of Dantrium Intravenous should be continuous until symptoms subside.
The effective dose to reverse the crisis is directly dependent upon the individual’s degree of
susceptibility to malignant hyperthermia, the amount and time of exposure to the triggering agent, and
the time elapsed between onset of the crisis and initiation of treatment.
Pediatric Dose: Experience to date indicates that the dose of Dantrium Intravenous for pediatric
patients is the same as for adults.
Preoperatively: Dantrium Intravenous and/or Dantrium Capsules may be administered
preoperatively to patients judged malignant hyperthermia susceptible as part of the overall patient
management to prevent or attenuate the development of clinical and laboratory signs of malignant
hyperthermia.
Dantrium Intravenous: The recommended prophylactic dose of Dantrium Intravenous is
2.5 mg/kg, starting approximately 1-1/4 hours before anticipated anesthesia and infused over
approximately 1 hour. This dose should prevent or attenuate the development of clinical and
laboratory signs of malignant hyperthermia provided that the usual precautions, such as
avoidance of established malignant hyperthermia triggering agents, are followed.
Additional Dantrium Intravenous may be indicated during anesthesia and surgery because of
the appearance of early clinical and/or blood gas signs of malignant hyperthermia or because of
prolonged surgery (see also CLINICAL PHARMACOLOGY, WARNINGS, and
PRECAUTIONS). Additional doses must be individualized.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-264/S-025
Page 9
Oral Administration of Dantrium Capsules: Administer 4 to 8 mg/kg/day of oral Dantrium
in three or four divided doses for 1 or 2 days prior to surgery, with the last dose being given
with a minimum of water approximately 3 to 4 hours before scheduled surgery. Adjustment
can usually be made within the recommended dosage range to avoid incapacitation (weakness,
drowsiness, etc.) or excessive gastrointestinal irritation (nausea and/or vomiting). See also the
package insert for Dantrium Capsules.
Post Crisis Follow-Up: Dantrium Capsules, 4 to 8 mg/kg/day, in four divided doses should be
administered for 1 to 3 days following a malignant hyperthermia crisis to prevent recurrence of the
manifestations of malignant hyperthermia.
Intravenous Dantrium may be used postoperatively to prevent or attenuate the recurrence of signs of
malignant hyperthermia when oral Dantrium administration is not practical. The i.v. dose of
Dantrium in the postoperative period must be individualized, starting with 1 mg/kg or more as the
clinical situation dictates.
PREPARATION: Each vial of Dantrium Intravenous should be reconstituted by adding 60 mL of
sterile water for injection USP (without a bacteriostatic agent), and the vial shaken until the solution is
clear. 5% Dextrose Injection USP, 0.9% Sodium Chloride Injection USP, and other acidic solutions
are not compatible with Dantrium Intravenous and should not be used. The contents of the vial must
be protected from direct light and used within 6 hours after reconstitution. Store reconstituted
solutions at controlled room temperature (59°F to 86°F or 15°C to 30°C).
Reconstituted Dantrium Intravenous should not be transferred to large glass bottles for prophylactic
infusion due to precipitate formation observed with the use of some glass bottles as reservoirs.
For prophylactic infusion, the required number of individual vials of Dantrium Intravenous should be
reconstituted as outlined above. The contents of individual vials are then transferred to a larger
volume sterile intravenous plastic bag. Stability data on file at Procter & Gamble Pharmaceuticals
indicate commercially available sterile plastic bags are acceptable drug delivery devices. However, it
is recommended that the prepared infusion be inspected carefully for cloudiness and/or precipitation
prior to dispensing and administration. Such solutions should not be used. While stable for 6 hours, it
is recommended that the infusion be prepared immediately prior to the anticipated dosage
administration time.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration.
HOW SUPPLIED: Dantrium Intravenous (NDC 0149-0734-02) is available in vials containing a
sterile lyophilized mixture of 20 mg dantrolene sodium, 3000 mg mannitol, and sufficient sodium
hydroxide to yield a pH of approximately 9.5 when reconstituted with 60 mL sterile water for injection
USP (without a bacteriostatic agent).
Store unreconstituted product at controlled room temperature (59°F to 86°F or 15°C to 30°C) and
avoid prolonged exposure to light.
Address medical inquiries to Procter & Gamble Pharmaceuticals, Medical Communications
Department, PO Box 8006, Mason, Ohio 45040-8006.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-264/S-025
Page 10
To place an order, call Procter & Gamble Pharmaceuticals Customer Service 800-448-4878.
Mfg. by: Ben Venue Laboratories
Bedford, OH 44146
Dist. By: Procter & Gamble Pharmaceuticals, TM Owner,
Cincinnati, Ohio 45202
REVISED OCTOBER 2007
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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K-TAB®
(potassium chloride extended-release tablets, USP)
DESCRIPTION
K-TAB (potassium chloride extended-release tablets) is a solid oral dosage form of potassium
chloride containing 8 mEq, 10 mEq and 20 mEq of potassium chloride, USP, equivalent to 600
mg, 750 mg and 1500 mg of potassium, respectively, in a film-coated (not enteric-coated), wax
matrix tablet. These formulations are intended to slow the release of potassium so that the
likelihood of a high localized concentration of potassium chloride within the gastrointestinal tract
is reduced. The expended inert, porous, wax/polymer matrix is not absorbed and may be excreted
intact in the stool.
K-TAB tablets are an electrolyte replenisher. The chemical name is potassium chloride, and the
structural formula is KCl. Potassium chloride, USP, occurs as a white, granular powder or as
colorless crystals. It is odorless and has a saline taste. Its solutions are neutral to litmus. It is
freely soluble in water and insoluble in alcohol.
Inactive Ingredients
8 mEq and 10 mEq Tablets
Castor oil, cellulosic polymers, colloidal silicon dioxide, D&C Yellow No. 10, magnesium
stearate, paraffin, polyvinyl acetate, titanium dioxide, vanillin and vitamin E.
20 mEq Tablets
Castor oil, cellulosic polymers, colloidal silicon dioxide, magnesium stearate, paraffin, polyvinyl
acetate, titanium dioxide, vanillin and vitamin E.
CLINICAL PHARMACOLOGY
Potassium ion is the principal intracellular cation of most body tissues. Potassium ions
participate in a number of essential physiological processes including the maintenance of
intracellular tonicity, the transmission of nerve impulses, the contraction of cardiac, skeletal and
smooth muscle, and the maintenance of normal renal function.
The intracellular concentration of potassium is approximately 150 to 160 mEq per liter. The
normal adult plasma concentration is 3.5 to 5 mEq per liter. An active ion transport system
maintains this gradient across the plasma membrane.
Reference ID: 3532969
Potassium is a normal dietary constituent and under steady state conditions the amount of
potassium absorbed from the gastrointestinal tract is equal to the amount excreted in the urine.
The usual dietary intake of potassium is 50 to 100 mEq per day.
Potassium depletion will occur whenever the rate of potassium loss through renal excretion
and/or loss from the gastrointestinal tract exceeds the rate of potassium intake. Such depletion
usually develops as a consequence of therapy with diuretics, primary or secondary
hyperaldosteronism, diabetic ketoacidosis, or inadequate replacement of potassium in patients on
prolonged parenteral nutrition. Depletion can develop rapidly with severe diarrhea, especially if
associated with vomiting. Potassium depletion due to these causes is usually accompanied by a
concomitant loss of chloride and is manifested by hypokalemia and metabolic alkalosis.
Potassium depletion may produce weakness, fatigue, disturbances of cardiac rhythm (primarily
ectopic beats), prominent U-waves in the electrocardiogram, and, in advanced cases, flaccid
paralysis and/or impaired ability to concentrate urine.
If potassium depletion associated with metabolic alkalosis cannot be managed by correcting the
fundamental cause of the deficiency, e.g., where the patient requires long term diuretic therapy,
supplemental potassium in the form of high potassium food or potassium chloride may restore
normal potassium levels.
In rare circumstances, (e.g., patients with renal tubular acidosis) potassium depletion may be
associated with metabolic acidosis and hyperchloremia. In such patients potassium replacement
should be accomplished with potassium salts other than the chloride, such as potassium
bicarbonate, potassium citrate, potassium acetate, or potassium gluconate.
INDICATIONS AND USAGE
BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND
BLEEDING WITH CONTROLLED-RELEASE POTASSIUM CHLORIDE
PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS
WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT
POTASSIUM PREPARATIONS, OR FOR PATIENTS WITH WHOM THERE IS A
PROBLEM OF COMPLIANCE WITH THESE PREPARATIONS.
1. For the treatment of patients with hypokalemia with or without metabolic alkalosis, in
digitalis intoxication, and in patients with hypokalemic familial periodic paralysis. If
hypokalemia is the result of diuretic therapy, consideration should be given to the use of a
lower dose of diuretic, which may be sufficient without leading to hypokalemia.
Reference ID: 3532969
2. For the prevention of hypokalemia in patients who would be at particular risk if hypokalemia
were to develop, e.g., digitalized patients or patients with significant cardiac arrhythmias.
The use of potassium salts in patients receiving diuretics for uncomplicated essential
hypertension is often unnecessary when such patients have a normal dietary pattern, and when
low doses of the diuretic are used. Serum potassium should be checked periodically, however,
and, if hypokalemia occurs, dietary supplementation with potassium-containing foods may be
adequate to control milder cases. In more severe cases and if dose adjustment of the diuretic is
ineffective or unwarranted supplementation with potassium salts may be indicated.
CONTRAINDICATIONS
Potassium supplements are contraindicated in patients with hyperkalemia since a further increase
in serum potassium concentration in such patients can produce cardiac arrest. Hyperkalemia may
complicate any of the following conditions: chronic renal failure, systemic acidosis such as
diabetic acidosis, acute dehydration, extensive tissue breakdown as in severe burns, adrenal
insufficiency, or the administration of a potassium-sparing diuretic, e.g., spironolactone,
triamterene, or amiloride (see OVERDOSAGE).
K-TAB tablets are contraindicated in patients with known hypersensitivity to any ingredient in
this product.
Controlled-release formulations of potassium chloride have produced esophageal ulceration in
certain cardiac patients with esophageal compression due to an enlarged left atrium. Potassium
supplementation, when indicated in such patients, should be given as a liquid preparation.
All solid oral dosage forms of potassium chloride are contraindicated in any patient in whom
there is structural, pathological, e.g., diabetic gastroparesis, or pharmacologic (use of
anticholinergic agents or other agents with anticholinergic properties at sufficient doses to exert
anticholinergic effects) cause for arrest or delay in tablet passage through the gastrointestinal
tract.
WARNINGS
Hyperkalemia (see OVERDOSAGE)
In patients with impaired mechanisms for excreting potassium, the administration of potassium
salts can produce hyperkalemia and cardiac arrest. This occurs most commonly in patients given
potassium intravenously, but may also occur in patients given potassium orally. Potentially fatal
hyperkalemia can develop rapidly and can be asymptomatic. The use of potassium salts in
Reference ID: 3532969
patients with chronic renal disease, or any other condition which impairs potassium excretion,
requires particularly careful monitoring of the serum potassium concentration and appropriate
dosage adjustment.
Interaction with Potassium-Sparing Diuretics
Hypokalemia should not be treated by the concomitant administration of potassium salts and a
potassium-sparing diuretic, e.g., spironolactone, triamterene, or amiloride, since the simultaneous
administration of these agents can produce severe hyperkalemia.
Interaction with Angiotensin Converting Enzyme Inhibitors
Angiotensin converting enzyme (ACE) inhibitors (e.g., captopril, enalapril) will produce some
potassium retention by inhibiting aldosterone production. Potassium supplements should be
given to patients receiving ACE inhibitors only with close monitoring.
Gastrointestinal Lesions
Solid oral dosage forms of potassium chloride can produce ulcerative and/or stenotic lesions of
the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric-coated
preparations of potassium chloride are associated with an increased frequency of small bowel
lesions (40-50 per 100,000 patient years) compared to sustained-release wax matrix formulations
(less than one per 100,000 patient years). Because of the lack of extensive marketing experience
with microencapsulated products, a comparison between such products and wax matrix or
enteric-coated products is not available. K-TAB tablets consist of a wax matrix formulated to
provide a controlled rate of release potassium chloride and thus to minimize the possibility of a
high local concentration of potassium near the gastrointestinal wall.
Prospective trials have been conducted in normal human volunteers in which the upper
gastrointestinal tract was evaluated by endoscopic inspection before and after one week of solid
oral potassium chloride therapy. The ability of this model to predict events occurring in usual
clinical practice is unknown. Trials which approximated usual clinical practice did not reveal any
clear differences between the wax matrix and microencapsulated dosage forms. In contrast, there
was a higher incidence of gastric and duodenal lesions in subjects receiving a high dose of a wax
matrix controlled-release formulation under conditions which did not resemble usual or
recommended clinical practice, i.e., 96 mEq per day in divided doses of potassium chloride
administered, to fasted patients in the presence of an anticholinergic drug to delay gastric
emptying. The upper gastrointestinal lesions observed by endoscopy were asymptomatic and
were not accompanied by evidence of bleeding (hemoccult testing). The relevance of these
findings to the usual conditions, i.e., nonfasting, no anticholinergic agent, and smaller doses,
Reference ID: 3532969
under which controlled-release potassium chloride products are used is uncertain. Epidemiologic
studies have not identified an elevated risk, compared to microencapsulated products, for upper
gastrointestinal lesions in patients receiving wax matrix formulations. K-TAB tablets should be
discontinued immediately and the possibility of ulceration, obstruction or perforation considered
if severe vomiting, abdominal pain, distention, or gastrointestinal bleeding occurs.
Metabolic Acidosis
Hypokalemia in patients with metabolic acidosis should be treated with an alkalinizing
potassium salt such as potassium bicarbonate, potassium citrate, potassium acetate, or potassium
gluconate.
PRECAUTIONS
General
The diagnosis of potassium depletion is ordinarily made by demonstrating hypokalemia in a
patient with a clinical history suggesting some cause for potassium depletion. In interpreting the
serum potassium level, the physician should bear in mind that acute alkalosis per se can produce
hypokalemia in the absence of a deficit in total body potassium, while acute acidosis per se can
increase the serum potassium concentration to within the normal range even in the presence of a
reduced total body potassium. The treatment of potassium depletion, particularly in the presence
of cardiac disease, renal disease, or acidosis, requires careful attention to acid-base balance and
appropriate monitoring of serum electrolytes, the electrocardiogram, and the clinical status of the
patient.
Information for Patients
Physicians should consider reminding the patient of the following:
To take each dose with meals and with a full glass of water or other liquid.
To take this medicine following the frequency and amount prescribed by the physician. This is
especially important if the patient is also taking diuretics and/or digitalis preparations.
To check with the physician if there is trouble swallowing tablets or if the tablets seem to stick in
the throat.
To check with the physician at once if tarry stools or other evidence of gastrointestinal bleeding
is noticed.
To take each dose without crushing, chewing or sucking the tablets.
Reference ID: 3532969
Laboratory Tests
When blood is drawn for analysis of plasma potassium it is important to recognize that
artifactual elevations can occur after improper venipuncture technique or as a result of in vitro
hemolysis of the sample.
Drug Interactions
Potassium-sparing diuretics, angiotensin converting enzyme inhibitors (see WARNINGS).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity, mutagenicity and fertility studies in animals have not been performed.
Potassium is a normal dietary constituent.
Pregnancy Category C
Animal reproduction studies have not been conducted with K-TAB tablets. It is unlikely that
potassium supplementation that does not lead to hyperkalemia would have an adverse effect on
the fetus or would affect reproductive capacity.
Nursing Mothers
The normal potassium ion content of human milk is about 13 mEq per liter. Since oral potassium
becomes part of the body potassium pool, as long as body potassium is not excessive, the
contribution of potassium chloride supplementation should have little or no effect on the level in
human milk.
Pediatric Use
Safety and effectiveness in children have not been established.
Geriatric Use
Clinical Studies of K-Tab tablets did not include sufficient numbers of subjects aged 65 and over
to determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end
of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac
function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because elderly patients are
Reference ID: 3532969
more likely to have decreased renal function, care should be taken in dose selection, and it may
be useful to monitor renal function.
ADVERSE REACTIONS
One of the most severe adverse effects is hyperkalemia (see CONTRAINDICATIONS,
WARNINGS, and OVERDOSAGE). There also have been reports of upper and lower
gastrointestinal conditions including obstruction, bleeding, ulceration, and perforation (see
CONTRAINDICATIONS and WARNINGS).
The most common adverse reactions to oral potassium salts are nausea, vomiting, flatulence,
abdominal pain/discomfort, and diarrhea. These symptoms are due to irritation of the
gastrointestinal tract and are best managed by taking the dose with meals, or reducing the amount
taken at one time.
Skin rash has been reported rarely.
OVERDOSAGE
The administration of oral potassium salts to persons with normal excretory mechanisms for
potassium rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired
or if intravenous administration is too rapid, potentially fatal hyperkalemia can result (see
CONTRAINDICATIONS and WARNINGS). It is important to recognize that hyperkalemia is
usually asymptomatic and may be manifested only by an increased serum potassium
concentration (6.5-8.0 mEq/L) and characteristic electrocardiographic changes (peaking of T-
waves, loss P-waves, depression of S-T segments, and prolongation of the QT intervals). Late
manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest (9-12
mEq/L).
Treatment measures for hyperkalemia include the following:
1. Elimination of foods and medications containing potassium and of any agents with
potassium-sparing properties;
2. Intravenous administration of 300 to 500 mL/hr of 10% dextrose solution containing 10-20
units of crystalline insulin per 1,000 mL;
3. Correction of acidosis, if present, with intravenous sodium bicarbonate;
4. Use of exchange resins, hemodialysis, or peritoneal dialysis.
Reference ID: 3532969
In treating hyperkalemia, it should be recalled that in patients who have been stabilized on
digitalis, lowering the serum potassium concentration too rapidly can produce digitalis toxicity.
The extended release feature means that absorption and toxic effects may be delayed for hours.
Consider standard measures to remove any unabsorbed drug.
DOSAGE AND ADMINISTRATION
The usual dietary potassium intake by the average adult is 50 to 100 mEq per day. Potassium
depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of
potassium from the total body store.
Dosage must be adjusted to the individual needs of each patient. The dose for the prevention of
hypokalemia is typically in the range of 20 mEq per day. Doses of 40-100 mEq per day or more
are used for the treatment of potassium depletion. Dosage should be divided if more than 20 mEq
per day is given such that no more than 20 mEq is given in a single dose.
K-TAB tablets provide 8 mEq, 10 mEq and 20 mEq of potassium chloride.
K-TAB tablets should be taken with meals and with a glass of water or other liquid. This product
should not be taken on an empty stomach because of its potential for gastric irritation (see
WARNINGS).
NOTE: K-TAB tablets are to be swallowed whole without crushing, chewing or sucking the
tablets.
HOW SUPPLIED
K-TAB (potassium chloride extended-release tablets, USP) contain 600 mg, 750 mg and 1500
mg of potassium chloride (equivalent to 8 mEq, 10 mEq and 20 mEq, respectively). K-TAB
tablets are provided as extended-release Filmtab® tablets. K-TAB 600 mg tablets are round in
shape, yellow in color and are debossed with the trademark K-TAB on one side. K-TAB 750 mg
tablets are ovaloid in shape, yellow in color and are debossed with the “a” logo on one side and
the trademark K-TAB on the other side. K-TAB 1500 mg tablets are ovaloid in shape, white in
color and are debossed with the trademark K-TAB on one side.
K-TAB Tablets are supplied as follows:
8 mEq
Bottles of 30
NDC 0074-3058-30
Bottles of 90
NDC 0074-3058-90
Reference ID: 3532969
Bottles of 100
NDC 0074-3058-41
Bottles of 1000
NDC 0074-3058-46
10 mEq
Bottles of 30
NDC 0074-7804-30
Bottles of 90
NDC 0074-7804-90
Bottles of 100
NDC 0074-7804-13
Bottles of 1000
NDC 0074-7804-19
Bottles of 5000
NDC 0074-7804-59
Unit dose packages of 100
NDC 0074-7804-11
20 mEq
Bottles of 30
NDC 0074-3023-30
Bottles of 90
NDC 0074-3023-90
Bottles of 100
NDC 0074-3023-13
Bottles of 500
NDC 0074-3023-53
Recommended Storage
Do not store above 77°F (25°C).
Filmtab® - Film-sealed tablets, AbbVie Inc.
©2013 AbbVie Inc.
Manufactured by:
AbbVie LTD
Barceloneta, PR 00617
For:
AbbVie Inc.
North Chicago, IL 60064
03-AXXX Month Year
Reference ID: 3532969
|
custom-source
|
2025-02-12T13:44:40.354790
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018279s034lbl.pdf', 'application_number': 18279, 'submission_type': 'SUPPL ', 'submission_number': 34}
|
11,190
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K-TAB®
(potassium chloride extended-release tablets, USP)
DESCRIPTION
K-TAB (potassium chloride extended-release tablets) is a solid oral dosage form of potassium
chloride containing 10 mEq and 20 mEq of potassium chloride, USP, equivalent to 750 mg and
1500 mg of potassium in a film-coated (not enteric-coated), wax matrix tablet. These
formulations are intended to slow the release of potassium so that the likelihood of a high
localized concentration of potassium chloride within the gastrointestinal tract is reduced. The
expended inert, porous, wax/polymer matrix is not absorbed and may be excreted intact in the
stool.
K-TAB tablets are an electrolyte replenisher. The chemical name is potassium chloride, and the
structural formula is KCl. Potassium chloride, USP, occurs as a white, granular powder or as
colorless crystals. It is odorless and has a saline taste. Its solutions are neutral to litmus. It is
freely soluble in water and insoluble in alcohol.
Inactive Ingredients
10 mEq Tablets
Castor oil, cellulosic polymers, colloidal silicon dioxide, D&C Yellow No. 10, magnesium
stearate, paraffin, polyvinyl acetate, titanium dioxide, vanillin and vitamin E.
20 mEq Tablets
Castor oil, cellulosic polymers, colloidal silicon dioxide, magnesium stearate, paraffin, polyvinyl
acetate, titanium dioxide, vanillin and vitamin E.
CLINICAL PHARMACOLOGY
Potassium ion is the principal intracellular cation of most body tissues. Potassium ions
participate in a number of essential physiological processes including the maintenance of
intracellular tonicity, the transmission of nerve impulses, the contraction of cardiac, skeletal and
smooth muscle, and the maintenance of normal renal function.
The intracellular concentration of potassium is approximately 150 to 160 mEq per liter. The
normal adult plasma concentration is 3.5 to 5 mEq per liter. An active ion transport system
maintains this gradient across the plasma membrane.
Reference ID: 3412444
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Potassium is a normal dietary constituent and under steady state conditions the amount of
potassium absorbed from the gastrointestinal tract is equal to the amount excreted in the urine.
The usual dietary intake of potassium is 50 to 100 mEq per day.
Potassium depletion will occur whenever the rate of potassium loss through renal excretion
and/or loss from the gastrointestinal tract exceeds the rate of potassium intake. Such depletion
usually develops as a consequence of therapy with diuretics, primary or secondary
hyperaldosteronism, diabetic ketoacidosis, or inadequate replacement of potassium in patients on
prolonged parenteral nutrition. Depletion can develop rapidly with severe diarrhea, especially if
associated with vomiting. Potassium depletion due to these causes is usually accompanied by a
concomitant loss of chloride and is manifested by hypokalemia and metabolic alkalosis.
Potassium depletion may produce weakness, fatigue, disturbances of cardiac rhythm (primarily
ectopic beats), prominent U-waves in the electrocardiogram, and, in advanced cases, flaccid
paralysis and/or impaired ability to concentrate urine.
If potassium depletion associated with metabolic alkalosis cannot be managed by correcting the
fundamental cause of the deficiency, e.g., where the patient requires long term diuretic therapy,
supplemental potassium in the form of high potassium food or potassium chloride may restore
normal potassium levels.
In rare circumstances, (e.g., patients with renal tubular acidosis) potassium depletion may be
associated with metabolic acidosis and hyperchloremia. In such patients potassium replacement
should be accomplished with potassium salts other than the chloride, such as potassium
bicarbonate, potassium citrate, potassium acetate, or potassium gluconate.
INDICATIONS AND USAGE
BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND
BLEEDING WITH CONTROLLED-RELEASE POTASSIUM CHLORIDE
PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS
WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT
POTASSIUM PREPARATIONS, OR FOR PATIENTS WITH WHOM THERE IS A
PROBLEM OF COMPLIANCE WITH THESE PREPARATIONS.
1. For the treatment of patients with hypokalemia with or without metabolic alkalosis, in
digitalis intoxication, and in patients with hypokalemic familial periodic paralysis. If
hypokalemia is the result of diuretic therapy, consideration should be given to the use of a
lower dose of diuretic, which may be sufficient without leading to hypokalemia.
Reference ID: 3412444
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2. For the prevention of hypokalemia in patients who would be at particular risk if hypokalemia
were to develop, e.g., digitalized patients or patients with significant cardiac arrhythmias.
The use of potassium salts in patients receiving diuretics for uncomplicated essential
hypertension is often unnecessary when such patients have a normal dietary pattern, and when
low doses of the diuretic are used. Serum potassium should be checked periodically, however,
and, if hypokalemia occurs, dietary supplementation with potassium-containing foods may be
adequate to control milder cases. In more severe cases and if dose adjustment of the diuretic is
ineffective or unwarranted supplementation with potassium salts may be indicated.
CONTRAINDICATIONS
Potassium supplements are contraindicated in patients with hyperkalemia since a further increase
in serum potassium concentration in such patients can produce cardiac arrest. Hyperkalemia may
complicate any of the following conditions: chronic renal failure, systemic acidosis such as
diabetic acidosis, acute dehydration, extensive tissue breakdown as in severe burns, adrenal
insufficiency, or the administration of a potassium-sparing diuretic, e.g., spironolactone,
triamterene, or amiloride (see OVERDOSAGE).
K-TAB tablets are contraindicated in patients with known hypersensitivity to any ingredient in
this product.
Controlled-release formulations of potassium chloride have produced esophageal ulceration in
certain cardiac patients with esophageal compression due to an enlarged left atrium. Potassium
supplementation, when indicated in such patients, should be given as a liquid preparation.
All solid oral dosage forms of potassium chloride are contraindicated in any patient in whom
there is structural, pathological, e.g., diabetic gastroparesis, or pharmacologic (use of
anticholinergic agents or other agents with anticholinergic properties at sufficient doses to exert
anticholinergic effects) cause for arrest or delay in tablet passage through the gastrointestinal
tract.
WARNINGS
Hyperkalemia (see OVERDOSAGE)
In patients with impaired mechanisms for excreting potassium, the administration of potassium
salts can produce hyperkalemia and cardiac arrest. This occurs most commonly in patients given
potassium intravenously, but may also occur in patients given potassium orally. Potentially fatal
hyperkalemia can develop rapidly and can be asymptomatic. The use of potassium salts in
Reference ID: 3412444
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
patients with chronic renal disease, or any other condition which impairs potassium excretion,
requires particularly careful monitoring of the serum potassium concentration and appropriate
dosage adjustment.
Interaction with Potassium-Sparing Diuretics
Hypokalemia should not be treated by the concomitant administration of potassium salts and a
potassium-sparing diuretic, e.g., spironolactone, triamterene, or amiloride, since the simultaneous
administration of these agents can produce severe hyperkalemia.
Interaction with Angiotensin Converting Enzyme Inhibitors
Angiotensin converting enzyme (ACE) inhibitors (e.g., captopril, enalapril) will produce some
potassium retention by inhibiting aldosterone production. Potassium supplements should be
given to patients receiving ACE inhibitors only with close monitoring.
Gastrointestinal Lesions
Solid oral dosage forms of potassium chloride can produce ulcerative and/or stenotic lesions of
the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric-coated
preparations of potassium chloride are associated with an increased frequency of small bowel
lesions (40-50 per 100,000 patient years) compared to sustained-release wax matrix formulations
(less than one per 100,000 patient years). Because of the lack of extensive marketing experience
with microencapsulated products, a comparison between such products and wax matrix or
enteric-coated products is not available. K-TAB tablets consist of a wax matrix formulated to
provide a controlled rate of release potassium chloride and thus to minimize the possibility of a
high local concentration of potassium near the gastrointestinal wall.
Prospective trials have been conducted in normal human volunteers in which the upper
gastrointestinal tract was evaluated by endoscopic inspection before and after one week of solid
oral potassium chloride therapy. The ability of this model to predict events occurring in usual
clinical practice is unknown. Trials which approximated usual clinical practice did not reveal any
clear differences between the wax matrix and microencapsulated dosage forms. In contrast, there
was a higher incidence of gastric and duodenal lesions in subjects receiving a high dose of a wax
matrix controlled-release formulation under conditions which did not resemble usual or
recommended clinical practice, i.e., 96 mEq per day in divided doses of potassium chloride
administered, to fasted patients in the presence of an anticholinergic drug to delay gastric
emptying. The upper gastrointestinal lesions observed by endoscopy were asymptomatic and
were not accompanied by evidence of bleeding (hemoccult testing). The relevance of these
findings to the usual conditions, i.e., nonfasting, no anticholinergic agent, and smaller doses,
Reference ID: 3412444
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
under which controlled-release potassium chloride products are used is uncertain. Epidemiologic
studies have not identified an elevated risk, compared to microencapsulated products, for upper
gastrointestinal lesions in patients receiving wax matrix formulations. K-TAB tablets should be
discontinued immediately and the possibility of ulceration, obstruction or perforation considered
if severe vomiting, abdominal pain, distention, or gastrointestinal bleeding occurs.
Metabolic Acidosis
Hypokalemia in patients with metabolic acidosis should be treated with an alkalinizing
potassium salt such as potassium bicarbonate, potassium citrate, potassium acetate, or potassium
gluconate.
PRECAUTIONS
General
The diagnosis of potassium depletion is ordinarily made by demonstrating hypokalemia in a
patient with a clinical history suggesting some cause for potassium depletion. In interpreting the
serum potassium level, the physician should bear in mind that acute alkalosis per se can produce
hypokalemia in the absence of a deficit in total body potassium, while acute acidosis per se can
increase the serum potassium concentration to within the normal range even in the presence of a
reduced total body potassium. The treatment of potassium depletion, particularly in the presence
of cardiac disease, renal disease, or acidosis, requires careful attention to acid-base balance and
appropriate monitoring of serum electrolytes, the electrocardiogram, and the clinical status of the
patient.
Information for Patients
Physicians should consider reminding the patient of the following:
To take each dose with meals and with a full glass of water or other liquid.
To take this medicine following the frequency and amount prescribed by the physician. This is
especially important if the patient is also taking diuretics and/or digitalis preparations.
To check with the physician if there is trouble swallowing tablets or if the tablets seem to stick in
the throat.
To check with the physician at once if tarry stools or other evidence of gastrointestinal bleeding
is noticed.
To take each dose without crushing, chewing or sucking the tablets.
Reference ID: 3412444
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Laboratory Tests
When blood is drawn for analysis of plasma potassium it is important to recognize that
artifactual elevations can occur after improper venipuncture technique or as a result of in vitro
hemolysis of the sample.
Drug Interactions
Potassium-sparing diuretics, angiotensin converting enzyme inhibitors (see WARNINGS).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity, mutagenicity and fertility studies in animals have not been performed.
Potassium is a normal dietary constituent.
Pregnancy Category C
Animal reproduction studies have not been conducted with K-TAB tablets. It is unlikely that
potassium supplementation that does not lead to hyperkalemia would have an adverse effect on
the fetus or would affect reproductive capacity.
Nursing Mothers
The normal potassium ion content of human milk is about 13 mEq per liter. Since oral potassium
becomes part of the body potassium pool, as long as body potassium is not excessive, the
contribution of potassium chloride supplementation should have little or no effect on the level in
human milk.
Pediatric Use
Safety and effectiveness in children have not been established.
Geriatric Use
Clinical Studies of K-Tab tablets did not include sufficient numbers of subjects aged 65 and over
to determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end
of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac
function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because elderly patients are
Reference ID: 3412444
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
more likely to have decreased renal function, care should be taken in dose selection, and it may
be useful to monitor renal function.
ADVERSE REACTIONS
One of the most severe adverse effects is hyperkalemia (see CONTRAINDICATIONS,
WARNINGS, and OVERDOSAGE). There also have been reports of upper and lower
gastrointestinal conditions including obstruction, bleeding, ulceration, and perforation (see
CONTRAINDICATIONS and WARNINGS).
The most common adverse reactions to oral potassium salts are nausea, vomiting, flatulence,
abdominal pain/discomfort, and diarrhea. These symptoms are due to irritation of the
gastrointestinal tract and are best managed by taking the dose with meals, or reducing the amount
taken at one time.
Skin rash has been reported rarely.
OVERDOSAGE
The administration of oral potassium salts to persons with normal excretory mechanisms for
potassium rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired
or if intravenous administration is too rapid, potentially fatal hyperkalemia can result (see
CONTRAINDICATIONS and WARNINGS). It is important to recognize that hyperkalemia is
usually asymptomatic and may be manifested only by an increased serum potassium
concentration (6.5-8.0 mEq/L) and characteristic electrocardiographic changes (peaking of T-
waves, loss P-waves, depression of S-T segments, and prolongation of the QT intervals). Late
manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest (9-12
mEq/L).
Treatment measures for hyperkalemia include the following:
1. Elimination of foods and medications containing potassium and of any agents with
potassium-sparing properties;
2. Intravenous administration of 300 to 500 mL/hr of 10% dextrose solution containing 10-20
units of crystalline insulin per 1,000 mL;
3. Correction of acidosis, if present, with intravenous sodium bicarbonate;
4. Use of exchange resins, hemodialysis, or peritoneal dialysis.
Reference ID: 3412444
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In treating hyperkalemia, it should be recalled that in patients who have been stabilized on
digitalis, lowering the serum potassium concentration too rapidly can produce digitalis toxicity.
The extended release feature means that absorption and toxic effects may be delayed for hours.
Consider standard measures to remove any unabsorbed drug.
DOSAGE AND ADMINISTRATION
The usual dietary potassium intake by the average adult is 50 to 100 mEq per day. Potassium
depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of
potassium from the total body store.
Dosage must be adjusted to the individual needs of each patient. The dose for the prevention of
hypokalemia is typically in the range of 20 mEq per day. Doses of 40-100 mEq per day or more
are used for the treatment of potassium depletion. Dosage should be divided if more than 20 mEq
per day is given such that no more than 20 mEq is given in a single dose.
K-TAB tablets provide 10 mEq and 20 mEq of potassium chloride.
K-TAB tablets should be taken with meals and with a glass of water or other liquid. This product
should not be taken on an empty stomach because of its potential for gastric irritation (see
WARNINGS).
NOTE:K-TAB tablets are to be swallowed whole without crushing, chewing or sucking the
tablets.
HOW SUPPLIED
K-TAB (potassium chloride extended-release tablets, USP) contain 750 mg and 1500 mg of
potassium chloride (equivalent to 10 mEq and 20 mEq, respectively). K-TAB tablets are
provided as ovaloid, extended-release Filmtab® tablets. K-TAB 750 mg are yellow in color and
are debossed with the “a” logo on one side and the trademark K-TAB on the other side. K-TAB
1500 mg are white in color and are debossed with the trademark K-TAB on one side.
K-TAB Tablets are supplied as follows:
10 mEq
Bottles of 30
Bottles of 90
Bottles of 100
NDC 0074-7804-30
NDC 0074-7804-90
NDC 0074-7804-13
Reference ID: 3412444
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Bottles of 1000
Bottles of 5000
Unit dose packages of 100
NDC 0074-7804-19
NDC 0074-7804-59
NDC 0074-7804-11
20 mEq
Bottles of 30
Bottles of 90
Bottles of 100
Bottles of 500
NDC 0074-3023-30
NDC 0074-3023-90
NDC 0074-3023-13
NDC 0074-3023-53
Recommended Storage
Do not store above 77°F (25°C).
Filmtab® - Film-sealed tablets, AbbVie Inc.
©2013 AbbVie Inc.
Manufactured by:
AbbVie LTD
Barceloneta, PR 00617
For:
AbbVie Inc.
North Chicago, IL 60064
03-AXXX Month, 2013
Reference ID: 3412444
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:40.469034
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018279s033lbl.pdf', 'application_number': 18279, 'submission_type': 'SUPPL ', 'submission_number': 33}
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Tegretol®
carbamazepine USP
Chewable Tablets of 100 mg - red-speckled, pink
Tablets of 200 mg – pink
Suspension of 100 mg/5 mL
Tegretol®-XR
(carbamazepine extended-release tablets)
100 mg, 200 mg, 400 mg
Rx only
Prescribing Information
WARNING
APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION
WITH THE USE OF TEGRETOL. DATA FROM A POPULATION-BASED CASE CONTROL
STUDY DEMONSTRATE THAT THE RISK OF DEVELOPING THESE REACTIONS IS 5-8
TIMES GREATER THAN IN THE GENERAL POPULATION. HOWEVER, THE OVERALL RISK
OF THESE REACTIONS IN THE UNTREATED GENERAL POPULATION IS LOW,
APPROXIMATELY SIX PATIENTS PER ONE MILLION POPULATION PER YEAR FOR
AGRANULOCYTOSIS AND TWO PATIENTS PER ONE MILLION POPULATION PER YEAR
FOR APLASTIC ANEMIA.
ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR
WHITE BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE
OF TEGRETOL, DATA ARE NOT AVAILABLE TO ESTIMATE ACCURATELY THEIR
INCIDENCE OR OUTCOME. HOWEVER, THE VAST MAJORITY OF THE CASES OF
LEUKOPENIA HAVE NOT PROGRESSED TO THE MORE SERIOUS CONDITIONS OF
APLASTIC ANEMIA OR AGRANULOCYTOSIS.
BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC
ANEMIA, THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN
MONITORING OF PATIENTS ON TEGRETOL ARE UNLIKELY TO SIGNAL THE
OCCURRENCE OF EITHER ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT
HEMATOLOGICAL TESTING SHOULD BE OBTAINED AS A BASELINE. IF A PATIENT IN
THE COURSE OF TREATMENT EXHIBITS LOW OR DECREASED WHITE BLOOD CELL OR
PLATELET
COUNTS,
THE
PATIENT
SHOULD
BE
MONITORED
CLOSELY.
DISCONTINUATION OF THE DRUG SHOULD BE CONSIDERED IF ANY EVIDENCE OF
SIGNIFICANT BONE MARROW DEPRESSION DEVELOPS.
Before prescribing Tegretol, the physician should be thoroughly familiar with the details of
this prescribing information, particularly regarding use with other drugs, especially those which
accentuate toxicity potential.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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DESCRIPTION
Tegretol, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia,
available for oral administration as chewable tablets of 100 mg, tablets of 200 mg, XR tablets of 100,
200, and 400 mg, and as a suspension of 100 mg/5 mL (teaspoon). Its chemical name is 5H-dibenz[b,f
]azepine-5-carboxamide, and its structural formula is
Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in
alcohol and in acetone. Its molecular weight is 236.27.
Inactive Ingredients. Tablets: Colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake
(chewable tablets only), FD&C Red No. 40 (200-mg tablets only), flavoring (chewable tablets only),
gelatin, glycerin, magnesium stearate, sodium starch glycolate (chewable tablets only), starch, stearic
acid, and sucrose (chewable tablets only). Suspension: Citric acid, FD&C Yellow No. 6, flavoring,
polymer, potassium sorbate, propylene glycol, purified water, sorbitol, sucrose, and xanthan gum.
Tegretol-XR tablets: cellulose compounds, dextrates, iron oxides, magnesium stearate, mannitol,
polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200-mg tablets only).
CLINICAL PHARMACOLOGY
In controlled clinical trials, Tegretol has been shown to be effective in the treatment of psychomotor
and grand mal seizures, as well as trigeminal neuralgia.
Mechanism of Action
Tegretol has demonstrated anticonvulsant properties in rats and mice with electrically and chemically
induced seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic
potentiation. Tegretol greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve
in cats and rats. It depresses thalamic potential and bulbar and polysynaptic reflexes, including the
linguomandibular reflex in cats. Tegretol is chemically unrelated to other anticonvulsants or other
drugs used to control the pain of trigeminal neuralgia. The mechanism of action remains unknown.
The principal metabolite of Tegretol, carbamazepine-10,11-epoxide, has anticonvulsant activity as
demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide
has been postulated, the significance of its activity with respect to the safety and efficacy of Tegretol
has not been established.
Pharmacokinetics
In clinical studies, Tegretol suspension, conventional tablets, and XR tablets delivered equivalent
amounts of drug to the systemic circulation. However, the suspension was absorbed somewhat faster,
and the XR tablet slightly slower, than the conventional tablet. The bioavailability of the XR tablet was
89% compared to suspension. Following a b.i.d. dosage regimen, the suspension provides higher peak
levels and lower trough levels than those obtained from the conventional tablet for the same dosage
regimen. On the other hand, following a t.i.d. dosage regimen, Tegretol suspension affords steady-state
plasma levels comparable to Tegretol tablets given b.i.d. when administered at the same total mg daily
dose. Following a b.i.d. dosage regimen, Tegretol-XR tablets afford steady-state plasma levels
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Page 5
comparable to conventional Tegretol tablets given q.i.d., when administered at the same total mg daily
dose. Tegretol in blood is 76% bound to plasma proteins. Plasma levels of Tegretol are variable and
may range from 0.5-25 µg/mL, with no apparent relationship to the daily intake of the drug. Usual
adult therapeutic levels are between 4 and 12 µg/mL. In polytherapy, the concentration of Tegretol
and concomitant drugs may be increased or decreased during therapy, and drug effects may be altered
(see PRECAUTIONS, Drug Interactions). Following chronic oral administration of suspension,
plasma levels peak at approximately 1.5 hours compared to 4-5 hours after administration of
conventional Tegretol tablets, and 3-12 hours after administration of Tegretol-XR tablets. The
CSF/serum ratio is 0.22, similar to the 24% unbound Tegretol in serum. Because Tegretol induces its
own metabolism, the half-life is also variable. Autoinduction is completed after 3-5 weeks of a fixed
dosing regimen. Initial half-life values range from 25-65 hours, decreasing to 12-17 hours on repeated
doses. Tegretol is metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform
responsible for the formation of carbamazepine-10,11-epoxide from Tegretol. After oral administration
of 14C-carbamazepine, 72% of the administered radioactivity was found in the urine and 28% in the
feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites,
with only 3% of unchanged Tegretol.
The pharmacokinetic parameters of Tegretol disposition are similar in children and in adults.
However, there is a poor correlation between plasma concentrations of carbamazepine and Tegretol
dose in children. Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide (a
metabolite shown to be equipotent to carbamazepine as an anticonvulsant in animal screens) in the
younger age groups than in adults. In children below the age of 15, there is an inverse relationship
between CBZ-E/CBZ ratio and increasing age (in one report from 0.44 in children below the age of 1
year to 0.18 in children between 10-15 years of age).
The effects of race and gender on carbamazepine pharmacokinetics have not been systematically
evaluated.
INDICATIONS AND USAGE
Epilepsy
Tegretol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of Tegretol as an
anticonvulsant was derived from active drug-controlled studies that enrolled patients with the
following seizure types:
1. Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these
seizures appear to show greater improvement than those with other types.
2. Generalized tonic-clonic seizures (grand mal).
3. Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence
seizures (petit mal) do not appear to be controlled by Tegretol (see PRECAUTIONS, General).
Trigeminal Neuralgia
Tegretol is indicated in the treatment of the pain associated with true trigeminal neuralgia.
Beneficial results have also been reported in glossopharyngeal neuralgia.
This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.
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Page 6
CONTRAINDICATIONS
Tegretol should not be used in patients with a history of previous bone marrow depression,
hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as
amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical
grounds its use with monoamine oxidase inhibitors is not recommended. Before administration of
Tegretol, MAO inhibitors should be discontinued for a minimum of 14 days, or longer if the clinical
situation permits.
Co-administration of carbamazepine and nefazodone may result in insufficient plasma concentrations
of nefazodone and its active metabolite to achieve a therapeutic effect. Co-administration of
carbamazepine with nefazodone is contraindicated.
WARNINGS
Patients with a history of adverse hematologic reaction to any drug may be particularly at risk.
Severe dermatologic reactions, including toxic epidermal necrolysis (Lyell’s syndrome) and
Stevens-Johnson syndrome, have been reported with Tegretol. These reactions have been extremely
rare. However, a few fatalities have been reported.
Tegretol has shown mild anticholinergic activity; therefore, patients with increased intraocular
pressure should be closely observed during therapy.
Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of
a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind.
The use of Tegretol should be avoided in patients with a history of hepatic porphyria (e.g., acute
intermittent porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported
in such patients receiving Tegretol therapy. Carbamazepine administration has also been demonstrated
to increase porphyrin precursors in rodents, a presumed mechanism for the induction of acute attacks
of porphyria.
As with all antiepileptic drugs, Tegretol should be withdrawn gradually to minimize the potential
of increased seizure frequency.
Usage in Pregnancy
Carbamazepine can cause fetal harm when administered to a pregnant woman.
Epidemiological data suggest that there may be an association between the use of carbamazepine
during pregnancy and congenital malformations, including spina bifida. There have also been reports
that associate carbamazepine with developmental disorders and congenital anomalies (e.g., craniofacial
defects, cardiovascular malformations and anomalies involving various body systems). Developmental
delays based on neurobehavioral assessments have been reported. In treating or counseling women of
childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against the
risks. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug,
the patient should be apprised of the potential hazard to the fetus.
Retrospective case reviews suggest that, compared with monotherapy, there may be a higher
prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy.
Therefore, if therapy is to be continued, monotherapy may be preferable for pregnant women.
In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is
accumulated in the fetal tissues, with higher levels found in liver and kidney than in brain and lung.
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Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given
orally in dosages 10-25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg
basis or 1.5-4 times the MHDD on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed
kinked ribs at 250 mg/kg and 4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate, 1;
talipes, 1; anophthalmos, 2). In reproduction studies in rats, nursing offspring demonstrated a lack of
weight gain and an unkempt appearance at a maternal dosage level of 200 mg/kg.
Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is
administered to prevent major seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and
frequency of the seizure disorder are such that removal of medication does not pose a serious threat to
the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it
cannot be said with any confidence that even minor seizures do not pose some hazard to the
developing embryo or fetus.
Tests to detect defects using currently accepted procedures should be considered a part of routine
prenatal care in childbearing women receiving carbamazepine.
There have been a few cases of neonatal seizures and/or respiratory depression associated with
maternal Tegretol and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting,
diarrhea, and/or decreased feeding have also been reported in association with maternal Tegretol use.
These symptoms may represent a neonatal withdrawal syndrome.
PRECAUTIONS
General
Before initiating therapy, a detailed history and physical examination should be made.
Tegretol should be used with caution in patients with a mixed seizure disorder that includes
atypical absence seizures, since in these patients Tegretol has been associated with increased frequency
of generalized convulsions (see INDICATIONS AND USAGE).
Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history
of cardiac conduction disturbance, including second and third degree AV heart block; cardiac, hepatic,
or renal damage; adverse hematologic or hypersensitivity reaction to other drugs, including reactions to
other anticonvulsants; or interrupted courses of therapy with Tegretol.
AV heart block, including second and third degree block, have been reported following, Tegretol
treatment. This occurred generally, but not solely, in patients with underling EKG abnormalities or risk
factors for conduction disturbances.
Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have
been reported (see ADVERSE REACTIONS and PRECAUTIONS, Laboratory Tests). In some cases,
hepatic effects may progress despite discontinuation of the drug.
Multi-organ hypersensitivity reactions occurring days to weeks or months after initiating treatment
have been reported in rare cases (see ADVERSE REACTIONS, Other and PRECAUTIONS,
Information for Patients).
Discontinuation of carbamazepine should be considered if any evidence of hypersensitivity
develops.
Hypersensitivity reactions to carbamazepine have been reported in patients who previously
experienced this reaction to anticonvulsants including phenytoin and phenobarbital. A history of
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Page 8
hypersensitivity reactions should be obtained for a patient and the immediate family members. If
positive, caution should be used in prescribing carbamazepine.
Since a given dose of Tegretol suspension will produce higher peak levels than the same dose
given as the tablet, it is recommended that patients given the suspension be started on lower doses and
increased slowly to avoid unwanted side effects (see DOSAGE AND ADMINISTRATION).
Information for Patients
Patients should be made aware of the early toxic signs and symptoms of a potential hematologic
problem, as well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include,
but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and
petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or
jaundice. The patient should be advised that, because these signs and symptoms may signal a serious
reaction, that they must report any occurrence immediately to a physician. In addition, the patient
should be advised that these signs and symptoms should be reported even if mild or when occurring
after extended use.
Tegretol may interact with some drugs. Therefore, patients should be advised to report to their doctors
the use of any other prescription or non-prescription medications or herbal products.
Caution should be exercised if alcohol is taken in combination with Tegretol therapy, due to a possible
additive sedative effect.
Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of
operating machinery or automobiles or engaging in other potentially dangerous tasks.
Laboratory Tests
Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron,
should be obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white
blood cell or platelet counts, the patient should be monitored closely. Discontinuation of the drug
should be considered if any evidence of significant bone marrow depression develops.
Baseline and periodic evaluations of liver function, particularly in patients with a history of liver
disease, must be performed during treatment with this drug since liver damage may occur (see
PRECAUTIONS, General and ADVERSE REACTIONS). Carbamazepine should be discontinued,
based on clinical judgment, if indicated by newly occurring or worsening clinical or laboratory
evidence of liver dysfunction or hepatic damage, or in the case of active liver disease.
Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are
recommended since many phenothiazines and related drugs have been shown to cause eye changes.
Baseline and periodic complete urinalysis and BUN determinations are recommended for patients
treated with this agent because of observed renal dysfunction.
Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and
safety of anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in
seizure frequency and for verification of compliance. In addition, measurement of drug serum levels
may aid in determining the cause of toxicity when more than one medication is being used.
Thyroid function tests have been reported to show decreased values with Tegretol administered
alone.
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Page 9
Hyponatremia has been reported in association with Tegretol use, either alone or in combination
with other drugs.
Interference with some pregnancy tests has been reported.
Drug Interactions
There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after
ingesting Tegretol suspension immediately followed by Thorazine® solution. Subsequent testing has
shown that mixing Tegretol suspension and chlorpromazine solution (both generic and brand name) as
well as Tegretol suspension and liquid Mellaril® resulted in the occurrence of this precipitate. Because
the extent to which this occurs with other liquid medications is not known, Tegretol suspension should
not be administered simultaneously with other liquid medicinal agents or diluents. (see Dosage and
Administration).
Clinically meaningful drug interactions have occurred with concomitant medications and include,
but are not limited to, the following:
Agents That May Affect Tegretol Plasma Levels
CYP 3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma carbamazepine levels.
Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels include
cimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin,
fluoxetine, fluvoxamine, nefazodone, loratadine, terfenadine, isoniazid, niacinamide,
nicotinamide,
propoxyphene,
azoles
(e.g.,
ketaconazole,
itraconazole,
fluconazole),
acetazolamide, verapamil, grapefruit juice, protease inhibitors, valproate.*
CYP 3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that
would be expected, to decrease plasma carbamazepine levels include
cisplatin, doxorubicin HCl, felbamate,† rifampin, phenobarbital, phenytoin, primidone,
methsuximide, theophylline.
When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close
monitoring of carbamazepine levels is indicated and dosage adjustment may be required.
*increased levels of the active 10,11-epoxide
†decreased levels of carbamazepine and increased levels of the 10,11-epoxide
Effect of Tegretol on Plasma Levels of Concomitant Agents
Increased levels: clomipramine HCl, phenytoin, primidone
Tegretol induces hepatic CYP activity. Tegretol causes, or would be expected to cause, decreased
levels of the following:
acetaminophen, alprazolam, dihydropyridine calcium channel blockers (e.g., felodipine),
cyclosporine, corticosteroids (e.g., prednisolone, dexamethasone), clonazepam, clozapine,
dicumarol, doxycycline, ethosuximide, haloperidol, itraconazole, lamotrigine, levothyroxine,
methadone, methsuximide, midazolam, olanzapine, oral and other hormonal contraceptives,
oxcarbazepine, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone,
theophylline, tiagabine, topiramate, tramadol, tricyclic antidepressants (e.g., imipramine,
amitriptyline, nortriptyline), valproate, warfarin,ziprasidone, zonisamide.
In concomitant use with Tegretol, dosage adjustment of the above agents may be necessary.
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Co-administration of carbamazepine with nefazodone results in insufficient plasma concentrations of
nefazodone and its active metabolite to achieve a therapeutic effect. Co-administration of
carbamazepine with nefazodone is contraindicated. (See CONTRAINDICATIONS).
Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side
effects.
Alterations of thyroid function have been reported in combination therapy with other
anticonvulsant medications.
Concomitant use of Tegretol with hormonal contraceptive products (e.g., oral, and levonorgestrel
subdermal implant contraceptives) may render the contraceptives less effective because the plasma
concentrations of the hormones may be decreased. Breakthrough bleeding and unintended pregnancies
have been reported. Alternative or back-up methods of contraception should be considered.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75,
and 250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular tumors in
females and of benign interstitial cell adenomas in the testes of males.
Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats.
Bacterial and mammalian mutagenicity studies using carbamazepine produced negative results. The
significance of these findings relative to the use of carbamazepine in humans is, at present, unknown.
Usage in Pregnancy
Pregnancy Category D (see WARNINGS).
Labor and Delivery
The effect of Tegretol on human labor and delivery is unknown.
Nursing Mothers
Tegretol and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in
breast milk to that in maternal plasma is about 0.4 for Tegretol and about 0.5 for the epoxide. The
estimated doses given to the newborn during breast feeding are in the range of 2-5 mg daily for
Tegretol and 1-2 mg daily for the epoxide.
Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a
decision should be made whether to discontinue nursing or to discontinue the drug, taking into account
the importance of the drug to the mother.
Pediatric Use
Substantial evidence of Tegretol’s effectiveness for use in the management of children with epilepsy
(see Indications for specific seizure types) is derived from clinical investigations performed in adults
and from studies in several in vitro systems which support the conclusion that (1) the pathogenetic
mechanisms underlying seizure propagation are essentially identical in adults and children, and (2) the
mechanism of action of carbamazepine in treating seizures is essentially identical in adults and
children.
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Taken as a whole, this information supports a conclusion that the generally accepted therapeutic
range of total carbamazepine in plasma (i.e., 4-12 mcg/mL) is the same in children and adults.
The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety
of carbamazepine in children has been systematically studied up to 6 months. No longer-term data
from clinical trials is available.
Geriatric Use
No systematic studies in geriatric patients have been conducted.
ADVERSE REACTIONS
If adverse reactions are of such severity that the drug must be discontinued, the physician must be
aware that abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead
to seizures or even status epilepticus with its life-threatening hazards.
The most severe adverse reactions have been observed in the hemopoietic system (see boxed
WARNING), the skin, liver, and the cardiovascular system.
The most frequently observed adverse reactions, particularly during the initial phases of therapy,
are dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such
reactions, therapy should be initiated at the low dosage recommended.
The following additional adverse reactions have been reported:
Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression,
thrombocytopenia, leukopenia, leukocytosis, eosinophilia, acute intermittent porphyria.
Skin: Pruritic and erythematous rashes, urticaria, toxic epidermal necrolysis (Lyell’s syndrome) (see
WARNINGS), Stevens-Johnson syndrome (see WARNINGS), photosensitivity reactions, alterations
in skin pigmentation, exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation
of disseminated lupus erythematosus, alopecia, and diaphoresis. In certain cases, discontinuation of
therapy may be necessary. Isolated cases of hirsutism have been reported, but a causal relationship is
not clear.
Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension,
syncope and collapse, aggravation of coronary artery disease, arrhythmias and AV block,
thrombophlebitis, thromboembolism, and adenopathy or lymphadenopathy.
Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has
been associated with other tricyclic compounds.
Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very
rare cases of hepatic failure.
Pancreatic: Pancreatitis.
Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or
pneumonia.
Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood
pressure, azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and
microscopic deposits in the urine have also been reported.
Testicular atrophy occurred in rats receiving Tegretol orally from 4-52 weeks at dosage levels of
50-400 mg/kg/day. Additionally, rats receiving Tegretol in the diet for 2 years at dosage levels of 25,
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Page 12
75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In
dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage
levels of 50 mg/kg and higher. Relevance of these findings to humans is unknown.
Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue,
blurred vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech
disturbances, abnormal involuntary movements, peripheral neuritis and paresthesias, depression with
agitation, talkativeness, tinnitus, and hyperacusis.
There have been reports of associated paralysis and other symptoms of cerebral arterial
insufficiency, but the exact relationship of these reactions to the drug has not been established.
Isolated cases of neuroleptic malignant syndrome have been reported with concomitant use of
psychotropic drugs.
Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation,
anorexia, and dryness of the mouth and pharynx, including glossitis and stomatitis.
Eyes: Scattered punctate cortical lens opacities, as well as conjunctivitis, have been reported. Although
a direct causal relationship has not been established, many phenothiazines and related drugs have been
shown to cause eye changes.
Musculoskeletal System: Aching joints and muscles, and leg cramps.
Metabolism: Fever and chills. Inappropriate antidiuretic hormone (ADH) secretion syndrome has
been reported. Cases of frank water intoxication, with decreased serum sodium (hyponatremia) and
confusion, have been reported in association with Tegretol use (see PRECAUTIONS, Laboratory
Tests). Decreased levels of plasma calcium have been reported.
Other: Multi-organ hypersensitivity reactions occurring days to weeks or months after initiating
treatment have been reported in rare cases. Signs or symptoms may include, but are not limited to
fever, skin rashes, vasculitis, lymphadenopathy, disorders mimicking lymphoma, arthralgia,
leukopenia, eosinophilia, hepato-splenomegaly and abnormal liver function tests. These signs and
symptoms may occur in various combinations and not necessarily concurrently. Signs and symptoms
may initially be mild. Various organs, including but not limited to, liver, skin, immune system, lungs,
kidneys, pancreas, myocardium, and colon may be affected (see PRECAUTIONS, General and
PRECAUTIONS, Information for Patients).
Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been
occasional reports of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients
taking anticonvulsants.
A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been
reported in a patient taking carbamazepine in combination with other medications. The patient was
successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.
DRUG ABUSE AND DEPENDENCE
No evidence of abuse potential has been associated with Tegretol, nor is there evidence of
psychological or physical dependence in humans.
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Page 13
OVERDOSAGE
Acute Toxicity
Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-
old man died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a
cardiac arrest), 1.6 g (a 3-year-old girl died of aspiration pneumonia).
Oral LD50 in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-2680; guinea pigs,
920.
Signs and Symptoms
The first signs and symptoms appear after 1-3 hours. Neuromuscular disturbances are the most
prominent. Cardiovascular disorders are generally milder, and severe cardiac complications occur only
when very high doses (> 60 g) have been ingested.
Respiration: Irregular breathing, respiratory depression.
Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders.
Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma.
Convulsions, especially in small children. Motor restlessness, muscular twitching, tremor, athetoid
movements, opisthotonos, ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia,
ballism, psychomotor disturbances, dysmetria. Initial hyperreflexia, followed by hyporeflexia.
Gastrointestinal Tract: Nausea, vomiting.
Kidneys and Bladder: Anuria or oliguria, urinary retention.
Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte
count, glycosuria, and acetonuria. EEG may show dysrhythmias.
Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at
the same time, the signs and symptoms of acute poisoning with Tegretol may be aggravated or
modified.
Treatment
The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug,
which may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps
to diminish absorption. If these measures cannot be implemented without risk on the spot, the patient
should be transferred at once to a hospital, while ensuring that vital functions are safeguarded. There is
no specific antidote.
Elimination of the Drug: Induction of vomiting.
Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the
stomach should be repeatedly irrigated, especially if the patient has also consumed alcohol.
Measures to Reduce Absorption: Activated charcoal, laxatives.
Measures to Accelerate Elimination: Forced diuresis.
Dialysis is indicated only in severe poisoning associated with renal failure. Replacement
transfusion is indicated in severe poisoning in small children.
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Page 14
Respiratory Depression: Keep the airways free; resort, if necessary, to endotracheal intubation,
artificial respiration, and administration of oxygen.
Hypotension, Shock: Keep the patient’s legs raised and administer a plasma expander. If blood
pressure fails to rise despite measures taken to increase plasma volume, use of vasoactive substances
should be considered.
Convulsions: Diazepam or barbiturates.
Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children),
hypotension, and coma. However, barbiturates should not be used if drugs that inhibit monoamine
oxidase have also been taken by the patient either in overdosage or in recent therapy (within 1 week).
Surveillance: Respiration, cardiac function (ECG monitoring), blood pressure, body temperature,
pupillary reflexes, and kidney and bladder function should be monitored for several days.
Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression
develops, the following recommendations are suggested: (1) stop the drug, (2) perform daily CBC,
platelet, and reticulocyte counts, (3) do a bone marrow aspiration and trephine biopsy immediately and
repeat with sufficient frequency to monitor recovery.
Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2)
59Fe-ferrokinetic studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and
peripheral blood, (5) bone marrow culture studies for colony-forming units, (6) hemoglobin
electrophoresis for A2 and F hemoglobin, and (7) serum folic acid and B12 levels.
A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for
which specialized consultation should be sought.
DOSAGE AND ADMINISTRATION (SEE TABLE BELOW)
Tegretol suspension in combination with liquid chlorpromazine or thioridazine results in
precipitate formation, and, in the case of chlorpromazine, there has been a report of a patient passing
an orange rubbery precipitate in the stool following coadministration of the two drugs. (See Drug
Interactions). Because the extent to which this occurs with other liquid medications is not known,
Tegretol suspension should not be administered simultaneously with other liquid medications or
diluents.
Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see
PRECAUTIONS, Laboratory Tests). Dosage should be adjusted to the needs of the individual patient.
A low initial daily dosage with a gradual increase is advised. As soon as adequate control is achieved,
the dosage may be reduced very gradually to the minimum effective level. Medication should be taken
with meals.
Since a given dose of Tegretol suspension will produce higher peak levels than the same dose
given as the tablet, it is recommended to start with low doses (children 6-12 years: 1/2 teaspoon q.i.d.)
and to increase slowly to avoid unwanted side effects.
Conversion of patients from oral Tegretol tablets to Tegretol suspension: Patients should be
converted by administering the same number of mg per day in smaller, more frequent doses (i.e., b.i.d.
tablets to t.i.d. suspension).
Tegretol-XR is an extended-release formulation for twice-a-day administration. When converting
patients from Tegretol conventional tablets to Tegretol-XR, the same total daily mg dose of
Tegretol-XR should be administered. Tegretol-XR tablets must be swallowed whole and never
crushed or chewed. Tegretol-XR tablets should be inspected for chips or cracks. Damaged tablets, or
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Page 15
tablets without a release portal, should not be consumed. Tegretol-XR tablet coating is not absorbed
and is excreted in the feces; these coatings may be noticeable in the stool.
Epilepsy (see INDICATIONS AND USAGE)
Adults and children over 12 years of age - Initial: Either 200 mg b.i.d. for tablets and XR tablets, or
1 teaspoon q.i.d. for suspension (400 mg/day). Increase at weekly intervals by adding up to 200
mg/day using a b.i.d. regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until
the optimal response is obtained. Dosage generally should not exceed 1000 mg daily in children 12-15
years of age, and 1200 mg daily in patients above 15 years of age. Doses up to 1600 mg daily have
been used in adults in rare instances. Maintenance: Adjust dosage to the minimum effective level,
usually 800-1200 mg daily.
Children 6-12 years of age - Initial: Either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon
q.i.d. for suspension (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a
b.i.d. regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal
response is obtained. Dosage generally should not exceed 1000 mg daily. Maintenance: Adjust
dosage to the minimum effective level, usually 400-800 mg daily.
Children under 6 years of age - Initial: 10-20 mg/kg/day b.i.d. or t.i.d. as tablets, or q.i.d. as
suspension. Increase weekly to achieve optimal clinical response administered t.i.d. or q.i.d.
Maintenance: Ordinarily, optimal clinical response is achieved at daily doses below 35 mg/kg. If
satisfactory clinical response has not been achieved, plasma levels should be measured to determine
whether or not they are in the therapeutic range. No recommendation regarding the safety of
carbamazepine for use at doses above 35 mg/kg/24 hours can be made.
Combination Therapy: Tegretol may be used alone or with other anticonvulsants. When added to
existing anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are
maintained or gradually decreased, except phenytoin, which may have to be increased (see
PRECAUTIONS, Drug Interactions, and Pregnancy Category D).
Trigeminal Neuralgia (see INDICATIONS AND USAGE)
Initial: On the first day, either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for
suspension, for a total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day
using increments of 100 mg every 12 hours for tablets or XR tablets, or 50 mg (1/2 teaspoon) q.i.d. for
suspension, only as needed to achieve freedom from pain. Do not exceed 1200 mg daily.
Maintenance: Control of pain can be maintained in most patients with 400-800 mg daily. However,
some patients may be maintained on as little as 200 mg daily, while others may require as much as
1200 mg daily. At least once every 3 months throughout the treatment period, attempts should be made
to reduce the dose to the minimum effective level or even to discontinue the drug.
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Page 16
Dosage Information
Initial Dose
Subsequent Dose
Maximum Daily Dose
Indication
Tablet*
XR
†
Suspension
Tablet*
XR
†
Suspension
Tablet*
XR
†
Suspension
Epilepsy
Under 6 yr
10-20 mg/kg/day
b.i.d. or t.i.d.
10-20 mg/kg/day
q.i.d.
Increase
weekly to
achieve
optimal clinical
response,
t.i.d. or q.i.d.
Increase weekly
to achieve
optimal clinical
response, t.i.d. or
q.i.d.
35 mg/kg/24 hr
(see Dosage and
Administration
section above)
35 mg/kg/24 hr
(see Dosage and
Administration
section above)
6-12 yr
100 mg b.i.d.
(200 mg/day)
100 mg b.i.d.
(200 mg/day)
½ tsp q.i.d.
(200 mg/day)
Add up to 100
mg/day at
weekly
intervals, t.i.d.
or q.i.d.
Add
100 mg/day
at weekly
intervals,
b.i.d.
Add up to 1 tsp
(100 mg)/day at
weekly intervals,
t.i.d. or q.i.d.
1000 mg/24 hr
Over 12 yr
200 mg b.i.d.
(400 mg/day)
200 mg b.i.d.
(400 mg/day)
1 tsp q.i.d.
(400 mg/day)
Add up to 200
mg/day at
weekly
intervals, t.i.d.
or q.i.d.
Add up to
200 mg/day
at weekly
intervals,
b.i.d.
Add up to 2 tsp
(200 mg)/day at
weekly intervals,
t.i.d. or q.i.d.
1000 mg/24 hr (12-15 yr)
1200 mg/24 hr (>15 yr)
1600 mg/24 hr (adults, in rare instances)
Trigeminal
Neuralgia
100 mg b.i.d.
(200 mg/day)
100 mg b.i.d.
(200 mg/day)
½ tsp q.i.d.
(200 mg/day)
Add up to 200
mg/day in
increments of
100 mg every
12 hr
Add up to
200 mg/day
in increments
of 100 mg
every 12 hr
Add up to 2 tsp
(200 mg)/day
in increments of
50 mg
(½ tsp) q.i.d.
1200 mg/24 hr
*Tablet = Chewable or conventional tablets
†XR = Tegretol
®-XR extended-release tablets
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
-------- ------- -- --------------------------------- ------------- -------
------ -- ------ --- -------- -
----- - ---- -- ---- - ---- --- --- -- - ---
----- - - --- ------------- ---
HOW SUPPLIED
Chewable Tablets 100 mg - round, red-speckled, pink, single-scored (imprinted Tegretol on one side
and 52 twice on the scored side)
Bottles of 100.........................................................................................NDC 0083-0052-30
Unit Dose (blister pack)
Box of 100 (strips of 10)..................................................................NDC 0083-0052-32
Do not store above 30°C (86°F). Protect from light and moisture.
Dispense in tight, light-resistant container (USP).
Meets USP Dissolution Test 1.
Tablets 200 mg - capsule-shaped, pink, single-scored (imprinted Tegretol on one side and 27 twice on
the partially scored side)
Bottles of 100.........................................................................................NDC 0083-0027-30
Bottles of 1000.......................................................................................NDC 0083-0027-40
Unit Dose (blister pack)
Box of 100 (strips of 10)..................................................................NDC 0083-0027-32
Do not store above 30°C (86°F). Protect from moisture. Dispense in tight container (USP).
Meets USP Dissolution Test 2.
XR Tablets 100 mg - round, yellow, coated (imprinted T on one side and 100 mg on the other), release
portal on one side
Bottles of 100.........................................................................................NDC 0083-0061-30
XR Tablets 200 mg - round, pink, coated (imprinted T on one side and 200 mg on the other), release
portal on one side
Bottles of 100.........................................................................................NDC 0083-0062-30
XR Tablets 400 mg - round, brown, coated (imprinted T on one side and 400 mg on the other), release
portal on one side
Bottles of 100.........................................................................................NDC 0083-0060-30
Store at controlled room temperature 15°C-30°C (59°F-86°F). Protect from moisture. Dispense in
tight, container (USP).
Suspension 100 mg/5 mL (teaspoon) - yellow-orange, citrus-vanilla flavored
Bottles of 450 mL..................................................................................NDC 0083-0019-76
Shake well before using.
Do not store above 30°C (86°F). Dispense in tight, light resistant container (USP).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 16-608/SLR-096; NDA 18-281/S-044;
NDA18-927/S-035; NDA 20-234/S-025
Page 2
Tegretol Chewable Tablets Manufactured by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
Tegretol Tablets Manufactured by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
Tegretol Suspension Manufactured by:
Patheon Inc.
Whitby Operations
Whitby Ontario, Canada
L1N 5Z5
Tegretol XR Tablets Manufactured by:
Novartis Pharma GmbH
D-79664 Wehr, Germany
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
REV: July 2007
© 2007Novartis
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
Russell Katz
8/16/2007 05:01:49 PM
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:40.549538
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/016608s096,018281s044,018927s035,020234s025REVISED_LABEL.pdf', 'application_number': 18281, 'submission_type': 'SUPPL ', 'submission_number': 44}
|
11,193
|
Page 3
Tegretol®
carbamazepine USP
Chewable Tablets of 100 mg - red-speckled, pink
Tablets of 200 mg – pink
Suspension of 100 mg/5 mL
Tegretol®-XR
(carbamazepine extended-release tablets)
100 mg, 200 mg, 400 mg
Rx only
Prescribing Information
WARNING
SERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELE
SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC
EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN
REPORTED
DURING
TREATMENT
WITH
TEGRETOL.
THESE
REACTIONS
ARE
ESTIMATED TO OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY
CAUCASIAN POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED
TO BE ABOUT 10 TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE
FOUND A STRONG ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND
THE PRESENCE OF HLA-B*1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B
GENE. HLA-B*1502 IS FOUND ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY
ACROSS BROAD AREAS OF ASIA. PATIENTS WITH ANCESTRY IN GENETICALLY AT-
RISK POPULATIONS SHOULD BE SCREENED FOR THE PRESENCE OF HLA-B*1502 PRIOR
TO INITIATING TREATMENT WITH TEGRETOL. PATIENTS TESTING POSITIVE FOR THE
ALLELE SHOULD NOT BE TREATED WITH TEGRETOL UNLESS THE BENEFIT CLEARLY
OUTWEIGHS THE RISK (SEE WARNINGS AND PRECAUTIONS/LABORATORY TESTS).
APLASTIC ANEMIA AND AGRANULOCYTOSIS
APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION
WITH THE USE OF TEGRETOL. DATA FROM A POPULATION-BASED CASE CONTROL
STUDY DEMONSTRATE THAT THE RISK OF DEVELOPING THESE REACTIONS IS 5-8
TIMES GREATER THAN IN THE GENERAL POPULATION. HOWEVER, THE OVERALL RISK
OF THESE REACTIONS IN THE UNTREATED GENERAL POPULATION IS LOW,
APPROXIMATELY SIX PATIENTS PER ONE MILLION POPULATION PER YEAR FOR
AGRANULOCYTOSIS AND TWO PATIENTS PER ONE MILLION POPULATION PER YEAR
FOR APLASTIC ANEMIA.
ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR
WHITE BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE
OF TEGRETOL, DATA ARE NOT AVAILABLE TO ESTIMATE ACCURATELY THEIR
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Page 4
INCIDENCE OR OUTCOME. HOWEVER, THE VAST MAJORITY OF THE CASES OF
LEUKOPENIA HAVE NOT PROGRESSED TO THE MORE SERIOUS CONDITIONS OF
APLASTIC ANEMIA OR AGRANULOCYTOSIS.
BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC
ANEMIA, THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN
MONITORING OF PATIENTS ON TEGRETOL ARE UNLIKELY TO SIGNAL THE
OCCURRENCE OF EITHER ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT
HEMATOLOGICAL TESTING SHOULD BE OBTAINED AS A BASELINE. IF A PATIENT IN
THE COURSE OF TREATMENT EXHIBITS LOW OR DECREASED WHITE BLOOD CELL OR
PLATELET
COUNTS,
THE
PATIENT
SHOULD
BE
MONITORED
CLOSELY.
DISCONTINUATION OF THE DRUG SHOULD BE CONSIDERED IF ANY EVIDENCE OF
SIGNIFICANT BONE MARROW DEPRESSION DEVELOPS.
Before prescribing Tegretol, the physician should be thoroughly familiar with the details of
this prescribing information, particularly regarding use with other drugs, especially those which
accentuate toxicity potential.
DESCRIPTION
Tegretol, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia,
available for oral administration as chewable tablets of 100 mg, tablets of 200 mg, XR tablets of 100,
200, and 400 mg, and as a suspension of 100 mg/5 mL (teaspoon). Its chemical name is 5H-dibenz[b,f
]azepine-5-carboxamide, and its structural formula is
Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in
alcohol and in acetone. Its molecular weight is 236.27.
Inactive Ingredients. Tablets: Colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake
(chewable tablets only), FD&C Red No. 40 (200-mg tablets only), flavoring (chewable tablets only),
gelatin, glycerin, magnesium stearate, sodium starch glycolate (chewable tablets only), starch, stearic
acid, and sucrose (chewable tablets only). Suspension: Citric acid, FD&C Yellow No. 6, flavoring,
polymer, potassium sorbate, propylene glycol, purified water, sorbitol, sucrose, and xanthan gum.
Tegretol-XR tablets: cellulose compounds, dextrates, iron oxides, magnesium stearate, mannitol,
polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200-mg tablets only).
CLINICAL PHARMACOLOGY
In controlled clinical trials, Tegretol has been shown to be effective in the treatment of psychomotor
and grand mal seizures, as well as trigeminal neuralgia.
Mechanism of Action
Tegretol has demonstrated anticonvulsant properties in rats and mice with electrically and chemically
induced seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic
potentiation. Tegretol greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve
in cats and rats. It depresses thalamic potential and bulbar and polysynaptic reflexes, including the
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Page 5
linguomandibular reflex in cats. Tegretol is chemically unrelated to other anticonvulsants or other
drugs used to control the pain of trigeminal neuralgia. The mechanism of action remains unknown.
The principal metabolite of Tegretol, carbamazepine-10,11-epoxide, has anticonvulsant activity as
demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide
has been postulated, the significance of its activity with respect to the safety and efficacy of Tegretol
has not been established.
Pharmacokinetics
In clinical studies, Tegretol suspension, conventional tablets, and XR tablets delivered equivalent
amounts of drug to the systemic circulation. However, the suspension was absorbed somewhat faster,
and the XR tablet slightly slower, than the conventional tablet. The bioavailability of the XR tablet was
89% compared to suspension. Following a b.i.d. dosage regimen, the suspension provides higher peak
levels and lower trough levels than those obtained from the conventional tablet for the same dosage
regimen. On the other hand, following a t.i.d. dosage regimen, Tegretol suspension affords steady-state
plasma levels comparable to Tegretol tablets given b.i.d. when administered at the same total mg daily
dose. Following a b.i.d. dosage regimen, Tegretol-XR tablets afford steady-state plasma levels
comparable to conventional Tegretol tablets given q.i.d., when administered at the same total mg daily
dose. Tegretol in blood is 76% bound to plasma proteins. Plasma levels of Tegretol are variable and
may range from 0.5-25 µg/mL, with no apparent relationship to the daily intake of the drug. Usual
adult therapeutic levels are between 4 and 12 µg/mL. In polytherapy, the concentration of Tegretol
and concomitant drugs may be increased or decreased during therapy, and drug effects may be altered
(see PRECAUTIONS, Drug Interactions). Following chronic oral administration of suspension,
plasma levels peak at approximately 1.5 hours compared to 4-5 hours after administration of
conventional Tegretol tablets, and 3-12 hours after administration of Tegretol-XR tablets. The
CSF/serum ratio is 0.22, similar to the 24% unbound Tegretol in serum. Because Tegretol induces its
own metabolism, the half-life is also variable. Autoinduction is completed after 3-5 weeks of a fixed
dosing regimen. Initial half-life values range from 25-65 hours, decreasing to 12-17 hours on repeated
doses. Tegretol is metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform
responsible for the formation of carbamazepine-10,11-epoxide from Tegretol. After oral administration
of 14C-carbamazepine, 72% of the administered radioactivity was found in the urine and 28% in the
feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites,
with only 3% of unchanged Tegretol.
The pharmacokinetic parameters of Tegretol disposition are similar in children and in adults.
However, there is a poor correlation between plasma concentrations of carbamazepine and Tegretol
dose in children. Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide (a
metabolite shown to be equipotent to carbamazepine as an anticonvulsant in animal screens) in the
younger age groups than in adults. In children below the age of 15, there is an inverse relationship
between CBZ-E/CBZ ratio and increasing age (in one report from 0.44 in children below the age of 1
year to 0.18 in children between 10-15 years of age).
The effects of race and gender on carbamazepine pharmacokinetics have not been systematically
evaluated.
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Page 6
INDICATIONS AND USAGE
Epilepsy
Tegretol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of Tegretol as an
anticonvulsant was derived from active drug-controlled studies that enrolled patients with the
following seizure types:
1. Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these
seizures appear to show greater improvement than those with other types.
2. Generalized tonic-clonic seizures (grand mal).
3. Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence
seizures (petit mal) do not appear to be controlled by Tegretol (see PRECAUTIONS, General).
Trigeminal Neuralgia
Tegretol is indicated in the treatment of the pain associated with true trigeminal neuralgia.
Beneficial results have also been reported in glossopharyngeal neuralgia.
This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.
CONTRAINDICATIONS
Tegretol should not be used in patients with a history of previous bone marrow depression,
hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as
amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical
grounds its use with monoamine oxidase inhibitors is not recommended. Before administration of
Tegretol, MAO inhibitors should be discontinued for a minimum of 14 days, or longer if the clinical
situation permits.
WARNINGS
Serious Dermatologic Reactions
Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN)
and Stevens-Johnson syndrome (SJS), have been reported with Tegretol treatment. The risk of these
events is estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian
populations. However, the risk in some Asian countries is estimated to be about 10 times higher.
Tegretol should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If
signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy
should be considered.
SJS/TEN and HLA-B*1502 Allele
Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong
association between the risk of developing SJS/TEN with carbamazepine treatment and the presence of
an inherited variant of the HLA-B gene, HLA-B*1502. The occurrence of higher rates of these
reactions in countries with higher frequencies of this allele suggests that the risk may be increased in
allele-positive individuals of any ethnicity.
Across Asian populations, notable variation exists in the prevalence of HLA-B*1502. Greater than
15% of the population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the
Philippines, compared to about 10% in Taiwan and 4% in North China. South Asians, including
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Indians, appear to have intermediate prevalence of HLA-B*1502, averaging 2 to 4%, but higher in
some groups. HLA-B*1502 is present in <1% of the population in Japan and Korea.
HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-
Americans, Hispanics, and Native Americans).
Prior to initiating Tegretol therapy, testing for HLA-B*1502 should be performed in patients
with ancestry in populations in which HLA-B*1502 may be present. In deciding which patients to
screen, the rates provided above for the prevalence of HLA-B*1502 may offer a rough guide, keeping
in mind the limitations of these figures due to wide variability in rates even within ethnic groups, the
difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry. Tegretol should not be
used in patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Tested
patients who are found to be negative for the allele are thought to have a low risk of SJS/TEN (see
WARNINGS and PRECAUTIONS/Laboratory Tests).
Over 90% of Tegretol treated patients who will experience SJS/TEN have this reaction within the
first few months of treatment. This information may be taken into consideration in determining the
need for screening of genetically at-risk patients currently on Tegretol.
The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous
reactions from Tegretol, such as anticonvulsant hypersensitivity syndrome or non-serious rash
(maculopapular eruption [MPE]).
Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of
SJS/TEN in patients of Chinese ancestry taking other anti-epileptic drugs associated with SJS/TEN.
Consideration should be given to avoiding use of other drugs associated with SJS/TEN in HLA-
B*1502 positive patients, when alternative therapies are otherwise equally acceptable.
Application of HLA-B*1502 genotyping as a screening tool has important limitations and must
never substitute for appropriate clinical vigilance and patient management. Many HLA-B*1502-
positive Asian patients treated with Tegretol will not develop SJS/TEN, and these reactions can still
occur infrequently in HLA-B*1502-negative patients of any ethnicity. The role of other possible
factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose,
compliance, concomitant medications, co-morbidities, and the level of dermatologic monitoring have
not been studied.
Aplastic Anemia and Agranulocytosis
Patients with a history of adverse hematologic reaction to any drug may be particularly at risk of bone
marrow depression
General
Tegretol has shown mild anticholinergic activity; therefore, patients with increased intraocular
pressure should be closely observed during therapy.
Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of
a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind.
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The use of Tegretol should be avoided in patients with a history of hepatic porphyria (e.g., acute
intermittent porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported
in such patients receiving Tegretol therapy. Carbamazepine administration has also been demonstrated
to increase porphyrin precursors in rodents, a presumed mechanism for the induction of acute attacks
of porphyria.
As with all antiepileptic drugs, Tegretol should be withdrawn gradually to minimize the potential
of increased seizure frequency.
Usage in Pregnancy
Carbamazepine can cause fetal harm when administered to a pregnant woman.
Epidemiological data suggest that there may be an association between the use of carbamazepine
during pregnancy and congenital malformations, including spina bifida. There have also been reports
that associate carbamazepine with developmental disorders and congenital anomalies (e.g., craniofacial
defects, cardiovascular malformations and anomalies involving various body systems). Developmental
delays based on neurobehavioral assessments have been reported. In treating or counseling women of
childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against the
risks. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug,
the patient should be apprised of the potential hazard to the fetus.
Retrospective case reviews suggest that, compared with monotherapy, there may be a higher
prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy.
Therefore, if therapy is to be continued, monotherapy may be preferable for pregnant women.
In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is
accumulated in the fetal tissues, with higher levels found in liver and kidney than in brain and lung.
Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given
orally in dosages 10-25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg
basis or 1.5-4 times the MHDD on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed
kinked ribs at 250 mg/kg and 4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate, 1;
talipes, 1; anophthalmos, 2). In reproduction studies in rats, nursing offspring demonstrated a lack of
weight gain and an unkempt appearance at a maternal dosage level of 200 mg/kg.
Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is
administered to prevent major seizures because of the strong possibility of precipitating status
epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and
frequency of the seizure disorder are such that removal of medication does not pose a serious threat to
the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it
cannot be said with any confidence that even minor seizures do not pose some hazard to the
developing embryo or fetus.
Tests to detect defects using currently accepted procedures should be considered a part of routine
prenatal care in childbearing women receiving carbamazepine.
There have been a few cases of neonatal seizures and/or respiratory depression associated with
maternal Tegretol and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting,
diarrhea, and/or decreased feeding have also been reported in association with maternal Tegretol use.
These symptoms may represent a neonatal withdrawal syndrome.
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PRECAUTIONS
General
Before initiating therapy, a detailed history and physical examination should be made.
Tegretol should be used with caution in patients with a mixed seizure disorder that includes
atypical absence seizures, since in these patients Tegretol has been associated with increased frequency
of generalized convulsions (see INDICATIONS AND USAGE).
Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history
of cardiac conduction disturbance, including second and third degree AV heart block; cardiac, hepatic,
or renal damage; adverse hematologic or hypersensitivity reaction to other drugs, including reactions to
other anticonvulsants; or interrupted courses of therapy with Tegretol.
AV heart block, including second and third degree block, have been reported following, Tegretol
treatment. This occurred generally, but not solely, in patients with underling EKG abnormalities or risk
factors for conduction disturbances.
Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have
been reported (see ADVERSE REACTIONS and PRECAUTIONS, Laboratory Tests). In some cases,
hepatic effects may progress despite discontinuation of the drug.
Multi-organ hypersensitivity reactions occurring days to weeks or months after initiating treatment
have been reported in rare cases (see ADVERSE REACTIONS, Other and PRECAUTIONS,
Information for Patients).
Discontinuation of carbamazepine should be considered if any evidence of hypersensitivity
develops.
Hypersensitivity reactions to carbamazepine have been reported in patients who previously
experienced this reaction to anticonvulsants including phenytoin and phenobarbital. A history of
hypersensitivity reactions should be obtained for a patient and the immediate family members. If
positive, caution should be used in prescribing carbamazepine.
Since a given dose of Tegretol suspension will produce higher peak levels than the same dose
given as the tablet, it is recommended that patients given the suspension be started on lower doses and
increased slowly to avoid unwanted side effects (see DOSAGE AND ADMINISTRATION).
Information for Patients
Patients should be made aware of the early toxic signs and symptoms of a potential hematologic
problem, as well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include,
but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and
petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or
jaundice. The patient should be advised that, because these signs and symptoms may signal a serious
reaction, that they must report any occurrence immediately to a physician. In addition, the patient
should be advised that these signs and symptoms should be reported even if mild or when occurring
after extended use.
Tegretol may interact with some drugs. Therefore, patients should be advised to report to their doctors
the use of any other prescription or non-prescription medications or herbal products.
Caution should be exercised if alcohol is taken in combination with Tegretol therapy, due to a possible
additive sedative effect.
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Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of
operating machinery or automobiles or engaging in other potentially dangerous tasks.
Laboratory Tests
For genetically at-risk patients (See WARNINGS), high-resolution ‘HLA-B*1502 typing’ is
recommended. The test is positive if either one or two HLA-B*1502 alleles are detected and negative
if no HLA-B*1502 alleles are detected.
Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron,
should be obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white
blood cell or platelet counts, the patient should be monitored closely. Discontinuation of the drug
should be considered if any evidence of significant bone marrow depression develops.
Baseline and periodic evaluations of liver function, particularly in patients with a history of liver
disease, must be performed during treatment with this drug since liver damage may occur (see
PRECAUTIONS, General and ADVERSE REACTIONS). Carbamazepine should be discontinued,
based on clinical judgment, if indicated by newly occurring or worsening clinical or laboratory
evidence of liver dysfunction or hepatic damage, or in the case of active liver disease.
Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are
recommended since many phenothiazines and related drugs have been shown to cause eye changes.
Baseline and periodic complete urinalysis and BUN determinations are recommended for patients
treated with this agent because of observed renal dysfunction.
Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and
safety of anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in
seizure frequency and for verification of compliance. In addition, measurement of drug serum levels
may aid in determining the cause of toxicity when more than one medication is being used.
Thyroid function tests have been reported to show decreased values with Tegretol administered
alone.
Hyponatremia has been reported in association with Tegretol use, either alone or in combination
with other drugs.
Interference with some pregnancy tests has been reported.
Drug Interactions
There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after
ingesting Tegretol suspension immediately followed by Thorazine® solution. Subsequent testing has
shown that mixing Tegretol suspension and chlorpromazine solution (both generic and brand name) as
well as Tegretol suspension and liquid Mellaril® resulted in the occurrence of this precipitate. Because
the extent to which this occurs with other liquid medications is not known, Tegretol suspension should
not be administered simultaneously with other liquid medicinal agents or diluents. (see Dosage and
Administration).
Clinically meaningful drug interactions have occurred with concomitant medications and include,
but are not limited to, the following:
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Agents That May Affect Tegretol Plasma Levels
CYP 3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma carbamazepine levels.
Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels include
cimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin,
fluoxetine, fluvoxamine, nefazodone, loratadine, terfenadine, isoniazid, niacinamide,
nicotinamide,
propoxyphene,
azoles
(e.g.,
ketaconazole,
itraconazole,
fluconazole),
acetazolamide, verapamil, grapefruit juice, protease inhibitors, valproate.*
CYP 3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that
would be expected, to decrease plasma carbamazepine levels include
cisplatin, doxorubicin HCl, felbamate,† rifampin, phenobarbital, phenytoin, primidone,
methsuximide, theophylline.
When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close
monitoring of carbamazepine levels is indicated and dosage adjustment may be required.
*increased levels of the active 10,11-epoxide
†decreased levels of carbamazepine and increased levels of the 10,11-epoxide
Effect of Tegretol on Plasma Levels of Concomitant Agents
Increased levels: clomipramine HCl, phenytoin, primidone
Tegretol induces hepatic CYP activity. Tegretol causes, or would be expected to cause, decreased
levels of the following:
acetaminophen, alprazolam, dihydropyridine calcium channel blockers (e.g., felodipine),
cyclosporine, corticosteroids (e.g., prednisolone, dexamethasone), clonazepam, clozapine,
dicumarol, doxycycline, ethosuximide, haloperidol, itraconazole, lamotrigine, levothyroxine,
methadone, methsuximide, midazolam, olanzapine, oral and other hormonal contraceptives,
oxcarbazepine, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone,
theophylline, tiagabine, topiramate, tramadol, tricyclic antidepressants (e.g., imipramine,
amitriptyline, nortriptyline), valproate, warfarin,ziprasidone, zonisamide.
In concomitant use with Tegretol, dosage adjustment of the above agents may be necessary.
Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side
effects.
Co-administration of carbamazepine with nefazodone results in insufficient plasma concentrations of
nefazodone and its active metabolite to achieve a therapeutic effect. Co-administration of
carbamazepine with nefazodone is contraindicated. (See CONTRAINDICATIONS).
Alterations of thyroid function have been reported in combination therapy with other
anticonvulsant medications.
Concomitant use of Tegretol with hormonal contraceptive products (e.g., oral, and levonorgestrel
subdermal implant contraceptives) may render the contraceptives less effective because the plasma
concentrations of the hormones may be decreased. Breakthrough bleeding and unintended pregnancies
have been reported. Alternative or back-up methods of contraception should be considered.
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Carcinogenesis, Mutagenesis, Impairment of Fertility
Carbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75,
and 250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular tumors in
females and of benign interstitial cell adenomas in the testes of males.
Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats.
Bacterial and mammalian mutagenicity studies using carbamazepine produced negative results. The
significance of these findings relative to the use of carbamazepine in humans is, at present, unknown.
Usage in Pregnancy
Pregnancy Category D (see WARNINGS).
Labor and Delivery
The effect of Tegretol on human labor and delivery is unknown.
Nursing Mothers
Tegretol and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in
breast milk to that in maternal plasma is about 0.4 for Tegretol and about 0.5 for the epoxide. The
estimated doses given to the newborn during breast feeding are in the range of 2-5 mg daily for
Tegretol and 1-2 mg daily for the epoxide.
Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a
decision should be made whether to discontinue nursing or to discontinue the drug, taking into account
the importance of the drug to the mother.
Pediatric Use
Substantial evidence of Tegretol’s effectiveness for use in the management of children with epilepsy
(see Indications for specific seizure types) is derived from clinical investigations performed in adults
and from studies in several in vitro systems which support the conclusion that (1) the pathogenetic
mechanisms underlying seizure propagation are essentially identical in adults and children, and (2) the
mechanism of action of carbamazepine in treating seizures is essentially identical in adults and
children.
Taken as a whole, this information supports a conclusion that the generally accepted therapeutic
range of total carbamazepine in plasma (i.e., 4-12 mcg/mL) is the same in children and adults.
The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety
of carbamazepine in children has been systematically studied up to 6 months. No longer-term data
from clinical trials is available.
Geriatric Use
No systematic studies in geriatric patients have been conducted.
ADVERSE REACTIONS
If adverse reactions are of such severity that the drug must be discontinued, the physician must be
aware that abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead
to seizures or even status epilepticus with its life-threatening hazards.
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The most severe adverse reactions have been observed in the hemopoietic system (see boxed
WARNING), the liver and the cardiovascular system.
The most frequently observed adverse reactions, particularly during the initial phases of therapy,
are dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such
reactions, therapy should be initiated at the low dosage recommended.
The following additional adverse reactions have been reported:
Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression,
thrombocytopenia, leukopenia, leukocytosis, eosinophilia, acute intermittent porphyria.
Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXED
WARNING), pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin
pigmentation, exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of
disseminated lupus erythematosus, alopecia, and diaphoresis. In certain cases, discontinuation of
therapy may be necessary. Isolated cases of hirsutism have been reported, but a causal relationship is
not clear.
Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension,
syncope and collapse, aggravation of coronary artery disease, arrhythmias and AV block,
thrombophlebitis, thromboembolism, and adenopathy or lymphadenopathy.
Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has
been associated with other tricyclic compounds.
Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very
rare cases of hepatic failure.
Pancreatic: Pancreatitis.
Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or
pneumonia.
Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood
pressure, azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and
microscopic deposits in the urine have also been reported.
Testicular atrophy occurred in rats receiving Tegretol orally from 4-52 weeks at dosage levels of
50-400 mg/kg/day. Additionally, rats receiving Tegretol in the diet for 2 years at dosage levels of 25,
75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In
dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage
levels of 50 mg/kg and higher. Relevance of these findings to humans is unknown.
Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue,
blurred vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech
disturbances, abnormal involuntary movements, peripheral neuritis and paresthesias, depression with
agitation, talkativeness, tinnitus, and hyperacusis.
There have been reports of associated paralysis and other symptoms of cerebral arterial
insufficiency, but the exact relationship of these reactions to the drug has not been established.
Isolated cases of neuroleptic malignant syndrome have been reported with concomitant use of
psychotropic drugs.
Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation,
anorexia, and dryness of the mouth and pharynx, including glossitis and stomatitis.
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Eyes: Scattered punctate cortical lens opacities, as well as conjunctivitis, have been reported. Although
a direct causal relationship has not been established, many phenothiazines and related drugs have been
shown to cause eye changes.
Musculoskeletal System: Aching joints and muscles, and leg cramps.
Metabolism: Fever and chills. Inappropriate antidiuretic hormone (ADH) secretion syndrome has
been reported. Cases of frank water intoxication, with decreased serum sodium (hyponatremia) and
confusion, have been reported in association with Tegretol use (see PRECAUTIONS, Laboratory
Tests). Decreased levels of plasma calcium have been reported.
Other: Multi-organ hypersensitivity reactions occurring days to weeks or months after initiating
treatment have been reported in rare cases. Signs or symptoms may include, but are not limited to
fever, skin rashes, vasculitis, lymphadenopathy, disorders mimicking lymphoma, arthralgia,
leukopenia, eosinophilia, hepato-splenomegaly and abnormal liver function tests. These signs and
symptoms may occur in various combinations and not necessarily concurrently. Signs and symptoms
may initially be mild. Various organs, including but not limited to, liver, skin, immune system, lungs,
kidneys, pancreas, myocardium, and colon may be affected (see PRECAUTIONS, General and
PRECAUTIONS, Information for Patients).
Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been
occasional reports of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients
taking anticonvulsants.
A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been
reported in a patient taking carbamazepine in combination with other medications. The patient was
successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.
DRUG ABUSE AND DEPENDENCE
No evidence of abuse potential has been associated with Tegretol, nor is there evidence of
psychological or physical dependence in humans.
OVERDOSAGE
Acute Toxicity
Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-
old man died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a
cardiac arrest), 1.6 g (a 3-year-old girl died of aspiration pneumonia).
Oral LD50 in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-2680; guinea pigs,
920.
Signs and Symptoms
The first signs and symptoms appear after 1-3 hours. Neuromuscular disturbances are the most
prominent. Cardiovascular disorders are generally milder, and severe cardiac complications occur only
when very high doses (> 60 g) have been ingested.
Respiration: Irregular breathing, respiratory depression.
Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders.
Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma.
Convulsions, especially in small children. Motor restlessness, muscular twitching, tremor, athetoid
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movements, opisthotonos, ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia,
ballism, psychomotor disturbances, dysmetria. Initial hyperreflexia, followed by hyporeflexia.
Gastrointestinal Tract: Nausea, vomiting.
Kidneys and Bladder: Anuria or oliguria, urinary retention.
Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte
count, glycosuria, and acetonuria. EEG may show dysrhythmias.
Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at
the same time, the signs and symptoms of acute poisoning with Tegretol may be aggravated or
modified.
Treatment
The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug,
which may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps
to diminish absorption. If these measures cannot be implemented without risk on the spot, the patient
should be transferred at once to a hospital, while ensuring that vital functions are safeguarded. There is
no specific antidote.
Elimination of the Drug: Induction of vomiting.
Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the
stomach should be repeatedly irrigated, especially if the patient has also consumed alcohol.
Measures to Reduce Absorption: Activated charcoal, laxatives.
Measures to Accelerate Elimination: Forced diuresis.
Dialysis is indicated only in severe poisoning associated with renal failure. Replacement
transfusion is indicated in severe poisoning in small children.
Respiratory Depression: Keep the airways free; resort, if necessary, to endotracheal intubation,
artificial respiration, and administration of oxygen.
Hypotension, Shock: Keep the patient’s legs raised and administer a plasma expander. If blood
pressure fails to rise despite measures taken to increase plasma volume, use of vasoactive substances
should be considered.
Convulsions: Diazepam or barbiturates.
Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children),
hypotension, and coma. However, barbiturates should not be used if drugs that inhibit monoamine
oxidase have also been taken by the patient either in overdosage or in recent therapy (within 1 week).
Surveillance: Respiration, cardiac function (ECG monitoring), blood pressure, body temperature,
pupillary reflexes, and kidney and bladder function should be monitored for several days.
Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression
develops, the following recommendations are suggested: (1) stop the drug, (2) perform daily CBC,
platelet, and reticulocyte counts, (3) do a bone marrow aspiration and trephine biopsy immediately and
repeat with sufficient frequency to monitor recovery.
Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2)
59Fe-ferrokinetic studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and
peripheral blood, (5) bone marrow culture studies for colony-forming units, (6) hemoglobin
electrophoresis for A2 and F hemoglobin, and (7) serum folic acid and B12 levels.
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A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for
which specialized consultation should be sought.
DOSAGE AND ADMINISTRATION (see table below)
Tegretol suspension in combination with liquid chlorpromazine or thioridazine results in
precipitate formation, and, in the case of chlorpromazine, there has been a report of a patient passing
an orange rubbery precipitate in the stool following coadministration of the two drugs. (See Drug
Interactions). Because the extent to which this occurs with other liquid medications is not known,
Tegretol suspension should not be administered simultaneously with other liquid medications or
diluents.
Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see
PRECAUTIONS, Laboratory Tests). Dosage should be adjusted to the needs of the individual patient.
A low initial daily dosage with a gradual increase is advised. As soon as adequate control is achieved,
the dosage may be reduced very gradually to the minimum effective level. Medication should be taken
with meals.
Since a given dose of Tegretol suspension will produce higher peak levels than the same dose
given as the tablet, it is recommended to start with low doses (children 6-12 years: 1/2 teaspoon q.i.d.)
and to increase slowly to avoid unwanted side effects.
Conversion of patients from oral Tegretol tablets to Tegretol suspension: Patients should be
converted by administering the same number of mg per day in smaller, more frequent doses (i.e., b.i.d.
tablets to t.i.d. suspension).
Tegretol-XR is an extended-release formulation for twice-a-day administration. When converting
patients from Tegretol conventional tablets to Tegretol-XR, the same total daily mg dose of
Tegretol-XR should be administered. Tegretol-XR tablets must be swallowed whole and never
crushed or chewed. Tegretol-XR tablets should be inspected for chips or cracks. Damaged tablets, or
tablets without a release portal, should not be consumed. Tegretol-XR tablet coating is not absorbed
and is excreted in the feces; these coatings may be noticeable in the stool.
Epilepsy (see INDICATIONS AND USAGE)
Adults and children over 12 years of age - Initial: Either 200 mg b.i.d. for tablets and XR tablets, or
1 teaspoon q.i.d. for suspension (400 mg/day). Increase at weekly intervals by adding up to 200
mg/day using a b.i.d. regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until
the optimal response is obtained. Dosage generally should not exceed 1000 mg daily in children 12-15
years of age, and 1200 mg daily in patients above 15 years of age. Doses up to 1600 mg daily have
been used in adults in rare instances. Maintenance: Adjust dosage to the minimum effective level,
usually 800-1200 mg daily.
Children 6-12 years of age - Initial: Either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon
q.i.d. for suspension (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a
b.i.d. regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal
response is obtained. Dosage generally should not exceed 1000 mg daily. Maintenance: Adjust
dosage to the minimum effective level, usually 400-800 mg daily.
Children under 6 years of age - Initial: 10-20 mg/kg/day b.i.d. or t.i.d. as tablets, or q.i.d. as
suspension. Increase weekly to achieve optimal clinical response administered t.i.d. or q.i.d.
Maintenance: Ordinarily, optimal clinical response is achieved at daily doses below 35 mg/kg. If
satisfactory clinical response has not been achieved, plasma levels should be measured to determine
This label may not be the latest approved by FDA.
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Page 17
whether or not they are in the therapeutic range. No recommendation regarding the safety of
carbamazepine for use at doses above 35 mg/kg/24 hours can be made.
Combination Therapy: Tegretol may be used alone or with other anticonvulsants. When added to
existing anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are
maintained or gradually decreased, except phenytoin, which may have to be increased (see
PRECAUTIONS, Drug Interactions, and Pregnancy Category D).
Trigeminal Neuralgia (see INDICATIONS AND USAGE)
Initial: On the first day, either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for
suspension, for a total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day
using increments of 100 mg every 12 hours for tablets or XR tablets, or 50 mg (1/2 teaspoon) q.i.d. for
suspension, only as needed to achieve freedom from pain. Do not exceed 1200 mg daily.
Maintenance: Control of pain can be maintained in most patients with 400-800 mg daily. However,
some patients may be maintained on as little as 200 mg daily, while others may require as much as
1200 mg daily. At least once every 3 months throughout the treatment period, attempts should be made
to reduce the dose to the minimum effective level or even to discontinue the drug.
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Page 18
Dosage Information
Initial Dose
Subsequent Dose
Maximum Daily Dose
Indication
Tablet*
XR
†
Suspension
Tablet*
XR
†
Suspension
Tablet*
XR
†
Suspension
Epilepsy
Under 6 yr
10-20 mg/kg/day
b.i.d. or t.i.d.
10-20 mg/kg/day
q.i.d.
Increase
weekly to
achieve
optimal clinical
response,
t.i.d. or q.i.d.
Increase weekly
to achieve
optimal clinical
response, t.i.d. or
q.i.d.
35 mg/kg/24 hr
(see Dosage and
Administration
section above)
35 mg/kg/24 hr
(see Dosage and
Administration
section above)
6-12 yr
100 mg b.i.d.
(200 mg/day)
100 mg b.i.d.
(200 mg/day)
½ tsp q.i.d.
(200 mg/day)
Add up to 100
mg/day at
weekly
intervals, t.i.d.
or q.i.d.
Add
100 mg/day
at weekly
intervals,
b.i.d.
Add up to 1 tsp
(100 mg)/day at
weekly intervals,
t.i.d. or q.i.d.
1000 mg/24 hr
Over 12 yr
200 mg b.i.d.
(400 mg/day)
200 mg b.i.d.
(400 mg/day)
1 tsp q.i.d.
(400 mg/day)
Add up to 200
mg/day at
weekly
intervals, t.i.d.
or q.i.d.
Add up to
200 mg/day
at weekly
intervals,
b.i.d.
Add up to 2 tsp
(200 mg)/day at
weekly intervals,
t.i.d. or q.i.d.
1000 mg/24 hr (12-15 yr)
1200 mg/24 hr (>15 yr)
1600 mg/24 hr (adults, in rare instances)
Trigeminal
Neuralgia
100 mg b.i.d.
(200 mg/day)
100 mg b.i.d.
(200 mg/day)
½ tsp q.i.d.
(200 mg/day)
Add up to 200
mg/day in
increments of
100 mg every
12 hr
Add up to
200 mg/day
in increments
of 100 mg
every 12 hr
Add up to 2 tsp
(200 mg)/day
in increments of
50 mg
(½ tsp) q.i.d.
1200 mg/24 hr
*Tablet = Chewable or conventional tablets
†XR = Tegretol
®-XR extended-release tablets
This label may not be the latest approved by FDA.
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HOW SUPPLIED
Chewable Tablets 100 mg - round, red-speckled, pink, single-scored (imprinted Tegretol on one side
and 52 twice on the scored side)
Bottles of 100.........................................................................................NDC 0083-0052-30
Unit Dose (blister pack)
Box of 100 (strips of 10)..................................................................NDC 0083-0052-32
Do not store above 30°C (86°F). Protect from light and moisture.
Dispense in tight, light-resistant container (USP).
Meets USP Dissolution Test 1.
Tablets 200 mg - capsule-shaped, pink, single-scored (imprinted Tegretol on one side and 27 twice on
the partially scored side)
Bottles of 100.........................................................................................NDC 0083-0027-30
Bottles of 1000.......................................................................................NDC 0083-0027-40
Unit Dose (blister pack)
Box of 100 (strips of 10)..................................................................NDC 0083-0027-32
Do not store above 30°C (86°F). Protect from moisture. Dispense in tight container (USP).
Meets USP Dissolution Test 2.
XR Tablets 100 mg - round, yellow, coated (imprinted T on one side and 100 mg on the other), release
portal on one side
Bottles of 100.........................................................................................NDC 0083-0061-30
XR Tablets 200 mg - round, pink, coated (imprinted T on one side and 200 mg on the other), release
portal on one side
Bottles of 100.........................................................................................NDC 0083-0062-30
XR Tablets 400 mg - round, brown, coated (imprinted T on one side and 400 mg on the other), release
portal on one side
Bottles of 100.........................................................................................NDC 0083-0060-30
Store at controlled room temperature 15°C-30°C (59°F-86°F). Protect from moisture. Dispense in
tight, container (USP).
Suspension 100 mg/5 mL (teaspoon) - yellow-orange, citrus-vanilla flavored
Bottles of 450 mL..................................................................................NDC 0083-0019-76
Shake well before using.
Do not store above 30°C (86°F). Dispense in tight, light resistant container (USP).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Tegretol Chewable Tablets Manufactured by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
Tegretol Tablets Manufactured by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
Tegretol Suspension Manufactured by:
Patheon Whitby Inc.Whitby Operations
Whitby Ontario, Canada
L1N 5Z5
Tegretol XR Tablets Manufactured by:
Novartis Pharma GmbH
D-79664 Wehr, Germany
Manufactured for
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
December 2007
© 2007 Novartis
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:40.555643
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018281s046lbl.pdf', 'application_number': 18281, 'submission_type': 'SUPPL ', 'submission_number': 46}
|
11,195
|
company logo
Tegretol®
carbamazepine USP
Chewable Tablets of 100 mg - red-speckled, pink
Tablets of 200 mg – pink
Suspension of 100 mg/5 mL
Tegretol®-XR
(carbamazepine extended-release tablets)
100 mg, 200 mg, 400 mg
Rx only
Prescribing Information
WARNINGS
SERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELE
SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC
EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN
REPORTED DURING TREATMENT WITH TEGRETOL. THESE REACTIONS ARE ESTIMATED TO
OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY CAUCASIAN
POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10
TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG
ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF
HLA-B*1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE. HLA-B*1502 IS FOUND
ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF ASIA.
PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS SHOULD BE SCREENED
FOR THE PRESENCE OF HLA-B*1502 PRIOR TO INITIATING TREATMENT WITH TEGRETOL.
PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH TEGRETOL
UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK (SEE WARNINGS AND PRECAUTIONS,
LABORATORY TESTS).
APLASTIC ANEMIA AND AGRANULOCYTOSIS
APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION WITH
THE USE OF TEGRETOL. DATA FROM A POPULATION-BASED CASE CONTROL STUDY
DEMONSTRATE THAT THE RISK OF DEVELOPING THESE REACTIONS IS 5-8 TIMES GREATER
THAN IN THE GENERAL POPULATION. HOWEVER, THE OVERALL RISK OF THESE REACTIONS
IN THE UNTREATED GENERAL POPULATION IS LOW, APPROXIMATELY SIX PATIENTS PER ONE
MILLION POPULATION PER YEAR FOR AGRANULOCYTOSIS AND TWO PATIENTS PER ONE
MILLION POPULATION PER YEAR FOR APLASTIC ANEMIA.
ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR WHITE
BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE OF TEGRETOL,
DATA ARE NOT AVAILABLE TO ESTIMATE ACCURATELY THEIR INCIDENCE OR OUTCOME.
HOWEVER, THE VAST MAJORITY OF THE CASES OF LEUKOPENIA HAVE NOT PROGRESSED TO
THE MORE SERIOUS CONDITIONS OF APLASTIC ANEMIA OR AGRANULOCYTOSIS.
Reference ID: 2912982
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BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC ANEMIA,
THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN MONITORING OF
PATIENTS ON TEGRETOL ARE UNLIKELY TO SIGNAL THE OCCURRENCE OF EITHER
ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT HEMATOLOGICAL TESTING
SHOULD BE OBTAINED AS A BASELINE. IF A PATIENT IN THE COURSE OF TREATMENT
EXHIBITS LOW OR DECREASED WHITE BLOOD CELL OR PLATELET COUNTS, THE PATIENT
SHOULD BE MONITORED CLOSELY. DISCONTINUATION OF THE DRUG SHOULD BE
CONSIDERED IF ANY EVIDENCE OF SIGNIFICANT BONE MARROW DEPRESSION DEVELOPS.
Before prescribing Tegretol, the physician should be thoroughly familiar with the details of this
prescribing information, particularly regarding use with other drugs, especially those which accentuate
toxicity potential.
DESCRIPTION
Tegretol, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for
oral administration as chewable tablets of 100 mg, tablets of 200 mg, XR tablets of 100, 200, and 400 mg, and
as a suspension of 100 mg/5 mL (teaspoon). Its chemical name is 5H-dibenz[b,f ]azepine-5-carboxamide, and
its structural formula is structural formula
Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in alcohol and in
acetone. Its molecular weight is 236.27.
Inactive Ingredients Tablets: Colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake (chewable tablets
only), FD&C Red No. 40 (200-mg tablets only), flavoring (chewable tablets only), gelatin, glycerin, magnesium
stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose (chewable tablets
only). Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate, propylene glycol,
purified water, sorbitol, sucrose, and xanthan gum. Tegretol-XR tablets: cellulose compounds, dextrates, iron
oxides, magnesium stearate, mannitol, polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200-mg
tablets only).
CLINICAL PHARMACOLOGY
In controlled clinical trials, Tegretol has been shown to be effective in the treatment of psychomotor and grand
mal seizures, as well as trigeminal neuralgia.
Mechanism of Action
Tegretol has demonstrated anticonvulsant properties in rats and mice with electrically and chemically induced
seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation.
Tegretol greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It
depresses thalamic potential and bulbar and polysynaptic reflexes, including the linguomandibular reflex in
cats. Tegretol is chemically unrelated to other anticonvulsants or other drugs used to control the pain of
trigeminal neuralgia. The mechanism of action remains unknown.
The principal metabolite of Tegretol, carbamazepine-10,11-epoxide, has anticonvulsant activity as
demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide has been
postulated, the significance of its activity with respect to the safety and efficacy of Tegretol has not been
established.
Reference ID: 2912982
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Pharmacokinetics
In clinical studies, Tegretol suspension, conventional tablets, and XR tablets delivered equivalent amounts of
drug to the systemic circulation. However, the suspension was absorbed somewhat faster, and the XR tablet
slightly slower, than the conventional tablet. The bioavailability of the XR tablet was 89% compared to
suspension. Following a b.i.d. dosage regimen, the suspension provides higher peak levels and lower trough
levels than those obtained from the conventional tablet for the same dosage regimen. On the other hand,
following a t.i.d. dosage regimen, Tegretol suspension affords steady-state plasma levels comparable to
Tegretol tablets given b.i.d. when administered at the same total mg daily dose. Following a b.i.d. dosage
regimen, Tegretol-XR tablets afford steady-state plasma levels comparable to conventional Tegretol tablets
given q.i.d., when administered at the same total mg daily dose. Tegretol in blood is 76% bound to plasma
proteins. Plasma levels of Tegretol are variable and may range from 0.5-25 µg/mL, with no apparent
relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 µg/mL. In
polytherapy, the concentration of Tegretol and concomitant drugs may be increased or decreased during
therapy, and drug effects may be altered (see PRECAUTIONS, Drug Interactions). Following chronic oral
administration of suspension, plasma levels peak at approximately 1.5 hours compared to 4-5 hours after
administration of conventional Tegretol tablets, and 3-12 hours after administration of Tegretol-XR tablets. The
CSF/serum ratio is 0.22, similar to the 24% unbound Tegretol in serum. Because Tegretol induces its own
metabolism, the half-life is also variable. Autoinduction is completed after 3-5 weeks of a fixed dosing regimen.
Initial half-life values range from 25-65 hours, decreasing to 12-17 hours on repeated doses. Tegretol is
metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the
formation of carbamazepine-10,11-epoxide from Tegretol. After oral administration of 14C-carbamazepine, 72%
of the administered radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was
composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged Tegretol.
The pharmacokinetic parameters of Tegretol disposition are similar in children and in adults. However, there is
a poor correlation between plasma concentrations of carbamazepine and Tegretol dose in children.
Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide (a metabolite shown to be
equipotent to carbamazepine as an anticonvulsant in animal screens) in the younger age groups than in adults. In
children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age (in
one report from 0.44 in children below the age of 1 year to 0.18 in children between 10-15 years of age).
The effects of race and gender on carbamazepine pharmacokinetics have not been systematically evaluated.
INDICATIONS AND USAGE
Epilepsy
Tegretol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of Tegretol as an
anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure
types:
1. Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures
appear to show greater improvement than those with other types.
2. Generalized tonic-clonic seizures (grand mal).
3. Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence seizures
(petit mal) do not appear to be controlled by Tegretol (see PRECAUTIONS, General).
Trigeminal Neuralgia
Tegretol is indicated in the treatment of the pain associated with true trigeminal neuralgia.
Beneficial results have also been reported in glossopharyngeal neuralgia.
This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.
Reference ID: 2912982
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CONTRAINDICATIONS
Tegretol should not be used in patients with a history of previous bone marrow depression, hypersensitivity to
the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine,
imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with monoamine oxidase
inhibitors is not recommended. Before administration of Tegretol, MAO inhibitors should be discontinued for a
minimum of 14 days, or longer if the clinical situation permits.
Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of
nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with
nefazodone is contraindicated.
WARNINGS
Serious Dermatologic Reactions
Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and
Stevens-Johnson syndrome (SJS), have been reported with Tegretol treatment. The risk of these events is
estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. However, the
risk in some Asian countries is estimated to be about 10 times higher. Tegretol should be discontinued at the
first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this
drug should not be resumed and alternative therapy should be considered.
SJS/TEN and HLA-B*1502 Allele
Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association
between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant
of the HLA-B gene, HLA-B*1502. The occurrence of higher rates of these reactions in countries with higher
frequencies of this allele suggests that the risk may be increased in allele-positive individuals of any ethnicity.
Across Asian populations, notable variation exists in the prevalence of HLA-B*1502. Greater than 15% of the
population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared to
about 10% in Taiwan and 4% in North China. South Asians, including Indians, appear to have intermediate
prevalence of HLA-B*1502, averaging 2 to 4%, but higher in some groups. HLA-B*1502 is present in <1% of
the population in Japan and Korea.
HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans,
Hispanics, and Native Americans).
Prior to initiating Tegretol therapy, testing for HLA-B*1502 should be performed in patients with
ancestry in populations in which HLA-B*1502 may be present. In deciding which patients to screen, the
rates provided above for the prevalence of HLA-B*1502 may offer a rough guide, keeping in mind the
limitations of these figures due to wide variability in rates even within ethnic groups, the difficulty in
ascertaining ethnic ancestry, and the likelihood of mixed ancestry. Tegretol should not be used in patients
positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Tested patients who are found to be
negative for the allele are thought to have a low risk of SJS/TEN (see WARNINGS and PRECAUTIONS,
Laboratory Tests).
Over 90% of Tegretol treated patients who will experience SJS/TEN have this reaction within the first few
months of treatment. This information may be taken into consideration in determining the need for screening of
genetically at-risk patients currently on Tegretol.
The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from
Tegretol, such as anticonvulsant hypersensitivity syndrome or nonserious rash (maculopapular eruption [MPE]).
Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients
of Chinese ancestry taking other antiepileptic drugs associated with SJS/TEN. Consideration should be given to
Reference ID: 2912982
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
avoiding use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when alternative
therapies are otherwise equally acceptable.
Application of HLA-B*1502 genotyping as a screening tool has important limitations and must never substitute
for appropriate clinical vigilance and patient management. Many HLA-B*1502-positive Asian patients treated
with Tegretol will not develop SJS/TEN, and these reactions can still occur infrequently in
HLA-B*1502-negative patients of any ethnicity. The role of other possible factors in the development of, and
morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications,
comorbidities, and the level of dermatologic monitoring have not been studied.
Aplastic Anemia and Agranulocytosis
Patients with a history of adverse hematologic reaction to any drug may be particularly at risk of bone marrow
depression.
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Tegretol, increase the risk of suicidal thoughts or behavior in patients
taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for
the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood
or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs
showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk
1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these
trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or
ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated
patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530
patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting
drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in
the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could
not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The
finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests
that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years)
in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
Table 1 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication
Placebo Patients
with Events Per
1,000 Patients
Drug Patients
with Events Per
1,000 Patients
Relative Risk:
Incidence of
Events in Drug
Patients/Incidence
in Placebo
Patients
Risk Difference:
Additional Drug
Patients with
Events Per 1,000
Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
Reference ID: 2912982
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The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials
for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric
indications.
Anyone considering prescribing Tegretol or any other AED must balance the risk of suicidal thoughts or
behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are
themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.
Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the
emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and
behavior and should be advised of the need to be alert for the emergence or worsening of the signs and
symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,
behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare
providers.
General
Tegretol has shown mild anticholinergic activity; therefore, patients with increased intraocular pressure should
be closely observed during therapy.
Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a latent
psychosis and, in elderly patients, of confusion or agitation should be borne in mind.
The use of Tegretol should be avoided in patients with a history of hepatic porphyria (e.g., acute intermittent
porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported in such patients
receiving Tegretol therapy. Carbamazepine administration has also been demonstrated to increase porphyrin
precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria.
As with all antiepileptic drugs, Tegretol should be withdrawn gradually to minimize the potential of increased
seizure frequency.
Usage in Pregnancy
Carbamazepine can cause fetal harm when administered to a pregnant woman.
Epidemiological data suggest that there may be an association between the use of carbamazepine during
pregnancy and congenital malformations, including spina bifida. There have also been reports that associate
carbamazepine with developmental disorders and congenital anomalies (e.g., craniofacial defects,
cardiovascular malformations, hypospadias and anomalies involving various body systems). Developmental
delays based on neurobehavioral assessments have been reported. In treating or counseling women of
childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against the risks. If
this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should
be apprised of the potential hazard to the fetus.
Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of
teratogenic effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to
be continued, monotherapy may be preferable for pregnant women.
In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is accumulated in
the fetal tissues, with higher levels found in liver and kidney than in brain and lung.
Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in
dosages 10-25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 1.5-4 times
the MHDD on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250 mg/kg and
4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate, 1; talipes, 1; anophthalmos, 2). In
reproduction studies in rats, nursing offspring demonstrated a lack of weight gain and an unkempt appearance at
a maternal dosage level of 200 mg/kg.
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Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent
major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and
threat to life. In individual cases where the severity and frequency of the seizure disorder are such that removal
of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior
to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose
some hazard to the developing embryo or fetus.
Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal care
in childbearing women receiving carbamazepine.
There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal
Tegretol and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or
decreased feeding have also been reported in association with maternal Tegretol use. These symptoms may
represent a neonatal withdrawal syndrome.
To provide information regarding the effects of in utero exposure to Tegretol, physicians are advised to
recommend that pregnant patients taking Tegretol enroll in the North American Antiepileptic Drug (NAAED)
Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by
patients themselves. Information on the registry can also be found at the website
http://www.aedpregnancyregistry.org/.
PRECAUTIONS
General
Before initiating therapy, a detailed history and physical examination should be made.
Tegretol should be used with caution in patients with a mixed seizure disorder that includes atypical absence
seizures, since in these patients Tegretol has been associated with increased frequency of generalized
convulsions (see INDICATIONS AND USAGE).
Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac
conduction disturbance, including second and third degree AV heart block; cardiac, hepatic, or renal damage;
adverse hematologic or hypersensitivity reaction to other drugs, including reactions to other anticonvulsants; or
interrupted courses of therapy with Tegretol.
AV heart block, including second and third degree block, have been reported following Tegretol treatment. This
occurred generally, but not solely, in patients with underlying EKG abnormalities or risk factors for conduction
disturbances.
Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have been
reported (see ADVERSE REACTIONS and PRECAUTIONS, Laboratory Tests). In some cases, hepatic effects
may progress despite discontinuation of the drug.
Multiorgan hypersensitivity reactions which can affect the skin, liver, hemopoietic organs and lymphatic system
or other organs and occurring days to weeks or months after initiating treatment have been reported in rare cases
(see ADVERSE REACTIONS, Other and PRECAUTIONS, Information for Patients).
Discontinuation of carbamazepine should be considered if any evidence of hypersensitivity develops.
Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this
reaction to anticonvulsants including phenytoin and phenobarbital. A history of hypersensitivity reactions
should be obtained for a patient and the immediate family members. If positive, caution should be used in
prescribing carbamazepine.
In patients who have exhibited hypersensitivity reactions to carbamazepine approximately 25 to 30% of these
patients may experience hypersensitivity reactions with oxcarbazepine (Trileptal®).
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Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the
tablet, it is recommended that patients given the suspension be started on lower doses and increased slowly to
avoid unwanted side effects (see DOSAGE AND ADMINISTRATION).
Tegretol suspension contains sorbitol and, therefore, should not be administered to patients with rare hereditary
problems of fructose intolerance.
Information for Patients
Patients should be informed of the availability of a Medication Guide and they should be instructed to read the
Medication Guide before taking Tegretol.
Patients should be made aware of the early toxic signs and symptoms of a potential hematologic problem, as
well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include, but are not limited to,
fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric
hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be
advised that, because these signs and symptoms may signal a serious reaction, that they must report any
occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms
should be reported even if mild or when occurring after extended use.
Patients, their caregivers, and families should be counseled that AEDs, including Tegretol, may increase the risk
of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening
of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,
behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare
providers
Patients should be advised that serious skin reactions have been reported in association with Tegretol. In the
event a skin reaction should occur while taking Tegretol, patients should consult with their physician
immediately (see WARNINGS).
Tegretol may interact with some drugs. Therefore, patients should be advised to report to their doctors the use
of any other prescription or nonprescription medications or herbal products.
Caution should be exercised if alcohol is taken in combination with Tegretol therapy, due to a possible additive
sedative effect.
Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of operating
machinery or automobiles or engaging in other potentially dangerous tasks.
Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This
registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients
can call the toll free number 1-888-233-2334 (see WARNINGS, Usage in Pregnancy subsection).
Laboratory Tests
For genetically at-risk patients (see WARNINGS), high-resolution ‘HLA-B*1502 typing’ is recommended. The
test is positive if either one or two HLA-B*1502 alleles are detected and negative if no HLA-B*1502 alleles are
detected.
Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, should be
obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white blood cell or
platelet counts, the patient should be monitored closely. Discontinuation of the drug should be considered if any
evidence of significant bone marrow depression develops.
Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must
be performed during treatment with this drug since liver damage may occur (see PRECAUTIONS, General and
ADVERSE REACTIONS). Carbamazepine should be discontinued, based on clinical judgment, if indicated by
newly occurring or worsening clinical or laboratory evidence of liver dysfunction or hepatic damage, or in the
case of active liver disease.
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Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are recommended
since many phenothiazines and related drugs have been shown to cause eye changes.
Baseline and periodic complete urinalysis and BUN determinations are recommended for patients treated with
this agent because of observed renal dysfunction.
Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and safety of
anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in seizure frequency
and for verification of compliance. In addition, measurement of drug serum levels may aid in determining the
cause of toxicity when more than one medication is being used.
Thyroid function tests have been reported to show decreased values with Tegretol administered alone.
Hyponatremia has been reported in association with Tegretol use, either alone or in combination with other
drugs.
Interference with some pregnancy tests has been reported.
Drug Interactions
There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting
Tegretol suspension immediately followed by Thorazine®* solution. Subsequent testing has shown that mixing
Tegretol suspension and chlorpromazine solution (both generic and brand name) as well as Tegretol suspension
and liquid Mellaril® resulted in the occurrence of this precipitate. Because the extent to which this occurs with
other liquid medications is not known, Tegretol suspension should not be administered simultaneously with
other liquid medicinal agents or diluents (see DOSAGE AND ADMINISTRATION).
Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not
limited to, the following:
Agents That May Affect Tegretol Plasma Levels
CYP 3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma carbamazepine levels. Drugs that
have been shown, or would be expected, to increase plasma carbamazepine levels include:
cimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine,
fluvoxamine, nefazodone, trazodone, loxapine*, olanzapine, quetiapine*, loratadine, terfenadine,
omeprazole, oxybutynin, dantrolene, isoniazid, niacinamide, nicotinamide, ibuprofen, propoxyphene,
azoles (e.g., ketaconazole, itraconazole, fluconazole, voriconazole), acetazolamide, verapamil,
ticlopidine, grapefruit juice, protease inhibitors, valproate*.
CYP 3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that would be
expected, to decrease plasma carbamazepine levels include:
cisplatin, doxorubicin HCl, felbamate†, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone,
methsuximide, theophylline, aminophylline.
When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring
of carbamazepine levels is indicated and dosage adjustment may be required.
*increased levels of the active 10,11-epoxide
†decreased levels of carbamazepine and increased levels of the 10,11-epoxide
Effect of Tegretol on Plasma Levels of Concomitant Agents
Increased levels: clomipramine HCl, phenytoin, primidone
Tegretol is a potent inducer of hepatic CYP 3A4 and may therefore reduce plasma concentrations of
comedications mainly metabolized by 3A4 through induction of their metabolism. Tegretol causes, or would be
expected to cause, decreased levels of the following:
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acetaminophen, alprazolam, bupropion, dihydropyridine calcium channel blockers (e.g., felodipine),
citalopram, cyclosporine, corticosteroids (e.g., prednisolone, dexamethasone), clonazepam, clozapine,
dicumarol, doxycycline, ethosuximide, everolimus, haloperidol, imatinib, itraconazole, lamotrigine,
levothyroxine, methadone, methsuximide, midazolam, olanzapine, oral and other hormonal
contraceptives, oxcarbazepine, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone,
theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants (e.g., imipramine,
amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, zonisamide.
In concomitant use with Tegretol, dosage adjustment of the above agents may be necessary.
Coadministration of carbamazepine with nefazodone results in insufficient plasma concentrations of nefazodone
and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is
contraindicated (see CONTRAINDICATIONS).
Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects.
Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced
hepatotoxicity.
Concomitant medication with Tegretol and some diuretics (hydrochlorothiazide, furosemide) may lead to
symptomatic hyponatremia.
Carbamazepine may antagonize the effects of nondepolarizing muscle relaxants (e.g., pancuronium).
Their dosage may need to be raised, and patients should be monitored closely for more rapid recovery from
neuromuscular blockade than expected.
Alterations of thyroid function have been reported in combination therapy with other anticonvulsant
medications.
Concomitant use of Tegretol with hormonal contraceptive products (e.g., oral, and levonorgestrel subdermal
implant contraceptives) may render the contraceptives less effective because the plasma concentrations of the
hormones may be decreased. Breakthrough bleeding and unintended pregnancies have been reported.
Alternative or back-up methods of contraception should be considered.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75, and
250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular tumors in females and of
benign interstitial cell adenomas in the testes of males.
Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Bacterial and
mammalian mutagenicity studies using carbamazepine produced negative results. The significance of these
findings relative to the use of carbamazepine in humans is, at present, unknown.
Usage in Pregnancy
Pregnancy Category D (see WARNINGS).
Labor and Delivery
The effect of Tegretol on human labor and delivery is unknown.
Nursing Mothers
Tegretol and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in breast milk
to that in maternal plasma is about 0.4 for Tegretol and about 0.5 for the epoxide. The estimated doses given to
the newborn during breast-feeding are in the range of 2-5 mg daily for Tegretol and 1-2 mg daily for the
epoxide.
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Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a decision should
be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the
drug to the mother.
Pediatric Use
Substantial evidence of Tegretol’s effectiveness for use in the management of children with epilepsy (see
INDICATIONS AND USAGE for specific seizure types) is derived from clinical investigations performed in
adults and from studies in several in vitro systems which support the conclusion that (1) the pathogenetic
mechanisms underlying seizure propagation are essentially identical in adults and children, and (2) the
mechanism of action of carbamazepine in treating seizures is essentially identical in adults and children.
Taken as a whole, this information supports a conclusion that the generally accepted therapeutic range of total
carbamazepine in plasma (i.e., 4-12 mcg/mL) is the same in children and adults.
The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety of
carbamazepine in children has been systematically studied up to 6 months. No longer-term data from clinical
trials is available.
Geriatric Use
No systematic studies in geriatric patients have been conducted.
ADVERSE REACTIONS
If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that
abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead to seizures or even
status epilepticus with its life-threatening hazards.
The most severe adverse reactions have been observed in the hemopoietic system and skin (see BOXED
WARNING), the liver, and the cardiovascular system.
The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness,
drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should
be initiated at the low dosage recommended.
The following additional adverse reactions have been reported:
Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression,
thrombocytopenia, leukopenia, leukocytosis, eosinophilia, anemia, acute intermittent porphyria, variegate
porphyria, porphyria cutanea tarda.
Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXED WARNING),
pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin pigmentation,
exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus
erythematosus, alopecia, and diaphoresis. In certain cases, discontinuation of therapy may be necessary. Isolated
cases of hirsutism have been reported, but a causal relationship is not clear.
Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope
and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis,
thromboembolism (e.g., pulmonary embolism), and adenopathy or lymphadenopathy.
Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been
associated with other tricyclic compounds.
Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very rare cases of
hepatic failure.
Pancreatic: Pancreatitis.
Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia.
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Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood pressure,
azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and microscopic deposits in the
urine have also been reported. There have been very rare reports of impaired male fertility and/or abnormal
spermatogenesis.
Testicular atrophy occurred in rats receiving Tegretol orally from 4-52 weeks at dosage levels of 50-400
mg/kg/day. Additionally, rats receiving Tegretol in the diet for 2 years at dosage levels of 25, 75, and 250
mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a
brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg and
higher. Relevance of these findings to humans is unknown.
Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred
vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances,
abnormal involuntary movements, peripheral neuritis and paresthesias, depression with agitation, talkativeness,
tinnitus, hyperacusis, neuroleptic malignant syndrome.
There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the
exact relationship of these reactions to the drug has not been established.
Isolated cases of neuroleptic malignant syndrome have been reported both with and without concomitant use of
psychotropic drugs.
Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia, and
dryness of the mouth and pharynx, including glossitis and stomatitis.
Eyes: Scattered punctate cortical lens opacities, increased intraocular pressure as well as conjunctivitis, have
been reported. Although a direct causal relationship has not been established, many phenothiazines and related
drugs have been shown to cause eye changes.
Musculoskeletal System: Aching joints and muscles, and leg cramps.
Metabolism: Fever and chills. Inappropriate antidiuretic hormone (ADH) secretion syndrome has been reported.
Cases of frank water intoxication, with decreased serum sodium (hyponatremia) and confusion, have been
reported in association with Tegretol use (see PRECAUTIONS, Laboratory Tests). Decreased levels of plasma
calcium leading to osteoporosis have been reported.
Other: Multiorgan hypersensitivity reactions occurring days to weeks or months after initiating treatment have
been reported in rare cases. Signs or symptoms may include, but are not limited to fever, skin rashes, vasculitis,
lymphadenopathy, disorders mimicking lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly
and abnormal liver function tests. These signs and symptoms may occur in various combinations and not
necessarily concurrently. Signs and symptoms may initially be mild. Various organs, including but not limited
to, liver, skin, immune system, lungs, kidneys, pancreas, myocardium, and colon may be affected (see
PRECAUTIONS, General and PRECAUTIONS, Information for Patients).
Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional reports
of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants.
A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a
patient taking carbamazepine in combination with other medications. The patient was successfully
dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.
DRUG ABUSE AND DEPENDENCE
No evidence of abuse potential has been associated with Tegretol, nor is there evidence of psychological or
physical dependence in humans.
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OVERDOSAGE
Acute Toxicity
Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-old man
died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a cardiac arrest), 1.6 g
(a 3-year-old girl died of aspiration pneumonia).
Oral LD50 in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-2680; guinea pigs, 920.
Signs and Symptoms
The first signs and symptoms appear after 1-3 hours. Neuromuscular disturbances are the most prominent.
Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high
doses (>60 g) have been ingested.
Respiration: Irregular breathing, respiratory depression.
Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders.
Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma. Convulsions,
especially in small children. Motor restlessness, muscular twitching, tremor, athetoid movements, opisthotonos,
ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism, psychomotor disturbances,
dysmetria. Initial hyperreflexia, followed by hyporeflexia.
Gastrointestinal Tract: Nausea, vomiting.
Kidneys and Bladder: Anuria or oliguria, urinary retention.
Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte count,
glycosuria, and acetonuria. EEG may show dysrhythmias.
Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same
time, the signs and symptoms of acute poisoning with Tegretol may be aggravated or modified.
Treatment
The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which
may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps to diminish
absorption. If these measures cannot be implemented without risk on the spot, the patient should be transferred
at once to a hospital, while ensuring that vital functions are safeguarded. There is no specific antidote.
Elimination of the Drug: Induction of vomiting.
Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the stomach should
be repeatedly irrigated, especially if the patient has also consumed alcohol.
Measures to Reduce Absorption: Activated charcoal, laxatives.
Measures to Accelerate Elimination: Forced diuresis.
Dialysis is indicated only in severe poisoning associated with renal failure. Replacement transfusion is indicated
in severe poisoning in small children.
Respiratory Depression: Keep the airways free; resort, if necessary, to endotracheal intubation, artificial
respiration, and administration of oxygen.
Hypotension, Shock: Keep the patient’s legs raised and administer a plasma expander. If blood pressure fails to
rise despite measures taken to increase plasma volume, use of vasoactive substances should be considered.
Convulsions: Diazepam or barbiturates.
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Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children), hypotension,
and coma. However, barbiturates should not be used if drugs that inhibit monoamine oxidase have also been
taken by the patient either in overdosage or in recent therapy (within 1 week).
Surveillance: Respiration, cardiac function (ECG monitoring), blood pressure, body temperature, pupillary
reflexes, and kidney and bladder function should be monitored for several days.
Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression develops, the
following recommendations are suggested: (1) stop the drug, (2) perform daily CBC, platelet, and reticulocyte
counts, (3) do a bone marrow aspiration and trephine biopsy immediately and repeat with sufficient frequency
to monitor recovery.
Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2) 59Fe-ferrokinetic
studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and peripheral blood, (5) bone
marrow culture studies for colony-forming units, (6) hemoglobin electrophoresis for A2 and F hemoglobin, and
(7) serum folic acid and B12 levels.
A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which
specialized consultation should be sought.
DOSAGE AND ADMINISTRATION (SEE TABLE BELOW)
Tegretol suspension in combination with liquid chlorpromazine or thioridazine results in precipitate formation,
and, in the case of chlorpromazine, there has been a report of a patient passing an orange rubbery precipitate in
the stool following coadministration of the two drugs (see PRECAUTIONS, Drug Interactions). Because the
extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be
administered simultaneously with other liquid medications or diluents.
Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see PRECAUTIONS,
Laboratory Tests). Dosage should be adjusted to the needs of the individual patient. A low initial daily dosage
with a gradual increase is advised. As soon as adequate control is achieved, the dosage may be reduced very
gradually to the minimum effective level. Medication should be taken with meals.
Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the
tablet, it is recommended to start with low doses (children 6-12 years: 1/2 teaspoon q.i.d.) and to increase
slowly to avoid unwanted side effects.
Conversion of patients from oral Tegretol tablets to Tegretol suspension: Patients should be converted by
administering the same number of mg per day in smaller, more frequent doses (i.e., b.i.d. tablets to t.i.d.
suspension).
Tegretol-XR is an extended-release formulation for twice-a-day administration. When converting patients from
Tegretol conventional tablets to Tegretol-XR, the same total daily mg dose of Tegretol-XR should be
administered. Tegretol-XR tablets must be swallowed whole and never crushed or chewed. Tegretol-XR
tablets should be inspected for chips or cracks. Damaged tablets, or tablets without a release portal, should not
be consumed. Tegretol-XR tablet coating is not absorbed and is excreted in the feces; these coatings may be
noticeable in the stool.
Epilepsy (SEE INDICATIONS AND USAGE)
Adults and children over 12 years of age - Initial: Either 200 mg b.i.d. for tablets and XR tablets, or 1 teaspoon
q.i.d. for suspension (400 mg/day). Increase at weekly intervals by adding up to 200 mg/day using a b.i.d.
regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is
obtained. Dosage generally should not exceed 1000 mg daily in children 12-15 years of age, and 1200 mg daily
in patients above 15 years of age. Doses up to 1600 mg daily have been used in adults in rare instances.
Maintenance: Adjust dosage to the minimum effective level, usually 800-1200 mg daily.
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Children 6-12 years of age - Initial: Either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for
suspension (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a b.i.d. regimen of
Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is obtained. Dosage
generally should not exceed 1000 mg daily. Maintenance: Adjust dosage to the minimum effective level,
usually 400-800 mg daily.
Children under 6 years of age - Initial: 10-20 mg/kg/day b.i.d. or t.i.d. as tablets, or q.i.d. as suspension.
Increase weekly to achieve optimal clinical response administered t.i.d. or q.i.d. Maintenance: Ordinarily,
optimal clinical response is achieved at daily doses below 35 mg/kg. If satisfactory clinical response has not
been achieved, plasma levels should be measured to determine whether or not they are in the therapeutic range.
No recommendation regarding the safety of carbamazepine for use at doses above 35 mg/kg/24 hours can be
made.
Combination Therapy: Tegretol may be used alone or with other anticonvulsants. When added to existing
anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are maintained or
gradually decreased, except phenytoin, which may have to be increased (see PRECAUTIONS, Drug
Interactions, and Pregnancy Category D).
Trigeminal Neuralgia (SEE INDICATIONS AND USAGE)
Initial: On the first day, either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for suspension, for a
total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day using increments of 100 mg
every 12 hours for tablets or XR tablets, or 50 mg (1/2 teaspoon) q.i.d. for suspension, only as needed to
achieve freedom from pain. Do not exceed 1200 mg daily. Maintenance: Control of pain can be maintained in
most patients with 400-800 mg daily. However, some patients may be maintained on as little as 200 mg daily,
while others may require as much as 1200 mg daily. At least once every 3 months throughout the treatment
period, attempts should be made to reduce the dose to the minimum effective level or even to discontinue the
drug.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Dosage Information
Initial Dose
Subsequent Dose
Maximum Daily Dose
Indication
Tablet*
XR
†
Suspension
Tablet*
XR
†
Suspension
Tablet*
XR
†
Suspension
Epilepsy
Under 6 yr
10-20 mg/kg/day
b.i.d. or t.i.d.
10-20 mg/kg/day
q.i.d.
Increase weekly
to achieve
optimal clinical
response, t.i.d.
or q.i.d.
Increase
weekly to
achieve optimal
clinical
response, t.i.d.
or q.i.d.
35 mg/kg/24 hr
(see Dosage
and
Administration
section above)
35 mg/kg/24 hr
(see Dosage
and
Administration
section above)
6-12 yr
100 mg b.i.d.
(200 mg/day)
100 mg b.i.d.
(200 mg/day)
½ tsp q.i.d.
(200 mg/day)
Add up to
100 mg/day at
weekly intervals,
t.i.d. or q.i.d.
Add
100 mg/day
at weekly
intervals,
b.i.d.
Add up to 1 tsp
(100 mg)/day at
weekly
intervals, t.i.d.
or q.i.d.
1000 mg/24 hr
Over 12 yr
200 mg b.i.d.
200 mg b.i.d.
1 tsp q.i.d.
Add up to
Add up to
Add up to 2 tsp
1000 mg/24 hr (12-15 yr)
(400 mg/day)
(400 mg/day)
(400 mg/day)
200 mg/day at
200 mg/day
(200 mg)/day at
1200 mg/24 hr (>15 yr)
weekly intervals,
t.i.d. or q.i.d.
at weekly
intervals,
b.i.d.
weekly
intervals, t.i.d.
or q.i.d.
1600 mg/24 hr (adults, in rare instances)
Trigeminal
100 mg b.i.d.
100 mg b.i.d.
½ tsp q.i.d.
Add up to
Add up to
Add up to 2 tsp
1200 mg/24 hr
Neuralgia
(200 mg/day)
(200 mg/day)
(200 mg/day)
200 mg/day in
increments of
100 mg every
12 hr
200 mg/day
in increments
of 100 mg
every 12 hr
(200 mg)/day
in increments
of 50 mg
(½ tsp) q.i.d.
*Tablet = Chewable or conventional tablets
†XR = Tegretol
®-XR extended-release tablets
Reference ID: 2912982
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For current labeling information, please visit https://www.fda.gov/drugsatfda
HOW SUPPLIED
Chewable Tablets 100 mg - round, red-speckled, pink, single-scored (imprinted Tegretol on one side and 52
twice on the scored side)
Bottles of 100............................................................................................................................ NDC 0078-0492-05
Unit Dose (blister pack)
Box of 100 (strips of 10)........................................................................................................... NDC 0078-0492-35
Do not store above 30°C (86°F). Protect from light and moisture.
Dispense in tight, light-resistant container (USP).
Meets USP Dissolution Test 1.
Tablets 200 mg - capsule-shaped, pink, single-scored (imprinted Tegretol on one side and 27 twice on the
partially scored side)
Bottles of 100............................................................................................................................ NDC 0078-0509-05
Do not store above 30°C (86°F). Protect from moisture.
Dispense in tight container (USP).
Meets USP Dissolution Test 2.
XR Tablets 100 mg - round, yellow, coated (imprinted T on one side and 100 mg on the other), release portal on
one side
Bottles of 100............................................................................................................................ NDC 0078-0510-05
XR Tablets 200 mg - round, pink, coated (imprinted T on one side and 200 mg on the other), release portal on
one side
Bottles of 100............................................................................................................................ NDC 0078-0511-05
XR Tablets 400 mg - round, brown, coated (imprinted T on one side and 400 mg on the other), release portal on
one side
Bottles of 100............................................................................................................................ NDC 0078-0512-05
Store at controlled room temperature 15°C-30°C (59°F-86°F). Protect from moisture.
Dispense in tight container (USP).
Suspension 100 mg/5 mL (teaspoon) – yellow-orange, citrus-vanilla flavored
Bottles of 450 mL ..................................................................................................................... NDC 0078-0508-83
Shake well before using.
Do not store above 30°C (86°F). Dispense in tight, light-resistant container (USP).
*Thorazine® is a registered trademark of GlaxoSmithKline.
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
REV: AUGUST 2010
T2010-XX
© Novartis
Reference ID: 2912982
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:40.753305
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/016608s100s102,018281s049s050,018927s041s042,020234s031s033lbl.pdf', 'application_number': 18281, 'submission_type': 'SUPPL ', 'submission_number': 50}
|
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N 016608/S-103
N 018281/S-051
N 020234/S-035
N 018927/S-044
FDA Approved labeling dated 01/16/2014
Page 1
Tegretol®
carbamazepine USP
Chewable Tablets of 100 mg - red-speckled, pink
Tablets of 200 mg – pink
Suspension of 100 mg/5 mL
Tegretol®-XR
(carbamazepine extended-release tablets)
100 mg, 200 mg, 400 mg
Rx only
Prescribing Information
WARNINGS
SERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELE
SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC
EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN
REPORTED DURING TREATMENT WITH TEGRETOL. THESE REACTIONS ARE ESTIMATED TO
OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY CAUCASIAN
POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10
TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG
ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF
HLA-B*1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE. HLA-B*1502 IS FOUND
ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF ASIA.
PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS SHOULD BE SCREENED
FOR THE PRESENCE OF HLA-B*1502 PRIOR TO INITIATING TREATMENT WITH TEGRETOL.
PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH TEGRETOL
UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK (SEE WARNINGS AND PRECAUTIONS,
LABORATORY TESTS).
APLASTIC ANEMIA AND AGRANULOCYTOSIS
APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION WITH
THE USE OF TEGRETOL. DATA FROM A POPULATION-BASED CASE CONTROL STUDY
DEMONSTRATE THAT THE RISK OF DEVELOPING THESE REACTIONS IS 5-8 TIMES GREATER
THAN IN THE GENERAL POPULATION. HOWEVER, THE OVERALL RISK OF THESE REACTIONS
IN THE UNTREATED GENERAL POPULATION IS LOW, APPROXIMATELY SIX PATIENTS PER ONE
MILLION POPULATION PER YEAR FOR AGRANULOCYTOSIS AND TWO PATIENTS PER ONE
MILLION POPULATION PER YEAR FOR APLASTIC ANEMIA.
ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR WHITE
BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE OF TEGRETOL,
Reference ID: 3437567
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Page 2
DATA ARE NOT AVAILABLE TO ESTIMATE ACCURATELY THEIR INCIDENCE OR OUTCOME.
HOWEVER, THE VAST MAJORITY OF THE CASES OF LEUKOPENIA HAVE NOT PROGRESSED TO
THE MORE SERIOUS CONDITIONS OF APLASTIC ANEMIA OR AGRANULOCYTOSIS.
BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC ANEMIA,
THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN MONITORING OF
PATIENTS ON TEGRETOL ARE UNLIKELY TO SIGNAL THE OCCURRENCE OF EITHER
ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT HEMATOLOGICAL TESTING
SHOULD BE OBTAINED AS A BASELINE. IF A PATIENT IN THE COURSE OF TREATMENT
EXHIBITS LOW OR DECREASED WHITE BLOOD CELL OR PLATELET COUNTS, THE PATIENT
SHOULD BE MONITORED CLOSELY. DISCONTINUATION OF THE DRUG SHOULD BE
CONSIDERED IF ANY EVIDENCE OF SIGNIFICANT BONE MARROW DEPRESSION DEVELOPS.
Before prescribing Tegretol, the physician should be thoroughly familiar with the details of this
prescribing information, particularly regarding use with other drugs, especially those which accentuate
toxicity potential.
DESCRIPTION
Tegretol, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for
oral administration as chewable tablets of 100 mg, tablets of 200 mg, XR tablets of 100, 200, and 400 mg, and
as a suspension of 100 mg/5 mL (teaspoon). Its chemical name is 5H-dibenz[b,f ]azepine-5-carboxamide, and
its structural formula is structural formula
Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in alcohol and in
acetone. Its molecular weight is 236.27.
Inactive Ingredients Tablets: Colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake (chewable tablets
only), FD&C Red No. 40 (200-mg tablets only), flavoring (chewable tablets only), gelatin, glycerin, magnesium
stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose (chewable tablets
only). Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate, propylene glycol,
purified water, sorbitol, sucrose, and xanthan gum. Tegretol-XR tablets: cellulose compounds, dextrates, iron
oxides, magnesium stearate, mannitol, polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200-mg
tablets only).
CLINICAL PHARMACOLOGY
In controlled clinical trials, Tegretol has been shown to be effective in the treatment of psychomotor and grand
mal seizures, as well as trigeminal neuralgia.
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Mechanism of Action
Tegretol has demonstrated anticonvulsant properties in rats and mice with electrically and chemically induced
seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation.
Tegretol greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It
depresses thalamic potential and bulbar and polysynaptic reflexes, including the linguomandibular reflex in
cats. Tegretol is chemically unrelated to other anticonvulsants or other drugs used to control the pain of
trigeminal neuralgia. The mechanism of action remains unknown.
The principal metabolite of Tegretol, carbamazepine-10,11-epoxide, has anticonvulsant activity as
demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide has been
postulated, the significance of its activity with respect to the safety and efficacy of Tegretol has not been
established.
Pharmacokinetics
In clinical studies, Tegretol suspension, conventional tablets, and XR tablets delivered equivalent amounts of
drug to the systemic circulation. However, the suspension was absorbed somewhat faster, and the XR tablet
slightly slower, than the conventional tablet. The bioavailability of the XR tablet was 89% compared to
suspension. Following a b.i.d. dosage regimen, the suspension provides higher peak levels and lower trough
levels than those obtained from the conventional tablet for the same dosage regimen. On the other hand,
following a t.i.d. dosage regimen, Tegretol suspension affords steady-state plasma levels comparable to
Tegretol tablets given b.i.d. when administered at the same total mg daily dose. Following a b.i.d. dosage
regimen, Tegretol-XR tablets afford steady-state plasma levels comparable to conventional Tegretol tablets
given q.i.d., when administered at the same total mg daily dose. Tegretol in blood is 76% bound to plasma
proteins. Plasma levels of Tegretol are variable and may range from 0.5-25 µg/mL, with no apparent
relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 µg/mL. In
polytherapy, the concentration of Tegretol and concomitant drugs may be increased or decreased during
therapy, and drug effects may be altered (see PRECAUTIONS, Drug Interactions). Following chronic oral
administration of suspension, plasma levels peak at approximately 1.5 hours compared to 4-5 hours after
administration of conventional Tegretol tablets, and 3-12 hours after administration of Tegretol-XR tablets. The
CSF/serum ratio is 0.22, similar to the 24% unbound Tegretol in serum. Because Tegretol induces its own
metabolism, the half-life is also variable. Autoinduction is completed after 3-5 weeks of a fixed dosing regimen.
Initial half-life values range from 25-65 hours, decreasing to 12-17 hours on repeated doses. Tegretol is
metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the
formation of carbamazepine-10,11-epoxide from Tegretol. After oral administration of 14C-carbamazepine, 72%
of the administered radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was
composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged Tegretol.
The pharmacokinetic parameters of Tegretol disposition are similar in children and in adults. However, there is
a poor correlation between plasma concentrations of carbamazepine and Tegretol dose in children.
Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide (a metabolite shown to be
equipotent to carbamazepine as an anticonvulsant in animal screens) in the younger age groups than in adults. In
children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age (in
one report from 0.44 in children below the age of 1 year to 0.18 in children between 10-15 years of age).
The effects of race and gender on carbamazepine pharmacokinetics have not been systematically evaluated.
Reference ID: 3437567
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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INDICATIONS AND USAGE
Epilepsy
Tegretol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of Tegretol as an
anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure
types:
1. Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures
appear to show greater improvement than those with other types.
2. Generalized tonic-clonic seizures (grand mal).
3. Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence seizures
(petit mal) do not appear to be controlled by Tegretol (see PRECAUTIONS, General).
Trigeminal Neuralgia
Tegretol is indicated in the treatment of the pain associated with true trigeminal neuralgia.
Beneficial results have also been reported in glossopharyngeal neuralgia.
This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.
CONTRAINDICATIONS
Tegretol should not be used in patients with a history of previous bone marrow depression, hypersensitivity to
the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine,
imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with monoamine oxidase
inhibitors is not recommended. Before administration of Tegretol, MAO inhibitors should be discontinued for a
minimum of 14 days, or longer if the clinical situation permits.
Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of
nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with
nefazodone is contraindicated.
WARNINGS
Serious Dermatologic Reactions
Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and
Stevens-Johnson syndrome (SJS), have been reported with Tegretol treatment. The risk of these events is
estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. However, the
risk in some Asian countries is estimated to be about 10 times higher. Tegretol should be discontinued at the
first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this
drug should not be resumed and alternative therapy should be considered.
SJS/TEN and HLA-B*1502 Allele
Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association
between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant
Reference ID: 3437567
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Page 5
of the HLA-B gene, HLA-B*1502. The occurrence of higher rates of these reactions in countries with higher
frequencies of this allele suggests that the risk may be increased in allele-positive individuals of any ethnicity.
Across Asian populations, notable variation exists in the prevalence of HLA-B*1502. Greater than 15% of the
population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared to
about 10% in Taiwan and 4% in North China. South Asians, including Indians, appear to have intermediate
prevalence of HLA-B*1502, averaging 2 to 4%, but higher in some groups. HLA-B*1502 is present in <1% of
the population in Japan and Korea.
HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans,
Hispanics, and Native Americans).
Prior to initiating Tegretol therapy, testing for HLA-B*1502 should be performed in patients with
ancestry in populations in which HLA-B*1502 may be present. In deciding which patients to screen, the
rates provided above for the prevalence of HLA-B*1502 may offer a rough guide, keeping in mind the
limitations of these figures due to wide variability in rates even within ethnic groups, the difficulty in
ascertaining ethnic ancestry, and the likelihood of mixed ancestry. Tegretol should not be used in patients
positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Tested patients who are found to be
negative for the allele are thought to have a low risk of SJS/TEN (see WARNINGS and PRECAUTIONS,
Laboratory Tests).
Over 90% of Tegretol treated patients who will experience SJS/TEN have this reaction within the first few
months of treatment. This information may be taken into consideration in determining the need for screening of
genetically at-risk patients currently on Tegretol.
The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from
Tegretol such as maculopapular eruption (MPE) or to predict Drug Reaction with Eosinophilia and Systemic
Symptoms (DRESS).
Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients
of Chinese ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin.
Consideration should be given to avoiding use of other drugs associated with SJS/TEN in HLA-B*1502
positive patients, when alternative therapies are otherwise equally acceptable.
Hypersensitivity Reactions and HLA-A*3101 Allele
Retrospective case-control studies in patients of European, Korean, and Japanese ancestry have found a
moderate association between the risk of developing hypersensitivity reactions and the presence of HLA
A*3101, an inherited allelic variant of the HLA-A gene, in patients using carbamazepine. These
hypersensitivity reactions include SJS/TEN, maculopapular eruptions, and Drug Reaction with Eosinophilia and
Systemic Symptoms (see DRESS/Multiorgan hypersensitivity below).
HLA-A*3101 is expected to be carried by more than 15% of patients of Japanese, Native American, Southern
Indian (for example, Tamil Nadu) and some Arabic ancestry; up to about 10% in patients of Han Chinese,
Korean, European, Latin American, and other Indian ancestry; and up to about 5% in African-Americans and
patients of Thai, Taiwanese, and Chinese (Hong Kong) ancestry.
The risks and benefits of Tegretol therapy should be weighed before considering Tegretol in patients known to
be positive for HLA-A*3101.
Reference ID: 3437567
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Application of HLA genotyping as a screening tool has important limitations and must never substitute for
appropriate clinical vigilance and patient management. Many HLA-B*1502-positive and HLA-A*3101-positive
patients treated with Tegretol will not develop SJS/TEN or other hypersensitivity reactions, and these reactions
can still occur infrequently in HLA-B*1502-negative and HLA-A*3101-negative patients of any ethnicity. The
role of other possible factors in the development of, and morbidity from, SJS/TEN and other hypersensitivity
reactions, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the
level of dermatologic monitoring, have not been studied.
Aplastic Anemia and Agranulocytosis
Aplastic anemia and agranulocytosis have been reported in association with the use of TEGRETOL (see
BOXED WARNING). Patients with a history of adverse hematologic reaction to any drug may be particularly
at risk of bone marrow depression.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan
hypersensitivity
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan
hypersensitivity, has occurred with Tegretol. Some of these events have been fatal or life-threatening. DRESS
typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other
organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis
sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its
expression, and other organ systems not noted here may be involved. It is important to note that early
manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not
evident. If such signs or symptoms are present, the patient should be evaluated immediately. Tegretol should be
discontinued if an alternative etiology for the signs or symptoms cannot be established.
Hypersensitivity
Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this
reaction to anticonvulsants including phenytoin, primidone, and phenobarbital. If such history is present,
benefits and risks should be carefully considered, and, if carbamazepine is initiated, the signs and symptoms of
hypersensitivity should be carefully monitored.
In patients who have exhibited hypersensitivity reactions to carbamazepine, approximately 25 to 30% may
experience hypersensitivity reactions with oxcarbazepine (Trileptal®).
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Tegretol, increase the risk of suicidal thoughts or behavior in patients
taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for
the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood
or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs
showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk
1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these
trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or
ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated
Reference ID: 3437567
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patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530
patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting
drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in
the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could
not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The
finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests
that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years)
in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
Table 1 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication
Placebo Patients
with Events Per
1,000 Patients
Drug Patients
with Events Per
1,000 Patients
Relative Risk:
Incidence of
Events in Drug
Patients/Incidence
in Placebo
Patients
Risk Difference:
Additional Drug
Patients with
Events Per 1,000
Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials
for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric
indications.
Anyone considering prescribing Tegretol or any other AED must balance the risk of suicidal thoughts or
behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are
themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.
Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the
emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and
behavior and should be advised of the need to be alert for the emergence or worsening of the signs and
symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,
behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare
providers.
General
Tegretol has shown mild anticholinergic activity; therefore, patients with increased intraocular pressure should
be closely observed during therapy.
Reference ID: 3437567
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Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a latent
psychosis and, in elderly patients, of confusion or agitation should be borne in mind.
The use of Tegretol should be avoided in patients with a history of hepatic porphyria (e.g., acute intermittent
porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported in such patients
receiving Tegretol therapy. Carbamazepine administration has also been demonstrated to increase porphyrin
precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria.
As with all antiepileptic drugs, Tegretol should be withdrawn gradually to minimize the potential of increased
seizure frequency.
Usage in Pregnancy
Carbamazepine can cause fetal harm when administered to a pregnant woman.
Epidemiological data suggest that there may be an association between the use of carbamazepine during
pregnancy and congenital malformations, including spina bifida. There have also been reports that associate
carbamazepine with developmental disorders and congenital anomalies (e.g., craniofacial defects,
cardiovascular malformations, hypospadias, and anomalies involving various body systems). Developmental
delays based on neurobehavioral assessments have been reported. In treating or counseling women of
childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against the risks. If
this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should
be apprised of the potential hazard to the fetus.
Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of
teratogenic effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to
be continued, monotherapy may be preferable for pregnant women.
In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is accumulated in
the fetal tissues, with higher levels found in liver and kidney than in brain and lung.
Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in
dosages 10-25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 1.5-4 times
the MHDD on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250 mg/kg and
4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate, 1; talipes, 1; anophthalmos, 2). In
reproduction studies in rats, nursing offspring demonstrated a lack of weight gain and an unkempt appearance at
a maternal dosage level of 200 mg/kg.
Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent
major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and
threat to life. In individual cases where the severity and frequency of the seizure disorder are such that removal
of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior
to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose
some hazard to the developing embryo or fetus.
Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal care
in childbearing women receiving carbamazepine.
There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal
Tegretol and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or
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decreased feeding have also been reported in association with maternal Tegretol use. These symptoms may
represent a neonatal withdrawal syndrome.
To provide information regarding the effects of in utero exposure to Tegretol, physicians are advised to
recommend that pregnant patients taking Tegretol enroll in the North American Antiepileptic Drug (NAAED)
Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by
patients themselves. Information on the registry can also be found at the website
http://www.aedpregnancyregistry.org/.
PRECAUTIONS
General
Before initiating therapy, a detailed history and physical examination should be made.
Tegretol should be used with caution in patients with a mixed seizure disorder that includes atypical absence
seizures, since in these patients Tegretol has been associated with increased frequency of generalized
convulsions (see INDICATIONS AND USAGE).
Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac
conduction disturbance, including second and third degree AV heart block; cardiac, hepatic, or renal damage;
adverse hematologic or hypersensitivity reaction to other drugs, including reactions to other anticonvulsants; or
interrupted courses of therapy with Tegretol.
AV heart block, including second and third degree block, have been reported following Tegretol treatment. This
occurred generally, but not solely, in patients with underlying EKG abnormalities or risk factors for conduction
disturbances.
Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have been
reported (see ADVERSE REACTIONS and PRECAUTIONS, Laboratory Tests). In some cases, hepatic effects
may progress despite discontinuation of the drug. In addition, rare instances of vanishing bile duct syndrome
have been reported. This syndrome consists of a cholestatic process with a variable clinical course ranging from
fulminant to indolent, involving the destruction and disappearance of the intrahepatic bile ducts. Some, but not
all, cases are associated with features that overlap with other immunoallergenic syndromes such as multiorgan
hypersensitivity (DRESS syndrome) and serious dermatologic reactions. As an example there has been a report
of vanishing bile duct syndrome associated with Stevens-Johnson syndrome and in another case an association
with fever and eosinophilia.
Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the
tablet, it is recommended that patients given the suspension be started on lower doses and increased slowly to
avoid unwanted side effects (see DOSAGE AND ADMINISTRATION).
Tegretol suspension contains sorbitol and, therefore, should not be administered to patients with rare hereditary
problems of fructose intolerance.
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Information for Patients
Patients should be informed of the availability of a Medication Guide and they should be instructed to read the
Medication Guide before taking Tegretol.
Patients should be made aware of the early toxic signs and symptoms of a potential hematologic problem, as
well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include, but are not limited to,
fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric
hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be
advised that, because these signs and symptoms may signal a serious reaction, that they must report any
occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms
should be reported even if mild or when occurring after extended use.
Patients should be advised that serious skin reactions have been reported in association with Tegretol. In the
event a skin reaction should occur while taking Tegretol, patients should consult with their physician
immediately (see WARNINGS).
Patients, their caregivers, and families should be counseled that AEDs, including Tegretol, may increase the risk
of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening
of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,
behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare
providers.
Tegretol may interact with some drugs. Therefore, patients should be advised to report to their doctors the use
of any other prescription or nonprescription medications or herbal products.
Caution should be exercised if alcohol is taken in combination with Tegretol therapy, due to a possible additive
sedative effect.
Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of operating
machinery or automobiles or engaging in other potentially dangerous tasks.
Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This
registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients
can call the toll free number 1-888-233-2334 (see WARNINGS, Usage in Pregnancy subsection).
Laboratory Tests
For genetically at-risk patients (see WARNINGS), high-resolution ‘HLA-B*1502 typing’ is recommended. The
test is positive if either one or two HLA-B*1502 alleles are detected and negative if no HLA-B*1502 alleles are
detected.
Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, should be
obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white blood cell or
platelet counts, the patient should be monitored closely. Discontinuation of the drug should be considered if any
evidence of significant bone marrow depression develops.
Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must
be performed during treatment with this drug since liver damage may occur (see PRECAUTIONS, General and
ADVERSE REACTIONS). Carbamazepine should be discontinued, based on clinical judgment, if indicated by
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newly occurring or worsening clinical or laboratory evidence of liver dysfunction or hepatic damage, or in the
case of active liver disease.
Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are recommended
since many phenothiazines and related drugs have been shown to cause eye changes.
Baseline and periodic complete urinalysis and BUN determinations are recommended for patients treated with
this agent because of observed renal dysfunction.
Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and safety of
anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in seizure frequency
and for verification of compliance. In addition, measurement of drug serum levels may aid in determining the
cause of toxicity when more than one medication is being used.
Thyroid function tests have been reported to show decreased values with Tegretol administered alone.
Hyponatremia has been reported in association with Tegretol use, either alone or in combination with other
drugs.
Interference with some pregnancy tests has been reported.
Drug Interactions
There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting
Tegretol suspension immediately followed by Thorazine®* solution. Subsequent testing has shown that mixing
Tegretol suspension and chlorpromazine solution (both generic and brand name) as well as Tegretol suspension
and liquid Mellaril® resulted in the occurrence of this precipitate. Because the extent to which this occurs with
other liquid medications is not known, Tegretol suspension should not be administered simultaneously with
other liquid medicinal agents or diluents (see DOSAGE AND ADMINISTRATION).
Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not
limited to, the following:
Agents That May Affect Tegretol Plasma Levels
When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring
of carbamazepine levels is indicated and dosage adjustment may be required.
Agents That Increase Carbamazepine Levels
CYP 3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma carbamazepine levels. Drugs that
have been shown, or would be expected, to increase plasma carbamazepine levels include:
Aprepitant, cimetidine, ciprofloxacin, danazol, diltiazem, macrolides, erythromycin, troleandomycin,
clarithromycin, fluoxetine, fluvoxamine, nefazodone, trazodone, loxapine,* olanzapine, quetiapine*,
loratadine, terfenadine, omeprazole, oxybutynin, dantrolene, isoniazid, niacinamide, nicotinamide,
ibuprofen, propoxyphene, azoles (e.g., ketaconazole, itraconazole, fluconazole, voriconazole),
acetazolamide, verapamil, ticlopidine, grapefruit juice, protease inhibitors, valproate*.
Agents That Decrease Carbamazepine Levels
CYP 3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that would be
expected, to decrease plasma carbamazepine levels include:
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cisplatin, doxorubicin HCl, felbamate†, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone,
methsuximide, theophylline, aminophylline.
*increased levels of the active carbamazepine-10,11-epoxide
†decreased levels of carbamazepine and increased levels of the 10,11-epoxide
Effect of Tegretol on Plasma Levels of Concomitant Agents
Decreased Levels of Concomitant Medications
Tegretol is a potent inducer of hepatic CYP 3A4 and may therefore reduce plasma concentrations of
comedications mainly metabolized by CYP3A4 through induction of their metabolism. Tegretol causes, or
would be expected to cause, decreased levels of the following:
acetaminophen, albendazole, alprazolam, aprepitant, buprenorphone, bupropion, citalopram,
clonazepam, clozapine, corticosteroids (e.g., prednisolone, dexamethasone), cyclosporine, dicumarol,
dihydropyridine calcium channel blockers (e.g., felodipine), doxycycline, ethosuximide, everolimus,
haloperidol, imatinib, itraconazole, lamotrigine, levothyroxine, methadone, methsuximide, mianserin,
midazolam, olanzapine, oral and other hormonal contraceptives, oxcarbazepine, paliperidone,
phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone, sertaline, sirolimus, tadalafil,
theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants (e.g., imipramine,
amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, zonisamide.
In concomitant use with Tegretol, monitoring of concentrations or dosage adjustment of the above agents may
be necessary.
Cyclophosphamide is an inactive prodrug and is converted to its active metabolite in part by CYP3A. The rate
of metabolism and the leukopenic activity of cyclophosphamide reportedly are increased by chronic
administration of high doses of another CYP3A4 inducer. There is a potential for increased cyclophosphamide
toxicity when coadministered with carbamazepine.
When carbamazepine is added to aripiprazole therapy, the aripiprazole dose should be doubled. Additional dose
increases should be based on clinical evaluation. When carbamazepine is withdrawn from the combination
therapy, the aripiprazole dose should be reduced.
When carbamazepine is used with tacrolimus, monitoring of tacrolimus blood concentrations and appropriate
dosage adjustments are recommended.
The use of concomitant strong CYP3A4 inducers such as carbamazepine should be avoided with temsirolimus.
Based on pharmacokinetic studies, if patients must be co-administered carbamazepine with temsirolimus, an
adjustment of temsirolimus dosage should be considered.
The use of carbamazepine with lapatinib should generally be avoided. Dosage adjustment should be considered
if lapatinib is coadministered with carbamazepine. If carbamazepine is started in a patient already taking
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lapatinib, the dose of lapatinib should be gradually titrated up. If carbamazepine is discontinued, the lapatinib
dose should be reduced.
Coadministration of carbamazepine with nefazodone results in insufficient plasma concentrations of nefazodone
and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is
contraindicated (see CONTRAINDICATIONS).
Other Drug Interactions
Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects.
Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced
hepatotoxicity.
Concomitant medication with Tegretol and some diuretics (hydrochlorothiazide, furosemide) may lead to
symptomatic hyponatremia.
Alterations of thyroid function have been reported in combination therapy with other anticonvulsant
medications.
Concomitant use of Tegretol with hormonal contraceptive products (e.g., oral, and levonorgestrel subdermal
implant contraceptives) may render the contraceptives less effective because the plasma concentrations of the
hormones may be decreased. Breakthrough bleeding and unintended pregnancies have been reported.
Alternative or back-up methods of contraception should be considered.
Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents
pancuronium, vecuronium, rocuronium and cisatracurium has occurred in patients chronically administered
carbamazepine. Whether or not carbamazepine has the same effect on other non-depolarizing agents is
unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than
expected, and infusion rate requirements may be higher.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75, and
250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular tumors in females and of
benign interstitial cell adenomas in the testes of males.
Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Bacterial and
mammalian mutagenicity studies using carbamazepine produced negative results. The significance of these
findings relative to the use of carbamazepine in humans is, at present, unknown.
Usage in Pregnancy
Pregnancy Category D (see WARNINGS).
Labor and Delivery
The effect of Tegretol on human labor and delivery is unknown.
Nursing Mothers
Tegretol and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in breast milk
to that in maternal plasma is about 0.4 for Tegretol and about 0.5 for the epoxide. The estimated doses given to
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the newborn during breast-feeding are in the range of 2-5 mg daily for Tegretol and 1-2 mg daily for the
epoxide.
Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a decision should
be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the
drug to the mother.
Pediatric Use
Substantial evidence of Tegretol’s effectiveness for use in the management of children with epilepsy (see
INDICATIONS AND USAGE for specific seizure types) is derived from clinical investigations performed in
adults and from studies in several in vitro systems which support the conclusion that (1) the pathogenetic
mechanisms underlying seizure propagation are essentially identical in adults and children, and (2) the
mechanism of action of carbamazepine in treating seizures is essentially identical in adults and children.
Taken as a whole, this information supports a conclusion that the generally accepted therapeutic range of total
carbamazepine in plasma (i.e., 4-12 mcg/mL) is the same in children and adults.
The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety of
carbamazepine in children has been systematically studied up to 6 months. No longer-term data from clinical
trials is available.
Geriatric Use
No systematic studies in geriatric patients have been conducted.
ADVERSE REACTIONS
If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that
abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead to seizures or even
status epilepticus with its life-threatening hazards.
The most severe adverse reactions have been observed in the hemopoietic system and skin (see BOXED
WARNING), the liver, and the cardiovascular system.
The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness,
drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should
be initiated at the low dosage recommended.
The following additional adverse reactions have been reported:
Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression,
thrombocytopenia, leukopenia, leukocytosis, eosinophilia, anemia, acute intermittent porphyria, variegate
porphyria, porphyria cutanea tarda.
Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXED WARNING),
Acute Generalized Exanthematous Pustulosis (AGEP), pruritic and erythematous rashes, urticaria,
photosensitivity reactions, alterations in skin pigmentation, exfoliative dermatitis, erythema multiforme and
nodosum, purpura, aggravation of disseminated lupus erythematosus, alopecia, diaphoresis and onychomadesis.
In certain cases, discontinuation of therapy may be necessary. Isolated cases of hirsutism have been reported,
but a causal relationship is not clear.
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Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope
and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis,
thromboembolism (e.g., pulmonary embolism), and adenopathy or lymphadenopathy.
Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been
associated with other tricyclic compounds.
Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very rare cases of
hepatic failure.
Pancreatic: Pancreatitis.
Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia.
Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood pressure,
azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and microscopic deposits in the
urine have also been reported. There have been very rare reports of impaired male fertility and/or abnormal
spermatogenesis.
Testicular atrophy occurred in rats receiving Tegretol orally from 4-52 weeks at dosage levels of 50-400
mg/kg/day. Additionally, rats receiving Tegretol in the diet for 2 years at dosage levels of 25, 75, and 250
mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a
brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg and
higher. Relevance of these findings to humans is unknown.
Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred
vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances,
abnormal involuntary movements, peripheral neuritis and paresthesias, depression with agitation, talkativeness,
tinnitus, hyperacusis, neuroleptic malignant syndrome.
There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the
exact relationship of these reactions to the drug has not been established.
Isolated cases of neuroleptic malignant syndrome have been reported both with and without concomitant use of
psychotropic drugs.
Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia, and
dryness of the mouth and pharynx, including glossitis and stomatitis.
Eyes: Scattered punctate cortical lens opacities, increased intraocular pressure as well as conjunctivitis, have
been reported. Although a direct causal relationship has not been established, many phenothiazines and related
drugs have been shown to cause eye changes.
Musculoskeletal System: Aching joints and muscles, and leg cramps.
Metabolism: Fever and chills. Inappropriate antidiuretic hormone (ADH) secretion syndrome has been reported.
Cases of frank water intoxication, with decreased serum sodium (hyponatremia) and confusion, have been
reported in association with Tegretol use (see PRECAUTIONS, Laboratory Tests). Decreased levels of plasma
calcium leading to osteoporosis have been reported.
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Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional reports
of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants.
A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a
patient taking carbamazepine in combination with other medications. The patient was successfully
dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.
DRUG ABUSE AND DEPENDENCE
No evidence of abuse potential has been associated with Tegretol, nor is there evidence of psychological or
physical dependence in humans.
OVERDOSAGE
Acute Toxicity
Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-old man
died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a cardiac arrest), 1.6 g
(a 3-year-old girl died of aspiration pneumonia).
Oral LD50 in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-2680; guinea pigs, 920.
Signs and Symptoms
The first signs and symptoms appear after 1-3 hours. Neuromuscular disturbances are the most prominent.
Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high
doses (>60 g) have been ingested.
Respiration: Irregular breathing, respiratory depression.
Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders.
Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma. Convulsions,
especially in small children. Motor restlessness, muscular twitching, tremor, athetoid movements, opisthotonos,
ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism, psychomotor disturbances,
dysmetria. Initial hyperreflexia, followed by hyporeflexia.
Gastrointestinal Tract: Nausea, vomiting.
Kidneys and Bladder: Anuria or oliguria, urinary retention.
Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte count,
glycosuria, and acetonuria. EEG may show dysrhythmias.
Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same
time, the signs and symptoms of acute poisoning with Tegretol may be aggravated or modified.
Treatment
The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which
may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps to diminish
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absorption. If these measures cannot be implemented without risk on the spot, the patient should be transferred
at once to a hospital, while ensuring that vital functions are safeguarded. There is no specific antidote.
Elimination of the Drug: Induction of vomiting.
Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the stomach should
be repeatedly irrigated, especially if the patient has also consumed alcohol.
Measures to Reduce Absorption: Activated charcoal, laxatives.
Measures to Accelerate Elimination: Forced diuresis.
Dialysis is indicated only in severe poisoning associated with renal failure. Replacement transfusion is indicated
in severe poisoning in small children.
Respiratory Depression: Keep the airways free; resort, if necessary, to endotracheal intubation, artificial
respiration, and administration of oxygen.
Hypotension, Shock: Keep the patient’s legs raised and administer a plasma expander. If blood pressure fails to
rise despite measures taken to increase plasma volume, use of vasoactive substances should be considered.
Convulsions: Diazepam or barbiturates.
Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children), hypotension,
and coma. However, barbiturates should not be used if drugs that inhibit monoamine oxidase have also been
taken by the patient either in overdosage or in recent therapy (within 1 week).
Surveillance: Respiration, cardiac function (ECG monitoring), blood pressure, body temperature, pupillary
reflexes, and kidney and bladder function should be monitored for several days.
Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression develops, the
following recommendations are suggested: (1) stop the drug, (2) perform daily CBC, platelet, and reticulocyte
counts, (3) do a bone marrow aspiration and trephine biopsy immediately and repeat with sufficient frequency
to monitor recovery.
Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2) 59Fe-ferrokinetic
studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and peripheral blood, (5) bone
marrow culture studies for colony-forming units, (6) hemoglobin electrophoresis for A2 and F hemoglobin, and
(7) serum folic acid and B12 levels.
A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which
specialized consultation should be sought.
DOSAGE AND ADMINISTRATION (SEE TABLE BELOW)
Tegretol suspension in combination with liquid chlorpromazine or thioridazine results in precipitate formation,
and, in the case of chlorpromazine, there has been a report of a patient passing an orange rubbery precipitate in
the stool following coadministration of the two drugs (see PRECAUTIONS, Drug Interactions). Because the
extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be
administered simultaneously with other liquid medications or diluents.
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Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see PRECAUTIONS,
Laboratory Tests). Dosage should be adjusted to the needs of the individual patient. A low initial daily dosage
with a gradual increase is advised. As soon as adequate control is achieved, the dosage may be reduced very
gradually to the minimum effective level. Medication should be taken with meals.
Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the
tablet, it is recommended to start with low doses (children 6-12 years: 1/2 teaspoon q.i.d.) and to increase
slowly to avoid unwanted side effects.
Conversion of patients from oral Tegretol tablets to Tegretol suspension: Patients should be converted by
administering the same number of mg per day in smaller, more frequent doses (i.e., b.i.d. tablets to t.i.d.
suspension).
Tegretol-XR is an extended-release formulation for twice-a-day administration. When converting patients from
Tegretol conventional tablets to Tegretol-XR, the same total daily mg dose of Tegretol-XR should be
administered. Tegretol-XR tablets must be swallowed whole and never crushed or chewed. Tegretol-XR
tablets should be inspected for chips or cracks. Damaged tablets, or tablets without a release portal, should not
be consumed. Tegretol-XR tablet coating is not absorbed and is excreted in the feces; these coatings may be
noticeable in the stool.
Epilepsy (SEE INDICATIONS AND USAGE)
Adults and children over 12 years of age - Initial: Either 200 mg b.i.d. for tablets and XR tablets, or 1 teaspoon
q.i.d. for suspension (400 mg/day). Increase at weekly intervals by adding up to 200 mg/day using a b.i.d.
regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is
obtained. Dosage generally should not exceed 1000 mg daily in children 12-15 years of age, and 1200 mg daily
in patients above 15 years of age. Doses up to 1600 mg daily have been used in adults in rare instances.
Maintenance: Adjust dosage to the minimum effective level, usually 800-1200 mg daily.
Children 6-12 years of age - Initial: Either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for
suspension (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a b.i.d. regimen of
Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is obtained. Dosage
generally should not exceed 1000 mg daily. Maintenance: Adjust dosage to the minimum effective level,
usually 400-800 mg daily.
Children under 6 years of age - Initial: 10-20 mg/kg/day b.i.d. or t.i.d. as tablets, or q.i.d. as suspension.
Increase weekly to achieve optimal clinical response administered t.i.d. or q.i.d. Maintenance: Ordinarily,
optimal clinical response is achieved at daily doses below 35 mg/kg. If satisfactory clinical response has not
been achieved, plasma levels should be measured to determine whether or not they are in the therapeutic range.
No recommendation regarding the safety of carbamazepine for use at doses above 35 mg/kg/24 hours can be
made.
Combination Therapy: Tegretol may be used alone or with other anticonvulsants. When added to existing
anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are maintained or
gradually decreased, except phenytoin, which may have to be increased (see PRECAUTIONS, Drug
Interactions, and Pregnancy Category D).
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N 016608/S-103
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Trigeminal Neuralgia (SEE INDICATIONS AND USAGE)
Initial: On the first day, either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for suspension, for a
total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day using increments of 100 mg
every 12 hours for tablets or XR tablets, or 50 mg (1/2 teaspoon) q.i.d. for suspension, only as needed to
achieve freedom from pain. Do not exceed 1200 mg daily. Maintenance: Control of pain can be maintained in
most patients with 400-800 mg daily. However, some patients may be maintained on as little as 200 mg daily,
while others may require as much as 1200 mg daily. At least once every 3 months throughout the treatment
period, attempts should be made to reduce the dose to the minimum effective level or even to discontinue the
drug.
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Dosage Information
Initial Dose
Subsequent Dos
e
Maximum Dail y Dose
Indication
Tablet*
XR
†
Suspension
Tablet*
XR
†
Suspension
Tablet*
XR
†
Suspension
Epileps
y
Under 6 yr
10-20 mg/kg/day
10-20 mg/kg/day
Increase weekl y
Increase
35 mg/kg/24 hr
35 mg/kg/24 hr
b.i.d. or t.i.d.
q.i.d.
to achieve
weekly to
(see Dosage
(see Dosage
optimal clinical
achieve optimal
and
and
response, t.i.d.
clinical
Administration
Administration
or q.i.d.
response, t.i.d.
section above)
section above)
or q.i.d.
6-12 yr
100 mg b.i.d.
100 mg b.i.d.
½ tsp q.i.d.
Add up to
Add
Add up to 1 tsp
1000 mg/24 h r
(200 mg/day)
(200 mg/day)
(200 mg/day)
100 mg/day at
100 mg/da y
(100 mg)/day at
weekly intervals,
at weekl y
weekl y
t.i.d. or q.i.d.
intervals,
intervals, t.i.d.
b.i.d.
or q.i.d.
Over 12 yr
200 mg b.i.d.
200 mg b.i.d.
1 tsp q.i.d.
Add up to
Add up to
Add up to 2 tsp
1000 mg/24 hr (12-15 yr)
(400 mg/day)
(400 mg/day)
(400 mg/day)
200 mg/day at
200 mg/da y
(200 mg)/day at
1200 mg/24 hr (>15 yr)
weekly intervals,
at weekl y
weekl y
1600 mg/24 hr (adults, in rare instances)
t.i.d. or q.i.d.
intervals,
intervals, t.i.d.
b.i.d.
or q.i.d.
Trigeminal
100 mg b.i.d.
100 mg b.i.d.
½ tsp q.i.d.
Add up to
Add up to
Add up to 2 tsp
1200 mg/24 h r
Neuralgia
(200 mg/day)
(200 mg/day)
(200 mg/day)
200 mg/day in
200 mg/da y
(200 mg)/day
increments of
in increments
in increments
100 mg every
of 100 mg
of 50 mg
12 hr
every 12 hr
(½ tsp) q.i.d.
*Tablet = Chewable or conventional tablets
†XR = Tegretol
®-XR extended-release tablets
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HOW SUPPLIED
Chewable Tablets 100 mg - round, red-speckled, pink, single-scored (imprinted Tegretol on one side and 52
twice on the scored side)
Bottles of 100 ............................................................................................................................ NDC 0078-0492-05
Unit Dose (blister pack)
Box of 100 (strips of 10) ........................................................................................................... NDC 0078-0492-35
Do not store above 30°C (86°F). Protect from light and moisture.
Dispense in tight, light-resistant container (USP).
Meets USP Dissolution Test 1.
Tablets 200 mg - capsule-shaped, pink, single-scored (imprinted Tegretol on one side and 27 twice on the
partially scored side)
Bottles of 100 ............................................................................................................................ NDC 0078-0509-05
Do not store above 30°C (86°F). Protect from moisture.
Dispense in tight container (USP).
Meets USP Dissolution Test 2.
XR Tablets 100 mg - round, yellow, coated (imprinted T on one side and 100 mg on the other), release portal on
one side
Bottles of 100 ............................................................................................................................ NDC 0078-0510-05
XR Tablets 200 mg - round, pink, coated (imprinted T on one side and 200 mg on the other), release portal on
one side
Bottles of 100 ............................................................................................................................ NDC 0078-0511-05
XR Tablets 400 mg - round, brown, coated (imprinted T on one side and 400 mg on the other), release portal on
one side
Bottles of 100 ............................................................................................................................ NDC 0078-0512-05
Store at controlled room temperature 15°C-30°C (59°F-86°F). Protect from moisture.
Dispense in tight container (USP).
Suspension 100 mg/5 mL (teaspoon) – yellow-orange, citrus-vanilla flavored
Bottles of 450 mL ..................................................................................................................... NDC 0078-0508-83
Shake well before using.
Do not store above 30°C (86°F). Dispense in tight, light-resistant container (USP).
*Thorazine® is a registered trademark of GlaxoSmithKline.
T20XX-XX
January 2014
Reference ID: 3437567
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MEDICATION GUIDE
TEGRETOL® and TEGRETOL®-XR (Teg-ret-ol)
(carbamazepine)
Tablets, Suspension, Chewable Tablets, Extended-Release Tablets
Read this Medication Guide before you start taking Tegretol or Tegretol –XR (TEGRETOL) and each time you
get a refill. There may be new information. This information does not take the place of talking to your
healthcare provider about your medical condition or treatment.
What is the most important information I should know about TEGRETOL?
Do not stop taking TEGRETOL without first talking to your healthcare provider.
Stopping TEGRETOL suddenly can cause serious problems.
TEGRETOL can cause serious side effects, including:
1. TEGRETOL may cause rare but serious skin rashes that may lead to death. These serious skin
reactions are more likely to happen when you begin taking TEGRETOL within the first four
months of treatment but may occur at later times. These reactions can happen in anyone, but
are more likely in people of Asian descent. If you are of Asian descent, you may need a genetic
blood test before you take TEGRETOL to see if you are at a higher risk for serious skin
reactions with this medicine. Symptoms may include:
skin rash
hives
sores in your mouth
blistering or peeling of the skin
2. TEGRETOL may cause rare but serious blood problems. Symptoms may include:
fever, sore throat, or other infections that come and go or do not go away
easy bruising
red or purple spots on your body
bleeding gums or nose bleeds
severe fatigue or weakness
3. Like other antiepileptic drugs, TEGRETOL may cause suicidal thoughts or actions in a very
small number of people, about 1 in 500.
Call your healthcare provider right away if you have any of these symptoms, especially if they
are new, worse, or worry you:
thoughts about suicide or dying
attempts to commit suicide
new or worse depression
new or worse anxiety
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feeling agitated or restless
panic attacks
trouble sleeping (insomnia)
new or worse irritability
acting aggressive, being angry, or violent
acting on dangerous impulses
an extreme increase in activity and talking (mania)
other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
Do not stop TEGRETOL without first talking to a healthcare provider.
Stopping TEGRETOL suddenly can cause serious problems. You should talk to your healthcare
provider before stopping.
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts
or actions, your healthcare provider may check for other causes.
What is TEGRETOL?
TEGRETOL is a prescription medicine used to treat:
certain types of seizures (partial, tonic-clonic, mixed)
certain types of nerve pain (trigeminal and glossopharyngeal neuralgia)
TEGRETOL is not a regular pain medicine and should not be used for aches or pains.
Who should not take TEGRETOL?
Do not take TEGRETOL if you:
have a history of bone marrow depression.
are allergic to carbamazepine or any of the ingredients in TEGRETOL. See the end of this Medication
Guide for a complete list of ingredients in TEGRETOL.
take nefazodone.
are allergic to medicines called tricyclic antidepressants (TCAs). Ask your healthcare provider or
pharmacist for a list of these medicines if you are not sure.
have taken a medicine called a Monoamine Oxidase Inhibitor (MAOI) in the last 14 days. Ask your
healthcare provider or pharmacist for a list of these medicines if you are not sure.
What should I tell my healthcare provider before taking TEGRETOL?
Before you take TEGRETOL, tell your healthcare provider if you:
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have or have had suicidal thoughts or actions, depression, or mood problems
have or ever had heart problems
have or ever had blood problems
have or ever had liver problems
have or ever had kidney problems
have or ever had allergic reactions to medicines
have or ever had increased pressure in your eye
have any other medical conditions
drink grapefruit juice or eat grapefruit
use birth control. TEGRETOL may make your birth control less effective. Tell your healthcare
provider if your menstrual bleeding changes while you take birth control and TEGRETOL.
are pregnant or plan to become pregnant. TEGRETOL may harm your unborn baby. Tell your
healthcare provider right away if you become pregnant while taking TEGRETOL. You and your
healthcare provider should decide if you should take TEGRETOL while you are pregnant.
▪ If you become pregnant while taking TEGRETOL, talk to your healthcare provider about registering
with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this
registry is to collect information about the safety of antiepileptic medicine during pregnancy. You can
enroll in this registry by calling 1-888-233-2334.
are breastfeeding or plan to breastfeed. TEGRETOL passes into breast milk. You and your healthcare
provider should discuss whether you should take TEGRETOL or breastfeed; you should not do both.
Tell your healthcare provider about all the medicines you take, including prescription and non-prescription
medicines, vitamins, and herbal supplements.
Taking TEGRETOL with certain other medicines may cause side effects or affect how well they work. Do not
start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when
you get a new medicine.
How should I take TEGRETOL?
Do not stop taking TEGRETOL without first talking to your healthcare provider. Stopping TEGRETOL
suddenly can cause serious problems. Stopping seizure medicine suddenly in a patient who has epilepsy
may cause seizures that will not stop (status epilepticus).
Take TEGRETOL exactly as prescribed. Your healthcare provider will tell you how much TEGRETOL to
take.
Your healthcare provider may change your dose. Do not change your dose of TEGRETOL without talking
to your healthcare provider.
Take TEGRETOL with food.
Reference ID: 3437567
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TEGRETOL-XR Tablets:
Do not crush, chew, or break TEGRETOL-XR tablets.
Tell you healthcare provider if you can not swallow TEGRETOL-XR whole.
TEGRETOL Suspension:
Shake the bottle well each time before use.
Do not take TEGRETOL suspension at the same time you take other liquid medicines.
If you take too much TEGRETOL, call your healthcare provider or local Poison Control Center right away.
What should I avoid while taking TEGRETOL?
Do not drink alcohol or take other drugs that make you sleepy or dizzy while taking TEGRETOL until
you talk to your healthcare provider. TEGRETOL taken with alcohol or drugs that cause sleepiness or
dizziness may make your sleepiness or dizziness worse.
Do not drive, operate heavy machinery, or do other dangerous activities until you know how
TEGRETOL affects you. TEGRETOL may slow your thinking and motor skills.
What are the possible side effects of TEGRETOL?
See “What is the most important information I should know about TEGRETOL?”
TEGRETOL may cause other serious side effects. These include:
Irregular heartbeat - symptoms include:
o Fast, slow, or pounding heartbeat
o Shortness of breath
o Feeling lightheaded
o Fainting
Liver problems - symptoms include:
o yellowing of your skin or the whites of your eyes
o dark urine
o pain on the right side of your stomach area (abdominal pain)
o easy bruising
o loss of appetite
o nausea or vomiting
Get medical help right away if you have any of the symptoms listed above or listed in “What is the most
important information I should know about TEGRETOL”.
The most common side effects of TEGRETOL include:
Reference ID: 3437567
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dizziness
drowsiness
problems with walking and coordination (unsteadiness)
nausea
vomiting
These are not all the possible side effects of TEGRETOL. For more information, ask your healthcare provider
or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA
1088.
How should I store TEGRETOL?
Do not store TEGRETOL Tablets above 30°C (86°F).
Keep TEGRETOL Tablets dry.
Do not store TEGRETOL Chewable Tablets above 30°C (86°F).
Keep TEGRETOL Chewable Tablets out of the light.
Keep TEGRETOL Chewable Tablets dry.
Store TEGRETOL-XR Tablets between 15°C to 30°C (59°F to 86°F).
Keep TEGRETOL-XR Tablets dry.
Do not store TEGRETOL Suspension above 30°C (86°F).
Shake well before using.
Keep TEGRETOL Suspension in a tight, light-resistant container.
Keep TEGRETOL and all medicines out of the reach of children.
General Information about TEGRETOL
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
TEGRETOL for a condition for which it was not prescribed. Do not give TEGRETOL to other people, even if
they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about TEGRETOL. If you would like more
information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for the full
prescribing information about TEGRETOL that is written for health professionals.
For more information, go to www.pharma.us.novartis.com or call 1-888-669-6682.
What are the ingredients in TEGRETOL?
Active ingredient: carbamazepine
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Inactive ingredients:
TEGRETOL Tablets: colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake (chewable tablets
only), FD&C Red No. 40 (200-mg tablets only), flavoring (chewable tablets only), gelatin, glycerin,
magnesium stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose
(chewable tablets only).
TEGRETOL Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate,
propylene glycol, purified water, sorbitol, sucrose, and xanthan gum.
TEGRETOL-XR Tablets: cellulose compounds, dextrates, iron oxides, magnesium stearate, mannitol,
polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200-mg tablets only).
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
T20XX-XX/T2013-24
January 2014/March 2013
Reference ID: 3437567
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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NDA 016608/S‐105
NDA 018281/S‐053
NDA 018927/S‐046
NDA 020234/S‐038
FDA Approved labeling dated 02/15/2013
Page 1
Tegretol®
carbamazepine USP
Chewable Tablets of 100 mg - red-speckled, pink
Tablets of 200 mg – pink
Suspension of 100 mg/5 mL
Tegretol®-XR
(carbamazepine extended-release tablets)
100 mg, 200 mg, 400 mg
Rx only
Prescribing Information
WARNINGS
SERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELE
SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC
EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN
REPORTED DURING TREATMENT WITH TEGRETOL. THESE REACTIONS ARE ESTIMATED TO
OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY CAUCASIAN
POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10
TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG
ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF
HLA-B*1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE. HLA-B*1502 IS FOUND
ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF ASIA.
PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS SHOULD BE SCREENED
FOR THE PRESENCE OF HLA-B*1502 PRIOR TO INITIATING TREATMENT WITH TEGRETOL.
PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH TEGRETOL
UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK (SEE WARNINGS AND PRECAUTIONS,
LABORATORY TESTS).
APLASTIC ANEMIA AND AGRANULOCYTOSIS
Reference ID: 3262556
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For current labeling information, please visit https://www.fda.gov/drugsatfda
structural formula
NDA 016608/S‐105
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FDA Approved labeling dated 02/15/2013
Page 2
APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION WITH
THE USE OF TEGRETOL. DATA FROM A POPULATION-BASED CASE CONTROL STUDY
DEMONSTRATE THAT THE RISK OF DEVELOPING THESE REACTIONS IS 5-8 TIMES GREATER
THAN IN THE GENERAL POPULATION. HOWEVER, THE OVERALL RISK OF THESE REACTIONS
IN THE UNTREATED GENERAL POPULATION IS LOW, APPROXIMATELY SIX PATIENTS PER ONE
MILLION POPULATION PER YEAR FOR AGRANULOCYTOSIS AND TWO PATIENTS PER ONE
MILLION POPULATION PER YEAR FOR APLASTIC ANEMIA.
ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR WHITE
BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE OF TEGRETOL,
DATA ARE NOT AVAILABLE TO ESTIMATE ACCURATELY THEIR INCIDENCE OR OUTCOME.
HOWEVER, THE VAST MAJORITY OF THE CASES OF LEUKOPENIA HAVE NOT PROGRESSED TO
THE MORE SERIOUS CONDITIONS OF APLASTIC ANEMIA OR AGRANULOCYTOSIS.
BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC ANEMIA,
THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN MONITORING OF
PATIENTS ON TEGRETOL ARE UNLIKELY TO SIGNAL THE OCCURRENCE OF EITHER
ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT HEMATOLOGICAL TESTING
SHOULD BE OBTAINED AS A BASELINE. IF A PATIENT IN THE COURSE OF TREATMENT
EXHIBITS LOW OR DECREASED WHITE BLOOD CELL OR PLATELET COUNTS, THE PATIENT
SHOULD BE MONITORED CLOSELY. DISCONTINUATION OF THE DRUG SHOULD BE
CONSIDERED IF ANY EVIDENCE OF SIGNIFICANT BONE MARROW DEPRESSION DEVELOPS.
Before prescribing Tegretol, the physician should be thoroughly familiar with the details of this
prescribing information, particularly regarding use with other drugs, especially those which accentuate
toxicity potential.
DESCRIPTION
Tegretol, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for
oral administration as chewable tablets of 100 mg, tablets of 200 mg, XR tablets of 100, 200, and 400 mg, and
as a suspension of 100 mg/5 mL (teaspoon). Its chemical name is 5H-dibenz[b,f ]azepine-5-carboxamide, and
its structural formula is
Reference ID: 3262556
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NDA 016608/S‐105
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FDA Approved labeling dated 02/15/2013
Page 3
Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in alcohol and in
acetone. Its molecular weight is 236.27.
Inactive Ingredients Tablets: Colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake (chewable tablets
only), FD&C Red No. 40 (200-mg tablets only), flavoring (chewable tablets only), gelatin, glycerin, magnesium
stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose (chewable tablets
only). Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate, propylene glycol,
purified water, sorbitol, sucrose, and xanthan gum. Tegretol-XR tablets: cellulose compounds, dextrates, iron
oxides, magnesium stearate, mannitol, polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200-mg
tablets only).
CLINICAL PHARMACOLOGY
In controlled clinical trials, Tegretol has been shown to be effective in the treatment of psychomotor and gran d
mal seizures, as well as trigeminal neuralgia.
Mechanism of Action
Tegretol has demonstrated anticonvulsant properties in rats and mice with electrically and chemically induced
seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation.
Tegretol greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It
depresses thalamic poten tial and bulbar and polysynaptic reflexes, including the linguomandibular reflex in
cats. Tegretol is chemica lly unrelated to other anticonvulsants or other drugs used to control the pain of
trigeminal neuralgia. The mechanism of action remains unknown.
The principal metabolite of Tegretol, carbamazepine-10,11-epoxide, has anticonvulsant activity as
demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide has been
postulated, the significance of its activity with respect to the safety and efficacy of Tegretol has not been
established.
Pharmacokinetics
In clinical studies, Tegretol suspension, conventional tablets, and XR tablets delivered equivalent amounts of
drug to the systemic circulation. However, the suspension was absorbed somewhat faster, and the XR tablet
slightly slower, than the conventional tablet. The bioavailability of the XR tablet was 89% compared to
suspension. Following a b.i.d. dosage regimen, the suspension provides higher peak levels and lower troug h
levels than those obtained from the conventional tablet for the same dosage regimen. On the other hand,
following a t.i.d. dosage regimen, Tegretol suspension affords steady-state plasma levels comparable to
Tegretol tablets given b.i.d. when administered at the same total mg daily dose. Following a b.i.d. dosage
regimen, Tegretol-XR tablets afford steady-state plasma levels comparable to conventional Tegretol tablets
given q.i.d., when administered at the same total mg daily dose. Tegretol in blood is 76% bound to plasma
proteins. Plasma levels of Tegretol are variable and may range from 0.5-25 µg/mL, with no apparent
relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 µg/mL. In
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polytherapy, the concentration of Tegretol and concomitant drugs may be increased or decreased during
therapy, and drug effects may be altered (see PRECAUTIONS, Drug Interactions). Following chronic oral
administration of suspension, plasma levels peak at approximately 1.5 hours compared to 4-5 hours after
administration of conventional Tegretol tablets, and 3-12 hours after administration of Tegretol-XR tablets. The
CSF/serum ratio is 0.22, similar to the 24% unbound Tegretol in serum. Because Tegretol induces its own
metabolism, the half-life is also variable. Autoinduction is completed after 3-5 weeks of a fixed dosing regimen.
Initial half-life values range from 25-65 hours, decreasing to 12-17 hours on repeated doses. Tegretol is
metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the
formation of carbamazepine-10,11-epoxide from Tegretol. After oral administration of 14C-carbamazepine , 72%
of the administered radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was
composed largely of hydroxylated and conjugated m etabolites, with only 3% of unchanged Tegretol.
The pharmacokinetic parameters of Te gretol disposition are similar in children and in adults. However, there is
a poor correlation between plasma concentrations of carbamazepine and Tegretol dose in children.
Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide (a metabolite shown to be
equipotent to carbamazepine as an anticonvulsant in animal screens) in the younger age groups than in adults. In
children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age (in
one report from 0.44 in children below the age of 1 year to 0.18 in children between 10-15 years of age).
The effects of race and gender on carbamazepine pharmacokinetics have not been systematically evaluated.
INDICATIONS AND USAGE
Epilepsy
Tegretol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of Tegretol as an
anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure
types:
1. Partial seizures with complex symptomatology (psychomotor, tempora l lobe). Patients with these seizures
appear to show greater improvement than those with other types.
2. Generalized tonic-clonic seizures (grand mal).
3. Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence seizures
(petit mal) do not appear to be controlled by Tegretol (see PRECAUTIONS, General).
Trigeminal Neuralgia
Tegretol is indicated in the treatment of the pain associated with true trigeminal neuralgia.
Beneficial results have also been reported in glossopharyngeal n euralgia.
This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.
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CONTRAINDICATIONS
Tegretol should not be used in patients with a history of previous bone marrow depression, hypersensitivity to
the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine,
imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with monoamine oxid ase
inhibitors is not recommended. Before administration of Tegretol, MAO inhibitors should be discontinued for a
minimum of 14 days, or longer if the clinical situation permits.
Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of
nefazodone and its active metabolite to achieve a therapeutic effect. Coadm inistration of carbamazepine with
nefazodone is contraindicated.
WARNINGS
Serious Dermatologic Reactions
Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and
Stevens-Johnson syndrome (SJS), have been reported with Tegretol treatment. The risk of these events is
estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. However, th e
risk in some Asian countries is estimated to be about 10 times higher. Tegretol should be discontinued at the
first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this
drug should not be resumed and alternative therapy should be considered.
SJS/TEN and HLA-B*1502 Allele
Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association
between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited v ariant
of the HLA-B gene, HLA-B*1502. The occurrence of higher rates of these reactions in countries with higher
frequencies of this allele suggests that the risk may be increased in allele-positive individuals of any ethnicity .
Across Asian populations, notable variation exists in the prevalence of HLA-B*1502. Greater than 15% of the
population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared t o
about 10% in Taiwan and 4% in North China. South Asians, including Indians, appear to have intermediate
prevalence of HLA-B*1502, averaging 2 to 4%, but higher in some groups. HLA-B*1502 is present in <1% of
the population in Japan and Korea.
HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans,
Hispanics, and Native Americans).
Prior to initiating Tegretol therapy, testing for HLA-B*1502 should be performed in patients with
ancestry in populations in which HLA-B*1502 may be present. In deciding which patients to screen, the
rates provided above for the prevalence of HLA-B*1502 may offer a rough guide, keeping in mind the
limitations of these fig ures due to wide variability in rates even within ethnic groups, the difficulty in
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ascertaining ethnic ancestry, and the likelihood of mixed ancestry . Tegretol should not be used in patients
positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Tested patients who are found to be
negative for the allele are thought to have a low risk of SJS/TEN (see WARNINGS and PRECAUTIONS,
Laboratory Tests).
Over 90% of Tegretol treated patients who will experience SJS/TEN have this reaction within the first few
months of treatment. This information may be taken into consideration in determining the need for screening of
genetically at-risk patients currently on Tegretol.
The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from
Tegretol such as maculopapular eruption (MPE) or to predict Drug Reaction with Eosinophilia and Systemic
Symptoms (DRESS).
Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients
of Chinese ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin.
Consideration should be given to avoiding use of other drugs associated with SJS/TEN in HLA-B*1502
positive patients, when alternative therapies are otherwise equally acceptable.
Hypersensitivity Reactions and HLA-A*3101 Allele
Retrospective case-control studies in patients of European, Korean, and Japanese ancestry have found a
moderate association between the risk of developing hypersensitivity reactions and the presence of HLA
A*3101, an inherited allelic variant of the HLA-A gene, in patients using carbamazepine. These
hypersensitivity reactions include SJS/TEN, maculopapul ar eruptions, and Drug Reaction with Eosinophilia and
Systemic Symptoms (see DRESS/Multiorgan hy persensitivity below).
HLA-A*3101 is expected to be carried by more than 15% of patients of Japanese, Native American, Southern
Indian (for example, Tamil Nadu) and some Arabic ancestry; up to about 10% in patients of Han Chinese,
Korean, European, Latin American, and other Indian ancestry; and up to about 5% in African-Americans and
patients of Thai, Taiwanese, and Chinese (Hong Kong) ancestry.
The risks and benefits of Tegretol therapy should be weighed before considering Tegretol in patients known to
be positive for HLA-A*3101.
Application of HLA genotyping as a screening tool has important limitations and must never substitute for
appropriate clinical vigilance and patient management. Many HLA-B*1502-positive and HLA-A*3101-positive
patients treated with Tegretol will not develop SJS/TEN or other hypersensitivity reactions, and these reactio ns
can still occur infrequently in HLA-B*1502-negative and HLA-A*3101-negative patients of any ethnicity. T he
role of other possible factors in the development of, and morbidity from, SJS/TEN and other hypersens itivity
reactions, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, an d the
level of dermatologic monitoring, have not been studied.
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Aplastic Anemia and Agranulocytosis
Aplastic anemia and agranulocytosis have been r eported in association with the use of TEGRETOL. [see Boxed
Warning.] Patients with a history of adverse hematologic reaction to any drug may be particularly at risk of
bone marrow depression.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan
hypersensitivity
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan
hypersensitivity, have occurred with Tegretol. Some of these events have been fatal or life-threatening. DRESS
typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other
organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis
sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its
expression, and other organ systems not noted here may be involved. It is important to note that early
manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not
evident. If such signs or symptoms are present, the patient should be evaluated immediately. Tegretol should be
discontinued if an alternative etiology for the signs or symptoms cannot be established.
Hypersensitivity
Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this
reaction to anticonvulsants including phenytoin, primidone, and phenobarbital. If such history is present,
benefits and risks should be carefully considered, and, if carbamazepine is initiated, the signs and symptoms of
hypersensitivity should be carefully monitored.
In patients who have exhibited hypersensitivity reactions to carbamazepine, approximately 25 to 30% may
experience hypersensitivity reactions with oxcarbazepine (Trileptal®).
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Tegretol, increase the risk of suicidal thoughts or behavior in patients
taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for
the emergenc e or worsening of depression, suicidal thoughts or behavior, and/or any unusual change s in mood
or behavior.
Pooled analyses of 199 placebo-con tro lled clinical trial s (mono- and adju nctive therapy) of 11 different AEDs
showed that patients randomized to one of the AEDs had approximately tw ice the risk (adjuste d Relative Risk
1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior com pared to patients ra ndomized to place bo. In these
trials, which had a median treatment duration of 12 weeks , the estimated incidence rate of suicidal behavior or
ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated
patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530
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patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting
drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials includ ed in
the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could
not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The
finding of increased risk with AEDs of varying mechanisms of action and across a range of ind ications suggests
that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years)
in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AE Ds.
Table 1 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication
Placebo Patients
with Events Per
1,000 Patients
Drug Patients
with Events Per
1,000 Patients
Relative Risk:
Incidence of
Patients/Incidence
Events in Drug
in Placebo
Patients
Risk Difference:
Additional Drug
Events Per 1,000
Patients with
Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials
for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric
indications.
Anyone considering prescribing Tegretol or any other AED must balance the ris k of suicidal thoughts or
behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescrib ed are
themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.
Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider w hether the
emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and
behavior and should be advised of the need to be alert for the emergence or worsening of the signs and
symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,
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behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare
providers.
General
Tegretol has shown mild anticholinergic activity; therefore, patients with increased intraocular pressure should
be closely observed during therapy.
Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a latent
psychosis and, in elderly patients, of confusion or agitation should be borne in mind.
The use of Tegretol should be avoided in patients with a history of hepatic porphyria (e.g., acute intermittent
porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported in such patients
receiving Tegretol therapy. Carbamazepine administration has also been demonstrated to increase porphyrin
precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria.
As with all antiepileptic drugs, Tegretol should be withdrawn gradually to minimize the potential of increased
seizure frequency.
Usage in Pregnancy
Carbamazepine can cause fetal harm when administered to a pregnant woman.
Epidemiological data suggest that there may be an association between the use of carbamazepine during
pregnancy and congenital malformations, including spina bifida. There have also been reports that associate
carbamazepine with developmental disorders and congenital anomalies (e.g., craniofacial defects,
cardiovascular malformations, hypospadias and anomalies involving various body systems). Developme ntal
delays based on neurobehavioral assessments have been reported. In treating or counseling women of
childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against the risks. If
this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient shou ld
be apprised of the potential hazard to the fetus.
Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of
teratogenic effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to
be continued, monotherapy may be preferable for pregnant women.
In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is accu mulated in
the fetal tissues, with higher levels found in liver and kidney than in brain and lung.
Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in
dosages 10-25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 1.5-4 times
the MHDD on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250 mg/kg and
4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate, 1; talipes, 1; anophthalmos, 2). In
reproduction studies in rats, nursing offspring demonstrated a lack of weight gain and an unkempt appearance at
a maternal dosage level of 200 mg/kg.
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Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent
major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and
threat to life. In individual cases where the severity and frequency of the seizure disorder are such that removal
of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered p rior
to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose
some hazard to the developing embryo or fetus.
Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal c are
in childbearing women receiving carbamazepine.
There have been a few cases of neonatal seizures and/or respiratory depres sion associated with maternal
Tegretol and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or
decreased feeding have also been reported in association with maternal Tegretol use. These symptoms may
represent a neonatal withdrawal sy ndrome.
To provide information regardin g the effects of in utero exposure to Tegretol, physicians are advised to
recommend that pregnant patients taking Tegretol enroll in the North American Antiepileptic Drug (NAAED)
Pregnancy Registry. This can be done by ca lling the toll free number 1-888-233-2334, and must be done by
patients themselves. Information on the registry can also be found at the website
http://www.aedpregnancyregistry.org/.
PRECAUTIONS
General
Before initiating therapy, a detailed history and physical examination should be made.
Tegretol should be used with caution in patients with a mixed seizure disorder that includes atypical absence
seizures, since in these patients Tegretol has been associated with increased frequency of generalized
convulsions (see INDICATIONS AND USAGE).
Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac
conduction disturbance, including second and third degree AV heart block; cardiac, hepatic, or renal damage;
adverse hematologic or hypersensitivity reaction to other drugs, including reactions to other anticonvulsants; or
interrupted courses of therapy with Tegretol.
AV heart block, including second and third degree block, have been reported following Tegretol treatment. This
occurred generally, but not solely, in patients with underlying EKG abnormalities or risk factors for conduction
disturbances.
Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have been
reported (see ADVERSE REACTIONS and PRECAUTIONS, Laboratory Tests). In some cases, hepatic effects
may progress despite discontinuation of the drug.
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Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the
tablet, it is recommended that patients given the suspension be started on lower doses and increased slowly to
avoid unwanted side effects (see DOSAGE AND ADMINISTRATION).
Tegretol suspension contains sorbitol and, therefore, should not be administered to patients with rare hereditary
problems of fructose intolerance.
Information for Patients
Patients should be informed of the availability of a Medication Guide and they should be instructed to read the
Medication Guide before taking Tegretol.
Patients should be made aware of the early toxic signs and symptoms of a potential hematologic problem, as
well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include, but are not limited to,
fever, sore throat, rash, ulcers in the mouth, easy bruising, l ymphadenopathy and petechial or purpuric
hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be
advised that, because these signs and symptoms may signal a serious reaction, that they must report any
occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms
should be reported even if mild or when occurring after extended use.
Patients should be advised that serious skin reactions have been reported in association with Tegretol. In the
event a skin reaction should occur while taking Tegretol, patients should consult with their physician
immediately (see WARNINGS).
Patients, their caregivers, and families should be counseled that AEDs, including Tegretol, may increase the risk
of suicidal thoughts and behavior and should be ad vised of the need to be alert for the emergence or worsening
of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thought s,
behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare
providers
Tegretol may interact with some drugs. Therefore, patients shoul d be advised to report to their doctors the use
of any other prescription or nonprescription medications or herbal products.
Caution should be exercised if alcohol is taken in combination with Tegretol therapy, due to a possible addit ive
sedative effect.
Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of operating
machinery or automobiles or engaging in other potentially d angerous tasks.
Patients should be encou raged to enroll in the NAAED Pregnancy Registry if they become pregnant. This
registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients
can call the toll free number 1-888-233-2334 (see WARNINGS, Usage in Pregnancy subsection).
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Laboratory Tests
For genetically at-risk pat ients (see WARNINGS), high-resolution ‘HLA-B*1502 typing’ is recommended. The
test is positive if either one or two HLA-B*1502 alleles are de tected and negative if no HLA-B*1502 alleles are
detected.
Complete pretreatment blood counts, including platelets and possibly reticulocy tes and serum iron, should be
obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white blood cell or
platelet counts, the patient should be monito red closely. Discontinuation of the drug should be considered if any
evidence of significant bone marrow depression develops.
Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must
be performed during treatment with this drug since liver damage may occur (see PRECAUTIONS, General an d
ADVERSE REACTIONS). Carbamazepine should be discontinued, based on clinical judgment, if indicated b y
newly occurring or worsening clinical or laboratory evidence of liver dysfunction or hepatic damage, or in the
case of active liver disease.
Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are re commended
since many phenothiazines and related drugs have been shown to caus e eye changes.
Baseline and periodic complete urinalysis and BUN determinations are recommended for patients treated with
this agent because of observed renal dysfunctio n.
Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and safety of
anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in seizure frequency
and for verification of compliance. In addition, measurement of drug serum levels may aid in determining the
cause of toxicity when more than one medication is being used.
Thyroid function tests have been reported to show dec reased values with Tegretol administered alone.
Hyponatremia has been reported in association with Tegretol use, either alone or in combination with other
drugs.
Interference with some pregnancy tests has been reported.
Drug Interactions
There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting
Tegretol suspension immediately followed by Thorazine®* solution. Subsequent testing has shown that mixing
Tegretol suspension and chlorpromazine solution (both generic and brand name) as well as Tegretol suspension
and liquid Mellaril® resulted in the occurrence of this precipitate. Because the extent to which this occurs with
other liquid medications is not known, Tegretol suspension should not be administered simultaneously with
other liquid medicinal agents or diluents (see DOSAGE AND ADMINISTRATION).
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Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not
limited to, the f ollowing:
Agents That May Affect Tegretol Plasma Levels
When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring
of carbamazepine levels is indicated and dosage adjustment may be required.
Agents That Increase Carbamazepine Levels
CYP 3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma carbamazepine levels. Drugs that
have been shown, or would be expected, to increas e plasma carbamazepine levels include:
Aprepitant, cimetidine, ciprofloxacin, danazol, diltiazem, macrolides, erythromycin, troleandomycin,
clarithromycin, fluoxetine, fluvox amine, nefazodone, trazodone, loxapine,* olanzapine, quetiapine*,
loratadine, terfenadine, omeprazole, oxybutynin, da ntrolene, isoniazid, niacinamide, nicotinamide,
ibuprofen, propoxyphene, azoles (e.g., ketaconazole, itraconazole, fluconazole, voriconazole),
acetazolamide, verapamil, ticlopidine, grapefruit juice, protease inhibitors, valproate*.
*increased levels of the active carbamazepine-10,11-epoxide
†decreased levels of carbamazepine and increased levels of the 10,11-epoxide
Agents That Decrease Carbamazepine Levels
CYP 3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that would be
expected, to decrease plasma carbamazepine levels include:
cisplatin, doxorubicin HCl, felbamate†, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone,
methsuximide, theophylline, aminophylline.
Effect of Tegretol on Plasma Levels of Concomitant Agent s
Decreased Levels of Conco mitant Medications
Tegretol is a potent inducer of hepatic CYP 3A4 and may therefore reduce plasma concentrations of
comedications mainly metabolized by CYP3A4 through induction of their metabolism. Tegre tol causes, or
would be expected to cause, decreased levels of the following:
acetaminophen, alben dazole, alprazolam, aprepitant, bupropion, citalopram, clonazepam, clozapine,
corticosteroids (e.g., prednisolone, dexamethasone), cyclosporine, dicumarol, dihydropyridi ne calcium
channel blockers (e.g., felodipine), doxycycline, ethosuximide, everolimus, haloperidol , imatinib,
itraconazole, lamotrigine, levothyroxine, methadone, methsuximide, midazolam, olanzapine, oral and
other hormonal contraceptives, oxcarbazepine, paliperidone, phensuximide, phenytoin, praziquante l,
protease inhibitors, risperidone, sirolimus, tadalafil, theophylline, tiagabine, topiramate, tramadol,
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Page 14
trazodone, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline), valproate, w arfarin,
ziprasidone, zonisamide.
In concomitant use with Tegretol, monitoring of concentrations or dosage adjustment of the above agents may
be necessary.
Cyclophosphamide is an inactive prodrug and is converted to its activ e metabolite in part by CYP3A. The rate
of metabolism and the leukopenic activity of cyclophosphamide reportedly are increased by chronic
administration of high doses of another CYP3A4 inducer. There is a potential for increased cyclophosphamide
toxicity when coadministered with carbamazepine.
When carbamazepine is added to aripiprazole therapy, the aripiprazole dose should be doubled. Additiona l dose
increases should be based on clinical evaluation. When carbamazepine is withdrawn from the combination
therapy, the aripiprazole dose should be reduced.
When carbamazepine is use d with tacrolimus, monitoring of tacrolimus blood concentrations and appropriate
dosage adjustments are recommended.
The use of concomitant st rong CYP3A4 inducers such as carbamazepine should be avoided with temsirolimus.
Based on pharmacokinetic studies, if patients must be co-adminis tered carbamazepine with temsirolimus, an
adjustment of temsiroli mus dosage should be considered.
The use of carbamazepine with lapatinib should generally be avoided. Dosage adjustment should be considered
if lapatinib is coadministered with carbamazepine. If carbamazepine is started in a patient already taking
lapatinib, the dose of lapatinib should be gradually titrated up. If carbamazepine is discontinued, the lapa tinib
dose should be reduced.
Coadministration of carbamazepine with nefazodone results in insufficient plasma concentrations of nefazodone
and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is
contraindicated (see CONTRAINDICATIONS).
Other Drug Inter actions
Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects.
Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced
hepatotoxicity.
Concomitant medication with Tegretol and some diuretics (hydrochlorothiazide, furosemide) may lead to
symptomatic hyponatremia.
Alterations of thyroid function have been reported in combination therapy with ot her anticonvulsant
medications.
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Concomitant use o f Tegretol with hormonal contraceptive products (e.g., oral, and levonorgestrel subdermal
implant contraceptives) may render the contraceptives less effect ive because the plasma concentrations of the
hormones may be decreased. Breakthrough bleeding and uninten ded pregnancies have been reported.
Alternative or back-up methods o f contraception should be considered.
Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents
pancuronium, vecuronium, rocuronium and cisatracurium has occurred in patients chronically administered
carbamazepine. Whether or not carbamazepine has the same effect on other non-depolarizing agents is
unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than
expected, and infusion rate requirements may be higher.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carbamazepine, when administered to Spragu e-Dawley rats for two years in the diet at doses of 25, 75, and
250 mg/kg/day, resulted in a dose-related increase in the inciden ce of hepatocellular tumors in females and of
benign interstitial cell adenomas in the testes of males.
Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Bacterial and
mammalian mutagenicity studies using carbamazepine produced negative results. The significance of these
findings relative to the use of carbam azepine in humans is, at present, unknown.
Usage in Pregnancy
Pregnancy Category D (see WARNINGS).
Labor and Delivery
The effect of Tegretol on human labo r and delivery is unknown.
Nursing Mothers
Tegretol and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in b reast milk
to that in maternal plasma is about 0.4 for Tegretol and about 0.5 for the epoxide. The e stimated doses given to
the newborn during breast-feeding are in the range of 2-5 mg daily for Tegretol and 1-2 mg daily for the
epoxide.
Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a decision should
be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the
drug to the mother.
Pediatric Use
Substantial evidence of Tegretol’s effectiveness for use in the management of children with epilepsy (see
INDICATIONS AND USAGE for specific seizure types) is derived from clinical investigations performed in
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adults and from studies in several in vitro systems which support the conclusion that (1) the pathogenetic
mechanisms underlying seizure propagation are essentially identical in adults and children, and (2) the
mechanism of action of carbamazepine in treating seizures is essentially identical in adults and children.
Taken as a whole, this information supports a conclusion that the generally accepted therapeutic range of t otal
carbamazepine in plasma (i.e., 4-12 mcg/mL) is the same in c hildren and adults.
The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety of
carbamazepine in children has been systematically studied up to 6 months. No longer-term data from clinical
trials is available.
Geriatric Use
No systematic studies in geriatric patients have been conducted.
ADVERSE REACTIONS
If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that
abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead to seizures or even
status epilepticus with its life-threatening hazards.
The most severe adverse reactions have been observed in the hemopoietic system and skin (see BOXED
WARNING), the liver, and the cardiovascular system.
The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness,
drowsiness, unsteadiness, nausea, and vomiting. To minimize the possi bility of such reactions, therapy should
be initiated at the low dosage recommended.
The following additional adverse reactions have been reported:
Hemopoietic System: Aplastic anemia, agranulocytos is, pancytopenia, bone marrow depression,
thrombocytopenia, leukopenia, leukocytosis, eosinophilia, anemia, acute intermittent porphyria, variegate
porphyria, porphyria cutanea tarda.
Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXED WARNING),
Acute Generalized Exanthematous Pustulosis (AGEP), pruritic and erythematous rashes, urticaria,
photosensitivity reactions, alterations in skin pigmentation, exfoliative dermatitis, erythema multifo rme and
nodosum, purpura, aggravation of disseminated lupus erythematosus, alopecia, diaph oresis and onychomadesis.
In certain cases, discontinuation of therapy may b e necessary. Isolated cases of hirsutism have been reported,
but a causal relationship is not clear.
Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope
and collapse, aggravation of coron ary artery disease, arrhythmias and AV block, thrombophlebitis,
thromboembolism (e.g., pulmonary embolism), and adenopathy or lymphadenopathy.
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Some of these cardiov ascular complications have resulted in fatalities. Myocardial infarction has been
associated with other tricyclic com pounds.
Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very rare cases of
hepatic failure.
Pancreatic: Pancreatitis.
Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneum onia.
Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood pressure,
azotemia, renal failure, and i mpotence. Albuminuria, glycosuria, elevated BUN, and microscopic deposits in the
urine have also been reported. There have been very rare reports of impaired male fertility and/or abnormal
spermatogenesis.
Testicular atrophy occurred in rats receiving Tegretol orally from 4-52 weeks at dosage levels of 50-400
mg/kg/day. Additionally, rats receiving Tegretol in the di et for 2 years at dosage levels of 25, 75, and 250
mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it pro duced a
brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg and
higher. Relevance of these findings to humans is unknown.
Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred
vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances,
abnormal involuntary movements, peripheral neuritis and pa resthesias, depression with agitation, talkativeness,
tinnitus, hyperacusis, neuroleptic malignant syndrome.
There have been reports of associated paralysis and other sym ptoms of cerebral arterial insufficiency, but the
exact relationship of these reactions to the drug has not been established.
Isolated cases of neuroleptic malignant syndrome have been reported both with and without concomitant use of
psychotropic drugs.
Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia, and
dryness of the mouth and pharynx, including glossitis and stomatitis.
Eyes: Scattered punctate cortical lens opacities, increased intraocular pressure as well as conjunctivitis, have
been reported. Although a direct causal relationship has not been established, many phenothiazines and rela ted
drugs have been shown to cause eye changes.
Musculoskeletal System: Aching joints and muscles, and leg cramps.
Metabolism: Fever and chills. Inappropriate antid iuretic hormone (ADH) secretion syndrome has been reported.
Cases of frank water intoxication, with decreased serum sodium (hyponatremia) and confusion, have been
reported in association with Tegretol use (see PRECAUTIONS, Laboratory Tests). Decreased levels of plasma
calcium leading to osteoporosis have been reported.
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Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional rep orts
of elevated levels of cholesterol, HDL chol esterol, and triglycerides in patients taking anticonvulsants.
A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a
patient taking carbamazepine in combination with other medications. The patient was successfully
dechallenged, and the meningitis reappea red upon rechallenge with carbamazepine.
DRUG ABUSE AND DEPENDENCE
No evidence of abuse potential has been associated with Tegretol, nor is there evidence of psychological or
physical dependence in humans.
OVERDOSAGE
Acute Toxicity
Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-old man
died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a cardiac arrest), 1.6 g
(a 3-year-old girl died of aspiration pneumonia).
Oral LD50 in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-2680; guinea pigs, 920.
Signs and Symptoms
The first signs and symptoms appear after 1-3 hours. Neuromuscular disturbances are the most prominent.
Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very hi gh
doses (>60 g) have been ingested.
Respiration: Irregular breathing, respiratory depression.
Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders.
Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma. Convulsions,
especially in small children. Motor restlessness, muscular twitching, tremor, athetoid movements, opisthotono s,
ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism, psychomotor disturbances,
dysmetria. Initial hyperreflexia, followed by hyporeflexia.
Gastrointestinal Tract: Nausea, vomiting.
Kidneys and Bladder: Anuria or oliguria, urinary retention.
Laboratory Findings: Isolated instances of overdosage have included leukocytosis , reduced leukocyte count,
glycosuria, and acetonuria. EEG may show dysrhythmias.
Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same
time, the signs and symptoms of acute p oisoning with Tegretol may be aggravated or modified.
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Treatment
The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which
may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps to diminish
absorption. If these measures cannot be implemented without risk on the spot, the patient should be transferred
at once to a hospital, while ensuring that vital functions are safeguarded. There is no specific antidote.
Elimination of the Drug: Induction of vomiting.
Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the stomach should
be repeatedly irrigated, especially if the patient has also consumed alcohol.
Measures to Reduce Absorption: Activated charcoal, laxatives.
Measures to Accelerate Elimination: Forced diuresis.
Dialysis is indicated only in severe poisoning associated with renal failure. Replacement tr ansfusion is indicated
in severe poisoning in small children.
Respiratory Depression: Keep the airways free; resort, if necessary, to endotracheal intubation, artificial
respiration, and administration of oxygen.
Hypotension, Shock: Keep the patient’s legs raised and administer a plasma expander. If blood pressure fa ils to
rise despite measures taken to increase plasma volume, use of vasoactive substances should be considered.
Convulsions: Diazepam or barbiturates.
Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children), hypotensio n,
and coma. However, barbiturates should not be used if drugs that inhibit monoamine oxidase have also been
taken by the patient either in overdosage or in recent therapy (within 1 week).
Surveillance: Respiration, cardiac function (ECG monitoring), blood pressure, body temperature, pupillary
reflexes, and kidney and bladder function should be monitored for several days.
Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression develops, the
following recommendations are suggested: (1) stop the drug, (2) perform daily CBC, platelet, and reti culocyte
counts, (3) do a bone marrow aspiration an d trephine biopsy immediately and repeat with sufficient frequency
to monitor recovery.
Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2) 59Fe-ferrokinetic
studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and peripheral blood, (5) bone
marrow culture studies for colony-forming units, (6) hemoglobin electrophoresis for A2 and F hemoglobin, and
(7) serum folic acid and B12 levels.
A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which
specialized consultation should be sought.
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DOSAGE AND ADMINISTRATION (SEE TABLE BELOW)
Tegretol su spension in c ombin ation with liquid c hlorpromazine or thioridazine results in precipitate formation,
and, in the case of chlorpromazine, there has been a report of a patient passing an orange rubbery precipitate in
the stool following coadminis tration of the two drugs (see PRECAUTIONS, Drug Interactions). Because the
extent to which thi
u
ith other liquid medi cations is not known, Tegretol suspension should not be
s occ rs w
administered simu ltaneously with other liquid medications or diluents.
Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see PRECAUTIONS,
Laboratory Tests). Dosage should be adjusted to the needs of the individual patient. A low initial daily dosage
with a gradual increase is advised. As soon as adequate contro l is achieved, the dosage may be reduced very
gradually to the mi nimum effective level. Medication should be taken with meals.
Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the
tablet, it is recommended to start with low doses (children 6-12 years: 1/2 teaspoon q.i.d.) and to increase
slowly to avoid unwanted side effects.
Conversion of patients from oral
o
uspension: Patients should be converted by
Tegret l tablets to Tegretol s
administering the same number of mg per day in smaller, more frequent doses (i.e., b.i.d. tablets to t.i.d.
suspension).
Tegretol-XR is an extended-release formulation for twice-a-day administration. When converting patients from
Tegretol conventional tablets to Tegreto l-XR, the same total daily mg dose of Tegretol-XR should be
administered. Tegretol-XR tablets must be swall owed whole and never crushed or chew ed. Tegretol-XR
tablets should be inspected for chips or cracks. Damaged table ts, or tablets without a release portal, should not
be consumed. Tegretol-XR tablet coating is not absorbed and is excreted in the feces; these coatings may be
noticeable in the stool.
Epilepsy (SEE IN DICATIONS AND USAGE)
Adults and children over 12 years of age - Initial: Either 200 mg b.i.d. for tablets and XR tablets, or 1 teaspoon
q.i.d. for suspension (400 mg/day). Increase at week ly in tervals by adding up to 200 mg/day using a b.i.d.
regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is
obtained. Dosage generally should n ot exceed 1000 mg daily in children 12-15 years of age, and 1200 mg daily
in patients above 15 years of age. Doses up to 1600 mg daily have been used in adults in rare instances.
Maintenance : Adjust dosage to the minim um effective level, usual ly 800-1200 mg daily.
Children 6-12 years of age - Initial: Either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for
suspension (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a b.i.d. regimen of
Tegretol-XR or a t. i.d. or q.i.d. regimen of the oth er form ulations until the optimal response is obtained. Dosage
generally should not exceed 1000 mg daily. Maintenance: Adjust dosage to the minimum effective level,
usually 400-800 mg daily.
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Children under 6 years of age - Initial: 10-20 mg/kg/day b.i.d. or t.i.d. as tablets, or q.i.d. as suspension.
Increase weekly to achieve optimal clinical response administered t.i.d. or q.i.d. Maintenance: Ordinarily,
optimal clinical response is achieved at daily doses below 35 mg/k g. If satisfactory clinical response has not
been achieved, plasma levels should be measured to determine whether or not they ar e in the therapeutic range.
No recommendation regarding the safety of carbam azepine for use at doses above 35 mg/kg/24 hours can be
made.
Combination Therapy: Tegretol may be used alone or with other anticonvulsants. When added to existing
anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are maintained or
gradually decreased, except phenytoin, which may have to be increased (see PRECAUTIONS, Drug
Interactions, and Pregnancy Category D).
Trigeminal Neuralgia (SEE INDICATIONS AND USAGE)
Initial: On the first day, either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for suspension, for a
total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day using increments of 100 mg
every 12 hours for tablets or XR tablets, or 50 mg (1/2 teaspoon) q.i.d. for suspension, only as needed to
achieve freedom from pain. Do not exceed 1200 mg daily. Maintenance: Control of pain can be maintained in
most patients with 400-800 mg daily. However, some patients may be maintained on as little as 200 mg daily,
while others may require as much as 1200 mg daily. At least once every 3 months throughout the treatment
period, attempts should be made to reduce the dose to the minimum effective level or even to discontinue the
drug.
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Dosage Information
In itial Dose
Subsequent Dose
Maximum D
aily Dose
Indication
Tablet*
XR
†
Tablet*
XR
†
Suspension
Tablet*
XR
†
Suspension
Epilepsy
Under 6 yr
1 0 20 mg/kg/ ay
d
b d. or t.i.d.
.i.
Suspension
10-20 mg/kg/day
q.i.d.
Increase weekl y
to achieve
optimal clinical
se
respon , t.i.d.
or q.i.d.
Increa se
weekl y to
achiev e opt imal
clinica l
respo nse, t. i.d.
or q.i. d.
35 mg/kg
/24 hr
(see
age
Dos
and
Adm
ation
inistr
sect ion a
bove)
35 mg/kg/24 hr
ee Dosage
(s
d
an
ministration
Ad
ction above)
se
6-12 yr
1 0 mg b.i.d.
0
(200 mg/day)
100 mgb.i.d.
(200 m g/day)
.
½ tsp q.i.d
00
(2
ay
mg/d )
to
Add up
/day at
100 mg
intervals,
weekly
t.i.d. or q.i.d.
Add
100 mg/day
at weekly
intervals,
b.i.d.
Add u p to 1 tsp
(100 m g)/da y at
weekl y
interv als, t.i .d.
or q.i. d.
1000 mg/
24 hr
Over 12 yr
2 00 mg b.i.d.
(400 mg/day)
200 mg b.i.d.
(400 m
g/day)
1 tsp q.i.d.
00
(4
ay
mg/d
)
d up to
Ad
0 mg/day at
20
ekly intervals,
we
d. or q.i.d.
t.i.
Add up to
200 mg/day
at weekly
intervals,
b.i.d.
Add u p to 2 tsp
(200 m g)/da y at
weekl y
interv als, t.i .d.
or q.i. d.
1000 mg/24 h r (12 15 yr)
1200 mg/24 hr (>1 5 yr)
00 mg
16
, in ra
/24 hr (adults
tance
re ins
s)
Trigeminal
100 mg b.i.d.
100 mg b.i.d.
½ tsp q.i.d.
Add up to
Add up to
Add u p to 2 tsp
1200 mg/
24 hr
Neuralgia
(200 mg/day)
(200
mg/day)
y
(200 mg/da )
200 mg/day in
increments of
100 mg every
12 hr
200 mg/day
in increments
of 100 mg
every 12 hr
(200 m g)/da y
in incr emen ts
of 50 mg
) q.i.d
(½ tsp
.
*Tablet = Chewab le or conventional tablets
†XR = Tegretol
®-XR exten ded-release tablets
eference ID: 3262556
R
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HOW SU P LIED
P
Chewable Tablets 100 mg - round, red-speckled, pink, single-scored (imprinted Tegretol on one side and 52
twice on the scored side)
Bottles of 1 0............................................................................................................................ NDC 0078-0492-05
0
Unit Dose (b lister pack)
Box of 100 (st rips of 10)........................................................... ................................................ NDC 0078-0492-35
Do not store above 30°C (86°F). Protect from light and moisture.
Dispense in tight, light-resistant container (USP).
Meets USP Dissolution Test 1.
Tablets 200 mg - capsule-shaped, pink, single-scored (imprinted Tegretol on one si de and 27 twice on the
partially scored side)
Bottles of 100............................................................................................................................ NDC 0078-0509-05
Do not store above 30°C (86°F). Protect from moisture.
Dispense in tight container (USP).
Meets USP Dissolution Test 2.
XR Tablets 100 mg - round, yellow, coated (imprinted T on one side and 100 mg on the other), release portal on
one side
Bottles of 100............................................................................................................................ NDC 0078-0510-05
XR Tablets 200 mg - round, pink, coated (imprinted T on one side and 200 mg on the other), release portal on
one side
Bottles of 100............................................................................. ............................................... NDC 0078-0511-05
XR Tablets 400 mg - round, brown, coated (imprinted T on one side and 400 mg on the other), release portal on
one side
Bottles of 100............................................................................................................................ NDC 0078-0512-05
Store at controlled room temperature 15 °C-30°C (59°F-86°F). Protect from moisture.
Dispense in tight container (USP).
Suspension 100 mg/5 mL (teaspoon) – yellow-orange, citrus-vanilla flavored
Bottles of 450 mL ..................................................... ................................................................ NDC 0078-0508-83
Shake well before using.
Do not store above 30°C ( 86°F). Dispense in tight, light-resistant container (USP).
*Thorazine® is a registered trademark of GlaxoSmithKline.
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MEDICATION GUIDE
TEGRETO L® and TEGRETOL®-XR (Teg-ret-ol)
(carbamazepine)
Tablets, Suspension , Chewable Tablets, Extended-Release Tablets
Read this Medication Guide before you start taking Tegretol or Tegretol –XR (TEG RETOL) and each time you
get a refill. There may be new information. This information does not tak e the place of talking to your
healthcare provider about your medical condition or trea tment.
What is the most important information I sh ould know about TEGRETOL?
Do not stop taking TEGRETOL without first talking to your healthcare provider.
Stopping TEGRETOL suddenly can cause serious problems.
TEGRETOL can cause serious side effects, including:
1. TEGRETOL may cause rare but serious skin rashes that may lead to death. These serious skin
reactions are more likely to happen when you begin taking TEGRETOL within the first four
months of treatment but may occur at later times. These reactions can happen in anyone, but
are more likely in people of Asian descent. If you are of Asian descent, you may need a ge netic
blood test before you take TEGRETOL to see if you are at a higher risk for serious skin
reactions with this medicine. Symptoms may include:
skin rash
hives
sores in your mouth
blistering or peeling of the skin
2. TEGRETOL may cause rare but serious blood problems. Symptoms may include:
fever, sore throat or other infections that come and go or do not go away
easy bruising
red or purple spots on your body
bleeding gums or n ose bleeds
severe fatigue or weakness
3. Like other antiepileptic drugs, TEGRETOL may cause suicidal thoughts or actions in a very
small number of people, about 1 in 500.
Call your healthcare provider right away if you have any of these symptoms, especially if they
are new, worse, or worry you:
thoughts about suicide or dying
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attempts to com mit suicide
new or worse depression
new or worse anxiety
feeling agitated or restless
panic attacks
trouble sleeping (insomnia)
new or worse irritability
acting aggressive, being angry, or violent
acting on dangerous impulses
an extreme increase in activity and talk ing (mania)
other unusual changes in behavior o r mood
How can I watch for early symptoms of suicidal thoughts and actions?
Pay attention to any changes, especially sudden chan ges, in mood, behaviors, thoughts, or feelings.
Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worri ed about symptoms.
Do not stop TEGRETOL without first talking to a healthcare provider.
Stopping TEGRETOL suddenly can cause serio us problems. You should talk to your healthcare
provider before stopping.
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts
or actions, your healthcare provider may check for other cau ses.
What is TEGRETOL?
TEGRETOL is a prescription medic ine used to treat:
certain types of seizures (par tial, tonic-clonic, mixed)
certain types of nerve pain (trigeminal and glossopharyngeal neuralgia)
TEGRETOL is not a regular pain medicine and should not be used for aches or pains.
Who should not take TEGRETOL?
Do not take TEGRETOL if you:
have a history of bone marrow depression.
are allergic to carbamaze pine or any of the ingredients in TEGRETOL. See the end of this Medication
Guide for a complete list of ingredie nts in TEGRETOL.
take nefazodone.
are allergic to medicines called tricyclic antidepressants (TCAs). Ask your healthcare provider or
pharmacist for a list of these medicines if you are not sur e.
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have taken a medicine called a Monoamine Oxidase Inhibitor (MAOI) in the last 14 days. Ask your
healthcare pr ovider or pharmacist for a list of these medicines if you are not sure.
What should I tell my healthcare provider before taking TEGRETOL?
Before you take TEGRETOL, tell your healthcare provider if you:
have or have had suicidal thoughts or actions, depression or mood problems
have or ever had heart problems
have or ever had blood problems
have or ever had liver problems
have or ever had kidney problems
have or ever had allergic reactions to medicines
have or ever had increased pressure in your eye
have any other medical conditions
drink grapefruit juice or eat grapefruit
use birth control. TEGRETOL may make your birth control less effective. Tell your healthcare
provider if your menstrual bleeding changes while you take birth control and TEGRETOL.
are pregnant or plan to become pregnant. TEGRETOL may harm your unborn baby. Tell your
healthcare provider right away if you become pre gnant while taking TEGRETOL. You and your
healthcare provider should decide if you should take TEGRETOL wh ile you are pregnant.
▪ If you become pregnant while taking TE GRETOL, talk to your healthcare provider about registering
with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this
registry is to collect information about the safety of antiepileptic medicine during pregnancy. You can
enroll in this registry by calling 1-888-233-2334.
are breastfeeding or plan to breastfeed. TEGRETOL passes into breast m ilk. You and your healthcare
provider should discuss whether you should take TEGRETOL o r breastfeed; you should not do both.
Tell your healthcare provider about all the medicines you take, including prescription and non-prescription
medicines, vitamins, and herbal supplements.
Taking TEGRETOL with certain other medicines m ay cause side effects or affect how well they work. Do not
start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when
you get a new medicine.
How should I take TEGRETOL?
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Do not stop taking TEGRETOL without first talking to your healthcare provider. Stopping TEGRETOL
suddenly can cause serious problems. Stopping seizure medicine suddenly in a patient who has epilepsy
may cause seizures that will not stop (status epilepticus).
Take TEGRETOL exactly as prescribed. Your healthcare provider will tell you how much TEGRETOL to
take.
Your healthcare provider may change your dose. Do not change your dose of TEGRETOL without talkin g
to your healthcare provider.
Take TEGRETOL with food.
TEGRETOL-XR tablets:
Do not crush, chew, or break TEGRETOL-XR tablets.
Tell you healthcare provider if you can not swallow TEGRETOL-XR whole.
TEGRETOL Suspension:
Shake the bottle well each time before use.
Do not take TEGRETOL suspension at the same time you take other liquid medicines.
If you take too much TEGRETOL, call your healthcare provider or local Poison Control Center right away.
What should I avoid while taking TEGRETOL?
Do not drink alcohol or take other drugs that make you sleepy or dizzy while taking TEGRETOL until
you talk to your healthcare provider. TEGRETOL taken with alcohol or drugs that cause sleepiness or
dizziness may make your sleepiness or dizziness worse.
Do not drive, operate heavy machinery, or do other dangerous activities until you know how
TEGRETOL affects you. TEGRETOL may slow your thinking and motor skills.
What are the possible side effects of TEGRETOL?
See “What is the most important information I should know about TEGRETOL?”
TEGRETOL may cause other serious side effects. These include:
Irregular heartbeat - symptoms include:
o Fast, slow, or pounding heartbeat
o Shortness of breath
o Feeling lightheaded
o Fainting
Liver problems - symptoms include:
o yellowing of your skin or the whites of your eyes
Reference ID: 3262556
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o dark urine
o pain on the right side of your stomach area (abdominal pain)
o easy bruising
o loss of appetite
o nausea or vomiting
Get medical help right away if you have any of the symptoms listed above or listed in “What is the most
important information I should know about TEGRETOL”.
The most common side effects of TEGRETOL include:
dizziness
drowsiness
problems with walking and coordination (unsteadiness)
nausea
vomiting
These are not all the possible side effects of TEGRETOL. For more information, ask your healthcare provider
or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA
1088.
How should I store TEGRETOL?
Do not store TEGRETOL Tablets above 30°C (86°F).
Keep TEGRETOL tablets dry.
Do not store TEGRETOL Chewable Tablets above 30°C (86°F).
Keep TEGRETOL Chewable Tablets out of the light.
Keep TEGRETOL Chewable Tablets dry.
Store TEGRETOL-XR tablets between 15°C to 30°C (59°F to 86°F).
Keep TEGRETOL XR tablets dry.
Do not store TEGRETOL Suspension above 30°C (86°F).
Shake well before using.
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c
ompany logo
Keep TEGRETOL Suspension in a tight, light-resistant container.
Keep TEGRETOL and all medicines out of the reach of children.
General Information about TEGRETOL
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
TEGRETOL for a condition for which it was not prescribed. Do not give TEGRETOL to other people, even if
they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about TEGRETOL. If you would like more
information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for the full
prescribing information about TEGRETOL that is written for health professionals.
For more information, go to Uwww.pharma.us.novartis.comU or call 1-888-669-6682.
What are the ingredients in TEGRETOL?
Active ingredient: carbamazepine
Inactive ingredients:
TEGRETOL tablets: colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake (chewable tablets
only), FD&C Red No. 40 (200-mg tablets only), flavoring (chewable tablets only), gelatin, glycerin,
magnesium stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose
(chewable tablets only).
TEGRETOL Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate,
propylene glycol, purified water, sorbitol, sucrose, and xanthan gum.
TEGRETOL-XR tablets: cellulose compounds, dextrates, iron oxides, magnesium stearate, mannitol,
polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200-mg tablets only).
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
T201X-XX/ T201X-XX
Month/Date
© Novartis
Reference ID: 3262556
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/016608s105,018281s053,018927s046,020234s038lbl.pdf', 'application_number': 18281, 'submission_type': 'SUPPL ', 'submission_number': 53}
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Novartis Logo
Tegretol®
carbamazepine USP
Chewable Tablets of 100 mg - red-speckled, pink
Tablets of 200 mg – pink
Suspension of 100 mg/5 mL
Tegretol®-XR
(carbamazepine extended-release tablets)
100 mg, 200 mg, 400 mg
Rx only
Prescribing Information
WARNINGS
SERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELE
SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC
EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN
REPORTED DURING TREATMENT WITH TEGRETOL. THESE REACTIONS ARE ESTIMATED TO
OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY CAUCASIAN
POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10
TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG
ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF
HLA-B*1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE. HLA-B*1502 IS FOUND
ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF ASIA.
PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS SHOULD BE SCREENED
FOR THE PRESENCE OF HLA-B*1502 PRIOR TO INITIATING TREATMENT WITH TEGRETOL.
PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH TEGRETOL
UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK (SEE WARNINGS AND PRECAUTIONS,
LABORATORY TESTS).
APLASTIC ANEMIA AND AGRANULOCYTOSIS
APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION WITH
THE USE OF TEGRETOL. DATA FROM A POPULATION-BASED CASE CONTROL STUDY
DEMONSTRATE THAT THE RISK OF DEVELOPING THESE REACTIONS IS 5-8 TIMES GREATER
THAN IN THE GENERAL POPULATION. HOWEVER, THE OVERALL RISK OF THESE REACTIONS
IN THE UNTREATED GENERAL POPULATION IS LOW, APPROXIMATELY SIX PATIENTS PER ONE
MILLION POPULATION PER YEAR FOR AGRANULOCYTOSIS AND TWO PATIENTS PER ONE
MILLION POPULATION PER YEAR FOR APLASTIC ANEMIA.
ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR WHITE
BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE OF TEGRETOL,
DATA ARE NOT AVAILABLE TO ESTIMATE ACCURATELY THEIR INCIDENCE OR OUTCOME.
HOWEVER, THE VAST MAJORITY OF THE CASES OF LEUKOPENIA HAVE NOT PROGRESSED TO
THE MORE SERIOUS CONDITIONS OF APLASTIC ANEMIA OR AGRANULOCYTOSIS.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC ANEMIA,
THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN MONITORING OF
PATIENTS ON TEGRETOL ARE UNLIKELY TO SIGNAL THE OCCURRENCE OF EITHER
ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT HEMATOLOGICAL TESTING
SHOULD BE OBTAINED AS A BASELINE. IF A PATIENT IN THE COURSE OF TREATMENT
EXHIBITS LOW OR DECREASED WHITE BLOOD CELL OR PLATELET COUNTS, THE PATIENT
SHOULD BE MONITORED CLOSELY. DISCONTINUATION OF THE DRUG SHOULD BE
CONSIDERED IF ANY EVIDENCE OF SIGNIFICANT BONE MARROW DEPRESSION DEVELOPS.
Before prescribing Tegretol, the physician should be thoroughly familiar with the details of this
prescribing information, particularly regarding use with other drugs, especially those which accentuate
toxicity potential.
DESCRIPTION
Tegretol, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for
oral administration as chewable tablets of 100 mg, tablets of 200 mg, XR tablets of 100, 200, and 400 mg, and
as a suspension of 100 mg/5 mL (teaspoon). Its chemical name is 5H-dibenz[b,f ]azepine-5-carboxamide, and
its structural formula is structural formula of dibenz[bf]azepine-5-carboxamide
Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in alcohol
and in acetone. Its molecular weight is 236.27.
Inactive Ingredients Tablets: Colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake (chewable tablets
only), FD&C Red No. 40 (200-mg tablets only), flavoring (chewable tablets only), gelatin, glycerin, magnesium
stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose (chewable tablets
only). Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate, propylene glycol,
purified water, sorbitol, sucrose, and xanthan gum. Tegretol-XR tablets: cellulose compounds, dextrates, iron
oxides, magnesium stearate, mannitol, polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200-mg
tablets only).
CLINICAL PHARMACOLOGY
In controlled clinical trials, Tegretol has been shown to be effective in the treatment of psychomotor and grand
mal seizures, as well as trigeminal neuralgia.
Mechanism of Action
Tegretol has demonstrated anticonvulsant properties in rats and mice with electrically and chemically induced
seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation.
Tegretol greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It
depresses thalamic potential and bulbar and polysynaptic reflexes, including the linguomandibular reflex in
cats. Tegretol is chemically unrelated to other anticonvulsants or other drugs used to control the pain of
trigeminal neuralgia. The mechanism of action remains unknown.
The principal metabolite of Tegretol, carbamazepine-10,11-epoxide, has anticonvulsant activity as
demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide has been
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
postulated, the significance of its activity with respect to the safety and efficacy of Tegretol has not been
established.
Pharmacokinetics
In clinical studies, Tegretol suspension, conventional tablets, and XR tablets delivered equivalent amounts of
drug to the systemic circulation. However, the suspension was absorbed somewhat faster, and the XR tablet
slightly slower, than the conventional tablet. The bioavailability of the XR tablet was 89% compared to
suspension. Following a b.i.d. dosage regimen, the suspension provides higher peak levels and lower trough
levels than those obtained from the conventional tablet for the same dosage regimen. On the other hand,
following a t.i.d. dosage regimen, Tegretol suspension affords steady-state plasma levels comparable to
Tegretol tablets given b.i.d. when administered at the same total mg daily dose. Following a b.i.d. dosage
regimen, Tegretol-XR tablets afford steady-state plasma levels comparable to conventional Tegretol tablets
given q.i.d., when administered at the same total mg daily dose. Tegretol in blood is 76% bound to plasma
proteins. Plasma levels of Tegretol are variable and may range from 0.5-25 µg/mL, with no apparent
relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 µg/mL. In
polytherapy, the concentration of Tegretol and concomitant drugs may be increased or decreased during
therapy, and drug effects may be altered (see PRECAUTIONS, Drug Interactions). Following chronic oral
administration of suspension, plasma levels peak at approximately 1.5 hours compared to 4-5 hours after
administration of conventional Tegretol tablets, and 3-12 hours after administration of Tegretol-XR tablets. The
CSF/serum ratio is 0.22, similar to the 24% unbound Tegretol in serum. Because Tegretol induces its own
metabolism, the half-life is also variable. Autoinduction is completed after 3-5 weeks of a fixed dosing regimen.
Initial half-life values range from 25-65 hours, decreasing to 12-17 hours on repeated doses. Tegretol is
metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the
formation of carbamazepine-10,11-epoxide from Tegretol. After oral administration of 14C-carbamazepine, 72%
of the administered radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was
composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged Tegretol.
The pharmacokinetic parameters of Tegretol disposition are similar in children and in adults. However,
there is a poor correlation between plasma concentrations of carbamazepine and Tegretol dose in children.
Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide (a metabolite shown to be
equipotent to carbamazepine as an anticonvulsant in animal screens) in the younger age groups than in adults.
In children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age
(in one report from 0.44 in children below the age of 1 year to 0.18 in children between 10-15 years of age).
The effects of race and gender on carbamazepine pharmacokinetics have not been systematically evaluated.
INDICATIONS AND USAGE
Epilepsy
Tegretol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of Tegretol as an
anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure
types:
1. Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures
appear to show greater improvement than those with other types.
2. Generalized tonic-clonic seizures (grand mal).
3. Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence seizures
(petit mal) do not appear to be controlled by Tegretol (see PRECAUTIONS, General).
Trigeminal Neuralgia
Tegretol is indicated in the treatment of the pain associated with true trigeminal neuralgia.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Beneficial results have also been reported in glossopharyngeal neuralgia.
This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.
CONTRAINDICATIONS
Tegretol should not be used in patients with a history of previous bone marrow depression, hypersensitivity to
the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine,
imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with monoamine oxidase
inhibitors is not recommended. Before administration of Tegretol, MAO inhibitors should be discontinued for a
minimum of 14 days, or longer if the clinical situation permits.
Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of
nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with
nefazodone is contraindicated.
WARNINGS
Serious Dermatologic Reactions
Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and
Stevens-Johnson syndrome (SJS), have been reported with Tegretol treatment. The risk of these events is
estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. However,
the risk in some Asian countries is estimated to be about 10 times higher. Tegretol should be discontinued at the
first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this
drug should not be resumed and alternative therapy should be considered.
SJS/TEN and HLA-B*1502 Allele
Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association
between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant
of the HLA-B gene, HLA-B*1502. The occurrence of higher rates of these reactions in countries with higher
frequencies of this allele suggests that the risk may be increased in allele-positive individuals of any ethnicity.
Across Asian populations, notable variation exists in the prevalence of HLA-B*1502. Greater than 15% of
the population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared to
about 10% in Taiwan and 4% in North China. South Asians, including Indians, appear to have intermediate
prevalence of HLA-B*1502, averaging 2 to 4%, but higher in some groups. HLA-B*1502 is present in <1% of
the population in Japan and Korea.
HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans,
Hispanics, and Native Americans).
Prior to initiating Tegretol therapy, testing for HLA-B*1502 should be performed in patients with
ancestry in populations in which HLA-B*1502 may be present. In deciding which patients to screen, the
rates provided above for the prevalence of HLA-B*1502 may offer a rough guide, keeping in mind the
limitations of these figures due to wide variability in rates even within ethnic groups, the difficulty in
ascertaining ethnic ancestry, and the likelihood of mixed ancestry. Tegretol should not be used in patients
positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Tested patients who are found to be
negative for the allele are thought to have a low risk of SJS/TEN (see WARNINGS and PRECAUTIONS,
Laboratory Tests).
Over 90% of Tegretol treated patients who will experience SJS/TEN have this reaction within the first few
months of treatment. This information may be taken into consideration in determining the need for screening of
genetically at-risk patients currently on Tegretol.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from
Tegretol, such as anticonvulsant hypersensitivity syndrome or nonserious rash (maculopapular eruption
[MPE]).
Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in
patients of Chinese ancestry taking other antiepileptic drugs associated with SJS/TEN. Consideration should be
given to avoiding use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when
alternative therapies are otherwise equally acceptable.
Application of HLA-B*1502 genotyping as a screening tool has important limitations and must never
substitute for appropriate clinical vigilance and patient management. Many HLA-B*1502-positive Asian
patients treated with Tegretol will not develop SJS/TEN, and these reactions can still occur infrequently in
HLA-B*1502-negative patients of any ethnicity. The role of other possible factors in the development of, and
morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications,
comorbidities, and the level of dermatologic monitoring have not been studied.
Aplastic Anemia and Agranulocytosis
Patients with a history of adverse hematologic reaction to any drug may be particularly at risk of bone marrow
depression.
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Tegretol, increase the risk of suicidal thoughts or behavior in patients
taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for
the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood
or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different
AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative
Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In
these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal
behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029
placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for
every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-
treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after
starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials
included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24
weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The
finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests
that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years)
in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
Table 1 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication
Placebo Patients
with Events Per
1,000 Patients
Drug Patients
with Events Per
1,000 Patients
Relative Risk:
Incidence of
Events in Drug
Patients/Incidence
in Placebo
Patients
Risk Difference:
Additional Drug
Patients with
Events Per 1,000
Patients
Epilepsy
1.0
3.4
3.5
2.4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical
trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and
psychiatric indications.
Anyone considering prescribing Tegretol or any other AED must balance the risk of suicidal thoughts or
behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are
themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.
Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the
emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts
and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and
symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,
behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare
providers.
General
Tegretol has shown mild anticholinergic activity; therefore, patients with increased intraocular pressure should
be closely observed during therapy.
Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a latent
psychosis and, in elderly patients, of confusion or agitation should be borne in mind.
The use of Tegretol should be avoided in patients with a history of hepatic porphyria (e.g., acute intermittent
porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported in such patients
receiving Tegretol therapy. Carbamazepine administration has also been demonstrated to increase porphyrin
precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria.
As with all antiepileptic drugs, Tegretol should be withdrawn gradually to minimize the potential of
increased seizure frequency.
Usage in Pregnancy
Carbamazepine can cause fetal harm when administered to a pregnant woman.
Epidemiological data suggest that there may be an association between the use of carbamazepine during
pregnancy and congenital malformations, including spina bifida. There have also been reports that associate
carbamazepine with developmental disorders and congenital anomalies (e.g., craniofacial defects,
cardiovascular malformations, hypospadias and anomalies involving various body systems). Developmental
delays based on neurobehavioral assessments have been reported. In treating or counseling women of
childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against the risks. If
this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should
be apprised of the potential hazard to the fetus.
Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of
teratogenic effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to
be continued, monotherapy may be preferable for pregnant women.
In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is accumulated
in the fetal tissues, with higher levels found in liver and kidney than in brain and lung.
This label may not be the latest approved by FDA.
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Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in
dosages 10-25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 1.5-4 times
the MHDD on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250 mg/kg and
4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate, 1; talipes, 1; anophthalmos, 2). In
reproduction studies in rats, nursing offspring demonstrated a lack of weight gain and an unkempt appearance at
a maternal dosage level of 200 mg/kg.
Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to
prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant
hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such
that removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be
considered prior to and during pregnancy, although it cannot be said with any confidence that even minor
seizures do not pose some hazard to the developing embryo or fetus.
Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal
care in childbearing women receiving carbamazepine.
There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal
Tegretol and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or
decreased feeding have also been reported in association with maternal Tegretol use. These symptoms may
represent a neonatal withdrawal syndrome.
To provide information regarding the effects of in utero exposure to Tegretol, physicians are advised to
recommend that pregnant patients taking Tegretol enroll in the North American Antiepileptic Drug (NAAED)
Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by
patients themselves. Information on the registry can also be found at the website
http://www.aedpregnancyregistry.org/.
PRECAUTIONS
General
Before initiating therapy, a detailed history and physical examination should be made.
Tegretol should be used with caution in patients with a mixed seizure disorder that includes atypical
absence seizures, since in these patients Tegretol has been associated with increased frequency of generalized
convulsions (see INDICATIONS AND USAGE).
Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac
conduction disturbance, including second and third degree AV heart block; cardiac, hepatic, or renal damage;
adverse hematologic or hypersensitivity reaction to other drugs, including reactions to other anticonvulsants; or
interrupted courses of therapy with Tegretol.
AV heart block, including second and third degree block, have been reported following Tegretol treatment.
This occurred generally, but not solely, in patients with underlying EKG abnormalities or risk factors for
conduction disturbances.
Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have been
reported (see ADVERSE REACTIONS and PRECAUTIONS, Laboratory Tests). In some cases, hepatic effects
may progress despite discontinuation of the drug.
Multiorgan hypersensitivity reactions occurring days to weeks or months after initiating treatment have
been reported in rare cases (see ADVERSE REACTIONS, Other and PRECAUTIONS, Information for
Patients).
Discontinuation of carbamazepine should be considered if any evidence of hypersensitivity develops.
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Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this
reaction to anticonvulsants including phenytoin and phenobarbital. A history of hypersensitivity reactions
should be obtained for a patient and the immediate family members. If positive, caution should be used in
prescribing carbamazepine.
Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the
tablet, it is recommended that patients given the suspension be started on lower doses and increased slowly to
avoid unwanted side effects (see DOSAGE AND ADMINISTRATION).
Information for Patients
Patients should be made aware of the early toxic signs and symptoms of a potential hematologic problem, as
well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include, but are not limited to,
fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric
hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be
advised that, because these signs and symptoms may signal a serious reaction, that they must report any
occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms
should be reported even if mild or when occurring after extended use.
Patients, their caregivers, and families should be counseled that AEDs, including Tegretol, may increase the
risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal
thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to
healthcare providers
Tegretol may interact with some drugs. Therefore, patients should be advised to report to their doctors the
use of any other prescription or nonprescription medications or herbal products.
Caution should be exercised if alcohol is taken in combination with Tegretol therapy, due to a possible
additive sedative effect.
Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of operating
machinery or automobiles or engaging in other potentially dangerous tasks.
Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This
registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients
can call the toll free number 1-888-233-2334 (see WARNINGS, Usage in Pregnancy subsection).
Laboratory Tests
For genetically at-risk patients (see WARNINGS), high-resolution ‘HLA-B*1502 typing’ is recommended. The
test is positive if either one or two HLA-B*1502 alleles are detected and negative if no HLA-B*1502 alleles are
detected.
Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, should
be obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white blood cell or
platelet counts, the patient should be monitored closely. Discontinuation of the drug should be considered if any
evidence of significant bone marrow depression develops.
Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease,
must be performed during treatment with this drug since liver damage may occur (see PRECAUTIONS,
General and ADVERSE REACTIONS). Carbamazepine should be discontinued, based on clinical judgment, if
indicated by newly occurring or worsening clinical or laboratory evidence of liver dysfunction or hepatic
damage, or in the case of active liver disease.
Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are recommended
since many phenothiazines and related drugs have been shown to cause eye changes.
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Baseline and periodic complete urinalysis and BUN determinations are recommended for patients treated
with this agent because of observed renal dysfunction.
Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and safety of
anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in seizure frequency
and for verification of compliance. In addition, measurement of drug serum levels may aid in determining the
cause of toxicity when more than one medication is being used.
Thyroid function tests have been reported to show decreased values with Tegretol administered alone.
Hyponatremia has been reported in association with Tegretol use, either alone or in combination with other
drugs.
Interference with some pregnancy tests has been reported.
Drug Interactions
There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting
Tegretol suspension immediately followed by Thorazine®* solution. Subsequent testing has shown that mixing
Tegretol suspension and chlorpromazine solution (both generic and brand name) as well as Tegretol suspension
and liquid Mellaril® resulted in the occurrence of this precipitate. Because the extent to which this occurs with
other liquid medications is not known, Tegretol suspension should not be administered simultaneously with
other liquid medicinal agents or diluents (see DOSAGE AND ADMINISTRATION).
Clinically meaningful drug interactions have occurred with concomitant medications and include, but are
not limited to, the following:
Agents That May Affect Tegretol Plasma Levels
CYP 3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma carbamazepine levels. Drugs that
have been shown, or would be expected, to increase plasma carbamazepine levels include:
cimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine,
fluvoxamine, nefazodone, loratadine, terfenadine, isoniazid, niacinamide, nicotinamide, propoxyphene,
azoles (e.g., ketaconazole, itraconazole, fluconazole), acetazolamide, verapamil, grapefruit juice,
protease inhibitors, valproate.*
CYP 3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that would
be expected, to decrease plasma carbamazepine levels include:
cisplatin, doxorubicin HCl, felbamate,† rifampin, phenobarbital, phenytoin, primidone, methsuximide,
theophylline.
When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close
monitoring of carbamazepine levels is indicated and dosage adjustment may be required.
*increased levels of the active 10,11-epoxide
†decreased levels of carbamazepine and increased levels of the 10,11-epoxide
Effect of Tegretol on Plasma Levels of Concomitant Agents
Increased levels: clomipramine HCl, phenytoin, primidone
Tegretol induces hepatic CYP activity. Tegretol causes, or would be expected to cause, decreased levels of the
following:
acetaminophen, alprazolam, dihydropyridine calcium channel blockers (e.g., felodipine), cyclosporine,
corticosteroids (e.g., prednisolone, dexamethasone), clonazepam, clozapine, dicumarol, doxycycline,
ethosuximide,haloperidol, itraconazole, lamotrigine, levothyroxine, methadone, methsuximide,
midazolam, olanzapine, oral and other hormonal contraceptives, oxcarbazepine, phensuximide,
phenytoin, praziquantel, protease inhibitors, risperidone, theophylline, tiagabine, topiramate, tramadol,
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tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline), valproate, warfarin, ziprasidone,
zonisamide.
In concomitant use with Tegretol, dosage adjustment of the above agents may be necessary.
Coadministration of carbamazepine with nefazodone results in insufficient plasma concentrations of
nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with
nefazodone is contraindicated (see CONTRAINDICATIONS).
Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects.
Alterations of thyroid function have been reported in combination therapy with other anticonvulsant
medications.
Concomitant use of Tegretol with hormonal contraceptive products (e.g., oral, and levonorgestrel subdermal
implant contraceptives) may render the contraceptives less effective because the plasma concentrations of the
hormones may be decreased. Breakthrough bleeding and unintended pregnancies have been reported.
Alternative or back-up methods of contraception should be considered.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75, and
250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular tumors in females and of
benign interstitial cell adenomas in the testes of males.
Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Bacterial and
mammalian mutagenicity studies using carbamazepine produced negative results. The significance of these
findings relative to the use of carbamazepine in humans is, at present, unknown.
Usage in Pregnancy
Pregnancy Category D (see WARNINGS).
Labor and Delivery
The effect of Tegretol on human labor and delivery is unknown.
Nursing Mothers
Tegretol and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in breast milk
to that in maternal plasma is about 0.4 for Tegretol and about 0.5 for the epoxide. The estimated doses given to
the newborn during breast-feeding are in the range of 2-5 mg daily for Tegretol and 1-2 mg daily for the
epoxide.
Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a decision
should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of
the drug to the mother.
Pediatric Use
Substantial evidence of Tegretol’s effectiveness for use in the management of children with epilepsy (see
INDICATIONS AND USAGE for specific seizure types) is derived from clinical investigations performed in
adults and from studies in several in vitro systems which support the conclusion that (1) the pathogenetic
mechanisms underlying seizure propagation are essentially identical in adults and children, and (2) the
mechanism of action of carbamazepine in treating seizures is essentially identical in adults and children.
Taken as a whole, this information supports a conclusion that the generally accepted therapeutic range of
total carbamazepine in plasma (i.e., 4-12 mcg/mL) is the same in children and adults.
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The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety of
carbamazepine in children has been systematically studied up to 6 months. No longer-term data from clinical
trials is available.
Geriatric Use
No systematic studies in geriatric patients have been conducted.
ADVERSE REACTIONS
If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that
abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead to seizures or even
status epilepticus with its life-threatening hazards.
The most severe adverse reactions have been observed in the hemopoietic system and skin (see BOXED
WARNING), the liver, and the cardiovascular system.
The most frequently observed adverse reactions, particularly during the initial phases of therapy, are
dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions,
therapy should be initiated at the low dosage recommended.
The following additional adverse reactions have been reported:
Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression,
thrombocytopenia, leukopenia, leukocytosis, eosinophilia, acute intermittent porphyria.
Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXED WARNING),
pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin pigmentation,
exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus
erythematosus, alopecia, and diaphoresis. In certain cases, discontinuation of therapy may be necessary.
Isolated cases of hirsutism have been reported, but a causal relationship is not clear.
Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope
and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis,
thromboembolism, and adenopathy or lymphadenopathy.
Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been
associated with other tricyclic compounds.
Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very rare cases of
hepatic failure.
Pancreatic: Pancreatitis.
Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia.
Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood pressure,
azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and microscopic deposits in the
urine have also been reported.
Testicular atrophy occurred in rats receiving Tegretol orally from 4-52 weeks at dosage levels of
50-400 mg/kg/day. Additionally, rats receiving Tegretol in the diet for 2 years at dosage levels of 25, 75, and
250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a
brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg and
higher. Relevance of these findings to humans is unknown.
Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred
vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances,
abnormal involuntary movements, peripheral neuritis and paresthesias, depression with agitation, talkativeness,
tinnitus and hyperacusis.
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There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but
the exact relationship of these reactions to the drug has not been established.
Isolated cases of neuroleptic malignant syndrome have been reported with concomitant use of psychotropic
drugs.
Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia, and
dryness of the mouth and pharynx, including glossitis and stomatitis.
Eyes: Scattered punctate cortical lens opacities, as well as conjunctivitis, have been reported. Although a direct
causal relationship has not been established, many phenothiazines and related drugs have been shown to cause
eye changes.
Musculoskeletal System: Aching joints and muscles, and leg cramps.
Metabolism: Fever and chills. Inappropriate antidiuretic hormone (ADH) secretion syndrome has been
reported. Cases of frank water intoxication, with decreased serum sodium (hyponatremia) and confusion, have
been reported in association with Tegretol use (see PRECAUTIONS, Laboratory Tests). Decreased levels of
plasma calcium have been reported.
Other: Multiorgan hypersensitivity reactions occurring days to weeks or months after initiating treatment have
been reported in rare cases. Signs or symptoms may include, but are not limited to fever, skin rashes, vasculitis,
lymphadenopathy, disorders mimicking lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly
and abnormal liver function tests. These signs and symptoms may occur in various combinations and not
necessarily concurrently. Signs and symptoms may initially be mild. Various organs, including but not limited
to, liver, skin, immune system, lungs, kidneys, pancreas, myocardium, and colon may be affected (see
PRECAUTIONS, General and PRECAUTIONS, Information for Patients).
Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional
reports of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants.
A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a
patient taking carbamazepine in combination with other medications. The patient was successfully
dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.
DRUG ABUSE AND DEPENDENCE
No evidence of abuse potential has been associated with Tegretol, nor is there evidence of psychological or
physical dependence in humans.
OVERDOSAGE
Acute Toxicity
Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-old man
died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a cardiac arrest), 1.6 g
(a 3-year-old girl died of aspiration pneumonia).
Oral LD50 in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-2680; guinea pigs, 920.
Signs and Symptoms
The first signs and symptoms appear after 1-3 hours. Neuromuscular disturbances are the most prominent.
Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high
doses (>60 g) have been ingested.
Respiration: Irregular breathing, respiratory depression.
Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders.
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Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma. Convulsions,
especially in small children. Motor restlessness, muscular twitching, tremor, athetoid movements, opisthotonos,
ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism, psychomotor disturbances,
dysmetria. Initial hyperreflexia, followed by hyporeflexia.
Gastrointestinal Tract: Nausea, vomiting.
Kidneys and Bladder: Anuria or oliguria, urinary retention.
Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte count,
glycosuria, and acetonuria. EEG may show dysrhythmias.
Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same
time, the signs and symptoms of acute poisoning with Tegretol may be aggravated or modified.
Treatment
The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which
may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps to diminish
absorption. If these measures cannot be implemented without risk on the spot, the patient should be transferred
at once to a hospital, while ensuring that vital functions are safeguarded. There is no specific antidote.
Elimination of the Drug: Induction of vomiting.
Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the stomach
should be repeatedly irrigated, especially if the patient has also consumed alcohol.
Measures to Reduce Absorption: Activated charcoal, laxatives.
Measures to Accelerate Elimination: Forced diuresis.
Dialysis is indicated only in severe poisoning associated with renal failure. Replacement transfusion is
indicated in severe poisoning in small children.
Respiratory Depression: Keep the airways free; resort, if necessary, to endotracheal intubation, artificial
respiration, and administration of oxygen.
Hypotension, Shock: Keep the patient’s legs raised and administer a plasma expander. If blood pressure fails to
rise despite measures taken to increase plasma volume, use of vasoactive substances should be considered.
Convulsions: Diazepam or barbiturates.
Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children), hypotension,
and coma. However, barbiturates should not be used if drugs that inhibit monoamine oxidase have also been
taken by the patient either in overdosage or in recent therapy (within 1 week).
Surveillance: Respiration, cardiac function (ECG monitoring), blood pressure, body temperature, pupillary
reflexes, and kidney and bladder function should be monitored for several days.
Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression develops, the
following recommendations are suggested: (1) stop the drug, (2) perform daily CBC, platelet, and reticulocyte
counts, (3) do a bone marrow aspiration and trephine biopsy immediately and repeat with sufficient frequency
to monitor recovery.
Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies,
(2) 59Fe-ferrokinetic studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and peripheral
blood, (5) bone marrow culture studies for colony-forming units, (6) hemoglobin electrophoresis for A2 and F
hemoglobin, and (7) serum folic acid and B12 levels.
A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which
specialized consultation should be sought.
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DOSAGE AND ADMINISTRATION (SEE TABLE BELOW)
Tegretol suspension in combination with liquid chlorpromazine or thioridazine results in precipitate formation,
and, in the case of chlorpromazine, there has been a report of a patient passing an orange rubbery precipitate in
the stool following coadministration of the two drugs (see PRECAUTIONS, Drug Interactions). Because the
extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be
administered simultaneously with other liquid medications or diluents.
Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see PRECAUTIONS,
Laboratory Tests). Dosage should be adjusted to the needs of the individual patient. A low initial daily dosage
with a gradual increase is advised. As soon as adequate control is achieved, the dosage may be reduced very
gradually to the minimum effective level. Medication should be taken with meals.
Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the
tablet, it is recommended to start with low doses (children 6-12 years: 1/2 teaspoon q.i.d.) and to increase
slowly to avoid unwanted side effects.
Conversion of patients from oral Tegretol tablets to Tegretol suspension: Patients should be converted by
administering the same number of mg per day in smaller, more frequent doses (i.e., b.i.d. tablets to t.i.d.
suspension).
Tegretol-XR is an extended-release formulation for twice-a-day administration. When converting patients
from Tegretol conventional tablets to Tegretol-XR, the same total daily mg dose of Tegretol-XR should be
administered. Tegretol-XR tablets must be swallowed whole and never crushed or chewed. Tegretol-XR
tablets should be inspected for chips or cracks. Damaged tablets, or tablets without a release portal, should not
be consumed. Tegretol-XR tablet coating is not absorbed and is excreted in the feces; these coatings may be
noticeable in the stool.
Epilepsy (SEE INDICATIONS AND USAGE)
Adults and children over 12 years of age - Initial: Either 200 mg b.i.d. for tablets and XR tablets, or
1 teaspoon q.i.d. for suspension (400 mg/day). Increase at weekly intervals by adding up to 200 mg/day using a
b.i.d. regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is
obtained. Dosage generally should not exceed 1000 mg daily in children 12-15 years of age, and 1200 mg daily
in patients above 15 years of age. Doses up to 1600 mg daily have been used in adults in rare instances.
Maintenance: Adjust dosage to the minimum effective level, usually 800-1200 mg daily.
Children 6-12 years of age - Initial: Either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for
suspension (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a b.i.d. regimen of
Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is obtained. Dosage
generally should not exceed 1000 mg daily. Maintenance: Adjust dosage to the minimum effective level,
usually 400-800 mg daily.
Children under 6 years of age - Initial: 10-20 mg/kg/day b.i.d. or t.i.d. as tablets, or q.i.d. as suspension.
Increase weekly to achieve optimal clinical response administered t.i.d. or q.i.d. Maintenance: Ordinarily,
optimal clinical response is achieved at daily doses below 35 mg/kg. If satisfactory clinical response has not
been achieved, plasma levels should be measured to determine whether or not they are in the therapeutic range.
No recommendation regarding the safety of carbamazepine for use at doses above 35 mg/kg/24 hours can be
made.
Combination Therapy: Tegretol may be used alone or with other anticonvulsants. When added to existing
anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are maintained or
gradually decreased, except phenytoin, which may have to be increased (see PRECAUTIONS, Drug
Interactions, and Pregnancy Category D).
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Trigeminal Neuralgia (SEE INDICATIONS AND USAGE)
Initial: On the first day, either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for suspension, for a
total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day using increments of 100 mg
every 12 hours for tablets or XR tablets, or 50 mg (1/2 teaspoon) q.i.d. for suspension, only as needed to
achieve freedom from pain. Do not exceed 1200 mg daily. Maintenance: Control of pain can be maintained in
most patients with 400-800 mg daily. However, some patients may be maintained on as little as 200 mg daily,
while others may require as much as 1200 mg daily. At least once every 3 months throughout the treatment
period, attempts should be made to reduce the dose to the minimum effective level or even to discontinue the
drug.
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Dosage Information
Initial Dose
Subsequent Dose
Maximum Daily Dose
Indication
Tablet*
XR
†
Suspension
Tablet*
XR
†
Suspension
Tablet*
XR
†
Suspension
Epilepsy
Under 6 yr
10-20 mg/kg/day
b.i.d. or t.i.d.
10-20 mg/kg/day
q.i.d.
Increase weekly
to achieve
optimal clinical
response, t.i.d.
or q.i.d.
Increase
weekly to
achieve optimal
clinical
response, t.i.d.
or q.i.d.
35 mg/kg/24 hr
(see Dosage
and
Administration
section above)
35 mg/kg/24 hr
(see Dosage
and
Administration
section above)
6-12 yr
100 mg b.i.d.
(200 mg/day)
100 mg b.i.d.
(200 mg/day)
½ tsp q.i.d.
(200 mg/day)
Add up to
100 mg/day at
weekly intervals,
t.i.d. or q.i.d.
Add
100 mg/day
at weekly
intervals,
b.i.d.
Add up to 1 tsp
(100 mg)/day at
weekly
intervals, t.i.d.
or q.i.d.
1000 mg/24 hr
Over 12 yr
200 mg b.i.d.
200 mg b.i.d.
1 tsp q.i.d.
Add up to
Add up to
Add up to 2 tsp
1000 mg/24 hr (12-15 yr)
(400 mg/day)
(400 mg/day)
(400 mg/day)
200 mg/day at
200 mg/day
(200 mg)/day at
1200 mg/24 hr (>15 yr)
weekly intervals,
t.i.d. or q.i.d.
at weekly
intervals,
b.i.d.
weekly
intervals, t.i.d.
or q.i.d.
1600 mg/24 hr (adults, in rare instances)
Trigeminal
100 mg b.i.d.
100 mg b.i.d.
½ tsp q.i.d.
Add up to
Add up to
Add up to 2 tsp
1200 mg/24 hr
Neuralgia
(200 mg/day)
(200 mg/day)
(200 mg/day)
200 mg/day in
increments of
100 mg every
12 hr
200 mg/day
in increments
of 100 mg
every 12 hr
(200 mg)/day
in increments
of 50 mg
(½ tsp) q.i.d.
*Tablet = Chewable or conventional tablets
†XR = Tegretol
®-XR extended-release tablets
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HOW SUPPLIED
Chewable Tablets 100 mg - round, red-speckled, pink, single-scored (imprinted Tegretol on one side and 52
twice on the scored side)
Bottles of 100...................................................................................................................... NDC 0078-0492-05
Unit Dose (blister pack)
Box of 100 (strips of 10)............................................................................................... NDC 0078-0492-35
Do not store above 30°C (86°F). Protect from light and moisture.
Dispense in tight, light-resistant container (USP).
Meets USP Dissolution Test 1.
Tablets 200 mg - capsule-shaped, pink, single-scored (imprinted Tegretol on one side and 27 twice on the
partially scored side)
Bottles of 100...................................................................................................................... NDC 0078-0509-05
Do not store above 30°C (86°F). Protect from moisture.
Dispense in tight container (USP).
Meets USP Dissolution Test 2.
XR Tablets 100 mg - round, yellow, coated (imprinted T on one side and 100 mg on the other), release portal on
one side
Bottles of 100...................................................................................................................... NDC 0078-0510-05
XR Tablets 200 mg - round, pink, coated (imprinted T on one side and 200 mg on the other), release portal on
one side
Bottles of 100...................................................................................................................... NDC 0078-0511-05
XR Tablets 400 mg - round, brown, coated (imprinted T on one side and 400 mg on the other), release portal on
one side
Bottles of 100...................................................................................................................... NDC 0078-0512-05
Store at controlled room temperature 15°C-30°C (59°F-86°F). Protect from moisture.
Dispense in tight container (USP).
Suspension 100 mg/5 mL (teaspoon) – yellow-orange, citrus-vanilla flavored
Bottles of 450 mL ............................................................................................................... NDC 0078-0508-83
Shake well before using.
Do not store above 30°C (86°F). Dispense in tight, light-resistant container (USP).
*Thorazine® is a registered trademark of GlaxoSmithKline. Novartis Logo
Distributed by:
Novartis Pharmaceuticals Corporation
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
East Hanover, New Jersey 07936
REV: FEBRUARY 2009
T2008-29
© Novartis
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:41.041974
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/016608s101,018281s048lbl.pdf', 'application_number': 18281, 'submission_type': 'SUPPL ', 'submission_number': 48}
|
11,198
|
NDA 016608/S-107
NDA 018281/S-055
NDA 018927/S-048
NDA 020234/S-040
FDA Approved Labeling Text dated 12/11/2012
Page 1 company logo
Tegretol®
carbamazepine USP
Chewable Tablets of 100 mg - red-speckled, pink
Tablets of 200 mg – pink
Suspension of 100 mg/5 mL
Tegretol®-XR
(carbamazepine extended-release tablets)
100 mg, 200 mg, 400 mg
Rx only
Prescribing Information
WARNINGS
SERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELE
SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC
EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN
REPORTED DURING TREATMENT WITH TEGRETOL. THESE REACTIONS ARE ESTIMATED TO
OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY CAUCASIAN
POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10
TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG
ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF
HLA-B*1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE. HLA-B*1502 IS FOUND
ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF ASIA.
PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS SHOULD BE SCREENED
FOR THE PRESENCE OF HLA-B*1502 PRIOR TO INITIATING TREATMENT WITH TEGRETOL.
PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH TEGRETOL
UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK (SEE WARNINGS AND PRECAUTIONS,
LABORATORY TESTS).
APLASTIC ANEMIA AND AGRANULOCYTOSIS
APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION WITH
THE USE OF TEGRETOL. DATA FROM A POPULATION-BASED CASE CONTROL STUDY
DEMONSTRATE THAT THE RISK OF DEVELOPING THESE REACTIONS IS 5-8 TIMES GREATER
THAN IN THE GENERAL POPULATION. HOWEVER, THE OVERALL RISK OF THESE REACTIONS
IN THE UNTREATED GENERAL POPULATION IS LOW, APPROXIMATELY SIX PATIENTS PER ONE
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FDA Approved Labeling Text dated 12/11/2012
Page 2
MILLION POPULATION PER YEAR FOR AGRANULOCYTOSIS AND TWO PATIENTS PER ONE
MILLION POPULATION PER YEAR FOR APLASTIC ANEMIA.
ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR WHITE
BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE OF TEGRETOL,
DATA ARE NOT AVAILABLE TO ESTIMATE ACCURATELY THEIR INCIDENCE OR OUTCOME.
HOWEVER, THE VAST MAJORITY OF THE CASES OF LEUKOPENIA HAVE NOT PROGRESSED TO
THE MORE SERIOUS CONDITIONS OF APLASTIC ANEMIA OR AGRANULOCYTOSIS.
BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC ANEMIA,
THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN MONITORING OF
PATIENTS ON TEGRETOL ARE UNLIKELY TO SIGNAL THE OCCURRENCE OF EITHER
ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT HEMATOLOGICAL TESTING
SHOULD BE OBTAINED AS A BASELINE. IF A PATIENT IN THE COURSE OF TREATMENT
EXHIBITS LOW OR DECREASED WHITE BLOOD CELL OR PLATELET COUNTS, THE PATIENT
SHOULD BE MONITORED CLOSELY. DISCONTINUATION OF THE DRUG SHOULD BE
CONSIDERED IF ANY EVIDENCE OF SIGNIFICANT BONE MARROW DEPRESSION DEVELOPS.
Before prescribing Tegretol, the physician should be thoroughly familiar with the details of this
prescribing information, particularly regarding use with other drugs, especially those which accentuate
toxicity potential.
DESCRIPTION
Tegretol, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for
oral administration as chewable tablets of 100 mg, tablets of 200 mg, XR tablets of 100, 200, and 400 mg, and
as a suspension of 100 mg/5 mL (teaspoon). Its chemical name is 5H-dibenz[b,f ]azepine-5-carboxamide, and
its structural formula is structural formula
Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in alcohol and in
acetone. Its molecular weight is 236.27.
Inactive Ingredients Tablets: Colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake (chewable tablets
only), FD&C Red No. 40 (200-mg tablets only), flavoring (chewable tablets only), gelatin, glycerin, magnesium
stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose (chewable tablets
only). Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate, propylene glycol,
purified water, sorbitol, sucrose, and xanthan gum. Tegretol-XR tablets: cellulose compounds, dextrates, iron
oxides, magnesium stearate, mannitol, polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200-mg
tablets only).
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FDA Approved Labeling Text dated 12/11/2012
Page 3
CLINICAL PHARMACOLOGY
In controlled clinical trials, Tegretol has been shown to be effective in the treatment of psychomotor and grand
mal seizures, as well as trigeminal neuralgia.
Mechanism of Action
Tegretol has demonstrated anticonvulsant properties in rats and mice with electrically and chemically induced
seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation.
Tegretol greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It
depresses thalamic potential and bulbar and polysynaptic reflexes, including the linguomandibular reflex in
cats. Tegretol is chemically unrelated to other anticonvulsants or other drugs used to control the pain of
trigeminal neuralgia. The mechanism of action remains unknown.
The principal metabolite of Tegretol, carbamazepine-10,11-epoxide, has anticonvulsant activity as
demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide has been
postulated, the significance of its activity with respect to the safety and efficacy of Tegretol has not been
established.
Pharmacokinetics
In clinical studies, Tegretol suspension, conventional tablets, and XR tablets delivered equivalent amounts of
drug to the systemic circulation. However, the suspension was absorbed somewhat faster, and the XR tablet
slightly slower, than the conventional tablet. The bioavailability of the XR tablet was 89% compared to
suspension. Following a b.i.d. dosage regimen, the suspension provides higher peak levels and lower trough
levels than those obtained from the conventional tablet for the same dosage regimen. On the other hand,
following a t.i.d. dosage regimen, Tegretol suspension affords steady-state plasma levels comparable to
Tegretol tablets given b.i.d. when administered at the same total mg daily dose. Following a b.i.d. dosage
regimen, Tegretol-XR tablets afford steady-state plasma levels comparable to conventional Tegretol tablets
given q.i.d., when administered at the same total mg daily dose. Tegretol in blood is 76% bound to plasma
proteins. Plasma levels of Tegretol are variable and may range from 0.5-25 µg/mL, with no apparent
relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 µg/mL. In
polytherapy, the concentration of Tegretol and concomitant drugs may be increased or decreased during
therapy, and drug effects may be altered (see PRECAUTIONS, Drug Interactions). Following chronic oral
administration of suspension, plasma levels peak at approximately 1.5 hours compared to 4-5 hours after
administration of conventional Tegretol tablets, and 3-12 hours after administration of Tegretol-XR tablets. The
CSF/serum ratio is 0.22, similar to the 24% unbound Tegretol in serum. Because Tegretol induces its own
metabolism, the half-life is also variable. Autoinduction is completed after 3-5 weeks of a fixed dosing regimen.
Initial half-life values range from 25-65 hours, decreasing to 12-17 hours on repeated doses. Tegretol is
metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the
formation of carbamazepine-10,11-epoxide from Tegretol. After oral administration of 14C-carbamazepine, 72%
of the administered radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was
composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged Tegretol.
The pharmacokinetic parameters of Tegretol disposition are similar in children and in adults. However, there is
a poor correlation between plasma concentrations of carbamazepine and Tegretol dose in children.
Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide (a metabolite shown to be
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FDA Approved Labeling Text dated 12/11/2012
Page 4
equipotent to carbamazepine as an anticonvulsant in animal screens) in the younger age groups than in adults. In
children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age (in
one report from 0.44 in children below the age of 1 year to 0.18 in children between 10-15 years of age).
The effects of race and gender on carbamazepine pharmacokinetics have not been systematically evaluated.
INDICATIONS AND USAGE
Epilepsy
Tegretol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of Tegretol as an
anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure
types:
1. Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures
appear to show greater improvement than those with other types.
2. Generalized tonic-clonic seizures (grand mal).
3. Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence seizures
(petit mal) do not appear to be controlled by Tegretol (see PRECAUTIONS, General).
Trigeminal Neuralgia
Tegretol is indicated in the treatment of the pain associated with true trigeminal neuralgia.
Beneficial results have also been reported in glossopharyngeal neuralgia.
This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.
CONTRAINDICATIONS
Tegretol should not be used in patients with a history of previous bone marrow depression, hypersensitivity to
the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine,
imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with monoamine oxidase
inhibitors is not recommended. Before administration of Tegretol, MAO inhibitors should be discontinued for a
minimum of 14 days, or longer if the clinical situation permits.
Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of
nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with
nefazodone is contraindicated.
WARNINGS
Serious Dermatologic Reactions
Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and
Stevens-Johnson syndrome (SJS), have been reported with Tegretol treatment. The risk of these events is
estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. However, the
risk in some Asian countries is estimated to be about 10 times higher. Tegretol should be discontinued at the
first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this
drug should not be resumed and alternative therapy should be considered.
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FDA Approved Labeling Text dated 12/11/2012
Page 5
SJS/TEN and HLA-B*1502 Allele
Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association
between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant
of the HLA-B gene, HLA-B*1502. The occurrence of higher rates of these reactions in countries with higher
frequencies of this allele suggests that the risk may be increased in allele-positive individuals of any ethnicity.
Across Asian populations, notable variation exists in the prevalence of HLA-B*1502. Greater than 15% of the
population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared to
about 10% in Taiwan and 4% in North China. South Asians, including Indians, appear to have intermediate
prevalence of HLA-B*1502, averaging 2 to 4%, but higher in some groups. HLA-B*1502 is present in <1% of
the population in Japan and Korea.
HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans,
Hispanics, and Native Americans).
Prior to initiating Tegretol therapy, testing for HLA-B*1502 should be performed in patients with
ancestry in populations in which HLA-B*1502 may be present. In deciding which patients to screen, the
rates provided above for the prevalence of HLA-B*1502 may offer a rough guide, keeping in mind the
limitations of these figures due to wide variability in rates even within ethnic groups, the difficulty in
ascertaining ethnic ancestry, and the likelihood of mixed ancestry. Tegretol should not be used in patients
positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Tested patients who are found to be
negative for the allele are thought to have a low risk of SJS/TEN (see WARNINGS and PRECAUTIONS,
Laboratory Tests).
Over 90% of Tegretol treated patients who will experience SJS/TEN have this reaction within the first few
months of treatment. This information may be taken into consideration in determining the need for screening of
genetically at-risk patients currently on Tegretol.
The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from
Tegretol, such as anticonvulsant hypersensitivity syndrome or nonserious rash (maculopapular eruption [MPE]).
Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients
of Chinese ancestry taking other antiepileptic drugs associated with SJS/TEN. Consideration should be given to
avoiding use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when alternative
therapies are otherwise equally acceptable.
Application of HLA-B*1502 genotyping as a screening tool has important limitations and must never substitute
for appropriate clinical vigilance and patient management. Many HLA-B*1502-positive Asian patients treated
with Tegretol will not develop SJS/TEN, and these reactions can still occur infrequently in
HLA-B*1502-negative patients of any ethnicity. The role of other possible factors in the development of, and
morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications,
comorbidities, and the level of dermatologic monitoring have not been studied.
Aplastic Anemia and Agranulocytosis
Patients with a history of adverse hematologic reaction to any drug may be particularly at risk of bone marrow
depression.
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Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Tegretol, increase the risk of suicidal thoughts or behavior in patients
taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for
the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood
or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs
showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk
1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these
trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or
ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated
patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530
patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated
patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting
drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in
the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could
not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The
finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests
that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years)
in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
Table 1 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication
Placebo Patients
with Events Per
1,000 Patients
Drug Patients
with Events Per
1,000 Patients
Relative Risk:
Incidence of
Events in Drug
Patients/Incidence
in Placebo
Patients
Risk Difference:
Additional Drug
Patients with
Events Per 1,000
Patients
Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials
for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric
indications.
Anyone considering prescribing Tegretol or any other AED must balance the risk of suicidal thoughts or
behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are
themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.
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Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the
emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and
behavior and should be advised of the need to be alert for the emergence or worsening of the signs and
symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,
behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare
providers.
General
Tegretol has shown mild anticholinergic activity; therefore, patients with increased intraocular pressure should
be closely observed during therapy.
Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a latent
psychosis and, in elderly patients, of confusion or agitation should be borne in mind.
The use of Tegretol should be avoided in patients with a history of hepatic porphyria (e.g., acute intermittent
porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported in such patients
receiving Tegretol therapy. Carbamazepine administration has also been demonstrated to increase porphyrin
precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria.
As with all antiepileptic drugs, Tegretol should be withdrawn gradually to minimize the potential of increased
seizure frequency.
Usage in Pregnancy
Carbamazepine can cause fetal harm when administered to a pregnant woman.
Epidemiological data suggest that there may be an association between the use of carbamazepine during
pregnancy and congenital malformations, including spina bifida. There have also been reports that associate
carbamazepine with developmental disorders and congenital anomalies (e.g., craniofacial defects,
cardiovascular malformations, hypospadias and anomalies involving various body systems). Developmental
delays based on neurobehavioral assessments have been reported. In treating or counseling women of
childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against the risks. If
this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should
be apprised of the potential hazard to the fetus.
Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of
teratogenic effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to
be continued, monotherapy may be preferable for pregnant women.
In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is accumulated in
the fetal tissues, with higher levels found in liver and kidney than in brain and lung.
Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in
dosages 10-25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 1.5-4 times
the MHDD on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250 mg/kg and
4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate, 1; talipes, 1; anophthalmos, 2). In
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reproduction studies in rats, nursing offspring demonstrated a lack of weight gain and an unkempt appearance at
a maternal dosage level of 200 mg/kg.
Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent
major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and
threat to life. In individual cases where the severity and frequency of the seizure disorder are such that removal
of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior
to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose
some hazard to the developing embryo or fetus.
Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal care
in childbearing women receiving carbamazepine.
There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal
Tegretol and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or
decreased feeding have also been reported in association with maternal Tegretol use. These symptoms may
represent a neonatal withdrawal syndrome.
To provide information regarding the effects of in utero exposure to Tegretol, physicians are advised to
recommend that pregnant patients taking Tegretol enroll in the North American Antiepileptic Drug (NAAED)
Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by
patients themselves. Information on the registry can also be found at the website
http://www.aedpregnancyregistry.org/.
PRECAUTIONS
General
Before initiating therapy, a detailed history and physical examination should be made.
Tegretol should be used with caution in patients with a mixed seizure disorder that includes atypical absence
seizures, since in these patients Tegretol has been associated with increased frequency of generalized
convulsions (see INDICATIONS AND USAGE).
Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac
conduction disturbance, including second and third degree AV heart block; cardiac, hepatic, or renal damage;
adverse hematologic or hypersensitivity reaction to other drugs, including reactions to other anticonvulsants; or
interrupted courses of therapy with Tegretol.
AV heart block, including second and third degree block, have been reported following Tegretol treatment. This
occurred generally, but not solely, in patients with underlying EKG abnormalities or risk factors for conduction
disturbances.
Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have been
reported (see ADVERSE REACTIONS and PRECAUTIONS, Laboratory Tests). In some cases, hepatic effects
may progress despite discontinuation of the drug.
Multiorgan hypersensitivity reactions which can affect the skin, liver, hemopoietic organs and lymphatic system
or other organs and occurring days to weeks or months after initiating treatment have been reported in rare cases
(see ADVERSE REACTIONS, Other and PRECAUTIONS, Information for Patients).
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Discontinuation of carbamazepine should be considered if any evidence of hypersensitivity develops.
Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this
reaction to anticonvulsants including phenytoin and phenobarbital. A history of hypersensitivity reactions
should be obtained for a patient and the immediate family members. If positive, caution should be used in
prescribing carbamazepine.
In patients who have exhibited hypersensitivity reactions to carbamazepine approximately 25 to 30% of these
patients may experience hypersensitivity reactions with oxcarbazepine (Trileptal®).
Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the
tablet, it is recommended that patients given the suspension be started on lower doses and increased slowly to
avoid unwanted side effects (see DOSAGE AND ADMINISTRATION).
Tegretol suspension contains sorbitol and, therefore, should not be administered to patients with rare hereditary
problems of fructose intolerance.
Information for Patients
Patients should be informed of the availability of a Medication Guide and they should be instructed to read the
Medication Guide before taking Tegretol.
Patients should be made aware of the early toxic signs and symptoms of a potential hematologic problem, as
well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include, but are not limited to,
fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric
hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be
advised that, because these signs and symptoms may signal a serious reaction, that they must report any
occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms
should be reported even if mild or when occurring after extended use.
Patients, their caregivers, and families should be counseled that AEDs, including Tegretol, may increase the risk
of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening
of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,
behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare
providers
Patients should be advised that serious skin reactions have been reported in association with Tegretol. In the
event a skin reaction should occur while taking Tegretol, patients should consult with their physician
immediately (see WARNINGS).
Tegretol may interact with some drugs. Therefore, patients should be advised to report to their doctors the use
of any other prescription or nonprescription medications or herbal products.
Caution should be exercised if alcohol is taken in combination with Tegretol therapy, due to a possible additive
sedative effect.
Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of operating
machinery or automobiles or engaging in other potentially dangerous tasks.
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Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This
registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients
can call the toll free number 1-888-233-2334 (see WARNINGS, Usage in Pregnancy subsection).
Laboratory Tests
For genetically at-risk patients (see WARNINGS), high-resolution ‘HLA-B*1502 typing’ is recommended. The
test is positive if either one or two HLA-B*1502 alleles are detected and negative if no HLA-B*1502 alleles are
detected.
Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, should be
obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white blood cell or
platelet counts, the patient should be monitored closely. Discontinuation of the drug should be considered if any
evidence of significant bone marrow depression develops.
Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must
be performed during treatment with this drug since liver damage may occur (see PRECAUTIONS, General and
ADVERSE REACTIONS). Carbamazepine should be discontinued, based on clinical judgment, if indicated by
newly occurring or worsening clinical or laboratory evidence of liver dysfunction or hepatic damage, or in the
case of active liver disease.
Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are recommended
since many phenothiazines and related drugs have been shown to cause eye changes.
Baseline and periodic complete urinalysis and BUN determinations are recommended for patients treated with
this agent because of observed renal dysfunction.
Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and safety of
anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in seizure frequency
and for verification of compliance. In addition, measurement of drug serum levels may aid in determining the
cause of toxicity when more than one medication is being used.
Thyroid function tests have been reported to show decreased values with Tegretol administered alone.
Hyponatremia has been reported in association with Tegretol use, either alone or in combination with other
drugs.
Interference with some pregnancy tests has been reported.
Drug Interactions
There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting
Tegretol suspension immediately followed by Thorazine®* solution. Subsequent testing has shown that mixing
Tegretol suspension and chlorpromazine solution (both generic and brand name) as well as Tegretol suspension
and liquid Mellaril® resulted in the occurrence of this precipitate. Because the extent to which this occurs with
other liquid medications is not known, Tegretol suspension should not be administered simultaneously with
other liquid medicinal agents or diluents (see DOSAGE AND ADMINISTRATION).
Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not
limited to, the following:
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Agents That May Affect Tegretol Plasma Levels
CYP 3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma carbamazepine levels. Drugs that
have been shown, or would be expected, to increase plasma carbamazepine levels include:
cimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine,
fluvoxamine, nefazodone, trazodone, loxapine*, olanzapine, quetiapine*, loratadine, terfenadine,
omeprazole, oxybutynin, dantrolene, isoniazid, niacinamide, nicotinamide, ibuprofen, propoxyphene,
azoles (e.g., ketaconazole, itraconazole, fluconazole, voriconazole), acetazolamide, verapamil,
ticlopidine, grapefruit juice, protease inhibitors, valproate*.
CYP 3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that would be
expected, to decrease plasma carbamazepine levels include:
cisplatin, doxorubicin HCl, felbamate†, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone,
methsuximide, theophylline, aminophylline.
When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring
of carbamazepine levels is indicated and dosage adjustment may be required.
*increased levels of the active 10,11-epoxide
†decreased levels of carbamazepine and increased levels of the 10,11-epoxide
Effect of Tegretol on Plasma Levels of Concomitant Agents
Increased levels: clomipramine HCl, phenytoin, primidone
Tegretol is a potent inducer of hepatic CYP 3A4 and may therefore reduce plasma concentrations of co
medications mainly metabolized by 3A4 through induction of their metabolism. Tegretol causes, or would be
expected to cause, decreased levels of the following:
acetaminophen, alprazolam, bupropion, dihydropyridine calcium channel blockers (e.g., felodipine),
citalopram, cyclosporine, corticosteroids (e.g., prednisolone, dexamethasone), clonazepam, clozapine,
dicumarol, doxycycline, ethosuximide, everolimus, haloperidol, imatinib, itraconazole, lamotrigine,
levothyroxine, methadone, methsuximide, midazolam, olanzapine, oral and other hormonal
contraceptives, oxcarbazepine, phensuximide, phenytoin, praziquantel, protease inhibitors,
risperidone, theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants (e.g.,
imipramine, amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, zonisamide.
In concomitant use with Tegretol, dosage adjustment of the above agents may be necessary.
Coadministration of carbamazepine with nefazodone results in insufficient plasma concentrations of nefazodone
and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is
contraindicated (see CONTRAINDICATIONS).
Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects.
Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced
hepatotoxicity.
Concomitant medication with Tegretol and some diuretics (hydrochlorothiazide, furosemide) may lead to
symptomatic hyponatremia.
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Carbamazepine may antagonize the effects of nondepolarizing muscle relaxants (e.g., pancuronium).
Their dosage may need to be raised, and patients should be monitored closely for more rapid recovery from
neuromuscular blockade than expected.
Alterations of thyroid function have been reported in combination therapy with other anticonvulsant
medications.
Concomitant use of Tegretol with hormonal contraceptive products (e.g., oral, and levonorgestrel subdermal
implant contraceptives) may render the contraceptives less effective because the plasma concentrations of the
hormones may be decreased. Breakthrough bleeding and unintended pregnancies have been reported.
Alternative or back-up methods of contraception should be considered.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75, and
250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular tumors in females and of
benign interstitial cell adenomas in the testes of males.
Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Bacterial and
mammalian mutagenicity studies using carbamazepine produced negative results. The significance of these
findings relative to the use of carbamazepine in humans is, at present, unknown.
Usage in Pregnancy
Pregnancy Category D (see WARNINGS).
Labor and Delivery
The effect of Tegretol on human labor and delivery is unknown.
Nursing Mothers
Tegretol and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in breast milk
to that in maternal plasma is about 0.4 for Tegretol and about 0.5 for the epoxide. The estimated doses given to
the newborn during breast-feeding are in the range of 2-5 mg daily for Tegretol and 1-2 mg daily for the
epoxide.
Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a decision should
be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the
drug to the mother.
Pediatric Use
Substantial evidence of Tegretol’s effectiveness for use in the management of children with epilepsy (see
INDICATIONS AND USAGE for specific seizure types) is derived from clinical investigations performed in
adults and from studies in several in vitro systems which support the conclusion that (1) the pathogenetic
mechanisms underlying seizure propagation are essentially identical in adults and children, and (2) the
mechanism of action of carbamazepine in treating seizures is essentially identical in adults and children.
Taken as a whole, this information supports a conclusion that the generally accepted therapeutic range of total
carbamazepine in plasma (i.e., 4-12 mcg/mL) is the same in children and adults.
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The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety of
carbamazepine in children has been systematically studied up to 6 months. No longer-term data from clinical
trials is available.
Geriatric Use
No systematic studies in geriatric patients have been conducted.
ADVERSE REACTIONS
If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that
abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead to seizures or even
status epilepticus with its life-threatening hazards.
The most severe adverse reactions have been observed in the hemopoietic system and skin (see BOXED
WARNING), the liver, and the cardiovascular system.
The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness,
drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should
be initiated at the low dosage recommended.
The following additional adverse reactions have been reported:
Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression,
thrombocytopenia, leukopenia, leukocytosis, eosinophilia, anemia, acute intermittent porphyria, variegate
porphyria, porphyria cutanea tarda.
Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXED WARNING),
pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin pigmentation,
exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus
erythematosus, alopecia, diaphoresis, and onychomadesis. In certain cases, discontinuation of therapy may be
necessary. Isolated cases of hirsutism have been reported, but a causal relationship is not clear.
Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope
and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis,
thromboembolism (e.g., pulmonary embolism), and adenopathy or lymphadenopathy.
Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been
associated with other tricyclic compounds.
Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very rare cases of
hepatic failure.
Pancreatic: Pancreatitis.
Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia.
Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood pressure,
azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and microscopic deposits in the
urine have also been reported. There have been very rare reports of impaired male fertility and/or abnormal
spermatogenesis.
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Testicular atrophy occurred in rats receiving Tegretol orally from 4-52 weeks at dosage levels of 50-400
mg/kg/day. Additionally, rats receiving Tegretol in the diet for 2 years at dosage levels of 25, 75, and 250
mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a
brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg and
higher. Relevance of these findings to humans is unknown.
Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred
vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances,
abnormal involuntary movements, peripheral neuritis and paresthesias, depression with agitation, talkativeness,
tinnitus, hyperacusis, neuroleptic malignant syndrome.
There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the
exact relationship of these reactions to the drug has not been established.
Isolated cases of neuroleptic malignant syndrome have been reported both with and without concomitant use of
psychotropic drugs.
Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia, and
dryness of the mouth and pharynx, including glossitis and stomatitis.
Eyes: Scattered punctate cortical lens opacities, increased intraocular pressure as well as conjunctivitis, have
been reported. Although a direct causal relationship has not been established, many phenothiazines and related
drugs have been shown to cause eye changes.
Musculoskeletal System: Aching joints and muscles, and leg cramps.
Metabolism: Fever and chills. Inappropriate antidiuretic hormone (ADH) secretion syndrome has been reported.
Cases of frank water intoxication, with decreased serum sodium (hyponatremia) and confusion, have been
reported in association with Tegretol use (see PRECAUTIONS, Laboratory Tests). Decreased levels of plasma
calcium leading to osteoporosis have been reported.
Other: Multiorgan hypersensitivity reactions occurring days to weeks or months after initiating treatment have
been reported in rare cases. Signs or symptoms may include, but are not limited to fever, skin rashes, vasculitis,
lymphadenopathy, disorders mimicking lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly
and abnormal liver function tests. These signs and symptoms may occur in various combinations and not
necessarily concurrently. Signs and symptoms may initially be mild. Various organs, including but not limited
to, liver, skin, immune system, lungs, kidneys, pancreas, myocardium, and colon may be affected (see
PRECAUTIONS, General and PRECAUTIONS, Information for Patients).
Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional reports
of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants.
A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a
patient taking carbamazepine in combination with other medications. The patient was successfully
dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.
DRUG ABUSE AND DEPENDENCE
No evidence of abuse potential has been associated with Tegretol, nor is there evidence of psychological or
physical dependence in humans.
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OVERDOSAGE
Acute Toxicity
Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-old man
died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a cardiac arrest), 1.6 g
(a 3-year-old girl died of aspiration pneumonia).
Oral LD50 in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-2680; guinea pigs, 920.
Signs and Symptoms
The first signs and symptoms appear after 1-3 hours. Neuromuscular disturbances are the most prominent.
Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high
doses (>60 g) have been ingested.
Respiration: Irregular breathing, respiratory depression.
Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders.
Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma. Convulsions,
especially in small children. Motor restlessness, muscular twitching, tremor, athetoid movements, opisthotonos,
ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism, psychomotor disturbances,
dysmetria. Initial hyperreflexia, followed by hyporeflexia.
Gastrointestinal Tract: Nausea, vomiting.
Kidneys and Bladder: Anuria or oliguria, urinary retention.
Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte count,
glycosuria, and acetonuria. EEG may show dysrhythmias.
Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same
time, the signs and symptoms of acute poisoning with Tegretol may be aggravated or modified.
Treatment
The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which
may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps to diminish
absorption. If these measures cannot be implemented without risk on the spot, the patient should be transferred
at once to a hospital, while ensuring that vital functions are safeguarded. There is no specific antidote.
Elimination of the Drug: Induction of vomiting.
Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the stomach should
be repeatedly irrigated, especially if the patient has also consumed alcohol.
Measures to Reduce Absorption: Activated charcoal, laxatives.
Measures to Accelerate Elimination: Forced diuresis.
Dialysis is indicated only in severe poisoning associated with renal failure. Replacement transfusion is indicated
in severe poisoning in small children.
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Respiratory Depression: Keep the airways free; resort, if necessary, to endotracheal intubation, artificial
respiration, and administration of oxygen.
Hypotension, Shock: Keep the patient’s legs raised and administer a plasma expander. If blood pressure fails to
rise despite measures taken to increase plasma volume, use of vasoactive substances should be considered.
Convulsions: Diazepam or barbiturates.
Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children), hypotension,
and coma. However, barbiturates should not be used if drugs that inhibit monoamine oxidase have also been
taken by the patient either in overdosage or in recent therapy (within 1 week).
Surveillance: Respiration, cardiac function (ECG monitoring), blood pressure, body temperature, pupillary
reflexes, and kidney and bladder function should be monitored for several days.
Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression develops, the
following recommendations are suggested: (1) stop the drug, (2) perform daily CBC, platelet, and reticulocyte
counts, (3) do a bone marrow aspiration and trephine biopsy immediately and repeat with sufficient frequency
to monitor recovery.
Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2) 59Fe-ferrokinetic
studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and peripheral blood, (5) bone
marrow culture studies for colony-forming units, (6) hemoglobin electrophoresis for A2 and F hemoglobin, and
(7) serum folic acid and B12 levels.
A fully developed aplastic anemia will require appropriate, intensive monitoring and therapy, for which
specialized consultation should be sought.
DOSAGE AND ADMINISTRATION (SEE TABLE BELOW)
Tegretol suspension in combination with liquid chlorpromazine or thioridazine results in precipitate formation,
and, in the case of chlorpromazine, there has been a report of a patient passing an orange rubbery precipitate in
the stool following coadministration of the two drugs (see PRECAUTIONS, Drug Interactions). Because the
extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be
administered simultaneously with other liquid medications or diluents.
Monitoring of blood levels has increased the efficacy and safety of anticonvulsants (see PRECAUTIONS,
Laboratory Tests). Dosage should be adjusted to the needs of the individual patient. A low initial daily dosage
with a gradual increase is advised. As soon as adequate control is achieved, the dosage may be reduced very
gradually to the minimum effective level. Medication should be taken with meals.
Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the
tablet, it is recommended to start with low doses (children 6-12 years: 1/2 teaspoon q.i.d.) and to increase
slowly to avoid unwanted side effects.
Conversion of patients from oral Tegretol tablets to Tegretol suspension: Patients should be converted by
administering the same number of mg per day in smaller, more frequent doses (i.e., b.i.d. tablets to t.i.d.
suspension).
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Tegretol-XR is an extended-release formulation for twice-a-day administration. When converting patients from
Tegretol conventional tablets to Tegretol-XR, the same total daily mg dose of Tegretol-XR should be
administered. Tegretol-XR tablets must be swallowed whole and never crushed or chewed. Tegretol-XR
tablets should be inspected for chips or cracks. Damaged tablets, or tablets without a release portal, should not
be consumed. Tegretol-XR tablet coating is not absorbed and is excreted in the feces; these coatings may be
noticeable in the stool.
Epilepsy (SEE INDICATIONS AND USAGE)
Adults and children over 12 years of age - Initial: Either 200 mg b.i.d. for tablets and XR tablets, or 1 teaspoon
q.i.d. for suspension (400 mg/day). Increase at weekly intervals by adding up to 200 mg/day using a b.i.d.
regimen of Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is
obtained. Dosage generally should not exceed 1000 mg daily in children 12-15 years of age, and 1200 mg daily
in patients above 15 years of age. Doses up to 1600 mg daily have been used in adults in rare instances.
Maintenance: Adjust dosage to the minimum effective level, usually 800-1200 mg daily.
Children 6-12 years of age - Initial: Either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for
suspension (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a b.i.d. regimen of
Tegretol-XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is obtained. Dosage
generally should not exceed 1000 mg daily. Maintenance: Adjust dosage to the minimum effective level,
usually 400-800 mg daily.
Children under 6 years of age - Initial: 10-20 mg/kg/day b.i.d. or t.i.d. as tablets, or q.i.d. as suspension.
Increase weekly to achieve optimal clinical response administered t.i.d. or q.i.d. Maintenance: Ordinarily,
optimal clinical response is achieved at daily doses below 35 mg/kg. If satisfactory clinical response has not
been achieved, plasma levels should be measured to determine whether or not they are in the therapeutic range.
No recommendation regarding the safety of carbamazepine for use at doses above 35 mg/kg/24 hours can be
made.
Combination Therapy: Tegretol may be used alone or with other anticonvulsants. When added to existing
anticonvulsant therapy, the drug should be added gradually while the other anticonvulsants are maintained or
gradually decreased, except phenytoin, which may have to be increased (see PRECAUTIONS, Drug
Interactions, and Pregnancy Category D).
Trigeminal Neuralgia (SEE INDICATIONS AND USAGE)
Initial: On the first day, either 100 mg b.i.d. for tablets or XR tablets, or 1/2 teaspoon q.i.d. for suspension, for a
total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day using increments of 100 mg
every 12 hours for tablets or XR tablets, or 50 mg (1/2 teaspoon) q.i.d. for suspension, only as needed to
achieve freedom from pain. Do not exceed 1200 mg daily. Maintenance: Control of pain can be maintained in
most patients with 400-800 mg daily. However, some patients may be maintained on as little as 200 mg daily,
while others may require as much as 1200 mg daily. At least once every 3 months throughout the treatment
period, attempts should be made to reduce the dose to the minimum effective level or even to discontinue the
drug.
Reference ID: 3219002
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Dosage Information
Initial Dose
Subsequent Dos
e
Maximum Dail y Dose
Indication
Tablet*
XR
†
Suspension
Tablet*
XR
†
Suspension
Tablet*
XR
†
Suspension
Epileps
y
Under 6 yr
10-20 mg/kg/day
10-20 mg/kg/day
Increase weekl y
Increase
35 mg/kg/24 hr
35 mg/kg/24 hr
b.i.d. or t.i.d.
q.i.d.
to achieve
weekly to
(see Dosage
(see Dosage
optimal clinical
achieve optimal
and
and
response, t.i.d.
clinical
Administration
Administration
or q.i.d.
response, t.i.d.
section above)
section above)
or q.i.d.
6-12 yr
100 mg b.i.d.
100 mg b.i.d.
½ tsp q.i.d.
Add up to
Add
Add up to 1 tsp
1000 mg/24 h r
(200 mg/day)
(200 mg/day)
(200 mg/day)
100 mg/day at
100 mg/da y
(100 mg)/day at
weekly intervals,
at weekl y
weekl y
t.i.d. or q.i.d.
intervals,
intervals, t.i.d.
b.i.d.
or q.i.d.
Over 12 yr
200 mg b.i.d.
200 mg b.i.d.
1 tsp q.i.d.
Add up to
Add up to
Add up to 2 tsp
1000 mg/24 hr (12-15 yr)
(400 mg/day)
(400 mg/day)
(400 mg/day)
200 mg/day at
200 mg/da y
(200 mg)/day at
1200 mg/24 hr (>15 yr)
weekly intervals,
at weekl y
weekl y
1600 mg/24 hr (adults, in rare instances)
t.i.d. or q.i.d.
intervals,
intervals, t.i.d.
b.i.d.
or q.i.d.
Trigeminal
100 mg b.i.d.
100 mg b.i.d.
½ tsp q.i.d.
Add up to
Add up to
Add up to 2 tsp
1200 mg/24 h r
Neuralgia
(200 mg/day)
(200 mg/day)
(200 mg/day)
200 mg/day in
200 mg/da y
(200 mg)/day
increments of
in increments
in increments
100 mg every
of 100 mg
of 50 mg
12 hr
every 12 hr
(½ tsp) q.i.d.
*Tablet = Chewable or conventional tablets
†XR = Tegretol
®-XR extended-release tablets
Reference ID: 3219002
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HOW SUPPLIED
Chewable Tablets 100 mg - round, red-speckled, pink, single-scored (imprinted Tegretol on one side and 52
twice on the scored side)
Bottles of 100………………………………………………………………………………….NDC 0078-0492-05
Unit Dose (blister pack)
Box of 100 (strips of 10)……………………………………………………………………....NDC 0078-0492-35
Do not store above 30°C (86°F). Protect from light and moisture.
Dispense in tight, light-resistant container (USP).
Meets USP Dissolution Test 1.
Tablets 200 mg - capsule-shaped, pink, single-scored (imprinted Tegretol on one side and 27 twice on the
partially scored side)
Bottles of 100.............................................................................................................................NDC 0078-0509-05
Do not store above 30°C (86°F). Protect from moisture.
Dispense in tight container (USP).
Meets USP Dissolution Test 2.
XR Tablets 100 mg - round, yellow, coated (imprinted T on one side and 100 mg on the other), release portal on
one side
Bottles of 100.............................................................................................................................NDC 0078-0510-05
XR Tablets 200 mg - round, pink, coated (imprinted T on one side and 200 mg on the other), release portal on
one side
Bottles of 100.............................................................................................................................NDC 0078-0511-05
XR Tablets 400 mg - round, brown, coated (imprinted T on one side and 400 mg on the other), release portal on
one side
Bottles of 100.............................................................................................................................NDC 0078-0512-05
Store at controlled room temperature 15°C-30°C (59°F-86°F). Protect from moisture.
Dispense in tight container (USP).
Suspension 100 mg/5 mL (teaspoon) – yellow-orange, citrus-vanilla flavored
Bottles of
450 mL.......................................................................................................................................NDC 0078-0508-83
Shake well before using.
Do not store above 30°C (86°F). Dispense in tight, light-resistant container (USP).
*Thorazine® is a registered trademark of GlaxoSmithKline.
Reference ID: 3219002
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEDICATION GUIDE
TEGRETOL® and TEGRETOL®-XR (Teg-ret-ol)
(carbamazepine)
Tablets, Suspension, Chewable Tablets, Extended-Release Tablets
Read this Medication Guide before you start taking Tegretol or Tegretol –XR (TEGRETOL) and each time you
get a refill. There may be new information. This information does not take the place of talking to your
healthcare provider about your medical condition or treatment.
What is the most important information I should know about TEGRETOL?
Do not stop taking TEGRETOL without first talking to your healthcare provider.
Stopping TEGRETOL suddenly can cause serious problems.
TEGRETOL can cause serious side effects, including:
1. TEGRETOL may cause rare but serious skin rashes that may lead to death. These serious skin
reactions are more likely to happen when you begin taking TEGRETOL within the first four
months of treatment but may occur at later times. These reactions can happen in anyone, but
are more likely in people of Asian descent. If you are of Asian descent, you may need a genetic
blood test before you take TEGRETOL to see if you are at a higher risk for serious skin
reactions with this medicine. Symptoms may include:
skin rash
hives
sores in your mouth
blistering or peeling of the skin
2. TEGRETOL may cause rare but serious blood problems. Symptoms may include:
fever, sore throat or other infections that come and go or do not go away
easy bruising
red or purple spots on your body
bleeding gums or nose bleeds
severe fatigue or weakness
3. Like other antiepileptic drugs, TEGRETOL may cause suicidal thoughts or actions in a very
small number of people, about 1 in 500.
Call your healthcare provider right away if you have any of these symptoms, especially if they
are new, worse, or worry you:
thoughts about suicide or dying
attempts to commit suicide
new or worse depression
new or worse anxiety
feeling agitated or restless
panic attacks
trouble sleeping (insomnia)
new or worse irritability
acting aggressive, being angry, or violent
Reference ID: 3219002
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
acting on dangerous impulses
an extreme increase in activity and talking (mania)
other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?
Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
Keep all follow-up visits with your healthcare provider as scheduled.
Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
Do not stop TEGRETOL without first talking to a healthcare provider.
Stopping TEGRETOL suddenly can cause serious problems. You should talk to your healthcare
provider before stopping.
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts
or actions, your healthcare provider may check for other causes.
What is TEGRETOL?
TEGRETOL is a prescription medicine used to treat:
certain types of seizures (partial, tonic-clonic, mixed)
certain types of nerve pain (trigeminal and glossopharyngeal neuralgia)
TEGRETOL is not a regular pain medicine and should not be used for aches or pains.
Who should not take TEGRETOL?
Do not take TEGRETOL if you:
have a history of bone marrow depression.
are allergic to carbamazepine or any of the ingredients in TEGRETOL. See the end of this Medication
Guide for a complete list of ingredients in TEGRETOL.
take nefazodone.
are allergic to medicines called tricyclic antidepressants (TCAs). Ask your healthcare provider or
pharmacist for a list of these medicines if you are not sure.
have taken a medicine called a Monoamine Oxidase Inhibitor (MAOI) in the last 14 days. Ask your
healthcare provider or pharmacist for a list of these medicines if you are not sure.
What should I tell my healthcare provider before taking TEGRETOL?
Before you take TEGRETOL, tell your healthcare provider if you:
have or have had suicidal thoughts or actions, depression or mood problems
have or ever had heart problems
have or ever had blood problems
have or ever had liver problems
have or ever had kidney problems
Reference ID: 3219002
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
have or ever had allergic reactions to medicines
have or ever had increased pressure in your eye
have any other medical conditions
drink grapefruit juice or eat grapefruit
use birth control. TEGRETOL may make your birth control less effective. Tell your healthcare
provider if your menstrual bleeding changes while you take birth control and TEGRETOL.
are pregnant or plan to become pregnant. TEGRETOL may harm your unborn baby. Tell your
healthcare provider right away if you become pregnant while taking TEGRETOL. You and your
healthcare provider should decide if you should take TEGRETOL while you are pregnant.
▪ If you become pregnant while taking TEGRETOL, talk to your healthcare provider about registering
with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this
registry is to collect information about the safety of antiepileptic medicine during pregnancy. You can
enroll in this registry by calling 1-888-233-2334.
are breastfeeding or plan to breastfeed. TEGRETOL passes into breast milk. You and your healthcare
provider should discuss whether you should take TEGRETOL or breastfeed; you should not do both.
Tell your healthcare provider about all the medicines you take, including prescription and non-prescription
medicines, vitamins, and herbal supplements.
Taking TEGRETOL with certain other medicines may cause side effects or affect how well they work. Do not
start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when
you get a new medicine.
How should I take TEGRETOL?
Do not stop taking TEGRETOL without first talking to your healthcare provider. Stopping TEGRETOL
suddenly can cause serious problems. Stopping seizure medicine suddenly in a patient who has epilepsy
may cause seizures that will not stop (status epilepticus).
Take TEGRETOL exactly as prescribed. Your healthcare provider will tell you how much TEGRETOL to
take.
Your healthcare provider may change your dose. Do not change your dose of TEGRETOL without talking
to your healthcare provider.
Take TEGRETOL with food.
TEGRETOL-XR tablets:
Do not crush, chew, or break TEGRETOL-XR tablets.
Tell you healthcare provider if you can not swallow TEGRETOL-XR whole.
TEGRETOL Suspension:
Shake the bottle well each time before use.
Do not take TEGRETOL suspension at the same time you take other liquid medicines.
If you take too much TEGRETOL, call your healthcare provider or local Poison Control Center right away.
What should I avoid while taking TEGRETOL?
Reference ID: 3219002
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Do not drink alcohol or take other drugs that make you sleepy or dizzy while taking TEGRETOL until
you talk to your healthcare provider. TEGRETOL taken with alcohol or drugs that cause sleepiness or
dizziness may make your sleepiness or dizziness worse.
Do not drive, operate heavy machinery, or do other dangerous activities until you know how
TEGRETOL affects you. TEGRETOL may slow your thinking and motor skills.
What are the possible side effects of TEGRETOL?
See “What is the most important information I should know about TEGRETOL?”
TEGRETOL may cause other serious side effects. These include:
Irregular heartbeat - symptoms include:
o Fast, slow, or pounding heartbeat
o Shortness of breath
o Feeling lightheaded
o Fainting
Liver problems - symptoms include:
o yellowing of your skin or the whites of your eyes
o dark urine
o pain on the right side of your stomach area (abdominal pain)
o easy bruising
o loss of appetite
o nausea or vomiting
Get medical help right away if you have any of the symptoms listed above or listed in “What is the most
important information I should know about TEGRETOL”.
The most common side effects of TEGRETOL include:
dizziness
drowsiness
problems with walking and coordination (unsteadiness)
nausea
vomiting
These are not all the possible side effects of TEGRETOL. For more information, ask your healthcare provider
or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA
1088.
How should I store TEGRETOL?
Do not store TEGRETOL Tablets above 30°C (86°F).
Keep TEGRETOL tablets dry.
Reference ID: 3219002
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Do not store TEGRETOL Chewable Tablets above 30°C (86°F).
Keep TEGRETOL Chewable Tablets out of the light.
Keep TEGRETOL Chewable Tablets tablets dry.
Store TEGRETOL-XR tablets between 15°C to 30°C (59°F to 86°F).
Keep TEGRETOL XR tablets dry.
Do not store TEGRETOL Suspension above 30°C (86°F).
Shake well before using.
Keep TEGRETOL Suspension in a tight, light-resistant container.
Keep TEGRETOL and all medicines out of the reach of children.
General Information about TEGRETOL
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use
TEGRETOL for a condition for which it was not prescribed. Do not give TEGRETOL to other people, even if
they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about TEGRETOL. If you would like more
information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for the full
prescribing information about TEGRETOL that is written for health professionals.
For more information, go to www.pharma.us.novartis.com or call 1-888-669-6682.
What are the ingredients in TEGRETOL?
Active ingredient: carbamazepine
Inactive ingredients:
TEGRETOL tablets: colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake (chewable tablets
only), FD&C Red No. 40 (200-mg tablets only), flavoring (chewable tablets only), gelatin, glycerin,
magnesium stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose
(chewable tablets only).
TEGRETOL Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate,
propylene glycol, purified water, sorbitol, sucrose, and xanthan gum.
TEGRETOL-XR tablets: cellulose compounds, dextrates, iron oxides, magnesium stearate, mannitol,
polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200-mg tablets only).
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
T2012-167/T2011-32
November 2012/March 2011
Reference ID: 3219002
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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|
2025-02-12T13:44:41.202453
|
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1
Visken®
T2007-60
Visken®
(pindolol)
tablets, USP
Rx only
DESCRIPTION
Visken ® (pindolol), a synthetic beta-adrenergic receptor blocking agent with intrinsic sympathomimetic activity
is 1-(Indol-4-yloxy)-3-(isopropylamino)-2-propanol.
Its structural formula is:
Pindolol is a white to off-white odorless powder soluble in organic solvents and aqueous acids. Visken ®
(pindolol) is intended for oral administration.
5 mg and 10 mg Tablets
Active Ingredient:pindolol
Inactive Ingredients:colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, and
pregelatinized starch.
CLINICAL PHARMACOLOGY
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
Visken ® (pindolol) is a non-selective beta-adrenergic antagonist (beta-blocker) which possesses intrinsic
sympathomimetic activity (ISA) in therapeutic dosage ranges but does not possess quinidine-like membrane
stabilizing activity.
PHARMACODYNAMICS
In standard pharmacologic tests in man and animals, Visken ® (pindolol) attenuates increases in heart rate,
systolic blood pressure, and cardiac output resulting from exercise and isoproterenol administration, thus
confirming its beta-blocking properties. The ISA or partial agonist activity of Visken® (pindolol) is mediated
directly at the adrenergic receptor sites and may be blocked by other beta-blockers. In catecholamine-depleted
animal experiments, ISA is manifested as an increase in the inotropic and chronotropic activity of the
myocardium. In man, ISA is manifested by a smaller reduction in the resting heart rate (4-8 beats/min) than is
seen with drugs lacking ISA. There is also a smaller reduction in resting cardiac output. The clinical
significance of this observation has not been evaluated and there is no evidence, or reason to believe, that
exercise cardiac output is less affected by Visken® (pindolol).
Visken ® (pindolol) has been shown in controlled, double-blind clinical studies to be an effective
antihypertensive agent when used as monotherapy, or when added to therapy with thiazide-type diuretics.
Divided dosages in the range of 10-60 mg daily have been shown to be effective. As monotherapy, Visken®
(pindolol) is as effective as propranolol, a-methyldopa, hydrochlorothiazide, and chlorthalidone in reducing
systolic and diastolic blood pressure. The effect on blood pressure is not orthostatic, i.e. Visken® (pindolol) was
equally effective in reducing the supine and standing blood pressure.
In open, long-term studies up to 4 years, no evidence of diminution of the blood pressure-lowering response was
observed.
An average 3-pound increase in body weight has been noted in patients treated with Visken ® (pindolol) alone, a
larger increase than was observed with propranolol or placebo. The weight gain appeared unrelated to blood
pressure response and was not associated with an increased risk of heart failure, although edema was more
common than in control patients. Visken® (pindolol) does not have a consistent effect on plasma renin activity.
The mechanism of the antihypertensive effects of beta-blocking agents has not been established, but several
mechanisms have been postulated: 1) an effect on the central nervous system resulting in a reduced sympathetic
outflow to the periphery, 2) competitive antagonism of catecholamines at peripheral (especially cardiac)
adrenergic receptor sites, leading to decreased cardiac output, 3) an inhibition of renin release. These
mechanisms appear less likely for pindolol than other beta-blockers in view of the modest effect on resting
cardiac output and renin.
Beta-blockade therapy is useful when it is necessary to suppress the effects of beta-adrenergic agonists in order
to achieve therapeutic goals. However, in certain clinical situations, (e.g., cardiac failure, heart block,
bronchospasm), the preservation of an adequate sympathetic tone may be necessary to maintain vital functions.
Although a beta-antagonist with ISA such as Visken ® (pindolol) does not eliminate sympathetic tone entirely,
there is no controlled evidence that it is safer than other beta-blockers in such conditions as heart failure, heart
block, or bronchospasm or is less likely to cause those conditions. In single dose studies of the effects of
beta-blockers on FEV1, Visken® (pindolol) was indistinguishable from other non-cardioselective agents in its
reduction of FEV1, and its reduction in the effectiveness of an exogenous beta agonist.
Exacerbation of angina and, in some cases, myocardial infarction and ventricular dysrhythmias have been
reported after abrupt discontinuation of therapy with beta-adrenergic blocking agents in patients with coronary
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
artery disease. Abrupt withdrawal of these agents in patients without coronary artery disease has resulted in
transient symptoms, including tremulousness, sweating, palpitation, headache, and malaise. Several
mechanisms have been proposed to explain these phenomena, among them increased sensitivity to
catecholamines because of increased numbers of beta receptors.
PHARMACOKINETICS AND METABOLISM
Visken ® (pindolol) is rapidly and reproducibly absorbed (greater than 95%), achieving peak plasma
concentrations within 1 hour of drug administration. Visken® (pindolol) has no significant first-pass effect. The
blood concentrations are proportional in a linear manner to the administered dose in the range of 5-20 mg. Upon
repeated administration to the same subject, variation is minimal. After a single dose, intersubject variation for
peak plasma concentrations was about 4fold (e.g., 45-167 ng/mL for a 20 mg dose). Upon multiple dosing,
intersubject variation decreased to 2-2.5 fold. Visken® (pindolol) is only 40% bound to plasma proteins and is
evenly distributed between plasma and red cells. The volume of distribution in healthy subjects is about 2 L/kg.
Visken ® (pindolol) undergoes extensive metabolism in animals and man. In man, 35%-40% is excreted
unchanged in the urine and 60%-65% is metabolized primarily to hydroxy-metabolites which are excreted as
glucuronides and ethereal sulfates. The polar metabolites are excreted with a half-life of approximately 8 hours
and thus multiple dosing therapy (q.8H) results in a less than 50% accumulation in plasma. About 6%-9% of an
administered intravenous dose is excreted by the bile into the feces.
The disposition of Visken ® (pindolol) after oral administration is monophasic with a half-life in healthy
subjects or hypertensive patients with normal renal function of approximately 3-4 hours. Following t.i.d.
administration (q.8H), no significant accumulation of Visken® (pindolol) is observed.
In elderly hypertensive patients with normal renal function, the half-life of Visken ® (pindolol) is more variable,
averaging about 7 hours, but with values as high as 15 hours.
In hypertensive patients with renal diseases, the half-life is within the range expected for healthy subjects.
However, a significant decrease (50%) in volume of distribution (V D) is observed in uremic patients and VD
appears to be directly correlated to creatinine clearance. Therefore, renal drug clearance is significantly reduced
in uremic patients, resulting in a significant decrease in urinary excretion of unchanged drug. Uremic patients
with a creatinine clearance of less than 20 mL/min generally excreted less than 15% of the administered dose
unchanged in the urine.
In patients with histologically diagnosed cirrhosis of the liver, the elimination of Visken ® (pindolol) was more
variable in rate and generally significantly slower than in healthy subjects. The total body clearance of Visken®
(pindolol) in cirrhotic patients ranged from about 50-300 mL/min and was directly correlated to antipyrine
clearance. The half-life ranges from 2.5 hours to greater than 30 hours. These findings strongly suggest that
caution should be exercised in dosage adjustments of Visken® (pindolol) in such patients.
The bioavailability of Visken ® (pindolol) is not significantly affected by co-administration of food, hydralazine,
hydrochlorothiazide or aspirin. Visken® (pindolol) has no effect on warfarin activity or the clinical effectiveness
of digoxin, although small transient decreases in plasma digoxin concentrations were noted.
INDICATIONS AND USAGE
Visken ® (pindolol) is indicated in the management of hypertension. It may be used alone or concomitantly with
other antihypertensive agents, particularly with a thiazide-type diuretic.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
CONTRAINDICATIONS
Visken ® (pindolol) is contraindicated in: 1) bronchial asthma; 2) overt cardiac failure; 3) cardiogenic shock; 4)
second and third degree heart block; 5) severe bradycardia.
(See WARNINGS)
WARNINGS
Cardiac Failure
Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive
heart failure, and its inhibition by beta-blockade may precipitate more severe failure. Although beta-blockers
should be avoided in overt congestive heart failure, if necessary, Visken ® (pindolol) can be used with caution in
patients with a history of failure who are well-compensated, usually with digitalis and diuretics. Both digitalis
glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can
increase risk of bradycardia. Beta-adrenergic blocking agents do not abolish the inotropic action of digitalis on
heart muscle.
In Patients Without History of Cardiac Failure
In patients with latent cardiac insufficiency, continued depression of the myocardium with beta-blocking agents
over a period of time can in some cases lead to cardiac failure. At the first sign or symptom of impending
cardiac failure, patients should be fully digitalized and/or be given a diuretic, and the response observed closely.
If cardiac failure continues, despite adequate digitalization and diuretic, Visken ® (pindolol) therapy should be
withdrawn (gradually if possible).
Exacerbation of Ischemic Heart Disease Following Abrupt Withdrawal
Hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy;
exacerbation of angina and, in some cases, myocardial infarction have occurred after abrupt discontinuation of
such therapy. When discontinuing chronically administered Visken® (pindolol), particularly in patients with
ischemic heart disease, the dosage should be gradually reduced over a period of 1-2 weeks and the patient
should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, Visken®
(pindolol) administration should be reinstituted promptly, at least temporarily, and other measures appropriate
for the management of unstable angina should be taken. Patients should be warned against interruption or
discontinuation of therapy without the physician’s advice. Because coronary artery disease is common and may
be unrecognized, it may be prudent not to discontinue Visken® (pindolol) therapy abruptly even in patients
treated only for hypertension.
Nonallergic Bronchospasm (e.g., chronic bronchitis, emphysema) - Patients with Bronchospastic Diseases
Should in General Not Receive Beta - Blockers
Visken ® (pindolol) should be administered with caution since it may block bronchodilation produced by
endogenous or exogenous catecholamine stimulation of beta2 receptors.
Major Surgery
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Because beta blockade impairs the ability of the heart to respond to reflex stimuli and may increase the risks of
general anesthesia and surgical procedures, resulting in protracted hypotension or low cardiac output, it has
generally been suggested that such therapy should be gradually withdrawn several days prior to surgery.
Recognition of the increased sensitivity to catecholamines of patients recently withdrawn from beta-blocker
therapy, however, has made this recommendation controversial. If possible, beta-blockers should be withdrawn
well before surgery takes place. In the event of emergency surgery, the anesthesiologist should be informed that
the patient is on beta-blocker therapy.
The effects of Visken ® (pindolol) can be reversed by administration of beta-receptor agonists such as
isoproterenol, dopamine, dobutamine, or levarterenol. Difficulty in restarting and maintaining the heart beat has
also been reported with beta-adrenergic receptor blocking agents.
Diabetes and Hypoglycemia
Beta-adrenergic blockade may prevent the appearance of premonitory signs and symptoms (e.g., tachycardia
and blood pressure changes) of acute hypoglycemia. This is especially important with labile diabetics.
Beta-blockade also reduces the release of insulin in response to hyperglycemia; therefore, it may be necessary to
adjust the dose of antidiabetic drugs.
Thyrotoxicosis
Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients
suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of
beta-blockade which might precipitate a thyroid crisis.
PRECAUTIONS
Impaired Renal or Hepatic Function
Beta-blocking agents should be used with caution in patients with impaired hepatic or renal function. Poor renal
function has only minor effects on Visken ® (pindolol) clearance, but poor hepatic function may cause blood
levels of Visken® (pindolol) to increase substantially.
Information for Patients
Patients, especially those with evidence of coronary artery insufficiency, should be warned against interruption
or discontinuation of Visken ® (pindolol) therapy without the physician’s advice. Although cardiac failure rarely
occurs in properly selected patients, patients being treated with beta-adrenergic blocking agents should be
advised to consult the physician at the first sign or symptom of impending failure.
Drug Interactions
Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking
agents. Patients receiving Visken ® (pindolol) plus a catecholamine-depleting agent should, therefore, be closely
observed for evidence of hypotension and/or marked bradycardia which may produce vertigo, syncope, or
postural hypotension.
Visken ® (pindolol) has been used with a variety of antihypertensive agents, including hydrochlorothiazide,
hydralazine, and guanethidine without unexpected adverse interactions.
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6
Visken ® (pindolol) has been shown to increase serum thioridazine levels when both drugs are co-administered.
Visken® (pindolol) levels may also be increased with this combination.
Risk of Anaphylactic Reaction:
While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may
be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be
unresponsive to the usual doses of epinephrine used to treat allergic reaction.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In chronic oral toxicologic studies (1-2 years) in mice, rats, and dogs, Visken ® (pindolol) did not produce any
significant toxic effects. In 2-year oral carcinogenicity studies in rats and mice in doses as high as 59 mg/kg/day
and 124 mg/kg/day (50 and 100 times the maximum recommended human dose), respectively, Visken®
(pindolol) did not produce any neoplastic, preneoplastic, or nonneoplastic pathologic lesions. In fertility and
general reproductive performance studies in rats, Visken® (pindolol) caused no adverse effects at a dose of
10 mg/kg.
In the male fertility and general reproductive performance test in rats, definite toxicity characterized by
mortality and decreased weight gain was observed in the group given 100 mg/kg/day. At 30 mg/kg/day,
decreased mating was associated with testicular atrophy and/or decreased spermatogenesis. This response is not
clearly drug related, however, as there was no dose response relationship within this experiment and no similar
effect on testes of rats administered Visken ® (pindolol) as a dietary admixture for 104 weeks. There appeared to
be an increase in prenatal mortality in males given 100 mg/kg but development of offspring was not impaired.
In females administered Visken ® (pindolol) prior to mating through day 21 of lactation, mating behavior was
decreased at 100 mg/kg and 30 mg/kg. At these dosages there also was increased mortality of offspring. Prenatal
mortality was increased at 10 mg/kg but there was not a clear dose response relationship in this experiment.
There was an increased resorption rate at 100 mg/kg observed in females necropsied on the 15th day of
gestation.
Pregnancy
Category B:
Studies in rats and rabbits exceeding 100 times the maximum recommended human doses, revealed no
embryotoxicity or teratogenicity. Since there are no adequate and well-controlled studies in pregnant women,
and since animal reproduction studies are not always predictive of human response, Visken ® (pindolol), as with
any drug, should be employed during pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Nursing Mothers
Since Visken ® (pindolol) is secreted in human milk, nursing should not be undertaken by mothers receiving the
drug.
Pediatric Use
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7
Safety and effectiveness in pediatric patients have not been established.
CLINICAL LABORATORY
Minor persistent elevations in serum transaminases (SGOT, SGPT) have been noted in 7% of patients during
Visken ® (pindolol) administration, but progressive elevations were not observed. These elevations were not
associated with any other abnormalities that would suggest hepatic impairment, such as decreased serum
albumin and total proteins. During more than a decade of worldwide marketing, there have been no reports in
the medical literature of overt hepatic injury. Alkaline phosphatase, lactic acid dehydrogenase (LDH), and uric
acid are also elevated on rare occasions. The significance of these findings is unknown.
ADVERSE REACTIONS
Most adverse reactions have been mild. The incidences listed in the following table are derived from 12-week
comparative double-blind, parallel design trials in hypertensive patients given Visken ® (pindolol) as
monotherapy, given various active control drugs as monotherapy, or given placebo. Data for Visken® (pindolol)
and the positive controls were pooled from several trials because no striking differences were seen in the
individual studies, with 1 exception. When considering all adverse reactions reported, the frequency of edema
was noticeably higher in positive control trials [16% Visken® (pindolol) vs. 9% positive control] than in placebo
controlled trials [6%Visken® (pindolol) vs. 3% placebo]. The table includes adverse reactions either volunteered
or elicited, and at least possibly drug related, which were reported in greater than 2% of Visken® (pindolol)
patients and other selected important reactions.
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8
Adverse Reactions Which Were Volunteered or Elicited(and at least possibly drug related)
*Active Controls: Patients received either propranolol, a-methyldopa or a diuretic (hydrochlorothiazide or
chlorthalidone).
The following selected (potentially important) adverse reactions were seen in 2% or fewer patients and their
relationship to Visken ® (pindolol) is uncertain. CENTRAL NERVOUS SYSTEM: anxiety, lethargy;
AUTONOMIC NERVOUS SYSTEM: visual disturbances, hyperhidrosis; CARDIOVASCULAR: bradycardia,
claudication, cold extremities, heart block, hypotension, syncope, tachycardia, weight gain;
GASTROINTESTINAL: diarrhea, vomiting; RESPIRATORY: wheezing; UROGENITAL: impotence,
pollakiuria; MISCELLANEOUS: eye discomfort or burning eyes.
POTENTIAL ADVERSE EFFECTS
In addition, other adverse effects not aforementioned have been reported with other beta-adrenergic blocking
agents and should be considered potential adverse effects of Visken ® (pindolol).
Body System/ Adverse
Reactions
Visken ® (pindolol) (N=322) %
Active Controls* (N=188) %
Placebo (N=78) %
Central Nervous System
Bizarre or Many Dreams
5
0
6
Dizziness
9
11
1
Fatigue
8
4
4
Hallucinations
<1
0
0
Insomnia
10
3
10
Nervousness
7
3
5
Weakness
4
2
1
Autonomic Nervous System
Paresthesia
3
1
6
Cardiovascular
Dyspnea
5
4
6
Edema
6
3
1
Heart Failure
<1
<1
0
Palpitations
<1
1
0
Musculoskeletal
Chest Pain
3
1
3
Joint Pain
7
4
4
Muscle Cramps
3
1
0
Muscle Pain
10
9
8
Gastrointestinal
Abdominal Discomfort
4
4
5
Nausea
5
2
1
Skin
Pruritus
1
<1
0
Rash
<1
<1
1
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9
Central Nervous System : Reversible mental depression progressing to catatonia; an acute reversible syndrome
characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded
sensorium, and decreased performance on neuropsychometrics.
Cardiovascular : Intensification of AV block. (See CONTRAINDICATIONS)
Allergic : Erythematous rash; fever combined with aching and sore throat; laryngospasm; respiratory distress.
Hematologic : Agranulocytosis; thrombocytopenic and nonthrombocytopenic purpura.
Gastrointestinal : Mesenteric arterial thrombosis; ischemic colitis.
Miscellaneous : Reversible alopecia; Peyronie’s disease.
The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with
Visken ® (pindolol) during investigational use and extensive foreign experience amounting to over 4 million
patient-years.
OVERDOSAGE
No specific information on emergency treatment of overdosage is available. Therefore, on the basis of the
pharmacologic actions of Visken ® (pindolol), the following general measures should be employed as
appropriate in addition to gastric lavage:
Excessive Bradycardia : administer atropine; if there is no response to vagal blockade, administer isoproterenol
cautiously.
Cardiac Failure : digitalize the patient and/or administer diuretic. It has been reported that glucagon may be
useful in this situation.
Hypotension : administer vasopressors, e.g., epinephrine or levarterenol, with serial monitoring of blood
pressure. (There is evidence that epinephrine may be the drug of choice.)
Bronchospasm : administer a beta 2 stimulating agent such as isoproterenol and/or a theophylline derivative.
A case of an acute overdosage has been reported with an intake of 500 mg of Visken ® (pindolol) by a
hypertensive patient. Blood pressure increased and heart rate was ³80 beats/min. Recovery was uneventful. In
another case, 250 mg of Visken® (pindolol) was taken with 150 mg diazepam and 50 mg nitrazepam, producing
coma and hypotension. The patient recovered in 24 hours.
DOSAGE AND ADMINISTRATION
The dosage of Visken ® (pindolol) should be individualized. The recommended initial dose of Visken®
(pindolol) is 5 mg b.i.d. alone or in combination with other antihypertensive agents. An antihypertensive
response usually occurs within the first week of treatment. Maximal response, however, may take as long as or
occasionally longer than 2 weeks. If a satisfactory reduction in blood pressure does not occur within 3-4 weeks,
the dose may be adjusted in increments of 10 mg/day at these intervals up to a maximum of 60 mg/day.
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10
HOW SUPPLIED
Visken ® (pindolol) tablets, USP
White, uncoated, heart-shaped tablets; 5 mg and 10 mg, packages of 100. 5 mg tablets engraved “VISKEN 5’’
on one side, and embossed “V’’ on other side (NDC 0078-0111-05). 10 mg tablets engraved “VISKEN 10’’ on
one side, and embossed “V’’ on other side (NDC 0078-0073-05).
Store and Dispense
Below 86°F (30°C); tight, light-resistant container.
Manufactured by:
Novartis Pharmaceuticals Canada Inc.
Dorval (Quebec) Canada H9R 4P5
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
REV: MAY 2007 T2007-60
© Novartis
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:41.250252
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018285s034lbl.pdf', 'application_number': 18285, 'submission_type': 'SUPPL ', 'submission_number': 34}
|
11,201
|
structural formula
Lopressor HCT®
metoprolol tartrate USP and hydrochlorothiazide USP
50/25 Tablets
100/25 Tablets
100/50 Tablets
Beta Blocker/Diuretic Antihypertensive
Rx only
Prescribing Information
DESCRIPTION
Lopressor HCT has the antihypertensive effect of Lopressor®, metoprolol tartrate, a selective
beta1-adrenoreceptor blocking agent, and the antihypertensive and diuretic actions of
hydrochlorothiazide. It is available as tablets for oral administration. The 50/25 tablets contain
50 mg of metoprolol tartrate USP and 25 mg of hydrochlorothiazide USP; the 100/25 tablets
contain 100 mg of metoprolol tartrate USP and 25 mg of hydrochlorothiazide USP; and the
100/50 tablets contain 100 mg of metoprolol tartrate USP and 50 mg of hydrochlorothiazide
USP. Metoprolol tartrate USP is (±)-1-(Isopropylamino)-3-[p-(2-methoxyethyl)phenoxy]-2
propanol L-(+)-tartrate (2:1) salt, and its structural formula is structural formula
Metoprolol tartrate USP is a white, crystalline powder. It is very soluble in water; freely soluble
in methylene chloride, in chloroform, and in alcohol; slightly soluble in acetone; and insoluble in
ether. Its molecular weight is 684.82.
Hydrochlorothiazide is 6-chloro-3, 4-dihydro-2 H-1,2,4-benzothiadiazine-7- sulfonamide 1,1
dioxide, and its structural formula is
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Hydrochlorothiazide USP is a white, or practically white, practically odorless, crystalline powder.
It is freely soluble in sodium hydroxide solution, in n-butylamine, and in dimethylformamide;
sparingly soluble in methanol; slightly soluble in water; and insoluble in ether, in chloroform, and
in dilute mineral acids. Its molecular weight is 297.73.
Inactive Ingredients: Cellulose compounds, colloidal silicon dioxide, D&C Yellow No. 10
(100/50-mg tablets), FD&C Blue No. 1 (50/25-mg tablets), FD&C Red No. 40 and FD&C
Yellow No. 6 (100/25-mg tablets), lactose, magnesium stearate, povidone, sodium starch
glycolate, corn starch, stearic acid, and sucrose.
CLINICAL PHARMACOLOGY
Lopressor
Lopressor is a beta-adrenergic receptor blocking agent. In vitro and in vivo animal studies have
shown that it has a preferential effect on beta1 adrenoreceptors, chiefly located in cardiac muscle.
This preferential effect is not absolute, however, and at higher doses, Lopressor also inhibits beta2
adrenoreceptors, chiefly located in the bronchial and vascular musculature.
Clinical pharmacology studies have confirmed the beta-blocking activity of metoprolol in man,
as shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction
of systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and
(4) reduction of reflex orthostatic tachycardia.
Relative beta1 selectivity has been confirmed by the following: (1) In normal subjects, Lopressor
is unable to reverse the beta2-mediated vasodilating effects of epinephrine. This contrasts with the
effect of nonselective (beta1 plus beta2) beta blockers, which completely reverse the vasodilating
effects of epinephrine. (2) In asthmatic patients, Lopressor reduces FEV1 and FVC significantly
less than a nonselective beta blocker, propranolol at equivalent beta1-receptor blocking doses.
Lopressor has no intrinsic sympathomimetic activity and only weak membrane-stabilizing
activity. Lopressor crosses the blood-brain barrier and has been reported in the CSF in a
concentration 78% of the simultaneous plasma concentration. Animal and human experiments
indicate that Lopressor slows the sinus rate and decreases AV nodal conduction.
In controlled clinical studies, Lopressor has been shown to be an effective antihypertensive agent
when used alone or as concomitant therapy with thiazide-type diuretics, at dosages of 100
450 mg daily. In controlled, comparative, clinical studies, Lopressor has been shown to be as
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effective an antihypertensive agent as propranolol, methyldopa, and thiazide-type diuretics, and
to be equally effective in supine and standing positions.
The mechanism of the antihypertensive effects of beta-blocking agents has not been elucidated.
However, several possible mechanisms have been proposed: (1) competitive antagonism of
catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased
cardiac output; (2) a central effect leading to reduced sympathetic outflow to the periphery; and
(3) suppression of renin activity.
Pharmacokinetics
In man, absorption of Lopressor is rapid and complete. Plasma levels following oral
administration, however, approximate 50% of levels following intravenous administration,
indicating about 50% first-pass metabolism.
Plasma levels achieved are highly variable after oral administration. Only a small fraction of the
drug (about 12%) is bound to human serum albumin. Metoprolol is a racemic mixture of R- and
S-enantiomers. Less than 5% of an oral dose of Lopressor is recovered unchanged in the urine;
the rest is excreted by the kidneys as metabolites that appear to have no clinical significance. The
systemic availability and half-life of Lopressor in patients with renal failure do not differ to a
clinically significant degree from those in normal subjects. Consequently, no reduction in dosage
is usually needed in patients with chronic renal failure.
In elderly subjects with clinically normal renal function, there are no significant differences in
Lopressor pharmacokinetics compared to young subjects.
Lopressor is extensively metabolized by the cytochrome P450 enzyme system in the liver. The
oxidative metabolism of Lopressor is under genetic control with a major contribution of the
polymorphic cytochrome P450 isoform 2D6 (CYP2D6). There are marked ethnic differences in
the prevalence of the poor metabolizers (PM) phenotype. Approximately 7% of Caucasians and
less than 1% Asian are poor metabolizers.
Poor CYP2D6 metabolizers exhibit several-fold higher plasma concentrations of Lopressor than
extensive metabolizers with normal CYP2D6 activity. The elimination half-life of metoprolol is
about 7.5 hours in poor metabolizers and 2.8 hours in extensive metabolizers. However, the
CYP2D6 dependent metabolism of Lopressor seems to have little or no effect on safety or
tolerability of the drug. None of the metabolites of Lopressor contribute significantly to its beta-
blocking effect.
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Pharmacodynamics
Significant beta-blocking effect (as measured by reduction of exercise heart rate) occurs within 1
hour after oral administration, and its duration is dose-related. For example, a 50% reduction of
the maximum registered effect after single oral doses of 20, 50, and 100 mg occurred at 3.3, 5.0,
and 6.4 hours, respectively, in normal subjects. After repeated oral dosages of 100 mg twice
daily, a significant reduction in exercise systolic blood pressure was evident at 12 hours.
There is a linear relationship between the log of plasma levels and reduction of exercise heart
rate. However, antihypertensive activity does not appear to be related to plasma levels. Because
of variable plasma levels attained with a given dose and lack of a consistent relationship of
antihypertensive activity to dose, selection of proper dosage requires individual titration.
Hydrochlorothiazide
Thiazides affect the renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic
dosage, all thiazides are approximately equal in their diuretic potency. Thiazides increase
excretion of sodium and chloride in approximately equivalent amounts. Natriuresis causes a
secondary loss of potassium.
The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not affect
normal blood pressure.
Pharmacokinetics
Hydrochlorothiazide is rapidly absorbed, as indicated by peak plasma concentrations 1-2.5 hours
after oral administration. Plasma levels of the drug are proportional to dose; the concentration in
whole blood is 1.6-1.8 times higher than in plasma. Thiazides are eliminated rapidly by the
kidney. After oral administration of 25- to 100-mg doses, 72-97% of the dose is excreted in the
urine, indicating dose-independent absorption. Hydrochlorothiazide is eliminated from plasma in
a biphasic fashion with a terminal half-life of 10-17 hours. Plasma protein binding is 67.9%.
Plasma clearance is 15.9-30.0 L/hr; volume of distribution is 3.6-7.8 L/kg.
Gastrointestinal absorption of hydrochlorothiazide is enhanced when administered with food.
Absorption is decreased in patients with congestive heart failure, and the pharmacokinetics are
considerably different in these patients.
Pharmacodynamics
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The onset of action of thiazides occurs in 2 hours and the peak effect at about 4 hours. The action
persists for approximately 6-12 hours.
INDICATIONS AND USAGE
Lopressor HCT is indicated for the management of hypertension.
This fixed-combination drug is not indicated for initial therapy of hypertension. If the fixed
combination represents the dose titrated to the individual patient’s needs, therapy with the
fixed combination may be more convenient than with the separate components.
CONTRAINDICATIONS
Lopressor
Lopressor is contraindicated in sinus bradycardia, heart block greater than first degree,
cardiogenic shock, and overt cardiac failure (see WARNINGS).
Hypersensitivity to Lopressor and related derivatives, or to any of the excipients; hypersensitivity
to other beta blockers (cross sensitivity between beta blockers can occur).
Sick-sinus syndrome.
Severe peripheral arterial circulatory disorders.
Hydrochlorothiazide
Hydrochlorothiazide is contraindicated in patients with anuria or hypersensitivity to this or other
sulfonamide-derived drugs (see WARNINGS).
WARNINGS
Lopressor
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Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function in
congestive heart failure, and beta blockade carries the potential hazard of further depressing
myocardial contractility and precipitating more severe failure. In hypertensive patients who have
congestive heart failure controlled by digitalis and diuretics, Lopressor should be administered
cautiously.
In Patients Without a History of Cardiac Failure: Continued depression of the myocardium
with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the
first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or
given a diuretic. The response should be observed closely. If cardiac failure continues, despite
adequate digitalization and diuretic therapy, Lopressor should be withdrawn.
Ischemic Heart Disease: Following abrupt cessation of therapy with certain beta-blocking
agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have been
reported. Even in the absence of overt angina pectoris, when discontinuing therapy, Lopressor
should not be withdrawn abruptly, and patients should be cautioned against interruption of
therapy without the physician’s advice (see PRECAUTIONS, Information for Patients).
Bronchospastic Diseases: PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD,
IN GENERAL, NOT RECEIVE BETA BLOCKERS, including Lopressor HCT. Because of
its relative beta1 selectivity, however, Lopressor may be used with caution in patients with
bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive
treatment. Since beta1 selectivity is not absolute, a beta2-stimulating agent should be
administered concomitantly, and the lowest possible dose of Lopressor should be used. In
these circumstances it would be prudent initially to administer Lopressor in smaller doses
three times daily, instead of larger doses two times daily, to avoid the higher plasma levels
associated with the longer dosing interval (see DOSAGE AND ADMINISTRATION).
Major Surgery: Chronically administered beta-blocking therapy should not be routinely
withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex
adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
Diabetes and Hypoglycemia: Lopressor should be used with caution in diabetic patients if a beta-
blocking agent is required. Beta blockers, including Lopressor HCT, may mask tachycardia
occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not
be significantly affected. Selective beta blockers do not potentiate insulin-induced hypoglycemia
and, unlike nonselective beta blockers, do not delay recovery of blood glucose to normal levels.
Pheochromocytoma: If Lopressor is used in the setting of pheochromocytoma, it should be given
in combination with an alpha blocker, and only after the alpha blocker has been initiated.
Reference ID: 2918685
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Administration of beta blockers alone in the setting of pheochromocytoma has been associated
with a paradoxical increase in blood pressure due to the attenuation of beta-mediated
vasodilatation in skeletal muscle.
Thyrotoxicosis: Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) or
hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to
avoid abrupt withdrawal of beta blockade, which might precipitate a thyroid storm.
Hydrochlorothiazide
Thiazides should be used with caution in patients with severe renal disease. In patients with renal
disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in
patients with impaired renal function.
Thiazides should be used with caution in patients with impaired hepatic function or progressive
liver disease, since minor alterations of fluid and electrolyte imbalance may precipitate hepatic
coma.
Thiazides may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs
with ganglionic or peripheral adrenergic blocking drugs.
Sensitivity reactions are more likely to occur in patients with a history of allergy or bronchial
asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
Acute Myopia and Secondary Angle-Closure Glaucoma: Hydrochlorothiazide, a sulfonamide,
can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure
glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically
occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead
to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly
as possible. Prompt medical or surgical treatments may need to be considered if the intraocular
pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may
include a history of sulfonamide or penicillin allergy.
PRECAUTIONS
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General
Lopressor: Lopressor should be used with caution in patients with impaired hepatic function.
Hydrochlorothiazide: All patients receiving thiazide therapy should be observed for clinical
signs of fluid or electrolyte imbalance, namely hyponatremia, hypochloremic alkalosis, and
hypokalemia (see Laboratory Tests and Drug/Drug Interactions). Warning signs are dryness of
mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular
fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbance, such as nausea or
vomiting.
Hypokalemia may develop, especially in cases of brisk diuresis or severe cirrhosis.
Interference with adequate oral intake of electrolytes will also contribute to hypokalemia.
Hypokalemia may be avoided or treated by the use of potassium supplements or foods with high
potassium content.
Any chloride deficit is generally mild and usually does not require specific treatment, except
under extraordinary circumstances (as in liver disease or renal disease). Dilutional hyponatremia
may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather
than administration of salt, except in rare instances when the hyponatremia is life-threatening. In
cases of actual salt depletion, appropriate replacement is the therapy of choice.
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide
therapy.
Latent diabetes may become manifest during thiazide administration (see Drug/Drug
Interactions).
The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.
If progressive renal impairment becomes evident, withholding or discontinuing diuretic therapy
should be considered.
Calcium excretion is decreased by thiazides. Pathological changes in the parathyroid gland with
hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged
thiazide therapy. The common complications of hyperparathyroidism, such as renal lithiasis,
bone resorption, and peptic ulceration, have not been seen.
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Thiazide diuretics have been shown to increase the urinary excretion of magnesium; this may
result in hypomagnesemia.
Information for Patients
Patients should be advised to take Lopressor HCT regularly and continuously, as directed, with or
immediately following meals. If a dose should be missed, the patient should take only the next
scheduled dose (without doubling it). Patients should not discontinue Lopressor HCT without
consulting the physician.
Patients should be advised (1) to avoid operating automobiles and machinery or engaging in other
tasks requiring alertness until the patient’s response to therapy with Lopressor HCT has been
determined; (2) to contact the physician if any difficulty in breathing occurs; (3) to inform the
physician or dentist before any type of surgery that he or she is taking Lopressor HCT.
Laboratory Tests
Lopressor: Clinical laboratory findings may include elevated levels of serum transaminase,
alkaline phosphatase, and lactate dehydrogenase.
Hydrochlorothiazide: Initial and periodic determinations of serum electrolytes to detect possible
electrolyte imbalance should be performed at appropriate intervals.
Serum and urine electrolyte determinations are particularly important when the patient is
vomiting excessively or receiving parenteral fluids.
Drug/Drug Interactions
Lopressor: Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when
given with beta-blocking agents. Patients treated with Lopressor plus a catecholamine depletor
should therefore be closely observed for evidence of hypotension or marked bradycardia, which
may produce vertigo, syncope, or postural hypotension.
Both digitalis glycosides and beta blockers slow atrioventricular conduction and decrease heart
rate. Concomitant use can increase the risk of bradycardia.
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Risk of Anaphylactic Reaction: While taking beta blockers, patients with a history of severe
anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either
accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of
epinephrine used to treat allergic reaction.
General Anesthetics
Some inhalation anesthetics may enhance the cardiodepressant effect of beta blockers (see
WARNINGS; Lopressor; Major Surgery).
CYP2D6 Inhibitors
Potent inhibitors of the CYP2D6 enzyme may increase the plasma concentration of Lopressor.
Strong inhibition of CYP2D6 would mimic the pharmacokinetics of CYP2D6 poor metabolizer.
Caution should therefore be exercised when administering potent CYP2D6 inhibitors with
Lopressor. Known clinically significant potent inhibitors of CYP2D6 are antidepressants such as
fluoxetine, paroxetine or bupropion, antipsychotics such as thioridazine, antiarrhythmics such as
quinidine or propafenone, antiretrovirals such as ritonavir, antihistamines such as
diphenhydramine, antimalarials such as hydroxychloroquine or quinidine, antifungals such as
terbinafine and medications for stomach ulcers such as cimetidine.
Clonidine
If a patient is treated with clonidine and Lopressor concurrently, and clonidine treatment is to be
discontinued, Lopressor should be stopped several days before clonidine is withdrawn. Rebound
hypertension that can follow withdrawal of clonidine may be increased in patients receiving
concurrent beta blocker treatment.
Hydrochlorothiazide: Hypokalemia can sensitize or exaggerate the response of the heart to the
toxic effects of digitalis (e.g., increased ventricular irritability).
Hypokalemia may develop during concomitant use of steroids or ACTH.
Insulin requirements in diabetic patients may be increased, decreased, or unchanged.
Thiazides may decrease arterial responsiveness to norepinephrine, but not enough to preclude
effectiveness of the pressor agent for therapeutic use.
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Thiazides may increase the responsiveness to tubocurarine.
Lithium renal clearance is reduced by thiazides, increasing the risk of lithium toxicity.
There have been rare reports in the literature of hemolytic anemia occurring with the concomitant
use of hydrochlorothiazide and methyldopa.
Concurrent administration of some nonsteroidal anti-inflammatory agents may reduce the
diuretic, natriuretic and antihypertensive effects of thiazide diuretics.
Cholestyramine and colestipol resins: Absorption of hydrochlorothiazide is impaired in the
presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins
bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to
85% and 43%, respectively.
Drug/Laboratory Test Interactions
Hydrochlorothiazide: Thiazides may decrease serum levels of protein-bound iodine without
signs of thyroid disturbance. Thiazides should be discontinued before tests for parathyroid
function are made. (see General, Hydrochlorothiazide, Calcium excretion).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Lopressor HCT: Carcinogenicity and mutagenicity studies have not been conducted with
Lopressor HCT. Lopressor HCT produced no evidence of impaired fertility in male or female rats
administered gavaged doses up to 200/50 mg/kg (100/50 times the maximum recommended daily
human dose) prior to mating and throughout gestation and rearing of young.
Lopressor: Long-term studies in animals have been conducted to evaluate carcinogenic potential.
In a 2-year study in rats at three oral dosage levels of up to 800 mg/kg per day, there was no
increase in the development of spontaneously occurring benign or malignant neoplasms of any
type. The only histologic changes that appeared to be drug related were an increased incidence of
generally mild focal accumulation of foamy macrophages in pulmonary alveoli and a slight
increase in biliary hyperplasia. In a 21-month study in Swiss albino mice at three oral dosage
levels of up to 750 mg/kg per day, benign lung tumors (small adenomas) occurred more
frequently in female mice receiving the highest dose than in untreated control animals. There was
no increase in malignant or total (benign plus malignant) lung tumors, or in the overall incidence
of tumors or malignant tumors. This 21-month study was repeated in CD-1 mice, and no
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statistically or biologically significant differences were observed between treated and control
mice of either sex for any type of tumor.
All mutagenicity tests performed (a dominant lethal study in mice, chromosome studies in
somatic cells, a Salmonella/mammalian-microsome mutagenicity test, and a nucleus anomaly test
in somatic interphase nuclei) were negative.
No evidence of impaired fertility due to Lopressor was observed in a study performed in rats at
doses up to 55.5 times the maximum daily human dose of 450 mg.
Hydrochlorothiazide: Two-year feeding studies in mice and rats conducted under the auspices of
the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of
hydrochlorothiazide in female mice (at doses up to approximately 600 mg/kg/day) or in male and
female rats (at doses up to approximately 100 mg/kg/day). The NTP, however, found equivocal
evidence for hepatocarcinogenicity in male mice.
Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535,
TA 1537, and TA 1538 of Salmonella typhimurium (Ames assay) and in the Chinese Hamster
Ovary (CHO) test for chromosomal aberrations, or in in vivo assays using mouse germinal cell
chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked
recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO Sister
Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays,
using concentrations of hydrochlorothiazide from 43 to 1300 µg/mL, and in the Aspergillus
nidulans nondisjunction assay at an unspecified concentration.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in
studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg/day,
respectively, prior to mating and throughout gestation.
Pregnancy: Teratogenic Effects. Pregnancy Category C
Lopressor HCT: No evidence of adverse effects on pregnancy or the fetus were observed in rats
when dams were administered gavaged doses up to 200/50 mg/kg of Lopressor HCT (100/50
times the maximum recommended daily human dose) during the period of organogenesis.
Increased postimplantation loss and decreased postnatal survival were observed with these doses
when administered later in pregnancy (gestation days 15-21). In rabbits, increased fetal loss was
observed with oral doses of 25/6.25 mg/kg of Lopressor HCT (12/6 times the maximum
recommended daily human dose), but not with lower doses. There are no adequate and well-
controlled studies of Lopressor HCT in pregnant women. Lopressor HCT should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
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Lopressor: Lopressor has been shown to increase postimplantation loss and decrease neonatal
survival in rats at doses up to 55.5 times the maximum daily human dose of 450 mg. Distribution
studies in mice confirm exposure of the fetus when Lopressor is administered to the pregnant
animal. These studies have revealed no evidence of teratogenicity.
Hydrochlorothiazide: Studies in which hydrochlorothiazide was orally administered to pregnant
mice and rats during their respective periods of major organogenesis at doses up to 3000 and
1000 mg/kg/day, respectively, provided no evidence of harm to the fetus.
Nonteratogenic Effects
Hydrochlorothiazide: Thiazides cross the placental barrier and appear in cord blood, and there is
a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that
have occurred in adults.
Nursing Mothers
Lopressor is excreted in breast milk in a very small quantity. An infant consuming 1 liter of
breast milk daily would receive a dose of metoprolol of less than 1 mg. Thiazides are also
excreted in breast milk. If the use of Lopressor HCT is deemed essential, the patient should stop
nursing.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of Lopressor HCT did not include sufficient numbers of subjects aged 65 and
over to determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients.
Hydrochlorothiazide is known to be substantially excreted by the kidney, and the risk of toxic
reactions to this drug may be greater in patients with impaired renal function. Because elderly
patients are more likely to have decreased renal function, care should be taken in dose selection,
and it may be useful to monitor renal function (see WARNINGS). In general, dose selection for
an elderly patient should be cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant
disease or other drug therapy.
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ADVERSE REACTIONS
Lopressor HCT
The following adverse reactions were reported in controlled clinical studies of the combination of
Lopressor and hydrochlorothiazide.
Body as a Whole: Fatigue or lethargy and flu syndrome have each been reported in about 10 in
100 patients.
Nervous System: Dizziness or vertigo, drowsiness or somnolence, and headache have each
occurred in about 10 in 100 patients. Nightmare has occurred in 1 in 100 patients.
Cardiovascular: Bradycardia has occurred in about 6 in 100 patients. Decreased exercise
tolerance and dyspnea have each occurred in about 1 of 100 patients.
Digestive: Diarrhea, digestive disorder, dry mouth, nausea or vomiting, and constipation have
each occurred in about 1 in 100 patients.
Metabolic and Nutritional: Hypokalemia has occurred in fewer than 10 in 100 patients. Edema,
gout, and anorexia have each occurred in 1 in 100 patients.
Special Senses: Blurred vision, tinnitus, and earache have each been reported in 1 in 100
patients.
Skin: Sweating and purpura have each occurred in 1 in 100 patients.
Urogenital: Impotence has occurred in 1 in 100 patients.
Musculoskeletal: Muscle pain has occurred in 1 in 100 patients.
Lopressor
Most adverse effects have been mild and transient.
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Central Nervous System: Tiredness and dizziness have occurred in about 10 of 100 patients.
Depression has been reported in about 5 of 100 patients. Mental confusion and short-term
memory loss have been reported. Headache, nightmares, and insomnia have also been reported,
but a drug relationship is not clear.
Cardiovascular: Shortness of breath and bradycardia have occurred in approximately 3 of 100
patients. Cold extremities; arterial insufficiency, usually of the Raynaud type; palpitations; and
congestive heart failure have been reported. Gangrene in patients with pre-existing severe
peripheral circulatory disorders has also been reported very rarely (see
CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS).
Respiratory: Wheezing (bronchospasm) has been reported in fewer than 1 of 100 patients (see
WARNINGS). Rhinitis has also been reported.
Gastrointestinal: Diarrhea has occurred in about 5 of 100 patients. Nausea, gastric pain,
constipation, flatulence, and heartburn have been reported in 1 of 100, or fewer, patients.
Vomiting was a common occurrence. Postmarketing experience reveals very rare reports of
hepatitis, jaundice and non-specific hepatic dysfunction. Isolated cases of transaminase, alkaline
phosphatase, and lactic dehydrogenase elevations have also been reported.
Hypersensitive Reactions: Pruritus has occurred in fewer than 1 of 100 patients. Rash has been
reported. Very rarely, photosensitivity and worsening of psoriasis has been reported.
Miscellaneous: Peyronie’s disease has been reported in fewer than 1 of 100,000 patients.
Alopecia has been reported. There have been very rare reports of weight gain, arthritis, and
retroperitoneal fibrosis (relationship to Lopressor has not been definitely established).
The oculomucocutaneous syndrome associated with the beta blocker practolol has not been
reported with Lopressor.
Potential Adverse Reactions
A variety of adverse reactions not listed above have been reported with other beta-adrenergic
blocking agents and should be considered potential adverse reactions to Lopressor.
Central Nervous System: Reversible mental depression progressing to catatonia; visual
disturbances; hallucinations; an acute reversible syndrome characterized by disorientation for
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time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and
decreased performance on neuropsychometrics.
Cardiovascular: Intensification of AV block (see CONTRAINDICATIONS).
Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.
Hypersensitive Reactions: Fever combined with aching and sore throat, laryngospasm, and
respiratory distress.
Postmarketing Experience
The following adverse reactions have been reported during postapproval use of Lopressor:
confusional state, an increase in blood triglycerides and a decrease in High Density Lipoprotein
(HDL). Because these reports are from a population of uncertain size and are subject to
confounding factors, it is not possible to reliably estimate their frequency.
Hydrochlorothiazide
The following adverse reactions have been observed, but there has not been enough systematic
collection of data to support an estimate of their frequency. Consequently the reactions are
categorized by organ systems and are listed in decreasing order of severity and not frequency.
Digestive: Pancreatitis, jaundice (intrahepatic cholestatic), sialadenitis, vomiting, diarrhea,
cramping, nausea, gastric irritation, constipation, anorexia.
Cardiovascular: Orthostatic hypotension (may be potentiated by alcohol, barbiturates, or
narcotics).
Neurologic: Vertigo, dizziness, transient blurred vision, headache, paresthesia, xanthopsia,
weakness, restlessness.
Musculoskeletal: Muscle spasm.
Hematologic: Aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.
Metabolic: Hyperglycemia, glycosuria, hyperuricemia.
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Hypersensitive Reactions: Necrotizing angiitis, Stevens-Johnson syndrome, respiratory distress
including pneumonitis and pulmonary edema, purpura, urticaria, rash, photosensitivity.
OVERDOSAGE
Acute Toxicity
Several cases of overdosage with Lopressor have been reported, some leading to death. No deaths
have been reported with hydrochlorothiazide.
Oral LD 50’s (mg/kg): mice, 1158 (Lopressor); rats, 3090 (Lopressor), 2750
(hydrochlorothiazide).
Signs and Symptoms
Lopressor: Potential signs and symptoms associated with overdosage with Lopressor are
bradycardia, hypotension, bronchospasm, and cardiac failure.
Hydrochlorothiazide: The most prominent feature of poisoning is acute loss of fluid and
electrolytes.
Cardiovascular: Tachycardia, hypotension, shock.
Neuromuscular: Weakness, confusion, dizziness, cramps of the calf muscles, paresthesia,
fatigue, impairment of consciousness.
Digestive: Nausea, vomiting, thirst.
Renal: Polyuria, oliguria, or anuria (due to hemoconcentration).
Laboratory Findings: Hypokalemia, hyponatremia, hypochloremia, alkalosis; increased BUN
(especially in patients with renal insufficiency).
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Combined Poisoning: Signs and symptoms may be aggravated or modified by concomitant
intake of antihypertensive medication, barbiturates, curare, digitalis (hypokalemia),
corticosteroids, narcotics, or alcohol.
Treatment
There is no specific antidote.
On the basis of the pharmacologic actions of Lopressor and hydrochlorothiazide, the following
general measures should be employed:
Elimination of the Drug: Inducement of vomiting, gastric lavage, and activated charcoal.
Bradycardia: Atropine should be administered. If there is no response to vagal blockade,
isoproterenol should be administered cautiously.
Hypotension: The patient’s legs should be elevated and lost fluid and electrolytes (potassium,
sodium) should be replaced. A vasopressor should be administered, e.g., levarterenol or
dopamine.
Bronchospasm: A beta2-stimulating agent and/or a theophylline derivative should be
administered.
Cardiac Failure: A digitalis glycoside and diuretic should be administered. In shock resulting
from inadequate cardiac contractility, administration of dobutamine, isoproterenol, or glucagon
may be considered.
Surveillance: Fluid and electrolyte balance (especially serum potassium) and renal function
should be monitored until conditions become normal.
DOSAGE AND ADMINISTRATION
Dosage should be determined by individual titration (see INDICATIONS AND USAGE).
Hydrochlorothiazide is usually given at a dosage of 12.5 to 50 mg per day. The usual initial
dosage of Lopressor is 100 mg daily in single or divided doses. Dosage may be increased
Reference ID: 2918685
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gradually until optimum blood pressure control is achieved. The effective dosage range is 100 to
450 mg per day. While once-daily dosing is effective and can maintain a reduction in blood
pressure throughout the day, lower doses (especially 100 mg) may not maintain a full effect at the
end of the 24-hour period, and larger or more frequent daily doses may be required. This can be
evaluated by measuring blood pressure near the end of the dosing interval to determine whether
satisfactory control is being maintained throughout the day. Beta1 selectivity diminishes as
dosage of Lopressor is increased.
The following dosage schedule may be used to administer from 100 to 200 mg of Lopressor per
day and from 25 to 50 mg of hydrochlorothiazide per day:
Lopressor HCT
Dosage
Tablets of 50/25
2 tablets per day in single or divided doses
Tablets of 100/25
1 to 2 tablets per day in single or divided doses
Tablets of 100/50
1 tablet per day in single or divided doses
Dosing regimens that exceed 50 mg of hydrochlorothiazide per day are not recommended. When
necessary, another antihypertensive agent may be added gradually, beginning with 50% of the
usual recommended starting dose to avoid an excessive fall in blood pressure.
HOW SUPPLIED
Tablets 50/25 -
capsule-shaped, white and mottled-blue, scored (imprinted Geigy on one side and 35
twice on the scored side), 50 mg of metoprolol tartrate and 25 mg of
hydrochlorothiazide
Bottles of 100……………………………………NDC 0078-0460-05
Tablets 100/25 -
capsule-shaped, white and mottled-pink, scored (imprinted Geigy on one side and 53
twice on the scored side), 100 mg of metoprolol tartrate and 25 mg of
hydrochlorothiazide
Bottles of 100……………………………………NDC 0078-0461-05
Tablets 100/50 -
capsule- shaped, white and mottled-yellow, scored (imprinted Geigy on one side and
73 twice on the scored side), 100 mg of metoprolol tartrate and 50 mg of
hydrochlorothiazide
Bottles of 100……………………………………NDC 0078-0462-05
Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF) [see USP Controlled Room
Temperature]. Protect from moisture.
Dispense in tight, light-resistant container (USP).
Reference ID: 2918685
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To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals
Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
Manufactured by:
Novartis Pharmaceuticals Corporation
Suffern, New York 10901
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
REV: March 2011
T2011-12
Reference ID: 2918685
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|
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2025-02-12T13:44:41.413233
|
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
LYMPHAZURIN™1% safely and effectively. See full prescribing
information for LYPHAZURIN™ 1%.
LYMPHAZURIN™ 1% (Isosulfan Blue) AQUEOUS SOULTION
Initial U.S. Approval: 1981
----------------------------RECENT MAJOR CHANGES-------------------
Warnings and Precautions, Interference with Oxygen Saturation and
Methemoglobin Measurements (5.3).
10/2007
----------------------------INDICATIONS AND USAGE---------------------
Lymphazurin™ 1% (isosulfan blue) upon subcutaneous administration,
delineates the lymphatic vessels draining the region of injection. It is an
adjunct to lymphography in: primary and secondary lymphedema of the
extremities; chyluria, chylous ascites or chylothorax; lymph node
involvement by primary or secondary neoplasm; lymph node response to
therapeutic modalities (1.1).
-----------------------DOSAGE AND ADMINISTRATION----------------
Lymphazurin™ 1% is to be administered subcutaneously, one-half
(1/2) ml into three (3) interdigital spaces of each extremity per study. A
maximum dose of 3 ml (30 mg) isosulfan blue is, therefore, injected
(2.1).
--------------------DOSAGE FORMS AND STRENGTHS-----------------
1% aqueous solution (isosulfan blue)
------------------------------CONTRAINDICATIONS------------------------
Hypersensitivity to triphenylmethane or related compounds
(4).
-------------------WARNINGS AND PRECAUTIONS---------------
•
Life-threatening anaphylactic reactions have occurred after
Lymphazurin 1% administration. Monitor patients closely for at
least 60 minutes after administration of Lymphazurin 1% (5.1).
•
The admixture of Lymphazurin 1% with local anesthetics results
in an immediate precipitation of 4-9% drug complex. Use a
separate syringe for anesthetics (5.2).
•
Lymphazurin 1% interferes with measurements in peripheral
blood pulse oximetry. Arterial blood gas analysis may be
needed (5.3).
-----------------------ADVERSE REACTIONS-----------------------------
Hypersensitivity Reactions: Hypersensitivity reactions occurring
approximately 2% of patients and include life-threatening
anaphylactic reactions with respiratory distress, shock, angioedema,
urticaria, pruritus. A death has been reported following IV
administration of a similar compound (6).
To report SUSPECTED ADVERSE REACTIONS, contact U. S.
Surgical at 1-800-522- 0263 option 5, or FDA at 1-800-FDA-1088
or www.fda.gov/medwatch.
----------------------------DRUG INTERACTIONS------------------------
No drug interactions have been identified for Lymphazurin 1% (7).
--------------------------USE IN SPECIFIC POPULATIONS-----------
•
Caution should be exercised when Lymphazurin 1% is
administered to nursing mothers (8.3).
•
Safety and effectiveness of Lymphazurin 1% in children has not
been established (8.4).
See 17 for PATIENT COUNSELING INFORMATION
Revised: 10/2007
_________________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Lymphatic Vessel Delineation
2
DOSAGE AND ADMINISTRATION
2.1 Subcutaneous administration
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions
5.2 Precipitation of Lymphazurin 1% by Lidocaine
5.3 Interference with Oxygen Saturation and Methemoglobin
Measurements
6
ADVERSE REACTIONS
6.1 Postmarketing Experience
7
DRUG INTERACTIONS
8
USE IN SPECIFIC POPULATIONS
8.3 Nursing Mothers
8.4 Pediatric Use
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Teratogenic Effects
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information
are not listed.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1 Lymphatic Vessel Delineation
Lymphazuirn™ 1% (isosulfan blue) upon subcutaneous
administration, delineates lymphatic vessels draining the region of
injection. It is an adjunct to lymphography in: primary and secondary
lymphedema of the extremities; chyluria, chylous ascites or
chylothorax; lymph node involvement by primary or secondary
neoplasm; and lymph node response to therapeutic modalities.
2
DOSAGE AND ADMINISTRATION
2.1 Subcutaneous administration
Lymphazurin™ 1% is to be administered subcutaneously, one-
half (1/2) ml into three (3) interdigital spaces of each extremity per
study. A maximum dose of 3 ml (30 mg) isosulfan blue is, therefore,
injected.
3
DOSAGE FORMS AND STRENGTHS
1% aqueous solution (isosulfan blue)
4
CONTRAINDICATIONS
Lymphazurin™ 1% (isosulfan blue) is contraindicated in those
individuals with known hypersensitivity to triphenylmethane or related
compounds.
5
WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions
Life-threatening anaphylactic reactions (respiratory distress,
shock, angioedema) have occurred after Lymphazurin 1%
administration. Reactions are more likely to occur in patients with a
history of bronchial asthma, allergies, drug reactions or previous
reactions to triphenylmethane dyes. Monitor patients closely for at least
60 minutes after administration of Lymphazurin 1%. Trained personnel
should be available to administer emergency care including
resuscitation.
5.2 Precipitation of Lymphazurin 1% by Lidocaine
The admixture of Lymphazurin 1% (with local anesthetics (i.e.
lidocaine)) in the same syringe results in an immediate precipitation of
4 – 9% drug complex. Use a separate syringe to administer a local
anesthetic.
5.3 Interference with Oxygen Saturation and
Methemoglobin Measurements
Lymphazurin 1% interferes with measurements of oxygen
saturation in peripheral blood by pulse oximetry and can cause falsely
low readings. The interference effect is maximal at 30 minutes and
minimal generally by four hours after administration. Arterial blood
gas analysis may be needed to verify decreased arterial partial pressure
of oxygen.
Lymphazurin 1% may also cause falsely elevated readings of
methemoglobin by arterial blood gas analyzer. Therefore, co-oximetry
may be needed to verify methemoglobin level.
6
ADVERSE REACTIONS
6.1 Postmarketing Experience
Hypersensitivity Reactions: Case series report an overall incidence
of hypersensitivity reactions in approximately 2% of patients. Life-
threatening anaphylactic reactions have occurred. Manifestations include
respiratory distress, shock, angioedema, urticaria, pruritus. A death has
been reported following administration of a similar compound employed
to estimate the depth of a severe burn. Reactions are more likely to occur
in patients with a personal or family history of bronchial asthma,
significant allergies, drug reactions or previous reactions to
triphenylmethane dyes [see Warnings and Precautions (5)].
Laboratory Tests: Lymphazurin 1% interferes with measurements
of oxygen saturation by pulse oximetry and of methemoglobin by gas
analyzer [see Warnings and Precautions (5)].
Skin: transient or long-term (tattooing) blue coloration.
7
DRUG INTERACTIONS
No drug interactions have been identified with Lymphazurin 1%.
8
USE IN SPECIFIC POPULATIONS
8.3 Nursing Mothers
It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk, caution should be
exercised when Lymphazurin™ 1% (isosulfan blue) is administered to
a nursing mother.
8.4 Pediatric Use
Safety and effectiveness of Lymphazurin™ 1% (isosulfan blue) in
children have not been established.
10
OVERDOSAGE
Do not exceed indicated recommended dosage as overdosage
levels have not been identified for Lymphazurin 1%.
11
DESCRIPTION
The chemical name of Lymphazurin 1% (isosulfan blue) is N-[4-
[[4-(diethylamino)phenyl] (2,5-disulfophenyl) methylene]-2,5-
cyclohexadien-1-ylidene]-N-ethylethanaminium hydroxide, inner salt,
sodium salt. Its structural formula is:
Lymphazurin 1% is a sterile aqueous solution for subcutaneous
administration. Phosphate buffer in sterile, pyrogen free water is added
in sufficient quantity to yield a final pH of 6.8-7.4. Each ml of solution
contains 10 mg Isosulfan blue, 6.6 mg sodium monohydrogen
phosphate and 2.7 mg potassium dihydrogen phosphate. The solution
contains no preservative. Lymphazurin 1% is a contrast agent for the
delineation of lymphatic vessels.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
CLINICAL PHARMACOLOGY
12.2 Pharmacodynamics
Following subcutaneous administration, Lymphazurin 1% binds
to serum proteins and is picked up by the lymphatic vessels. Thus, the
lymphatic vessels are delineated by the blue dye.
12.3 Pharmacokinetics
Up to 10% of the subcutaneously administered dose of Lymphazurin
1% is excreted unchanged in the urine in 24 hours in human.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have not been performed to evaluate
the carcinogenic potential of Lymphazurin 1%. Reproduction studies in
animals have not been conducted and, therefore, it is unknown if a
problem concerning mutagenesis or impairment of fertility in either
males or females exists.
13.2 Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not
been conducted with Lymphazurin 1%. It is not known whether
Lymphazurin 1% can cause fetal harm when administered to a pregnant
woman or can affect reproduction capacity. Lymphazurin 1% should be
given to a pregnant woman only if clearly needed.
16
HOW SUPPLIED/STORAGE AND HANDLING
Lymphazurin 1% is supplied as a 5 ml single dose vial, 1%
aqueous solution in a phosphate buffer prepared by appropriate
manufacturing to be sterile and pyrogen-free.
17
PATIENT COUNSELING INFORMATION
Inform patients that urine color may be blue for 24 hours
following administration of Lymphazurin 1%.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:41.529174
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018310s011lbl.pdf', 'application_number': 18310, 'submission_type': 'SUPPL ', 'submission_number': 11}
|
11,202
|
company logo
2
451106E/Revised: August 2013
3
4
Sensorcaine® (bupivacaine HCl Injection, USP)
5
Sensorcaine®-MPF (bupivacaine HCl Injection, USP)
6
Sensorcaine® with Epinephrine (bupivacaine HCl and epinephrine Injection, USP)
7
1:200,000 (as bitartrate)
8
Sensorcaine®-MPF with Epinephrine (bupivacaine HCl and epinephrine Injection,
9
USP) 1:200,000 (as bitartrate)
10
Rx only
11
DESCRIPTION:
12
Sensorcaine® (bupivacaine HCl) injections are sterile isotonic solutions that contain a
13
local anesthetic agent with and without epinephrine (as bitartrate) 1:200,000 and are
14
administered parenterally by injection. See INDICATIONS AND USAGE for specific
15
uses. Solutions of bupivacaine HCl may be autoclaved if they do not contain
16
epinephrine.
17
Sensorcaine injections contain bupivacaine HCl which is chemically designated
18
as 2-piperidinecarboxamide, 1-butyl-N-(2, 6-dimethylphenyl)-, monohydrochloride,
19
monohydrate and has the following structure:
structural formula
1
Reference ID: 3790412
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Epinephrine is (-)-3, 4-Dihydroxy-α [(methylamino)methyl] benzyl alcohol. It
2
has the following structural formula:
structural formula
4
The pKa of bupivacaine (8.1) is similar to that of lidocaine (7.86). However,
5
bupivacaine possesses a greater degree of lipid solubility and is protein bound to a greater
6
extent than lidocaine.
7
Bupivacaine is related chemically and pharmacologically to the aminoacyl local
8
anesthetics. It is a homologue of mepivacaine and is chemically related to lidocaine. All
9
three of these anesthetics contain an amide linkage between the aromatic nucleus and the
10
amino, or
piperidine group. They differ in this respect from the procaine-type local
11
anesthetics, which have an ester linkage.
12
Dosage forms listed as Sensorcaine-MPF indicates single dose solutions that
13
are Methyl Paraben Free (MPF).
14
Sensorcaine-MPF is a sterile isotonic solution containing sodium chloride.
15
Sensorcaine in multiple dose vials, each mL also contains 1 mg methylparaben as
16
antiseptic preservative. The pH of these solutions is adjusted to between 4.0 and 6.5 with
17
sodium hydroxide and/or hydrochloric acid.
18
Sensorcaine-MPF with Epinephrine 1:200,000 (as bitartrate) is a sterile isotonic
19
solution containing sodium chloride. Each mL contains bupivacaine hydrochloride and
20
0.005 mg epinephrine, with 0.5 m
g sodium metabisulfite as an antioxidant and 0.2 mg
21
citric acid (anhydrous) as stabilizer. Sensorcaine with Epinephrine 1:200,000 (as
2
Reference ID: 3790412
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
bitartrate) in multiple dose vials, each mL also contains 1 mg methylparaben as antiseptic
2
preservative. The pH of these solutions is adjusted to between 3.3 to 5.5 with sodium
3
hydroxide and/or hydrochloric acid. Filled under nitrogen.
4
Note: The user should have an appreciation and awareness of the formulations
5
and their intended uses (see DOSAGE AND AD
MINISTRATION).
6
CLINICAL PHARMACOLOGY:
7
Local anesthetics block the generation and the conduction of nerve impulses, presumably
8
by increasing the threshold for electrical excitation in the nerve, by slowing the
9
propagation of the nerve impulse, and by reducing the rate of rise of the action potential.
10
In general, the progression of anesthesia is related to the diameter, myelination, a nd
11
conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve
12
function is as follows: (1) pain, ( 2) temperature, (3) touch, (4) proprioception, and (5)
13
skeletal muscle tone.
14
Systemic absorption of local anesthetics produces effects on the cardiovascular
15
and central nervous systems CNS. At blood c oncentrations achieved with normal
16
therapeutic doses, changes in cardiac conduction, excitability, refractoriness,
17
contractility, and peripheral vascular resistance are minimal. However, toxic blood
18
concentrations depress cardiac conduction and excitability, which may lead to
19
atrioventricular block, ventricular arrhythmias and cardiac arrest, sometimes resulting in
20
fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation
21
occurs, leading to decreased cardiac output and arterial blood pr
essure. Recent clinical
22
reports and animal research suggest that these cardiovascular changes are more likely to
23
occur after unintended intravascular injection of bupivacaine. Therefore, incremental
3
Reference ID: 3790412
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
dosing is necessary.
2
Following systemic absorption, local anesthetics can produce central nervous
3
system stimulation, depression, or
both. Apparent central stimulation is manifested as
4
restlessness, tremors and shivering progressing to convulsions, followed by depression
5
and coma progressing ultimately to respiratory arrest. However, the local anesthetics
6
have a primary depressant effect on the medulla and on higher centers. The depressed
7
stage may occur without a p rior excited state.
8
Pharmacokinetics
9
The rate of systemic absorption of local anesthetics is dependent upon the total dose and
10
concentration of drug administered, the route of administration, the vascularity of the
11
administration site, and the presence or absence of epinephrine in the anesthetic solution.
12
A dilute concentration of epinephrine (1:200,000 or 5 mcg/mL) usually reduces the rate
13
of absorption and peak plasma concentration of bupivacaine, permitting the use of
14
moderately larger total doses and sometimes prolonging the duration of action.
15
The onset of action with bupivacaine is rapid and anesthesia is long lasting. The
16
duration of anesthesia is significantly longer with bupivacaine than with any other
17
commonly used local anesthetic. It has also been noted that there is a period of analgesia
18
that persists after the return of sensation, during which time the need for strong analgesics
19
is reduced.
20
The onset of action following dental injections is usually 2 to 10 minutes and
21
anesthesia may last two or three times longer than lidocaine and mepivacaine for dental
22
use, in many patients up to 7 hours. The duration of anesthetic effect is prolonged by the
23
addition of
epinephrine 1:200,000.
4
Reference ID: 3790412
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Local anesthetics are bound to plasma proteins in varying degrees. Generally, the
2
lower the plasma concentration of drug the higher the percentage of drug bound to
3
plasma proteins.
4
Local anesthetics appear to cross the placenta by passive diffusion. The rate and
5
degree of diffusion is governed by (1) the degree of plasma protein binding, (2) the
6
degree of ionization, and (3) the degree of lipid solubility. Fetal/maternal ratios of local
7
anesthetics appear to be inversely related to the degree of plasma protein binding,
8
because only the free, unbound drug is available for placental transfer. Bupivacaine with
9
a high protein binding capacity (95%) has a low fetal/maternal ratio (0.2 to 0.4). The
10
extent of placental transfer is also determined by the degree of ionization and lipid
11
solubility of the drug. Lipid soluble, nonionized drugs readily enter the fetal blood from
12
the maternal circulation.
13
Depending upon the route of administration, local anesthetics are distributed to
14
some extent to all body tissues, with high concentrations found in highly perfused organs
15
such as the liver, lungs, heart, and brain.
16
Pharmacokinetic studies on the plasma profile of bupivacaine after direct
17
intravenous injection suggest a three-compartment open m
odel. The first compartment is
18
represented by the rapid intravascular distribution of the drug. The second compartment
19
represents the equilibration of the drug throughout the highly perfused organs such as the
20
brain, myocardium, lungs, kidneys, a nd liver. The third compartment represents an
21
equilibration of the drug w
ith poorly perfused tissues, such as muscle and fat. The
22
elimination of drug from tissue distribution depends largely upon the ability of binding
23
sites in the circulation to carry it to the liver where it is metabolized.
5
Reference ID: 3790412
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
After injection of Sensorcaine (bupivacaine HCl) for caudal, epidural, or
2
peripheral nerve block in man, peak levels of bupivacaine in the blood are reached in 30
3
to 45 minutes, followed by a decline to insignificant levels during the next 3 to 6 hours.
4
Various pharmacokinetic parameters of the local anesthetics can be significantly
5
altered by the presence of hepatic or renal disease, addition of epinephrine, factors
6
affecting urinary pH, renal blood f low, the route of drug administration, and the age of
7
the patient. The half-life of bupivacaine in adults is 2.7 hours and in neonates 8.1 hours.
8
In clinical studies, elderly patients reached the maximal spread of analgesia and
9
maximal motor blockade more rapidly than younger patients. Elderly patients also
10
exhibited higher peak plasma concentrations following administration of this product.
11
The total plasma clearance was decreased in these patients.
12
Amide-type local anesthetics such as bupivacaine are metabolized primarily in the
13
liver via conjugation with glucuronic acid. Patients with hepatic disease, especially those
14
with severe hepatic disease, may be more susceptible to the potential toxicities of the
15
amide-type local anesthetics. Pipecoloxylidine is the major metabolite of bupivacaine.
16
The kidney is the main excretory organ for most local anesthetics and their
17
metabolites. Urinary excretion is affected by urinary perfusion and factors affecting
18
urinary pH. Only 6% of bupivacaine is excreted unchanged in the u rine.
19
When administered in recommended doses and concentrations, Sensorcaine
20
(bupivacaine HCl) does not ordinarily produce irritation or
tissue damage and does not
21
cause methemoglobinemia.
22
INDICATIONS AND USAGE:
23
Sensorcaine (bupivacaine HCl) is indicated for the production of local or regional
6
Reference ID: 3790412
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
anesthesia or analgesia for surgery, dental and oral surgery procedures, diagnostic and
2
therapeutic procedures, and for obstetrical procedures. Only the 0.25% and 0.5%
3
concentrations are indicated for obstetrical anesthesia (see WARNINGS).
4
Experience with nonobstetrical surgical procedures in pregnant patients is not
5
sufficient to recommend use of the 0.75% concentration of bupivacaine HCl in these
6
patients.
7
Sensorcaine is not recommended for intravenous regional anesthesia (Bier Block)
8
(see WARNINGS).
9
The routes of administration and indicated Sensorcaine concentrations are:
10
• local infiltration
11
• peripheral nerve block
12
• retrobulbar block
13
• sympathetic block
14
• lumbar epidural
15
16
• caudal
17
• epidural test dose
18
• dental blocks
0.25%
0.25% and 0.5%
0.75%
0.25%
0.25%, 0.5%, and 0.75% (0.75% not for obstetrical
anesthesia)
0.25% and 0.5%
0.5% with epinephrine 1:200,000
0.5% with epinephrine 1:200,000
19
(See DOSAGE AND ADMINISTRATION for additional information).
20
Standard textbooks should be consulted to determine the accepted procedures and
21
techniques for the administration of Sensorcaine.
22
CONTRAINDICATIONS:
23
Sensorcaine (bupivacaine HCl) is contraindicated in obstetrical paracervical block
7
Reference ID: 3790412
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
anesthesia. Its use in this technique has resulted in fetal bradycardia and death.
2
Sensorcaine is contraindicated in patients with a known hypersensitivity to it or to
3
any local anesthetic agent of the amide-type or to other components of bupivacaine
4
solutions.
5
WARNINGS:
THE 0.75% CONCENTRATION OF SENSORCAINE INJECTION IS NOT
RECOMMENDED FOR OBSTETRICAL ANESTHESIA. THERE HAVE
BEEN REPORTS OF CARDIAC ARREST WITH DIFFICULT
RESUSCITATION OR DEATH DURING USE OF BUPIVACAINE FOR
EPIDURAL ANESTHESIA IN OBSTETRICAL PATIENTS. IN MOST
CASES, THIS HAS FOLLOWED USE OF THE 0.75% CONCENTRATION.
RESUSCITATION HAS BEEN DIFFICULT OR IMPOSSIBLE DESPITE
APPARENTLY ADEQUATE PREPARATION AND APPROPRIATE
MANAGEMENT. CARDIAC ARREST HAS OCCURRED AFTER
CONVULSIONS RESULTING FROM SYSTEMIC TOXICITY,
PRESUMABLY FOLLOWING UNINTENTIONAL INTRAVASCULAR
INJECTION. THE 0.75% CONCENTRATION SHOULD BE RESERVED
FOR SURGICAL PROCEDURES WHERE A HIGH DEGREE OF MUSCLE
RELAXATION AND PROLONGED EFFECT ARE NECESSARY.
6
7
LOCAL ANESTHETICS SHOULD ONLY BE EMPLOYED BY CLINICIANS WHO
8
ARE WELL VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE-RELATED
9
TOXICITY AND OTHER ACUTE EMERGENCIES WHICH MIGHT ARISE FROM
8
Reference ID: 3790412
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
THE BLOCK TO BE EMPLOYED, AND THEN ONLY AFTER INSURING THE
2
IMMEDIATE AVAILABILITY OF OXYGEN, OTHER RESUSCITATIVE DRUGS,
3
CARDIOPULMONARY RESUSCITATIVE EQUIPMENT, AND THE PERSONNEL
4
RESOURCES NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS
5
AND RELATED EMERGENCIES (see also ADVERSE REACTIONS,
6
PRECAUTIONS, and OVERDOSAGE). DELAY IN PROPER MANAGEMENT OF
7
DOSE-RELATED TOXICITY, UNDERVENTILATION FROM ANY CAUSE
8
AND/OR ALTERED SENSITIVITY MAY LEAD TO THE DEVELOPMENT OF
9
ACIDOSIS, CARDIAC ARREST AND, POSSIBLY, DEATH.
10
Local anesthetic solutions containing antimicrobial preservatives, i.e., those
11
supplied in multiple-dose vials, should not be used for epidural or caudal anesthesia
12
because safety has not been established with regard to intrathecal injection, either
13
intentionally or unintentionally, of such preservatives.
14
Intra-articular infusions of local anesthetics following arthroscopic and other
15
surgical procedures is an unapproved use, and there have been post-marketing reports of
16
chondrolysis in patients receiving such infusions. The majority of reported cases of
17
chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have
18
been described in pediatric and adult patients following intra-articular infusions of local
19
anesthetics with and without epinephrine for periods of 48 to 72 hours. There is
20
insufficient information to determine whether shorter infusion periods are not associated
21
with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss
22
of motion can be variable, but may begin as early as the 2nd month after surgery.
23
Currently, there is no effective treatment for chondrolysis; patients who experienced
9
Reference ID: 3790412
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
chondrolysis have required additional diagnostic and therapeutic procedures and some
2
required arthroplasty or shoulder replacement.
3
It is essential that aspiration for blood or cerebrospinal fluid (where applicable) be
4
done prior to injecting any local anesthetic, both the original dose and all subsequent
5
doses, to avoid intravascular or subarachnoid injection. However, a negative aspiration
6
does not ensure against an intravascular or subarachnoid injection.
7
Bupivacaine with Epinephrine 1:200,000 or
other vasopressors should not be used
8
concomitantly with ergot-type oxytocic drugs, because a severe persistent hypertension
9
may occur. Likewise, solutions of bupivacaine containing a vasoconstrictor, such as
10
epinephrine, should be used with extreme caution in patients receiving monoamine
11
oxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types,
12
because severe prolonged hypertension may result.
13
Until further experience is gained in pediatric patients younger than 12 years,
14
administration of bupivacaine in this age group is not recommended.
15
Mixing or the prior or intercurrent use of any local anesthetic with bupivacaine
16
cannot be recommended because of insufficient data on the clinical use of such mixtures.
17
There have been reports of cardiac arrest and death during the use of bupivacaine
18
for intravenous regional anesthesia (Bier Block). Information on safe dosages and
19
techniques of administration of bupivacaine in this procedure is lacking. Therefore,
20
bupivacaine is not recommended for use in this technique.
21
Sensorcaine with epinephrine 1:200,000 solutions contains sodium metabisulfite,
22
a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life
23
threatening or less severe asthmatic episodes in certain susceptible people. The overall
10
Reference ID: 3790412
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
prevalence of sulfite sensitivity in the general population is unknown a nd probably low.
2
Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
3
Sensorcaine and Sensorcaine - MPF without epinephrine single dose vials do not contain
4
sodium metabisulfite.
5
PRECAUTIONS:
6
General
7
The safety and effectiveness of local anesthetics depend on proper dosage, correct
8
technique, adequate precautions, and readiness for emergencies. Resuscitative
9
equipment, oxygen, and other resuscitative drugs should be available for immediate use
10
(see WARNINGS, ADVERSE REACTIONS, and OVERDOSAGE). During major
11
regional nerve blocks, the patient should have IV fluids running via an indwelling
12
catheter to assure a functioning intravenous pathway. The lowest dosage of local
13
anesthetic that results in effective anesthesia should be used to avoid high plasma levels
14
and serious adverse effects. The rapid injection of a large volume of local anesthetic
15
solution should be avoided and fractional (incremental) doses should be used when
16
feasible.
17
Epidural Anesthesia
18
During e pidural administration of Sensorcaine (bupivacaine HCl), 0.5%
and 0.75%
19
solutions should be administered in incremental doses of 3 mL to 5 mL with sufficient
20
time between doses to detect toxic manifestations of unintentional intravascular or
21
intrathecal injection. Injections should be made slowly, with frequent aspirations before
22
and during the injection to avoid intravascular injection. Syringe aspirations should also
23
be performed before and during each supplemental injection in continuous (intermittent)
11
Reference ID: 3790412
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
catheter techniques. An intravascular injection is still possible even if aspirations for
2
blood are negative.
3
During the administration of epidural anesthesia, it is recommended that a test
4
dose be administered initially and the effects monitored be
fore the full dose is given.
5
When using a “continuous” catheter technique, test doses should be given prior to both
6
the original and a ll reinforcing doses, because plastic tubing in the epidural space can
7
migrate into a blood vessel or through the dura. When clinical conditions permit, the test
8
dose should contain epinephrine (10 mcg to 15 mcg has been suggested) to serve as a
9
warning of unintended intravascular injection. If injected into a blood vessel, t his amount
10
of epinephrine is likely to produce a transient “epinephrine response” within 45 seconds,
11
consisting of an increase in heart rate and/or systolic blood pressure, circumoral pallor,
12
palpitations, a nd nervousness in the unsedated patient. The sedated patient may exhibit
13
only a pulse rate increase of 20 or more beats per minute for 15 or more seconds.
14
Therefore, following the test dose, the heart rate should be monitored for a heart rate
15
increase. Patients on beta-blockers may not manifest changes in heart rate, but blood
16
pressure monitoring can detect a transient rise in systolic blood pressure. The test dose
17
should also contain 10 mg to 15 m
g of Sensorcaine or an equivalent amount of another
18
local anesthetic to detect an unintended intrathecal administration. This will be
19
evidenced within a few minutes by signs of spinal block (e.g., decreased sensation of the
20
buttocks, paresis of the legs, or, in t he sedated patient, absent knee jerk). An
21
intravascular or subarachnoid injection is still possible even if results of the test dose are
22
negative. The test dose itself may produce a systemic toxic reaction, high spinal or
23
epinephrine-induced cardiovascular effects.
12
Reference ID: 3790412
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Injection of repeated doses of local anesthetics may cause significant increases in
2
plasma levels with each repeated dose due to slow accumulation of the drug or its
3
metabolites, or
to slow metabolic degradation. Tolerance to elevated blood levels varies
4
with the status of the patient. Debilitated, elderly patients and acutely ill patients should
5
be given reduced doses commensurate with their age and physical status. Local
6
anesthetics should also be used with caution in patients with hypotension or heartblock.
7
Careful and constant monitoring of cardiovascular and respiratory (adequacy of
8
ventilation) vital signs and the patient’s state of consciousness should be performed after
9
each local anesthetic injection. It should be kept in mind at such times that restlessness,
10
anxiety, incoherent speech, lightheadedness, numbness and t ingling of the mouth and
11
lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, depression, or
12
drowsiness may be early warning signs of central nervous system toxicity.
13
Local anesthetic solutions containing a vasoconstrictor should be used cautiously
14
and in carefully restricted quantities in areas of the body supplied by end arteries or
15
having otherwise compromised bl
ood supply such as digits, nose, external ear, or penis.
16
Patients with hypertensive vascular disease may exhibit exaggerated vasoconstrictor
17
response. Ischemic injury or necrosis may result.
18
Because amide-local anesthetics such as bupivacaine are m
etabolized by the liver,
19
these drugs, especially repeat doses, should be used cautiously in patients with hepatic
20
disease. Patients with severe hepatic disease, because of their inability to metabolize
21
local anesthetics normally, are at a greater risk of developing toxic plasma
22
concentrations. Local anesthetics should also be used with caution in patients with
23
impaired cardiovascular function because they may be less able to compensate for
13
Reference ID: 3790412
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
functional changes associated with the prolongation of AV conduction produced by these
2
drugs.
3
Serious dose-related cardiac arrhythmias may occur if preparations containing a
4
vasoconstrictor such as epinephrine are employed in pa
tients during or following the
5
administration of potent inhalation anesthetics. In deciding w
hether to use these products
6
concurrently in the same patient, the combined action of both agents upon the
7
myocardium, the concentration and volume of vasoconstrictor used, and the time since
8
injection, when applicable, should be taken into a ccount.
9
Many drugs used during the conduct of anesthesia are considered potential
10
triggering agents for familial malignant hyperthermia. Because it is not known whether
11
amide-type local anesthetics may trigger this reaction and because the need for
12
supplemental general anesthesia cannot be predicted in advance, it is suggested that a
13
standard protocol for management should be available. Early unexplained signs of
14
tachycardia, tachypnea, labile blood pressure, and metabolic acidosis may precede
15
temperature elevation. Successful outcome is dependent on early diagnosis, prompt
16
discontinuance of the suspect triggering agent(s) and prompt institution of treatment,
17
including oxygen therapy, indicated supportive measures and dantrolene (consult
18
dantrolene sodium intravenous package insert before using).
19
Use in Head and Neck Area
20
Small doses of local anesthetics injected into the head and neck area, including
21
retrobulbar, dental and stellate ganglion blocks, may produce adverse reactions similar to
22
systemic toxicity seen with unintentional intravascular injections of larger doses. The
23
injection procedures require the utmost care. Confusion, convulsions, respiratory
14
Reference ID: 3790412
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
depression, and/or respiratory arrest, and c ardiovascular stimulation or depression have
2
been reported. These reactions may be due to intra-arterial injection of the local
3
anesthetic with retrograde flow to the cerebral circulation. They may also be due to
4
puncture of the dural sheath of the optic nerve during retrobulbar block with diffusion of
5
any local anesthetic along the subdural space to the midbrain. Patients receiving these
6
blocks should have their circulation and respiration monitored and be constantly
7
observed. Resuscitative equipment and personnel for treating adverse reactions should be
8
immediately available. Dosage recommendations should not be exceeded (see DOSAGE
9
AND AD
MINISTRATION).
10
Use in Ophthalmic Surgery
11
Clinicians who perform retrobulbar blocks should be aware that there have been reports
12
of respiratory arrest following local anesthetic injection. Prior to retrobulbar block, as
13
with all other regional procedures, the immediate availability of equipment, drugs, and
14
personnel to manage respiratory arrest or depression, c onvulsions, and cardiac
15
stimulation or depression should be assured (see also WARNINGS and Use in Head and
16
Neck Area, a bove). As with other anesthetic procedures, patients should be constantly
17
monitored following ophthalmic blocks for signs of these adverse reactions, which may
18
occur following relatively low total doses.
19
A concentration of 0.75% bupivacaine is indicated for retrobulbar block;
20
however, this concentration is not indicated for any other peripheral nerve block,
21
including the facial nerve, a nd not indicated for local infiltration, including the
22
conjunctiva (see INDICATIONS and PRECAUTIONS, General). Mixing Sensorcaine
23
(bupivacaine HCl) with other local anesthetics is not recommended because of
15
Reference ID: 3790412
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
insufficient data on the clinical use of such mixtures.
2
When Sensorcaine (bupivacaine HCl) 0.75% is used for retrobulbar block,
3
complete corneal anesthesia usually precedes onset of clinically acceptable external
4
ocular muscle akinesia. Therefore, presence of akinesia rather than anesthesia alone
5
should de
termine readiness of the patient for surgery.
6
Use in Dentistry
7
Because of the long duration of anesthesia, when Sensorcaine 0.5% with epinephrine is
8
used for dental injections, patients should be cautioned about the possibility of
9
inadvertent trauma to the tongue, lips, and buccal mucosa and advised not to chew solid
10
foods or test the anesthetized area by biting or probing.
11
Information for Patients
12
When appropriate, patients should be informed in advance that they may experience
13
temporary loss of sensation and motor activity, us
ually in the lower half of the body,
14
following proper administration of caudal or epidural anesthesia. Also, when
15
appropriate, t he physician should discuss other information including adverse reactions in
16
the package insert of Sensorcaine.
17
Patients receiving dental injections of Sensorcaine should be cautioned not to
18
chew solid foods or test the anesthetized area by biting or probing until anesthesia has
19
worn off (up to 7 hours).
20
Clinically Significant Drug Interactions
21
The administration of local anesthetic solutions containing epinephrine or norepinephrine
22
to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may
23
produce severe, prolonged hypertension. Concurrent use of these agents should generally
16
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1
be avoided. In situations when concurrent therapy is necessary, careful patient
2
monitoring is essential.
3
Concurrent administration of vasopressor drugs and of ergot-type oxytocic drugs
4
may cause severe, persistent hypertension or cerebrovascular accidents.
5
Phenothiazines and butyrophenones may reduce or reverse the pressor effect of
6
epinephrine.
7
Carcinogenesis, Mutagenesis, Impairment of Fertility
8
Long-term studies in animals to evaluate the carcinogenic potential of bupivacaine
9
hydrochloride have not been conducted. The mutagenic potential and the effect on
10
fertility have not been d etermined.
11
Pregnancy Category C
12
There are no adequate and well-controlled studies in pregnant women. Sensorcaine
13
should be used during pregnancy only if the potential benefit justifies the potential risk to
14
the fetus. Bupivacaine hydrochloride produced developmental toxicity when
15
administered subcutaneously to pregnant rats and rabbits at clinically relevant doses.
16
This does not exclude the use of Sensorcaine at term for obstetrical anesthesia or
17
analgesia (see Labor and Delivery).
18
Bupivacaine hydrochloride was administered subcutaneously to rats at doses of 4.4,
19
13.3, & 40 mg/kg and to rabbits at doses of 1.3, 5.8, & 22.2 mg/kg during the period of
20
organogenesis (implantation to closure of the hard palate). The high doses are comparable to
21
the daily maximum recommended human dose (MRHD) of 400 mg/day on a mg/m
2 body
22
surface area (BSA) basis. No embryo-fetal effects were observed in rats at the high dose
23
which caused increased maternal lethality. An increase in embryo-fetal deaths was observed
17
Reference ID: 3790412
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1
in rabbits at the high dose in the absence of maternal toxicity with the fetal No Observed
2
Adverse Effect Level representing approximately 1/5th the MRHD on a BSA basis.
3
In a rat pre- and post-natal development study (dosing f rom implantation through
4
weaning) conducted at subcutaneous doses of 4.4, 13.3, & 40 mg/kg mg/kg/day, decreased
5
pup survival was observed at the high dose. The high dose is comparable to the daily MRHD
6
of 400 mg/day on a BSA basis.
7
Labor and Delivery
8
SEE BOX WARNING REGARDING OBSTETRICAL USE of 0.75% Sensorcaine.
9
Sensorcaine is contraindicated for obstetrical paracervical block anesthesia.
10
Local anesthetics rapidly cross the placenta, and when used for epidural, caudal,
11
or pudendal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal
12
toxicity (see CLINICAL PHARMACOLOGY, Pharmacokinetics ). The incidence and
13
degree of toxicity depend upon the procedure performed, the type, a nd amount of drug
14
used, and the technique of drug administration. Adverse reactions in the parturient, fetus,
15
and neonate involve alterations of the central nervous system, pe
ripheral vascular tone,
16
and cardiac function.
17
Maternal hypotension has resulted from regional anesthesia. Local anesthetics
18
produce vasodilation by blocking sympathetic nerves. Elevating the patient’s legs and
19
positioning her on her left side will help prevent decreases in blood pressure. The fetal
20
heart rate also should be monitored c ontinuously and electronic fetal monitoring is highly
21
advisable.
22
Epidural, caudal, or pudendal anesthesia may alter the forces of parturition
23
through changes in uterine contractility or maternal expulsive efforts. Epidural
18
Reference ID: 3790412
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1
anesthesia has been reported to prolong the second stage of labor by removing the
2
parturient’s reflex urge to bear down or by interfering with motor function. The use of
3
obstetrical anesthesia may increase the need for forceps assistance.
4
The use of some local anesthetic drug products during labor and delivery may be
5
followed by diminished muscle strength and tone for the first day or two of life. This has
6
not been reported with b upivacaine.
7
It is extremely important to avoid aortocaval compression by the gravid uterus
8
during administration of regional block to parturients. To do this, the patient must be
9
maintained in the left lateral decubitus position or a blanket roll or sandbag m
ay be
10
placed beneath the right hip and gr
avid uterus displaced to the left.
11
Nursing Mothers
12
Bupivacaine has been reported to be excreted in human milk s uggesting that the nursing
13
infant could be theoretically exposed to a dose of the drug. Because of the potential for
14
serious adverse reactions in nursing infants from bupivacaine, a decision should be made
15
whether to discontinue nursing or not administer bupivacaine, t aking into account the
16
importance of the drug to the mother.
17
Pediatric Use
18
Until further experience is gained in pediatric patients younger than 12 years,
19
administration of Sensorcaine (bupivacaine HCl) Injection i n this age group is not
20
recommended. Continuous infusions of bupivacaine in children have been reported to
21
result in high systemic levels of bupivacaine and seizures; high plasma levels may also be
22
associated with cardiovascular abnormalities (see WARNINGS, PRECAUTIONS, and
23
OVERDOSAGE).
19
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1
Geriatric Use
2
Patients over 65 years, particularly those with hypertension, may be at increased risk for
3
developing hypotension while undergoing anesthesia with bupivacaine (see ADVERSE
4
REACTIONS).
5
Elderly patients may require lower doses of bupivacaine (see PRECAUTIONS,
6
Epidural Anesthesia and DOSAGE AND ADMINISTRATION).
7
In clinical studies, differences in various pharmacokinetic parameters have been
8
observed between elderly and younger patients (see CLINICAL PHARMACOLOGY).
9
This product is known to be substantially excreted by the kidney, and the risk of
10
toxic reactions to this drug may be greater in patients with impaired renal function.
11
Because elderly patients are more likely to have decreased renal function, care should be
12
taken in dose selection, and it may be useful to monitor renal function (see CLINICAL
13
PHARMACOLOGY).
14
ADVERSE REACTIONS:
15
Reactions to Sensorcaine (bupivacaine HCl) are characteristic of those associated with
16
other amide-type local anesthetics. A major cause of adverse reactions to this group of
17
drugs is excessive plasma levels, which may be due to overdosage, unintentional
18
intravascular injection, or slow metabolic degradation.
19
Systemic
20
The most commonly encountered acute adverse experiences which demand immediate
21
counter-measures are related to the central nervous system and the cardiovascular system.
22
These adverse experiences are generally dose related and due to high plasma levels which
23
may result from overdosage, rapid absorption from the injection site, diminished
20
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1
tolerance, or from unintentional intravascular injection of the local anesthetic solution. In
2
addition to systemic dose-related toxicity, unintentional subarachnoid injection of drug
3
during the intended performance of caudal or lumbar epidural block or nerve blocks near
4
the vertebral column (especially in the head and neck region) may result in
5
underventilation or apnea (“Total or High Spinal”). Also, hypotension due to loss of
6
sympathetic tone and respiratory paralysis or underventilation due to cephalad extension
7
of the motor level of anesthesia may occur. This may lead to secondary cardiac arrest if
8
untreated. Patients over 65 years, particularly those with hypertension, may be at
9
increased risk for experiencing the hypotensive effects of bupivacaine. Factors
10
influencing plasma protein binding, such as acidosis, systemic diseases which alter
11
protein production, or competition of other drugs for protein binding sites, may diminish
12
individual tolerance.
13
Central Nervous System Reactions
14
These are characterized by excitation and/or depression. Restlessness, anxiety, dizziness,
15
tinnitus, blurred vision, or tremors may occur, possibly proceeding to convulsions.
16
However, excitement may be transient or absent, with depression being the first
17
manifestation of an adverse reaction. This may quickly be followed by drowsiness
18
merging into unconsciousness and respiratory arrest. Other central nervous system
19
effects may be nausea, vomiting, chills, and constriction of the pupils.
20
The incidence of convulsions associated with the use of local anesthetics varies
21
with the procedure used and the total dose administered. In a survey of studies of
22
epidural anesthesia, overt toxicity progressing to convulsions occurred in approximately
23
0.1% of local anesthetic administrations.
21
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1
Cardiovascular System Reactions
2
High doses or unintentional intravascular injection may lead to high plasma levels and
3
related depression of the myocardium, decreased cardiac output, heartblock, hypotension,
4
bradycardia, ventricular arrhythmias, including ventricular tachycardia and ventricular
5
fibrillation, and cardiac arrest (see WARNINGS, PRECAUTIONS, and
6
OVERDOSAGE).
7
Allergic
8
Allergic-type reactions are rare and may occur as a result of sensitivity to the local
9
anesthetic or to other formulation ingredients, such as the antimicrobial preservative
10
methylparaben contained in multiple dose vials or sulfites in epinephrine-containing
11
solutions. These reactions are characterized by signs such as urticaria, pruritus,
12
erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing,
13
nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and
14
possibly, anaphylactoid-like symptomatology (including severe hypotension). Cross
15
sensitivity among members of the amide-type local anesthetic group has been reported.
16
The usefulness of screening for sensitivity has not been definitely established.
17
Neurologic
18
The incidence of adverse neurologic reactions associated with the use of local anesthetics
19
may be related to the total dose of local anesthetic administered and are also dependent
20
upon the particular drug used, the route of administration, and the physical status of the
21
patient. Many of these effects may be related to local anesthetic techniques, with or
22
without a contribution from the drug.
23
In the practice of caudal or lumbar epidural block, occasional unintentional
22
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1
penetration of the subarachnoid space by the catheter or needle may occur. Subsequent
2
adverse effects may depend partially on the amount of drug administered intrathecally
3
and the physiological and physical effects of a dural puncture. A high spinal is
4
characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and
5
bradycardia.
6
Neurologic effects following epidural or caudal anesthesia may include spinal
7
block of varying magnitude (including high or total spinal block); hypotension secondary
8
to spinal block; urinary retention; fecal and urinary incontinence; loss of perineal
9
sensation and sexual function; persistent anesthesia, paresthesia, weakness, paralysis of
10
the lower extremities and loss of sphincter control all of which may have slow,
11
incomplete, or no recovery; headache; backache; septic meningitis; meningismus;
12
slowing of labor; increased incidence of forceps delivery; or cranial nerve palsies due to
13
traction on nerves from loss of cerebrospinal fluid.
14
Neurologic effects following other procedures or routes of administration may
15
include persistent anesthesia, paresthesia, weakness, paralysis, all of which may have
16
slow, incomplete, or no recovery.
17
OVERDOSAGE:
18
Acute emergencies from local anesthetics are generally related to high plasma levels
19
encountered during therapeutic use of local anesthetics or to unintended subarachnoid
20
injection of local anesthetic solution (see ADVERSE REACTIONS, WARNINGS, and
21
PRECAUTIONS).
22
Management of Local Anesthetic Emergencies
23
The first consideration is prevention, best accomplished by careful and constant
23
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1
monitoring of cardiovascular and respiratory vital signs and the patient’s state of
2
consciousness after each local anesthetic injection. At the first sign of change, oxygen
3
should be administered.
4
The first step in the management of systemic toxic reactions, as well as
5
underventilation or apnea due to unintentional subarachnoid injection of drug solution,
6
consists of immediate attention to the establishment and maintenance of a patent airway
7
and effective assisted or controlled ventilation with 100% oxygen with a delivery system
8
capable of permitting immediate positive airway pressure by mask. This may prevent
9
convulsions if they have not already occurred.
10
If necessary, use drugs to control the convulsions. A 50 mg to 100 mg bolus IV
11
injection of succinylcholine will paralyze the patient without depressing the central
12
nervous or cardiovascular systems and facilitate ventilation. A bolus IV dose of 5 mg to
13
10 mg of diazepam or 50 mg to 100 mg of thiopental will permit ventilation and
14
counteract central nervous system stimulation, but these drugs also depress the central
15
nervous system, respiratory, and cardiac function, add to postictal depression and may
16
result in apnea. Intravenous barbiturates, anticonvulsant agents, or muscle relaxants
17
should only be administered by those familiar with their use. Immediately after the
18
institution of these ventilatory measures, the adequacy of the circulation should be
19
evaluated. Supportive treatment of circulatory depression may require administration of
20
intravenous fluids, and when appropriate, a vasopressor dictated by the clinical situation
21
(such as ephedrine or epinephrine to enhance myocardial contractile force).
22
Endotracheal intubation, employing drugs and techniques familiar to the
23
clinician, may be indicated after initial administration of oxygen by mask if difficulty is
24
Reference ID: 3790412
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1
encountered in the maintenance of a patent airway, or if prolonged ventilatory support
2
(assisted or controlled) is indicated.
3
Recent clinical data from patients experiencing local anesthetic-induced
4
convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis with
5
bupivacaine within a minute of the onset of convulsions. These observations suggest that
6
oxygen consumption and carbon dioxide production are greatly increased during local
7
anesthetic convulsions and emphasize the importance of immediate and effective
8
ventilation with oxygen which may avoid cardiac arrest.
9
If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia,
10
and acidosis plus myocardial depression from the direct effects of the local anesthetic
11
may result in cardiac arrhythmias, bradycardia, asystole, ventricular fibrillation, or
12
cardiac arrest. Respiratory abnormalities, including apnea, may occur. Underventilation
13
or apnea due to unintentional subarachnoid injection of local anesthetic solution may
14
produce these same signs and also lead to cardiac arrest if ventilatory support is not
15
instituted. If cardiac arrest should occur, successful outcome may require prolonged
16
resuscitative efforts.
17
The supine position is dangerous in pregnant women at term because of
18
aortocaval compression by the gravid uterus. Therefore during treatment of systemic
19
toxicity, maternal hypotension or fetal bradycardia following regional block, the
20
parturient should be maintained in the left lateral decubitus position if possible, or manual
21
displacement of the uterus off the great vessels should be accomplished.
22
The mean seizure dosage of bupivacaine in rhesus monkeys was found to be 4.4
23
mg/kg with mean arterial plasma concentration of 4.5 mcg/mL. The intravenous and
25
Reference ID: 3790412
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1
subcutaneous LD50 in mice is 6 mg/kg to 8 mg/kg and 38 mg/kg to 54 mg/kg
2
respectively.
3
DOSAGE AND ADMINISTRATION:
4
The dose of any local anesthetic administered varies with the anesthetic procedure, the
5
area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to
6
be blocked, the depth of anesthesia and degree of muscle relaxation required, the duration
7
of anesthesia desired, individual tolerance, and the physical condition of the patient. The
8
smallest dose and concentration required to produce the desired result should be
9
administered. Dosages of Sensorcaine should be reduced for elderly and/or debilitated
10
patients and patients with cardiac and/or liver disease. The rapid injection of a large
11
volume of local anesthetic solution should be avoided and fractional (incremental) doses
12
should be used when feasible.
13
For specific techniques and procedures, refer to standard textbooks.
14
There have been adverse event reports of chondrolysis in patients receiving intra
15
articular infusions of local anesthetics following arthroscopic and other surgical
16
procedures. Sensorcaine is not approved for this use (see WARNINGS and DOSAGE
17
AND ADMINISTRATION).
18
In recommended doses, Sensorcaine (bupivacaine HCl) produces complete
19
sensory block, but the effect on motor function differs among the three concentrations.
20
0.25%—when used for caudal, epidural, or peripheral nerve block, produces
21
incomplete motor block. Should be used for operations in which muscle relaxation is not
22
important, or when another means of providing muscle relaxation is used concurrently.
23
Onset of action may be slower than with the 0.5% or 0.75% solutions.
26
Reference ID: 3790412
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1
0.5%—provides motor blockade for caudal, epidural, or nerve block, but muscle
2
relaxation may be inadequate for operations in which complete muscle relaxation is
3
essential.
4
0.75%—produces complete motor block. Most useful for epidural block in
5
abdominal operations requiring complete muscle relaxation, and for retrobulbar
6
anesthesia. Not for obstetrical anesthesia.
7
The duration of anesthesia with Sensorcaine is such that for most indications, a
8
single dose is sufficient.
9
Maximum dosage limit must be individualized in each case after evaluating the
10
size and physical status of the patient, as well as the usual rate of systemic absorption
11
from a particular injection site. Most experience to date is with single doses of
12
Sensorcaine up to 225 mg with epinephrine 1:200,000 and 175 mg without epinephrine;
13
more or less drug may be used depending on individualization of each case.
14
These doses may be repeated up to once every three hours. In clinical studies to
15
date, total daily doses have been up to 400 mg. Until further experience is gained, this
16
dose should not be exceeded in 24 hours. The duration of anesthetic effect may be
17
prolonged by the addition of epinephrine.
18
The dosages in Table 1 have generally proved satisfactory and are recommended
19
as a guide for use in the average adult. These dosages should be reduced for elderly or
20
debilitated patients. Until further experience is gained, Sensorcaine is not recommended
21
for pediatric patients younger than 12 years. Sensorcaine is contraindicated for
22
obstetrical paracervical blocks, and is not recommended for intravenous regional
23
anesthesia (Bier Block).
27
Reference ID: 3790412
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1
Use in Epidural Anesthesia
2
During epidural administration of Sensorcaine, 0.5% and 0.75% solutions should be
3
administered in incremental doses of 3 mL to 5 mL with sufficient time between doses to
4
detect toxic manifestations of unintentional intravascular or intrathecal injection. In
5
obstetrics, only the 0.5% and 0.25% concentrations should be used; incremental doses of
6
3 mL to 5 mL of the 0.5% solution not exceeding 50 mg to 100 mg at any dosing interval
7
are recommended. Repeat doses should be preceded by a test dose containing
8
epinephrine if not contraindicated. Use only the single dose ampules and single dose
9
vials for caudal or epidural anesthesia; the multiple dose vials contain a preservative and
10
therefore should not be used for these procedures.
11
12
Test Dose for Caudal and Lumbar Epidural Blocks
13
The Test Dose of Sensorcaine (0.5% bupivacaine with 1:200,000 epinephrine in a 3 mL
14
ampule) is recommended for use as a test dose when clinical conditions permit prior to
15
caudal and lumbar epidural blocks. This may serve as a warning of unintended
16
intravascular or subarachnoid injection (see PRECAUTIONS). The pulse rate and
17
other signs should be monitored carefully immediately following each test dose
18
administration to detect possible intravascular injection, and adequate time for onset of
19
spinal block should be allotted to detect possible intrathecal injection. An intravascular
20
or subarachnoid injection is still possible even if results of the test dose are negative.
21
The test dose itself may produce a systemic toxic reaction, high spinal or cardiovascular
22
effects from the epinephrine (see WARNINGS and OVERDOSAGE).
23
24
28
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1
TABLE 1. Recommended Concentrations and Doses of SENSORCAINE
2
(bupivacaine HCl) INJECTIONS
3
Type of Block
Conc.
Each Dose
(mL)
(mg)
Motor Block1
Local Infiltration
Epidural
Caudal
Peripheral Nerves
Retrobulbar3
Sympathetic
Dental3
Epidural3
Test Dose
0.25%4
0.75%2,4
0.5%4
0.25%4
0.5%4
0.25%4
0.5%4
0.25%4
0.75%4
0.25%
0.5%
w/epi
0.5%
w/epi
up to max.
up to max.
—
10 to 20
75 to 150
complete
10 to 20
50 to 100
moderate to complete
10 to 20
25 to 50
partial to moderate
15 to 30
75 to 150
moderate to complete
15 to 30
37.5 to 75
moderate
5 to max.
25 to max.
moderate to complete
5 to max.
12.5 to max. moderate to complete
2 to 4
15 to 30
complete
20 t0 50
50 to 125
—
1.8 to 3.6
per site
9 to 18
per site
—
2 to 3
10 to 15
10 to15 mcg epinephrine
(see PRECAUTIONS)
4
5
1 With continuous (intermittent) techniques, repeat doses increase the degree of motor
6
block. The first repeat dose of 0.5% may produce complete motor block. Intercostal
7
nerve block with 0.25% may also produce complete motor block for intra-abdominal
8
surgery.
29
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1
2 For single dose use, not for intermittent epidural technique. Not for obstetric
2
anesthesia.
3
3 See PRECAUTIONS.
4
4 Solutions with or without epinephrine.
5
HOW SUPPLIED:
6
These solutions are not for spinal anesthesia.
7
Sensorcaine-MPF (methylparaben free) is available in the following forms:
8
With Epinephrine:
Product
NDC
No.
No.
Strength
Size
460837
63323-468-37
0.25%
30 mL Single Dose Vials
packaged in trays of twenty-five.
460817
63323-468-17
0.25%
10 mL Single Dose Vials
packaged in trays of twenty-five.
460217
63323-462-17
0.5%
10 mL Single Dose Vials
packaged in trays of twenty-five.
460237
63323-462-37
0.5%
30 mL Single Dose Vials
packaged in trays of twenty-five.
460231
63323-462-31
0.5%
30 mL Single Dose Vials
packaged in fives.
461037
63323-460-37
0.75%
30 mL Single Dose Vials
packaged in trays of twenty-five.
30
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1
Without Epinephrine:
Product
NDC
No.
No.
Strength
Size
460417
63323-464-17
0.25%
10 mL Single Dose Vials
packaged in trays of twenty-five.
460437
63323-464-37
0.25%
30 mL Single Dose Vials
packaged in trays of twenty-five.
460431
63323-464-31
0.25%
30 mL Single Dose Vials
packaged in fives.
460617
63323-466-17
0.5%
10 mL Single Dose Vials
packaged in trays of twenty-five.
460637
63323-466-37
0.5%
30 mL Single Dose Vials
packaged in trays of twenty-five.
460631
63323-466-31
0.5%
30 mL Single Dose Vials
packaged in fives.
470217
63323-472-17
0.75%
10 mL Single Dose Vials
packaged in trays of twenty-five.
470237
63323-472-37
0.75%
30 mL Single Dose Vials
packaged in trays of twenty-five.
2
Sensorcaine (preserved with methylparaben) is available in the following forms:
3
With Epinephrine:
Product
NDC
No.
No.
Strength
Size
460157
63323-461-57
0.25%
50 mL Multiple Dose Vials
packaged in trays of twenty-five.
460357
63323-463-57
0.5%
50 mL Multiple Dose Vials
packaged in trays of twenty-five.
31
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1
Without Epinephrine:
Product
NDC
No.
No.
Strength
Size
460557
63323-465-57
0.25%
50 mL Multiple Dose Vials
packaged in trays of twenty-five.
460757
63323-467-57
0.5%
50 mL Multiple Dose Vials
packaged in trays of twenty-five.
2
3
Solutions should be stored at 20° to 25°C (68° to 77°F) [see USP Controlled
4
Room Temperature].
5
Solutions containing epinephrine should be protected from light.
6
7
All trademarks are the property of Fresenius Kabi USA, LLC.
8
Manufactured for:
9
10
11
12
Fresenius Kabi USA, LLC
Lake Zurich, IL 60047
13
14
451106E
15
Revised: August 2013
32
Reference ID: 3790412
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2025-02-12T13:44:41.637647
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/018304s044s045lbl.pdf', 'application_number': 18304, 'submission_type': 'SUPPL ', 'submission_number': 45}
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NDA 018327/S-005
Page 5
Xenon Xe 133 Gas
Rx only
Diagnostic
DESCRIPTION
Xenon Xe 133 Gas is for diagnostic inhalation use only. It is supplied in vials containing
either 370 or 740 megabecquerels (10 or 20 millicuries) of Xenon Xe 133 Gas in
2 milliliters of carrier xenon and atmospheric air.
Xenon Xe 133 Gas is chemically and physiologically similar to elemental xenon, a non
radioactive gas which is physiologically inert except for anesthetic properties at high
doses.
Xenon Xe 133 is produced by fission of Uranium U 235. At the time of calibration, it
contains no more than 0.3% Xenon Xe 133m, no more than 1.5% Xenon Xe 131m, no
more than 0.06% Krypton Kr 85 and no more than 0.01% Iodine I 131, with no less than
99.9% total radioactivity as radioxenon. Table 1 shows the effect of time on
radionuclidic composition.
Table 1. Radionuclidic Composition
Percent of Total Radioactivity
Days
% Xe-133
% Xe-133m
% Xe-131m
% Kr-85
% I-131
-5
0*
7
14**
>98.3
>98.1
>97.2
>95.7
<0.6
<0.3
<0.08
<0.02
<1.0
<1.5
<2.5
<4.1
<0.03
<0.06
<0.15
<0.37
<0.01
<0.01
<0.02
<0.02
*Calibration Date
**Expiration Date
PHYSICAL CHARACTERISTICS
Xenon Xe 133 decays by beta and gamma emissions with a physical half-life of
5.245 days.1 Photons that are useful for detection and imaging studies as well as the
principal beta emission are listed in Table 2.
1Kocher, David C., "Radioactive Decay Data Tables," DOE/TIC-11026, 138 (1981).
Reference ID: 3899046
NDA 018327/S-005
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Table 2. Principal Radiation Emission Data
Radiation
Mean % Per
Disintegration
Energy
(keV)
Beta-2
99.3
100.6 Avg.
Gamma-2
36.5
81.0
K alpha x-rays
38.9
30.8 Avg.
K beta x-rays
9.1
35.0 Avg.
EXTERNAL RADIATION
The specific gamma ray constant for Xenon Xe 133 is 0.51 R/hr-mCi at 1 cm. The first
half-value thickness is 0.0035 cm of Pb.
A range of values for the relative attenuation of the radiation emitted by this radionuclide
that results from interposition of various thicknesses of Pb is shown in Table 3. For
example, the use of 0.2 cm of Pb will decrease the external radiation exposure by a
factor of about 1000.
Table 3. Radiation Attenuation by Lead Shielding
Shield
Thickness (Pb),
cm
Coefficient
of Attenuation
0.0035
0.5
0.037
10-1
0.12
10-2
0.20
10-3
0.29
10-4
To correct for physical decay of this radionuclide, the fractions that remain at selected
time intervals after the date of calibration are shown in Table 4.
Table 4. Physical Decay Chart; Xenon Xe 133, Half-life 5.245 Days
Fraction
Fraction
Days Remaining Days Remaining
0*
1.000
8
0.347
1
0.876
9
0.304
2
0.768
10
0.267
3
0.673
11
0.234
Reference ID: 3899046
NDA 018327/S-005
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4
0.589
12
0.205
5
0.516
13
0.179
6
0.453
14
0.157
7
0.397
*Calibration Day
CLINICAL PHARMACOLOGY
Xenon Xe 133 is a readily diffusible gas which is neither utilized nor produced by the
body. It passes through cell membranes, freely exchanges between blood and tissue,
and tends to concentrate more in body fat than in blood, plasma, water or protein
solutions. In the concentrations recommended for diagnostic studies, it is physiologically
inactive. Inhaled Xenon Xe 133 Gas will enter the alveolar wall and the pulmonary
venous circulation via capillaries. Most of the Xenon Xe 133 Gas that enters the
circulation from a single breath is returned to the lungs and exhaled after a single pass
through the peripheral circulation.
INDICATIONS AND USAGE
Xenon Xe 133 Gas has been shown to be valuable for diagnostic inhalation studies for
the evaluation of pulmonary function, for imaging the lungs and may also be applied to
assessment of cerebral blood flow.
CONTRAINDICATIONS
None known.
WARNINGS
Xenon Xe 133 Gas delivery systems, i.e., respirators or spirometers, and associated
tubing assemblies must be leakproof to avoid loss of radioactivity into the laboratory
environs not specifically protected by exhaust systems.
Xenon Xe 133 Gas adheres to some plastics and rubber and should not be allowed to
stand in tubing or respirator containers. Loss of radioactivity due to such adherence
may render the study nondiagnostic.
PRECAUTIONS
General
Xenon Xe 133 Gas as well as other radioactive drugs, must be handled with care and
appropriate safety measures should be used to minimize radiation exposure to clinical
Reference ID: 3899046
NDA 018327/S-005
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personnel. Also, care should be taken to minimize radiation exposure to the patients
consistent with proper patient management.
Exhaled Xenon Xe 133 Gas should be controlled in a manner that is in compliance with
the appropriate regulations of the government agency authorized to license the use of
radionuclides.
Radiopharmaceuticals should be used only by physicians who are qualified by training
and experience in the safe use and handling of radionuclides and whose experience
and training have been approved by the appropriate government agency authorized to
license the use of radionuclides.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term animal studies have been performed to evaluate carcinogenic potential,
mutagenic potential or whether this drug affects fertility in males or females.
Pregnancy Category C
Animal reproduction studies have not been conducted with Xenon Xe 133 Gas. It is also
not known whether Xenon Xe 133 Gas can cause fetal harm when administered to a
pregnant woman or can affect reproduction capacity. Xenon Xe 133 Gas should be
given to a pregnant woman only if clearly needed.
Ideally, all examinations that use radiopharmaceuticals, especially those elective in
nature, of a woman of childbearing capability should be performed during the first few
(approximately 10) days following the onset of menses.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised when Xenon Xe 133 Gas is
administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
ADVERSE REACTIONS
Adverse reactions specifically attributable to Xenon Xe 133 Gas have not been
reported.
DOSAGE AND ADMINISTRATION
Xenon Xe 133 Gas is administered by inhalation from a closed respirator system or
spirometer. The final patient dose should be measured by a suitable radioactivity
calibration system immediately prior to administration.
Reference ID: 3899046
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The recommended activity range employed for inhalation by the average patient (70 kg)
is:
Pulmonary function including imaging: 74 to 1110 megabecquerels (2 to
30 millicuries)
Cerebral blood flow: 370 to 1110 megabecquerels (10 to 30 millicuries)
This may be administered as a bolus into the tubing near the patient's mouthpiece or
mask after the completion of a tidal exhalation, or by rebreathing for a period of
approximately 5 minutes of the Xenon Xe 133 gas in equilibrium with the air contained
in the closed system at concentrations of the radionuclide that may vary from 37 to
222 megabecquerels (1.0 to 6.0 millicuries) per liter.
RADIATION DOSIMETRY
The estimated absorbed radiation doses to an average patient (70 kg) for inhalation
studies from a maximum dose of Xenon Xe 133 gas in 5, 7.5 and 10 liters are shown in
Table 5. The values are the maximum absorbed dose that could be anticipated under
the given conditions.
Table 5. Radiation Dose Estimates of Xenon Xe 1332: Absorbed Dose per
1110 megabecquerels (30 millicuries) of Xenon Xe 133 Gas Administered by Inhalation
Tissue
Spirometer Volume (liters)
5
7.5
10
Absorbed Radiation Doses
mGy
Rad
mGy
Rad
mGy
Rad
Lung
Red
Marrow
Ovaries
Testes
Total Body
3.3
0.33
2.46
0.246
1.95
0.195
0.45
0.045
0.36
0.036
0.27
0.027
0.39
0.039
0.30
0.030
0.24
0.024
0.36
0.036
0.27
0.027
0.21
0.021
0.42
0.042
0.33
0.033
0.27
0.027
2Atkins, Harold L., et al., Estimates of Radiation Absorbed Doses from Radioxenons in
Lung Imaging. Task Group of the Medical Internal Radiation Dose Committee, Society
of Nuclear Medicine, J. Nucl. Med., 21:459-465,1980.
Reference ID: 3899046
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DIRECTIONS FOR DISPENSING
Transfer the appropriate Xenon Xe 133 Gas dose from the Xenon Xe 133 Gas unit dose
vial(s) to a breathing device or spirometer utilizing the Xenotron™ I Xenon Gas
Dispenser. Follow the directions for use that are provided with the Xenotron™ I Xenon
Gas Dispenser.
Xenon Xe 133 Gas should not be used after 14 days from the date of calibration stated
on the label.
ACTIVITY MEASUREMENTS
Calibrate a suitable commercial ionization chamber dose calibrator according to the
manufacturer's instructions for that particular instrument. An instrument that gives direct
radioactivity readouts is recommended.
Use a National Institute of Standards and Technology (NIST) Xenon Xe 133 standard
for the initial calibration. Also establish a secondary standard, such as Americium
Am 241, at that time for subsequent routine use. Other suitable radionuclides may also
be used. Determine the effective readout of the secondary standard compared to the
Xenon Xe 133 standard over the range of activities expected for routine measurements.
Determine the radioactivities of the dose for administration as follows:
1. Check the dose calibrator for proper response with the secondary standard.
2. Insert the Xenon Xe 133 Gas unit dose vial in the dose calibrator and measure the
apparent radioactivity of the Xenon Xe 133.
3. Correct for decay as necessary.
The radioactivity determined by this method is within 25% of the true value. This degree
of accuracy includes variations attributed to small differences in geometry and radiation
attenuation between the NIST standard ampule and the Xenon Xe 133 Gas unit dose
vial.
HOW SUPPLIED
Xenon Xe 133 Gas is available in 2 milliliter vials with color-coded labels in
370 megabecquerel (10 millicurie; Catalog No. 097) and 740 megabecquerel
(20 millicurie; Catalog No. 098) sizes. Both sizes are available in packages of 1, 3 and
5 vials, each with individual lead shielding.
Reference ID: 3899046
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custom-source
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2025-02-12T13:44:41.670803
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/018327s005lbl.pdf', 'application_number': 18327, 'submission_type': 'SUPPL ', 'submission_number': 5}
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Lopressor HCT ®
Lopressor HCT®
T2007-77
metoprolol tartrate USP and hydrochlorothiazide USP
50/25 Tablets
100/25 Tablets
100/50 Tablets
Beta Blocker/Diuretic Antihypertensive
Rx only
Prescribing Information
DESCRIPTION
Lopressor HCT has the antihypertensive effect of Lopressor ®, metoprolol tartrate, a
selective beta1-adrenoreceptor blocking agent, and the antihypertensive and diuretic
actions of hydrochlorothiazide. It is available as tablets for oral administration. The 50/25
tablets contain 50 mg of metoprolol tartrate USP and 25 mg of hydrochlorothiazide USP;
the 100/25 tablets contain 100 mg of metoprolol tartrate USP and 25 mg of
hydrochlorothiazide USP; and the 100/50 tablets contain 100 mg of metoprolol tartrate USP
and 50 mg of hydrochlorothiazide USP. Metoprolol tartrate USP is (±)-1-(Isopropylamino)-3-
[p-(2-methoxyethyl)phenoxy]-2-propanol L-(+)-tartrate (2:1) salt, and its structural formula is
Metoprolol tartrate USP is a white, crystalline powder. It is very soluble in water; freely
soluble in methylene chloride, in chloroform, and in alcohol; slightly soluble in acetone; and
insoluble in ether. Its molecular weight is 684.82.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Hydrochlorothiazide is 6-chloro-3, 4-dihydro-2 H-1,2,4-benzothiadiazine-7- sulfonamide
1,1-dioxide, and its structural formula is
Hydrochlorothiazide USP is a white, or practically white, practically odorless, crystalline
powder. It is freely soluble in sodium hydroxide solution, in n-butylamine, and in
dimethylformamide; sparingly soluble in methanol; slightly soluble in water; and insoluble in
ether, in chloroform, and in dilute mineral acids. Its molecular weight is 297.73.
Inactive Ingredients.Cellulose compounds, colloidal silicon dioxide, D&C Yellow No. 10
(100/50-mg tablets), FD&C Blue No. 1 (50/25-mg tablets), FD&C Red No. 40 and FD&C
Yellow No. 6 (100/25-mg tablets), lactose, magnesium stearate, povidone, sodium starch
glycolate, corn starch, stearic acid, and sucrose.
CLINICAL PHARMACOLOGY
Lopressor
Lopressor is a beta-adrenergic receptor blocking agent. In vitro and in vivo animal studies
have shown that it has a preferential effect on beta 1 adrenoreceptors, chiefly located in
cardiac muscle. This preferential effect is not absolute, however, and at higher doses,
Lopressor also inhibits beta2 adrenoreceptors, chiefly located in the bronchial and vascular
musculature.
Clinical pharmacology studies have confirmed the beta-blocking activity of metoprolol in
man, as shown by (1) reduction in heart rate and cardiac output at rest and upon exercise,
(2) reduction of systolic blood pressure upon exercise, (3) inhibition of isoproterenol-
induced tachycardia, and (4) reduction of reflex orthostatic tachycardia.
Relative beta 1 selectivity has been confirmed by the following: (1) In normal subjects,
Lopressor is unable to reverse the beta2-mediated vasodilating effects of epinephrine. This
contrasts with the effect of nonselective (beta1 plus beta2) beta blockers, which completely
reverse the vasodilating effects of epinephrine. (2) In asthmatic patients, Lopressor reduces
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FEV1 and FVC significantly less than a nonselective beta blocker, propranolol at equivalent
beta1-receptor blocking doses.
Lopressor has no intrinsic sympathomimetic activity and only weak membrane-
stabilizing activity. Lopressor crosses the blood-brain barrier and has been reported in the
CSF in a concentration 78% of the simultaneous plasma concentration. Animal and human
experiments indicate that Lopressor slows the sinus rate and decreases AV nodal
conduction.
In controlled clinical studies, Lopressor has been shown to be an effective
antihypertensive agent when used alone or as concomitant therapy with thiazide-type
diuretics, at dosages of 100-450 mg daily. In controlled, comparative, clinical studies,
Lopressor has been shown to be as effective an antihypertensive agent as propranolol,
methyldopa, and thiazide-type diuretics, and to be equally effective in supine and standing
positions.
The mechanism of the antihypertensive effects of beta-blocking agents has not been
elucidated. However, several possible mechanisms have been proposed: (1) competitive
antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites,
leading to decreased cardiac output; (2) a central effect leading to reduced sympathetic
outflow to the periphery; and (3) suppression of renin activity.
Pharmacokinetics
In man, absorption of Lopressor is rapid and complete. Plasma levels following oral
administration, however, approximate 50% of levels following intravenous administration,
indicating about 50% first-pass metabolism. Plasma levels achieved are highly variable
after oral administration. Only a small fraction of the drug (about 12%) is bound to human
serum albumin. Metoprolol is a racemic mixture of R- and S-enantiomers. Less than 5% of
an oral dose of Lopressor is recovered unchanged in the urine; the rest is excreted by the
kidneys as metabolites that appear to have no clinical significance. The systemic availability
and half-life of Lopressor in patients with renal failure do not differ to a clinically significant
degree from those in normal subjects. Consequently, no reduction in dosage is usually
needed in patients with chronic renal failure.
This label may not be the latest approved by FDA.
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In elderly subjects with clinically normal renal function, there are no significant
differences in Lopressor pharmacokinetics compared to young subjects.
Lopressor is extensively metabolized by the cytochrome P450 enzyme system in the
liver. The oxidative metabolism of Lopressor is under genetic control with a major
contribution of the polymorphic cytochrome P450 isoform 2D6 (CYP2D6). There are
marked ethnic differences in the prevalence of the poor metabolizers (PM) phenotype.
Approximately 7% of Caucasians and less than 1% Asian are poor metabolizers.
Poor CYP2D6 metabolizers exhibit several-fold higher plasma concentrations of
Lopressor than extensive metabolizers with normal CYP2D6 activity. The elimination half-
life of metoprolol is about 7.5 hours in poor metabolizers and 2.8 hours in extensive
metabolizers. However, the CYP2D6 dependent metabolism of Lopressor seems to have
little or no effect on safety or tolerability of the drug. None of the metabolites of Lopressor
contribute significantly to its beta-blocking effect.
Pharmacodynamics
Significant beta-blocking effect (as measured by reduction of exercise heart rate) occurs
within 1 hour after oral administration, and its duration is dose-related. For example, a 50%
reduction of the maximum registered effect after single oral doses of 20, 50, and 100 mg
occurred at 3.3, 5.0, and 6.4 hours, respectively, in normal subjects. After repeated oral
dosages of 100 mg twice daily, a significant reduction in exercise systolic blood pressure
was evident at 12 hours.
There is a linear relationship between the log of plasma levels and reduction of exercise
heart rate. However, antihypertensive activity does not appear to be related to plasma
levels. Because of variable plasma levels attained with a given dose and lack of a
consistent relationship of antihypertensive activity to dose, selection of proper dosage
requires individual titration.
Hydrochlorothiazide
Thiazides affect the renal tubular mechanism of electrolyte reabsorption. At maximal
therapeutic dosage, all thiazides are approximately equal in their diuretic potency.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Thiazides increase excretion of sodium and chloride in approximately equivalent amounts.
Natriuresis causes a secondary loss of potassium.
The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not
affect normal blood pressure.
Pharmacokinetics
Hydrochlorothiazide is rapidly absorbed, as indicated by peak plasma concentrations 1-
2.5 hours after oral administration. Plasma levels of the drug are proportional to dose; the
concentration in whole blood is 1.6-1.8 times higher than in plasma. Thiazides are
eliminated rapidly by the kidney. After oral administration of 25- to 100-mg doses, 72-97%
of the dose is excreted in the urine, indicating dose-independent absorption.
Hydrochlorothiazide is eliminated from plasma in a biphasic fashion with a terminal half-life
of 10-17 hours. Plasma protein binding is 67.9%. Plasma clearance is 15.9-30.0 L/hr;
volume of distribution is 3.6-7.8 L/kg.
Gastrointestinal absorption of hydrochlorothiazide is enhanced when administered with
food. Absorption is decreased in patients with congestive heart failure, and the
pharmacokinetics are considerably different in these patients.
Pharmacodynamics
The onset of action of thiazides occurs in 2 hours and the peak effect at about 4 hours. The
action persists for approximately 6-12 hours.
INDICATIONS AND USAGE
Lopressor HCT is indicated for the management of hypertension.
This fixed-combination drug is not indicated for initial therapy of hypertension. If the fixed
combination represents the dose titrated to the individual patient’s needs, therapy with the
fixed combination may be more convenient than with the separate components.
CONTRAINDICATIONS
Lopressor
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lopressor is contraindicated in sinus bradycardia, heart block greater than first degree,
cardiogenic shock, and overt cardiac failure (see WARNINGS).
Hypersensitivity to Lopressor and related derivatives, or to any of the excipients;
hypersensitivity to other beta-blockers (cross sensitivity between beta-blockers an occur).
Sick-sinus syndrome.
Severe peripheral arterial circulatory disorders.
Pheochromocytoma (see WARNINGS).
Hydrochlorothiazide
Hydrochlorothiazide is contraindicated in patients with anuria or hypersensitivity to this or
other sulfonamide-derived drugs (see WARNINGS).
WARNINGS
Lopressor
Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function
in congestive heart failure, and beta blockade carries the potential hazard of further
depressing myocardial contractility and precipitating more severe failure. In hypertensive
patients who have congestive heart failure controlled by digitalis and diuretics, Lopressor
should be administered cautiously.
In Patients Without a History of Cardiac Failure: Continued depression of the myocardium
with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure.
At the first sign or symptom of impending cardiac failure, patients should be fully digitalized
and/or given a diuretic. The response should be observed closely. If cardiac failure
continues, despite adequate digitalization and diuretic therapy, Lopressor should be
withdrawn.
Ischemic Heart Disease:Following abrupt cessation of therapy with certain beta-blocking
agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have
been reported. Even in the absence of overt angina pectoris, when discontinuing therapy,
Lopressor should not be withdrawn abruptly, and patients should be cautioned against
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
interruption of therapy without the physician’s advice (see PRECAUTIONS, Information for
Patients).
Bronchospastic Diseases: PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD,
IN GENERAL, NOT RECEIVE BETA BLOCKERS. Because of its relative beta1 selectivity,
however, Lopressor may be used with caution in patients with bronchospastic disease who
do not respond to, or cannot tolerate, other antihypertensive treatment. Since beta1
selectivity is not absolute, a beta2-stimulating agent should be administered concomitantly,
and the lowest possible dose of Lopressor should be used. In these circumstances it would
be prudent initially to administer Lopressor in smaller doses three times daily, instead of
larger doses two times daily, to avoid the higher plasma levels associated with the longer
dosing interval (see DOSAGE AND ADMINISTRATION).
Major Surgery: The necessity or desirability of withdrawing beta-blocking therapy prior to
major surgery is controversial; the impaired ability of the heart to respond to reflex
adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
Lopressor, like other beta blockers, is a competitive inhibitor of beta-receptor agonists, and
its effects can be reversed by administration of such agents, e.g., dobutamine or
isoproterenol. However, such patients may be subject to protracted severe hypotension.
Difficulty in restarting and maintaining the heart beat has also been reported with beta
blockers.
Diabetes and Hypoglycemia: Lopressor should be used with caution in diabetic patients if a
beta-blocking agent is required. Beta blockers may mask tachycardia occurring with
hypoglycemia, but other manifestations such as dizziness and sweating may not be
significantly affected. Selective beta blockers do not potentiate insulin-induced
hypoglycemia and, unlike nonselective beta blockers, do not delay recovery of blood
glucose to normal levels.
Pheochromocytoma: In patients known to have, or suspected of having, a
pheochromocytoma, Lopressor is contraindicated (see CONTRAINDICATIONS). If
Lopressor is required, it should be given in combination with an alpha blocker, and only
after the alpha blocker has been initiated . Administration of beta blockers alone in the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
setting of pheochromocytoma have been associated with a paradoxical increase in blood
pressure due to the attenuation of beta-mediated vasodilatation in skeletal muscle.
Thyrotoxicosis:Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia)
or hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed
carefully to avoid abrupt withdrawal of beta blockade, which might precipitate a thyroid
storm.
Hydrochlorothiazide
Thiazides should be used with caution in patients with severe renal disease. In patients with
renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may
develop in patients with impaired renal function.
Thiazides should be used with caution in patients with impaired hepatic function or
progressive liver disease, since minor alterations of fluid and electrolyte imbalance may
precipitate hepatic coma.
Thiazides may add to or potentiate the action of other antihypertensive drugs.
Potentiation occurs with ganglionic or peripheral adrenergic blocking drugs.
Sensitivity reactions are more likely to occur in patients with a history of allergy or
bronchial asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus has been
reported.
PRECAUTIONS
General
Lopressor: Lopressor should be used with caution in patients with impaired hepatic
function.
Hydrochlorothiazide: All patients receiving thiazide therapy should be observed for clinical
signs of fluid or electrolyte imbalance, namely hyponatremia, hypochloremic alkalosis, and
hypokalemia (see Laboratory Tests and Drug/Drug Interactions). Warning signs are
dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal
disturbance, such as nausea or vomiting.
Hypokalemia may develop, especially in cases of brisk diuresis or severe cirrhosis.
Interference with adequate oral intake of electrolytes will also contribute to hypokalemia.
Hypokalemia may be avoided or treated by the use of potassium supplements or foods with
a high potassium content.
Any chloride deficit is generally mild and usually does not require specific treatment,
except under extraordinary circumstances (as in liver disease or renal disease). Dilutional
hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water
restriction, rather than administration of salt, except in rare instances when the
hyponatremia is life-threatening. In cases of actual salt depletion, appropriate replacement
is the therapy of choice.
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving
thiazide therapy.
Latent diabetes may become manifest during thiazide administration (see Drug/Drug
Interactions).
The antihypertensive effects of the drug may be enhanced in the postsympathectomy
patient.
If progressive renal impairment becomes evident, withholding or discontinuing diuretic
therapy should be considered.
Calcium excretion is decreased by thiazides. Pathological changes in the parathyroid
gland with hypercalcemia and hypophosphatemia have been observed in a few patients on
prolonged thiazide therapy. The common complications of hyperparathyroidism, such as
renal lithiasis, bone resorption, and peptic ulceration, have not been seen.
Thiazide diuretics have been shown to increase the urinary excretion of magnesium;
this may result in hypomagnesemia.
Information for Patients
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients should be advised to take Lopressor HCT regularly and continuously, as directed,
with or immediately following meals. If a dose should be missed, the patient should take
only the next scheduled dose (without doubling it). Patients should not discontinue
Lopressor HCT without consulting the physician.
Patients should be advised (1) to avoid operating automobiles and machinery or
engaging in other tasks requiring alertness until the patient’s response to therapy with
Lopressor HCT has been determined; (2) to contact the physician if any difficulty in
breathing occurs; (3) to inform the physician or dentist before any type of surgery that he or
she is taking Lopressor HCT.
Laboratory Tests
Lopressor: Clinical laboratory findings may include elevated levels of serum transaminase,
alkaline phosphatase, and lactate dehydrogenase.
Hydrochlorothiazide:Initial and periodic determinations of serum electrolytes to detect
possible electrolyte imbalance should be performed at appropriate intervals.
Serum and urine electrolyte determinations are particularly important when the patient
is vomiting excessively or receiving parenteral fluids.
Drug/Drug Interactions
Lopressor: Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect
when given with beta-blocking agents. Patients treated with Lopressor plus a
catecholamine depletor should therefore be closely observed for evidence of hypotension
or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.
Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease
heart rate. Concomitant use can increase the risk of bradycardia.
Risk of Anaphylactic Reaction:While taking beta-blockers, patients with a history of severe
anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge,
either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the
usual doses of epinephrine used to treat allergic reaction.
General Anesthetics
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Some inhalation anesthetics may enhance the cardiodepressant effect of beta-blockers
(see WARNINGS; Lopressor; Major Surgery).
CYP2D6 Inhibitors
Potent inhibitors of the CYP2D6 enzyme may increase the plasma concentration of
Lopressor. Strong inhibition of CYP2D6 would mimic the pharmacokinetics of CYP2D6 poor
metabolizer. Caution should therefore be exercised when administering potent CYP2D6
inhibitors with Lopressor. Known clinically significant potent inhibitors of CYP2D6 are
antidepressants such as fluoxetine, paroxetine or bupropion, antipsychotics such as
thioridazine, antiarrhythmics such as quinidine or propafenone, antiretrovirals such as
ritonavir, antihistamines such as diphenhydramine, antimalarials such as
hydroxychloroquine or quinidine, antifungals such as terbinafine and medications for
stomach ulcers such as cimetidine.
Clonidine
If a patient is treated with clonidine and Lopressor concurrently, and clonidine treatment is
to be discontinued, Lopressor should be stopped several days before clonidine is
withdrawn. Rebound hypertension that can follow withdrawal of clonidine may be increased
in patients receiving concurrent beta-blocker treatment.
Hydrochlorothiazide.Hypokalemia can sensitize or exaggerate the response of the heart to
the toxic effects of digitalis (e.g., increased ventricular irritability).
Hypokalemia may develop during concomitant use of steroids or ACTH.
Insulin requirements in diabetic patients may be increased, decreased, or unchanged.
Thiazides may decrease arterial responsiveness to norepinephrine, but not enough to
preclude effectiveness of the pressor agent for therapeutic use.
Thiazides may increase the responsiveness to tubocurarine.
Lithium renal clearance is reduced by thiazides, increasing the risk of lithium toxicity.
There have been rare reports in the literature of hemolytic anemia occurring with the
concomitant use of hydrochlorothiazide and methyldopa.
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Concurrent administration of some nonsteroidal anti-inflammatory agents may reduce
the diuretic, natriuretic and antihypertensive effects of thiazide diuretics.
Cholestyramine and colestipol resins: Absorption of hydrochlorothiazide is impaired in
the presence of anionic exchange resins. Single doses of either cholestyramine or
colestipol resins bind the hydrochlorothiazide and reduce its absorption from the
gastrointestinal tract by up to 85% and 43%, respectively.
Drug/Laboratory Test Interactions
Hydrochlorothiazide: Thiazides may decrease serum levels of protein-bound iodine without
signs of thyroid disturbance. Thiazides should be discontinued before tests for parathyroid
function are made. (See General, Hydrochlorothiazide, Calcium excretion.)
Carcinogenesis, Mutagenesis, Impairment of Fertility
Lopressor HCT:Carcinogenicity and mutagenicity studies have not been conducted with
Lopressor HCT. Lopressor HCT produced no evidence of impaired fertility in male or female
rats administered gavaged doses up to 200/50 mg/kg (100/50 times the maximum
recommended daily human dose) prior to mating and throughout gestation and rearing of
young.
Lopressor: Long-term studies in animals have been conducted to evaluate carcinogenic
potential. In a 2-year study in rats at three oral dosage levels of up to 800 mg/kg per day,
there was no increase in the development of spontaneously occurring benign or malignant
neoplasms of any type. The only histologic changes that appeared to be drug related were
an increased incidence of generally mild focal accumulation of foamy macrophages in
pulmonary alveoli and a slight increase in biliary hyperplasia. In a 21-month study in Swiss
albino mice at three oral dosage levels of up to 750 mg/kg per day, benign lung tumors
(small adenomas) occurred more frequently in female mice receiving the highest dose than
in untreated control animals. There was no increase in malignant or total (benign plus
malignant) lung tumors, nor in the overall incidence of tumors or malignant tumors. This 21-
month study was repeated in CD-1 mice, and no statistically or biologically significant
differences were observed between treated and control mice of either sex for any type of
tumor.
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All mutagenicity tests performed (a dominant lethal study in mice, chromosome studies
in somatic cells, a Salmonella/mammalian-microsome mutagenicity test, and a nucleus
anomaly test in somatic interphase nuclei) were negative.
No evidence of impaired fertility due to Lopressor was observed in a study performed in
rats at doses up to 55.5 times the maximum daily human dose of 450 mg.
Hydrochlorothiazide: Two-year feeding studies in mice and rats conducted under the
auspices of the National Toxicology Program (NTP) uncovered no evidence of a
carcinogenic potential of hydrochlorothiazide in female mice (at doses up to approximately
600 mg/kg/day) or in male and female rats (at doses up to approximately 100 mg/kg/day).
The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.
Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100,
TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (Ames assay) and in the
Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in in vivo assays using
mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the
Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained only in
the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma
Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to
1300 µg/mL, and in the Aspergillus nidulans nondisjunction assay at an unspecified
concentration.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex
in studies wherein these species were exposed, via their diet, to doses of up to 100 and
4 mg/kg/day, respectively, prior to mating and throughout gestation.
Pregnancy: Teratogenic Effects. Pregnancy Category C
Lopressor HCT:No evidence of adverse effects on pregnancy or the fetus were observed in
rats when dams were administered gavaged doses up to 200/50 mg/kg of Lopressor HCT
(100/50 times the maximum recommended daily human dose) during the period of
organogenesis. Increased postimplantation loss and decreased postnatal survival were
observed with these doses when administered later in pregnancy (gestation days 15-21). In
rabbits, increased fetal loss was observed with oral doses of 25/6.25 mg/kg of Lopressor
HCT (12/6 times the maximum recommended daily human dose), but not with lower doses.
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There are no adequate and well-controlled studies of Lopressor HCT in pregnant women.
Lopressor HCT should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
Lopressor:Lopressor has been shown to increase postimplantation loss and decrease
neonatal survival in rats at doses up to 55.5 times the maximum daily human dose of 450
mg. Distribution studies in mice confirm exposure of the fetus when Lopressor is
administered to the pregnant animal. These studies have revealed no evidence of
teratogenicity.
Hydrochlorothiazide:Studies in which hydrochlorothiazide was orally administered to
pregnant mice and rats during their respective periods of major organogenesis at doses up
to 3000 and 1000 mg/kg/day, respectively, provided no evidence of harm to the fetus.
Nonteratogenic Effects
Hydrochlorothiazide:Thiazides cross the placental barrier and appear in cord blood, and
there is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse
reactions that have occurred in adults.
Nursing Mothers
Lopressor is excreted in breast milk in very small quantity. An infant consuming 1 liter of
breast milk daily would receive a dose of metoprolol of less than 1 mg. Thiazides are also
excreted in breast milk. If the use of Lopressor HCT is deemed essential, the patient should
stop nursing.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of Lopressor HCT did not include sufficient numbers of subjects aged 65
and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in responses between the elderly
and younger patients. Hydrochlorothiazide is known to be substantially excreted by the
kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired
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renal function. Because elderly patients are more likely to have decreased renal function,
care should be taken in dose selection, and it may be useful to monitor renal function (see
WARNINGS). In general, dose selection for an elderly patient should be cautious, usually
starting at the low end of the dosing range, reflecting the greater frequency of decreased
hepatic, renal, or cardiac function, and concomitant disease or other drug therapy.
ADVERSE REACTIONS
Lopressor HCT
The following adverse reactions were reported in controlled clinical studies of the
combination of Lopressor and hydrochlorothiazide.
Body as a Whole: Fatigue or lethargy and flu syndrome have each been reported in about
10 in 100 patients.
Nervous System: Dizziness or vertigo, drowsiness or somnolence, and headache have
each occurred in about 10 in 100 patients. Nightmare has occurred in 1 in 100 patients.
Cardiovascular: Bradycardia has occurred in about 6 in 100 patients. Decreased exercise
tolerance and dyspnea have each occurred in about 1 of 100 patients.
Digestive:Diarrhea, digestive disorder, dry mouth, nausea or vomiting, and constipation
have each occurred in about 1 in 100 patients.
Metabolic and Nutritional: Hypokalemia has occurred in fewer than 10 in 100 patients.
Edema, gout, and anorexia have each occurred in 1 in 100 patients.
Special Senses: Blurred vision, tinnitus, and earache have each been reported in 1 in 100
patients.
Skin:Sweating and purpura have each occurred in 1 in 100 patients.
Urogenital:Impotence has occurred in 1 in 100 patients.
Musculoskeletal: Muscle pain has occurred in 1 in 100 patients.
Lopressor
Most adverse effects have been mild and transient.
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Central Nervous System: Tiredness and dizziness have occurred in about 10 of 100
patients. Depression has been reported in about 5 of 100 patients. Mental confusion and
short-term memory loss have been reported. Headache, nightmares, and insomnia have
also been reported, but a drug relationship is not clear.
Cardiovascular: Shortness of breath and bradycardia have occurred in approximately 3 of
100 patients. Cold extremities; arterial insufficiency, usually of the Raynaud type;
palpitations; and congestive heart failure have been reported. Gangrene in patients with
pre-existing severe peripheral circulatory disorders has also been reported very rarely (see
CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS).
Respiratory: Wheezing (bronchospasm) has been reported in fewer than 1 of 100 patients
(see WARNINGS). Rhinitis has also been reported.
Gastrointestinal:Diarrhea has occurred in about 5 of 100 patients. Nausea, gastric pain,
constipation, flatulence, and heartburn have been reported in 1 of 100, or fewer, patients.
Vomiting was a common occurrence. Post-marketing experience reveals very rare reports
of hepatitis, jaundice and non-specific hepatic dysfunction. Isolated cases of transaminase,
alkaline phosphatase, and lactic dehydrogenase elevations have also been reported.
Hypersensitive Reactions:Pruritus has occurred in fewer than 1 of 100 patients. Rash has
been reported. Very rarely, photosensitivity and worsening of psoriasis has been reported.
Miscellaneous: Peyronie’s disease has been reported in fewer than 1 of 100,000 patients.
Alopecia has been reported. There have been very rare reports of weight gain, arthritis, and
retroperitoneal fibrosis (relationship to Lopressor has not been definitely established).
The oculomucocutaneous syndrome associated with the beta blocker practolol has not
been reported with Lopressor.
Potential Adverse Reactions
A variety of adverse reactions not listed above have been reported with other beta-
adrenergic blocking agents and should be considered potential adverse reactions to
Lopressor.
Central Nervous System: Reversible mental depression progressing to catatonia; visual
disturbances; hallucinations; an acute reversible syndrome characterized by disorientation
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for time and place, short-term memory loss, emotional lability, slightly clouded sensorium,
and decreased performance on neuropsychometrics.
Cardiovascular: Intensification of AV block (see CONTRAINDICATIONS).
Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.
Hypersensitive Reactions:Fever combined with aching and sore throat, laryngospasm, and
respiratory distress.
Hydrochlorothiazide
The following adverse reactions have been observed, but there has not been enough
systematic collection of data to support an estimate of their frequency. Consequently the
reactions are categorized by organ systems and are listed in decreasing order of severity
and not frequency.
Digestive:Pancreatitis, jaundice (intrahepatic cholestatic), sialadenitis, vomiting, diarrhea,
cramping, nausea, gastric irritation, constipation, anorexia.
Cardiovascular:Orthostatic hypotension (may be potentiated by alcohol, barbiturates, or
narcotics).
Neurologic:Vertigo, dizziness, transient blurred vision, headache, paresthesia, xanthopsia,
weakness, restlessness.
Musculoskeletal:Muscle spasm.
Hematologic:Aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.
Metabolic:Hyperglycemia, glycosuria, hyperuricemia.
Hypersensitive Reactions:Necrotizing angiitis, Stevens-Johnson syndrome, respiratory
distress including pneumonitis and pulmonary edema, purpura, urticaria, rash, photo-
sensitivity.
OVERDOSAGE
Acute Toxicity
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Several cases of overdosage with Lopressor have been reported, some leading to death.
No deaths have been reported with hydrochlorothiazide.
Oral LD 50’s (mg/kg): mice, 1158 (Lopressor); rats, 3090 (Lopressor), 2750
(hydrochlorothiazide).
Signs and Symptoms
Lopressor. Potential signs and symptoms associated with overdosage with Lopressor are
bradycardia, hypotension, bronchospasm, and cardiac failure.
Hydrochlorothiazide. The most prominent feature of poisoning is acute loss of fluid and
electrolytes.
Cardiovascular: Tachycardia, hypotension, shock.
Neuromuscular: Weakness, confusion, dizziness, cramps of the calf muscles, paresthesia,
fatigue, impairment of consciousness.
Digestive: Nausea, vomiting, thirst.
Renal:Polyuria, oliguria, or anuria (due to hemoconcentration).
Laboratory Findings:Hypokalemia, hyponatremia, hypochloremia, alkalosis; increased BUN
(especially in patients with renal insufficiency).
Combined Poisoning:Signs and symptoms may be aggravated or modified by concomitant
intake of antihypertensive medication, barbiturates, curare, digitalis (hypokalemia),
corticosteroids, narcotics, or alcohol.
Treatment
There is no specific antidote.
On the basis of the pharmacologic actions of Lopressor and hydrochlorothiazide, the
following general measures should be employed:
Elimination of the Drug:Inducement of vomiting, gastric lavage, and activated charcoal.
Bradycardia:Atropine should be administered. If there is no response to vagal blockade,
isoproterenol should be administered cautiously.
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Hypotension: The patient’s legs should be elevated, and lost fluid and electrolytes
(potassium, sodium) should be replaced. A vasopressor should be administered, e.g.,
levarterenol or dopamine.
Bronchospasm:A beta 2-stimulating agent and/or a theophylline derivative should be
administered.
Cardiac Failure: A digitalis glycoside and diuretic should be administered. In shock resulting
from inadequate cardiac contractility, administration of dobutamine, isoproterenol, or
glucagon may be considered.
Surveillance: Fluid and electrolyte balance (especially serum potassium) and renal function
should be monitored until conditions become normal.
DOSAGE AND ADMINISTRATION
Dosage should be determined by individual titration (see INDICATIONS AND USAGE).
Hydrochlorothiazide is usually given at a dosage of 12.5 to 50 mg per day. The usual
initial dosage of Lopressor is 100 mg daily in single or divided doses. Dosage may be
increased gradually until optimum blood pressure control is achieved. The effective dosage
range is 100 to 450 mg per day. While once-daily dosing is effective and can maintain a
reduction in blood pressure throughout the day, lower doses (especially 100 mg) may not
maintain a full effect at the end of the 24-hour period, and larger or more frequent daily
doses may be required. This can be evaluated by measuring blood pressure near the end
of the dosing interval to determine whether satisfactory control is being maintained
throughout the day. Beta 1 selectivity diminishes as dosage of Lopressor is increased.
The following dosage schedule may be used to administer from 100 to 200 mg of
Lopressor per day and from 25 to 50 mg of hydrochlorothiazide per day:
Lopressor HCT
Dosage
Tablets of 50/25
2 tablets per day in single or divided doses
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Lopressor HCT
Dosage
Tablets of 100/25
1 to 2 tablets per day in single or divided doses
Tablets of 100/50
1 tablet per day in single or divided doses
Dosing regimens that exceed 50 mg of hydrochlorothiazide per day are not recommended.
When necessary, another antihypertensive agent may be added gradually, beginning with
50% of the usual recommended starting dose to avoid an excessive fall in blood pressure.
HOW SUPPLIED
Tablets
50/25 -
capsule-shaped, white and mottled-blue, scored (imprinted Geigy on one side and 35 twice on the scored side),
50 mg of metoprolol tartrate and 25 mg of hydrochlorothiazideBottles of 100……………………………………NDC
0078-0460-05
Tablets
100/25 -
capsule-shaped, white and mottled-pink, scored (imprinted Geigy on one side and 53 twice on the scored side),
100 mg of metoprolol tartrate and 25 mg of hydrochlorothiazideBottles of 100……………………………………NDC
0078-0461-05
Tablets
100/50 -
capsule- shaped, white and mottled-yellow, scored (imprinted Geigy on one side and 73 twice on the scored
side), 100 mg of metoprolol tartrate and 50 mg of hydrochlorothiazideBottles of
100……………………………………NDC 0078-0462-05
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Tablets
50/25 -
capsule-shaped, white and mottled-blue, scored (imprinted Geigy on one side and 35 twice on the scored side),
50 mg of metoprolol tartrate and 25 mg of hydrochlorothiazideBottles of 100……………………………………NDC
0078-0460-05
Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF) [see USP Controlled Room
Temperature]. Protect from moisture.
Dispense in tight, light-resistant container (USP).
Manufactured by:
Novartis Pharmaceuticals Corporation
Suffern, New York 10901
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
REV: September 2007 T2007-77
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:44:41.714701
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018303s032lbl.pdf', 'application_number': 18303, 'submission_type': 'SUPPL ', 'submission_number': 32}
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11,207
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CARAFATE®
(sucralfate)
Suspension
DESCRIPTION
CARAFATE Suspension contains sucralfate and sucralfate is an α-D-glucopyranoside, β-D
fructofuranosyl-, octakis-(hydrogen sulfate), aluminum complex.
st
ruc
tur
al
fo
rm
ula
[Al(OH)3] x [H2O]y
(x=8 to 10 and y= 22 to 31)
R= SO3Al(OH)2
CARAFATE Suspension for oral administration contains 1 g of sucralfate per 10 mL.
CARAFATE Suspension also contains: colloidal silicon dioxide NF, FD&C Red #40, flavor,
glycerin USP, methylcellulose USP, methylparaben NF, microcrystalline cellulose NF, purified
water USP, simethicone USP, and sorbitol solution USP. Therapeutic category: antiulcer.
CLINICAL PHARMACOLOGY
Sucralfate is only minimally absorbed from the gastrointestinal tract. The small amounts of the
sulfated disaccharide that are absorbed are excreted primarily in the urine.
Although the mechanism of sucralfate’s ability to accelerate healing of duodenal ulcers remains to
be fully defined, it is known that it exerts its effect through a local, rather than systemic, action.
The following observations also appear pertinent:
1. Studies in human subjects and with animal models of ulcer disease have shown that
sucralfate forms an ulcer-adherent complex with proteinaceous exudate at the ulcer site.
2. In vitro, a sucralfate-albumin film provides a barrier to diffusion of hydrogen ions.
3. In human subjects, sucralfate given in doses recommended for ulcer therapy inhibits pepsin
activity in gastric juice by 32%.
In vitro, sucralfate adsorbs bile salts.
These observations suggest that sucralfate’s antiulcer activity is the result of formation of an
ulcer-adherent complex that covers the ulcer site and protects it against further attack by acid,
pepsin, and bile salts. There are approximately 14 to 16 mEq of acid-neutralizing capacity per 1
g dose of sucralfate.
CLINICAL TRIALS
In a multicenter, double-blind, placebo-controlled study of CARAFATE Suspension, a dosage
regimen of 1 g (10 mL) four times daily was demonstrated to be superior to placebo in ulcer
healing.
Reference ID: 3270329
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Results from Clinical Trials Healing Rates for Acute Duodenal
Ulcer
Treatment
n
Week 2
Healing
Rates
Week 4
Healing
Rates
Week 8
Healing
Rates
CARAFATE
Suspension
145
23(16%)*
66(46%)†
95(66%)‡
Placebo
147
10(7%)
39(27%)
58(39%)
*P=0.016
†P=0.001
‡P=0.0001
Equivalence of sucralfate suspension to sucralfate tablets has not been demonstrated.
INDICATIONS AND USAGE
CARAFATE (sucralfate) Suspension is indicated in the short-term (up to 8 weeks) treatment of
active duodenal ulcer.
CONTRAINDICATIONS
Carafate is contraindicated for patients with known hypersensitivity reactions to the active
substance or to any of the excipients.
PRECAUTIONS
The physician should read the "PRECAUTIONS" section when considering the use of Carafate in
pregnant or pediatric patients, or patients of childbearing potential.
Duodenal ulcer is a chronic, recurrent disease. While short-term treatment with sucralfate can
result in complete healing of the ulcer, a successful course of treatment with sucralfate should not
be expected to alter the post healing frequency or severity of duodenal ulceration.
Episodes of hyperglycemia have been reported in diabetic patients. Close monitoring of glycemia
in diabetic patients treated with sucralfate suspension is recommended. Adjustment of the anti-
diabetic treatment dose during the use of sucralfate suspension might be necessary.
Special Populations: Chronic Renal Failure and Dialysis Patients
When sucralfate is administered orally, small amounts of aluminum are absorbed from the
gastrointestinal tract. Concomitant use of sucralfate with other products that contain aluminum,
such as aluminum-containing antacids, may increase the total body burden of aluminum.
Patients with normal renal function receiving the recommended doses of sucralfate and
aluminum-containing products adequately excrete aluminum in the urine. Patients with chronic
renal failure or those receiving dialysis have impaired excretion of absorbed aluminum. In
addition, aluminum does not cross dialysis membranes because it is bound to albumin and
transferrin plasma proteins. Aluminum accumulation and toxicity (aluminum osteodystrophy,
osteomalacia, encephalopathy) have been described in patients with renal impairment.
Sucralfate should be used with caution in patients with chronic renal failure.
Drug Interactions
Some studies have shown that simultaneous sucralfate administration in healthy volunteers
reduced the extent of absorption (bioavailability) of single doses of the following: cimetidine,
digoxin, fluoroquinolone antibiotics, ketoconazole, l-thyroxine, phenytoin, quinidine, ranitidine,
tetracycline, and theophylline. Subtherapeutic prothrombin times with concomitant warfarin and
sucralfate therapy have been reported in spontaneous and published case reports. However, two
clinical studies have demonstrated no change in either serum warfarin concentration or
prothrombin time with the addition of sucralfate to chronic warfarin therapy.
The mechanism of these interactions appears to be nonsystemic in nature, presumably resulting
from sucralfate binding to the concomitant agent in the gastrointestinal tract. In all cases studied
to date (cimetidine, ciprofloxacin, digoxin, norfloxacin, ofloxacin, and ranitidine), dosing the
Reference ID: 3270329
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
concomitant medication 2 hours before sucralfate eliminated the interaction. Due to
CARAFATE`s potential to alter the absorption of some drugs, CARAFATE should be
administered separately from other drugs when alterations in bioavailability are felt to be critical.
In these cases, patients should be monitored appropriately.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Chronic oral toxicity studies of 24 months’ duration were conducted in mice and rats at doses up
to 1 g/kg (12 times the human dose).
There was no evidence of drug-related tumorigenicity. A reproduction study in rats at doses up to
38 times the human dose did not reveal any indication of fertility impairment. Mutagenicity
studies were not conducted.
Pregnancy
Teratogenic effects. Pregnancy Category B.
Teratogenicity studies have been performed in mice, rats, and rabbits at doses up to 50 times the
human dose and have revealed no evidence of harm to the fetus due to sucralfate. There are,
however, no adequate and well-controlled studies in pregnant women.
Because animal
reproduction studies are not always predictive of human response, this drug should be used
during pregnancy only if clearly needed.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when sucralfate is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of CARAFATE Suspension did not include sufficient numbers of subjects aged 65
and over to determine whether they respond differently from younger subjects. Other reported
clinical experience has not identified differences in responses between the elderly and younger
patients. In general, dose selection for an elderly patient should be cautious, usually starting at
the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function, and of concomitant disease or other drug therapy (See DOSAGE AND
ADMINISTRATION).
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function (See PRECAUTIONS Special
Populations: Chronic Renal Failure and Dialysis Patients). Because elderly patients are more
likely to have decreased renal function, care should be taken in dose selection, and it may be
useful to monitor renal function.
ADVERSE REACTIONS
Adverse reactions to sucralfate tablets in clinical trials were minor and only rarely led to
discontinuation of the drug. In studies involving over 2700 patients treated with sucralfate,
adverse effects were reported in 129 (4.7%).
Constipation was the most frequent complaint (2%). Other adverse effects reported in less than
0.5% of the patients are listed below by body system:
Gastrointestinal: diarrhea, dry mouth, flatulence, gastric discomfort, indigestion, nausea,
vomiting
Dermatological: pruritus, rash
Nervous System: dizziness, insomnia, sleepiness, vertigo
Other: back pain, headache
Post-marketing cases of hypersensitivity have been reported with the use of sucralfate
suspension, including anaphylactic reactions, dyspnea, lip swelling, edema of the mouth,
pharyngeal edema, pruritus, rash, swelling of the face and urticaria.
Reference ID: 3270329
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Cases of bronchospasm, laryngeal edema and respiratory tract edema have been reported with
an unknown oral formulation of sucralfate.
Cases of hyperglycemia have been reported with sucralfate.
Bezoars have been reported in patients treated with sucralfate. The majority of patients had
underlying medical conditions that may predispose to bezoar formation (such as delayed gastric
emptying) or were receiving concomitant enteral tube feedings.
Inadvertent injection of insoluble
complications, including pulmonary
intravenous administration.
sucralfate
and cer
and
ebral
its insoluble
emboli. Su
excipients
cralfate is
has led
not inten
to
ded
fatal
for
OVERDOSAGE
Due to limited experience in humans with overdosage of sucralfate, no specific treatment
recommendations can be given. Acute oral studies in animals, however, using doses up to 12
g/kg body weight, could not find a lethal dose. Sucralfate is only minimally absorbed from the
gastrointestinal tract. Risks associated with acute overdosage should, therefore, be minimal. In
rare reports describing sucralfate overdose, most patients remained asymptomatic. Those few
reports where adverse events were described included symptoms of dyspepsia, abdominal pain,
nausea, and vomiting.
DOSAGE AND ADMINISTRATION
Active Duodenal Ulcer. The recommended adult oral dosage for duodenal ulcer is 1 g (10 mL/2
teaspoons) four times per day. CARAFATE should be administered on an empty stomach.
Antacids may be prescribed as needed for relief of pain but should not be taken within one-half
hour before or after sucralfate.
While healing with sucralfate may occur during the first week or two, treatment should be
continued for 4 to 8 weeks unless healing has been demonstrated by x-ray or endoscopic
examination.
Elderly. In general, dose selection for an elderly patient should be cautious, usually starting at
the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function, and of concomitant disease or other drug therapy (See PRECAUTIONS
Geriatric Use).
Call your doctor for medical advice about side effects. You may report side effects to Aptalis
Pharma US, Inc. at 1-800-472-2634 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
HOW SUPPLIED
CARAFATE (sucralfate) Suspension 1 g/10 mL is a pink suspension supplied in bottles of 14 fl oz
(NDC 58914-170-14).
SHAKE WELL BEFORE USING. AVOID FREEZING.
Store at controlled room temperature 20-25°C (68-77°F)[see USP].
Rx Only
Prescribing Information rev. March 2013
Aptalis Pharma US, Inc.
100 Somerset Corporate Boulevard
Bridgewater, NJ 08807
USA
CARAFATE® is a registered trademark of Aptalis Pharma Canada Inc., which is an affiliate of
Aptalis Pharma US, Inc.
www.aptalispharma.com
Reference ID: 3270329
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CARAFATE® (sucralfate) Tablets
U.S. Package Insert
CARAFATE® Tablets
(sucralfate)
DESCRIPTION
CARAFATE Tablets contain sucralfate and sucralfate is an α-D-glucopyranoside, β-D
fructofuranosyl-, octakis-(hydrogen sulfate), aluminum complex.
st
ruc
tur
al
fo
rm
ula
[Al(OH)3] x [H2O]y
(x=8 to 10 and y= 22 to 31)
R= SO3Al(OH)2
Tablets for oral administration contain 1 g of sucralfate.
Also contain: D & C Red #30 Lake, FD&C Blue #1 Lake, magnesium stearate, microcrystalline
cellulose, and starch. Therapeutic category: antiulcer.
CLINICAL PHARMACOLOGY
Sucralfate is only minimally absorbed from the gastrointestinal tract. The small amounts of the
sulfated disaccharide that are absorbed are excreted primarily in the urine.
Although the mechanism of sucralfate’s ability to accelerate healing of duodenal ulcers remains to
be fully defined, it is known that it exerts its effect through a local, rather than systemic, action.
The following observations also appear pertinent:
1. Studies in human subjects and with animal models of ulcer disease have shown that
sucralfate forms an ulcer-adherent complex with proteinaceous exudate at the ulcer site.
2. In vitro, a sucralfate-albumin film provides a barrier to diffusion of hydrogen ions.
3. In human subjects, sucralfate given in doses recommended for ulcer therapy inhibits pepsin
activity in gastric juice by 32%.
4. In vitro, sucralfate adsorbs bile salts.
These observations suggest that sucralfate’s antiulcer activity is the result of formation of an
ulcer-adherent complex that covers the ulcer site and protects it against further attack by acid,
pepsin, and bile salts. There are approximately 14 to 16 mEq of acid-neutralizing capacity per 1
g dose of sucralfate.
CLINICAL TRIALS
Acute Duodenal Ulcer
Over 600 patients have participated in well-controlled clinical trials worldwide. Multicenter trials
conducted in the United States, both of them placebo-controlled studies with endoscopic
evaluation at 2 and 4 weeks, showed:
1
Reference ID: 3270329
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CARAFATE® (sucralfate) Tablets
U.S. Package Insert
STUDY 1
Treatment Groups
Ulcer Healing/ No. Patients
2 wk
4 wk (Overall)
Sucralfate
Placebo
37/105 (35.2%)
26/106 (24.5%)
82/109 (75.2%)
68/107 (63.6%)
STUDY 2
Treatment Groups
Ulcer Healing/ No. Patients
2 wk
4 wk (Overall)
Sucralfate
Placebo
8/24 (33%)
4/31 (13%)
22/24 (92%)
18/31 (58%)
The sucralfate-placebo differences were statistically significant in both studies at 4 weeks but not
at 2 weeks. The poorer result in the first study may have occurred because sucralfate was given
2 hours after meals and at bedtime rather than 1 hour before meals and at bedtime, the regimen
used in international studies and in the second United States study. In addition, in the first study
liquid antacid was utilized as needed, whereas in the second study antacid tablets were used.
Maintenance Therapy After Healing of Duodenal Ulcer
Two double-blind randomized placebo-controlled U.S. multicenter trials have demonstrated that
sucralfate (1 g bid) is effective as maintenance therapy following healing of duodenal ulcers.
In one study, endoscopies were performed monthly for 4 months. Of the 254 patients who
enrolled, 239 were analyzed in the intention-to-treat life table analysis presented below.
Duodenal Ulcer Recurrence Rate (%)
Drug
Months of Therapy
n
1
2
3
4
CARAFATE
Placebo
122
117
20*
33
30*
46
38†
55
42†
63
*P<0.05, †P<0.01
In this study, prn antacids were not permitted.
In the other study, scheduled endoscopies were performed at 6 and 12 months, but for-cause
endoscopies were permitted as symptoms dictated. Median symptom scores between the
sucralfate and placebo groups were not significantly different. A life table intention-to-treat
analysis for the 94 patients enrolled in the trial had the following results:
Duodenal Ulcer Recurrence Rate (%)
Drug
n
6 months
12 months
CARAFATE
48
19*
27*
Placebo
46
54
65
*P<0.002
In this study, prn antacids were permitted.
Data from placebo-controlled studies longer than 1 year are not available.
INDICATIONS AND USAGE
CARAFATE® (sucralfate) is indicated in:
Short-term treatment (up to 8 weeks) of active duodenal ulcer. While healing with sucralfate
may occur during the first week or two, treatment should be continued for 4 to 8 weeks unless
healing has been demonstrated by x-ray or endoscopic examination.
2
Reference ID: 3270329
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CARAFATE® (sucralfate) Tablets
U.S. Package Insert
Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of acute
ulcers.
CONTRAINDICATIONS
Carafate is contraindicated in patients with known hypersensitivity reactions to the active
substance or to any of the excipients.
PRECAUTIONS
The physician should read the "PRECAUTIONS" section when considering the use of this drug in
pregnant or pediatric patients, or patients of childbearing potential.
Duodenal ulcer is a chronic, recurrent disease. While short-term treatment with sucralfate can
result in complete healing of the ulcer, a successful course of treatment with sucralfate should not
be expected to alter the post healing frequency or severity of duodenal ulceration.
Isolated reports of sucralfate tablet aspiration with accompanying respiratory complications have
been received. Therefore, sucralfate tablets should be used with caution by patients who have
known conditions that may impair swallowing, such as recent or prolonged intubation,
tracheostomy, prior history of aspiration, dysphagia, or any other conditions that may alter gag
and cough reflexes, or diminish oropharyngeal coordination or motility.
Special Populations: Chronic Renal Failure and Dialysis Patients
When sucralfate is administered orally, small amounts of aluminum are absorbed from the
gastrointestinal tract. Concomitant use of sucralfate with other products that contain aluminum,
such as aluminum-containing antacids, may increase the total body burden of aluminum.
Patients with normal renal function receiving the recommended doses of sucralfate and
aluminum-containing products adequately excrete aluminum in the urine. Patients with chronic
renal failure or those receiving dialysis have impaired excretion of absorbed aluminum. In
addition, aluminum does not cross dialysis membranes because it is bound to albumin and
transferrin plasma proteins. Aluminum accumulation and toxicity (aluminum osteodystrophy,
osteomalacia, encephalopathy) have been described in patients with renal impairment.
Sucralfate should be used with caution in patients with chronic renal failure.
Drug Interactions
Some studies have shown that simultaneous sucralfate administration in healthy volunteers
reduced the extent of absorption (bioavailability) of single doses of the following: cimetidine,
digoxin, fluoroquinolone antibiotics, ketoconazole, l-thyroxine, phenytoin, quinidine, ranitidine,
tetracycline, and theophylline. Subtherapeutic prothrombin times with concomitant warfarin and
sucralfate therapy have been reported in spontaneous and published case reports. However, two
clinical studies have demonstrated no change in either serum warfarin concentration or
prothrombin time with the addition of sucralfate to chronic warfarin therapy.
The mechanism of these interactions appears to be nonsystemic in nature, presumably resulting
from sucralfate binding to the concomitant agent in the gastrointestinal tract. In all case studies to
date (cimetidine, ciprofloxacin, digoxin, norfloxacin, ofloxacin, and ranitidine), dosing the
concomitant medication 2 hours before sucralfate eliminated the interaction. Because of the
potential of CARAFATE to alter the absorption of some drugs, CARAFATE should be
administered separately from other drugs when alterations in bioavailability are felt to be critical.
In these cases, patients should be monitored appropriately.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Chronic oral toxicity studies of 24 months’ duration were conducted in mice and rats at doses up
to 1 g/kg (12 times the human dose).
There was no evidence of drug-related tumorigenicity. A reproduction study in rats at doses up to
38 times the human dose did not reveal any indication of fertility impairment. Mutagenicity
studies were not conducted.
3
Reference ID: 3270329
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CARAFATE® (sucralfate) Tablets
U.S. Package Insert
Pregnancy
Teratogenic effects. Pregnancy Category B.
Teratogenicity studies have been performed in mice, rats, and rabbits at doses up to 50 times the
human dose and have revealed no evidence of harm to the fetus due to sucralfate. There are,
however, no adequate and well-controlled studies in pregnant women.
Because animal
reproduction studies are not always predictive of human response, this drug should be used
during pregnancy only if clearly needed.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when sucralfate is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of CARAFATE (sucralfate) Tablets did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in responses between the elderly and
younger patients. In general, dose selection for an elderly patient should be cautious, usually
starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic,
renal, or cardiac function, and of concomitant disease or other drug therapy (See DOSAGE AND
ADMINISTRATION).
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function (See PRECAUTIONS Special
Populations: Chronic Renal Failure and Dialysis Patients). Because elderly patients are more
likely to have decreased renal function, care should be taken in dose selection, and it may be
useful to monitor renal function.
ADVERSE REACTIONS
Adverse reactions to sucralfate in clinical trials were minor and only rarely led to discontinuation
of the drug. In studies involving over 2700 patients treated with sucralfate tablets, adverse effects
were reported in 129 (4.7%).
Constipation was the most frequent complaint (2%). Other adverse effects reported in less than
0.5% of the patients are listed below by body system:
Gastrointestinal: diarrhea, nausea, vomiting, gastric discomfort, indigestion, flatulence, dry
mouth
Dermatological: pruritus, rash
Nervous System: dizziness, insomnia, sleepiness, vertigo
Other: back pain, headache
Post-marketing cases of hypersensitivity have been reported with the use of sucralfate tablets,
including dyspnea, lip swelling, pruritus, rash, and urticaria.
Cases of anaphylactic reactions, bronchospasm, laryngeal edema, edema of the mouth,
pharyngeal edema, respiratory tract edema and swelling of the face have been reported with an
unknown oral formulation of sucralfate.
Bezoars have been reported in patients treated with sucralfate. The majority of patients had
underlying medical conditions that may predispose to bezoar formation (such as delayed gastric
emptying) or were receiving concomitant enteral tube feedings.
Inadvertent injection of insoluble sucralfate and its insolu
complications, including pulmonary and cerebral emboli.
intravenous administration.
ble
Su
excipients
cralfate is
has
not
led
inten
to
ded
fatal
for
OVERDOSAGE
4
Reference ID: 3270329
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CARAFATE® (sucralfate) Tablets
U.S. Package Insert
Due to limited experience in humans with overdosage of sucralfate, no specific treatment
recommendations can be given. Acute oral toxicity studies in animals, however, using doses up
to 12 g/kg body weight, could not find a lethal dose. Sucralfate is only minimally absorbed from
the gastrointestinal tract. Risks associated with acute overdosage should, therefore, be minimal.
In rare reports describing sucralfate overdose, most patients remained asymptomatic. Those few
reports where adverse events were described included symptoms of dyspepsia, abdominal pain,
nausea, and vomiting.
DOSAGE AND ADMINISTRATION
Active Duodenal Ulcer. The recommended adult oral dosage for duodenal ulcer is 1 g four
times per day on an empty stomach.
Antacids may be prescribed as needed for relief of pain but should not be taken within one-half
hour before or after sucralfate.
While healing with sucralfate may occur during the first week or two, treatment should be
continued for 4 to 8 weeks unless healing has been demonstrated by x-ray or endoscopic
examination.
Maintenance Therapy: The recommended adult oral dosage is 1 g twice a day.
Elderly: In general, dose selection for an elderly patient should be cautious, usually starting at
the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function, and of concomitant disease or other drug therapy (See PRECAUTIONS
Geriatric Use).
Call your doctor for medical advice about side effects. You may report side effects to Aptalis
Pharma US, Inc. at 1-800-472-2634 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
HOW SUPPLIED
CARAFATE (sucralfate) 1g tablets are supplied in bottles of 100 (NDC 58914-171-10). Light
pink, scored, oblong tablets are embossed with CARAFATE on one side and 1712 on the other.
Rx Only
Prescribing Information rev March 2013
Aptalis Pharma US, Inc.
100 Somerset Corporate Boulevard
Bridgewater, NJ 08807
CARAFATE® is a registered trademark of Aptalis Pharma Canada Inc., which is an affiliate of
Aptalis Pharma US, Inc.
www.aptalispharma.com
5
Reference ID: 3270329
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:41.919575
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018333s034,019183s016lbl.pdf', 'application_number': 18333, 'submission_type': 'SUPPL ', 'submission_number': 34}
|
11,206
|
DESCRIPTION
CARAFATE Tablets contain sucralfate and sucralfate is an a-D-glucopyranoside, ß-D-
fructofuranosyl-, octakis-(hydrogen sulfate), aluminum complex.
Tablets for oral administration contain 1 g of sucralfate.
Also contain: D & C Red #30 Lake, FD&C Blue #1 Lake, magnesium stearate,
microcrystalline cellulose, and starch. Therapeutic category: antiulcer.
CLINICAL PHARMACOLOGY
Sucralfate is only minimally absorbed from the gastrointestinal tract. The small amounts of
the sulfated disaccharide that are absorbed are excreted primarily in the urine.
Although the mechanism of sucralfate’s ability to accelerate healing of duodenal ulcers
remains to be fully defined, it is known that it exerts its effect through a local, rather than
systemic, action. The following observations also appear pertinent:
1. Studies in human subjects and with animal models of ulcer disease have shown that
sucralfate forms an ulcer-adherent complex with proteinaceous exudate at the ulcer
site.
2. In vitro, a sucralfate-albumin film provides a barrier to diffusion of hydrogen ions.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3. In human subjects, sucralfate given in doses recommended for ulcer therapy inhibits
pepsin activity in gastric juice by 32%.
4. In vitro, sucralfate adsorbs bile salts.
These observations suggest that sucralfate’s antiulcer activity is the result of formation of
an ulcer-adherent complex that covers the ulcer site and protects it against further attack by
acid, pepsin, and bile salts. There are approximately 14 to 16 mEq of acid-neutralizing
capacity per 1 g dose of sucralfate.
CLINICAL TRIALS
Acute Duodenal Ulcer
Over 600 patients have participated in well-controlled clinical trials worldwide. Multicenter
trials conducted in the United States, both of them placebo-controlled studies with
endoscopic evaluation at 2 and 4 weeks,showed:
STUDY 1
Ulcer Healing/ No. Patients
Treatment Groups
2 wk
4 wk (Overall)
Sucralfate
37/105 (35.2%)
82/109 (75.2%)
Placebo
26/106 (24.5%)
68/107 (63.6%)
STUDY 2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Ulcer Healing/ No. Patients
Treatment Groups
2 wk
4 wk (Overall)
Sucralfate
8/24 (33%)
22/24 (92%)
Placebo
4/31 (13%)
18/31 (58%)
The sucralfate-placebo differences were statistically significant in both studies at 4 weeks
but not at 2 weeks. The poorer result in the first study may have occurred because
sucralfate was given 2 hours after meals and at bedtime rather than 1 hour before meals
and at bedtime, the regimen used in international studies and in the second United States
study. In addition, in the first study liquid antacid was utilized as needed, whereas in the
second study antacid tablets were used.
Maintenance Therapy After Healing of Duodenal Ulcer
Two double-blind randomized placebo-controlled U.S. multicenter trials have demonstrated
that sucralfate (1 g bid) is effective as maintenance therapy following healing of duodenal
ulcers.
In one study, endoscopies were performed monthly for 4 months. Of the 254 patients who
enrolled, 239 were analyzed in the intention-to-treat life table analysis presented below.
Duodenal Ulcer Recurrence Rate (%)
Drug
Months of Therapy
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
n
1
2
3
4
CARAFATE
122
20*
30*
38†
42†
Placebo
117
33
46
55
63
*P<0.05
†P<0.01
In this study, prn antacids were not permitted.
In the other study, scheduled endoscopies were performed at 6 and 12 months, but for-
cause endoscopies were permitted as symptoms dictated. Median symptom scores
between the sucralfate and placebo groups were not significantly different. A life table
intention-to-treat analysis for the 94 patients enrolled in the trial had the following results:
Duodenal Ulcer Recurrence Rate (%)
Drug
n
6 months
12 months
CARAFATE
48
19*
27*
Placebo
46
54
65
*P<0.002
In this study, prn antacids were permitted.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Data from placebo-controlled studies longer than 1 year are not available.
INDICATIONS AND USAGE
CARAFATE® (sucralfate) is indicated in:
• Short-term treatment (up to 8 weeks) of active duodenal ulcer. While healing with
sucralfate may occur during the first week or two, treatment should be continued for
4 to 8 weeks unless healing has been demonstrated by x-ray or endoscopic
examination.
• Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of
acute ulcers.
CONTRAINDICATIONS
There are no known contraindications to the use of sucralfate.
PRECAUTIONS
Duodenal ulcer is a chronic, recurrent disease. While short-term treatment with sucralfate
can result in complete healing of the ulcer, a successful course of treatment with sucralfate
should not be expected to alter the posthealing frequency or severity of duodenal
ulceration.
Special Populations: Chronic Renal Failure and Dialysis Patients
When sucralfate is administered orally, small amounts of aluminum are absorbed from the
gastrointestinal tract. Concomitant use of sucralfate with other products that contain
aluminum, such as aluminum-containing antacids, may increase the total body burden of
aluminum. Patients with normal renal function receiving the recommended doses of
sucralfate and aluminum-containing products adequately excrete aluminum in the urine.
Patients with chronic renal failure or those receiving dialysis have impaired excretion of
absorbed aluminum. In addition, aluminum does not cross dialysis membranes because it is
bound to albumin and transferrin plasma proteins. Aluminum accumulation and toxicity
(aluminum osteodystrophy, osteomalacia, encephalopathy) have been described in patients
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
with renal impairment. Sucralfate should be used with caution in patients with chronic renal
failure.
Drug Interactions
Some studies have shown that simultaneous sucralfate administration in healthy volunteers
reduced the extent of absorption (bioavailability) of single doses of the following cimetidine,
digoxin, fluoroquinolone antibiotics, ketoconazole, l-thyroxine, phenytoin, quinidine,
ranitidine, tetracycline, and theophylline. Subtherapeutic prothrombin times with
concomitant warfarin and sucralfate therapy have been reported in spontaneous and
published case reports. However, two clinical studies have demonstrated no change in
either serum warfarin concentration or prothrombin time with the addition of sucralfate to
chronic warfarin therapy.
The mechanism of these interactions appears to be nonsystemic in nature, presumably
resulting from sucralfate binding to the concomitant agent in the gastrointestinal tract. In all
case studies to date (cimetidine, ciprofloxacin, digoxin, norfloxacin, ofloxacin, and
ranitidine), dosing the concomitant medication 2 hours before sucralfate eliminated the
interaction. Because of the potential of CARAFATE to alter the absorption of some drugs,
CARAFATE should be administered separately from other drugs when alterations in
bioavailability are felt to be critical. In these cases, patients should be monitored
appropriately.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Chronic oral toxicity studies of 24 months’ duration were conducted in mice and rats at
doses up to 1 g/kg (12 times the human dose).
There was no evidence of drug-related tumorigenicity. A reproduction study in rats at doses
up to 38 times the human dose did not reveal any indication of fertility impairment.
Mutagenicity studies were not conducted.
Pregnancy
Teratogenic effects. Pregnancy Category B.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Teratogenicity studies have been performed in mice, rats, and rabbits at doses up to 50
times the human dose and have revealed no evidence of harm to the fetus due to
sucralfate. There are, however, no adequate and well-controlled studies in pregnant
women. Because animal reproduction studies are not always predictive of human response,
this drug should be used during pregnancy only if clearly needed.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised when sucralfate is administered to a
nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of CARAFATE (sucralfate) Tablets did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience has not identified differences in responses
between the elderly and younger patients. In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range, reflecting the
greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or other drug therapy. (See DOSAGE AND ADMINISTRATION)
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions
to this drug may be greater in patients with impaired renal function. (See PRECAUTIONS
Special Populations: Chronic Renal Failure and Dialysis Patients) Because elderly patients
are more likely to have decreased renal function, care should be taken in dose selection,
and it may be useful to monitor renal function.
ADVERSE REACTIONS
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Adverse reactions to sucralfate in clinical trials were minor and only rarely led to
discontinuation of the drug. In studies involving over 2700 patients treated with sucralfate
tablets, adverse effects were reported in 129 (4.7%).
Constipation was the most frequent complaint (2%). Other adverse effects reported in less
than 0.5% of the patients are listed below by body system:
Gastrointestinal: diarrhea, nausea, vomiting, gastric discomfort, indigestion, flatulence, dry
mouth
Dermatological: pruritus, rash
Nervous System: dizziness, insomnia, sleepiness, vertigo
Other: back pain, headache
Postmarketing reports of hypersensitivity reactions, including urticaria (hives), angioedema,
respiratory difficulty, rhinitis, laryngospasm, and facial swelling have been reported in
patients receiving sucralfate tablets. Similar events were reported with sucralfate
suspension. However, a causal relationship has not been established.
Bezoars have been reported in patients treated with sucralfate. The majority of patients had
underlying medical conditions that may predispose to bezoar formation (such as delayed
gastric emptying) or were receiving concomitant enteral tube feedings.
Inadvertent injection of insoluble sucralfate and its insoluble excipients has led to fatal
complications, including pulmonary and cerebral emboli. Sucralfate is not intended for
intravenous administration.
OVERDOSAGE
Due to limited experience in humans with overdosage of sucralfate, no specific treatment
recommendations can be given. Acute oral toxicity studies in animals, however, using
doses up to 12 g/kg body weight, could not find a lethal dose. Sucralfate is only minimally
absorbed from the gastrointestinal tract. Risks associated with acute overdosage should,
therefore, be minimal. In rare reports describing sucralfate overdose, most patients
remained asymptomatic. Those few reports where adverse events were described included
symptoms of dyspepsia, abdominal pain, nausea, and vomiting.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DOSAGE AND ADMINISTRATION
Active Duodenal Ulcer. The recommended adult oral dosage for duodenal ulcer is 1 g four
times per day on an empty stomach.
Antacids may be prescribed as needed for relief of pain but should not be taken within one-
half hour before or after sucralfate.
While healing with sucralfate may occur during the first week or two, treatment should be
continued for 4 to 8 weeks unless healing has been demonstrated by x-ray or endoscopic
examination.
Maintenance Therapy: The recommended adult oral dosage is 1 g twice a day.
Elderly: In general, dose selection for an elderly patient should be cautious, usually starting
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic,
renal, or cardiac function, and of concomitant disease or other drug therapy. (See
PRECAUTIONS Geriatric Use)
HOW SUPPLIED
CARAFATE (sucralfate) 1 g tablets are supplied in bottles of 100 (NDC 58914-171-10), 120
(NDC 58914-171-21), and 500 (NDC 58914-171-50). Light pink, scored, oblong tablets are
embossed with CARAFATE on one side and 1712 on the other.
Rx Only
Prescribing Information as of April 2004
Axcan Scandipharm Inc.
22 Inverness Center Parkway
Birmingham, AL 35242
www.axcan.com
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:42.005280
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018333s032lbl.pdf', 'application_number': 18333, 'submission_type': 'SUPPL ', 'submission_number': 32}
|
11,205
|
9676002
CAPSULES, ORAL SUSPENSION
and SUPPOSITORIES
INDOCIN®
(INDOMETHACIN)
Cardiovascular Risk
•
NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial
infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients
with cardiovascular disease or risk factors for cardiovascular disease may be at a greater risk.
(See WARNINGS.)
•
INDOCIN is contraindicated for the treatment of peri-operative pain in the setting of coronary
artery bypass graft (CABG) surgery (see WARNINGS).
Gastrointestinal Risk
•
NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding,
ulceration, and perforation of the stomach or intestines, which can be fatal. These events can
occur at any time during use and without warning symptoms. Elderly patients are at greater risk
for serious gastrointestinal events. (See WARNINGS.)
DESCRIPTION
INDOCIN∗ is supplied in three dosage forms. Capsules INDOCIN for oral administration contain either
25 mg or 50 mg of indomethacin and the following inactive ingredients: colloidal silicon dioxide, FD&C
Blue 1, FD&C Red 3, gelatin, lactose, lecithin, magnesium stearate, and titanium dioxide. Suspension
INDOCIN for oral use contains 25 mg of indomethacin per 5 mL, alcohol 1%, and sorbic acid 0.1% added
as a preservative and the following inactive ingredients: antifoam AF emulsion, flavors, purified water,
sodium hydroxide or hydrochloric acid to adjust pH, sorbitol solution, and tragacanth. Suppositories
INDOCIN for rectal use contain 50 mg of indomethacin and the following inactive ingredients: butylated
hydroxyanisole, butylated hydroxytoluene, edetic acid, glycerin, polyethylene glycol 3350, polyethylene
glycol 8000 and sodium chloride. Indomethacin is a non-steroidal anti-inflammatory indole derivative
designated chemically as 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid. Indomethacin
is practically insoluble in water and sparingly soluble in alcohol. It has a pKa of 4.5 and is stable in neutral
or slightly acidic media and decomposes in strong alkali. The suspension has a pH of 4.0-5.0. The
structural formula is:
CLINICAL PHARMACOLOGY
INDOCIN is a non-steroidal anti-inflammatory drug (NSAID) that exhibits antipyretic and analgesic
properties. Its mode of action, like that of other anti-inflammatory drugs, is not known. However, its
therapeutic action is not due to pituitary-adrenal stimulation.
∗ Registered trademark of MERCK & CO., Inc.
COPYRIGHT © 1988, 2005 MERCK & CO., Inc.
All rights reserved
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INDOCIN is a potent inhibitor of prostaglandin synthesis in vitro. Concentrations are reached during
therapy which have been demonstrated to have an effect in vivo as well. Prostaglandins sensitize afferent
nerves and potentiate the action of bradykinin in inducing pain in animal models. Moreover,
prostaglandins are known to be among the mediators of inflammation. Since indomethacin is an inhibitor
of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral
tissues.
INDOCIN has been shown to be an effective anti-inflammatory agent, appropriate for long-term use in
rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis.
INDOCIN affords relief of symptoms; it does not alter the progressive course of the underlying
disease.
INDOCIN suppresses inflammation in rheumatoid arthritis as demonstrated by relief of pain, and
reduction of fever, swelling and tenderness. Improvement in patients treated with INDOCIN for
rheumatoid arthritis has been demonstrated by a reduction in joint swelling, average number of joints
involved, and morning stiffness; by increased mobility as demonstrated by a decrease in walking time;
and by improved functional capability as demonstrated by an increase in grip strength. INDOCIN may
enable the reduction of steroid dosage in patients receiving steroids for the more severe forms of
rheumatoid arthritis. In such instances the steroid dosage should be reduced slowly and the patients
followed very closely for any possible adverse effects.
Indomethacin has been reported to diminish basal and CO2 stimulated cerebral blood flow in healthy
volunteers following acute oral and intravenous administration. In one study after one week of treatment
with orally administered indomethacin, this effect on basal cerebral blood flow had disappeared. The
clinical significance of this effect has not been established.
Capsules INDOCIN have been found effective in relieving the pain, reducing the fever, swelling,
redness, and tenderness of acute gouty arthritis — see INDICATIONS AND USAGE.
Following single oral doses of Capsules INDOCIN 25 mg or 50 mg, indomethacin is readily absorbed,
attaining peak plasma concentrations of about 1 and 2 mcg/mL, respectively, at about 2 hours. Orally
administered Capsules INDOCIN are virtually 100% bioavailable, with 90% of the dose absorbed within 4
hours. A single 50 mg dose of Oral Suspension INDOCIN was found to be bioequivalent to a 50 mg
INDOCIN capsule when each was administered with food.
Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin
undergoes appreciable enterohepatic circulation. The mean half-life of indomethacin is estimated to be
about 4.5 hours. With a typical therapeutic regimen of 25 or 50 mg t.i.d., the steady-state plasma
concentrations of indomethacin are an average 1.4 times those following the first dose.
The rate of absorption is more rapid from the rectal suppository than from Capsules INDOCIN.
Ordinarily, therefore, the total amount absorbed from the suppository would be expected to be at least
equivalent to the capsule. In controlled clinical trials, however, the amount of indomethacin absorbed was
found to be somewhat less (80-90%) than that absorbed from Capsules INDOCIN. This is probably
because some subjects did not retain the material from the suppository for the one hour necessary to
assure complete absorption. Since the suppository dissolves rather quickly rather than melting slowly, it is
seldom recovered in recognizable form if the patient retains the suppository for more than a few minutes.
Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyl-
desbenzoyl metabolites, all in the unconjugated form. About 60 percent of an oral dosage is recovered in
urine as drug and metabolites (26 percent as indomethacin and its glucuronide), and 33 percent is
recovered in feces (1.5 percent as indomethacin).
About 99% of indomethacin is bound to protein in plasma over the expected range of therapeutic
plasma concentrations. Indomethacin has been found to cross the blood-brain barrier and the placenta.
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of INDOCIN and other treatment options before
deciding to use INDOCIN. Use the lowest effective dose for the shortest duration consistent with
individual patient treatment goals (see WARNINGS).
Indomethacin has been found effective in active stages of the following:
1. Moderate to severe rheumatoid arthritis including acute flares of chronic disease.
2. Moderate to severe ankylosing spondylitis.
3. Moderate to severe osteoarthritis.
4. Acute painful shoulder (bursitis and/or tendinitis).
5. Acute gouty arthritis.
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CONTRAINDICATIONS
INDOCIN is contraindicated in patients with known hypersensitivity to indomethacin or the excipients
(see DESCRIPTION).
INDOCIN should not be given to patients who have experienced asthma, urticaria, or allergic-type
reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic/anaphylactoid reactions
to NSAIDs have been reported in such patients (see WARNINGS – Anaphylactic/Anaphylactoid
Reactions, and PRECAUTIONS – Preexisting Asthma).
INDOCIN is contraindicated for the treatment of peri-operative pain in the setting of coronary artery
bypass graft (CABG) surgery (see WARNINGS).
Suppositories INDOCIN are contraindicated in patients with a history of proctitis or recent rectal
bleeding.
WARNINGS
CARDIOVASCULAR EFFECTS
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have
shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and
stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk.
Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the
potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should
be used for the shortest duration possible. Physicians and patients should remain alert for the
development of such events, even in the absence of previous CV symptoms. Patients should be informed
about the signs and/or symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious
CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does
increase the risk of serious GI events (see GI WARNINGS).
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-
14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see
CONTRAINDICATIONS).
Hypertension
NSAIDs, including INDOCIN, can lead to onset of new hypertension or worsening of pre-existing
hypertension, either of which may contribute to the increased incidence of CV events. Patients taking
thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs,
including INDOCIN, should be used with caution in patients with hypertension. Blood pressure (BP)
should be monitored closely during the initiation of NSAID treatment and throughout the course of
therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs. INDOCIN should be
used with caution in patients with fluid retention or heart failure.
In a study of patients with severe heart failure and hyponatremia, INDOCIN was associated with
significant deterioration of circulatory hemodynamics, presumably due to inhibition of prostaglandin
dependent compensatory mechanisms.
Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation
NSAIDs, including INDOCIN, can cause serious gastrointestinal (GI) adverse events including
inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large
intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning
symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI
adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused
by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients
treated for one year. These trends continue with longer duration of use, increasing the likelihood of
developing a serious GI event at some time during the course of therapy. However, even short-term
therapy is not without risk.
Rarely, in patients taking INDOCIN, intestinal ulceration has been associated with stenosis and
obstruction. Gastrointestinal bleeding without obvious ulcer formation and perforation of pre-existing
sigmoid lesions (diverticulum, carcinoma, etc.) have occurred. Increased abdominal pain in ulcerative
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colitis patients or the development of ulcerative colitis and regional ileitis have been reported to occur
rarely.
NSAIDs should be prescribed with extreme caution in those with prior history of ulcer disease or
gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal
bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared
to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients
treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of
NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous
reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken
in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest possible duration. Patients and physicians should remain
alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate
additional evaluation and treatment if a serious GI adverse event is suspected. This should include
discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate
therapies that do not involve NSAIDs should be considered.
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in
the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory
drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood
flow, which may precipitate over renal decompensation. Patients at greatest risk of this reaction are those
with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors,
patients with volume depletion, and the elderly. Discontinuation of NSAID therapy is usually followed by
recovery to the pretreatment state.
Increases in serum potassium concentration, including hyperkalemia, have been reported with use of
INDOCIN, even in some patients without renal impairment. In patients with normal renal function, these
effects have been attributed to a hyporeninemic-hypoaldosteronism state (see PRECAUTIONS, Drug
Interactions).
Advanced Renal Disease
No information is available from controlled clinical studies regarding the use of INDOCIN in patients
with advanced renal disease. Therefore, treatment with INDOCIN is not recommended in these patients
with advanced renal disease. If INDOCIN therapy must be initiated, close monitoring of the patient’s renal
function is advisable.
Anaphylactic/Anaphylactoid Reactions
As with other NSAIDs, anaphylactic/anaphylactoid reactions may occur in patients without known prior
exposure to INDOCIN. INDOCIN should not be given to patients with the aspirin triad. This symptom
complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who
exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see
CONTRAINDICATIONS and PRECAUTIONS – Preexisting Asthma). Emergency help should be
sought in cases where an anaphylactic/anaphylactoid reaction occurs.
Skin Reactions
NSAIDs, including INDOCIN, can cause serious skin adverse events such as exfoliative dermatitis,
Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These
serious events may occur without warning. Patients should be informed about the signs and symptoms of
serious skin manifestations and use of the drug should be discontinued at the first appearance of skin
rash or any other sign of hypersensitivity.
Pregnancy
In late pregnancy, as with other NSAIDs, INDOCIN should be avoided because it may cause
premature closure of the ductus arteriosus.
Ocular Effects:
Corneal deposits and retinal disturbances, including those of the macula, have been observed in
some patients who had received prolonged therapy with INDOCIN. The prescribing physician should be
alert to the possible association between the changes noted and INDOCIN. It is advisable to discontinue
therapy if such changes are observed. Blurred vision may be a significant symptom and warrants a
thorough ophthalmological examination. Since these changes may be asymptomatic, ophthalmologic
examination at periodic intervals is desirable in patients where therapy is prolonged.
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Central Nervous System Effects:
INDOCIN may aggravate depression or other psychiatric disturbances, epilepsy, and parkinsonism,
and should be used with considerable caution in patients with these conditions. If severe CNS adverse
reactions develop, INDOCIN should be discontinued.
INDOCIN may cause drowsiness; therefore, patients should be cautioned about engaging in activities
requiring mental alertness and motor coordination, such as driving a car. INDOCIN may also cause
headache. Headache which persists despite dosage reduction requires cessation of therapy with
INDOCIN.
PRECAUTIONS
General
INDOCIN cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency.
Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged
corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue
corticosteroids.
The pharmacological activity of INDOCIN in reducing fever and inflammation may diminish the utility of
these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs
including INDOCIN. These laboratory abnormalities may progress, may remain unchanged, or may be
transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times
the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with
NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant
hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test
has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction
while on therapy with INDOCIN. If clinical signs and symptoms consistent with liver disease develop, or if
systemic manifestations occur (e.g., eosinophilia, rash, etc.), INDOCIN should be discontinued.
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including INDOCIN. This may be due to fluid
retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients
on long-term treatment with NSAIDs, including INDOCIN, should have their hemoglobin or hematocrit
checked if they exhibit any signs or symptoms of anemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients.
Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible.
Patients receiving INDOCIN who may be adversely affected by alterations in platelet function, such as
those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-
sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross
reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has
been reported in such aspirin-sensitive patients, INDOCIN should not be administered to patients with
this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
Information for Patients
Patients should be informed of the following information before initiating therapy with an
NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged
to read the NSAID Medication Guide that accompanies each prescription dispensed.
1. INDOCIN, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may
result in hospitalization and even death. Although serious CV events can occur without warning
symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath,
weakness, slurring of speech, and should ask for medical advice when observing any indicative sign
or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS,
CARDIOVASCULAR EFFECTS).
2. INDOCIN, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as
ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract
ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs
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and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any
indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis.
Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal
Effects - Risk of Ulceration, Bleeding, and Perforation).
3. INDOCIN, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS,
and TEN, which may result in hospitalizations and even death. Although serious skin reactions may
occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters,
fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when
observing any indicative signs or symptoms. Patients should be advised to stop the drug
immediately if they develop any type of rash and contact their physicians as soon as possible.
4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their
physicians.
5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea,
fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If
these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
6. Patients should be informed of the signs of an anaphylactic/anaphylactoid reaction (e.g. difficulty
breathing, swelling of the face or throat). If these occur, patients should be instructed to seek
immediate emergency help (see WARNINGS).
7. In late pregnancy, as with other NSAIDs, INDOCIN should be avoided because it may cause
premature closure of the ductus arteriosus.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians
should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs
should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms
consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash,
etc.) or if abnormal liver tests persist or worsen, INDOCIN should be discontinued.
Drug Interactions
ACE-Inhibitors and Angiotensin II Antagonists
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors and
angiotensin II antagonists. INDOCIN can reduce the antihypertensive effects of captopril and losartan.
These interactions should be given consideration in patients taking NSAIDs concomitantly with ACE-
inhibitors or angiotensin II antagonists. In some patients with compromised renal function, the co-
administration of an NSAID and an ACE-inhibitor or an angiotensin II antagonist may result in further
deterioration of renal function, including possible acute renal failure, which is usually reversible.
Aspirin
When INDOCIN is administered with aspirin, its protein binding is reduced, although the clearance of
free INDOCIN is not altered. The clinical significance of this interaction is not known.
The use of INDOCIN in conjunction with aspirin or other salicylates is not recommended. Controlled
clinical studies have shown that the combined use of INDOCIN and aspirin does not produce any greater
therapeutic effect than the use of INDOCIN alone. In a clinical study of the combined use of INDOCIN
and aspirin, the incidence of gastrointestinal side effects was significantly increased with combined
therapy.
In a study in normal volunteers, it was found that chronic concurrent administration of 3.6 g of aspirin
per day decreases indomethacin blood levels approximately 20%.
Beta-adrenoceptor blocking agents
Blunting of the antihypertensive effect of beta-adrenoceptor blocking agents by non-steroidal anti-
inflammatory drugs including INDOCIN has been reported. Therefore, when using these blocking agents
to treat hypertension, patients should be observed carefully in order to confirm that the desired
therapeutic effect has been obtained.
Cyclosporine
Administration of non-steroidal anti-inflammatory drugs concomitantly with cyclosporine has been
associated with an increase in cyclosporine-induced toxicity, possibly due to decreased synthesis of renal
prostacyclin. NSAIDs should be used with caution in patients taking cyclosporine, and renal function
should be carefully monitored.
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Diflunisal
In normal volunteers receiving indomethacin, the administration of diflunisal decreased the renal
clearance and significantly increased the plasma levels of indomethacin. In some patients, combined use
of INDOCIN and diflunisal has been associated with fatal gastrointestinal hemorrhage. Therefore,
diflunisal and INDOCIN should not be used concomitantly.
Digoxin
INDOCIN given concomitantly with digoxin has been reported to increase the serum concentration
and prolong the half-life of digoxin. Therefore, when INDOCIN and digoxin are used concomitantly, serum
digoxin levels should be closely monitored.
Diuretics
In some patients, the administration of INDOCIN can reduce the diuretic, natriuretic, and
antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. This response has been
attributed to inhibition of renal prostaglandin synthesis.
INDOCIN reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced by
furosemide administration, or salt or volume depletion. These facts should be considered when
evaluating plasma renin activity in hypertensive patients.
It has been reported that the addition of triamterene to a maintenance schedule of INDOCIN resulted
in reversible acute renal failure in two of four healthy volunteers. INDOCIN and triamterene should not be
administered together.
INDOCIN and potassium-sparing diuretics each may be associated with increased serum potassium
levels. The potential effects of INDOCIN and potassium-sparing diuretics on potassium kinetics and renal
function should be considered when these agents are administered concurrently.
Most of the above effects concerning diuretics have been attributed, at least in part, to mechanisms
involving inhibition of prostaglandin synthesis by INDOCIN.
During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal
failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy.
Lithium
Capsules INDOCIN 50 mg t.i.d. produced a clinically relevant elevation of plasma lithium and
reduction in renal lithium clearance in psychiatric patients and normal subjects with steady state plasma
lithium concentrations. This effect has been attributed to inhibition of prostaglandin synthesis. As a
consequence, when NSAIDs and lithium are given concomitantly, the patient should be carefully
observed for signs of lithium toxicity. (Read circulars for lithium preparations before use of such
concomitant therapy.) In addition, the frequency of monitoring serum lithium concentration should be
increased at the outset of such combination drug treatment.
Methotrexate
NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices.
This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when
NSAIDs are administered concomitantly with methotrexate.
NSAIDs
The concomitant use of INDOCIN with other NSAIDs is not recommended due to the increased
possibility of gastrointestinal toxicity, with little or no increase in efficacy.
Oral anticoagulants
Clinical studies have shown that INDOCIN does not influence the hypoprothrombinemia produced by
anticoagulants. However, when any additional drug, including INDOCIN, is added to the treatment of
patients on anticoagulant therapy, the patients should be observed for alterations of the prothrombin time.
In post-marketing experience, bleeding has been reported in patients on concomitant treatment with
anticoagulants and INDOCIN. Caution should be exercised when INDOCIN and anticoagulants are
administered concomitantly. The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that
users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.
Probenecid
When INDOCIN is given to patients receiving probenecid, the plasma levels of indomethacin are likely
to be increased. Therefore, a lower total daily dosage of INDOCIN may produce a satisfactory therapeutic
effect. When increases in the dose of INDOCIN are made, they should be made carefully and in small
increments.
Drug/Laboratory Test Interactions
False-negative results in the dexamethasone suppression test (DST) in patients being treated with
INDOCIN have been reported. Thus, results of the DST should be interpreted with caution in these
patients.
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Carcinogenesis, Mutagenesis, Impairment of Fertility
In an 81-week chronic oral toxicity study in the rat at doses up to 1 mg/kg/day, indomethacin had no
tumorigenic effect.
Indomethacin produced no neoplastic or hyperplastic changes related to treatment in carcinogenic
studies in the rat (dosing period 73-110 weeks) and the mouse (dosing period 62-88 weeks) at doses up
to 1.5 mg/kg/day.
Indomethacin did not have any mutagenic effect in in vitro bacterial tests (Ames test and E. coli with or
without metabolic activation) and a series of in vivo tests including the host-mediated assay, sex-linked
recessive lethals in Drosophila, and the micronucleus test in mice.
Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in a two
generation reproduction study or a two litter reproduction study in rats.
Pregnancy
Teratogenic Effects. Pregnancy Category C.
Teratogenic studies were conducted in mice and rats at dosages of 0.5, 1.0, 2.0, and 4.0 mg/kg/day.
Except for retarded fetal ossification at 4 mg/kg/day considered secondary to the decreased average fetal
weights, no increase in fetal malformations was observed as compared with control groups. Other studies
in mice reported in the literature using higher doses (5 to 15 mg/kg/day) have described maternal toxicity
and death, increased fetal resorptions, and fetal malformations. Comparable studies in rodents using high
doses of aspirin have shown similar maternal and fetal effects. However, animal reproduction studies are
not always predictive of human response. There are no adequate and well-controlled studies in pregnant
women.
INDOCIN should be used during pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Nonteratogenic Effects
Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular
system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be
avoided.
The known effects of indomethacin and other drugs of this class on the human fetus during the third
trimester of pregnancy include: constriction of the ductus arteriosus prenatally, tricuspid incompetence,
and pulmonary hypertension; non-closure of the ductus arteriosus postnatally which may be resistant to
medical management; myocardial degenerative changes, platelet dysfunction with resultant bleeding,
intracranial bleeding, renal dysfunction or failure, renal injury/dysgenesis which may result in prolonged or
permanent renal failure, oligohydramnios, gastrointestinal bleeding or perforation, and increased risk of
necrotizing enterocolitis.
In rats and mice, 4.0 mg/kg/day given during the last three days of gestation caused a decrease in
maternal weight gain and some maternal and fetal deaths. An increased incidence of neuronal necrosis in
the diencephalon in the live-born fetuses was observed. At 2.0 mg/kg/day, no increase in neuronal
necrosis was observed as compared to the control groups. Administration of 0.5 or 4.0 mg/kg/day during
the first three days of life did not cause an increase in neuronal necrosis at either dose level.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased
incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of INDOCIN
on labor and delivery in pregnant women are unknown.
Use in Nursing Mothers
INDOCIN is excreted in the milk of lactating mothers. INDOCIN is not recommended for use in nursing
mothers.
Pediatric Use
Safety and effectiveness in pediatric patients 14 years of age and younger has not been established.
INDOCIN should not be prescribed for pediatric patients 14 years of age and younger unless toxicity
or lack of efficacy associated with other drugs warrants the risk.
In experience with more than 900 pediatric patients reported in the literature or to the manufacturer
who were treated with Capsules INDOCIN, side effects in pediatric patients were comparable to those
reported in adults. Experience in pediatric patients has been confined to the use of Capsules INDOCIN.
If a decision is made to use indomethacin for pediatric patients two years of age or older, such
patients should be monitored closely and periodic assessment of liver function is recommended. There
have been cases of hepatotoxicity reported in pediatric patients with juvenile rheumatoid arthritis,
including fatalities. If indomethacin treatment is instituted, a suggested starting dose is 1-2 mg/kg/day
given in divided doses. Maximum daily dosage should not exceed 3 mg/kg/day or 150-200 mg/day,
whichever is less. Limited data are available to support the use of a maximum daily dosage of 4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
INDOCIN (Indomethacin)
9676002
9
mg/kg/day or 150-200 mg/day, whichever is less. As symptoms subside, the total daily dosage should be
reduced to the lowest level required to control symptoms, or the drug should be discontinued.
Geriatric Use
As with any NSAID, caution should be exercised in treating the elderly (65 years and older) since
advancing age appears to increase the possibility of adverse reactions (see WARNINGS,
Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation and DOSAGE AND
ADMINISTRATION). Elderly patients seem to tolerate ulceration or bleeding less well than other
individuals and many spontaneous reports of fatal GI events are in this population (see WARNINGS,
Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).
Indomethacin may cause confusion or, rarely, psychosis (see ADVERSE REACTIONS); physicians
should remain alert to the possibility of such adverse effects in the elderly.
This drug is known to be substantially excreted by the kidney and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely to
have decreased renal function, care should be taken in dose selection and it may be useful to monitor
renal function (see WARNINGS, Renal Effects).
ADVERSE REACTIONS
In a gastroscopic study in 45 healthy subjects, the number of gastric mucosal abnormalities was
significantly higher in the group receiving Capsules INDOCIN than in the group taking Suppositories
INDOCIN or placebo.
In a double-blind comparative clinical study involving 175 patients with rheumatoid arthritis, however,
the incidence of upper gastrointestinal adverse effects with Suppositories or Capsules INDOCIN was
comparable. The incidence of lower gastrointestinal adverse effects was greater in the suppository group.
The adverse reactions for Capsules INDOCIN listed in the following table have been arranged into two
groups: (1) incidence greater than 1%; and (2) incidence less than 1%. The incidence for group (1) was
obtained from 33 double-blind controlled clinical trials reported in the literature (1,092 patients). The
incidence for group (2) was based on reports in clinical trials, in the literature, and on voluntary reports
since marketing. The probability of a causal relationship exists between INDOCIN and these adverse
reactions, some of which have been reported only rarely.
The adverse reactions reported with Capsules INDOCIN may occur with use of the suppositories. In
addition, rectal irritation and tenesmus have been reported in patients who have received the
suppositories.
The adverse reactions reported with Capsules INDOCIN may also occur with use of the suspension.
Incidence greater
than 1%
Incidence less
than 1%
GASTROINTESTINAL
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
INDOCIN (Indomethacin)
9676002
10
nausea** with or without
vomiting
dyspepsia** (including
indigestion, heartburn
and epigastric pain)
diarrhea
abdominal distress or
pain
constipation
anorexia
bloating (includes
distension)
flatulence
peptic ulcer
gastroenteritis
rectal bleeding
proctitis
single or multiple
ulcerations, including
perforation and
hemorrhage of the
esophagus,
stomach, duodenum
or small and large
intestines
intestinal ulceration
associated with
stenosis and
obstruction
gastrointestinal bleeding
without obvious ulcer
formation and
perforation of pre-
existing sigmoid lesions
(diverticulum,
carcinoma, etc.)
development of
ulcerative colitis and
regional ileitis
ulcerative stomatitis
toxic hepatitis and jaundice
(some fatal cases have
been reported)
intestinal strictures
(diaphragms)
CENTRAL NERVOUS SYSTEM
headache (11.7%)
dizziness**
vertigo
somnolence
depression and fatigue
(including malaise and
listlessness)
anxiety (includes
nervousness)
muscle weakness
involuntary muscle
movements
insomnia
muzziness
psychic disturbances
including psychotic
episodes
mental confusion
drowsiness
light-headedness
syncope
paresthesia
aggravation of epilepsy
and parkinsonism
depersonalization
coma
peripheral neuropathy
convulsion
dysarthria
SPECIAL SENSES
tinnitus
ocular — corneal
deposits and retinal
disturbances,
including those of the
macula, have been
reported in some
patients on prolonged
therapy with INDOCIN
blurred vision
diplopia
hearing disturbances,
deafness
CARDIOVASCULAR
none
hypertension
hypotension
tachycardia
chest pain
congestive heart failure
arrhythmia; palpitations
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
INDOCIN (Indomethacin)
9676002
11
METABOLIC
none
edema
weight gain
fluid retention
flushing or sweating
hyperglycemia
glycosuria
hyperkalemia
INTEGUMENTARY
none
pruritus
rash; urticaria
petechiae or ecchymosis
exfoliative dermatitis
erythema nodosum
loss of hair
Stevens-Johnson
syndrome
erythema multiforme
toxic epidermal necrolysis
HEMATOLOGIC
none
leukopenia
bone marrow depression
anemia secondary to
obvious or occult
gastrointestinal
bleeding
aplastic anemia
hemolytic anemia
agranulocytosis
thrombocytopenic purpura
disseminated intravascular
coagulation
HYPERSENSITIVITY
none
acute anaphylaxis
acute respiratory distress
rapid fall in blood
pressure resembling a
shock-like state
angioedema
dyspnea
asthma
purpura
angiitis
pulmonary edema
fever
GENITOURINARY
none
hematuria
vaginal bleeding
proteinuria
nephrotic syndrome
interstitial nephritis
BUN elevation
renal insufficiency,
including renal failure
MISCELLANEOUS
none
epistaxis
breast changes,
including enlargement
and tenderness, or
gynecomastia
** Reactions occurring in 3% to 9% of patients treated with INDOCIN. (Those reactions occurring in less than
3% of the patients are unmarked.)
Causal relationship unknown: Other reactions have been reported but occurred under circumstances
where a causal relationship could not be established. However, in these rarely reported events, the
possibility cannot be excluded. Therefore, these observations are being listed to serve as alerting
information to physicians:
Cardiovascular: Thrombophlebitis
Hematologic: Although there have been several reports of leukemia, the supporting information is
weak
Genitourinary: Urinary frequency.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
INDOCIN (Indomethacin)
9676002
12
A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group A β hemolytic
streptococcus, has been described in persons treated with non-steroidal anti-inflammatory agents,
including indomethacin, sometimes with fatal outcome (see also PRECAUTIONS, General).
OVERDOSAGE
The following symptoms may be observed following overdosage: nausea, vomiting, intense headache,
dizziness, mental confusion, disorientation, or lethargy. There have been reports of paresthesias,
numbness, and convulsions.
Treatment is symptomatic and supportive. The stomach should be emptied as quickly as possible if
the ingestion is recent. If vomiting has not occurred spontaneously, the patient should be induced to vomit
with syrup of ipecac. If the patient is unable to vomit, gastric lavage should be performed. Once the
stomach has been emptied, 25 or 50 g of activated charcoal may be given. Depending on the condition of
the patient, close medical observation and nursing care may be required. The patient should be followed
for several days because gastrointestinal ulceration and hemorrhage have been reported as adverse
reactions of indomethacin. Use of antacids may be helpful.
The oral LD50 of indomethacin in mice and rats (based on 14 day mortality response) was 50 and
12 mg/kg, respectively.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of INDOCIN and other treatment options before
deciding to use INDOCIN. Use the lowest effective dose for the shortest duration consistent with
individual patient treatment goals (see WARNINGS).
After observing the response to initial therapy with INDOCIN, the dose and frequency should be
adjusted to suit an individual patient’s needs.
INDOCIN is available as 25 and 50 mg Capsules INDOCIN, Oral Suspension INDOCIN, containing
25 mg of indomethacin per 5 mL, and 50 mg Suppositories INDOCIN for rectal use.
Adverse reactions appear to correlate with the size of the dose of INDOCIN in most patients but not
all. Therefore, every effort should be made to determine the smallest effective dosage for the individual
patient.
Pediatric Use
INDOCIN ordinarily should not be prescribed for pediatric patients 14 years of age and under (see
PRECAUTIONS, Pediatric Use).
Adult Use
Dosage Recommendations for Active Stages of the Following:
1. Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe
ankylosing spondylitis; and moderate to severe osteoarthritis.
Suggested Dosage:
Capsules INDOCIN 25 mg b.i.d. or t.i.d. If this is well tolerated, increase the daily dosage by 25 or by
50 mg, if required by continuing symptoms, at weekly intervals until a satisfactory response is
obtained or until a total daily dose of 150-200 mg is reached. DOSES ABOVE THIS AMOUNT
GENERALLY DO NOT INCREASE THE EFFECTIVENESS OF THE DRUG.
In patients who have persistent night pain and/or morning stiffness, the giving of a large portion, up to
a maximum of 100 mg, of the total daily dose at bedtime, either orally or by rectal suppositories, may be
helpful in affording relief. The total daily dose should not exceed 200 mg. In acute flares of chronic
rheumatoid arthritis, it may be necessary to increase the dosage by 25 mg or, if required, by 50 mg daily.
If minor adverse effects develop as the dosage is increased, reduce the dosage rapidly to a tolerated
dose and OBSERVE THE PATIENT CLOSELY.
If severe adverse reactions occur, STOP THE DRUG. After the acute phase of the disease is under
control, an attempt to reduce the daily dose should be made repeatedly until the patient is receiving the
smallest effective dose or the drug is discontinued.
Careful instructions to, and observations of, the individual patient are essential to the prevention of
serious, irreversible, including fatal, adverse reactions.
As advancing years appear to increase the possibility of adverse reactions, INDOCIN should be used
with greater care in the elderly (see PRECAUTIONS, Geriatric Use).
2. Acute painful shoulder (bursitis and/or tendinitis).
Initial Dose:
75-150 mg daily in 3 or 4 divided doses.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
INDOCIN (Indomethacin)
9676002
13
The drug should be discontinued after the signs and symptoms of inflammation have been controlled
for several days. The usual course of therapy is 7-14 days.
3. Acute gouty arthritis.
Suggested Dosage:
Capsules INDOCIN 50 mg t.i.d. until pain is tolerable. The dose should then be rapidly reduced to
complete cessation of the drug. Definite relief of pain has been reported within 2 to 4 hours.
Tenderness and heat usually subside in 24 to 36 hours, and swelling gradually disappears in 3 to 5
days.
HOW SUPPLIED
No. 3316 — Capsules INDOCIN, 25 mg are opaque blue and white capsules, coded INDOCIN and
MSD 25. They are supplied as follows:
NDC 0006-0025-68 bottles of 100
NDC 0006-0025-82 bottles of 1000.
No. 3317 — Capsules INDOCIN, 50 mg are opaque blue and white capsules, coded INDOCIN and
MSD 50. They are supplied as follows:
NDC 0006-0050-68 bottles of 100.
No. 3376 — Oral Suspension INDOCIN, 25 mg per 5 mL, is an off-white suspension with a pineapple
coconut mint flavor. It is supplied as follows:
NDC 0006-3376-66 in bottles of 237 mL.
No. 3354 — Suppositories INDOCIN, 50 mg each, are white, opaque, rectal suppositories and are
supplied as follows:
NDC 0006-0150-30, boxes of 30.
Storage
Store Oral Suspension INDOCIN below 30°C (86°F). Avoid temperatures above 50°C (122°F). Protect
from freezing.
Store Suppositories INDOCIN below 30°C (86°F). Avoid transient temperatures above 40°C (104°F).
Suppositories INDOCIN® are distributed by:
Manufactured by:
MERCK SHARP & DOHME
(Italia) S.p.A.
27100 — Pavia, Italy
Capsules and Oral Suspension INDOCIN® are distributed and manufactured by:
Issued February 2006
Printed in USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9676002
Medication Guide
for
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID medicines.)
What is the most important information I should know about medicines called Non-
Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or stroke that can lead to
death. This chance increases:
•
with longer use of NSAID medicines
•
in people who have heart disease
NSAID medicines should never be used right before or after a heart surgery called a
“coronary artery bypass graft (CABG).”
NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any
time during treatment.
Ulcers and bleeding:
•
can happen without warning symptoms
•
may cause death
The chance of a person getting an ulcer or bleeding increases with:
•
taking medicines called “corticosteroids” and “anticoagulants”
•
longer use
•
smoking
•
drinking alcohol
•
older age
•
having poor health
NSAID medicines should only be used:
•
exactly as prescribed
•
at the lowest dose possible for your treatment
•
for the shortest time needed
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from
medical conditions such as:
•
different types of arthritis
•
menstrual cramps and other types of short-term pain
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
•
if you had an asthma attack, hives, or other allergic reaction with aspirin or any other
NSAID medicine
•
for pain right before or after heart bypass surgery
Tell your healthcare provider:
•
about all of your medical conditions.
•
about all of the medicines you take. NSAIDs and some other medicines can interact
with each other and cause serious side effects. Keep a list of your medicines to
show to your healthcare provider and pharmacist.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9676002
2
•
if you are pregnant. NSAID medicines should not be used by pregnant women
late in their pregnancy.
•
if you are breastfeeding. Talk to your doctor.
What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
Serious side effects include:
•
heart attack
•
stroke
•
high blood pressure
•
heart failure from body swelling (fluid
retention)
•
kidney problems including kidney failure
•
bleeding and ulcers in the stomach and
intestine
•
low red blood cells (anemia)
•
life-threatening skin reactions
•
life-threatening allergic reactions
•
liver problems including liver failure
•
asthma attacks in people who have asthma
Other side effects include:
•
stomach pain
•
constipation
•
diarrhea
•
gas
•
heartburn
•
nausea
•
vomiting
•
dizziness
Get emergency help right away if you have any of the following symptoms:
•
shortness of breath or trouble breathing
•
slurred speech
•
chest pain
•
swelling of the face or throat
•
weakness in one part or side of your body
Stop your NSAID medicine and call your healthcare provider right away if you have any of
the following symptoms:
•
nausea
•
more tired or weaker than usual
•
itching
•
there is blood in your bowel
movement or it is black and
sticky like tar
•
your skin or eyes look yellow
•
unusual weight gain
•
stomach pain
•
flu-like symptoms
•
skin rash or blisters with fever
•
vomit blood
•
swelling of the arms and legs,
hands and feet
These are not all the side effects with NSAID medicines. Talk to your healthcare provider or
pharmacist for more information about NSAID medicines.
Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
•
Aspirin is an NSAID medicine but it does not increase the chance of a heart attack.
Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause
ulcers in the stomach and intestines.
•
Some of these NSAID medicines are sold in lower doses without a prescription (over-the-
counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more
than 10 days.
NSAID medicines that need a prescription
Generic Name
Tradename
Celecoxib
Celebrex
Diclofenac
Cataflam, Voltaren, Arthrotec (combined with misoprostol)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9676002
* Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is
usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term
continuous use may increase the risk of heart attack or stroke.
3
Diflunisal
Dolobid
Etodolac
Lodine, Lodine XL
Fenoprofen
Nalfon, Nalfon 200
Flurbiprofen
Ansaid
Ibuprofen
Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone),
Combunox (combined with oxycodone)
Indomethacin
Indocin, Indocin SR, Indo-Lemmon, Indomethegan
Ketoprofen
Oruvail
Ketorolac
Toradol
Mefenamic Acid
Ponstel
Meloxicam
Mobic
Nabumetone
Relafen
Naproxen
Naprosyn, Anaprox, Anaprox DS, EC-Naprosyn, Naprelan,
Naprapac (copackaged with lansoprazole)
Oxaprozin
Daypro
Piroxicam
Feldene
Sulindac
Clinoril
Tolmetin
Tolectin, Tolectin DS, Tolectin 600
This Medication Guide has been approved by the U.S. Food and Drug Administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/016059s097,017814s040,018332s030lbl.pdf', 'application_number': 18332, 'submission_type': 'SUPPL ', 'submission_number': 30}
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018337Orig1s032lbl.pdf', 'application_number': 18337, 'submission_type': 'SUPPL ', 'submission_number': 32}
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CAPOTEN® (Captopril Tablets, USP)
Rx Only
WARNING: FETAL TOXICITY
• When pregnancy is detected, discontinue Capoten as soon as possible.
• Drugs that act directly on the renin-angiotensin system can cause injury and death to the
developing fetus. See Warnings: Fetal Toxicity
DESCRIPTION
CAPOTEN® (captopril tablets, USP) is a specific competitive inhibitor of angiotensin I-
converting enzyme (ACE), the enzyme responsible for the conversion of angiotensin I to
angiotensin II.
CAPOTEN is designated chemically as 1-[(2S)-3-mercapto-2-methylpropionyl]-Lproline [MW
217.29] and has the following structure: structure
Captopril is a white to off-white crystalline powder that may have a slight sulfurous odor; it is
soluble in water (approx. 160 mg/mL), methanol, and ethanol and sparingly soluble in
chloroform and ethyl acetate.
CAPOTEN is available in potencies of 12.5 mg, 25 mg, 50 mg, and 100 mg as scored tablets for
oral administration.
Inactive ingredients: microcrystalline cellulose, corn starch, lactose, and stearic acid.
CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism of action of CAPOTEN has not yet been fully elucidated. Its beneficial effects in
hypertension and heart failure appear to result primarily from suppression of the renin
angiotensin-aldosterone system. However, there is no consistent correlation between renin levels
and response to the drug. Renin, an enzyme synthesized by the kidneys, is released into the
circulation where it acts on a plasma globulin substrate to produce angiotensin I, a relatively
inactive decapeptide. Angiotensin I is then converted by angiotensin converting enzyme (ACE)
to angiotensin II, a potent endogenous vasoconstrictor substance. Angiotensin II also stimulates
aldosterone secretion from the adrenal cortex, thereby contributing to sodium and fluid retention.
CAPOTEN prevents the conversion of angiotensin I to angiotensin II by inhibition of ACE, a
peptidyldipeptide carboxy hydrolase. This inhibition has been demonstrated in both healthy
human subjects and in animals by showing that the elevation of blood pressure caused by
exogenously administered angiotensin I was attenuated or abolished by captopril. In animal
1
Reference ID: 3174695
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
studies, captopril did not alter the pressor responses to a number of other agents, including
angiotensin II and norepinephrine, indicating specificity of action.
ACE is identical to ''bradykininase'', and CAPOTEN may also interfere with the degradation of
the vasodepressor peptide, bradykinin. Increased concentrations of bradykinin or prostaglandin
E2 may also have a role in the therapeutic effect of CAPOTEN.
Inhibition of ACE results in decreased plasma angiotensin II and increased plasma renin activity
(PRA), the latter resulting from loss of negative feedback on renin release caused by reduction in
angiotensin II. The reduction of angiotensin II leads to decreased aldosterone secretion, and, as a
result, small increases in serum potassium may occur along with sodium and fluid loss.
The antihypertensive effects persist for a longer period of time than does demonstrable inhibition
of circulating ACE. It is not known whether the ACE present in vascular endothelium is
inhibited longer than the ACE in circulating blood.
Pharmacokinetics
After oral administration of therapeutic doses of CAPOTEN, rapid absorption occurs with peak
blood levels at about one hour. The presence of food in the gastrointestinal tract reduces
absorption by about 30 to 40 percent; captopril therefore should be given one hour before meals.
Based on carbon-14 labeling, average minimal absorption is approximately 75 percent. In a 24
hour period, over 95 percent of the absorbed dose is eliminated in the urine; 40 to 50 percent is
unchanged drug; most of the remainder is the disulfide dimer of captopril and captopril-cysteine
disulfide.
Approximately 25 to 30 percent of the circulating drug is bound to plasma proteins. The apparent
elimination half-life for total radioactivity in blood is probably less than 3 hours. An accurate
determination of half-life of unchanged captopril is not, at present, possible, but it is probably
less than 2 hours. In patients with renal impairment, however, retention of captopril occurs (see
DOSAGE AND ADMINISTRATION).
Pharmacodynamics
Administration of CAPOTEN results in a reduction of peripheral arterial resistance in
hypertensive patients with either no change, or an increase, in cardiac output. There is an
increase in renal blood flow following administration of CAPOTEN and glomerular filtration
rate is usually unchanged.
Reductions of blood pressure are usually maximal 60 to 90 minutes after oral administration of
an individual dose of CAPOTEN. The duration of effect is dose related. The reduction in blood
pressure may be progressive, so to achieve maximal therapeutic effects, several weeks of therapy
may be required. The blood pressure lowering effects of captopril and thiazide-type diuretics are
additive. In contrast, captopril and beta-blockers have a less than additive effect.
Blood pressure is lowered to about the same extent in both standing and supine positions.
Orthostatic effects and tachycardia are infrequent but may occur in volume-depleted patients.
Abrupt withdrawal of CAPOTEN has not been associated with a rapid increase in blood
pressure.
In patients with heart failure, significantly decreased peripheral (systemic vascular) resistance
and blood pressure (afterload), reduced pulmonary capillary wedge pressure (preload) and
pulmonary vascular resistance, increased cardiac output, and increased exercise tolerance time
(ETT) have been demonstrated. These hemodynamic and clinical effects occur after the first dose
2
Reference ID: 3174695
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
and appear to persist for the duration of therapy. Placebo controlled studies of 12 weeks duration
in patients who did not respond adequately to diuretics and digitalis show no tolerance to
beneficial effects on ETT; open studies, with exposure up to 18 months in some cases, also
indicate that ETT benefit is maintained. Clinical improvement has been observed in some
patients where acute hemodynamic effects were minimal.
The Survival and Ventricular Enlargement (SAVE) study was a multicenter, randomized,
double-blind, placebo-controlled trial conducted in 2,231 patients (age 21-79 years) who
survived the acute phase of myocardial infarction and did not have active ischemia. Patients had
left ventricular dysfunction (LVD), defined as a resting left ventricular ejection fraction ≤40%,
but at the time of randomization were not sufficiently symptomatic to require ACE inhibitor
therapy for heart failure. About half of the patients had symptoms of heart failure in the past.
Patients were given a test dose of 6.25 mg oral CAPOTEN and were randomized within 3-16
days post-infarction to receive either CAPOTEN or placebo in addition to conventional therapy.
CAPOTEN was initiated at 6.25 mg or 12.5 mg t.i.d. and after two weeks titrated to a target
maintenance dose of 50 mg t.i.d. About 80% of patients were receiving the target dose at the end
of the study. Patients were followed for a minimum of two years and for up to five years, with an
average follow-up of 3.5 years.
Baseline blood pressure was 113/70 mmHg and 112/70 mmHg for the placebo and CAPOTEN
groups, respectively. Blood pressure increased slightly in both treatment groups during the study
and was somewhat lower in the CAPOTEN group (119/74 vs. 125/77 mmHg at 1 yr).
Therapy with CAPOTEN improved long-term survival and clinical outcomes compared to
placebo. The risk reduction for all cause mortality was 19% (P=0.02) and for cardiovascular
death was 21% (P=0.014). Captopril treated subjects had 22% (P=0.034) fewer first
hospitalizations for heart failure. Compared to placebo, 22% fewer patients receiving captopril
developed symptoms of overt heart failure. There was no significant difference between groups
in total hospitalizations for all cause (2056 placebo; 2036 captopril).
CAPOTEN was well tolerated in the presence of other therapies such as aspirin, beta blockers,
nitrates, vasodilators, calcium antagonists and diuretics.
In a multicenter, double-blind, placebo controlled trial, 409 patients, age 18-49 of either gender,
with or without hypertension, with type I (juvenile type, onset before age 30) insulin-dependent
diabetes mellitus, retinopathy, proteinuria ≥500 mg per day and serum creatinine ≤ 2.5 mg/dL,
were randomized to placebo or CAPOTEN (25 mg t.i.d.) and followed for up to 4.8 years
(median 3 years). To achieve blood pressure control, additional antihypertensive agents
(diuretics, beta blockers, centrally acting agents or vasodilators) were added as needed for
patients in both groups.
The CAPOTEN group had a 51% reduction in risk of doubling of serum creatinine (P<0.01) and
a 51% reduction in risk for the combined endpoint of end-stage renal disease (dialysis or
transplantation) or death (P<0.01). CAPOTEN treatment resulted in a 30% reduction in urine
protein excretion within the first 3 months (P<0.05), which was maintained throughout the trial.
The CAPOTEN group had somewhat better blood pressure control than the placebo group, but
the effects of CAPOTEN on renal function were greater than would be expected from the group
differences in blood pressure reduction alone. CAPOTEN was well tolerated in this patient
population.
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Reference ID: 3174695
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For current labeling information, please visit https://www.fda.gov/drugsatfda
In two multicenter, double-blind, placebo controlled studies, a total of 235 normotensive patients
with insulin-dependent diabetes mellitus, retinopathy and microalbuminuria (20-200 µg/min)
were randomized to placebo or CAPOTEN (50 mg b.i.d.) and followed for up to 2 years.
CAPOTEN delayed the progression to overt nephropathy (proteinuria ≥ 500 mg/day) in both
studies (risk reduction 67% to 76%; P<0.05). CAPOTEN also reduced the albumin excretion
rate. However, the long term clinical benefit of reducing the progression from microalbuminuria
to proteinuria has not been established.
Studies in rats and cats indicate that CAPOTEN does not cross the blood-brain barrier to any
significant extent.
INDICATIONS AND USAGE
Hypertension: CAPOTEN (captopril tablets, USP) is indicated for the treatment of
hypertension.
In using CAPOTEN, consideration should be given to the risk of neutropenia/agranulocytosis
(see WARNINGS).
CAPOTEN may be used as initial therapy for patients with normal renal function, in whom the
risk is relatively low. In patients with impaired renal function, particularly those with collagen
vascular disease, captopril should be reserved for hypertensives who have either developed
unacceptable side effects on other drugs, or have failed to respond satisfactorily to drug
combinations.
CAPOTEN is effective alone and in combination with other antihypertensive agents, especially
thiazide-type diuretics. The blood pressure lowering effects of captopril and thiazides are
approximately additive.
Heart Failure: CAPOTEN is indicated in the treatment of congestive heart failure usually in
combination with diuretics and digitalis. The beneficial effect of captopril in heart failure does
not require the presence of digitalis, however, most controlled clinical trial experience with
captopril has been in patients receiving digitalis, as well as diuretic treatment.
Left Ventricular Dysfunction After Myocardial Infarction: CAPOTEN is indicated to
improve survival following myocardial infarction in clinically stable patients with left ventricular
dysfunction manifested as an ejection fraction ≤40% and to reduce the incidence of overt heart
failure and subsequent hospitalizations for congestive heart failure in these patients.
Diabetic Nephropathy: CAPOTEN is indicated for the treatment of diabetic nephropathy
(proteinuria >500 mg/day) in patients with type I insulin-dependent diabetes mellitus and
retinopathy. CAPOTEN decreases the rate of progression of renal insufficiency and development
of serious adverse clinical outcomes (death or need for renal transplantation or dialysis).
In considering use of CAPOTEN, it should be noted that in controlled trials ACE inhibitors have
an effect on blood pressure that is less in black patients than in non-blacks. In addition, ACE
inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than
in non-black patients (see WARNINGS: Head and Neck Angioedema and Intestinal
Angioedema).
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CONTRAINDICATIONS
CAPOTEN is contraindicated in patients who are hypersensitive to this product or any other
angiotensin-converting enzyme inhibitor (e.g., a patient who has experienced angioedema during
therapy with any other ACE inhibitor).
WARNINGS
Anaphylactoid and Possibly Related Reactions
Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of
eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE
inhibitors (including CAPOTEN) may be subject to a variety of adverse reactions, some of them
serious.
Do not co-administer aliskiren with Capoten in patients with diabetes (see PRECAUTIONS,
Drug Interactions).
Head and Neck Angioedema: Angioedema involving the extremities, face, lips, mucous
membranes, tongue, glottis or larynx has been seen in patients treated with ACE inhibitors,
including captopril. If angioedema involves the tongue, glottis or larynx, airway obstruction may
occur and be fatal. Emergency therapy, including but not necessarily limited to, subcutaneous
administration of a 1:1000 solution of epinephrine should be promptly instituted.
Swelling confined to the face, mucous membranes of the mouth, lips and extremities has usually
resolved with discontinuation of captopril; some cases required medical therapy. (See
PRECAUTIONS: Information for Patients and ADVERSE REACTIONS.)
Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE
inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in
some cases there was no prior history of facial angioedema and C-1 esterase levels were normal.
The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at
surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should
be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal
pain.
Anaphylactoid reactions during desensitization: Two patients undergoing desensitizing
treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening
anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors
were temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid reactions during membrane exposure: Anaphylactoid reactions have been
reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE
inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density
lipoprotein apheresis with dextran sulfate absorption.
Neutropenia/Agranulocytosis
Neutropenia (<1000/mm3) with myeloid hypoplasia has resulted from use of captopril. About
half of the neutropenic patients developed systemic or oral cavity infections or other features of
the syndrome of agranulocytosis.
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Reference ID: 3174695
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For current labeling information, please visit https://www.fda.gov/drugsatfda
The risk of neutropenia is dependent on the clinical status of the patient:
In clinical trials in patients with hypertension who have normal renal function (serum
creatinine less than 1.6 mg/dL and no collagen vascular disease), neutropenia has been
seen in one patient out of over 8,600 exposed.
In patients with some degree of renal failure (serum creatinine at least 1.6 mg/dL) but no
collagen vascular disease, the risk of neutropenia in clinical trials was about 1 per 500, a
frequency over 15 times that for uncomplicated hypertension. Daily doses of captopril
were relatively high in these patients, particularly in view of their diminished renal
function. In foreign marketing experience in patients with renal failure, use of allopurinol
concomitantly with captopril has been associated with neutropenia but this association
has not appeared in U.S. reports.
In patients with collagen vascular diseases (e.g., systemic lupus erythematosus,
scleroderma) and impaired renal function, neutropenia occurred in 3.7 percent of patients
in clinical trials.
While none of the over 750 patients in formal clinical trials of heart failure developed
neutropenia, it has occurred during the subsequent clinical experience. About half of the
reported cases had serum creatinine ≥1.6 mg/dL and more than 75 percent were in
patients also receiving procainamide. In heart failure, it appears that the same risk factors
for neutropenia are present.
The neutropenia has usually been detected within three months after captopril was started. Bone
marrow examinations in patients with neutropenia consistently showed myeloid hypoplasia,
frequently accompanied by erythroid hypoplasia and decreased numbers of megakaryocytes
(e.g., hypoplastic bone marrow and pancytopenia); anemia and thrombocytopenia were
sometimes seen.
In general, neutrophils returned to normal in about two weeks after captopril was discontinued,
and serious infections were limited to clinically complex patients. About 13 percent of the cases
of neutropenia have ended fatally, but almost all fatalities were in patients with serious illness,
having collagen vascular disease, renal failure, heart failure or immunosuppressant therapy, or a
combination of these complicating factors.
Evaluation of the hypertensive or heart failure patient should always include assessment of
renal function.
If captopril is used in patients with impaired renal function, white blood cell and differential
counts should be evaluated prior to starting treatment and at approximately two-week intervals
for about three months, then periodically.
In patients with collagen vascular disease or who are exposed to other drugs known to affect the
white cells or immune response, particularly when there is impaired renal function, captopril
should be used only after an assessment of benefit and risk, and then with caution.
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Reference ID: 3174695
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
All patients treated with captopril should be told to report any signs of infection (e.g., sore throat,
fever). If infection is suspected, white cell counts should be performed without delay.
Since discontinuation of captopril and other drugs has generally led to prompt return of the white
count to normal, upon confirmation of neutropenia (neutrophil count <1000/mm3) the physician
should withdraw captopril and closely follow the patient’s course.
Proteinuria
Total urinary proteins greater than 1 g per day were seen in about 0.7 percent of patients
receiving captopril. About 90 percent of affected patients had evidence of prior renal disease or
received relatively high doses of captopril (in excess of 150 mg/day), or both. The nephrotic
syndrome occurred in about one-fifth of proteinuric patients. In most cases, proteinuria subsided
or cleared within six months whether or not captopril was continued. Parameters of renal
function, such as BUN and creatinine, were seldom altered in the patients with proteinuria.
Hypotension
Excessive hypotension was rarely seen in hypertensive patients but is a possible consequence of
captopril use in salt/volume depleted persons (such as those treated vigorously with diuretics),
patients with heart failure or those patients undergoing renal dialysis. (See PRECAUTIONS:
Drug Interactions.)
In heart failure, where the blood pressure was either normal or low, transient decreases in mean
blood pressure greater than 20 percent were recorded in about half of the patients. This transient
hypotension is more likely to occur after any of the first several doses and is usually well
tolerated, producing either no symptoms or brief mild lightheadedness, although in rare instances
it has been associated with arrhythmia or conduction defects. Hypotension was the reason for
discontinuation of drug in 3.6 percent of patients with heart failure.
BECAUSE OF THE POTENTIAL FALL IN BLOOD PRESSURE IN THESE PATIENTS,
THERAPY SHOULD BE STARTED UNDER VERY CLOSE MEDICAL SUPERVISION.
A starting dose of 6.25 or 12.5 mg t.i.d. may minimize the hypotensive effect. Patients should be
followed closely for the first two weeks of treatment and whenever the dose of captopril and/or
diuretic is increased. In patients with heart failure, reducing the dose of diuretic, if feasible, may
minimize the fall in blood pressure.
Hypotension is not per se a reason to discontinue captopril. Some decrease of systemic blood
pressure is a common and desirable observation upon initiation of CAPOTEN (captopril tablets,
USP) treatment in heart failure. The magnitude of the decrease is greatest early in the course of
treatment; this effect stabilizes within a week or two, and generally returns to pretreatment
levels, without a decrease in therapeutic efficacy, within two months.
Fetal Toxicity
Pregnancy Category D
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of
pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.
Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal
deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension,
renal failure, and death. When pregnancy is detected, discontinue Capoten as soon as possible.
These adverse outcomes are usually associated with use of these drugs in the second and third
trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure
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Reference ID: 3174695
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For current labeling information, please visit https://www.fda.gov/drugsatfda
to antihypertensive use in the first trimester have not distinguished drugs affecting the renin
angiotensin system from other antihypertensive agents. Appropriate management of maternal
hypertension during pregnancy is important to optimize outcomes for both mothers and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the
renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the
fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If
oligohydramnios is observed, discontinue Capoten, unless it is considered lifesaving for the
mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and
physicians should be aware, however, that oligohydramnios may not appear until after the fetus
has sustained irreversible injury. Closely observe infants with histories of in utero exposure to
Capoten for hypotension, oliguria, and hyperkalemia. [See PRECAUTIONS, Pediatric Use].
When captopril was given to rabbits at doses about 0.8 to 70 times (on a mg/kg basis) the
maximum recommended human dose, low incidences of craniofacial malformations were seen.
No teratogenic effects of captopril were seen in studies of pregnant rats and hamsters. On a
mg/kg basis, the doses used were up to 150 times (in hamsters) and 625 times (in rats) the
maximum recommended human dose.
Hepatic Failure
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic
jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of
this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or
marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive
appropriate medical follow-up.
PRECAUTIONS
General
Impaired Renal Function
Hypertension—Some patients with renal disease, particularly those with severe renal artery
stenosis, have developed increases in BUN and serum creatinine after reduction of blood
pressure with captopril. Captopril dosage reduction and/or discontinuation of diuretic may be
required. For some of these patients, it may not be possible to normalize blood pressure and
maintain adequate renal perfusion.
Heart Failure—About 20 percent of patients develop stable elevations of BUN and serum
creatinine greater than 20 percent above normal or baseline upon long-term treatment with
captopril. Less than 5 percent of patients, generally those with severe preexisting renal disease,
required discontinuation of treatment due to progressively increasing creatinine; subsequent
improvement probably depends upon the severity of the underlying renal disease.
See CLINICAL PHARMACOLOGY, DOSAGE AND ADMINISTRATION, ADVERSE
REACTIONS: Altered Laboratory Findings.
Hyperkalemia: Elevations in serum potassium have been observed in some patients treated with
ACE inhibitors, including captopril. When treated with ACE inhibitors, patients at risk for the
development of hyperkalemia include those with: renal insufficiency; diabetes mellitus; and
those using concomitant potassium-sparing diuretics, potassium supplements or potassium-
containing salt substitutes; or other drugs associated with increases in serum potassium in a trial
of type I diabetic patients with proteinuria, the incidence of withdrawal of treatment with
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captopril for hyperkalemia was 2% (4/207). In two trials of normotensive type I diabetic patients
with microalbuminuria, no captopril group subjects had hyperkalemia (0/116). (See
PRECAUTIONS: Information for Patients and Drug Interactions; ADVERSE
REACTIONS: Altered Laboratory Findings.)
Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent
nonproductive cough has been reported with all ACE inhibitors, always resolving after
discontinuation of therapy. ACE inhibitor-induced cough should be considered in the
differential diagnosis of cough.
Valvular Stenosis: There is concern, on theoretical grounds, that patients with aortic stenosis
might be at particular risk of decreased coronary perfusion when treated with vasodilators
because they do not develop as much afterload reduction as others.
Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that
produce hypotension, captopril will block angiotensin II formation secondary to compensatory
renin release. If hypotension occurs and is considered to be due to this mechanism, it can be
corrected by volume expansion.
Hemodialysis
Recent clinical observations have shown an association of hypersensitivity-like (anaphylactoid)
reactions during hemodialysis with high-flux dialysis membranes (e.g., AN69) in patients
receiving ACE inhibitors. In these patients, consideration should be given to using a different
type of dialysis membrane or a different class of medication. (See WARNINGS:
Anaphylactoid reactions during membrane exposure.)
Information for Patients
Patients should be advised to immediately report to their physician any signs or symptoms
suggesting angioedema (e.g., swelling of face, eyes, lips, tongue, larynx and extremities;
difficulty in swallowing or breathing; hoarseness) and to discontinue therapy. (See
WARNINGS: Head and Neck Angioedema and Intestinal Angioedema.)
Patients should be told to report promptly any indication of infection (e.g., sore throat, fever),
which may be a sign of neutropenia, or of progressive edema which might be related to
proteinuria and nephrotic syndrome.
All patients should be cautioned that excessive perspiration and dehydration may lead to an
excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume
depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should
be advised to consult with the physician.
Patients should be advised not to use potassium-sparing diuretics, potassium supplements or
potassium-containing salt substitutes without consulting their physician. (See PRECAUTIONS:
General and Drug Interactions; ADVERSE REACTIONS.)
Patients should be warned against interruption or discontinuation of medication unless instructed
by the physician.
Heart failure patients on captopril therapy should be cautioned against rapid increases in physical
activity.
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Patients should be informed that CAPOTEN should be taken one hour before meals (see
DOSAGE AND ADMINISTRATION).
Pregnancy: Female patients of childbearing age should be told about the consequences of
exposure to Capoten during pregnancy. Discuss treatment options with women planning to
become pregnant. Patients should be asked to report pregnancies to their physicians as soon as
possible.
Drug Interactions
Dual Blockade of the Renin-Angiotensin System (RAS)
Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is
associated with increased risks of hypotension, hyperkalemia, and changes in renal function
(including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal
function and electrolytes in patients on Capoten and other agents that affect the RAS.
Do not co-administer aliskiren with Capoten in patients with diabetes. Avoid use of aliskiren
with Capoten in patients with renal impairment (GFR <60 ml/min).
Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase – 2 Inhibitors
(COX-2 Inhibitors)
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with
compromised renal function, co-administration of NSAIDs, including selective COX-2
inhibitors, with ACE inhibitors, including captopril, may result in deterioration of renal function,
including possible acute renal failure. These effects are usually reversible. Monitor renal
function periodically in patients receiving captopril and NSAID therapy. The antihypertensive
effect of ACE inhibitors, including captopril, may be attenuated by NSAIDs.
Hypotension—Patients on Diuretic Therapy: Patients on diuretics and especially those in whom
diuretic therapy was recently instituted, as well as those on severe dietary salt restriction or
dialysis, may occasionally experience a precipitous reduction of blood pressure usually within
the first hour after receiving the initial dose of captopril.
The possibility of hypotensive effects with captopril can be minimized by either discontinuing
the diuretic or increasing the salt intake approximately one week prior to initiation of treatment
with CAPOTEN (captopril tablets, USP) or initiating therapy with small doses (6.25 or 12.5 mg).
Alternatively, provide medical supervision for at least one hour after the initial dose. If
hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an
intravenous infusion of normal saline. This transient hypotensive response is not a
contraindication to further doses which can be given without difficulty once the blood pressure
has increased after volume expansion.
Agents Having Vasodilator Activity: Data on the effect of concomitant use of other vasodilators
in patients receiving CAPOTEN for heart failure are not available; therefore, nitroglycerin or
other nitrates (as used for management of angina) or other drugs having vasodilator activity
should, if possible, be discontinued before starting CAPOTEN. If resumed during CAPOTEN
therapy, such agents should be administered cautiously, and perhaps at lower dosage.
Agents Causing Renin Release: Captopril’s effect will be augmented by antihypertensive agents
that cause renin release. For example, diuretics (e.g., thiazides) may activate the renin
angiotensin-aldosterone system.
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Reference ID: 3174695
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Agents Affecting Sympathetic Activity: The sympathetic nervous system may be especially
important in supporting blood pressure in patients receiving captopril alone or with diuretics.
Therefore, agents affecting sympathetic activity (e.g., ganglionic blocking agents or adrenergic
neuron blocking agents) should be used with caution. Beta-adrenergic blocking drugs add some
further antihypertensive effect to captopril, but the overall response is less than additive.
Agents Increasing Serum Potassium: Since captopril decreases aldosterone production, elevation
of serum potassium may occur. Potassium-sparing diuretics such as spironolactone, triamterene,
or amiloride, or potassium supplements should be given only for documented hypokalemia, and
then with caution, since they may lead to a significant increase of serum potassium. Salt
substitutes containing potassium should also be used with caution.
Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in
patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be
coadministered with caution and frequent monitoring of serum lithium levels is recommended. If
a diuretic is also used, it may increase the risk of lithium toxicity.
Cardiac Glycosides: In a study of young healthy male subjects no evidence of a direct
pharmacokinetic captopril-digoxin interaction could be found.
Loop Diuretics: Furosemide administered concurrently with captopril does not alter the
pharmacokinetics of captopril in renally impaired hypertensive patients.
Allopurinol: In a study of healthy male volunteers no significant pharmacokinetic interaction
occurred when captopril and allopurinol were administered concomitantly for 6 days.
Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension)
have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate)
and concomitant ACE inhibitor therapy including CAPOTEN.
Drug/Laboratory Test Interaction
Captopril may cause a false-positive urine test for acetone.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Two-year studies with doses of 50 to 1350 mg/kg/day in mice and rats failed to show any
evidence of carcinogenic potential. The high dose in these studies is 150 times the maximum
recommended human dose of 450 mg, assuming a 50-kg subject. On a body-surface-area basis,
the high doses for mice and rats are 13 and 26 times the maximum recommended human dose,
respectively.
Studies in rats have revealed no impairment of fertility.
Animal Toxicology
Chronic oral toxicity studies were conducted in rats (2 years), dogs (47 weeks; 1 year), mice (2
years), and monkeys (1 year). Significant drug-related toxicity included effects on
hematopoiesis, renal toxicity, erosion/ulceration of the stomach, and variation of retinal blood
vessels.
Reductions in hemoglobin and/or hematocrit values were seen in mice, rats, and monkeys at
doses 50 to 150 times the maximum recommended human dose (MRHD) of 450 mg, assuming a
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50-kg subject. On a body-surface-area basis, these doses are 5 to 25 times maximum
recommended dose (MRHD). Anemia, leukopenia, thrombocytopenia, and bone marrow
suppression occurred in dogs at doses 8 to 30 times MRHD on a body-weight basis (4 to 15
times MRHD on a surface-area basis). The reductions in hemoglobin and hematocrit values in
rats and mice were only significant at 1 year and returned to normal with continued dosing by the
end of the study. Marked anemia was seen at all dose levels (8 to 30 times MRHD) in dogs,
whereas moderate to marked leukopenia was noted only at 15 and 30 times MRHD and
thrombocytopenia at 30 times MRHD. The anemia could be reversed upon discontinuation of
dosing. Bone marrow suppression occurred to a varying degree, being associated only with dogs
that died or were sacrificed in a moribund condition in the 1 year study. However, in the 47
week study at a dose 30 times MRHD, bone marrow suppression was found to be reversible
upon continued drug administration.
Captopril caused hyperplasia of the juxtaglomerular apparatus of the kidneys in mice and rats at
doses 7 to 200 times MRHD on a body-weight basis (0.6 to 35 times MRHD on a surface-area
basis); in monkeys at 20 to 60 times MRHD on a body-weight basis (7 to 20 times MRHD on a
surface-area basis); and in dogs at 30 times MRHD on a body-weight basis (15 times MRHD on
a surface-area basis).
Gastric erosions/ulcerations were increased in incidence in male rats at 20 to 200 times MRHD
on a body-weight basis (3.5 and 35 times MRHD on a surface-area basis); in dogs at 30 times
MRHD on a body-weight basis (15 times on MRHD on a surface-area basis); and in monkeys at
65 times MRHD on a body-weight basis (20 times MRHD on a surface-area basis). Rabbits
developed gastric and intestinal ulcers when given oral doses approximately 30 times MRHD on
a body-weight basis (10 times MRHD on surface-area basis) for only 5 to 7 days.
In the two-year rat study, irreversible and progressive variations in the caliber of retinal vessels
(focal sacculations and constrictions) occurred at all dose levels (7 to 200 times MRHD) on a
body-weight basis; 1 to 35 times MRHD on a surface-area basis in a dose-related fashion. The
effect was first observed in the 88th week of dosing, with a progressively increased incidence
thereafter, even after cessation of dosing.
Nursing Mothers
Concentrations of captopril in human milk are approximately one percent of those in maternal
blood. Because of the potential for serious adverse reactions in nursing infants from captopril, a
decision should be made whether to discontinue nursing or to discontinue the drug, taking into
account the importance of CAPOTEN to the mother. (See PRECAUTIONS: Pediatric Use.)
Pediatric Use
Neonates with a history of in utero exposure to Capoten.
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal
perfusion. Exchange transfusions or dialysis may be required as a means of reversing
hypotension and/or substituting for disordered renal function. While captopril may be removed
from the adult circulation by hemodialysis, there is inadequate data concerning the effectiveness
of hemodialysis for removing it from the circulation of neonates or children. Peritoneal dialysis
is not effective for removing captopril; there is no information concerning exchange transfusion
for removing captopril form the general circulation.
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Safety and effectiveness in pediatric patients have not been established. There is limited
experience reported in the literature with the use of captopril in the pediatric population; dosage,
on a weight basis, was generally reported to be comparable to or less than that used in adults.
Infants, especially newborns, may be more susceptible to the adverse hemodynamic effects of
captopril. Excessive, prolonged and unpredictable decreases in blood pressure and associated
complications, including oliguria and seizures, have been reported.
CAPOTEN should be used in pediatric patients only if other measures for controlling blood
pressure have not been effective.
ADVERSE REACTIONS
Reported incidences are based on clinical trials involving approximately 7000 patients.
Renal: About one of 100 patients developed proteinuria (see WARNINGS).
Each of the following has been reported in approximately 1 to 2 of 1000 patients and are of
uncertain relationship to drug use: renal insufficiency, renal failure, nephrotic syndrome,
polyuria, oliguria, and urinary frequency.
Hematologic: Neutropenia/agranulocytosis has occurred (see WARNINGS). Cases of anemia,
thrombocytopenia, and pancytopenia have been reported.
Dermatologic: Rash, often with pruritus, and sometimes with fever, arthralgia, and eosinophilia,
occurred in about 4 to 7 (depending on renal status and dose) of 100 patients, usually during the
first four weeks of therapy. It is usually maculopapular, and rarely urticarial. The rash is usually
mild and disappears within a few days of dosage reduction, short-term treatment with an
antihistaminic agent, and/or discontinuing therapy; remission may occur even if captopril is
continued. Pruritus, without rash, occurs in about 2 of 100 patients. Between 7 and 10 percent of
patients with skin rash have shown an eosinophilia and/or positive ANA titers. A reversible
associated pemphigoid-like lesion, and photosensitivity, have also been reported.
Flushing or pallor has been reported in 2 to 5 of 1000 patients.
Cardiovascular: Hypotension may occur; see WARNINGS and PRECAUTIONS [Drug
Interactions] for discussion of hypotension with captopril therapy.
Tachycardia, chest pain, and palpitations have each been observed in approximately 1 of 100
patients.
Angina pectoris, myocardial infarction, Raynaud’s syndrome, and congestive heart failure have
each occurred in 2 to 3 of 1000 patients.
Dysgeusia: Approximately 2 to 4 (depending on renal status and dose) of 100 patients developed
a diminution or loss of taste perception. Taste impairment is reversible and usually self-limited
(2 to 3 months) even with continued drug administration. Weight loss may be associated with the
loss of taste.
Angioedema: Angioedema involving the extremities, face, lips, mucous membranes, tongue,
glottis or larynx has been reported in approximately one in 1000 patients. Angioedema involving
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Reference ID: 3174695
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the upper airways has caused fatal airway obstruction. (See WARNINGS: Head and Neck
Angioedema, Intestinal Angioedema and PRECAUTIONS: Information for Patients.)
Cough: Cough has been reported in 0.5 to 2% of patients treated with captopril in clinical trials
(see PRECAUTIONS: General, Cough).
The following have been reported in about 0.5 to 2 percent of patients but did not appear at
increased frequency compared to placebo or other treatments used in controlled trials: gastric
irritation, abdominal pain, nausea, vomiting, diarrhea, anorexia, constipation, aphthous ulcers,
peptic ulcer, dizziness, headache, malaise, fatigue, insomnia, dry mouth, dyspnea, alopecia,
paresthesias.
Other clinical adverse effects reported since the drug was marketed are listed below by body
system. In this setting, an incidence or causal relationship cannot be accurately determined.
Body as a whole: Anaphylactoid reactions (see WARNINGS: Anaphylactoid and possible
related reactions and PRECAUTIONS: Hemodialysis).
General: Asthenia, gynecomastia.
Cardiovascular: Cardiac arrest, cerebrovascular accident/insufficiency, rhythm disturbances,
orthostatic hypotension, syncope.
Dermatologic: Bullous pemphigus, erythema multiforme (including Stevens-Johnson syndrome),
exfoliative dermatitis.
Gastrointestinal: Pancreatitis, glossitis, dyspepsia.
Hematologic: Anemia, including aplastic and hemolytic.
Hepatobiliary: Jaundice, hepatitis, including rare cases of necrosis, cholestasis.
Metabolic: Symptomatic hyponatremia.
Musculoskeletal: Myalgia, myasthenia.
Nervous/Psychiatric: Ataxia, confusion, depression, nervousness, somnolence.
Respiratory: Bronchospasm, eosinophilic pneumonitis, rhinitis.
Special Senses: Blurred vision.
Urogenital: Impotence.
As with other ACE inhibitors, a syndrome has been reported which may include: fever, myalgia,
arthralgia, interstitial nephritis, vasculitis, rash or other dermatologic manifestations, eosinophilia
and an elevated ESR.
Altered Laboratory Findings
Serum Electrolytes: Hyperkalemia: small increases in serum potassium,especially in patients
with renal impairment (see PRECAUTIONS).
14
Reference ID: 3174695
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Hyponatremia: particularly in patients receiving a low sodium diet or concomitant diuretics.
BUN/Serum Creatinine: Transient elevations of BUN or serum creatinine especially in volume or
salt depleted patients or those with renovascular hypertension may occur. Rapid reduction of
longstanding or markedly elevated blood pressure can result in decreases in the glomerular
filtration rate and, in turn, lead to increases in BUN or serum creatinine.
Hematologic: A positive ANA has been reported.
Liver Function Tests: Elevations of liver transaminases, alkaline phosphatase, and serum
bilirubin have occurred.
OVERDOSAGE
Correction of hypotension would be of primary concern. Volume expansion with an intravenous
infusion of normal saline is the treatment of choice for restoration of blood pressure.
While captopril may be removed from the adult circulation by hemodialysis, there is inadequate
data concerning the effectiveness of hemodialysis for removing it from the circulation of
neonates or children. Peritoneal dialysis is not effective for removing captopril; there is no
information concerning exchange transfusion for removing captopril from the general
circulation.
DOSAGE AND ADMINISTRATION
CAPOTEN should be taken one hour before meals. Dosage must be individualized.
Hypertension: Initiation of therapy requires consideration of recent antihypertensive drug
treatment, the extent of blood pressure elevation, salt restriction, and other clinical
circumstances. If possible, discontinue the patient’s previous antihypertensive drug regimen for
one week before starting CAPOTEN.
The initial dose of CAPOTEN (captopril tablets, USP) is 25 mg b.i.d. or t.i.d. If satisfactory
reduction of blood pressure has not been achieved after one or two weeks, the dose may be
increased to 50 mg b.i.d. or t.i.d. Concomitant sodium restriction may be beneficial when
CAPOTEN is used alone.
The dose of CAPOTEN in hypertension usually does not exceed 50 mg t.i.d. Therefore, if the
blood pressure has not been satisfactorily controlled after one to two weeks at this dose, (and the
patient is not already receiving a diuretic), a modest dose of a thiazide-type diuretic (e.g.,
hydrochlorothiazide, 25 mg daily), should be added. The diuretic dose may be increased at one-
to two-week intervals until its highest usual antihypertensive dose is reached.
If CAPOTEN is being started in a patient already receiving a diuretic, CAPOTEN therapy should
be initiated under close medical supervision (see WARNINGS and PRECAUTIONS: Drug
Interactions regarding hypotension), with dosage and titration of CAPOTEN as noted above.
If further blood pressure reduction is required, the dose of CAPOTEN may be increased to 100
mg b.i.d. or t.i.d. and then, if necessary, to 150 mg b.i.d. or t.i.d. (while continuing the diuretic).
The usual dose range is 25 to 150 mg b.i.d. or t.i.d. A maximum daily dose of 450 mg
CAPOTEN should not be exceeded.
15
Reference ID: 3174695
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For current labeling information, please visit https://www.fda.gov/drugsatfda
For patients with severe hypertension (e.g., accelerated or malignant hypertension), when
temporary discontinuation of current antihypertensive therapy is not practical or desirable, or
when prompt titration to more normotensive blood pressure levels is indicated, diuretic should be
continued but other current antihypertensive medication stopped and CAPOTEN dosage
promptly initiated at 25 mg b.i.d. or t.i.d., under close medical supervision.
When necessitated by the patient’s clinical condition, the daily dose of CAPOTEN may be
increased every 24 hours or less under continuous medical supervision until a satisfactory blood
pressure response is obtained or the maximum dose of CAPOTEN is reached. In this regimen,
addition of a more potent diuretic, e.g., furosemide, may also be indicated.
Beta-blockers may also be used in conjunction with CAPOTEN therapy (see PRECAUTIONS:
Drug Interactions), but the effects of the two drugs are less than additive.
Heart Failure: Initiation of therapy requires consideration of recent diuretic therapy and the
possibility of severe salt/volume depletion. In patients with either normal or low blood pressure,
who have been vigorously treated with diuretics and who may be hyponatremic and/or
hypovolemic, a starting dose of 6.25 or 12.5 mg t.i.d. may minimize the magnitude or duration of
the hypotensive effect (see WARNINGS: Hypotension); for these patients, titration to the usual
daily dosage can then occur within the next several days.
For most patients the usual initial daily dosage is 25 mg t.i.d. After a dose of 50 mg t.i.d. is
reached, further increases in dosage should be delayed, where possible, for at least two weeks to
determine if a satisfactory response occurs. Most patients studied have had a satisfactory clinical
improvement at 50 or 100 mg t.i.d. A maximum daily dose of 450 mg of CAPOTEN should not
be exceeded.
CAPOTEN should generally be used in conjunction with a diuretic and digitalis.
CAPOTEN therapy must be initiated under very close medical supervision.
Left Ventricular Dysfunction After Myocardial Infarction: The recommended dose for long-
term use in patients following a myocardial infarction is a target maintenance dose of 50 mg t.i.d.
Therapy may be initiated as early as three days following a myocardial infarction. After a single
dose of 6.25 mg, CAPOTEN therapy should be initiated at 12.5 mg t.i.d. CAPOTEN should then
be increased to 25 mg t.i.d. during the next several days and to a target dose of 50 mg t.i.d. over
the next several weeks as tolerated (see CLINICAL PHARMACOLOGY).
CAPOTEN may be used in patients treated with other post-myocardial infarction therapies, e.g.,
thrombolytics, aspirin, beta blockers.
Diabetic Nephropathy: The recommended dose of CAPOTEN for long term use to treat
diabetic nephropathy is 25 mg t.i.d.
Other antihypertensives such as diuretics, beta blockers, centrally acting agents or vasodilators
may be used in conjunction with CAPOTEN if additional therapy is required to further lower
blood pressure.
Dosage Adjustment in Renal Impairment: Because CAPOTEN is excreted primarily by the
kidneys, excretion rates are reduced in patients with impaired renal function. These patients will
take longer to reach steady-state captopril levels and will reach higher steady-state levels for a
16
Reference ID: 3174695
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
given daily dose than patients with normal renal function. Therefore, these patients may respond
to smaller or less frequent doses.
Accordingly, for patients with significant renal impairment, initial daily dosage of CAPOTEN
should be reduced, and smaller increments utilized for titration, which should be quite slow (one-
to two-week intervals). After the desired therapeutic effect has been achieved, the dose should be
slowly back-titrated to determine the minimal effective dose. When concomitant diuretic therapy
is required, a loop diuretic (e.g., furosemide), rather than a thiazide diuretic, is preferred in
patients with severe renal impairment. (See WARNINGS: Anaphylactoid reactions during
membrane exposure and PRECAUTIONS: Hemodialysis.)
HOW SUPPLIED
CAPOTEN® (Captopril Tablets, USP)
12.5 mg tablets in bottles of 100 (NDC 49884-793-01), 25 mg tablets in bottles of 100 (NDC
49884-794-01) and 1000 (NDC 49884-794-10), 50 mg tablets in bottles of 100 (NDC 49884
795-01) and 1000 (NDC 49884-795-10), and 100 mg tablets in bottles of 100 (NDC 49884-796
01). Bottles contain a desiccant-charcoal canister.
The 12.5 mg tablet is a biconvex oval with a partial bisect bar; the 25 mg tablet is a biconvex
rounded square with a quadrisect bar; the 50 and 100 mg tablets are biconvex ovals with a
bisect bar.
All captopril tablets are white and may exhibit a slight sulfurous odor.
Storage
Do not store above 30º C (86º F). Keep bottles tightly closed (protect from moisture).
®Registered Trademark of Par Pharmaceutical, Inc.
Manufactured and Distributed by:
Par Pharmaceutical Companies, Inc.
Spring Valley, NY 10977
R06/2012
17
Reference ID: 3174695
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/018343s084lbl.pdf', 'application_number': 18343, 'submission_type': 'SUPPL ', 'submission_number': 84}
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11,209
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Taro Pharmaceuticals U.S.A., Inc.
NDA #018337
FeverAll® (Acetaminophen Rectal Suppositories) 80 mg, 120 mg, 325 mg and 650 mg
CBE-0 Labeling Supplement
1
SUPPOSITORY SIDE BY SIDE COMPARISON
CURRENT DRUG LABELING 80 mg PROPOSED DRUG LABELING
1.
Changed color scheme and design
2.
Bar code and numbers revised from Actavis to Taro’s.
3.
Updated Distributor statement from Actavis to Taro’s.
Reference ID: 3805210
(b) (4)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Taro Pharmaceuticals U.S.A., Inc.
NDA #018337
FeverAll® (Acetaminophen Rectal Suppositories) 80 mg, 120 mg, 325 mg and 650 mg
CBE-0 Labeling Supplement
2
CURRENT DRUG LABELING 120 mg PROPOSED DRUG LABELING
1.
Changed color scheme and design.
2.
Bar code number revised from Actavis to Taro’s.
3.
Updated Distributor statement from Actavis to Taro’s.
Reference ID: 3805210
(b) (4)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Taro Pharmaceuticals U.S.A., Inc.
NDA #018337
FeverAll® (Acetaminophen Rectal Suppositories) 80 mg, 120 mg, 325 mg and 650 mg
CBE-0 Labeling Supplement
3
CURRENT DRUG LABELING 325 mg PROPOSED DRUG LABELING
1.
Changed color scheme and design.
2.
Added Jr. Strength before 325mg.
3.
Bar code number revised from Actavis to Taro’s.
4.
Updated Distributor statement from Actavis to Taro’s.
Reference ID: 3805210
(b) (4)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Taro Pharmaceuticals U.S.A., Inc.
NDA #018337
FeverAll® (Acetaminophen Rectal Suppositories) 80 mg, 120 mg, 325 mg and 650 mg
CBE-0 Labeling Supplement
4
CURRENT DRUG LABELING 650 mg PROPOSED DRUG LABELING
1.
No change to colors.
2.
Bar code number revised from Actavis to Taro’s.
3.
Updated Distributor statement from Actavis to Taro’s.
Reference ID: 3805210
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
---------------------------------------------------------------------------------------------------------
/s/
----------------------------------------------------
KAREN M MAHONEY
08/12/2015
Reference ID: 3805210
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:44:42.391966
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/018337Orig1s034lbl.pdf', 'application_number': 18337, 'submission_type': 'SUPPL ', 'submission_number': 34}
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Roxane Laboratories, Inc.
Columbus, Ohio 43216
LITHIUM CARBONATE Tablets USP, LITHIUM CARBONATE Capsules
USP, LITHIUM Oral Solution USP
Rx only
WARNING
Lithium toxicity is closely related to serum lithium levels, and can occur at doses close to therapeutic
levels. Facilities for prompt and accurate serum lithium determinations should be available before
initiating therapy (see DOSAGE AND ADMINISTRATION).
DESCRIPTION
Each tablet for oral administration contains:
Lithium Carbonate . . . . . . . . . . 300 mg
Each capsule for oral administration contains:
Lithium Carbonate . . . . . . . . . . 150 mg, 300 mg or 600 mg
Each 5 mL of solution for oral administration contains:
Lithium ion (Li+) . . . . . . . . . . 8 mEq
(equivalent to amount of lithium in 300 mg of lithium carbonate), alcohol 0.3% v/v.
Inactive Ingredients
The tablets contain calcium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate, and
sodium starch glycolate. The capsules contain FD&C Red No. 40, gelatin, sodium lauryl sulfate, talc,
titanium dioxide, and the imprinting ink contains FD&C Blue No. 2, FD&C Yellow No. 6, FD&C Red
No. 40, iron oxide, polyvinly pyrrolidone, shellac. The solution contains citric acid, raspberry blend,
sodium benzoate, sorbitol and water.
Lithium Oral Solution is a palatable oral dosage form of lithium ion. It is prepared in solution from
lithium hydroxide and citric acid in a ratio approximately di-lithium citrate.
Lithium is an element of the alkali-metal group with atomic number 3, atomic weight 6.94, and an
emission line at 671 nm on the flame photometer.
The empirical formula for Lithium Citrate is C6H 5Li3O7; molecular weight 209.92. Lithium acts as an
antimanic.
Lithium Carbonate is a white, light, alkaline powder with molecular formula Li2CO3 and molecular
weight 73.89.
CLINICAL PHARMACOLOGY
Preclinical studies have shown that lithium alters sodium transport in nerve and muscle cells and effects a
shift toward intraneuronal metabolism of catecholamines, but the specific biochemical mechanism of
lithium action in mania is unknown.
Reference ID: 3031563
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INDICATIONS AND USAGE
Lithium is indicated in the treatment of manic episodes of Bipolar Disorder. Bipolar Disorder, Manic
(DSM-III) is equivalent to Manic Depressive illness, Manic, in the older DSM-II terminology.
Lithium is also indicated as a maintenance treatment for individuals with a diagnosis of Bipolar Disorder.
Maintenance therapy reduces the frequency of manic episodes and diminishes the intensity of those
episodes which may occur.
Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep,
flight of ideas, grandiosity, elation, poor judgment, aggressiveness, and possibly hostility. When given to
a patient experiencing a manic episode, lithium may produce a normalization of symptomatology within 1
to 3 weeks.
CONTRAINDICATIONS
Lithium should generally not be given to patients with significant renal or cardiovascular disease, severe
debilitation or dehydration, or sodium depletion, and to patients receiving diuretics, since the risk of
lithium toxicity is very high in such patients. If the psychiatric indication is life-threatening, and if such a
patient fails to respond to other measures, lithium treatment may be undertaken with extreme caution,
including daily serum lithium determinations and adjustment to the usually low doses ordinarily tolerated
by these individuals. In such instances, hospitalization is a necessity.
WARNINGS
Lithium toxicity is closely related to serum lithium levels, and can occur at doses close to therapeutic
levels (see DOSAGE AND ADMINISTRATION).
Unmasking of Brugada Syndrome
There have been postmarketing reports of a possible association between treatment with lithium and the
unmasking of Brugada Syndrome. Brugada Syndrome is a disorder characterized by abnormal
electrocardiographic (ECG) findings and a risk of sudden death. Lithium should generally be avoided in
patients with Brugada Syndrome or those suspected of having Brugada Syndrome. Consultation with a
cardiologist is recommended if: (1) treatment with lithium is under consideration for patients suspected of
having Brugada Syndrome or patients who have risk factors for Brugada Syndrome, e.g., unexplained
syncope, a family history of Brugada Syndrome, or a family history of sudden unexplained death before
the age of 45 years, (2) patients who develop unexplained syncope or palpitations after starting lithium
therapy.
Pregnancy
Lithium may cause fetal harm when administered to a pregnant woman. There have been reports of
lithium having adverse effects on nidations in rats, embryo viability in mice, and metabolism in-vitro of
rat testis and human spermatozoa have been attributed to lithium, as have teratogenicity in submammalian
species and cleft palates in mice. Studies in rats, rabbits and monkeys have shown no evidence of lithium-
induced teratology. Data from lithium birth registries suggest an increase in cardiac and other anomalies,
especially Ebstein’s anomaly. If the patient becomes pregnant while taking lithium, she should be
apprised of the potential risk to the fetus. If possible, lithium should be withdrawn for at least the first
trimester unless it is determined that this would seriously endanger the mother.
Reference ID: 3031563
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Lithium-Induced Renal Effects
Chronic lithium therapy may be associated with diminution of renal concentrating ability, occasionally
presenting as nephrogenic diabetes insipidus, with polyuria and polydipsia. Such patients should be
carefully managed to avoid dehydration with resulting lithium retention and toxicity. This condition is
usually reversible when lithium is discontinued.
Morphologic changes with glomerular and interstitial fibrosis and nephron-atrophy have been reported in
patients on chronic lithium therapy. Morphologic changes have also been seen in bipolar patients never
exposed to lithium. The relationship between renal functional and morphologic changes and their
association with lithium therapy has not been established.
When kidney function is assessed, for baseline data prior to starting lithium therapy or thereafter, routine
urinalysis and other tests may be used to evaluate tubular function (e.g., urine specific gravity or
osmolality following a period of water deprivation, or 24-hour urine volume) and glomerular function
(e.g., serum creatinine or creatinine clearance). During lithium therapy, progressive or sudden changes in
renal function, even within the normal range, indicate the need for reevaluation of treatment.
PRECAUTIONS
General
The ability to tolerate lithium is greater during the acute manic phase and decreases when manic
symptoms subside (see DOSAGE AND ADMINISTRATION).
The distribution space of lithium approximates that of total body water. Lithium is primarily excreted in
urine with insignificant excretion in feces. Renal excretion of lithium is proportional to its plasma
concentration. The half-life of elimination of lithium is approximately 24 hours. Lithium decreases
sodium reabsorption by the renal tubules which could lead to sodium depletion. Therefore, it is essential
for the patient to maintain a normal diet, including salt, and an adequate fluid intake (2500-3000 mL) at
least during the initial stabilization period. Decreased tolerance to lithium has been reported to ensue from
protracted sweating or diarrhea and, if such occur, supplemental fluid and salt should be administered.
In addition to sweating and diarrhea, concomitant infection with elevated temperatures may also
necessitate a temporary reduction or cessation of medication.
Previously existing underlying thyroid disorders do not necessarily constitute a contraindication to
lithium treatment; where hypothyroidism exists, careful monitoring of thyroid function during lithium
stabilization and maintenance allows for correction of changing thyroid parameters, if any. Where
hypothyroidism occurs during lithium stabilization and maintenance, supplemental thyroid treatment may
be used.
Information for the Patients
A condition known as Brugada Syndrome may pre-exist and be unmasked by lithium therapy. Brugada
Syndrome is a heart disorder characterized by abnormal electrocardiographic (ECG) findings and risk of
sudden death. Patients should be advised to seek immediate emergency assistance if they experience
fainting, lightheadedness, abnormal heart beats, or shortness of breath.
Outpatients and their families should be warned that the patient must discontinue lithium therapy and
contact his physician if such clinical signs of lithium toxicity as diarrhea, vomiting, tremor, mild ataxia,
drowsiness, or muscular weakness occur.
Lithium may impair mental and/or physical abilities. Caution patients about activities requiring alertness
(e.g., operating vehicles or machinery).
Reference ID: 3031563
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Drug Interactions
Combined Use of Haloperidol and Lithium.
An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion,
extrapyramidal symptoms, leucocytosis, elevated serum enzymes, BUN and FBS) followed by
irreversible brain damage has occurred in a few patients treated with lithium plus haloperidol. A causal
relationship between these events and the concomitant administration of lithium and haloperidol has not
been established; however, patients receiving such combined therapy should be monitored closely for
early evidence of neurological toxicity and treatment discontinued promptly if such signs appear.
The possibility of similar adverse interactions with other antipsychotic medication exists.
Lithium may prolong the effects of neuromuscular blocking agents. Therefore, neuromuscular blocking
agents should be given with caution to patients receiving lithium.
Caution should be used when lithium and diuretics or angiotensin converting enzyme (ACE) inhibitors
are used concomitantly because sodium loss may reduce the renal clearance of lithium and increase serum
lithium levels with risk of lithium toxicity. When such combinations are used, the lithium dosage may
need to be decreased, and more frequent monitoring of lithium plasma levels is recommended.
Non-Steroidal Anti-Inflammatory Drugs (NSAIDS)
Lithium levels should be closely monitored when patients initiate or discontinue NSAID use. In some
cases, lithium toxicity has resulted from interactions between an NSAID and lithium. Indomethacin and
piroxicam have been reported to increase significantly steady-state plasma lithium concentrations. There
is also evidence that other nonsteroidal anti-inflammatory agents, including the selective cyclooxygenase
2 (COX-2) inhibitors, have the same effect. In a study conducted in healthy subjects, mean steady-state
lithium plasma levels increased approximately 17% in subjects receiving lithium 450 mg BID with
celecoxib 200 mg BID as compared to subjects receiving lithium alone.
Pregnancy, Teratogenic Effects
Teratogenic Effects: Pregnancy Category D:
See WARNINGS section.
Nursing Mothers
Lithium is excreted in human milk. Nursing should not be undertaken during lithium therapy except in
rare and unusual circumstances where, in the view of the physician, the potential benefits to the mother
outweigh possible hazards to the child.
Usage in Children
Since information regarding the safety and effectiveness of lithium in children under 12 years of age is
not available, its use in such patients is not recommended at this time. There has been a report of a
transient syndrome of acute dystonia and hyperreflexia occurring in a 15 kg child who ingested 300 mg of
lithium carbonate.
Reference ID: 3031563
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For current labeling information, please visit https://www.fda.gov/drugsatfda
ADVERSE REACTIONS
Lithium Toxicity
The likelihood of toxicity increases with increasing serum lithium levels. Serum lithium levels greater
than 1.5 mEq/l carry a greater risk than lower levels. However, patients sensitive to lithium may exhibit
toxic signs at serum levels below 1.5 mEq/l.
Diarrhea, vomiting, drowsiness, muscular weakness and lack of coordination may be early signs of
lithium toxicity, and can occur at lithium levels below 2.0 mEq/l. At higher levels, giddiness, ataxia,
blurred vision, tinnitus and a large output of dilute urine may be seen. Serum lithium levels above 3.0
mEq/l may produce a complex clinical picture involving multiple organs and organ systems. Serum
lithium levels should not be permitted to exceed 2.0 mEq/l during the acute treatment phase.
Fine hand tremor, polyuria and mild thirst may occur during initial therapy for the acute manic phase, and
may persist throughout treatment. Transient and mild nausea and general discomfort may also appear
during the first few days of lithium administration.
These side effects are an inconvenience rather than a disabling condition, and usually subside with
continued treatment or a temporary reduction or cessation of dosage. If persistent, a cessation of dosage is
indicated.
The following adverse reactions have been reported and do not appear to be directly related to serum
lithium levels.
Neuromuscular
Tremor, muscle hyperirritability (fasciculations, twitching, clonic movements of whole limbs), ataxia,
choreo-athetotic movements, hyperactive deep tendon reflexes.
Central Nervous System
Blackout spells, epileptiform seizures, slurred speech, dizziness, vertigo, incontinence of urine or feces,
somnolence, psychomotor retardation, restlessness, confusion, stupor, coma, acute dystonia, downbeat
nystagmus.
Cardiovascular
Cardiac arrhythmia, hypotension, peripheral circulatory collapse, sinus node dysfunction with severe
bradycardia (which may result in syncope), unmasking of Brugada Syndrome (See WARNINGS:
Unmasking of Brugada Syndrome and PRECAUTIONS: Information for the Patients).
Neurological
Cases of pseudotumor cerebri (increased intracranial pressure and papilledema) have been reported with
lithium use. If undetected, this condition may result in enlargement of the blind spot, constriction of
visual fields and eventual blindness due to optic atrophy. Lithium should be discontinued, if clinically
possible, if this syndrome occurs.
Gastrointestinal
Anorexia, nausea, vomiting, diarrhea.
Reference ID: 3031563
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Genitourinary
Albuminuria, oliguria, polyuria, glycosuria.
Dermatologic
Drying and thinning of hair, anesthesia of skin, chronic folliculitis, xerosis cutis, alopecia and
exacerbation of psoriasis.
Autonomic Nervous System
Blurred vision, dry mouth.
Thyroid Abnormalities
Euthyroid goiter and/or hypothyroidism (including myxedema) accompanied by lower T3 and T4. Iodine
131 uptake may be elevated. (See PRECAUTIONS). Paradoxically, rare cases of hyperthyroidism have
been reported.
EEG Changes
Diffuse slowing, widening of frequency spectrum, potentiation and disorganization of background
rhythm.
EKG Changes
Reversible flattening, isoelectricity or inversion of T-waves.
Miscellaneous
Fatigue, lethargy, transient scotomata, dehydration, weight loss, tendency to sleep.
Miscellaneous Reactions Unrelated to Dosage are:
Transient electroencephalographic and electrocardiographic changes, leucocytosis, headache, diffuse non
toxic goiter with or without hypothyroidism, transient hyperglycemia, generalized pruritus with or
without rash, cutaneous ulcers, albuminuria, worsening of organic brain syndromes, excessive weight
gain, edematous swelling of ankles or wrists, and thirst or polyuria, sometimes resembling diabetes
insipidus, and metallic taste.
A single report has been received of the development of painful discoloration of fingers and toes and
coldness of the extremities within one day of the starting of treatment of lithium. The mechanism through
which these symptoms (resembling Raynaud’s Syndrome) developed is not known. Recovery followed
discontinuance.
Reference ID: 3031563
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OVERDOSAGE
The toxic levels for lithium are close to the therapeutic levels. It is therefore important that patients and
their families be cautioned to watch for early symptoms and to discontinue the drug and inform the
physician should they occur. Toxic symptoms are listed in detail under ADVERSE REACTIONS.
Treatment
No specific antidote for lithium poisoning is known. Early symptoms of lithium toxicity can usually be
treated by reduction of cessation of dosage of the drug and resumption of the treatment at a lower dose
after 24 to 48 hours. In severe cases of lithium poisoning, the first and foremost goal of treatment consists
of elimination of this ion from the patient.
Treatment is essentially the same as that used in barbiturate poisoning: 1) gastric lavage, 2) correction of
fluid and electrolyte imbalance and 3) regulation of kidney functioning. Urea, mannitol, and
aminophylline all produce significant increases in lithium excretion. Hemodialysis is an effective and
rapid means of removing the ion from the severely toxic patient. Infection prophylaxis, regular chest X-
rays, and preservation of adequate respiration are essential.
DOSAGE AND ADMINISTRATION
Acute Mania
Optimal patient response to Lithium Carbonate usually can be established and maintained with 600 mg
t.i.d. Optimal patient response to Lithium Oral Solution usually can be established and maintained with
10 mL (2 full teaspoons) (16 mEq of lithium) t.i.d. Such doses will normally produce an effective serum
lithium level ranging between 1.0 and 1.5 mEq/l. Dosage must be individualized according to serum
levels and clinical response. Regular monitoring of the patient’s clinical state and of serum lithium levels
is necessary. Serum levels should be determined twice per week during the acute phase, and until the
serum level and clinical condition of the patient have been stabilized.
Long-Term Control
The desirable serum lithium levels are 0.6 to 1.2 mEq/l. Dosage will vary from one individual to another,
but usually 300 mg of Lithium Carbonate t.i.d. or q.i.d., or 5 mL (1 full teaspoon) (8 mEq of Lithium) of
Lithium Oral Solution t.i.d. or q.i.d. will maintain this level. Serum lithium levels in uncomplicated cases
receiving maintenance therapy during remission should be monitored at least every two months.
Patients abnormally sensitive to lithium may exhibit toxic signs at serum levels of 1.0 to 1.5 mEq/l.
Elderly patients often respond to reduced dosage, and may exhibit signs of toxicity at serum levels
ordinarily tolerated by other patients.
N.B.
Blood samples for serum lithium determination should be drawn immediately prior to the next dose when
lithium concentrations are relatively stable (i.e., 8-12 hours after the previous dose). Total reliance must
not be placed on serum levels alone. Accurate patient evaluation requires both clinical and laboratory
analysis.
Reference ID: 3031563
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HOW SUPPLIED
Lithium Carbonate Tablets USP
300 mg white, scored tablets (Identified 54 452)
NDC 0054-8528-25: Unit dose, 10 tablets per strip, 10 strips per shelf pack, 10 shelf packs per shipper.
(For Institutional Use Only).
NDC 0054-4527-25: Bottles of 100 tablets.
NDC 0054-4527-31: Bottles of 1000 tablets.
Lithium Carbonate Capsules USP
150 mg white opaque colored capsules (size 4)
(Identified 54 213).
NDC 0054-8526-25: Unit dose, 10 capsules per strip, 10 strips per shelf pack, 10 shelf packs per shipper.
(For Institutional Use Only).
NDC 0054-2526-25: Bottles of 100 capsules.
300 mg flesh-colored capsules (size 2)
(Identified 54 463).
NDC 0054-8527-25: Unit dose, 10 capsules per strip, 10 strips per shelf pack, 10 shelf packs per shipper.
(For Institutional Use Only).
NDC 0054-2527-25: Bottles of 100 capsules.
NDC 0054-2527-31: Bottles of 1000 capsules.
600 mg white opaque/flesh colored capsules
(size 0) (Identified 54 702).
NDC 0054-8531-25: Unit dose, 10 capsules per strip, 10 strips per shelf pack, 10 shelf packs per shipper.
(For Institutional Use Only).
NDC 0054-2531-25: Bottles of 100 capsules.
Store and Dispense:
Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room
Temperature]. Protect from moisture. Dispense in a tight container as defined in the USP/NF.
Lithium Oral Solution USP, 8 mEq per 5 mL.
NDC 0054-8529-04: Unit dose Patient Cup™ filled to deliver 5 mL, ten 5 mL Patient Cup™ per shelf
pack, ten shelf packs per shipper.
(For Institutional Use Only).
NDC 0054-3527-63: Bottles of 500 mL.
Reference ID: 3031563
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Store and Dispense:
Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room
Temperature]. Dispense in a tight container as defined in the USP/NF.
4055500/08
Revised September 2011
© RLI, 2011
Reference ID: 3031563
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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2025-02-12T13:44:42.551314
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/017812s028,018421s027lbl.pdf', 'application_number': 18421, 'submission_type': 'SUPPL ', 'submission_number': 27}
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11,212
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AYGESTIN®
(norethindrone acetate tablets, USP)
Rx only
DESCRIPTION
AYGESTIN® (norethindrone acetate tablets, USP) - 5 mg oral tablets.
AYGESTIN®, (17-hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one acetate), a synthetic, orally
active progestin, is the acetic acid ester of norethindrone. It is a white, or creamy white,
crystalline powder.
AYGESTIN® tablets contain the following inactive ingredients: lactose, magnesium stearate, and
microcrystalline cellulose.
CLINICAL PHARMACOLOGY
Norethindrone acetate induces secretory changes in an estrogen-primed endometrium. On a
weight basis, it is twice as potent as norethindrone.
PHARMACOKINETICS
Absorption:
Norethindrone acetate is completely and rapidly deacetylated to norethindrone (NET) after oral
administration, and the disposition of norethindrone acetate is indistinguishable from that of
orally administered norethindrone. Norethindrone acetate is rapidly absorbed from
AYGESTIN® tablets, with maximum plasma concentration of norethindrone generally occurring
at about 2 hours post-dose. The pharmacokinetic parameters of norethindrone following single
oral administration of AYGESTIN® in 29 healthy female volunteers are summarized in Table 1.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1
Pharmacokinetic Parameters after a Single Dose of
AYGESTIN® in Healthy Women
AYGESTIN® (n=29) Arithmetic Mean ± SD
Norethindrone (NET)
AUC (0-inf)(ng/ml*h)
166.90±56.28
Cmax (ng/ml)
26.19 ± 6.19
tmax (h)
1.83 ± 0.58
t1/2 (h)
8.51 ± 2.19
AUC = area under the curve,
Cmax = maximum plasma concentration,
tmax = time at maximum plasma concentration,
t1/2 = half-life,
SD = standard deviation
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Effect of Food:
The effect of food administration on the pharmacokinetics of AYGESTIN® has not been studied.
Distribution:
Norethindrone is 36% bound to sex hormone-binding globulin (SHBG) and 61% bound to
albumin. Volume of distribution of norethindrone is about 4 L/kg.
Metabolism:
Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by
sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates,
with glucuronides accounting for most of the urinary metabolites.
Excretion:
Plasma clearance value for norethindrone is approximately 0.4 L/hr/kg. Norethindrone is
excreted in both urine and feces, primarily as metabolites. The mean terminal elimination half-
life of norethindrone following a single dose administration of AYGESTIN® is approximately 9
hours.
SPECIAL POPULATIONS
Geriatrics
The effect of age on the pharmacokinetics of norethindrone after AYGESTIN® administration
has not been evaluated.
Race
The effect of race on the disposition of norethindrone after AYGESTIN® administration has not
been evaluated.
Renal Insufficiency
The effect of renal disease on the disposition of norethindrone after AYGESTIN® administration
has not been evaluated. In premenopausal women with chronic renal failure undergoing
peritoneal dialysis who received multiple doses of an oral contraceptive containing ethinyl
estradiol and norethindrone, plasma norethindrone concentration was unchanged compared to
concentrations in premenopausal women with normal renal function.
Hepatic Insufficiency
The effect of hepatic disease on the disposition of norethindrone after AYGESTIN®
administration has not been evaluated. However, AYGESTIN® is contraindicated in markedly
impaired liver function or liver disease.
Drug Interactions
No pharmacokinetic drug interaction studies investigating any drug-drug interactions with
AYGESTIN® have been conducted.
July 2007
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
INDICATIONS AND USAGE
AYGESTIN®
AYGESTIN® is indicated for the treatment of secondary amenorrhea, endometriosis, and
abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such
as submucous fibroids or uterine cancer. AYGESTIN® is not intended, recommended or
approved to be used with concomitant estrogen therapy in postmenopausal women for
endometrial protection.
CONTRAINDICATIONS
• Known or suspected pregnancy. There is no indication for AYGESTIN® in pregnancy.
(See PRECAUTIONS.)
• Undiagnosed vaginal bleeding
• Known, suspected or history of cancer of the breast
• Active deep vein thrombosis, pulmonary embolism or history of these conditions
• Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke,
myocardial infarction)
• Impaired liver function or liver disease
• As a diagnostic test for pregnancy
• Hypersensitivity to any of the drug components
WARNINGS
1. Cardiovascular disorders
Patients with risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus,
tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g.,
personal history or family history of VTE, obesity, and systemic lupus erythematosus) should
be managed appropriately.
2. Visual abnormalities
Discontinue medication pending examination if there is a sudden partial or complete loss of
vision or if there is sudden onset of proptosis, diplopia, or migraine. If examination reveals
papilledema or retinal vascular lesions, medication should be discontinued.
July 2007
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For current labeling information, please visit https://www.fda.gov/drugsatfda
PRECAUTIONS
1. General Precautions
• Because this drug may cause some degree of fluid retention, conditions which might be
influenced by this factor, such as epilepsy, migraine, cardiac or renal dysfunctions,
require careful observation
• In cases of breakthrough bleeding, and in all cases of irregular bleeding per vagina,
nonfunctional causes should be borne in mind. In cases of undiagnosed vaginal bleeding,
adequate diagnostic measures are indicated
• Patients who have a history of clinical depression should be carefully observed and the
drug discontinued if the depression recurs to a serious degree
• Data suggest that progestin therapy may have adverse effects on lipid and carbohydrate
metabolism. The choice of progestin, its dose, and its regimen may be important in
minimizing these adverse effects, but these issues will require further study before they
are clarified. Women with hyperlipidemias and/or diabetes should be monitored closely
during progestin therapy
• The pathologist should be advised of progestin therapy when relevant specimens are
submitted
2. Information for the Patient
Healthcare providers are advised to discuss the PATIENT INFORMATION leaflet with patients
for whom they prescribe AYGESTIN®.
3. Drug/Laboratory Tests Interactions
The following laboratory test results may be altered by the use of estrogen/progestin combination
drugs:
1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time;
increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant
activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased
levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased
levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
2. Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid
hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by
radioimmunoassay) or T3 levels by radio immunoassay. T3 resin uptake is decreased,
reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on
thyroid replacement therapy may require higher doses of thyroid hormone.
3. Other binding proteins may be elevated in serum (i.e., corticosteroid binding globulin (CBG),
sex hormone binding globulin (SHBG)) leading to increased circulating corticosteroid and
sex steroids, respectively. Free or biologically active hormone concentrations are unchanged.
Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-
antitrypsin, ceruloplasmin).
July 2007
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4. Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL
cholesterol concentration, increased triglycerides levels.
5. Impaired glucose metabolism.
6. Reduced response to metyrapone test.
4. Carcinogenesis, Mutagenesis, and Impairment of Fertility
Some beagle dogs treated with medroxyprogesterone acetate developed mammary nodules.
Although nodules occasionally appeared in control animals, they were intermittent in nature,
whereas nodules in treated animals were larger and more numerous, and persisted. There is no
general agreement as to whether the nodules are benign or malignant. Their significance with
respect to humans has not been established.
5. Pregnancy Category X
Norethindrone acetate is contraindicated during pregnancy as it may cause fetal harm when
administered to pregnant women. Several reports suggest an association between intrauterine
exposure to progestational drugs in the first trimester of pregnancy and congenital abnormalities
in male and female fetuses. Some progestational drugs induce mild virilization of the external
genitalia of female fetuses.
6. Nursing Mothers
Detectable amounts of progestins have been identified in the milk of mothers receiving them.
Caution should be exercised when progestins are administered to a nursing woman.
7. Pediatric Use
AYGESTIN® tablets are not indicated in children.
ADVERSE REACTIONS
See WARNINGS and PRECAUTIONS.
The following adverse reactions have been observed in women taking progestins:
• Breakthrough bleeding
• Spotting
• Change in menstrual flow
• Amenorrhea
• Edema
• Changes in weight (decreases, increases)
• Changes in the cervical squamo-columnar junction and cervical secretions
• Cholestatic jaundice
• Rash (allergic) with and without pruritus
• Melasma or chloasma
• Clinical depression
• Acne
• Breast enlargement/tenderness
July 2007
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• Headache/migraine
• Urticaria
• Abnormalities of liver tests (i.e., AST, ALT, Bilirubin)
• Decreased HDL cholesterol and increased LDL/HDL ratio
• Mood swings
• Nausea
• Insomnia
• Anaphylactic/anaphylactoid reactions
• Thrombotic and thromboembolic events (e.g., deep vein thrombosis, pulmonary
embolism, retinal vascular thrombosis, cerebral thrombosis and embolism)
• Optic neuritis (which may lead to partial or complete loss of vision)
DOSAGE AND ADMINISTRATION
AYGESTIN®
Therapy with AYGESTIN® must be adapted to the specific indications and therapeutic response
of the individual patient.
Secondary amenorrhea, abnormal uterine bleeding due to hormonal imbalance in the absence of
organic pathology: 2.5 to 10 mg AYGESTIN® may be given daily for 5 to 10 days to produce
secretory transformation of an endometrium that has been adequately primed with either
endogenous or exogenous estrogen.
Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing
AYGESTIN® therapy. Patients with a past history of recurrent episodes of abnormal uterine
bleeding may benefit from planned menstrual cycling with AYGESTIN®.
Endometriosis: Initial daily dosage of 5 mg AYGESTIN® for two weeks. Dosage should be
increased by 2.5 mg per day every two weeks until 15 mg per day of AYGESTIN® is reached.
Therapy may be held at this level for six to nine months or until annoying breakthrough bleeding
demands temporary termination.
HOW SUPPLIED
AYGESTIN® (norethindrone acetate tablets, USP) are available as:
5 mg: White, oval, flat-faced, beveled edge tablet scored on one side. Debossed with 5
AYGESTIN® on the unscored side and B /424 on the scored side.
Available as follows:
Bottle of 50
NDC 51285-424-10
Blister Pack of 10 tablets
NDC 51285-424-69
Store at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature].
July 2007
Page 7 of 11
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For current labeling information, please visit https://www.fda.gov/drugsatfda
PATIENT INFORMATION
AYGESTIN®
(norethindrone acetate tablets)
Read this PATIENT INFORMATION before you start taking AYGESTIN® tablets and read
what you get each time you refill AYGESTIN® tablets. There may be new information. This
information does not take the place of talking to your healthcare provider about your medical
condition.
What is the most important information I should know about AYGESTIN® (A Progestin
Hormone) tablets?
• Do not use AYGESTIN® if you are pregnant, breast-feeding or are trying to
conceive.
• Do not use AYGESTIN® if you have had a previous blood clot, stroke, or heart
attack.
• Do not use AYGESTIN® if you are postmenopausal.
What is AYGESTIN®?
AYGESTIN® is similar to the progesterone hormones naturally produced by the body. Your
healthcare provider may provide AYGESTIN® as individual tablets or in a blister pack of 10
tablets.
What are AYGESTIN® tablets used for?
AYGESTIN® tablets are used for the treatment of secondary amenorrhea (absence of menstrual
periods in women who have previously had a menstrual period who are not pregnant), the
treatment of endometriosis, and the treatment of irregular menstrual periods due to hormone
imbalance.
Who should not take AYGESTIN® tablets?
You should not take AYGESTIN® tablets if you are postmenopausal, pregnant or breast-
feeding.
You should not take AYGESTIN® tablets if you have the following conditions:
• Known or suspected pregnancy. AYGESTIN® tablets are not indicated during
pregnancy as it may cause fetal harm when administered to pregnant women. There is an
increased risk of minor birth defects in children whose mothers take AYGESTIN® during
July 2007
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For current labeling information, please visit https://www.fda.gov/drugsatfda
the first 4 months of pregnancy (mild masculinization of the external genitalia of the
female fetus, as well as hypospadias in the male fetus). If you take AYGESTIN® and
later find out you were pregnant, talk with your healthcare provider right away
• History of blood clots in the legs, lungs, eyes, brain, or elsewhere, or a past history of
these conditions
• Liver impairment or disease
• Known or suspected cancer of the breast. If you have or had cancer of the breast, talk
with your healthcare provider about whether you should take AYGESTIN®
• Undiagnosed vaginal bleeding
• Hypersensitivity to AYGESTIN® tablets. See the end of this leaflet for a list of all of
the ingredients in AYGESTIN®
What are the risks associated with AYGESTIN® tablets?
• Risk to the Fetus:
AYGESTIN® tablets should not be used if you are pregnant. AYGESTIN® tablets are
contraindicated during pregnancy as it may cause fetal harm when administered to pregnant
women. There is an increased risk of minor birth defects in children whose mothers take this
drug during the first 4 months of pregnancy. Several reports suggest an association between
mothers who take these drugs in the first trimester of pregnancy and congenital abnormalities
in male and female babies. Although it is not clear that these events were drug related, you
should check with your healthcare provider about the risks to your unborn child of any
medication taken during pregnancy.
You should avoid using AYGESTIN® tablets during pregnancy. If you take AYGESTIN®
(norethindrone acetate tablets, USP) and later find you were pregnant when you took it, be
sure to discuss this with your healthcare provider as soon as possible.
• Abnormal Blood Clotting:
Use of progestational drugs, such as AYGESTIN®, has been associated with changes in the
blood-clotting system. These changes allow the blood to clot more easily, possibly allowing
clots to form in the bloodstream. If blood clots do form in your bloodstream, they can cut off
the blood supply to vital organs, causing serious problems. These problems may include a
stroke (by cutting off blood to part of the brain), a heart attack (by cutting off blood to part of
the heart), a pulmonary embolus (by cutting off blood to part of the lungs), visual loss or
blindness (by cutting off blood vessels in the eye), or other problems. Any of these
conditions may cause death or serious long-term disability. Call your healthcare provider
right away if you suspect you have any of these conditions. He or she may advise you to stop
using the drug.
• Eye Abnormalities:
Discontinue AYGESTIN® tablets and call your healthcare provider right away if you
experience sudden partial or complete loss of vision, blurred vision, or sudden onset of
bulging eyes, double vision, or migraine.
July 2007
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For current labeling information, please visit https://www.fda.gov/drugsatfda
These are some of the warning signs of serious side effects with progestin therapy:
• Breast lumps
• Dizziness and faintness
• Changes in speech
• Severe headaches
• Chest pain
• Shortness of breath
• Pains in your legs
• Changes in vision
Call your healthcare provider right away if you get any of these warning signs, or any other
unusual symptom that concerns you.
Common side effects include:
• Headache
• Breast pain
• Irregular vaginal bleeding or spotting
• Stomach/abdominal cramps/bloating
• Nausea and vomiting
• Hair loss
Other side effects include:
• High blood pressure
• Liver problems
• High blood sugar
• Fluid retention
• Enlargements of benign tumors of the uterus (“fibroids”)
• Vaginal yeast infections
• Mental depression
These are not all the possible side effects of progestin and/or estrogen therapy. For more
information, ask your healthcare provider or pharmacist.
What can I do to lower my chances of getting a serious side effect with AYGESTIN®?
• Talk with your healthcare provider regularly about whether you should continue taking
AYGESTIN®
• Have a breast exam and mammogram (breast x-ray) every year unless your healthcare
provider tells you something else. If members of your family have had breast cancer or if you
July 2007
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have ever had breast lumps or an abnormal mammogram, you may need to have breast exams
more often
• If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight,
or if you use tobacco, you may have higher chances for getting heart disease. Ask your
healthcare provider for ways to lower your chances of getting heart attacks
General information about the safe and effective use of AYGESTIN® tablets
Medicines are sometimes prescribed for conditions that are not mentioned in patient information
leaflets. Do not take AYGESTIN® tablets for conditions for which it was not prescribed. Do not
give AYGESTIN® tablets to other people, even if they have the same symptoms you have. It
may harm them.
Keep AYGESTIN® tablets out of the reach of children.
This leaflet provides a summary of the most important information about progestin and/or
estrogen therapy. If you would like more information, talk with your healthcare provider or
pharmacist. You can ask for information about AYGESTIN® that is written for health
professionals.
What are the ingredients in AYGESTIN® tablets?
AYGESTIN® tablets contain the following inactive ingredients: lactose, magnesium stearate, and
microcrystalline cellulose
DURAMED PHARMACEUTICALS, INC.
A subsidiary of Barr Laboratories, Inc.
Pomona, NY 10970
Revised July 2007/ BR-424
July 2007
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018405s023lbl.pdf', 'application_number': 18405, 'submission_type': 'SUPPL ', 'submission_number': 23}
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LOPID
(Gemfibrozil Tablets, USP)
DESCRIPTION
LOPID® (gemfibrozil tablets, USP) is a lipid regulating agent. It is available as tablets for oral
administration. Each tablet contains 600 mg gemfibrozil. Each also contains calcium stearate,
NF; candelilla wax, FCC; microcrystalline cellulose, NF; hydroxypropyl cellulose, NF;
hydroxypropylmethylcellulose, USP; methylparaben, NF; Opaspray white; polyethylene glycol,
NF; polysorbate 80, NF; propylparaben, NF; colloidal silicon dioxide, NF; pregelatinized starch,
NF. The chemical name is 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, with the
following structural formula:
The empirical formula is C15H22O3 and the molecular weight is 250.35; the solubility in water
and acid is 0.0019% and in dilute base it is greater than 1%. The melting point is 58° -61° C.
Gemfibrozil is a white solid which is stable under ordinary conditions.
CLINICAL PHARMACOLOGY
LOPID (gemfibrozil tablets, USP) is a lipid regulating agent which decreases serum triglycerides
and very low density lipoprotein (VLDL) cholesterol, and increases high density lipoprotein
(HDL) cholesterol. While modest decreases in total and low density lipoprotein (LDL)
cholesterol may be observed with LOPID therapy, treatment of patients with elevated
triglycerides due to Type IV hyperlipoproteinemia often results in a rise in LDL-cholesterol.
LDL-cholesterol levels in Type IIb patients with elevations of both serum LDL-cholesterol and
triglycerides are, in general, minimally affected by LOPID treatment; however, LOPID usually
raises HDL-cholesterol significantly in this group. LOPID increases levels of high density
lipoprotein (HDL) subfractions HDL2 and HDL3, as well as apolipoproteins AI and AII.
Epidemiological studies have shown that both low HDL-cholesterol and high LDL-cholesterol
are independent risk factors for coronary heart disease.
In the primary prevention component of the Helsinki Heart Study (refs. 1,2), in which 4081 male
patients between the ages of 40 and 55 were studied in a randomized, double-blind, placebo-
controlled fashion, LOPID therapy was associated with significant reductions in total plasma
triglycerides and a significant increase in high density lipoprotein cholesterol. Moderate
reductions in total plasma cholesterol and low density lipoprotein cholesterol were observed for
the LOPID treatment group as a whole, but the lipid response was heterogeneous, especially
among different Fredrickson types. The study involved subjects with serum non-HDL-
cholesterol of over 200 mg/dL and no previous history of coronary heart disease. Over the five-
year study period, the LOPID group experienced a 1.4% absolute (34% relative) reduction in the
rate of serious coronary events (sudden cardiac deaths plus fatal and nonfatal myocardial
infarctions) compared to placebo, p=0.04 (see Table I). There was a 37% relative reduction in the
rate of nonfatal myocardial infarction compared to placebo, equivalent to a treatment-related
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
difference of 13.1 events per thousand persons. Deaths from any cause during the double-blind
portion of the study totaled 44 (2.2%) in the LOPID randomization group and 43 (2.1%) in the
placebo group.
Among Fredrickson types, during the 5-year double-blind portion of the primary prevention
component of the Helsinki Heart Study, the greatest reduction in the incidence of serious
coronary events occurred in Type IIb patients who had elevations of both LDL-cholesterol and
total plasma triglycerides. This subgroup of Type IIb gemfibrozil group patients had a lower
mean HDL-cholesterol level at baseline than the Type IIa subgroup that had elevations of LDL-
cholesterol and normal plasma triglycerides. The mean increase in HDL-cholesterol among the
Type IIb patients in this study was 12.6% compared to placebo. The mean change in LDL-
cholesterol among Type IIb patients was –4.1% with LOPID compared to a rise of 3.9% in the
placebo subgroup. The Type IIb subjects in the Helsinki Heart Study had 26 fewer coronary
events per thousand persons over five years in the gemfibrozil group compared to placebo. The
difference in coronary events was substantially greater between LOPID and placebo for that
subgroup of patients with the triad of LDL-cholesterol >175 mg/dL (>4.5 mmol), triglycerides
>200 mg/dL (>2.2 mmol), and HDL-cholesterol <35 mg/dL (<0.90 mmol) (see Table I).
Further information is available from a 3.5 year (8.5 year cumulative) follow-up of all subjects
who had participated in the Helsinki Heart Study. At the completion of the Helsinki Heart
Study, subjects could choose to start, stop, or continue to receive LOPID; without knowledge of
their own lipid values or double-blind treatment, 60% of patients originally randomized to
placebo began therapy with LOPID and 60% of patients originally randomized to LOPID
continued medication. After approximately 6.5 years following randomization, all patients were
informed of their original treatment group and lipid values during the five years of the double-
blind treatment. After further elective changes in LOPID treatment status, 61% of patients in the
group originally randomized to LOPID were taking drug; in the group originally randomized to
placebo, 65% were taking LOPID. The event rate per 1000 occurring during the open-label
follow-up period is detailed in Table II.
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Cumulative mortality through 8.5 years showed a 20% relative excess of deaths in the group
originally randomized to LOPID versus the originally randomized placebo group and a 20%
relative decrease in cardiac events in the group originally randomized to LOPID versus the
originally randomized placebo group (see Table III). This analysis of the originally randomized
“intent-to-treat’’ population neglects the possible complicating effects of treatment switching
during the open-label phase. Adjustment of hazard ratios taking into account open-label
treatment status from years 6.5 to 8.5 could change the reported hazard ratios for mortality
toward unity.
It is not clear to what extent the findings of the primary prevention component of the Helsinki
Heart Study can be extrapolated to other segments of the dyslipidemic population not studied
(such as women, younger or older males, or those with lipid abnormalities limited solely to
HDL-cholesterol) or to other lipid-altering drugs.
The secondary prevention component of the Helsinki Heart Study was conducted over five years
in parallel and at the same centers in Finland in 628 middle-aged males excluded from the
primary prevention component of the Helsinki Heart Study because of a history of angina,
myocardial infarction or unexplained ECG changes (ref. 3). The primary efficacy endpoint of the
study was cardiac events (the sum of fatal and non-fatal myocardial infarctions and sudden
cardiac deaths). The hazard ratio (LOPID:placebo) for cardiac events was 1.47 (95% confidence
limits 0.88-2.48, p=0.14). Of the 35 patients in the LOPID group who experienced cardiac
events, 12 patients suffered events after discontinuation from the study. Of the 24 patients in the
placebo group with cardiac events, 4 patients suffered events after discontinuation from the
study. There were 17 cardiac deaths in the LOPID group and 8 in the placebo group (hazard ratio
2.18; 95% confidence limits 0.94-5.05, p=0.06). Ten of these deaths in the LOPID group and 3
in the placebo group occurred after discontinuation from therapy. In this study of patients with
known or suspected coronary heart disease, no benefit from LOPID treatment was observed in
reducing cardiac events or cardiac deaths. Thus, LOPID has shown benefit only in selected
dyslipidemic patients without suspected or established coronary heart disease. Even in patients
with coronary heart disease and the triad of elevated LDL-cholesterol, elevated triglycerides,
plus low HDL-cholesterol, the possible effect of LOPID on coronary events has not been
adequately studied.
No efficacy in the patients with established coronary heart disease was observed during the
Coronary Drug Project with the chemically and pharmacologically related drug, clofibrate. The
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Coronary Drug Project was a 6-year randomized, double-blind study involving 1000 clofibrate,
1000 nicotinic acid, and 3000 placebo patients with known coronary heart disease. A clinically
and statistically significant reduction in myocardial infarctions was seen in the concurrent
nicotinic acid group compared to placebo; no reduction was seen with clofibrate.
The mechanism of action of gemfibrozil has not been definitely established. In man, LOPID has
been shown to inhibit peripheral lipolysis and to decrease the hepatic extraction of free fatty
acids, thus reducing hepatic triglyceride production. LOPID inhibits synthesis and increases
clearance of VLDL carrier apolipoprotein B, leading to a decrease in VLDL production.
Animal studies suggest that gemfibrozil may, in addition to elevating HDL-cholesterol, reduce
incorporation of long-chain fatty acids into newly formed triglycerides, accelerate turnover and
removal of cholesterol from the liver, and increase excretion of cholesterol in the feces. LOPID
is well absorbed from the gastrointestinal tract after oral administration. Peak plasma levels
occur in 1 to 2 hours with a plasma half-life of 1.5 hours following multiple doses.
Gemfibrozil is completely absorbed after oral administration of LOPID tablets, reaching peak
plasma concentrations 1 to 2 hours after dosing. Gemfibrozil pharmacokinetics are affected by
the timing of meals relative to time of dosing. In one study (ref. 4), both the rate and extent of
absorption of the drug were significantly increased when administered 0.5 hour before meals.
Average AUC was reduced by 14-44% when LOPID was administered after meals compared to
0.5 hour before meals. In a subsequent study (ref. 4), rate of absorption of LOPID was
maximum when administered 0.5 hour before meals with the Cmax 50-60% greater than when
given either with meals or fasting. In this study, there were no significant effects on AUC of
timing of dose relative to meals (see DOSAGE AND ADMINISTRATION).
LOPID mainly undergoes oxidation of a ring methyl group to successively form a
hydroxymethyl and a carboxyl metabolite. Approximately seventy percent of the administered
human dose is excreted in the urine, mostly as the glucuronide conjugate, with less than 2%
excreted as unchanged gemfibrozil. Six percent of the dose is accounted for in the feces.
Gemfibrozil is highly bound to plasma proteins and there is potential for displacement
interactions with other drugs (see PRECAUTIONS).
INDICATIONS AND USAGE
LOPID (gemfibrozil tablets, USP) is indicated as adjunctive therapy to diet for:
1. Treatment of adult patients with very high elevations of serum triglyceride levels (Types IV
and V hyperlipidemia) who present a risk of pancreatitis and who do not respond adequately
to a determined dietary effort to control them. Patients who present such risk typically have
serum triglycerides over 2000 mg/dL and have elevations of VLDL-cholesterol as well as
fasting chylomicrons (Type V hyperlipidemia). Subjects who consistently have total serum or
plasma triglycerides below 1000 mg/dL are unlikely to present a risk of pancreatitis. LOPID
therapy may be considered for those subjects with triglyceride elevations between 1000 and
2000 mg/dL who have a history of pancreatitis or of recurrent abdominal pain typical of
pancreatitis. It is recognized that some Type IV patients with triglycerides under 1000 mg/dL
may, through dietary or alcoholic indiscretion, convert to a Type V pattern with massive
triglyceride elevations accompanying fasting chylomicronemia, but the influence of LOPID
therapy on the risk of pancreatitis in such situations has not been adequately studied. Drug
therapy is not indicated for patients with Type I hyperlipoproteinemia, who have elevations
of chylomicrons and plasma triglycerides, but who have normal levels of very low density
lipoprotein (VLDL). Inspection of plasma refrigerated for 14 hours is helpful in
distinguishing Types I, IV, and V hyperlipoproteinemia (ref. 5).
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2. Reducing the risk of developing coronary heart disease only in Type IIb patients without
history of or symptoms of existing coronary heart disease who have had an inadequate
response to weight loss, dietary therapy, exercise, and other pharmacologic agents (such as
bile acid sequestrants and nicotinic acid, known to reduce LDL- and raise HDL-cholesterol)
and who have the following triad of lipid abnormalities: low HDL-cholesterol levels in
addition to elevated LDL-cholesterol and elevated triglycerides (see WARNINGS,
PRECAUTIONS, and CLINICAL PHARMACOLOGY). The National Cholesterol
Education Program has defined a serum HDL-cholesterol value that is consistently below 35
mg/dL as constituting an independent risk factor for coronary heart disease (ref. 6). Patients
with significantly elevated triglycerides should be closely observed when treated with
gemfibrozil. In some patients with high triglyceride levels, treatment with gemfibrozil is
associated with a significant increase in LDL-cholesterol. BECAUSE OF POTENTIAL
TOXICITY SUCH AS MALIGNANCY, GALLBLADDER DISEASE, ABDOMINAL
PAIN LEADING TO APPENDECTOMY AND OTHER ABDOMINAL SURGERIES, AN
INCREASED INCIDENCE IN NON-CORONARY MORTALITY, AND THE 44%
RELATIVE INCREASE DURING THE TRIAL PERIOD IN AGE-ADJUSTED ALL-
CAUSE MORTALITY SEEN WITH THE CHEMICALLY AND
PHARMACOLOGICALLY RELATED DRUG, CLOFIBRATE, THE POTENTIAL
BENEFIT OF GEMFIBROZIL IN TREATING TYPE IIA PATIENTS WITH
ELEVATIONS OF LDL-CHOLESTEROL ONLY IS NOT LIKELY TO OUTWEIGH THE
RISKS. LOPID IS ALSO NOT INDICATED FOR THE TREATMENT OF PATIENTS
WITH LOW HDL-CHOLESTEROL AS THEIR ONLY LIPID ABNORMALITY.
In a subgroup analysis of patients in the Helsinki Heart Study with above-median HDL-
cholesterol values at baseline (greater than 46.4 mg/dL), the incidence of serious coronary events
was similar for gemfibrozil and placebo subgroups (see Table I).
The initial treatment for dyslipidemia is dietary therapy specific for the type of lipoprotein
abnormality. Excess body weight and excess alcohol intake may be important factors in
hypertriglyceridemia and should be managed prior to any drug therapy. Physical exercise can be
an important ancillary measure, and has been associated with rises in HDL-cholesterol. Diseases
contributory to hyperlipidemia such as hypothyroidism or diabetes mellitus should be looked for
and adequately treated. Estrogen therapy is sometimes associated with massive rises in plasma
triglycerides, especially in subjects with familial hypertriglyceridemia. In such cases,
discontinuation of estrogen therapy may obviate the need for specific drug therapy of
hypertriglyceridemia. The use of drugs should be considered only when reasonable attempts
have been made to obtain satisfactory results with nondrug methods. If the decision is made to
use drugs, the patient should be instructed that this does not reduce the importance of adhering to
diet.
CONTRAINDICATIONS
1. Combination therapy of LOPID with cerivastatin due to the increased risk of myopathy
and rhabdomyolysis (see WARNINGS).
2. Hepatic or severe renal dysfunction, including primary biliary cirrhosis.
3. Preexisting gallbladder disease (see WARNINGS).
4. Hypersensitivity to gemfibrozil.
WARNINGS
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1. Because of chemical, pharmacological, and clinical similarities between gemfibrozil and
clofibrate, the adverse findings with clofibrate in two large clinical studies may also apply to
gemfibrozil. In the first of those studies, the Coronary Drug Project, 1000 subjects with previous
myocardial infarction were treated for five years with clofibrate. There was no difference in
mortality between the clofibrate-treated subjects and 3000 placebo-treated subjects, but twice as
many clofibrate-treated subjects developed cholelithiasis and cholecystitis requiring surgery. In
the other study, conducted by the World Health Organization (WHO), 5000 subjects without
known coronary heart disease were treated with clofibrate for five years and followed one year
beyond. There was a statistically significant, 44%, higher age-adjusted total mortality in the
clofibrate-treated than in a comparable placebo-treated control group during the trial period. The
excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy,
post-cholecystectomy complications, and pancreatitis. The higher risk of clofibrate-treated
subjects for gallbladder disease was confirmed.
Because of the more limited size of the Helsinki Heart Study, the observed difference in
mortality from any cause between the LOPID and placebo group is not statistically significantly
different from the 29% excess mortality reported in the clofibrate group in the separate WHO
study at the nine year follow-up (see CLINICAL PHARMACOLOGY). Noncoronary heart
disease related mortality showed an excess in the group originally randomized to LOPID
primarily due to cancer deaths observed during the open-label extension.
During the five year primary prevention component of the Helsinki Heart Study, mortality from
any cause was 44 (2.2%) in the LOPID group and 43 (2.1%) in the placebo group; including the
3.5 year follow-up period since the trial was completed, cumulative mortality from any cause
was 101 (4.9%) in the LOPID group and 83 (4.1%) in the group originally randomized to
placebo (hazard ratio 1:20 in favor of placebo). Because of the more limited size of the Helsinki
Heart Study, the observed difference in mortality from any cause between the LOPID and
placebo groups at Year-5 or at Year-8.5 is not statistically significantly different from the 29%
excess mortality reported in the clofibrate group in the separate WHO study at the nine year
follow-up. Noncoronary heart disease related mortality showed an excess in the group originally
randomized to LOPID at the 8.5 year follow-up (65 LOPID versus 45 placebo noncoronary
deaths).
The incidence of cancer (excluding basal cell carcinoma) discovered during the trial and in the
3.5 years after the trial was completed was 51 (2.5%) in both originally randomized groups. In
addition, there were 16 basal cell carcinomas in the group originally randomized to LOPID and 9
in the group randomized to placebo (p=0.22). There were 30 (1.5%) deaths attributed to cancer in
the group originally randomized to LOPID and 18 (0.9%) in the group originally randomized to
placebo (p=0.11). Adverse outcomes, including coronary events, were higher in gemfibrozil
patients in a corresponding study in men with a history of known or suspected coronary heart
disease in the secondary prevention component of the Helsinki Heart Study. (See CLINICAL
PHARMACOLOGY.)
A comparative carcinogenicity study was also done in rats comparing three drugs in this class:
fenofibrate (10 and 60 mg/kg; 0.3 and 1.6 times the human dose), clofibrate
(400 mg/kg; 1.6 times the human dose), and gemfibrozil (250 mg/kg; 1.7 times the human dose).
Pancreatic acinar adenomas were increased in males and females on fenofibrate; hepatocellular
carcinoma and pancreatic acinar adenomas were increased in males and hepatic neoplastic
nodules in females treated with clofibrate; hepatic neoplastic nodules were increased in males
and females treated with clofibrate; hepatic neoplastic nodules were increased in males and
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females treated with gemfibrozil while testicular interstitial cell (Leydig cell) tumors were
increased in males on all three drugs.
2. A gallstone prevalence substudy of 450 Helsinki Heart Study participants showed a trend
toward a greater prevalence of gallstones during the study within the LOPID treatment group
(7.5% vs 4.9% for the placebo group, a 55% excess for the gemfibrozil group). A trend toward a
greater incidence of gallbladder surgery was observed for the LOPID group (17 vs 11 subjects, a
54% excess). This result did not differ statistically from the increased incidence of
cholecystectomy observed in the WHO study in the group treated with clofibrate. Both clofibrate
and gemfibrozil may increase cholesterol excretion into the bile leading to cholelithiasis. If
cholelithiasis is suspected, gallbladder studies are indicated. LOPID therapy should be
discontinued if gallstones are found.
3. Since a reduction of mortality from coronary heart disease has not been demonstrated and
because liver and interstitial cell testicular tumors were increased in rats, LOPID should be
administered only to those patients described in the INDICATIONS AND USAGE section. If a
significant serum lipid response is not obtained, LOPID should be discontinued.
4. Concomitant Anticoagulants–Caution should be exercised when anticoagulants are given in
conjunction with LOPID. The dosage of the anticoagulant should be reduced to maintain the
prothrombin time at the desired level to prevent bleeding complications. Frequent prothrombin
determinations are advisable until it has been definitely determined that the prothrombin level
has stabilized.
5. Concomitant therapy with LOPID and an HMG-CoA reductase inhibitor is associated with an
increased risk of skeletal muscle toxicity manifested as rhabdomyolysis, markedly elevated
creatine kinase (CPK)levels and myoglobinuria, leading in a high proportion of cases to acute
renal failure and death. Because of an observed marked increased risk of myopathy and
rhabdomyolysis, the specific combination of LOPID and cerivastatin is absolutely
contraindicated (see CONTRAINDICATIONS). IN PATIENTS WHO HAVE HAD AN
UNSATISFACTORY LIPID RESPONSE TO EITHER DRUG ALONE, THE BENEFIT OF
COMBINED THERAPY WITH LOPID AND HMG-CoA REDUCTASE INHIBITORS
OTHER THAN CERIVASTATIN DOES NOT OUTWEIGH THE RISKS OF SEVERE
MYOPATHY, RHABDOMYOLYSIS, AND ACUTE RENAL FAILURE (refs. 7, 8, 9, 10) (see
Drug Interactions). The use of fibrates alone, including LOPID may occasionally be associated
with myositis. Patients receiving LOPID and complaining of muscle pain, tenderness, or
weakness should have prompt medical evaluation for myositis, including serum creatine-kinease
level determination. If myositis is suspected or diagnosed, LOPID therapy should be withdrawn.
6. Cataracts–Subcapsular bilateral cataracts occurred in 10% and unilateral in 6.3% of male rats
treated with gemfibrozil at 10 times the human dose.
PRECAUTIONS
1. Initial Therapy–Laboratory studies should be done to ascertain that the lipid levels are
consistently abnormal. Before instituting LOPID therapy, every attempt should be made to
control serum lipids with appropriate diet, exercise, weight loss in obese patients, and control of
any medical problems such as diabetes mellitus and hypothyroidism that are contributing to the
lipid abnormalities.
2. Continued Therapy–Periodic determination of serum lipids should be obtained, and the drug
withdrawn if lipid response is inadequate after three months of therapy.
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3. Drug Interactions–(A) HMG-CoA reductase inhibitors: The risk of myopathy and
rhabdomyolysis is increased with combined gemfibrozil and HMG-CoA reductase inhibitor
therapy (see CONTRAINDICATIONS). Myopathy or rhabdomyolysis with or without acute
renal failure have been reported as early as three weeks after initiation of combined therapy or
after several months (refs. 7, 8, 9, 10). (See WARNINGS.) There is no assurance that periodic
monitoring of creatine kinase will prevent the occurrence of severe myopathy and kidney
damage.
(B) Anticoagulants: CAUTION SHOULD BE EXERCISED WHEN ANTI-COAGULANTS
ARE GIVEN IN CONJUNCTION WITH LOPID. THE DOSAGE OF THE
ANTICOAGULANT SHOULD BE REDUCED TO MAINTAIN THE PROTHROMBIN TIME
AT THE DESIRED LEVEL TO PREVENT BLEEDING COMPLICATIONS. FREQUENT
PROTHROMBIN DETERMINATIONS ARE ADVISABLE UNTIL IT HAS BEEN
DEFINITELY DETERMINED THAT THE PROTHROMBIN LEVEL HAS STABILIZED.
4. Carcinogenesis, Mutagenesis, Impairment of Fertility–Long-term studies have been
conducted in rats at 0.2 and 1.3 times the human exposure (based on AUC). The incidence of
benign liver nodules and liver carcinomas was significantly increased in high dose male rats. The
incidence of liver carcinomas increased also in low dose males, but this increase was not
statistically significant (p=0.1). Male rats had a dose-related and statistically significant increase
of benign Leydig cell tumors. The higher dose female rats had a significant increase in the
combined incidence of benign and malignant liver neoplasms.
Long-term studies have been conducted in mice at 0.1 and 0.7 times the human exposure (based
on AUC). There were no statistically significant differences from controls in the incidence of
liver tumors, but the doses tested were lower than those shown to be carcinogenic with other
fibrates.
Electron microscopy studies have demonstrated a florid hepatic peroxisome proliferation
following LOPID administration to the male rat. An adequate study to test for peroxisome
proliferation has not been done in humans but changes in peroxisome morphology have been
observed. Peroxisome proliferation has been shown to occur in humans with either of two other
drugs of the fibrate class when liver biopsies were compared before and after treatment in the
same individual.
Administration of approximately 2 times the human dose (based on surface area) to male rats for
10 weeks resulted in a dose-related decrease of fertility. Subsequent studies demonstrated that
this effect was reversed after a drug-free period of about eight weeks, and it was not transmitted
to the offspring.
5. Pregnancy Category C–LOPID has been shown to produce adverse effects in rats and rabbits
at doses between 0.5 and 3 times the human dose (based on surface area). There are no adequate
and well-controlled studies in pregnant women. LOPID should be used during pregnancy only if
the potential benefit justifies the potential risk to the fetus.
Administration of LOPID to female rats 2 times the human dose (based on surface area) before
and throughout gestation caused a dose-related decrease in conception rate and an increase in
stillborns and a slight reduction in pup weight during lactation. There were also dose-related
increased skeletal variations. Anophthalmia occurred, but rarely.
Administration of 0.6 and 2 times the human dose (based on surface area) of LOPID to female
rats from gestation day 15 through weaning caused dose-related decreases in birth weight and
suppressions of pup growth during lactation.
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Administration of 1 and 3 times the human dose (based on surface area) of LOPID to female
rabbits during organogenesis caused a dose-related decrease in litter size and, at the high dose, an
increased incidence of parietal bone variations.
6. Nursing Mothers–It is not known whether this drug is excreted in human milk. Because
many drugs are excreted in human milk and because of the potential for tumorigenicity shown
for LOPID in animal studies, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
7. Hematologic Changes–Mild hemoglobin, hematocrit and white blood cell decreases have
been observed in occasional patients following initiation of LOPID therapy. However, these
levels stabilize during long-term administration. Rarely, severe anemia, leukopenia,
thrombocytopenia, and bone marrow hypoplasia have been reported. Therefore, periodic blood
counts are recommended during the first 12 months of LOPID administration.
8. Liver Function–Abnormal liver function tests have been observed occasionally during
LOPID administration, including elevations of AST (SGOT), ALT (SGPT), LDH, bilirubin, and
alkaline phosphatase. These are usually reversible when LOPID is discontinued. Therefore,
periodic liver function studies are recommended and LOPID therapy should be terminated if
abnormalities persist.
9. Kidney Function–There have been reports of worsening renal insufficiency upon the addition
of LOPID therapy in individuals with baseline plasma creatinine >2.0 mg/dL. In such patients,
the use of alternative therapy should be considered against the risks and benefits of a lower dose
of LOPID.
10. Pediatric Use–Safety and efficacy in pediatric patients have not been established.
ADVERSE REACTIONS
In the double-blind controlled phase of the primary prevention component of the Helsinki Heart
Study, 2046 patients received LOPID for up to five years. In that study, the following adverse
reactions were statistically more frequent in subjects in the LOPID group:
Gallbladder surgery was performed in 0.9% of LOPID and 0.5% of placebo subjects in the
primary prevention component, a 64% excess, which is not statistically different from the excess
of gallbladder surgery observed in the clofibrate compared to the placebo group of the WHO
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study. Gallbladder surgery was also performed more frequently in the LOPID group compared to
placebo (1.9% vs 0.3%, p=0.07) in the secondary prevention component. A statistically
significant increase in appendectomy in the gemfibrozil group was seen also in the secondary
prevention component (6 on gemfibrozil vs 0 on placebo, p=0.014).
Nervous system and special senses adverse reactions were more common in the LOPID group.
These included hypesthesia, paresthesias, and taste perversion. Other adverse reactions that were
more common among LOPID treatment group subjects but where a causal relationship was not
established include cataracts, peripheral vascular disease, and intracerebral hemorrhage.
From other studies it seems probable that LOPID is causally related to the occurrence of
MUSCULOSKELETAL SYMPTOMS (see WARNINGS), and to ABNORMAL LIVER
FUNCTION TESTS and HEMATOLOGIC CHANGES (see PRECAUTIONS).
Reports of viral and bacterial infections (common cold, cough, urinary tract infections) were
more common in gemfibrozil treated patients in other controlled clinical trials of 805 patients.
Additional adverse reactions that have been reported for gemfibrozil are listed below by system.
These are categorized according to whether a causal relationship to treatment with LOPID is
probable or not established:
DOSAGE AND ADMINISTRATION
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The recommended dose for adults is 1200 mg administered in two divided doses 30 minutes
before the morning and evening meal (see CLINICAL PHARMACOLOGY).
OVERDOSAGE
There have been reported cases of overdosage with LOPID. In one case, a 7-year-old child
recovered after ingesting up to 9 grams of LOPID. Symptoms reported with overdosage were
abdominal cramps, abnormal liver function tests, diarrhea, increased CPK, joint and muscle pain,
nausea and vomiting. Symptomatic supportive measures should be taken, should an overdose
occur.
HOW SUPPLIED
LOPID (Tablet 737), white, elliptical, film-coated, scored tablets, each containing 600 mg
gemfibrozil, are available as follows:
N 0071-0737-20: Bottles of 60
N 0071-0737-30: Bottles of 500
Parcode® No. 737
Store at controlled room temperature 20° - 25°C (68° - 77°F) [see USP]. Protect from light and
humidity.
REFERENCES
1. Frick MH, Elo O, Haapa K, et al: Helsinki Heart Study: Primary prevention trial with
gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med 1987; 317:1237-1245.
2. Manninen V, Elo O, Frick MH, et al: Lipid alterations and decline in the incidence of coronary
heart disease in the Helsinki Heart Study. JAMA 1988; 260:641-651.
3. Frick MH, Heinonen OP, et al: Efficacy of gemfibrozil in dyslipidemic subjects with
suspected heart disease. An ancillary study in the Helsinki Heart Study frame population. Annals
of Medicine 1993; 25:41-45.
4. Data on file. Parke-Davis; Morris Plains, NJ.
5. Nikkila EA: Familial lipoprotein lipase deficiency and related disorders of chylomicron
metabolism. In Stanbury JB et al. (eds.): The Metabolic Basis of Inherited Disease, 5th ed.,
McGraw-Hill, 1983, Chap. 30, pp. 622-642.
6. Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation,
and Treatment of High Blood Cholesterol. Arch Int Med 1988;148:36-69.
7. Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdomyolysis associated with
lovastatin/gemfibrozil combination therapy. JAMA 1990;264:71-75.
8. Bermingham RP, Whitsitt TB, Smart ML et al. Rhabdomyolysis in a patient receiving the
combination of cerivastatin and gemfibrozil. Am J Health-Syst Pharm 2000;57:461-464.
9. Duell PB, Connor WE, Illingworth DR. Rhabdomyolysis after taking atorvastatin with
gemfibrozil. Am J Cardiol 1998;81:368-369.
10. Tal A, Rajeshawari M, Isley W. Rhabdomyolysis associated with simvastatin/gemfibrozil
therapy. South Med J 1997;90:546-547.
Rx only
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Revised July 2001
Manufactured by:
Parke Davis Pharmaceuticals, Ltd.
Vega Baja, PR 00694
Distributed by:
PARKE-DAVIS
Div of Warner-Lambert Co
Morris Plains, NJ 07950 USA
©1997-'01, PDPL
0737G303.2
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
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/s/
---------------------
Mary Parks
8/7/01 02:00:54 PM
acting for Dr. Orloff
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/18422s40s41lbl.pdf', 'application_number': 18422, 'submission_type': 'SUPPL ', 'submission_number': 41}
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LOPID®
(Gemfibrozil Tablets, USP)
DESCRIPTION
LOPID® (gemfibrozil tablets, USP) is a lipid regulating agent. It is available as tablets
for oral administration. Each tablet contains 600 mg gemfibrozil. Each also contains
calcium stearate, NF; candelilla wax, FCC; microcrystalline cellulose, NF;
hydroxypropyl cellulose, NF; hypromellose, USP; methylparaben, NF; Opaspray white;
polyethylene glycol, NF; polysorbate 80, NF; propylparaben, NF; colloidal silicon
dioxide, NF; pregelatinized starch, NF. The chemical name is 5-(2,5-dimethylphenoxy)
2,2-dimethylpentanoic acid, with the following structural formula: structural formula
The empirical formula is C15H22O3 and the molecular weight is 250.35; the solubility in
water and acid is 0.0019% and in dilute base it is greater than 1%. The melting point is
58° –61° C. Gemfibrozil is a white solid which is stable under ordinary conditions.
CLINICAL PHARMACOLOGY
LOPID (gemfibrozil tablets, USP) is a lipid regulating agent which decreases serum
triglycerides and very low density lipoprotein (VLDL) cholesterol, and increases high
density lipoprotein (HDL) cholesterol. While modest decreases in total and low density
lipoprotein (LDL) cholesterol may be observed with LOPID therapy, treatment of
patients with elevated triglycerides due to Type IV hyperlipoproteinemia often results in
a rise in LDL-cholesterol. LDL-cholesterol levels in Type IIb patients with elevations of
both serum LDL-cholesterol and triglycerides are, in general, minimally affected by
LOPID treatment; however, LOPID usually raises HDL-cholesterol significantly in this
group. LOPID increases levels of high density lipoprotein (HDL) subfractions HDL2 and
HDL3, as well as apolipoproteins AI and AII. Epidemiological studies have shown that
both low HDL-cholesterol and high LDL-cholesterol are independent risk factors for
coronary heart disease.
In the primary prevention component of the Helsinki Heart Study, in which 4081 male
patients between the ages of 40 and 55 were studied in a randomized, double-blind,
placebo-controlled fashion, LOPID therapy was associated with significant reductions in
total plasma triglycerides and a significant increase in high density lipoprotein
cholesterol. Moderate reductions in total plasma cholesterol and low density lipoprotein
cholesterol were observed for the LOPID treatment group as a whole, but the lipid
response was heterogeneous, especially among different Fredrickson types. The study
involved subjects with serum non-HDL-cholesterol of over 200 mg/dL and no previous
history of coronary heart disease. Over the five-year study period, the LOPID group
experienced a 1.4% absolute (34% relative) reduction in the rate of serious coronary
events (sudden cardiac deaths plus fatal and nonfatal myocardial infarctions) compared to
placebo, p=0.04 (see Table I). There was a 37% relative reduction in the rate of nonfatal
myocardial infarction compared to placebo, equivalent to a treatment-related difference
of 13.1 events per thousand persons. Deaths from any cause during the double-blind
portion of the study totaled 44 (2.2%) in the LOPID randomization group and 43 (2.1%)
in the placebo group.
Table I
Reduction in CHD Rates (events per 1000 patients) by Baseline Lipids1 in the
Helsinki Heart Study, Years 0–52
All
LDL-C>175;
LDL-C>175;
LDL-C>175;
Patients
HDL-C>46.4
TG>177
TG>200;
HDL-C<35
P
L
Dif
3
P
L
Dif
P
L
Dif
P
L
Dif
Incidence of
Events
4
41
27
14
32
29
3
71
44
27
149
64
85
1lipid values in mg/dL at baseline Reduction in CHD Rates (events per 1000 patients) by Baseline Lipids1 in the
Helsinki Heart Study, Years 0–52
2P = placebo group; L= LOPID group
3difference in rates between placebo and LOPID groups
4fatal and nonfatal myocardial infarctions plus sudden cardiac deaths (events per 1000 patients over 5
years)
Among Fredrickson types, during the 5-year double-blind portion of the primary
prevention component of the Helsinki Heart Study, the greatest reduction in the incidence
of serious coronary events occurred in Type IIb patients who had elevations of both LDL-
cholesterol and total plasma triglycerides. This subgroup of Type IIb gemfibrozil group
patients had a lower mean HDL-cholesterol level at baseline than the Type IIa subgroup
that had elevations of LDL-cholesterol and normal plasma triglycerides. The mean
increase in HDL-cholesterol among the Type IIb patients in this study was 12.6%
compared to placebo. The mean change in LDL-cholesterol among Type IIb patients was
–4.1% with LOPID compared to a rise of 3.9% in the placebo subgroup. The Type IIb
subjects in the Helsinki Heart Study had 26 fewer coronary events per thousand persons
over five years in the gemfibrozil group compared to placebo. The difference in coronary
events was substantially greater between LOPID and placebo for that subgroup of
patients with the triad of LDL-cholesterol >175 mg/dL (>4.5 mmol), triglycerides >200
mg/dL (>2.2 mmol), and HDL-cholesterol <35 mg/dL (<0.90 mmol) (see Table I).
Further information is available from a 3.5 year (8.5 year cumulative) follow-up of all
subjects who had participated in the Helsinki Heart Study. At the completion of the
Helsinki Heart Study, subjects could choose to start, stop, or continue to receive LOPID;
without knowledge of their own lipid values or double-blind treatment, 60% of patients
originally randomized to placebo began therapy with LOPID and 60% of patients
originally randomized to LOPID continued medication. After approximately 6.5 years
following randomization, all patients were informed of their original treatment group and
lipid values during the five years of the double-blind treatment. After further elective
changes in LOPID treatment status, 61% of patients in the group originally randomized to
LOPID were taking drug; in the group originally randomized to placebo, 65% were
taking LOPID. The event rate per 1000 occurring during the open-label follow-up period
is detailed in Table II.
Table II
Cardiac Events and All-Cause Mortality (events per 1000 patients) Occurring During the
3.5 Year Open-Label Follow-up to the Helsinki HeartStudy
1
Group:
PDrop
PN
PL
LDrop
LN
LL
N=215
N=494
N=1283
N=221
N=574
N=1207
Cardiac
Events
38.8
22.9
22.5
37.2
28.3
25.4
All-Cause
Mortality
41.9
22.3
15.6
72.3
19.2
24.9
1The six open-label groups are designated first by the original randomization
(P = placebo, L = LOPID) and then by the drug taken in the follow-up period (N = Attend
clinic but took no drug, L = LOPID, Drop = No attendance at clinic during open-label).
Cumulative mortality through 8.5 years showed a 20% relative excess of deaths in the
group originally randomized to LOPID versus the originally randomized placebo group
and a 20% relative decrease in cardiac events in the group originally randomized to
LOPID versus the originally randomized placebo group (see Table III). This analysis of
the originally randomized “intent-to-treat’’ population neglects the possible complicating
effects of treatment switching during the open-label phase. Adjustment of hazard ratios
taking into account open-label treatment status from years 6.5 to 8.5 could change the
reported hazard ratios for mortality toward unity.
Table III
Cardiac Events, Cardiac Deaths, Non-Cardiac Deaths and All-Cause Mortality in the
Helsinki Heart Study, Years 0–8.5
1
Event
LOPID
Placebo
LOPID:Placebo
at Study
at Study
Hazard
Cl Hazard
Start
Start
Ratio
2
Ratio
3
Cardiac
Events
4
110
131
0.80
0.62–1.03
Cardiac
Deaths
36
38
0.98
0.63–1.54
Non-Cardiac
Deaths
65
45
1.40
0.95–2.05
All-Cause
Mortality
101
83
1.20
0.90–1.61
1Intention-to-Treat Analysis of originally randomized patients neglecting the open-label
treatment switches and exposure to study conditions.
2Hazard ration for risk event in the group originally randomized to LOPID compared to
the group originally randomized to placebo neglecting open-label treatment switch and
exposure to study condition.
395% confidence intervals of LOPID:placebo group hazard ratio
4Fatal and non-fatal myocardial infarctions plus sudden cardiac deaths over the 8.5 year
period.
It is not clear to what extent the findings of the primary prevention component of the
Helsinki Heart Study can be extrapolated to other segments of the dyslipidemic
population not studied (such as women, younger or older males, or those with lipid
abnormalities limited solely to HDL-cholesterol) or to other lipid-altering drugs.
The secondary prevention component of the Helsinki Heart Study was conducted over
five years in parallel and at the same centers in Finland in 628 middle-aged males
excluded from the primary prevention component of the Helsinki Heart Study because of
a history of angina, myocardial infarction or unexplained ECG changes. The primary
efficacy endpoint of the study was cardiac events (the sum of fatal and non-fatal
myocardial infarctions and sudden cardiac deaths). The hazard ratio (LOPID:placebo) for
cardiac events was 1.47 (95% confidence limits 0.88–2.48, p=0.14). Of the 35 patients in
the LOPID group who experienced cardiac events, 12 patients suffered events after
discontinuation from the study. Of the 24 patients in the placebo group with cardiac
events, 4 patients suffered events after discontinuation from the study. There were 17
cardiac deaths in the LOPID group and 8 in the placebo group (hazard ratio 2.18; 95%
confidence limits 0.94–5.05, p=0.06). Ten of these deaths in the LOPID group and 3 in
the placebo group occurred after discontinuation from therapy. In this study of patients
with known or suspected coronary heart disease, no benefit from LOPID treatment was
observed in reducing cardiac events or cardiac deaths. Thus, LOPID has shown benefit
only in selected dyslipidemic patients without suspected or established coronary heart
disease. Even in patients with coronary heart disease and the triad of elevated LDL-
cholesterol, elevated triglycerides, plus low HDL-cholesterol, the possible effect of
LOPID on coronary events has not been adequately studied.
No efficacy in the patients with established coronary heart disease was observed during
the Coronary Drug Project with the chemically and pharmacologically related drug,
clofibrate. The Coronary Drug Project was a 6-year randomized, double-blind study
involving 1000 clofibrate, 1000 nicotinic acid, and 3000 placebo patients with known
coronary heart disease. A clinically and statistically significant reduction in myocardial
infarctions was seen in the concurrent nicotinic acid group compared to placebo; no
reduction was seen with clofibrate.
The mechanism of action of gemfibrozil has not been definitely established. In man,
LOPID has been shown to inhibit peripheral lipolysis and to decrease the hepatic
extraction of free fatty acids, thus reducing hepatic triglyceride production. LOPID
inhibits synthesis and increases clearance of VLDL carrier apolipoprotein B, leading to a
decrease in VLDL production.
Animal studies suggest that gemfibrozil may, in addition to elevating HDL-cholesterol,
reduce incorporation of long-chain fatty acids into newly formed triglycerides, accelerate
turnover and removal of cholesterol from the liver, and increase excretion of cholesterol
in the feces. LOPID is well absorbed from the gastrointestinal tract after oral
administration. Peak plasma levels occur in 1 to 2 hours with a plasma half-life of 1.5
hours following multiple doses.
Gemfibrozil is completely absorbed after oral administration of LOPID tablets, reaching
peak plasma concentrations 1 to 2 hours after dosing. Gemfibrozil pharmacokinetics are
affected by the timing of meals relative to time of dosing. In one study (ref. 4), both the
rate and extent of absorption of the drug were significantly increased when administered
0.5 hour before meals. Average AUC was reduced by 14–44% when LOPID was
administered after meals compared to 0.5 hour before meals. In a subsequent study, rate
of absorption of LOPID was maximum when administered 0.5 hour before meals with the
Cmax 50–60% greater than when given either with meals or fasting. In this study, there
were no significant effects on AUC of timing of dose relative to meals (see DOSAGE
AND ADMINISTRATION).
LOPID mainly undergoes oxidation of a ring methyl group to successively form a
hydroxymethyl and a carboxyl metabolite. Approximately seventy percent of the
administered human dose is excreted in the urine, mostly as the glucuronide conjugate,
with less than 2% excreted as unchanged gemfibrozil. Six percent of the dose is
accounted for in the feces. Gemfibrozil is highly bound to plasma proteins and there is
potential for displacement interactions with other drugs (see PRECAUTIONS).
INDICATIONS AND USAGE
LOPID (gemfibrozil tablets, USP) is indicated as adjunctive therapy to diet for:
1. Treatment of adult patients with very high elevations of serum triglyceride levels
(Types IV and V hyperlipidemia) who present a risk of pancreatitis and who do not
respond adequately to a determined dietary effort to control them. Patients who
present such risk typically have serum triglycerides over 2000 mg/dL and have
elevations of VLDL-cholesterol as well as fasting chylomicrons (Type V
hyperlipidemia). Subjects who consistently have total serum or plasma triglycerides
below 1000 mg/dL are unlikely to present a risk of pancreatitis. LOPID therapy may
be considered for those subjects with triglyceride elevations between 1000 and 2000
mg/dL who have a history of pancreatitis or of recurrent abdominal pain typical of
pancreatitis. It is recognized that some Type IV patients with triglycerides under 1000
mg/dL may, through dietary or alcoholic indiscretion, convert to a Type V pattern
with massive triglyceride elevations accompanying fasting chylomicronemia, but the
influence of LOPID therapy on the risk of pancreatitis in such situations has not been
adequately studied. Drug therapy is not indicated for patients with Type I
hyperlipoproteinemia, who have elevations of chylomicrons and plasma triglycerides,
but who have normal levels of very low density lipoprotein (VLDL). Inspection of
plasma refrigerated for 14 hours is helpful in distinguishing Types I, IV, and V
hyperlipoproteinemia.
2. Reducing the risk of developing coronary heart disease only in Type IIb patients
without history of or symptoms of existing coronary heart disease who have had an
inadequate response to weight loss, dietary therapy, exercise, and other
pharmacologic agents (such as bile acid sequestrants and nicotinic acid, known to
reduce LDL- and raise HDL-cholesterol) and who have the following triad of lipid
abnormalities: low HDL-cholesterol levels in addition to elevated LDL-cholesterol
and elevated triglycerides (see WARNINGS, PRECAUTIONS, and CLINICAL
PHARMACOLOGY). The National Cholesterol Education Program has defined a
serum HDL-cholesterol value that is consistently below 35 mg/dL as constituting an
independent risk factor for coronary heart disease. Patients with significantly elevated
triglycerides should be closely observed when treated with gemfibrozil. In some
patients with high triglyceride levels, treatment with gemfibrozil is associated with a
significant increase in LDL-cholesterol. BECAUSE OF POTENTIAL TOXICITY
SUCH AS MALIGNANCY, GALLBLADDER DISEASE, ABDOMINAL PAIN
LEADING TO APPENDECTOMY AND OTHER ABDOMINAL SURGERIES, AN
INCREASED INCIDENCE IN NON-CORONARY MORTALITY, AND THE 44%
RELATIVE INCREASE DURING THE TRIAL PERIOD IN AGE-ADJUSTED
ALL-CAUSE MORTALITY SEEN WITH THE CHEMICALLY AND
PHARMACOLOGICALLY RELATED DRUG, CLOFIBRATE, THE POTENTIAL
BENEFIT OF GEMFIBROZIL IN TREATING TYPE IIA PATIENTS WITH
ELEVATIONS OF LDL-CHOLESTEROL ONLY IS NOT LIKELY TO
OUTWEIGH THE RISKS. LOPID IS ALSO NOT INDICATED FOR THE
TREATMENT OF PATIENTS WITH LOW HDL-CHOLESTEROL AS THEIR
ONLY LIPID ABNORMALITY.
In a subgroup analysis of patients in the Helsinki Heart Study with above-median HDL-
cholesterol values at baseline (greater than 46.4 mg/dL), the incidence of serious
coronary events was similar for gemfibrozil and placebo subgroups (see Table I).
The initial treatment for dyslipidemia is dietary therapy specific for the type of
lipoprotein abnormality. Excess body weight and excess alcohol intake may be important
factors in hypertriglyceridemia and should be managed prior to any drug therapy.
Physical exercise can be an important ancillary measure, and has been associated with
rises in HDL-cholesterol. Diseases contributory to hyperlipidemia such as
hypothyroidism or diabetes mellitus should be looked for and adequately treated.
Estrogen therapy is sometimes associated with massive rises in plasma triglycerides,
especially in subjects with familial hypertriglyceridemia. In such cases, discontinuation
of estrogen therapy may obviate the need for specific drug therapy of
hypertriglyceridemia. The use of drugs should be considered only when reasonable
attempts have been made to obtain satisfactory results with nondrug methods. If the
decision is made to use drugs, the patient should be instructed that this does not reduce
the importance of adhering to diet.
CONTRAINDICATIONS
1. Hepatic or severe renal dysfunction, including primary biliary cirrhosis.
2. Preexisting gallbladder disease (see WARNINGS).
3. Hypersensitivity to gemfibrozil.
4. Combination therapy of gemfibrozil with repaglinide (see PRECAUTIONS).
WARNINGS
1. Because of chemical, pharmacological, and clinical similarities between gemfibrozil
and clofibrate, the adverse findings with clofibrate in two large clinical studies may also
apply to gemfibrozil. In the first of those studies, the Coronary Drug Project, 1000
subjects with previous myocardial infarction were treated for five years with clofibrate.
There was no difference in mortality between the clofibrate-treated subjects and 3000
placebo-treated subjects, but twice as many clofibrate-treated subjects developed
cholelithiasis and cholecystitis requiring surgery. In the other study, conducted by the
World Health Organization (WHO), 5000 subjects without known coronary heart disease
were treated with clofibrate for five years and followed one year beyond. There was a
statistically significant, 44%, higher age-adjusted total mortality in the clofibrate-treated
than in a comparable placebo-treated control group during the trial period. The excess
mortality was due to a 33% increase in non-cardiovascular causes, including malignancy,
post-cholecystectomy complications, and pancreatitis. The higher risk of clofibrate-
treated subjects for gallbladder disease was confirmed.
Because of the more limited size of the Helsinki Heart Study, the observed difference in
mortality from any cause between the LOPID and placebo group is not statistically
significantly different from the 29% excess mortality reported in the clofibrate group in
the separate WHO study at the nine year follow-up (see CLINICAL
PHARMACOLOGY). Noncoronary heart disease related mortality showed an excess in
the group originally randomized to LOPID primarily due to cancer deaths observed
during the open-label extension.
During the five year primary prevention component of the Helsinki Heart Study,
mortality from any cause was 44 (2.2%) in the LOPID group and 43 (2.1%) in the
placebo group; including the 3.5 year follow-up period since the trial was completed,
cumulative mortality from any cause was 101 (4.9%) in the LOPID group and 83 (4.1%)
in the group originally randomized to placebo (hazard ratio 1:20 in favor of placebo).
Because of the more limited size of the Helsinki Heart Study, the observed difference in
mortality from any cause between the LOPID and placebo groups at Year-5 or at Year
8.5 is not statistically significantly different from the 29% excess mortality reported in
the clofibrate group in the separate WHO study at the nine year follow-up. Noncoronary
heart disease related mortality showed an excess in the group originally randomized to
LOPID at the 8.5 year follow-up (65 LOPID versus 45 placebo noncoronary deaths).
The incidence of cancer (excluding basal cell carcinoma) discovered during the trial and
in the 3.5 years after the trial was completed was 51 (2.5%) in both originally randomized
groups. In addition, there were 16 basal cell carcinomas in the group originally
randomized to LOPID and 9 in the group randomized to placebo (p=0.22). There were 30
(1.5%) deaths attributed to cancer in the group originally randomized to LOPID and 18
(0.9%) in the group originally randomized to placebo (p=0.11). Adverse outcomes,
including coronary events, were higher in gemfibrozil patients in a corresponding study
in men with a history of known or suspected coronary heart disease in the secondary
prevention component of the Helsinki Heart Study (see CLINICAL
PHARMACOLOGY).
A comparative carcinogenicity study was also done in rats comparing three drugs in this
class: fenofibrate (10 and 60 mg/kg; 0.3 and 1.6 times the human dose), clofibrate (400
mg/kg; 1.6 times the human dose), and gemfibrozil (250 mg/kg; 1.7 times the human
dose). Pancreatic acinar adenomas were increased in males and females on fenofibrate;
hepatocellular carcinoma and pancreatic acinar adenomas were increased in males and
hepatic neoplastic nodules in females treated with clofibrate; hepatic neoplastic nodules
were increased in males and females treated with clofibrate; hepatic neoplastic nodules
were increased in males and females treated with gemfibrozil while testicular interstitial
cell (Leydig cell) tumors were increased in males on all three drugs.
2. A gallstone prevalence substudy of 450 Helsinki Heart Study participants showed a
trend toward a greater prevalence of gallstones during the study within the LOPID
treatment group (7.5% vs 4.9% for the placebo group, a 55% excess for the gemfibrozil
group). A trend toward a greater incidence of gallbladder surgery was observed for the
LOPID group (17 vs 11 subjects, a 54% excess). This result did not differ statistically
from the increased incidence of cholecystectomy observed in the WHO study in the
group treated with clofibrate. Both clofibrate and gemfibrozil may increase cholesterol
excretion into the bile leading to cholelithiasis. If cholelithiasis is suspected, gallbladder
studies are indicated. LOPID therapy should be discontinued if gallstones are found.
Cases of cholelithiasis have been reported with gemfibrozil therapy.
3. Since a reduction of mortality from coronary heart disease has not been demonstrated
and because liver and interstitial cell testicular tumors were increased in rats, LOPID
should be administered only to those patients described in the INDICATIONS AND
USAGE section. If a significant serum lipid response is not obtained, LOPID should be
discontinued.
4. Concomitant Anticoagulants–Caution should be exercised when anticoagulants are
given in conjunction with LOPID. The dosage of the anticoagulant should be reduced to
maintain the prothrombin time at the desired level to prevent bleeding complications.
Frequent prothrombin determinations are advisable until it has been definitely determined
that the prothrombin level has stabilized.
5. Concomitant therapy with LOPID and an HMG-CoA reductase inhibitor is associated
with an increased risk of skeletal muscle toxicity manifested as rhabdomyolysis,
markedly elevated creatine kinase (CPK) levels and myoglobinuria, leading in a high
proportion of cases to acute renal failure and death. IN PATIENTS WHO HAVE HAD
AN UNSATISFACTORY LIPID RESPONSE TO EITHER DRUG ALONE, THE
BENEFIT OF COMBINED THERAPY WITH LOPID AND an HMG-CoA
REDUCTASE INHIBITOR DOES NOT OUTWEIGH THE RISKS OF SEVERE
MYOPATHY, RHABDOMYOLYSIS, AND ACUTE RENAL FAILURE (see
PRECAUTIONS, Drug Interactions). The use of fibrates alone, including LOPID, may
occasionally be associated with myositis. Patients receiving LOPID and complaining of
muscle pain, tenderness or weakness should have prompt medical evaluation for
myositis, including serum creatine–kinase level determination. If myositis is suspected
or diagnosed, LOPID therapy should be withdrawn.
6. Cataracts–Subcapsular bilateral cataracts occurred in 10%, and unilateral in 6.3%, of
male rats treated with gemfibrozil at 10 times the human dose.
PRECAUTIONS
1. Initial Therapy–Laboratory studies should be done to ascertain that the lipid levels are
consistently abnormal. Before instituting LOPID therapy, every attempt should be made
to control serum lipids with appropriate diet, exercise, weight loss in obese patients, and
control of any medical problems such as diabetes mellitus and hypothyroidism that are
contributing to the lipid abnormalities.
2. Continued Therapy–Periodic determination of serum lipids should be obtained, and
the drug withdrawn if lipid response is inadequate after three months of therapy.
3. Drug Interactions–(A) HMG-CoA reductase inhibitors: The risk of myopathy and
rhabdomyolysis is increased with combined gemfibrozil and HMG-CoA reductase
inhibitor therapy. Myopathy or rhabdomyolysis with or without acute renal failure have
been reported as early as three weeks after initiation of combined therapy or after several
months (see WARNINGS). There is no assurance that periodic monitoring of creatine
kinase will prevent the occurrence of severe myopathy and kidney damage.
(B) Anticoagulants: CAUTION SHOULD BE EXERCISED WHEN ANTI
COAGULANTS ARE GIVEN IN CONJUNCTION WITH LOPID. THE DOSAGE OF
THE ANTICOAGULANT SHOULD BE REDUCED TO MAINTAIN THE
PROTHROMBIN TIME AT THE DESIRED LEVEL TO PREVENT BLEEDING
COMPLICATIONS. FREQUENT PROTHROMBIN DETERMINATIONS ARE
ADVISABLE UNTIL IT HAS BEEN DEFINITELY DETERMINED THAT THE
PROTHROMBIN LEVEL HAS STABILIZED.
(C ) Repaglinide: In healthy volunteers, co-administration with gemfibrozil increased the
plasma concentration of repaglinide and prolonged its hypoglycemic effects. Co
administration of gemfibrozil and repaglinide increases the risk for severe hypoglycemia
and is contraindicated (see CONTRAINDICATIONS).
4. Carcinogenesis, Mutagenesis, Impairment of Fertility–Long-term studies have
been conducted in rats at 0.2 and 1.3 times the human exposure (based on AUC). The
incidence of benign liver nodules and liver carcinomas was significantly increased in
high dose male rats. The incidence of liver carcinomas increased also in low dose males,
but this increase was not statistically significant (p=0.1). Male rats had a dose-related and
statistically significant increase of benign Leydig cell tumors. The higher dose female
rats had a significant increase in the combined incidence of benign and malignant liver
neoplasms.
Long-term studies have been conducted in mice at 0.1 and 0.7 times the human exposure
(based on AUC). There were no statistically significant differences from controls in the
incidence of liver tumors, but the doses tested were lower than those shown to be
carcinogenic with other fibrates.
Electron microscopy studies have demonstrated a florid hepatic peroxisome proliferation
following LOPID administration to the male rat. An adequate study to test for
peroxisome proliferation has not been done in humans but changes in peroxisome
morphology have been observed. Peroxisome proliferation has been shown to occur in
humans with either of two other drugs of the fibrate class when liver biopsies were
compared before and after treatment in the same individual.
Administration of approximately 2 times the human dose (based on surface area) to male
rats for 10 weeks resulted in a dose-related decrease of fertility. Subsequent studies
demonstrated that this effect was reversed after a drug-free period of about eight weeks,
and it was not transmitted to the offspring.
5. Pregnancy Category C–LOPID has been shown to produce adverse effects in rats and
rabbits at doses between 0.5 and 3 times the human dose (based on surface area). There
are no adequate and well-controlled studies in pregnant women. LOPID should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Administration of LOPID to female rats at 2 times the human dose (based on surface
area) before and throughout gestation caused a dose-related decrease in conception rate
and, an increase in stillborns and a slight reduction in pup weight during lactation. There
were also dose-related increased skeletal variations. Anophthalmia occurred, but rarely.
Administration of 0.6 and 2 times the human dose (based on surface area) of LOPID to
female rats from gestation day 15 through weaning caused dose-related decreases in birth
weight and suppressions of pup growth during lactation.
Administration of 1 and 3 times the human dose (based on surface area) of LOPID to
female rabbits during organogenesis caused a dose-related decrease in litter size and, at
the high dose, an increased incidence of parietal bone variations.
6. Nursing Mothers–It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk and because of the potential for
tumorigenicity shown for LOPID in animal studies, a decision should be made whether to
discontinue nursing or to discontinue the drug, taking into account the importance of the
drug to the mother.
7. Hematologic Changes–Mild hemoglobin, hematocrit and white blood cell decreases
have been observed in occasional patients following initiation of LOPID therapy.
However, these levels stabilize during long-term administration. Rarely, severe anemia,
leukopenia, thrombocytopenia, and bone marrow hypoplasia have been reported.
Therefore, periodic blood counts are recommended during the first 12 months of LOPID
administration.
8. Liver Function–Abnormal liver function tests have been observed occasionally during
LOPID administration, including elevations of AST (SGOT), ALT (SGPT), LDH,
bilirubin, and alkaline phosphatase. These are usually reversible when LOPID is
discontinued. Therefore, periodic liver function studies are recommended and LOPID
therapy should be terminated if abnormalities persist.
9. Kidney Function–There have been reports of worsening renal insufficiency upon the
addition of LOPID therapy in individuals with baseline plasma creatinine >2.0 mg/dL. In
such patients, the use of alternative therapy should be considered against the risks and
benefits of a lower dose of LOPID.
10. Pediatric Use–Safety and efficacy in pediatric patients have not been established.
ADVERSE REACTIONS
In the double-blind controlled phase of the primary prevention component of the Helsinki
Heart Study, 2046 patients received LOPID for up to five years. In that study, the
following adverse reactions were statistically more frequent in subjects in the LOPID
group:
LOPID
PLACEBO
(N = 2046)
(N = 2035)
Frequency in
percent of subjects
Gastrointestinal reactions
34.2
23.8
Dyspepsia
19.6
11.9
Abdominal pain
9.8
5.6
Acute appendicitis
1.2
0.6
(histologically confirmed in most
cases where data were available)
Atrial fibrillation
0.7
0.1
LOPID
PLACEBO
(N = 2046)
(N = 2035)
Frequency in
percent of subjects
Adverse events reported by more than 1% of subjects, but without a significant
difference between groups:
Diarrhea
7.2
6.5
Fatigue
3.8
3.5
Nausea/Vomiting
2.5
2.1
Eczema
1.9
1.2
Rash
1.7
1.3
Vertigo
1.5
1.3
Constipation
1.4
1.3
Headache
1.2
1.1
Gallbladder surgery was performed in 0.9% of LOPID and 0.5% of placebo subjects in
the primary prevention component, a 64% excess, which is not statistically different from
the excess of gallbladder surgery observed in the clofibrate compared to the placebo
group of the WHO study. Gallbladder surgery was also performed more frequently in the
LOPID group compared to placebo (1.9% vs 0.3%, p=0.07) in the secondary prevention
component. A statistically significant increase in appendectomy in the gemfibrozil group
was seen also in the secondary prevention component (6 on gemfibrozil vs 0 on placebo,
p=0.014).
Nervous system and special senses adverse reactions were more common in the LOPID
group. These included hypesthesia, paresthesias, and taste perversion. Other adverse
reactions that were more common among LOPID treatment group subjects but where a
causal relationship was not established include cataracts, peripheral vascular disease, and
intracerebral hemorrhage.
From other studies it seems probable that LOPID is causally related to the occurrence of
MUSCULOSKELETAL SYMPTOMS (see WARNINGS), and to ABNORMAL LIVER
FUNCTION TESTS and HEMATOLOGIC CHANGES (see PRECAUTIONS).
Reports of viral and bacterial infections (common cold, cough, urinary tract infections)
were more common in gemfibrozil treated patients in other controlled clinical trials of
805 patients. Additional adverse reactions that have been reported for gemfibrozil are
listed below by system. These are categorized according to whether a causal relationship
to treatment with LOPID is probable or not established:
CAUSAL RELATIONSHIP
CAUSAL RELATIONSHIP
PROBABLE
NOT ESTABLISHED
General:
weight loss
Cardiac:
extrasystoles
Gastrointestinal:
cholestatic jaundice
pancreatitis
hepatoma
colitis
Central Nervous System: dizziness
confusion
somnolence
convulsions
paresthesia
syncope
peripheral neuritis
decreased libido
depression
headache
Eye:
blurred vision
retinal edema
Genitourinary:
impotence
decreased male fertility
renal dysfunction
Musculoskeletal:
myopathy
myasthenia
myalgia
painful extremities
arthralgia
synovitis
rhabdomyolysis (see WARNINGS
and Drug Interactions under
PRECAUTIONS)
Clinical Laboratory:
increased creatine phosphokinase positive antinuclear antibody
increased bilirubin
increased liver transaminases
(AST [SGOT], ALT [SGPT])
increased alkaline phosphatase
Hematopoietic:
anemia
thrombocytopenia
leukopenia
bone marrow hypoplasia
eosinophilia
Immunologic:
angioedema
anaphylaxis
laryngeal edema
Lupus-like syndrome
urticaria
vasculitis
Integumentary:
exfoliative dermatitis
alopecia
rash
photosensitivity
dermatitis
pruritus
Additional adverse reactions that have been reported include cholecystitis and
cholelithiasis (see WARNINGS).
DOSAGE AND ADMINISTRATION
The recommended dose for adults is 1200 mg administered in two divided doses 30
minutes before the morning and evening meal (see CLINICAL PHARMACOLOGY).
OVERDOSAGE
There have been reported cases of overdosage with LOPID. In one case, a 7-year-old
child recovered after ingesting up to 9 grams of LOPID. Symptoms reported with
overdosage were abdominal cramps, abnormal liver function tests, diarrhea, increased
CPK, joint and muscle pain, nausea and vomiting. Symptomatic supportive measures
should be taken, should an overdose occur.
HOW SUPPLIED
LOPID (Tablet 737), white, elliptical, film-coated, scored tablets, each containing 600
mg gemfibrozil, are available as follows:
N 0071-0737-20: Bottles of 60
N 0071-0737-30: Bottles of 500
Parcode® No. 737
Store at controlled room temperature 20° – 25°C (68° – 77°F) [see USP]. Protect
from light and humidity.
Rx only Pfizer Logo
LAB-0107-7.0
Revised November 2008
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018422s048lbl.pdf', 'application_number': 18422, 'submission_type': 'SUPPL ', 'submission_number': 48}
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LOPID®
(Gemfibrozil Tablets, USP)
DESCRIPTION
LOPID® (gemfibrozil tablets, USP) is a lipid regulating agent. It is available as tablets
for oral administration. Each tablet contains 600 mg gemfibrozil. Each tablet also
contains calcium stearate, NF; candelilla wax, FCC; microcrystalline cellulose, NF;
hydroxypropyl cellulose, NF; hypromellose, USP; methylparaben, NF; Opaspray white;
polyethylene glycol, NF; polysorbate 80, NF; propylparaben, NF; colloidal silicon
dioxide, NF; pregelatinized starch, NF. The chemical name is 5-(2,5-dimethylphenoxy)
2,2-dimethylpentanoic acid, with the following structural formula: structural formula
The empirical formula is C15H22O3 and the molecular weight is 250.35; the solubility in
water and acid is 0.0019% and in dilute base it is greater than 1%. The melting point is
58° –61°C. Gemfibrozil is a white solid which is stable under ordinary conditions.
CLINICAL PHARMACOLOGY
LOPID is a lipid regulating agent which decreases serum triglycerides and very low
density lipoprotein (VLDL) cholesterol, and increases high density lipoprotein (HDL)
cholesterol. While modest decreases in total and low density lipoprotein (LDL)
cholesterol may be observed with LOPID therapy, treatment of patients with elevated
triglycerides due to Type IV hyperlipoproteinemia often results in a rise in LDL-
cholesterol. LDL-cholesterol levels in Type IIb patients with elevations of both serum
LDL-cholesterol and triglycerides are, in general, minimally affected by LOPID
treatment; however, LOPID usually raises HDL-cholesterol significantly in this group.
LOPID increases levels of high density lipoprotein (HDL) subfractions HDL2 and HDL3,
as well as apolipoproteins AI and AII. Epidemiological studies have shown that both low
HDL-cholesterol and high LDL-cholesterol are independent risk factors for coronary
heart disease.
In the primary prevention component of the Helsinki Heart Study, in which 4081 male
patients between the ages of 40 and 55 were studied in a randomized, double-blind,
placebo-controlled fashion, LOPID therapy was associated with significant reductions in
total plasma triglycerides and a significant increase in high density lipoprotein
cholesterol. Moderate reductions in total plasma cholesterol and low density lipoprotein
cholesterol were observed for the LOPID treatment group as a whole, but the lipid
response was heterogeneous, especially among different Fredrickson types. The study
involved subjects with serum non-HDL-cholesterol of over 200 mg/dL and no previous
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
history of coronary heart disease. Over the five-year study period, the LOPID group
experienced a 1.4% absolute (34% relative) reduction in the rate of serious coronary
events (sudden cardiac deaths plus fatal and nonfatal myocardial infarctions) compared to
placebo, p=0.04 (see Table I). There was a 37% relative reduction in the rate of nonfatal
myocardial infarction compared to placebo, equivalent to a treatment-related difference
of 13.1 events per thousand persons. Deaths from any cause during the double-blind
portion of the study totaled 44 (2.2%) in the LOPID randomization group and 43 (2.1%)
in the placebo group.
Table I
Reduction in CHD Rates (events per 1000 patients) by Baseline Lipids1 in the
Helsinki Heart Study, Years 0–52
All
LDL-C>175;
LDL-C>175;
LDL-C>175;
Patients
HDL-C>46.4
TG>177
TG>200;
HDL-C<35
P
L
Dif
3
P
L
Dif
P
L
Dif
P
L
Dif
Incidence of
Events
4
41
27
14
32
29
3
71
44
27
149
64
85
1lipid values in mg/dL at baseline Reduction in CHD Rates (events per 1000 patients) by Baseline Lipids1 in the
Helsinki Heart Study, Years 0–52
2P = placebo group; L= LOPID group
3difference in rates between placebo and LOPID groups
4fatal and nonfatal myocardial infarctions plus sudden cardiac deaths (events per 1000 patients over 5
years)
Among Fredrickson types, during the 5-year double-blind portion of the primary
prevention component of the Helsinki Heart Study, the greatest reduction in the incidence
of serious coronary events occurred in Type IIb patients who had elevations of both LDL-
cholesterol and total plasma triglycerides. This subgroup of Type IIb gemfibrozil group
patients had a lower mean HDL-cholesterol level at baseline than the Type IIa subgroup
that had elevations of LDL-cholesterol and normal plasma triglycerides. The mean
increase in HDL-cholesterol among the Type IIb patients in this study was 12.6%
compared to placebo. The mean change in LDL-cholesterol among Type IIb patients was
–4.1% with LOPID compared to a rise of 3.9% in the placebo subgroup. The Type IIb
subjects in the Helsinki Heart Study had 26 fewer coronary events per thousand persons
over five years in the gemfibrozil group compared to placebo. The difference in coronary
events was substantially greater between LOPID and placebo for that subgroup of
patients with the triad of LDL-cholesterol >175 mg/dL (>4.5 mmol), triglycerides >200
mg/dL (>2.2 mmol), and HDL-cholesterol <35 mg/dL (<0.90 mmol) (see Table I).
Further information is available from a 3.5 year (8.5 year cumulative) follow-up of all
subjects who had participated in the Helsinki Heart Study. At the completion of the
Helsinki Heart Study, subjects could choose to start, stop, or continue to receive LOPID;
without knowledge of their own lipid values or double-blind treatment, 60% of patients
originally randomized to placebo began therapy with LOPID and 60% of patients
originally randomized to LOPID continued medication. After approximately 6.5 years
following randomization, all patients were informed of their original treatment group and
lipid values during the five years of the double-blind treatment. After further elective
changes in LOPID treatment status, 61% of patients in the group originally randomized to
LOPID were taking drug; in the group originally randomized to placebo, 65% were
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taking LOPID. The event rate per 1000 occurring during the open-label follow-up period
is detailed in Table II.
Table II
Cardiac Events and All-Cause Mortality (events per 1000 patients) Occurring During the
3.5 Year Open-Label Follow-up to the Helsinki Heart Study
1
Group:
PDrop
PN
PL
LDrop
LN
LL
N=215
N=494
N=1283
N=221
N=574
N=1207
Cardiac
Events
38.8
22.9
22.5
37.2
28.3
25.4
All-Cause
Mortality
41.9
22.3
15.6
72.3
19.2
24.9
1The six open-label groups are designated first by the original randomization
(P = placebo, L = LOPID) and then by the drug taken in the follow-up period (N = Attend
clinic but took no drug, L = LOPID, Drop = No attendance at clinic during open-label).
Cumulative mortality through 8.5 years showed a 20% relative excess of deaths in the
group originally randomized to LOPID versus the originally randomized placebo group
and a 20% relative decrease in cardiac events in the group originally randomized to
LOPID versus the originally randomized placebo group (see Table III). This analysis of
the originally randomized “intent-to-treat’’ population neglects the possible complicating
effects of treatment switching during the open-label phase. Adjustment of hazard ratios,
taking into account open-label treatment status from years 6.5 to 8.5, could change the
reported hazard ratios for mortality toward unity.
Table III
Cardiac Events, Cardiac Deaths, Non-Cardiac Deaths, and All-Cause Mortality in the
Helsinki Heart Study, Years 0–8.5
1
Event
LOPID
Placebo
LOPID:Placebo
at Study
at Study
Hazard
Cl Hazard
Start
Start
Ratio
2
Ratio
3
Cardiac
Events
4
110
131
0.80
0.62–1.03
Cardiac
Deaths
36
38
0.98
0.63–1.54
Non-Cardiac
Deaths
65
45
1.40
0.95–2.05
All-Cause
Mortality
101
83
1.20
0.90–1.61
1Intention-to-Treat Analysis of originally randomized patients neglecting the open-label
treatment switches and exposure to study conditions.
2Hazard ratio for risk event in the group originally randomized to LOPID compared to the
group originally randomized to placebo neglecting open-label treatment switch and
exposure to study conditions.
395% confidence intervals of LOPID:placebo group hazard ratio
4Fatal and non-fatal myocardial infarctions plus sudden cardiac deaths over the 8.5 year
period.
It is not clear to what extent the findings of the primary prevention component of the
Helsinki Heart Study can be extrapolated to other segments of the dyslipidemic
population not studied (such as women, younger or older males, or those with lipid
abnormalities limited solely to HDL-cholesterol) or to other lipid-altering drugs.
The secondary prevention component of the Helsinki Heart Study was conducted over
five years in parallel and at the same centers in Finland in 628 middle-aged males
excluded from the primary prevention component of the Helsinki Heart Study because of
a history of angina, myocardial infarction, or unexplained ECG changes. The primary
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efficacy endpoint of the study was cardiac events (the sum of fatal and non-fatal
myocardial infarctions and sudden cardiac deaths). The hazard ratio (LOPID:placebo) for
cardiac events was 1.47 (95% confidence limits 0.88–2.48, p=0.14). Of the 35 patients in
the LOPID group who experienced cardiac events, 12 patients suffered events after
discontinuation from the study. Of the 24 patients in the placebo group with cardiac
events, 4 patients suffered events after discontinuation from the study. There were 17
cardiac deaths in the LOPID group and 8 in the placebo group (hazard ratio 2.18; 95%
confidence limits 0.94–5.05, p=0.06). Ten of these deaths in the LOPID group and 3 in
the placebo group occurred after discontinuation from therapy. In this study of patients
with known or suspected coronary heart disease, no benefit from LOPID treatment was
observed in reducing cardiac events or cardiac deaths. Thus, LOPID has shown benefit
only in selected dyslipidemic patients without suspected or established coronary heart
disease. Even in patients with coronary heart disease and the triad of elevated LDL-
cholesterol, elevated triglycerides, plus low HDL-cholesterol, the possible effect of
LOPID on coronary events has not been adequately studied.
No efficacy in the patients with established coronary heart disease was observed during
the Coronary Drug Project with the chemically and pharmacologically related drug,
clofibrate. The Coronary Drug Project was a 6-year randomized, double-blind study
involving 1000 clofibrate, 1000 nicotinic acid, and 3000 placebo patients with known
coronary heart disease. A clinically and statistically significant reduction in myocardial
infarctions was seen in the concurrent nicotinic acid group compared to placebo; no
reduction was seen with clofibrate.
The mechanism of action of gemfibrozil has not been definitely established. In man,
LOPID has been shown to inhibit peripheral lipolysis and to decrease the hepatic
extraction of free fatty acids, thus reducing hepatic triglyceride production. LOPID
inhibits synthesis and increases clearance of VLDL carrier apolipoprotein B, leading to a
decrease in VLDL production.
Animal studies suggest that gemfibrozil may, in addition to elevating HDL-cholesterol,
reduce incorporation of long-chain fatty acids into newly formed triglycerides, accelerate
turnover and removal of cholesterol from the liver, and increase excretion of cholesterol
in the feces. LOPID is well absorbed from the gastrointestinal tract after oral
administration. Peak plasma levels occur in 1 to 2 hours with a plasma half-life of 1.5
hours following multiple doses.
Gemfibrozil is completely absorbed after oral administration of LOPID tablets, reaching
peak plasma concentrations 1 to 2 hours after dosing. Gemfibrozil pharmacokinetics are
affected by the timing of meals relative to time of dosing. In one study (ref. 4), both the
rate and extent of absorption of the drug were significantly increased when administered
0.5 hour before meals. Average AUC was reduced by 14–44% when LOPID was
administered after meals compared to 0.5 hour before meals. In a subsequent study, rate
of absorption of LOPID was maximum when administered 0.5 hour before meals with the
Cmax 50–60% greater than when given either with meals or fasting. In this study, there
were no significant effects on AUC of timing of dose relative to meals (see DOSAGE
AND ADMINISTRATION).
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LOPID mainly undergoes oxidation of a ring methyl group to successively form a
hydroxymethyl and a carboxyl metabolite. Approximately seventy percent of the
administered human dose is excreted in the urine, mostly as the glucuronide conjugate,
with less than 2% excreted as unchanged gemfibrozil. Six percent of the dose is
accounted for in the feces. Gemfibrozil is highly bound to plasma proteins and there is
potential for displacement interactions with other drugs (see PRECAUTIONS).
INDICATIONS AND USAGE
LOPID (gemfibrozil tablets, USP) is indicated as adjunctive therapy to diet for:
1. Treatment of adult patients with very high elevations of serum triglyceride levels
(Types IV and V hyperlipidemia) who present a risk of pancreatitis and who do not
respond adequately to a determined dietary effort to control them. Patients who
present such risk typically have serum triglycerides over 2000 mg/dL and have
elevations of VLDL-cholesterol as well as fasting chylomicrons (Type V
hyperlipidemia). Subjects who consistently have total serum or plasma triglycerides
below 1000 mg/dL are unlikely to present a risk of pancreatitis. LOPID therapy may
be considered for those subjects with triglyceride elevations between 1000 and 2000
mg/dL who have a history of pancreatitis or of recurrent abdominal pain typical of
pancreatitis. It is recognized that some Type IV patients with triglycerides under 1000
mg/dL may, through dietary or alcoholic indiscretion, convert to a Type V pattern
with massive triglyceride elevations accompanying fasting chylomicronemia, but the
influence of LOPID therapy on the risk of pancreatitis in such situations has not been
adequately studied. Drug therapy is not indicated for patients with Type I
hyperlipoproteinemia, who have elevations of chylomicrons and plasma triglycerides,
but who have normal levels of very low density lipoprotein (VLDL). Inspection of
plasma refrigerated for 14 hours is helpful in distinguishing Types I, IV, and V
hyperlipoproteinemia.
2. Reducing the risk of developing coronary heart disease only in Type IIb patients
without history of or symptoms of existing coronary heart disease who have had an
inadequate response to weight loss, dietary therapy, exercise, and other
pharmacologic agents (such as bile acid sequestrants and nicotinic acid, known to
reduce LDL- and raise HDL-cholesterol) and who have the following triad of lipid
abnormalities: low HDL-cholesterol levels in addition to elevated LDL-cholesterol
and elevated triglycerides (see WARNINGS, PRECAUTIONS, and CLINICAL
PHARMACOLOGY). The National Cholesterol Education Program has defined a
serum HDL-cholesterol value that is consistently below 35 mg/dL as constituting an
independent risk factor for coronary heart disease. Patients with significantly elevated
triglycerides should be closely observed when treated with gemfibrozil. In some
patients with high triglyceride levels, treatment with gemfibrozil is associated with a
significant increase in LDL-cholesterol. BECAUSE OF POTENTIAL TOXICITY
SUCH AS MALIGNANCY, GALLBLADDER DISEASE, ABDOMINAL PAIN
LEADING TO APPENDECTOMY AND OTHER ABDOMINAL SURGERIES, AN
INCREASED INCIDENCE IN NON-CORONARY MORTALITY, AND THE 44%
RELATIVE INCREASE DURING THE TRIAL PERIOD IN AGE-ADJUSTED
ALL-CAUSE MORTALITY SEEN WITH THE CHEMICALLY AND
PHARMACOLOGICALLY RELATED DRUG, CLOFIBRATE, THE POTENTIAL
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BENEFIT OF GEMFIBROZIL IN TREATING TYPE IIA PATIENTS WITH
ELEVATIONS OF LDL-CHOLESTEROL ONLY IS NOT LIKELY TO
OUTWEIGH THE RISKS. LOPID IS ALSO NOT INDICATED FOR THE
TREATMENT OF PATIENTS WITH LOW HDL-CHOLESTEROL AS THEIR
ONLY LIPID ABNORMALITY.
In a subgroup analysis of patients in the Helsinki Heart Study with above-median HDL-
cholesterol values at baseline (greater than 46.4 mg/dL), the incidence of serious
coronary events was similar for gemfibrozil and placebo subgroups (see Table I).
The initial treatment for dyslipidemia is dietary therapy specific for the type of
lipoprotein abnormality. Excess body weight and excess alcohol intake may be important
factors in hypertriglyceridemia and should be managed prior to any drug therapy.
Physical exercise can be an important ancillary measure, and has been associated with
rises in HDL-cholesterol. Diseases contributory to hyperlipidemia such as
hypothyroidism or diabetes mellitus should be looked for and adequately treated.
Estrogen therapy is sometimes associated with massive rises in plasma triglycerides,
especially in subjects with familial hypertriglyceridemia. In such cases, discontinuation
of estrogen therapy may obviate the need for specific drug therapy of
hypertriglyceridemia. The use of drugs should be considered only when reasonable
attempts have been made to obtain satisfactory results with nondrug methods. If the
decision is made to use drugs, the patient should be instructed that this does not reduce
the importance of adhering to diet.
CONTRAINDICATIONS
1. Hepatic or severe renal dysfunction, including primary biliary cirrhosis.
2. Preexisting gallbladder disease (see WARNINGS).
3. Hypersensitivity to gemfibrozil.
4. Combination therapy of gemfibrozil with repaglinide (see PRECAUTIONS).
WARNINGS
1. Because of chemical, pharmacological, and clinical similarities between gemfibrozil
and clofibrate, the adverse findings with clofibrate in two large clinical studies may also
apply to gemfibrozil. In the first of those studies, the Coronary Drug Project, 1000
subjects with previous myocardial infarction were treated for five years with clofibrate.
There was no difference in mortality between the clofibrate-treated subjects and 3000
placebo-treated subjects, but twice as many clofibrate-treated subjects developed
cholelithiasis and cholecystitis requiring surgery. In the other study, conducted by the
World Health Organization (WHO), 5000 subjects without known coronary heart disease
were treated with clofibrate for five years and followed one year beyond. There was a
statistically significant (44%) higher age-adjusted total mortality in the clofibrate-treated
group than in a comparable placebo-treated control group during the trial period. The
excess mortality was due to a 33% increase in non-cardiovascular causes, including
malignancy, post-cholecystectomy complications, and pancreatitis. The higher risk of
clofibrate-treated subjects for gallbladder disease was confirmed.
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Because of the more limited size of the Helsinki Heart Study, the observed difference in
mortality from any cause between the LOPID and placebo groups is not statistically
significantly different from the 29% excess mortality reported in the clofibrate group in
the separate WHO study at the nine year follow-up (see CLINICAL
PHARMACOLOGY). Noncoronary heart disease related mortality showed an excess in
the group originally randomized to LOPID primarily due to cancer deaths observed
during the open-label extension.
During the five year primary prevention component of the Helsinki Heart Study,
mortality from any cause was 44 (2.2%) in the LOPID group and 43 (2.1%) in the
placebo group; including the 3.5 year follow-up period since the trial was completed,
cumulative mortality from any cause was 101 (4.9%) in the LOPID group and 83 (4.1%)
in the group originally randomized to placebo (hazard ratio 1:20 in favor of placebo).
Because of the more limited size of the Helsinki Heart Study, the observed difference in
mortality from any cause between the LOPID and placebo groups at Year-5 or at Year
8.5 is not statistically significantly different from the 29% excess mortality reported in
the clofibrate group in the separate WHO study at the nine year follow-up. Noncoronary
heart disease related mortality showed an excess in the group originally randomized to
LOPID at the 8.5 year follow-up (65 LOPID versus 45 placebo noncoronary deaths).
The incidence of cancer (excluding basal cell carcinoma) discovered during the trial and
in the 3.5 years after the trial was completed was 51 (2.5%) in both originally randomized
groups. In addition, there were 16 basal cell carcinomas in the group originally
randomized to LOPID and 9 in the group originally randomized to placebo (p=0.22).
There were 30 (1.5%) deaths attributed to cancer in the group originally randomized to
LOPID and 18 (0.9%) in the group originally randomized to placebo (p=0.11). Adverse
outcomes, including coronary events, were higher in gemfibrozil patients in a
corresponding study in men with a history of known or suspected coronary heart disease
in the secondary prevention component of the Helsinki Heart Study (see CLINICAL
PHARMACOLOGY).
A comparative carcinogenicity study was also done in rats comparing three drugs in this
class: fenofibrate (10 and 60 mg/kg; 0.3 and 1.6 times the human dose, respectively),
clofibrate (400 mg/kg; 1.6 times the human dose), and gemfibrozil (250 mg/kg; 1.7 times
the human dose). Pancreatic acinar adenomas were increased in males and females on
fenofibrate; hepatocellular carcinoma and pancreatic acinar adenomas were increased in
males and hepatic neoplastic nodules in females treated with clofibrate; hepatic
neoplastic nodules were increased in males and females treated with clofibrate; hepatic
neoplastic nodules were increased in males and females treated with gemfibrozil while
testicular interstitial cell (Leydig cell) tumors were increased in males on all three drugs.
2. A gallstone prevalence substudy of 450 Helsinki Heart Study participants showed a
trend toward a greater prevalence of gallstones during the study within the LOPID
treatment group (7.5% versus 4.9% for the placebo group, a 55% excess for the
gemfibrozil group). A trend toward a greater incidence of gallbladder surgery was
observed for the LOPID group (17 versus 11 subjects, a 54% excess). This result did not
differ statistically from the increased incidence of cholecystectomy observed in the WHO
study in the group treated with clofibrate. Both clofibrate and gemfibrozil may increase
cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected,
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gallbladder studies are indicated. LOPID therapy should be discontinued if gallstones are
found. Cases of cholelithiasis have been reported with gemfibrozil therapy.
3. Since a reduction of mortality from coronary heart disease has not been demonstrated
and because liver and interstitial cell testicular tumors were increased in rats, LOPID
should be administered only to those patients described in the INDICATIONS AND
USAGE section. If a significant serum lipid response is not obtained, LOPID should be
discontinued.
4. Concomitant Anticoagulants – Caution should be exercised when anticoagulants are
given in conjunction with LOPID. The dosage of the anticoagulant should be reduced to
maintain the prothrombin time at the desired level to prevent bleeding complications.
Frequent prothrombin determinations are advisable until it has been definitely determined
that the prothrombin level has stabilized.
5. Concomitant therapy with LOPID and an HMG-CoA reductase inhibitor is associated
with an increased risk of skeletal muscle toxicity manifested as rhabdomyolysis,
markedly elevated creatine kinase (CPK) levels, and myoglobinuria, leading in a high
proportion of cases to acute renal failure and death. IN PATIENTS WHO HAVE HAD
AN UNSATISFACTORY LIPID RESPONSE TO EITHER DRUG ALONE, THE
BENEFIT OF COMBINED THERAPY WITH LOPID AND an HMG-CoA
REDUCTASE INHIBITOR DOES NOT OUTWEIGH THE RISKS OF SEVERE
MYOPATHY, RHABDOMYOLYSIS, AND ACUTE RENAL FAILURE (see
PRECAUTIONS, Drug Interactions). The use of fibrates alone, including LOPID, may
occasionally be associated with myositis. Patients receiving LOPID and complaining of
muscle pain, tenderness, or weakness should have prompt medical evaluation for
myositis, including serum creatine–kinase level determination. If myositis is suspected or
diagnosed, LOPID therapy should be withdrawn.
6. Cataracts – Subcapsular bilateral cataracts occurred in 10%, and unilateral in 6.3%, of
male rats treated with gemfibrozil at 10 times the human dose.
PRECAUTIONS
1. Initial Therapy – Laboratory studies should be done to ascertain that the lipid levels
are consistently abnormal. Before instituting LOPID therapy, every attempt should be
made to control serum lipids with appropriate diet, exercise, weight loss in obese patients,
and control of any medical problems such as diabetes mellitus and hypothyroidism that
are contributing to the lipid abnormalities.
2. Continued Therapy – Periodic determination of serum lipids should be obtained, and
the drug withdrawn if lipid response is inadequate after three months of therapy.
3. Drug Interactions – (A) HMG-CoA Reductase Inhibitors: The risk of myopathy
and rhabdomyolysis is increased with combined gemfibrozil and HMG-CoA reductase
inhibitor therapy. Myopathy or rhabdomyolysis with or without acute renal failure have
been reported as early as three weeks after initiation of combined therapy or after several
months (see WARNINGS). There is no assurance that periodic monitoring of creatine
kinase will prevent the occurrence of severe myopathy and kidney damage.
(B) Anticoagulants: CAUTION SHOULD BE EXERCISED WHEN ANTI
COAGULANTS ARE GIVEN IN CONJUNCTION WITH LOPID. THE DOSAGE OF
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THE ANTICOAGULANT SHOULD BE REDUCED TO MAINTAIN THE
PROTHROMBIN TIME AT THE DESIRED LEVEL TO PREVENT BLEEDING
COMPLICATIONS. FREQUENT PROTHROMBIN DETERMINATIONS ARE
ADVISABLE UNTIL IT HAS BEEN DEFINITELY DETERMINED THAT THE
PROTHROMBIN LEVEL HAS STABILIZED.
(C) Repaglinide: In healthy volunteers, co-administration with gemfibrozil (600 mg
twice daily for 3 days) resulted in an 8.1-fold (range 5.5- to 15.0- fold) higher repaglinide
AUC and a 28.6-fold (range 18.5- to 80.1-fold) higher repaglinide plasma concentration 7
hours after the dose. In the same study, gemfibrozil (600 mg twice daily for 3 days) +
itraconazole (200 mg in the morning and 100 mg in the evening at Day 1, then 100 mg
twice daily at Day 2-3) resulted in a 19.4- (range 12.9- to 24.7-fold) higher repaglinide
AUC and a 70.4-fold (range 42.9- to 119.2-fold) higher repaglinide plasma concentration
7 hours after the dose. In addition, gemfibrozil alone or gemfibrozil + itraconazole
prolonged the hypoglycemic effects of repaglinide. Co-administration of gemfibrozil and
repaglinide increases the risk of severe hypoglycemia and is contraindicated (see
CONTRAINDICATIONS).
(D) Bile Acid-Binding Resins: Gemfibrozil AUC was reduced by 30% when
gemfibrozil was given (600 mg) simultaneously with resin-granule drugs such as
colestipol (5 g). Administration of the drugs two hours or more apart is recommended
because gemfibrozil exposure was not significantly affected when it was administered
two hours apart from colestipol
4. Carcinogenesis, Mutagenesis, Impairment of Fertility – Long-term studies have
been conducted in rats at 0.2 and 1.3 times the human exposure (based on AUC). The
incidence of benign liver nodules and liver carcinomas was significantly increased in
high dose male rats. The incidence of liver carcinomas increased also in low dose males,
but this increase was not statistically significant (p=0.1). Male rats had a dose-related and
statistically significant increase of benign Leydig cell tumors. The higher dose female
rats had a significant increase in the combined incidence of benign and malignant liver
neoplasms.
Long-term studies have been conducted in mice at 0.1 and 0.7 times the human exposure
(based on AUC). There were no statistically significant differences from controls in the
incidence of liver tumors, but the doses tested were lower than those shown to be
carcinogenic with other fibrates.
Electron microscopy studies have demonstrated a florid hepatic peroxisome proliferation
following LOPID administration to the male rat. An adequate study to test for
peroxisome proliferation has not been done in humans but changes in peroxisome
morphology have been observed. Peroxisome proliferation has been shown to occur in
humans with either of two other drugs of the fibrate class when liver biopsies were
compared before and after treatment in the same individual.
Administration of approximately 2 times the human dose (based on surface area) to male
rats for 10 weeks resulted in a dose-related decrease of fertility. Subsequent studies
demonstrated that this effect was reversed after a drug-free period of about eight weeks,
and it was not transmitted to the offspring.
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5. Pregnancy Category C – LOPID has been shown to produce adverse effects in rats
and rabbits at doses between 0.5 and 3 times the human dose (based on surface area).
There are no adequate and well-controlled studies in pregnant women. LOPID should be
used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Administration of LOPID to female rats at 2 times the human dose (based on surface
area) before and throughout gestation caused a dose-related decrease in conception rate,
an increase in stillborns, and a slight reduction in pup weight during lactation. There were
also dose-related increased skeletal variations. Anophthalmia occurred, but rarely.
Administration of 0.6 and 2 times the human dose (based on surface area) of LOPID to
female rats from gestation day 15 through weaning caused dose-related decreases in birth
weight and suppressions of pup growth during lactation.
Administration of 1 and 3 times the human dose (based on surface area) of LOPID to
female rabbits during organogenesis caused a dose-related decrease in litter size and, at
the high dose, an increased incidence of parietal bone variations.
6. Nursing Mothers – It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk and because of the potential for
tumorigenicity shown for LOPID in animal studies, a decision should be made whether to
discontinue nursing or to discontinue the drug, taking into account the importance of the
drug to the mother.
7. Hematologic Changes – Mild hemoglobin, hematocrit, and white blood cell decreases
have been observed in occasional patients following initiation of LOPID therapy.
However, these levels stabilize during long-term administration. Rarely, severe anemia,
leukopenia, thrombocytopenia, and bone marrow hypoplasia have been reported.
Therefore, periodic blood counts are recommended during the first 12 months of LOPID
administration.
8. Liver Function – Abnormal liver function tests have been observed occasionally
during LOPID administration, including elevations of AST, ALT, LDH, bilirubin, and
alkaline phosphatase. These are usually reversible when LOPID is discontinued.
Therefore, periodic liver function studies are recommended and LOPID therapy should
be terminated if abnormalities persist.
9. Kidney Function – There have been reports of worsening renal insufficiency upon the
addition of LOPID therapy in individuals with baseline plasma creatinine >2.0 mg/dL. In
such patients, the use of alternative therapy should be considered against the risks and
benefits of a lower dose of LOPID.
10. Pediatric Use – Safety and efficacy in pediatric patients have not been established.
ADVERSE REACTIONS
In the double-blind controlled phase of the primary prevention component of the Helsinki
Heart Study, 2046 patients received LOPID for up to five years. In that study, the
following adverse reactions were statistically more frequent in subjects in the LOPID
group:
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LOPID
PLACEBO
(N = 2046)
(N = 2035)
Frequency in
percent of subjects
Gastrointestinal reactions
34.2
23.8
Dyspepsia
19.6
11.9
Abdominal pain
9.8
5.6
Acute appendicitis
1.2
0.6
(histologically confirmed in most
cases where data were available)
Atrial fibrillation
0.7
0.1
Adverse events reported by more than 1% of subjects, but without a significant
difference between groups:
Diarrhea
7.2
6.5
Fatigue
3.8
3.5
Nausea/Vomiting
2.5
2.1
Eczema
1.9
1.2
Rash
1.7
1.3
Vertigo
1.5
1.3
Constipation
1.4
1.3
Headache
1.2
1.1
Gallbladder surgery was performed in 0.9% of LOPID and 0.5% of placebo subjects in
the primary prevention component, a 64% excess, which is not statistically different from
the excess of gallbladder surgery observed in the clofibrate group compared to the
placebo group of the WHO study. Gallbladder surgery was also performed more
frequently in the LOPID group compared to the placebo group (1.9% versus 0.3%,
p=0.07) in the secondary prevention component. A statistically significant increase in
appendectomy in the gemfibrozil group was seen also in the secondary prevention
component (6 on gemfibrozil versus 0 on placebo, p=0.014).
Nervous system and special senses adverse reactions were more common in the LOPID
group. These included hypesthesia, paresthesias, and taste perversion. Other adverse
reactions that were more common among LOPID treatment group subjects but where a
causal relationship was not established include cataracts, peripheral vascular disease, and
intracerebral hemorrhage.
From other studies it seems probable that LOPID is causally related to the occurrence of
MUSCULOSKELETAL SYMPTOMS (see WARNINGS), and to ABNORMAL LIVER
FUNCTION TESTS and HEMATOLOGIC CHANGES (see PRECAUTIONS).
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Reports of viral and bacterial infections (common cold, cough, urinary tract infections)
were more common in gemfibrozil treated patients in other controlled clinical trials of
805 patients. Additional adverse reactions that have been reported for gemfibrozil are
listed below by system. These are categorized according to whether a causal relationship
to treatment with LOPID is probable or not established:
CAUSAL RELATIONSHIP
CAUSAL RELATIONSHIP
PROBABLE
NOT ESTABLISHED
General:
weight loss
Cardiac:
extrasystoles
Gastrointestinal:
cholestatic jaundice
pancreatitis
hepatoma
colitis
Central Nervous System: dizziness
confusion
somnolence
convulsions
paresthesia
syncope
peripheral neuritis
decreased libido
depression
headache
Eye:
blurred vision
retinal edema
Genitourinary:
impotence
decreased male fertility
renal dysfunction
Musculoskeletal:
myopathy
myasthenia
myalgia
painful extremities
arthralgia
synovitis
rhabdomyolysis (see
WARNINGS and Drug
Interactions under
PRECAUTIONS)
Clinical Laboratory:
increased creatine phosphokinase positive antinuclear antibody
increased bilirubin
increased liver transaminases
(AST, ALT)
increased alkaline phosphatase
Hematopoietic:
anemia
thrombocytopenia
leukopenia
bone marrow hypoplasia
eosinophilia
Immunologic:
angioedema
anaphylaxis
laryngeal edema
Lupus-like syndrome
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urticaria
vasculitis
Integumentary:
exfoliative dermatitis
alopecia
rash
photosensitivity
dermatitis
pruritus
Additional adverse reactions that have been reported include cholecystitis and
cholelithiasis (see WARNINGS).
DOSAGE AND ADMINISTRATION
The recommended dose for adults is 1200 mg administered in two divided doses 30
minutes before the morning and evening meals (see CLINICAL PHARMACOLOGY).
OVERDOSAGE
There have been reported cases of overdosage with LOPID. In one case, a 7-year-old
child recovered after ingesting up to 9 grams of LOPID. Symptoms reported with
overdosage were abdominal cramps, abnormal liver function tests, diarrhea, increased
CPK, joint and muscle pain, nausea and vomiting. Symptomatic supportive measures
should be taken, should an overdose occur.
HOW SUPPLIED
LOPID (Tablet 737), white, elliptical, film-coated, scored tablets, each containing 600
mg gemfibrozil, are available as follows:
NDC 0071-0737-20: Bottles of 60
NDC 0071-0737-30: Bottles of 500
Store at controlled room temperature 20° – 25°C (68° – 77°F) [see USP]. Protect
from light and humidity.
Rx only Pfizer
LAB-0107-8.0
Revised September 2009
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2025-02-12T13:44:42.960026
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018422s050lbl.pdf', 'application_number': 18422, 'submission_type': 'SUPPL ', 'submission_number': 50}
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LOPID
(Gemfibrozil Tablets, USP)
DESCRIPTION
LOPID® (gemfibrozil tablets, USP) is a lipid regulating agent. It is available as tablets for
oral administration. Each tablet contains 600 mg gemfibrozil. Each tablet also contains
calcium stearate, NF; candelilla wax, FCC; microcrystalline cellulose, NF;
hydroxypropyl cellulose, NF; hypromellose, USP; methylparaben, NF; Opaspray white;
polyethylene glycol, NF; polysorbate 80, NF; propylparaben, NF; colloidal silicon
dioxide, NF; pregelatinized starch, NF. The chemical name is 5-(2,5-dimethylphenoxy)
2,2-dimethylpentanoic acid, with the following structural formula: structural formula
The empirical formula is C15H22O3 and the molecular weight is 250.35; the solubility in
water and acid is 0.0019% and in dilute base it is greater than 1%. The melting point is
58° –61°C. Gemfibrozil is a white solid which is stable under ordinary conditions.
CLINICAL PHARMACOLOGY
LOPID is a lipid regulating agent which decreases serum triglycerides and very low
density lipoprotein (VLDL) cholesterol, and increases high density lipoprotein (HDL)
cholesterol. While modest decreases in total and low density lipoprotein (LDL)
cholesterol may be observed with LOPID therapy, treatment of patients with elevated
triglycerides due to Type IV hyperlipoproteinemia often results in a rise in LDL-
cholesterol. LDL-cholesterol levels in Type IIb patients with elevations of both serum
LDL-cholesterol and triglycerides are, in general, minimally affected by LOPID
treatment; however, LOPID usually raises HDL-cholesterol significantly in this group.
LOPID increases levels of high density lipoprotein (HDL) subfractions HDL2 and HDL3,
as well as apolipoproteins AI and AII. Epidemiological studies have shown that both low
HDL-cholesterol and high LDL-cholesterol are independent risk factors for coronary
heart disease.
In the primary prevention component of the Helsinki Heart Study, in which 4081 male
patients between the ages of 40 and 55 were studied in a randomized, double-blind,
placebo-controlled fashion, LOPID therapy was associated with significant reductions in
total plasma triglycerides and a significant increase in high density lipoprotein
cholesterol. Moderate reductions in total plasma cholesterol and low density lipoprotein
cholesterol were observed for the LOPID treatment group as a whole, but the lipid
response was heterogeneous, especially among different Fredrickson types. The study
involved subjects with serum non-HDL-cholesterol of over 200 mg/dL and no previous
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history of coronary heart disease. Over the five-year study period, the LOPID group
experienced a 1.4% absolute (34% relative) reduction in the rate of serious coronary
events (sudden cardiac deaths plus fatal and nonfatal myocardial infarctions) compared to
placebo, p=0.04 (see Table I). There was a 37% relative reduction in the rate of nonfatal
myocardial infarction compared to placebo, equivalent to a treatment-related difference
of 13.1 events per thousand persons. Deaths from any cause during the double-blind
portion of the study totaled 44 (2.2%) in the LOPID randomization group and 43 (2.1%)
in the placebo group.
Table I
Reduction in CHD Rates (events per 1000 patients) by Baseline Lipids1 in the
Helsinki Heart Study, Years 0–52
Incidence of
Events4
All
Patients
LDL-C>175;
HDL-C>46.4
LDL-C>175;
TG>177
LDL-C>175;
TG>200;
HDL-C<35
P
L
Dif3
P
L
Dif
P
L
Dif
P
L
Dif
41
27
14
32
29
3
71
44
27
149
64
85
1lipid values in mg/dL at baseline
2P = placebo group; L= LOPID group
3difference in rates between placebo and LOPID groups
4fatal and nonfatal myocardial infarctions plus sudden cardiac deaths (events per 1000 patients over 5
years)
Among Fredrickson types, during the 5-year double-blind portion of the primary
prevention component of the Helsinki Heart Study, the greatest reduction in the incidence
of serious coronary events occurred in Type IIb patients who had elevations of both LDL-
cholesterol and total plasma triglycerides. This subgroup of Type IIb gemfibrozil group
patients had a lower mean HDL-cholesterol level at baseline than the Type IIa subgroup
that had elevations of LDL-cholesterol and normal plasma triglycerides. The mean
increase in HDL-cholesterol among the Type IIb patients in this study was 12.6%
compared to placebo. The mean change in LDL-cholesterol among Type IIb patients was
–4.1% with LOPID compared to a rise of 3.9% in the placebo subgroup. The Type IIb
subjects in the Helsinki Heart Study had 26 fewer coronary events per thousand persons
over five years in the gemfibrozil group compared to placebo. The difference in coronary
events was substantially greater between LOPID and placebo for that subgroup of
patients with the triad of LDL-cholesterol >175 mg/dL (>4.5 mmol), triglycerides >200
mg/dL (>2.2 mmol), and HDL-cholesterol <35 mg/dL (<0.90 mmol) (see Table I).
Further information is available from a 3.5 year (8.5 year cumulative) follow-up of all
subjects who had participated in the Helsinki Heart Study. At the completion of the
Helsinki Heart Study, subjects could choose to start, stop, or continue to receive LOPID;
without knowledge of their own lipid values or double-blind treatment, 60% of patients
originally randomized to placebo began therapy with LOPID and 60% of patients
originally randomized to LOPID continued medication. After approximately 6.5 years
following randomization, all patients were informed of their original treatment group and
lipid values during the five years of the double-blind treatment. After further elective
changes in LOPID treatment status, 61% of patients in the group originally randomized to
LOPID were taking drug; in the group originally randomized to placebo, 65% were
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taking LOPID. The event rate per 1000 occurring during the open-label follow-up period
is detailed in Table II.
Table II
Cardiac Events and All-Cause Mortality (events per 1000 patients) Occurring During the
3.5 Year Open-Label Follow-up to the Helsinki Heart Study1
Group:
PDrop
PN
PL
LDrop
LN
LL
N=215
N=494
N=1283
N=221
N=574
N=1207
Cardiac
Events
38.8
22.9
22.5
37.2
28.3
25.4
All-Cause
Mortality
41.9
22.3
15.6
72.3
19.2
24.9
1The six open-label groups are designated first by the original randomization
(P = placebo, L = LOPID) and then by the drug taken in the follow-up period (N = Attend
clinic but took no drug, L = LOPID, Drop = No attendance at clinic during open-label).
Cumulative mortality through 8.5 years showed a 20% relative excess of deaths in the
group originally randomized to LOPID versus the originally randomized placebo group
and a 20% relative decrease in cardiac events in the group originally randomized to
LOPID versus the originally randomized placebo group (see Table III). This analysis of
the originally randomized “intent-to-treat’’ population neglects the possible complicating
effects of treatment switching during the open-label phase. Adjustment of hazard ratios,
taking into account open-label treatment status from years 6.5 to 8.5, could change the
reported hazard ratios for mortality toward unity.
Table III
Cardiac Events, Cardiac Deaths, Non-Cardiac Deaths, and All-Cause Mortality in the
Helsinki Heart Study, Years 0–8.51
Event
LOPID
Placebo
LOPID:Placebo
at Study
at Study
Hazard
Cl Hazard
Start
Start
Ratio2
Ratio3
Cardiac
Events4
110
131
0.80
0.62–1.03
Cardiac
Deaths
36
38
0.98
0.63–1.54
Non-Cardiac
Deaths
65
45
1.40
0.95–2.05
All-Cause
Mortality
101
83
1.20
0.90–1.61
1Intention-to-Treat Analysis of originally randomized patients neglecting the open-label
treatment switches and exposure to study conditions.
2Hazard ratio for risk event in the group originally randomized to LOPID compared to the
group originally randomized to placebo neglecting open-label treatment switch and
exposure to study conditions.
395% confidence intervals of LOPID:placebo group hazard ratio
4Fatal and non-fatal myocardial infarctions plus sudden cardiac deaths over the 8.5 year
period.
It is not clear to what extent the findings of the primary prevention component of the
Helsinki Heart Study can be extrapolated to other segments of the dyslipidemic
population not studied (such as women, younger or older males, or those with lipid
abnormalities limited solely to HDL-cholesterol) or to other lipid-altering drugs.
The secondary prevention component of the Helsinki Heart Study was conducted over
five years in parallel and at the same centers in Finland in 628 middle-aged males
excluded from the primary prevention component of the Helsinki Heart Study because of
a history of angina, myocardial infarction, or unexplained ECG changes. The primary
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efficacy endpoint of the study was cardiac events (the sum of fatal and non-fatal
myocardial infarctions and sudden cardiac deaths). The hazard ratio (LOPID:placebo) for
cardiac events was 1.47 (95% confidence limits 0.88–2.48, p=0.14). Of the 35 patients in
the LOPID group who experienced cardiac events, 12 patients suffered events after
discontinuation from the study. Of the 24 patients in the placebo group with cardiac
events, 4 patients suffered events after discontinuation from the study. There were 17
cardiac deaths in the LOPID group and 8 in the placebo group (hazard ratio 2.18; 95%
confidence limits 0.94–5.05, p=0.06). Ten of these deaths in the LOPID group and 3 in
the placebo group occurred after discontinuation from therapy. In this study of patients
with known or suspected coronary heart disease, no benefit from LOPID treatment was
observed in reducing cardiac events or cardiac deaths. Thus, LOPID has shown benefit
only in selected dyslipidemic patients without suspected or established coronary heart
disease. Even in patients with coronary heart disease and the triad of elevated LDL-
cholesterol, elevated triglycerides, plus low HDL-cholesterol, the possible effect of
LOPID on coronary events has not been adequately studied.
No efficacy in the patients with established coronary heart disease was observed during
the Coronary Drug Project with the chemically and pharmacologically related drug,
clofibrate. The Coronary Drug Project was a 6-year randomized, double-blind study
involving 1000 clofibrate, 1000 nicotinic acid, and 3000 placebo patients with known
coronary heart disease. A clinically and statistically significant reduction in myocardial
infarctions was seen in the concurrent nicotinic acid group compared to placebo; no
reduction was seen with clofibrate.
The mechanism of action of gemfibrozil has not been definitely established. In man,
LOPID has been shown to inhibit peripheral lipolysis and to decrease the hepatic
extraction of free fatty acids, thus reducing hepatic triglyceride production. LOPID
inhibits synthesis and increases clearance of VLDL carrier apolipoprotein B, leading to a
decrease in VLDL production.
Animal studies suggest that gemfibrozil may, in addition to elevating HDL-cholesterol,
reduce incorporation of long-chain fatty acids into newly formed triglycerides, accelerate
turnover and removal of cholesterol from the liver, and increase excretion of cholesterol
in the feces. LOPID is well absorbed from the gastrointestinal tract after oral
administration. Peak plasma levels occur in 1 to 2 hours with a plasma half-life of 1.5
hours following multiple doses.
Gemfibrozil is completely absorbed after oral administration of LOPID tablets, reaching
peak plasma concentrations 1 to 2 hours after dosing. Gemfibrozil pharmacokinetics are
affected by the timing of meals relative to time of dosing. In one study (ref. 4), both the
rate and extent of absorption of the drug were significantly increased when administered
0.5 hour before meals. Average AUC was reduced by 14–44% when LOPID was
administered after meals compared to 0.5 hour before meals. In a subsequent study, rate
of absorption of LOPID was maximum when administered 0.5 hour before meals with the
Cmax 50–60% greater than when given either with meals or fasting. In this study, there
were no significant effects on AUC of timing of dose relative to meals (see DOSAGE
AND ADMINISTRATION).
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LOPID mainly undergoes oxidation of a ring methyl group to successively form a
hydroxymethyl and a carboxyl metabolite. Approximately seventy percent of the
administered human dose is excreted in the urine, mostly as the glucuronide conjugate,
with less than 2% excreted as unchanged gemfibrozil. Six percent of the dose is
accounted for in the feces. Gemfibrozil is highly bound to plasma proteins and there is
potential for displacement interactions with other drugs (see PRECAUTIONS).
INDICATIONS AND USAGE
LOPID (gemfibrozil tablets, USP) is indicated as adjunctive therapy to diet for:
1. Treatment of adult patients with very high elevations of serum triglyceride levels
(Types IV and V hyperlipidemia) who present a risk of pancreatitis and who do not
respond adequately to a determined dietary effort to control them. Patients who
present such risk typically have serum triglycerides over 2000 mg/dL and have
elevations of VLDL-cholesterol as well as fasting chylomicrons (Type V
hyperlipidemia). Subjects who consistently have total serum or plasma triglycerides
below 1000 mg/dL are unlikely to present a risk of pancreatitis. LOPID therapy may
be considered for those subjects with triglyceride elevations between 1000 and 2000
mg/dL who have a history of pancreatitis or of recurrent abdominal pain typical of
pancreatitis. It is recognized that some Type IV patients with triglycerides under 1000
mg/dL may, through dietary or alcoholic indiscretion, convert to a Type V pattern
with massive triglyceride elevations accompanying fasting chylomicronemia, but the
influence of LOPID therapy on the risk of pancreatitis in such situations has not been
adequately studied. Drug therapy is not indicated for patients with Type I
hyperlipoproteinemia, who have elevations of chylomicrons and plasma triglycerides,
but who have normal levels of very low density lipoprotein (VLDL). Inspection of
plasma refrigerated for 14 hours is helpful in distinguishing Types I, IV, and V
hyperlipoproteinemia.
2. Reducing the risk of developing coronary heart disease only in Type IIb patients
without history of or symptoms of existing coronary heart disease who have had an
inadequate response to weight loss, dietary therapy, exercise, and other
pharmacologic agents (such as bile acid sequestrants and nicotinic acid, known to
reduce LDL- and raise HDL-cholesterol) and who have the following triad of lipid
abnormalities: low HDL-cholesterol levels in addition to elevated LDL-cholesterol
and elevated triglycerides (see WARNINGS, PRECAUTIONS, and CLINICAL
PHARMACOLOGY). The National Cholesterol Education Program has defined a
serum HDL-cholesterol value that is consistently below 35 mg/dL as constituting an
independent risk factor for coronary heart disease. Patients with significantly elevated
triglycerides should be closely observed when treated with gemfibrozil. In some
patients with high triglyceride levels, treatment with gemfibrozil is associated with a
significant increase in LDL-cholesterol. BECAUSE OF POTENTIAL TOXICITY
SUCH AS MALIGNANCY, GALLBLADDER DISEASE, ABDOMINAL PAIN
LEADING TO APPENDECTOMY AND OTHER ABDOMINAL SURGERIES, AN
INCREASED INCIDENCE IN NON-CORONARY MORTALITY, AND THE 44%
RELATIVE INCREASE DURING THE TRIAL PERIOD IN AGE-ADJUSTED
ALL-CAUSE MORTALITY SEEN WITH THE CHEMICALLY AND
PHARMACOLOGICALLY RELATED DRUG, CLOFIBRATE, THE POTENTIAL
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BENEFIT OF GEMFIBROZIL IN TREATING TYPE IIA PATIENTS WITH
ELEVATIONS OF LDL-CHOLESTEROL ONLY IS NOT LIKELY TO
OUTWEIGH THE RISKS. LOPID IS ALSO NOT INDICATED FOR THE
TREATMENT OF PATIENTS WITH LOW HDL-CHOLESTEROL AS THEIR
ONLY LIPID ABNORMALITY.
In a subgroup analysis of patients in the Helsinki Heart Study with above-median HDL-
cholesterol values at baseline (greater than 46.4 mg/dL), the incidence of serious
coronary events was similar for gemfibrozil and placebo subgroups (see Table I).
The initial treatment for dyslipidemia is dietary therapy specific for the type of
lipoprotein abnormality. Excess body weight and excess alcohol intake may be important
factors in hypertriglyceridemia and should be managed prior to any drug therapy.
Physical exercise can be an important ancillary measure, and has been associated with
rises in HDL-cholesterol. Diseases contributory to hyperlipidemia such as
hypothyroidism or diabetes mellitus should be looked for and adequately treated.
Estrogen therapy is sometimes associated with massive rises in plasma triglycerides,
especially in subjects with familial hypertriglyceridemia. In such cases, discontinuation
of estrogen therapy may obviate the need for specific drug therapy of
hypertriglyceridemia. The use of drugs should be considered only when reasonable
attempts have been made to obtain satisfactory results with nondrug methods. If the
decision is made to use drugs, the patient should be instructed that this does not reduce
the importance of adhering to diet.
CONTRAINDICATIONS
1. Hepatic or severe renal dysfunction, including primary biliary cirrhosis.
2. Preexisting gallbladder disease (see WARNINGS).
3. Hypersensitivity to gemfibrozil.
4. Combination therapy of gemfibrozil with repaglinide (see PRECAUTIONS).
5. Combination therapy of gemfibrozil with simvastatin (see WARNINGS and
PRECAUTIONS).
WARNINGS
1. Because of chemical, pharmacological, and clinical similarities between gemfibrozil
and clofibrate, the adverse findings with clofibrate in two large clinical studies may also
apply to gemfibrozil. In the first of those studies, the Coronary Drug Project, 1000
subjects with previous myocardial infarction were treated for five years with clofibrate.
There was no difference in mortality between the clofibrate-treated subjects and 3000
placebo-treated subjects, but twice as many clofibrate-treated subjects developed
cholelithiasis and cholecystitis requiring surgery. In the other study, conducted by the
World Health Organization (WHO), 5000 subjects without known coronary heart disease
were treated with clofibrate for five years and followed one year beyond. There was a
statistically significant (44%) higher age-adjusted total mortality in the clofibrate-treated
group than in a comparable placebo-treated control group during the trial period. The
excess mortality was due to a 33% increase in non-cardiovascular causes, including
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malignancy, post-cholecystectomy complications, and pancreatitis. The higher risk of
clofibrate-treated subjects for gallbladder disease was confirmed.
Because of the more limited size of the Helsinki Heart Study, the observed difference in
mortality from any cause between the LOPID and placebo groups is not statistically
significantly different from the 29% excess mortality reported in the clofibrate group in
the separate WHO study at the nine year follow-up (see CLINICAL
PHARMACOLOGY). Noncoronary heart disease related mortality showed an excess in
the group originally randomized to LOPID primarily due to cancer deaths observed
during the open-label extension.
During the five year primary prevention component of the Helsinki Heart Study,
mortality from any cause was 44 (2.2%) in the LOPID group and 43 (2.1%) in the
placebo group; including the 3.5 year follow-up period since the trial was completed,
cumulative mortality from any cause was 101 (4.9%) in the LOPID group and 83 (4.1%)
in the group originally randomized to placebo (hazard ratio 1:20 in favor of placebo).
Because of the more limited size of the Helsinki Heart Study, the observed difference in
mortality from any cause between the LOPID and placebo groups at Year-5 or at Year
8.5 is not statistically significantly different from the 29% excess mortality reported in
the clofibrate group in the separate WHO study at the nine year follow-up. Noncoronary
heart disease related mortality showed an excess in the group originally randomized to
LOPID at the 8.5 year follow-up (65 LOPID versus 45 placebo noncoronary deaths).
The incidence of cancer (excluding basal cell carcinoma) discovered during the trial and
in the 3.5 years after the trial was completed was 51 (2.5%) in both originally randomized
groups. In addition, there were 16 basal cell carcinomas in the group originally
randomized to LOPID and 9 in the group originally randomized to placebo (p=0.22).
There were 30 (1.5%) deaths attributed to cancer in the group originally randomized to
LOPID and 18 (0.9%) in the group originally randomized to placebo (p=0.11). Adverse
outcomes, including coronary events, were higher in gemfibrozil patients in a
corresponding study in men with a history of known or suspected coronary heart disease
in the secondary prevention component of the Helsinki Heart Study (see CLINICAL
PHARMACOLOGY).
A comparative carcinogenicity study was also done in rats comparing three drugs in this
class: fenofibrate (10 and 60 mg/kg; 0.3 and 1.6 times the human dose, respectively),
clofibrate (400 mg/kg; 1.6 times the human dose), and gemfibrozil (250 mg/kg; 1.7 times
the human dose). Pancreatic acinar adenomas were increased in males and females on
fenofibrate; hepatocellular carcinoma and pancreatic acinar adenomas were increased in
males and hepatic neoplastic nodules in females treated with clofibrate; hepatic
neoplastic nodules were increased in males and females treated with clofibrate; hepatic
neoplastic nodules were increased in males and females treated with gemfibrozil while
testicular interstitial cell (Leydig cell) tumors were increased in males on all three drugs.
2. A gallstone prevalence substudy of 450 Helsinki Heart Study participants showed a
trend toward a greater prevalence of gallstones during the study within the LOPID
treatment group (7.5% versus 4.9% for the placebo group, a 55% excess for the
gemfibrozil group). A trend toward a greater incidence of gallbladder surgery was
observed for the LOPID group (17 versus 11 subjects, a 54% excess). This result did not
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differ statistically from the increased incidence of cholecystectomy observed in the WHO
study in the group treated with clofibrate. Both clofibrate and gemfibrozil may increase
cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected,
gallbladder studies are indicated. LOPID therapy should be discontinued if gallstones are
found. Cases of cholelithiasis have been reported with gemfibrozil therapy.
3. Since a reduction of mortality from coronary heart disease has not been demonstrated
and because liver and interstitial cell testicular tumors were increased in rats, LOPID
should be administered only to those patients described in the INDICATIONS AND
USAGE section. If a significant serum lipid response is not obtained, LOPID should be
discontinued.
4. Concomitant Anticoagulants – Caution should be exercised when warfarin is given in
conjunction with LOPID. The dosage of warfarin should be reduced to maintain the
prothrombin time at the desired level to prevent bleeding complications. Frequent
prothrombin determinations are advisable until it has been definitely determined that the
prothrombin level has stabilized.
5. The concomitant administration of LOPID with simvastatin is contraindicated (see
CONTRAINDICATIONS and PRECAUTIONS). Concomitant therapy with LOPID
and an HMG-CoA reductase inhibitor is associated with an increased risk of skeletal
muscle toxicity manifested as rhabdomyolysis, markedly elevated creatine kinase (CPK)
levels, and myoglobinuria, leading in a high proportion of cases to acute renal failure and
death. IN PATIENTS WHO HAVE HAD AN UNSATISFACTORY LIPID RESPONSE
TO EITHER DRUG ALONE, THE BENEFIT OF COMBINED THERAPY WITH
LOPID AND an HMG-CoA REDUCTASE INHIBITOR DOES NOT OUTWEIGH THE
RISKS OF SEVERE MYOPATHY, RHABDOMYOLYSIS, AND ACUTE RENAL
FAILURE (see PRECAUTIONS, Drug Interactions). The use of fibrates alone,
including LOPID, may occasionally be associated with myositis. Patients receiving
LOPID and complaining of muscle pain, tenderness, or weakness should have prompt
medical evaluation for myositis, including serum creatine–kinase level determination. If
myositis is suspected or diagnosed, LOPID therapy should be withdrawn.
6. Cataracts – Subcapsular bilateral cataracts occurred in 10%, and unilateral in 6.3%, of
male rats treated with gemfibrozil at 10 times the human dose.
PRECAUTIONS
1. Initial Therapy – Laboratory studies should be done to ascertain that the lipid levels
are consistently abnormal. Before instituting LOPID therapy, every attempt should be
made to control serum lipids with appropriate diet, exercise, weight loss in obese patients,
and control of any medical problems such as diabetes mellitus and hypothyroidism that
are contributing to the lipid abnormalities.
2. Continued Therapy – Periodic determination of serum lipids should be obtained, and
the drug withdrawn if lipid response is inadequate after three months of therapy.
3. Drug Interactions – (A) HMG-CoA Reductase Inhibitors: The concomitant
administration of LOPID with simvastatin is contraindicated (see
CONTRAINDICATIONS and WARNINGS). The risk of myopathy and
rhabdomyolysis is increased with combined gemfibrozil and HMG-CoA reductase
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inhibitor therapy. Myopathy or rhabdomyolysis with or without acute renal failure have
been reported as early as three weeks after initiation of combined therapy or after several
months (see WARNINGS). There is no assurance that periodic monitoring of creatine
kinase will prevent the occurrence of severe myopathy and kidney damage.
(B) Anticoagulants: CAUTION SHOULD BE EXERCISED WHEN WARFARIN IS
GIVEN IN CONJUNCTION WITH LOPID. THE DOSAGE OF WARFARIN SHOULD
BE REDUCED TO MAINTAIN THE PROTHROMBIN TIME AT THE DESIRED
LEVEL TO PREVENT BLEEDING COMPLICATIONS. FREQUENT
PROTHROMBIN DETERMINATIONS ARE ADVISABLE UNTIL IT HAS BEEN
DEFINITELY DETERMINED THAT THE PROTHROMBIN LEVEL HAS
STABILIZED.
(C) Repaglinide: In healthy volunteers, co-administration with gemfibrozil (600 mg
twice daily for 3 days) resulted in an 8.1-fold (range 5.5- to 15.0- fold) higher repaglinide
AUC and a 28.6-fold (range 18.5- to 80.1-fold) higher repaglinide plasma concentration 7
hours after the dose. In the same study, gemfibrozil (600 mg twice daily for 3 days) +
itraconazole (200 mg in the morning and 100 mg in the evening at Day 1, then 100 mg
twice daily at Day 2-3) resulted in a 19.4- (range 12.9- to 24.7-fold) higher repaglinide
AUC and a 70.4-fold (range 42.9- to 119.2-fold) higher repaglinide plasma concentration
7 hours after the dose. In addition, gemfibrozil alone or gemfibrozil + itraconazole
prolonged the hypoglycemic effects of repaglinide. Co-administration of gemfibrozil and
repaglinide increases the risk of severe hypoglycemia and is contraindicated (see
CONTRAINDICATIONS).
(D) Bile Acid-Binding Resins: Gemfibrozil AUC was reduced by 30% when
gemfibrozil was given (600 mg) simultaneously with resin-granule drugs such as
colestipol (5 g). Administration of the drugs two hours or more apart is recommended
because gemfibrozil exposure was not significantly affected when it was administered
two hours apart from colestipol.
(E) Colchicine: Myopathy, including rhabdomyolysis, has been reported with chronic
administration of colchicine at therapeutic doses. Concomitant use of LOPID may
potentiate the development of myopathy. Patients with renal dysfunction and elderly
patients are at increased risk. Caution should be exercised when prescribing LOPID with
colchicine, especially in elderly patients or patients with renal dysfunction.
4. Carcinogenesis, Mutagenesis, Impairment of Fertility – Long-term studies have
been conducted in rats at 0.2 and 1.3 times the human exposure (based on AUC). The
incidence of benign liver nodules and liver carcinomas was significantly increased in
high dose male rats. The incidence of liver carcinomas increased also in low dose males,
but this increase was not statistically significant (p=0.1). Male rats had a dose-related and
statistically significant increase of benign Leydig cell tumors. The higher dose female
rats had a significant increase in the combined incidence of benign and malignant liver
neoplasms.
Long-term studies have been conducted in mice at 0.1 and 0.7 times the human exposure
(based on AUC). There were no statistically significant differences from controls in the
incidence of liver tumors, but the doses tested were lower than those shown to be
carcinogenic with other fibrates.
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Electron microscopy studies have demonstrated a florid hepatic peroxisome proliferation
following LOPID administration to the male rat. An adequate study to test for
peroxisome proliferation has not been done in humans but changes in peroxisome
morphology have been observed. Peroxisome proliferation has been shown to occur in
humans with either of two other drugs of the fibrate class when liver biopsies were
compared before and after treatment in the same individual.
Administration of approximately 2 times the human dose (based on surface area) to male
rats for 10 weeks resulted in a dose-related decrease of fertility. Subsequent studies
demonstrated that this effect was reversed after a drug-free period of about eight weeks,
and it was not transmitted to the offspring.
5. Pregnancy Category C – LOPID has been shown to produce adverse effects in rats
and rabbits at doses between 0.5 and 3 times the human dose (based on surface area).
There are no adequate and well-controlled studies in pregnant women. LOPID should be
used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Administration of LOPID to female rats at 2 times the human dose (based on surface
area) before and throughout gestation caused a dose-related decrease in conception rate,
an increase in stillborns, and a slight reduction in pup weight during lactation. There were
also dose-related increased skeletal variations. Anophthalmia occurred, but rarely.
Administration of 0.6 and 2 times the human dose (based on surface area) of LOPID to
female rats from gestation day 15 through weaning caused dose-related decreases in birth
weight and suppressions of pup growth during lactation.
Administration of 1 and 3 times the human dose (based on surface area) of LOPID to
female rabbits during organogenesis caused a dose-related decrease in litter size and, at
the high dose, an increased incidence of parietal bone variations.
6. Nursing Mothers – It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk and because of the potential for
tumorigenicity shown for LOPID in animal studies, a decision should be made whether to
discontinue nursing or to discontinue the drug, taking into account the importance of the
drug to the mother.
7. Hematologic Changes – Mild hemoglobin, hematocrit, and white blood cell decreases
have been observed in occasional patients following initiation of LOPID therapy.
However, these levels stabilize during long-term administration. Rarely, severe anemia,
leukopenia, thrombocytopenia, and bone marrow hypoplasia have been reported.
Therefore, periodic blood counts are recommended during the first 12 months of LOPID
administration.
8. Liver Function – Abnormal liver function tests have been observed occasionally
during LOPID administration, including elevations of AST, ALT, LDH, bilirubin, and
alkaline phosphatase. These are usually reversible when LOPID is discontinued.
Therefore, periodic liver function studies are recommended and LOPID therapy should
be terminated if abnormalities persist.
9. Kidney Function – There have been reports of worsening renal insufficiency upon the
addition of LOPID therapy in individuals with baseline plasma creatinine >2.0 mg/dL. In
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such patients, the use of alternative therapy should be considered against the risks and
benefits of a lower dose of LOPID.
10. Pediatric Use – Safety and efficacy in pediatric patients have not been established.
ADVERSE REACTIONS
In the double-blind controlled phase of the primary prevention component of the Helsinki
Heart Study, 2046 patients received LOPID for up to five years. In that study, the
following adverse reactions were statistically more frequent in subjects in the LOPID
group:
LOPID
PLACEBO
(N = 2046)
(N = 2035)
Frequency in
percent of subjects
Gastrointestinal reactions
34.2
23.8
Dyspepsia
19.6
11.9
Abdominal pain
9.8
5.6
Acute appendicitis
1.2
0.6
(histologically confirmed in most
cases where data were available)
Atrial fibrillation
0.7
0.1
Adverse events reported by more than 1% of subjects, but without a significant
difference between groups:
Diarrhea
7.2
6.5
Fatigue
3.8
3.5
Nausea/Vomiting
2.5
2.1
Eczema
1.9
1.2
Rash
1.7
1.3
Vertigo
1.5
1.3
Constipation
1.4
1.3
Headache
1.2
1.1
Gallbladder surgery was performed in 0.9% of LOPID and 0.5% of placebo subjects in
the primary prevention component, a 64% excess, which is not statistically different from
the excess of gallbladder surgery observed in the clofibrate group compared to the
placebo group of the WHO study. Gallbladder surgery was also performed more
frequently in the LOPID group compared to the placebo group (1.9% versus 0.3%,
p=0.07) in the secondary prevention component. A statistically significant increase in
appendectomy in the gemfibrozil group was seen also in the secondary prevention
component (6 on gemfibrozil versus 0 on placebo, p=0.014).
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Nervous system and special senses adverse reactions were more common in the LOPID
group. These included hypesthesia, paresthesias, and taste perversion. Other adverse
reactions that were more common among LOPID treatment group subjects but where a
causal relationship was not established include cataracts, peripheral vascular disease, and
intracerebral hemorrhage.
From other studies it seems probable that LOPID is causally related to the occurrence of
MUSCULOSKELETAL SYMPTOMS (see WARNINGS), and to ABNORMAL LIVER
FUNCTION TESTS and HEMATOLOGIC CHANGES (see PRECAUTIONS).
Reports of viral and bacterial infections (common cold, cough, urinary tract infections)
were more common in gemfibrozil treated patients in other controlled clinical trials of
805 patients. Additional adverse reactions that have been reported for gemfibrozil are
listed below by system. These are categorized according to whether a causal relationship
to treatment with LOPID is probable or not established:
CAUSAL RELATIONSHIP
CAUSAL RELATIONSHIP
PROBABLE
NOT ESTABLISHED
General:
weight loss
Cardiac:
extrasystoles
Gastrointestinal:
cholestatic jaundice
pancreatitis
hepatoma
colitis
Central Nervous System: dizziness
confusion
somnolence
convulsions
paresthesia
syncope
peripheral neuritis
decreased libido
depression
headache
Eye:
blurred vision
retinal edema
Genitourinary:
impotence
decreased male fertility
renal dysfunction
Musculoskeletal:
myopathy
myasthenia
myalgia
painful extremities
arthralgia
synovitis
rhabdomyolysis (see
WARNINGS and Drug
Interactions under
PRECAUTIONS)
Clinical Laboratory:
increased creatine phosphokinase positive antinuclear antibody
increased bilirubin
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Hematopoietic:
Immunologic:
Integumentary:
increased liver transaminases
(AST, ALT)
increased alkaline phosphatase
anemia
leukopenia
bone marrow hypoplasia
eosinophilia
angioedema
laryngeal edema
urticaria
exfoliative dermatitis
rash
dermatitis
pruritus
thrombocytopenia
anaphylaxis
Lupus-like syndrome
vasculitis
alopecia
photosensitivity
Additional adverse reactions that have been reported include cholecystitis and
cholelithiasis (see WARNINGS).
DOSAGE AND ADMINISTRATION
The recommended dose for adults is 1200 mg administered in two divided doses 30
minutes before the morning and evening meals (see CLINICAL PHARMACOLOGY).
OVERDOSAGE
There have been reported cases of overdosage with LOPID. In one case, a 7-year-old
child recovered after ingesting up to 9 grams of LOPID. Symptoms reported with
overdosage were abdominal cramps, abnormal liver function tests, diarrhea, increased
CPK, joint and muscle pain, nausea and vomiting. Symptomatic supportive measures
should be taken, should an overdose occur.
HOW SUPPLIED
LOPID (Tablet 737), white, elliptical, film-coated, scored tablets, each containing 600
mg gemfibrozil, are available as follows:
NDC 0071-0737-20: Bottles of 60
NDC 0071-0737-30: Bottles of 500
Store at controlled room temperature 20° – 25°C (68° – 77°F) [see USP]. Protect
from light and humidity.
Rx only company logo
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LAB-0107-10.1
Revised Month 2014
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|
custom-source
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2025-02-12T13:44:43.148431
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018422s054lbl.pdf', 'application_number': 18422, 'submission_type': 'SUPPL ', 'submission_number': 54}
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9676203
TABLETS
DOLOBID®
(DIFLUNISAL)
Cardiovascular Risk
•
NSAIDS may cause an increased risk of serious cardiovascular thrombotic events, myocardial
infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with
cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. (See
WARNINGS.)
•
DOLOBID is contraindicated for the treatment of peri-operative pain in the setting of coronary artery
bypass graft (CABG) surgery (see WARNINGS).
Gastrointestinal Risk
•
NSAIDS cause an increased risk of serious gastrointestinal adverse events including bleeding,
ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur
at any time during use and without warning symptoms. Elderly patients are at greater risk for
serious gastrointestinal events. (See WARNINGS.)
DESCRIPTION
Diflunisal is 2', 4'-difluoro-4-hydroxy-3-biphenylcarboxylic acid. Its empirical formula is C13H8F2O3 and
its structural formula is:
Diflunisal has a molecular weight of 250.20. It is a stable, white, crystalline compound with a melting
point of 211-213°C. It is practically insoluble in water at neutral or acidic pH. Because it is an organic
acid, it dissolves readily in dilute alkali to give a moderately stable solution at room temperature. It is
soluble in most organic solvents including ethanol, methanol, and acetone.
DOLOBID* (Diflunisal) is available in 250 and 500 mg tablets for oral administration. Tablets DOLOBID
contain the following inactive ingredients: cellulose, FD&C Yellow 6, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, magnesium stearate, starch, talc, and titanium dioxide.
CLINICAL PHARMACOLOGY
Action
DOLOBID is a non-steroidal drug with analgesic, anti-inflammatory and antipyretic properties. It is a
peripherally-acting non-narcotic analgesic drug. Habituation, tolerance and addiction have not been
reported.
Diflunisal is a difluorophenyl derivative of salicylic acid. Chemically, diflunisal differs from aspirin
(acetylsalicylic acid) in two respects. The first of these two is the presence of a difluorophenyl substituent
at carbon 1. The second difference is the removal of the 0-acetyl group from the carbon 4 position.
Diflunisal is not metabolized to salicylic acid, and the fluorine atoms are not displaced from the
difluorophenyl ring structure.
The precise mechanism of the analgesic and anti-inflammatory actions of diflunisal is not known.
Diflunisal is a prostaglandin synthetase inhibitor. In animals, prostaglandins sensitize afferent nerves and
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT © 1988, 2005 MERCK & CO., Inc.
All rights reserved
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DOLOBID® (Diflunisal)
9676203
2
potentiate the action of bradykinin in inducing pain. Since prostaglandins are known to be among the
mediators of pain and inflammation, the mode of action of diflunisal may be due to a decrease of
prostaglandins in peripheral tissues.
Pharmacokinetics and Metabolism
DOLOBID is rapidly and completely absorbed following oral administration with peak plasma
concentrations occurring between 2 to 3 hours. The drug is excreted in the urine as two soluble
glucuronide conjugates accounting for about 90% of the administered dose. Little or no diflunisal is
excreted in the feces. Diflunisal appears in human milk in concentrations of 2-7% of those in plasma.
More than 99% of diflunisal in plasma is bound to proteins.
As is the case with salicylic acid, concentration-dependent pharmacokinetics prevail when DOLOBID
is administered; a doubling of dosage produces a greater than doubling of drug accumulation. The effect
becomes more apparent with repetitive doses. Following single doses, peak plasma concentrations of 41
± 11 µg/mL (mean ± S.D.) were observed following 250 mg doses, 87 ± 17 µg/mL were observed
following 500 mg and 124 ± 11 µg/mL following single 1000 mg doses. However, following administration
of 250 mg b.i.d., a mean peak level of 56 ± 14 µg/mL was observed on day 8, while the mean peak level
after 500 mg b.i.d. for 11 days was 190 ± 33 µg/mL. In contrast to salicylic acid which has a plasma half-
life of 2½ hours, the plasma half-life of diflunisal is 3 to 4 times longer (8 to 12 hours), because of a
difluorophenyl substituent at carbon 1. Because of its long half-life and nonlinear pharmacokinetics,
several days are required for diflunisal plasma levels to reach steady state following multiple doses. For
this reason, an initial loading dose is necessary to shorten the time to reach steady state levels, and 2 to
3 days of observation are necessary for evaluating changes in treatment regimens if a loading dose is not
used.
Studies in baboons to determine passage across the blood-brain barrier have shown that only small
quantities of diflunisal, under normal or acidotic conditions are transported into the cerebrospinal fluid
(CSF). The ratio of blood/CSF concentrations after intravenous doses of 50 mg/kg or oral doses of
100 mg/kg of diflunisal was 100:1. In contrast, oral doses of 500 mg/kg of aspirin resulted in a blood/CSF
ratio of 5:1.
Mild to Moderate Pain
DOLOBID is a peripherally-acting analgesic agent with a long duration of action. DOLOBID produces
significant analgesia within 1 hour and maximum analgesia within 2 to 3 hours.
Consistent with its long half-life, clinical effects of DOLOBID mirror its pharmacokinetic behavior,
which is the basis for recommending a loading dose when instituting therapy. Patients treated with
DOLOBID, on the first dose, tend to have a slower onset of pain relief when compared with drugs
achieving comparable peak effects. However, DOLOBID produces longer-lasting responses than the
comparative agents.
Comparative single dose clinical studies have established the analgesic efficacy of DOLOBID at
various dose levels relative to other analgesics. Analgesic effect measurements were derived from hourly
evaluations by patients during eight and twelve-hour postdosing observation periods. The following
information may serve as a guide for prescribing DOLOBID.
DOLOBID 500 mg was comparable in analgesic efficacy to aspirin 650 mg, acetaminophen 600 mg or
650 mg, and acetaminophen 650 mg with propoxyphene napsylate 100 mg. Patients treated with
DOLOBID had longer lasting responses than the patients treated with the comparative analgesics.
DOLOBID 1000 mg was comparable in analgesic efficacy to acetaminophen 600 mg with codeine
60 mg. Patients treated with DOLOBID had longer lasting responses than the patients who received
acetaminophen with codeine.
A loading dose of 1000 mg provides faster onset of pain relief, shorter time to peak analgesic effect,
and greater peak analgesic effect than an initial 500 mg dose.
In contrast to the comparative analgesics, a significantly greater proportion of patients treated with
DOLOBID did not remedicate and continued to have a good analgesic effect eight to twelve hours after
dosing. Seventy-five percent (75%) of patients treated with DOLOBID continued to have a good analgesic
response at four hours. When patients having a good analgesic response at four hours were followed,
78% of these patients continued to have a good analgesic response at eight hours and 64% at twelve
hours.
Chronic Anti-inflammatory Therapy in Osteoarthritis and Rheumatoid Arthritis
In the controlled, double-blind clinical trials in which DOLOBID (500 mg to 1000 mg a day) was
compared with anti-inflammatory doses of aspirin (2-4 grams a day), patients treated with DOLOBID had
a significantly lower incidence of tinnitus and of adverse effects involving the gastrointestinal system than
patients treated with aspirin. (See also Effect on Fecal Blood Loss).
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DOLOBID® (Diflunisal)
9676203
3
Osteoarthritis
The effectiveness of DOLOBID for the treatment of osteoarthritis was studied in patients with
osteoarthritis of the hip and/or knee. The activity of DOLOBID was demonstrated by clinical improvement
in the signs and symptoms of disease activity.
In a double-blind multicenter study of 12 weeks' duration in which dosages were adjusted according to
patient response, DOLOBID, 500 or 750 mg daily, was shown to be comparable in effectiveness to
aspirin, 2000 or 3000 mg daily. In open-label extensions of this study to 24 or 48 weeks, DOLOBID
continued to show similar effectiveness and generally was well tolerated.
Rheumatoid Arthritis
In controlled clinical trials, the effectiveness of DOLOBID was established for both acute
exacerbations and long-term management of rheumatoid arthritis. The activity of DOLOBID was
demonstrated by clinical improvement in the signs and symptoms of disease activity.
In a double-blind multicenter study of 12 weeks' duration in which dosages were adjusted according to
patient response, DOLOBID 500 or 750 mg daily was comparable in effectiveness to aspirin 2600 or
3900 mg daily. In open-label extensions of this study to 52 weeks, DOLOBID continued to be effective
and was generally well tolerated.
DOLOBID 500, 750, or 1000 mg daily was compared with aspirin 2000, 3000, or 4000 mg daily in a
multicenter study of 8 weeks' duration in which dosages were adjusted according to patient response. In
this study, DOLOBID was comparable in efficacy to aspirin.
In a double-blind multicenter study of 12 weeks' duration in which dosages were adjusted according to
patient needs, DOLOBID 500 or 750 mg daily and ibuprofen 1600 or 2400 mg daily were comparable in
effectiveness and tolerability.
In a double-blind multicenter study of 12 weeks' duration, DOLOBID 750 mg daily was comparable in
efficacy to naproxen 750 mg daily. The incidence of gastrointestinal adverse effects and tinnitus was
comparable for both drugs. This study was extended to 48 weeks on an open-label basis. DOLOBID
continued to be effective and generally well tolerated.
In patients with rheumatoid arthritis, DOLOBID and gold salts may be used in combination at their
usual dosage levels. In clinical studies, DOLOBID added to the regimen of gold salts usually resulted in
additional symptomatic relief but did not alter the course of the underlying disease.
Antipyretic Activity
DOLOBID is not recommended for use as an antipyretic agent. In single 250 mg, 500 mg, or 750 mg
doses, DOLOBID produced measurable but not clinically useful decreases in temperature in patients with
fever; however, the possibility that it may mask fever in some patients, particularly with chronic or high
doses, should be considered.
Uricosuric Effect
In normal volunteers, an increase in the renal clearance of uric acid and a decrease in serum uric acid
was observed when DOLOBID was administered at 500 mg or 750 mg daily in divided doses. Patients on
long-term therapy taking DOLOBID at 500 mg to 1000 mg daily in divided doses showed a prompt and
consistent reduction across studies in mean serum uric acid levels, which were lowered as much as
1.4 mg%. It is not known whether DOLOBID interferes with the activity of other uricosuric agents.
Effect on Platelet Function
As an inhibitor of prostaglandin synthetase, DOLOBID has a dose-related effect on platelet function
and bleeding time. In normal volunteers, 250 mg b.i.d. for 8 days had no effect on platelet function, and
500 mg b.i.d., the usual recommended dose, had a slight effect. At 1000 mg b.i.d., which exceeds the
maximum recommended dosage, however, DOLOBID inhibited platelet function. In contrast to aspirin,
these effects of DOLOBID were reversible, because of the absence of the chemically labile and
biologically reactive 0-acetyl group at the carbon 4 position. Bleeding time was not altered by a dose of
250 mg b.i.d., and was only slightly increased at 500 mg b.i.d. At 1000 mg b.i.d., a greater increase
occurred, but was not statistically significantly different from the change in the placebo group.
Effect on Fecal Blood Loss
When DOLOBID was given to normal volunteers at the usual recommended dose of 500 mg twice
daily, fecal blood loss was not significantly different from placebo. Aspirin at 1000 mg four times daily
produced the expected increase in fecal blood loss. DOLOBID at 1000 mg twice daily (NOTE: exceeds
the recommended dosage) caused a statistically significant increase in fecal blood loss, but this increase
was only one-half as large as that associated with aspirin 1300 mg twice daily.
Effect on Blood Glucose
DOLOBID did not affect fasting blood sugar in diabetic patients who were receiving tolbutamide or
placebo.
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DOLOBID® (Diflunisal)
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4
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of DOLOBID and other treatment options before
deciding to use DOLOBID. Use the lowest effective dose for the shortest duration consistent with
individual patient treatment goals (see WARNINGS).
DOLOBID is indicated for acute or long-term use for symptomatic treatment of the following:
1. Mild to moderate pain
2. Osteoarthritis
3. Rheumatoid arthritis
CONTRAINDICATIONS
DOLOBID is contraindicated in patients with known hypersensitivity to diflunisal or the excipients (see
DESCRIPTION).
DOLOBID should not be given to patients who have experienced asthma, urticaria, or allergic-type
reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic/anaphylactoid reactions
to NSAIDS have been reported in such patients (see WARNINGS – Anaphylactic/Anaphylactoid
Reactions, and PRECAUTIONS – Preexisting asthma).
DOLOBID is contraindicated for the treatment of peri-operative pain in the setting of coronary artery
bypass graft (CABG) surgery (see WARNINGS).
WARNINGS
CARDIOVASCULAR EFFECTS
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have
shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and
stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk.
Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the
potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should
be used for the shortest duration possible. Physicians and patients should remain alert for the
development of such events, even in the absence of previous CV symptoms. Patients should be informed
about the signs and/or symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious
CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does
increase the risk of serious GI events (see GI WARNINGS).
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-
14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see
CONTRAINDICATIONS).
Hypertension
NSAIDs, including DOLOBID, can lead to onset of new hypertension or worsening of pre-existing
hypertension, either of which may contribute to the increased incidence of CV events. Patients taking
thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs,
including DOLOBID, should be used with caution in patients with hypertension. Blood pressure (BP)
should be monitored closely during the initiation of NSAID treatment and throughout the course of
therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs. DOLOBID should be
used with caution in patients with fluid retention or heart failure.
Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation
NSAIDs, including DOLOBID, can cause serious gastrointestinal (GI) adverse events including
inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine,
which can be fatal. These serious adverse events can occur at any time, with or without warning
symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI
adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused
by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients
treated for one year. These trends continue with longer duration of use, increasing the likelihood of
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5
developing a serious GI event at some time during the course of therapy. However, even short-term
therapy is not without risk.
NSAIDs should be prescribed with extreme caution in those with prior history of ulcer disease or
gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal
bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared
to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients
treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of
NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous
reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken
in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest
effective dose should be used for the shortest possible duration. Patients and physicians should remain
alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate
additional evaluation and treatment if a serious GI adverse event is suspected. This should include
discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate
therapies that do not involve NSAIDs should be considered.
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in
the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory
drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood
flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are
those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE
inhibitors, patients who are volume-depleted, and the elderly. Discontinuation of NSAID therapy is usually
followed by recovery to the pretreatment state.
Advanced Renal Disease
No information is available from controlled clinical studies regarding the use of DOLOBID in patients
with advanced renal disease. Therefore, treatment with DOLOBID is not recommended in these patients
with advanced renal disease. If DOLOBID therapy must be initiated, close monitoring of the patient’s
renal function is advisable.
Anaphylactic/Anaphylactoid Reactions
As with other NSAIDs, anaphylactic/anaphylactoid reactions may occur in patients without known prior
exposure to DOLOBID. DOLOBID should not be given to patients with the aspirin triad. This symptom
complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who
exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see
CONTRAINDICATIONS and PRECAUTIONS – Preexisting Asthma). Emergency help should be
sought in cases where an anaphylactic/anaphylactoid reaction occurs.
Skin Reactions
NSAIDs, including DOLOBID, can cause serious skin adverse events such as exfoliative dermatitis,
Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These
serious events may occur without warning. Patients should be informed about the signs and symptoms of
serious skin manifestations and use of the drug should be discontinued at the first appearance of skin
rash or any other sign of hypersensitivity.
Hypersensitivity Syndrome
A potentially life-threatening, apparent hypersensitivity syndrome has been reported. This multisystem
syndrome includes constitutional symptoms (fever, chills), and cutaneous findings (see ADVERSE
REACTIONS, Dermatologic). It may also include involvement of major organs (changes in liver function,
jaundice, leukopenia, thrombocytopenia, eosinophilia, disseminated intravascular coagulation, renal
impairment, including renal failure), and less specific findings (adenitis, arthralgia, myalgia, arthritis,
malaise, anorexia, disorientation). If evidence of hypersensitivity occurs, therapy with DOLOBID should
be discontinued.
Pregnancy
In late pregnancy, as with other NSAIDs, DOLOBID should be avoided because it may cause
premature closure of the ductus arteriosus.
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DOLOBID® (Diflunisal)
9676203
6
PRECAUTIONS
General
DOLOBID cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency.
Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged
corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue
corticosteroids.
The pharmacological activity of DOLOBID in reducing fever and inflammation may diminish the utility
of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs
including DOLOBID. These laboratory abnormalities may progress, may remain unchanged, or may be
transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times
the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with
NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant
hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test
has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction
while on therapy with DOLOBID. If clinical signs and symptoms consistent with liver disease develop, or if
systemic manifestations occur (e.g., eosinophilia, rash, etc.), DOLOBID should be discontinued.
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including DOLOBID. This may be due to
fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis.
Patients on long-term treatment with NSAIDs, including DOLOBID, should have their hemoglobin or
hematocrit checked if they exhibit any signs or symptoms of anemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients.
Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible.
Patients receiving DOLOBID who may be adversely affected by alterations in platelet function, such as
those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-
sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross
reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has
been reported in such aspirin-sensitive patients, DOLOBID should not be administered to patients with
this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
Ocular Effects
Because of reports of adverse eye findings with agents of this class, it is recommended that patients
who develop eye complaints during treatment with DOLOBID have ophthalmologic studies.
Reye’s Syndrome
Acetylsalicylic acid has been associated with Reye’s syndrome. Because diflunisal is a derivative of
salicylic acid, the possibility of its association with Reye’s syndrome cannot be excluded.
Information for Patients
Patients should be informed of the following information before initiating therapy with an
NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged
to read the NSAID Medication Guide that accompanies each prescription dispensed.
1. DOLOBID, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may
result in hospitalization and even death. Although serious CV events can occur without warning
symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath,
weakness, slurring of speech, and should ask for medical advice when observing any indicative
sign or symptoms. Patients should be apprised of the importance of this follow-up (see
WARNINGS, CARDIOVASCULAR EFFECTS).
2. DOLOBID, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as
ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract
ulcerations and bleeding can occur without warning symptoms, patients should be alert for the
signs and symptoms of ulcerations and bleeding, and should ask for medical advice when
observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and
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DOLOBID® (Diflunisal)
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7
hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS,
Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation).
3. DOLOBID, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis,
SJS, and TEN, which may result in hospitalizations and even death. Although serious skin
reactions may occur without warning, patients should be alert for the signs and symptoms of skin
rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for
medical advice when observing any indicative signs or symptoms. Patients should be advised to
stop the drug immediately if they develop any type of rash and contact their physicians as soon as
possible.
4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their
physicians.
5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea,
fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If
these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
6. Patients should be informed of the signs of an anaphylactic/anaphylactoid reaction (e.g. difficulty
breathing, swelling of the face or throat). If these occur, patients should be instructed to seek
immediate emergency help (see WARNINGS).
7. In late pregnancy, as with other NSAIDs, DOLOBID should be avoided because it may cause
premature closure of the ductus arteriosus.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians
should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs
should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms
consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash,
etc.) or if abnormal liver tests persist or worsen, DOLOBID should be discontinued.
Drug Interactions
ACE-Inhibitors and Angiotensin II Antagonists
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors and
angiotensin II antagonists. These interactions should be given consideration in patients taking NSAIDs
concomitantly with ACE-inhibitors or angiotensin II antagonists. In some patients with compromised renal
function, the co-administration of an NSAID and an ACE-inhibitor or an angiotensin II antagonist may
result in further deterioration of renal function, including possible acute renal failure, which is usually
reversible.
Acetaminophen
In normal volunteers, concomitant administration of DOLOBID and acetaminophen resulted in an
approximate 50% increase in plasma levels of acetaminophen. Acetaminophen had no effect on plasma
levels of DOLOBID. Since acetaminophen in high doses has been associated with hepatotoxicity,
concomitant administration of DOLOBID and acetaminophen should be used cautiously, with careful
monitoring of patients.
Concomitant administration of DOLOBID and acetaminophen in dogs, but not in rats, at approximately
2 times the recommended maximum human therapeutic dose of each (40-52 mg/kg/day of
DOLOBID/acetaminophen), resulted in greater gastrointestinal toxicity than when either drug was
administered alone. The clinical significance of these findings has not been established.
Antacids
Concomitant administration of antacids may reduce plasma levels of DOLOBID. This effect is small
with occasional doses of antacids, but may be clinically significant when antacids are used on a
continuous schedule.
Aspirin
When DOLOBID is administered with aspirin, its protein binding is reduced, although the clearance of
free DOLOBID is not altered. The clinical significance of this interaction is not known; however, as with
other NSAIDs, concomitant administration of diflunisal and aspirin is not generally recommended
because of the potential of increased adverse effects.
In normal volunteers, a small decrease in diflunisal levels was observed when multiple doses of
DOLOBID and aspirin were administered concomitantly.
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8
Cyclosporine
Administration of non-steroidal anti-inflammatory drugs concomitantly with cyclosporine has been
associated with an increase in cyclosporine-induced toxicity, possibly due to decreased synthesis of renal
prostacyclin. NSAIDs should be used with caution in patients taking cyclosporine, and renal function
should be carefully monitored.
Diuretics
Clinical studies, as well as post marketing observations, have shown that DOLOBID can reduce the
natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to
inhibition of renal prostaglandin synthesis.
In normal volunteers, concomitant administration of DOLOBID and hydrochlorothiazide resulted in
significantly increased plasma levels of hydrochlorothiazide. DOLOBID decreased the hyperuricemic
effect of hydrochlorothiazide. During concomitant therapy with NSAIDs, the patient should be observed
closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy.
Lithium
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium
clearance. The mean minimum lithium concentration increased 15% and the renal clearance was
decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin
synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should
be observed carefully for signs of lithium toxicity.
Methotrexate
NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices.
This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when
NSAIDs are administered concomitantly with methotrexate.
NSAIDs
The administration of diflunisal to normal volunteers receiving indomethacin decreased the renal
clearance and significantly increased the plasma levels of indomethacin. In some patients the combined
use of indomethacin and DOLOBID has been associated with fatal gastrointestinal hemorrhage.
Therefore, indomethacin and DOLOBID should not be used concomitantly.
The concomitant use of DOLOBID and other NSAIDs is not recommended due to the increased
possibility of gastrointestinal toxicity, with little or no increase in efficacy. The following information was
obtained from studies in normal volunteers.
Sulindac: The concomitant administration of DOLOBID and sulindac in normal volunteers resulted in
lowering of the plasma levels of the active sulindac sulfide metabolite by approximately one-third.
Naproxen: The concomitant administration of DOLOBID and naproxen in normal volunteers had no
effect on the plasma levels of naproxen, but significantly decreased the urinary excretion of naproxen and
its glucuronide metabolite. Naproxen had no effect on plasma levels of DOLOBID.
Oral Anticoagulants
In some normal volunteers, the concomitant administration of DOLOBID and warfarin, acenocoumarol,
or phenprocoumon resulted in prolongation of prothrombin time. This may occur because diflunisal
competitively displaces coumarins from protein binding sites. Accordingly, when DOLOBID is
administered with oral anticoagulants, the prothrombin time should be closely monitored during and for
several days after concomitant drug administration. Adjustment of dosage of oral anticoagulants may be
required. The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both
drugs together have a risk of serious GI bleeding higher than users of either drug alone.
Tolbutamide
In diabetic patients receiving DOLOBID and tolbutamide, no significant effects were seen on
tolbutamide plasma levels or fasting blood glucose.
Drug/Laboratory Test Interactions
Serum Salicylate Assays: Caution should be used in interpreting the results of serum salicylate assays
when diflunisal is present. Salicylate levels have been found to be falsely elevated with some assay
methods.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Diflunisal did not affect the type or incidence of neoplasia in a 105-week study in the rat given doses
up to 40 mg/kg/day (equivalent to approximately 1.3 times the maximum recommended human dose), or
in long-term carcinogenic studies in mice given diflunisal at doses up to 80 mg/kg/day (equivalent to
approximately 2.7 times the maximum recommended human dose). It was concluded that there was no
carcinogenic potential for DOLOBID.
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Diflunisal passes the placental barrier to a minor degree in the rat. Diflunisal had no mutagenic activity
after oral administration in the dominant lethal assay, in the Ames microbial mutagen test or in the V-79
Chinese hamster lung cell assay.
No evidence of impaired fertility was found in reproduction studies in rats at doses up to 50 mg/kg/day.
Pregnancy
Teratogenic Effects. Pregnancy Category C
A dose of 60 mg/kg/day of diflunisal (equivalent to two times the maximum human dose) was
maternotoxic, embryotoxic, and teratogenic in rabbits. In three of six studies in rabbits, evidence of
teratogenicity was observed at doses ranging from 40 to 50 mg/kg/day. Teratology studies in mice, at
doses up to 45 mg/kg/day, and in rats at doses up to 100 mg/kg/day, revealed no harm to the fetus due to
diflunisal. Aspirin and other salicylates have been shown to be teratogenic in a wide variety of species,
including the rat and rabbit, at doses ranging from 50 to 400 mg/kg/day (approximately one to eight times
the human dose). Animal reproduction studies are not always predictive of human response. There are
no adequate and well controlled studies with diflunisal in pregnant women. DOLOBID should be used in
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects
Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular
system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be
avoided.
The known effects of drugs of this class on the human fetus during the third trimester of pregnancy
include: constriction of the ductus arteriosus prenatally, tricuspid incompetence, and pulmonary
hypertension; non-closure of the ductus arteriosus postnatally which may be resistant to medical
management; myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial
bleeding, renal dysfunction or failure, renal injury/dysgenesis which may result in prolonged or permanent
renal failure, oligohydramnios, gastrointestinal bleeding or perforation, and increased risk of necrotizing
enterocolitis.
In rats at a dose of one and one-half times the maximum human dose, there was an increase in the
average length of gestation. Similar increases in the length of gestation have been observed with aspirin,
indomethacin, and phenylbutazone, and may be related to inhibition of prostaglandin synthetase.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased
incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of DOLOBID
on labor and delivery in pregnant women are unknown.
Nursing Mothers
Diflunisal is excreted in human milk in concentrations of 2-7% of those in plasma. Because of the
potential for serious adverse reactions in nursing infants from DOLOBID, a decision should be made
whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug
to the mother.
Pediatric Use
Safety and effectiveness of DOLOBID in pediatric patients below the age of 12 have not been
established. Use of DOLOBID in pediatric patients below the age of 12 is not recommended.
The adverse effects observed following diflunisal administration to neonatal animals appear to be
species, age, and dose-dependent. At dose levels approximately 3 times the usual human therapeutic
dose, both aspirin (200 to 400 mg/kg/day) and diflunisal (80 mg/kg/day) resulted in death, leukocytosis,
weight loss, and bilateral cataracts in neonatal (4 to 5-day-old) beagle puppies after 2 to 10 doses.
Administration of an 80 mg/kg/day dose of diflunisal to 25-day-old puppies resulted in lower mortality, and
did not produce cataracts. In newborn rats, a 400 mg/kg/day dose of aspirin resulted in increased
mortality and some cataracts, whereas the effects of diflunisal administration at doses up to 140
mg/kg/day were limited to a decrease in average body weight gain.
Geriatric Use
As with any NSAID, caution should be exercised in treating the elderly (65 years and older) since
advancing age appears to increase the possibility of adverse reactions. Elderly patients seem to tolerate
ulceration or bleeding less well than other individuals and many spontaneous reports of fatal GI events
are in this population (see WARNINGS, Gastrointestinal Effects – Risk of Ulceration, Bleeding, and
Perforation).
This drug is known to be substantially excreted by the kidney and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely to
have decreased renal function, care should be taken in dose selection and it may be useful to monitor
renal function (see WARNINGS, Renal Effects).
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ADVERSE REACTIONS
The adverse reactions observed in controlled clinical trials encompass observations in 2,427 patients.
Listed below are the adverse reactions reported in the 1,314 of these patients who received treatment
in studies of two weeks or longer. Five hundred thirteen patients were treated for at least 24 weeks, 255
patients were treated for at least 48 weeks, and 46 patients were treated for 96 weeks. In general, the
adverse reactions listed below were 2 to 14 times less frequent in the 1,113 patients who received short-
term treatment for mild to moderate pain.
Incidence Greater Than 1%
Gastrointestinal
The most frequent types of adverse reactions occurring with DOLOBID are gastrointestinal: these
include nausea** , vomiting, dyspepsia**, gastrointestinal pain**, diarrhea**, constipation, and flatulence.
Psychiatric
Somnolence, insomnia.
Central Nervous System
Dizziness.
Special Senses
Tinnitus.
Dermatologic
Rash**.
Miscellaneous
Headache**, fatigue/tiredness.
Incidence Less Than 1 in 100
The following adverse reactions, occurring less frequently than 1 in 100, were reported in clinical trials
or since the drug was marketed. The probability exists of a causal relationship between DOLOBID and
these adverse reactions.
Dermatologic
Erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis,
urticaria, pruritus, sweating, dry mucous membranes, stomatitis, photosensitivity.
Gastrointestinal
Peptic ulcer, gastrointestinal bleeding, anorexia, eructation, gastrointestinal perforation, gastritis.
Liver function abnormalities; jaundice, sometimes with fever; cholestasis; hepatitis.
Hematologic
Thrombocytopenia; agranulocytosis; hemolytic anemia.
Genitourinary
Dysuria; renal impairment, including renal failure; interstitial nephritis; hematuria; proteinuria.
Psychiatric
Nervousness, depression, hallucinations, confusion, disorientation.
Central Nervous System
Vertigo; light-headedness; paresthesias.
Special Senses
Transient visual disturbances including blurred vision.
Hypersensitivity Reactions
Acute anaphylactic reaction with bronchospasm; angioedema; flushing.
Hypersensitivity vasculitis.
Hypersensitivity syndrome (see WARNINGS, Hypersensitivity Syndrome).
Miscellaneous
Asthenia, edema.
Causal Relationship Unknown
Other reactions have been reported in clinical trials or since the drug was marketed, but occurred
under circumstances where a causal relationship could not be established. However, in these rarely
reported events, that possibility cannot be excluded. Therefore, these observations are listed to serve as
alerting information to physicians.
**Incidence between 3% and 9%. Those reactions occurring in 1% to 3% are not marked with an asterisk.
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Respiratory
Dyspnea.
Cardiovascular
Palpitation, syncope.
Musculoskeletal
Muscle cramps.
Genitourinary
Nephrotic syndrome.
Special Senses
Hearing loss.
Miscellaneous
Chest pain.
A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group A β-hemolytic
streptococcus, has been described in persons treated with non-steroidal anti-inflammatory agents,
including diflunisal, sometimes with fatal outcome (see also PRECAUTIONS, General).
Potential Adverse Effects
In addition, a variety of adverse effects not observed with DOLOBID in clinical trials or in marketing
experience, but reported with other non-steroidal analgesic/anti-inflammatory agents, should be
considered potential adverse effects of DOLOBID.
OVERDOSAGE
Cases of overdosage have occurred and deaths have been reported. Most patients recovered without
evidence of permanent sequelae. The most common signs and symptoms observed with overdosage
were drowsiness, vomiting, nausea, diarrhea, hyperventilation, tachycardia, sweating, tinnitus,
disorientation, stupor and coma. Diminished urine output and cardiorespiratory arrest have also been
reported. The lowest dosage of DOLOBID at which a death has been reported was 15 grams without the
presence of other drugs. In a mixed drug overdose, ingestion of 7.5 grams of DOLOBID resulted in death.
In the event of overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage,
and the patient carefully observed and given symptomatic and supportive treatment. Because of the high
degree of protein binding, hemodialysis may not be effective.
The oral LD50 of the drug is 500 mg/kg and 826 mg/kg in female mice and female rats respectively.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of DOLOBID and other treatment options before
deciding to use DOLOBID. Use the lowest effective dose for the shortest duration consistent with
individual patient treatment goals (see WARNINGS).
After observing the response to initial therapy with DOLOBID, the dose and frequency should be
adjusted to suit an individual patient’s needs.
Concentration-dependent pharmacokinetics prevail when DOLOBID is administered; a doubling of
dosage produces a greater than doubling of drug accumulation. The effect becomes more apparent with
repetitive doses.
For mild to moderate pain, an initial dose of 1000 mg followed by 500 mg every 12 hours is
recommended for most patients. Following the initial dose, some patients may require 500 mg every 8
hours.
A lower dosage may be appropriate depending on such factors as pain severity, patient response,
weight, or advanced age; for example, 500 mg initially, followed by 250 mg every 8-12 hours.
For osteoarthritis and rheumatoid arthritis, the suggested dosage range is 500 mg to 1000 mg daily in
two divided doses. The dosage of DOLOBID may be increased or decreased according to patient
response.
Maintenance doses higher than 1500 mg a day are not recommended.
Tablets should be swallowed whole, not crushed or chewed.
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12
HOW SUPPLIED
Tablets DOLOBID are capsule-shaped, film-coated tablets supplied as follows:
No. 3390 250 mg peach colored, coded DOLOBID on one side and MSD 675 on the other.
NDC 0006-0675-61 unit of use bottles of 60
(6505-01-164-0501, 250 mg 60's).
No. 3392 500 mg orange colored, coded DOLOBID on one side and MSD 697 on the other.
NDC 0006-0697-61 unit of use bottles of 60
(6505-01-144-9724, 500 mg 60's).
Distributed by:
Issued January 2007
Printed in USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9676203
Medication Guide
for
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID medicines.)
What is the most important information I should know about medicines called Non-
Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or stroke that can lead to
death. This chance increases:
•
with longer use of NSAID medicines
•
in people who have heart disease
NSAID medicines should never be used right before or after a heart surgery called a
“coronary artery bypass graft (CABG).”
NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any
time during treatment.
Ulcers and bleeding:
•
can happen without warning symptoms
•
may cause death
The chance of a person getting an ulcer or bleeding increases with:
•
taking medicines called “corticosteroids” and “anticoagulants”
•
longer use
•
smoking
•
drinking alcohol
•
older age
•
having poor health
NSAID medicines should only be used:
•
exactly as prescribed
•
at the lowest dose possible for your treatment
•
for the shortest time needed
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from
medical conditions such as:
•
different types of arthritis
•
menstrual cramps and other types of short-term pain
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
•
if you had an asthma attack, hives, or other allergic reaction with aspirin or any other
NSAID medicine
•
for pain right before or after heart bypass surgery
Tell your healthcare provider:
•
about all of your medical conditions.
•
about all of the medicines you take. NSAIDs and some other medicines can interact
with each other and cause serious side effects. Keep a list of your medicines to
show to your healthcare provider and pharmacist.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9676203
2
•
if you are pregnant. NSAID medicines should not be used by pregnant women
late in their pregnancy.
•
if you are breastfeeding. Talk to your doctor.
What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
Serious side effects include:
•
heart attack
•
stroke
•
high blood pressure
•
heart failure from body swelling (fluid
retention)
•
kidney problems including kidney failure
•
bleeding and ulcers in the stomach and
intestine
•
low red blood cells (anemia)
•
life-threatening skin reactions
•
life-threatening allergic reactions
•
liver problems including liver failure
•
asthma attacks in people who have asthma
Other side effects include:
•
stomach pain
•
constipation
•
diarrhea
•
gas
•
heartburn
•
nausea
•
vomiting
•
dizziness
Get emergency help right away if you have any of the following symptoms:
•
shortness of breath or trouble breathing
•
slurred speech
•
chest pain
•
swelling of the face or throat
•
weakness in one part or side of your body
Stop your NSAID medicine and call your healthcare provider right away if you have any of
the following symptoms:
•
nausea
•
more tired or weaker than usual
•
itching
•
there is blood in your bowel
movement or it is black and
sticky like tar
•
your skin or eyes look yellow
•
unusual weight gain
•
stomach pain
•
flu-like symptoms
•
skin rash or blisters with fever
•
vomit blood
•
swelling of the arms and legs,
hands and feet
These are not all the side effects with NSAID medicines. Talk to your healthcare provider or
pharmacist for more information about NSAID medicines.
Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
•
Aspirin is an NSAID medicine but it does not increase the chance of a heart attack.
Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause
ulcers in the stomach and intestines.
•
Some of these NSAID medicines are sold in lower doses without a prescription (over-the-
counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more
than 10 days.
NSAID medicines that need a prescription
Generic Name
Tradename
Celecoxib
Celebrex
Diclofenac
Cataflam, Voltaren, Arthrotec (combined with misoprostol)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9676203
* Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is
usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term
continuous use may increase the risk of heart attack or stroke.
3
Diflunisal
Dolobid
Etodolac
Lodine, Lodine XL
Fenoprofen
Nalfon, Nalfon 200
Flurbiprofen
Ansaid
Ibuprofen
Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone),
Combunox (combined with oxycodone)
Indomethacin
Indocin, Indocin SR, Indo-Lemmon, Indomethegan
Ketoprofen
Oruvail
Ketorolac
Toradol
Mefenamic Acid
Ponstel
Meloxicam
Mobic
Nabumetone
Relafen
Naproxen
Naprosyn, Anaprox, Anaprox DS, EC-Naprosyn, Naprelan,
Naprapac (copackaged with lansoprazole)
Oxaprozin
Daypro
Piroxicam
Feldene
Sulindac
Clinoril
Tolmetin
Tolectin, Tolectin DS, Tolectin 600
This Medication Guide has been approved by the U.S. Food and Drug Administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:43.187758
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018445s058lbl.pdf', 'application_number': 18445, 'submission_type': 'SUPPL ', 'submission_number': 58}
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11,217
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LOPID
(Gemfibrozil Tablets, USP)
DESCRIPTION
LOPID® (gemfibrozil tablets, USP) is a lipid regulating agent. It is available as tablets for
oral administration. Each tablet contains 600 mg gemfibrozil. Each tablet also contains
calcium stearate, NF; candelilla wax, FCC; microcrystalline cellulose, NF;
hydroxypropyl cellulose, NF; hypromellose, USP; methylparaben, NF; Opaspray white;
polyethylene glycol, NF; polysorbate 80, NF; propylparaben, NF; colloidal silicon
dioxide, NF; pregelatinized starch, NF. The chemical name is 5-(2,5-dimethylphenoxy)
2,2-dimethylpentanoic acid, with the following structural formula: structural formula
The empirical formula is C15H22O3 and the molecular weight is 250.35; the solubility in
water and acid is 0.0019% and in dilute base it is greater than 1%. The melting point is
58° –61°C. Gemfibrozil is a white solid which is stable under ordinary conditions.
CLINICAL PHARMACOLOGY
LOPID is a lipid regulating agent which decreases serum triglycerides and very low
density lipoprotein (VLDL) cholesterol, and increases high density lipoprotein (HDL)
cholesterol. While modest decreases in total and low density lipoprotein (LDL)
cholesterol may be observed with LOPID therapy, treatment of patients with elevated
triglycerides due to Type IV hyperlipoproteinemia often results in a rise in LDL-
cholesterol. LDL-cholesterol levels in Type IIb patients with elevations of both serum
LDL-cholesterol and triglycerides are, in general, minimally affected by LOPID
treatment; however, LOPID usually raises HDL-cholesterol significantly in this group.
LOPID increases levels of high density lipoprotein (HDL) subfractions HDL2 and HDL3,
as well as apolipoproteins AI and AII. Epidemiological studies have shown that both low
HDL-cholesterol and high LDL-cholesterol are independent risk factors for coronary
heart disease.
In the primary prevention component of the Helsinki Heart Study, in which 4081 male
patients between the ages of 40 and 55 were studied in a randomized, double-blind,
placebo-controlled fashion, LOPID therapy was associated with significant reductions in
total plasma triglycerides and a significant increase in high density lipoprotein
cholesterol. Moderate reductions in total plasma cholesterol and low density lipoprotein
cholesterol were observed for the LOPID treatment group as a whole, but the lipid
response was heterogeneous, especially among different Fredrickson types. The study
involved subjects with serum non-HDL-cholesterol of over 200 mg/dL and no previous
Reference ID: 3399646
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history of coronary heart disease. Over the five-year study period, the LOPID group
experienced a 1.4% absolute (34% relative) reduction in the rate of serious coronary
events (sudden cardiac deaths plus fatal and nonfatal myocardial infarctions) compared to
placebo, p=0.04 (see Table I). There was a 37% relative reduction in the rate of nonfatal
myocardial infarction compared to placebo, equivalent to a treatment-related difference
of 13.1 events per thousand persons. Deaths from any cause during the double-blind
portion of the study totaled 44 (2.2%) in the LOPID randomization group and 43 (2.1%)
in the placebo group.
Table I
Reduction in CHD Rates (events per 1000 patients) by Baseline Lipids1 in the
Helsinki Heart Study, Years 0–52
All
LDL-C>175;
LDL-C>175;
LDL-C>175;
Patients
HDL-C>46.4
TG>177
TG>200;
HDL-C<35
P
L
Dif3
P
L
Dif
P
L
Dif
P
L
Dif
Incidence of
Events4
41
27
14
32
29
3
71
44
27
149
64
85
1lipid values in mg/dL at baseline
2P = placebo group; L= LOPID group
3difference in rates between placebo and LOPID groups
4fatal and nonfatal myocardial infarctions plus sudden cardiac deaths (events per 1000 patients over 5
years)
Among Fredrickson types, during the 5-year double-blind portion of the primary
prevention component of the Helsinki Heart Study, the greatest reduction in the incidence
of serious coronary events occurred in Type IIb patients who had elevations of both LDL-
cholesterol and total plasma triglycerides. This subgroup of Type IIb gemfibrozil group
patients had a lower mean HDL-cholesterol level at baseline than the Type IIa subgroup
that had elevations of LDL-cholesterol and normal plasma triglycerides. The mean
increase in HDL-cholesterol among the Type IIb patients in this study was 12.6%
compared to placebo. The mean change in LDL-cholesterol among Type IIb patients was
–4.1% with LOPID compared to a rise of 3.9% in the placebo subgroup. The Type IIb
subjects in the Helsinki Heart Study had 26 fewer coronary events per thousand persons
over five years in the gemfibrozil group compared to placebo. The difference in coronary
events was substantially greater between LOPID and placebo for that subgroup of
patients with the triad of LDL-cholesterol >175 mg/dL (>4.5 mmol), triglycerides >200
mg/dL (>2.2 mmol), and HDL-cholesterol <35 mg/dL (<0.90 mmol) (see Table I).
Further information is available from a 3.5 year (8.5 year cumulative) follow-up of all
subjects who had participated in the Helsinki Heart Study. At the completion of the
Helsinki Heart Study, subjects could choose to start, stop, or continue to receive LOPID;
without knowledge of their own lipid values or double-blind treatment, 60% of patients
originally randomized to placebo began therapy with LOPID and 60% of patients
originally randomized to LOPID continued medication. After approximately 6.5 years
following randomization, all patients were informed of their original treatment group and
lipid values during the five years of the double-blind treatment. After further elective
changes in LOPID treatment status, 61% of patients in the group originally randomized to
LOPID were taking drug; in the group originally randomized to placebo, 65% were
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taking LOPID. The event rate per 1000 occurring during the open-label follow-up period
is detailed in Table II.
Table II
Cardiac Events and All-Cause Mortality (events per 1000 patients) Occurring During the
3.5 Year Open-Label Follow-up to the Helsinki Heart Study1
Group:
PDrop
PN
PL
LDrop
LN
LL
N=215
N=494
N=1283
N=221
N=574
N=1207
Cardiac
Events
38.8
22.9
22.5
37.2
28.3
25.4
All-Cause
Mortality
41.9
22.3
15.6
72.3
19.2
24.9
1The six open-label groups are designated first by the original randomization
(P = placebo, L = LOPID) and then by the drug taken in the follow-up period (N = Attend
clinic but took no drug, L = LOPID, Drop = No attendance at clinic during open-label).
Cumulative mortality through 8.5 years showed a 20% relative excess of deaths in the
group originally randomized to LOPID versus the originally randomized placebo group
and a 20% relative decrease in cardiac events in the group originally randomized to
LOPID versus the originally randomized placebo group (see Table III). This analysis of
the originally randomized “intent-to-treat’’ population neglects the possible complicating
effects of treatment switching during the open-label phase. Adjustment of hazard ratios,
taking into account open-label treatment status from years 6.5 to 8.5, could change the
reported hazard ratios for mortality toward unity.
Table III
Cardiac Events, Cardiac Deaths, Non-Cardiac Deaths, and All-Cause Mortality in the
Helsinki Heart Study, Years 0–8.51
Event
LOPID
Placebo
LOPID:Placebo
at Study
at Study
Hazard
Cl Hazard
Start
Start
Ratio2
Ratio3
Cardiac
Events4
110
131
0.80
0.62–1.03
Cardiac
Deaths
36
38
0.98
0.63–1.54
Non-Cardiac
Deaths
65
45
1.40
0.95–2.05
All-Cause
Mortality
101
83
1.20
0.90–1.61
1Intention-to-Treat Analysis of originally randomized patients neglecting the open-label
treatment switches and exposure to study conditions.
2Hazard ratio for risk event in the group originally randomized to LOPID compared to the
group originally randomized to placebo neglecting open-label treatment switch and
exposure to study conditions.
395% confidence intervals of LOPID:placebo group hazard ratio
4Fatal and non-fatal myocardial infarctions plus sudden cardiac deaths over the 8.5 year
period.
It is not clear to what extent the findings of the primary prevention component of the
Helsinki Heart Study can be extrapolated to other segments of the dyslipidemic
population not studied (such as women, younger or older males, or those with lipid
abnormalities limited solely to HDL-cholesterol) or to other lipid-altering drugs.
The secondary prevention component of the Helsinki Heart Study was conducted over
five years in parallel and at the same centers in Finland in 628 middle-aged males
excluded from the primary prevention component of the Helsinki Heart Study because of
a history of angina, myocardial infarction, or unexplained ECG changes. The primary
Reference ID: 3399646
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efficacy endpoint of the study was cardiac events (the sum of fatal and non-fatal
myocardial infarctions and sudden cardiac deaths). The hazard ratio (LOPID:placebo) for
cardiac events was 1.47 (95% confidence limits 0.88–2.48, p=0.14). Of the 35 patients in
the LOPID group who experienced cardiac events, 12 patients suffered events after
discontinuation from the study. Of the 24 patients in the placebo group with cardiac
events, 4 patients suffered events after discontinuation from the study. There were 17
cardiac deaths in the LOPID group and 8 in the placebo group (hazard ratio 2.18; 95%
confidence limits 0.94–5.05, p=0.06). Ten of these deaths in the LOPID group and 3 in
the placebo group occurred after discontinuation from therapy. In this study of patients
with known or suspected coronary heart disease, no benefit from LOPID treatment was
observed in reducing cardiac events or cardiac deaths. Thus, LOPID has shown benefit
only in selected dyslipidemic patients without suspected or established coronary heart
disease. Even in patients with coronary heart disease and the triad of elevated LDL-
cholesterol, elevated triglycerides, plus low HDL-cholesterol, the possible effect of
LOPID on coronary events has not been adequately studied.
No efficacy in the patients with established coronary heart disease was observed during
the Coronary Drug Project with the chemically and pharmacologically related drug,
clofibrate. The Coronary Drug Project was a 6-year randomized, double-blind study
involving 1000 clofibrate, 1000 nicotinic acid, and 3000 placebo patients with known
coronary heart disease. A clinically and statistically significant reduction in myocardial
infarctions was seen in the concurrent nicotinic acid group compared to placebo; no
reduction was seen with clofibrate.
The mechanism of action of gemfibrozil has not been definitely established. In man,
LOPID has been shown to inhibit peripheral lipolysis and to decrease the hepatic
extraction of free fatty acids, thus reducing hepatic triglyceride production. LOPID
inhibits synthesis and increases clearance of VLDL carrier apolipoprotein B, leading to a
decrease in VLDL production.
Animal studies suggest that gemfibrozil may, in addition to elevating HDL-cholesterol,
reduce incorporation of long-chain fatty acids into newly formed triglycerides, accelerate
turnover and removal of cholesterol from the liver, and increase excretion of cholesterol
in the feces. LOPID is well absorbed from the gastrointestinal tract after oral
administration. Peak plasma levels occur in 1 to 2 hours with a plasma half-life of 1.5
hours following multiple doses.
Gemfibrozil is completely absorbed after oral administration of LOPID tablets, reaching
peak plasma concentrations 1 to 2 hours after dosing. Gemfibrozil pharmacokinetics are
affected by the timing of meals relative to time of dosing. In one study (ref. 4), both the
rate and extent of absorption of the drug were significantly increased when administered
0.5 hour before meals. Average AUC was reduced by 14–44% when LOPID was
administered after meals compared to 0.5 hour before meals. In a subsequent study, rate
of absorption of LOPID was maximum when administered 0.5 hour before meals with the
Cmax 50–60% greater than when given either with meals or fasting. In this study, there
were no significant effects on AUC of timing of dose relative to meals (see DOSAGE
AND ADMINISTRATION).
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LOPID mainly undergoes oxidation of a ring methyl group to successively form a
hydroxymethyl and a carboxyl metabolite. Approximately seventy percent of the
administered human dose is excreted in the urine, mostly as the glucuronide conjugate,
with less than 2% excreted as unchanged gemfibrozil. Six percent of the dose is
accounted for in the feces. Gemfibrozil is highly bound to plasma proteins and there is
potential for displacement interactions with other drugs (see PRECAUTIONS).
INDICATIONS AND USAGE
LOPID (gemfibrozil tablets, USP) is indicated as adjunctive therapy to diet for:
1. Treatment of adult patients with very high elevations of serum triglyceride levels
(Types IV and V hyperlipidemia) who present a risk of pancreatitis and who do not
respond adequately to a determined dietary effort to control them. Patients who
present such risk typically have serum triglycerides over 2000 mg/dL and have
elevations of VLDL-cholesterol as well as fasting chylomicrons (Type V
hyperlipidemia). Subjects who consistently have total serum or plasma triglycerides
below 1000 mg/dL are unlikely to present a risk of pancreatitis. LOPID therapy may
be considered for those subjects with triglyceride elevations between 1000 and 2000
mg/dL who have a history of pancreatitis or of recurrent abdominal pain typical of
pancreatitis. It is recognized that some Type IV patients with triglycerides under 1000
mg/dL may, through dietary or alcoholic indiscretion, convert to a Type V pattern
with massive triglyceride elevations accompanying fasting chylomicronemia, but the
influence of LOPID therapy on the risk of pancreatitis in such situations has not been
adequately studied. Drug therapy is not indicated for patients with Type I
hyperlipoproteinemia, who have elevations of chylomicrons and plasma triglycerides,
but who have normal levels of very low density lipoprotein (VLDL). Inspection of
plasma refrigerated for 14 hours is helpful in distinguishing Types I, IV, and V
hyperlipoproteinemia.
2. Reducing the risk of developing coronary heart disease only in Type IIb patients
without history of or symptoms of existing coronary heart disease who have had an
inadequate response to weight loss, dietary therapy, exercise, and other
pharmacologic agents (such as bile acid sequestrants and nicotinic acid, known to
reduce LDL- and raise HDL-cholesterol) and who have the following triad of lipid
abnormalities: low HDL-cholesterol levels in addition to elevated LDL-cholesterol
and elevated triglycerides (see WARNINGS, PRECAUTIONS, and CLINICAL
PHARMACOLOGY). The National Cholesterol Education Program has defined a
serum HDL-cholesterol value that is consistently below 35 mg/dL as constituting an
independent risk factor for coronary heart disease. Patients with significantly elevated
triglycerides should be closely observed when treated with gemfibrozil. In some
patients with high triglyceride levels, treatment with gemfibrozil is associated with a
significant increase in LDL-cholesterol. BECAUSE OF POTENTIAL TOXICITY
SUCH AS MALIGNANCY, GALLBLADDER DISEASE, ABDOMINAL PAIN
LEADING TO APPENDECTOMY AND OTHER ABDOMINAL SURGERIES, AN
INCREASED INCIDENCE IN NON-CORONARY MORTALITY, AND THE 44%
RELATIVE INCREASE DURING THE TRIAL PERIOD IN AGE-ADJUSTED
ALL-CAUSE MORTALITY SEEN WITH THE CHEMICALLY AND
PHARMACOLOGICALLY RELATED DRUG, CLOFIBRATE, THE POTENTIAL
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BENEFIT OF GEMFIBROZIL IN TREATING TYPE IIA PATIENTS WITH
ELEVATIONS OF LDL-CHOLESTEROL ONLY IS NOT LIKELY TO
OUTWEIGH THE RISKS. LOPID IS ALSO NOT INDICATED FOR THE
TREATMENT OF PATIENTS WITH LOW HDL-CHOLESTEROL AS THEIR
ONLY LIPID ABNORMALITY.
In a subgroup analysis of patients in the Helsinki Heart Study with above-median HDL-
cholesterol values at baseline (greater than 46.4 mg/dL), the incidence of serious
coronary events was similar for gemfibrozil and placebo subgroups (see Table I).
The initial treatment for dyslipidemia is dietary therapy specific for the type of
lipoprotein abnormality. Excess body weight and excess alcohol intake may be important
factors in hypertriglyceridemia and should be managed prior to any drug therapy.
Physical exercise can be an important ancillary measure, and has been associated with
rises in HDL-cholesterol. Diseases contributory to hyperlipidemia such as
hypothyroidism or diabetes mellitus should be looked for and adequately treated.
Estrogen therapy is sometimes associated with massive rises in plasma triglycerides,
especially in subjects with familial hypertriglyceridemia. In such cases, discontinuation
of estrogen therapy may obviate the need for specific drug therapy of
hypertriglyceridemia. The use of drugs should be considered only when reasonable
attempts have been made to obtain satisfactory results with nondrug methods. If the
decision is made to use drugs, the patient should be instructed that this does not reduce
the importance of adhering to diet.
CONTRAINDICATIONS
1. Hepatic or severe renal dysfunction, including primary biliary cirrhosis.
2. Preexisting gallbladder disease (see WARNINGS).
3. Hypersensitivity to gemfibrozil.
4. Combination therapy of gemfibrozil with repaglinide (see PRECAUTIONS).
5. Combination therapy of gemfibrozil with simvastatin (see WARNINGS and
PRECAUTIONS).
WARNINGS
1. Because of chemical, pharmacological, and clinical similarities between gemfibrozil
and clofibrate, the adverse findings with clofibrate in two large clinical studies may also
apply to gemfibrozil. In the first of those studies, the Coronary Drug Project, 1000
subjects with previous myocardial infarction were treated for five years with clofibrate.
There was no difference in mortality between the clofibrate-treated subjects and 3000
placebo-treated subjects, but twice as many clofibrate-treated subjects developed
cholelithiasis and cholecystitis requiring surgery. In the other study, conducted by the
World Health Organization (WHO), 5000 subjects without known coronary heart disease
were treated with clofibrate for five years and followed one year beyond. There was a
statistically significant (44%) higher age-adjusted total mortality in the clofibrate-treated
group than in a comparable placebo-treated control group during the trial period. The
excess mortality was due to a 33% increase in non-cardiovascular causes, including
Reference ID: 3399646
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malignancy, post-cholecystectomy complications, and pancreatitis. The higher risk of
clofibrate-treated subjects for gallbladder disease was confirmed.
Because of the more limited size of the Helsinki Heart Study, the observed difference in
mortality from any cause between the LOPID and placebo groups is not statistically
significantly different from the 29% excess mortality reported in the clofibrate group in
the separate WHO study at the nine year follow-up (see CLINICAL
PHARMACOLOGY). Noncoronary heart disease related mortality showed an excess in
the group originally randomized to LOPID primarily due to cancer deaths observed
during the open-label extension.
During the five year primary prevention component of the Helsinki Heart Study,
mortality from any cause was 44 (2.2%) in the LOPID group and 43 (2.1%) in the
placebo group; including the 3.5 year follow-up period since the trial was completed,
cumulative mortality from any cause was 101 (4.9%) in the LOPID group and 83 (4.1%)
in the group originally randomized to placebo (hazard ratio 1:20 in favor of placebo).
Because of the more limited size of the Helsinki Heart Study, the observed difference in
mortality from any cause between the LOPID and placebo groups at Year-5 or at Year
8.5 is not statistically significantly different from the 29% excess mortality reported in
the clofibrate group in the separate WHO study at the nine year follow-up. Noncoronary
heart disease related mortality showed an excess in the group originally randomized to
LOPID at the 8.5 year follow-up (65 LOPID versus 45 placebo noncoronary deaths).
The incidence of cancer (excluding basal cell carcinoma) discovered during the trial and
in the 3.5 years after the trial was completed was 51 (2.5%) in both originally randomized
groups. In addition, there were 16 basal cell carcinomas in the group originally
randomized to LOPID and 9 in the group originally randomized to placebo (p=0.22).
There were 30 (1.5%) deaths attributed to cancer in the group originally randomized to
LOPID and 18 (0.9%) in the group originally randomized to placebo (p=0.11). Adverse
outcomes, including coronary events, were higher in gemfibrozil patients in a
corresponding study in men with a history of known or suspected coronary heart disease
in the secondary prevention component of the Helsinki Heart Study (see CLINICAL
PHARMACOLOGY).
A comparative carcinogenicity study was also done in rats comparing three drugs in this
class: fenofibrate (10 and 60 mg/kg; 0.3 and 1.6 times the human dose, respectively),
clofibrate (400 mg/kg; 1.6 times the human dose), and gemfibrozil (250 mg/kg; 1.7 times
the human dose). Pancreatic acinar adenomas were increased in males and females on
fenofibrate; hepatocellular carcinoma and pancreatic acinar adenomas were increased in
males and hepatic neoplastic nodules in females treated with clofibrate; hepatic
neoplastic nodules were increased in males and females treated with clofibrate; hepatic
neoplastic nodules were increased in males and females treated with gemfibrozil while
testicular interstitial cell (Leydig cell) tumors were increased in males on all three drugs.
2. A gallstone prevalence substudy of 450 Helsinki Heart Study participants showed a
trend toward a greater prevalence of gallstones during the study within the LOPID
treatment group (7.5% versus 4.9% for the placebo group, a 55% excess for the
gemfibrozil group). A trend toward a greater incidence of gallbladder surgery was
observed for the LOPID group (17 versus 11 subjects, a 54% excess). This result did not
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differ statistically from the increased incidence of cholecystectomy observed in the WHO
study in the group treated with clofibrate. Both clofibrate and gemfibrozil may increase
cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected,
gallbladder studies are indicated. LOPID therapy should be discontinued if gallstones are
found. Cases of cholelithiasis have been reported with gemfibrozil therapy.
3. Since a reduction of mortality from coronary heart disease has not been demonstrated
and because liver and interstitial cell testicular tumors were increased in rats, LOPID
should be administered only to those patients described in the INDICATIONS AND
USAGE section. If a significant serum lipid response is not obtained, LOPID should be
discontinued.
4. Concomitant Anticoagulants – Caution should be exercised when anticoagulants are
given in conjunction with LOPID. The dosage of the anticoagulant should be reduced to
maintain the prothrombin time at the desired level to prevent bleeding complications.
Frequent prothrombin determinations are advisable until it has been definitely determined
that the prothrombin level has stabilized.
5. The concomitant administration of LOPID with simvastatin is contraindicated (see
CONTRAINDICATIONS and PRECAUTIONS). Concomitant therapy with LOPID
and an HMG-CoA reductase inhibitor is associated with an increased risk of skeletal
muscle toxicity manifested as rhabdomyolysis, markedly elevated creatine kinase (CPK)
levels, and myoglobinuria, leading in a high proportion of cases to acute renal failure and
death. IN PATIENTS WHO HAVE HAD AN UNSATISFACTORY LIPID RESPONSE
TO EITHER DRUG ALONE, THE BENEFIT OF COMBINED THERAPY WITH
LOPID AND an HMG-CoA REDUCTASE INHIBITOR DOES NOT OUTWEIGH THE
RISKS OF SEVERE MYOPATHY, RHABDOMYOLYSIS, AND ACUTE RENAL
FAILURE (see PRECAUTIONS, Drug Interactions). The use of fibrates alone,
including LOPID, may occasionally be associated with myositis. Patients receiving
LOPID and complaining of muscle pain, tenderness, or weakness should have prompt
medical evaluation for myositis, including serum creatine–kinase level determination. If
myositis is suspected or diagnosed, LOPID therapy should be withdrawn.
6. Cataracts – Subcapsular bilateral cataracts occurred in 10%, and unilateral in 6.3%, of
male rats treated with gemfibrozil at 10 times the human dose.
PRECAUTIONS
1. Initial Therapy – Laboratory studies should be done to ascertain that the lipid levels
are consistently abnormal. Before instituting LOPID therapy, every attempt should be
made to control serum lipids with appropriate diet, exercise, weight loss in obese patients,
and control of any medical problems such as diabetes mellitus and hypothyroidism that
are contributing to the lipid abnormalities.
2. Continued Therapy – Periodic determination of serum lipids should be obtained, and
the drug withdrawn if lipid response is inadequate after three months of therapy.
3. Drug Interactions – (A) HMG-CoA Reductase Inhibitors: The concomitant
administration of LOPID with simvastatin is contraindicated (see
CONTRAINDICATIONS and WARNINGS). The risk of myopathy and
rhabdomyolysis is increased with combined gemfibrozil and HMG-CoA reductase
Reference ID: 3399646
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inhibitor therapy. Myopathy or rhabdomyolysis with or without acute renal failure have
been reported as early as three weeks after initiation of combined therapy or after several
months (see WARNINGS). There is no assurance that periodic monitoring of creatine
kinase will prevent the occurrence of severe myopathy and kidney damage.
(B) Anticoagulants: CAUTION SHOULD BE EXERCISED WHEN ANTI
COAGULANTS ARE GIVEN IN CONJUNCTION WITH LOPID. THE DOSAGE OF
THE ANTICOAGULANT SHOULD BE REDUCED TO MAINTAIN THE
PROTHROMBIN TIME AT THE DESIRED LEVEL TO PREVENT BLEEDING
COMPLICATIONS. FREQUENT PROTHROMBIN DETERMINATIONS ARE
ADVISABLE UNTIL IT HAS BEEN DEFINITELY DETERMINED THAT THE
PROTHROMBIN LEVEL HAS STABILIZED.
(C) Repaglinide: In healthy volunteers, co-administration with gemfibrozil (600 mg
twice daily for 3 days) resulted in an 8.1-fold (range 5.5- to 15.0- fold) higher repaglinide
AUC and a 28.6-fold (range 18.5- to 80.1-fold) higher repaglinide plasma concentration 7
hours after the dose. In the same study, gemfibrozil (600 mg twice daily for 3 days) +
itraconazole (200 mg in the morning and 100 mg in the evening at Day 1, then 100 mg
twice daily at Day 2-3) resulted in a 19.4- (range 12.9- to 24.7-fold) higher repaglinide
AUC and a 70.4-fold (range 42.9- to 119.2-fold) higher repaglinide plasma concentration
7 hours after the dose. In addition, gemfibrozil alone or gemfibrozil + itraconazole
prolonged the hypoglycemic effects of repaglinide. Co-administration of gemfibrozil and
repaglinide increases the risk of severe hypoglycemia and is contraindicated (see
CONTRAINDICATIONS).
(D) Bile Acid-Binding Resins: Gemfibrozil AUC was reduced by 30% when
gemfibrozil was given (600 mg) simultaneously with resin-granule drugs such as
colestipol (5 g). Administration of the drugs two hours or more apart is recommended
because gemfibrozil exposure was not significantly affected when it was administered
two hours apart from colestipol.
(E) Colchicine: Myopathy, including rhabdomyolysis, has been reported with chronic
administration of colchicine at therapeutic doses. Concomitant use of LOPID may
potentiate the development of myopathy. Patients with renal dysfunction and elderly
patients are at increased risk. Caution should be exercised when prescribing LOPID with
colchicine, especially in elderly patients or patients with renal dysfunction.
4. Carcinogenesis, Mutagenesis, Impairment of Fertility – Long-term studies have
been conducted in rats at 0.2 and 1.3 times the human exposure (based on AUC). The
incidence of benign liver nodules and liver carcinomas was significantly increased in
high dose male rats. The incidence of liver carcinomas increased also in low dose males,
but this increase was not statistically significant (p=0.1). Male rats had a dose-related and
statistically significant increase of benign Leydig cell tumors. The higher dose female
rats had a significant increase in the combined incidence of benign and malignant liver
neoplasms.
Long-term studies have been conducted in mice at 0.1 and 0.7 times the human exposure
(based on AUC). There were no statistically significant differences from controls in the
incidence of liver tumors, but the doses tested were lower than those shown to be
carcinogenic with other fibrates.
Reference ID: 3399646
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Electron microscopy studies have demonstrated a florid hepatic peroxisome proliferation
following LOPID administration to the male rat. An adequate study to test for
peroxisome proliferation has not been done in humans but changes in peroxisome
morphology have been observed. Peroxisome proliferation has been shown to occur in
humans with either of two other drugs of the fibrate class when liver biopsies were
compared before and after treatment in the same individual.
Administration of approximately 2 times the human dose (based on surface area) to male
rats for 10 weeks resulted in a dose-related decrease of fertility. Subsequent studies
demonstrated that this effect was reversed after a drug-free period of about eight weeks,
and it was not transmitted to the offspring.
5. Pregnancy Category C – LOPID has been shown to produce adverse effects in rats
and rabbits at doses between 0.5 and 3 times the human dose (based on surface area).
There are no adequate and well-controlled studies in pregnant women. LOPID should be
used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Administration of LOPID to female rats at 2 times the human dose (based on surface
area) before and throughout gestation caused a dose-related decrease in conception rate,
an increase in stillborns, and a slight reduction in pup weight during lactation. There were
also dose-related increased skeletal variations. Anophthalmia occurred, but rarely.
Administration of 0.6 and 2 times the human dose (based on surface area) of LOPID to
female rats from gestation day 15 through weaning caused dose-related decreases in birth
weight and suppressions of pup growth during lactation.
Administration of 1 and 3 times the human dose (based on surface area) of LOPID to
female rabbits during organogenesis caused a dose-related decrease in litter size and, at
the high dose, an increased incidence of parietal bone variations.
6. Nursing Mothers – It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk and because of the potential for
tumorigenicity shown for LOPID in animal studies, a decision should be made whether to
discontinue nursing or to discontinue the drug, taking into account the importance of the
drug to the mother.
7. Hematologic Changes – Mild hemoglobin, hematocrit, and white blood cell decreases
have been observed in occasional patients following initiation of LOPID therapy.
However, these levels stabilize during long-term administration. Rarely, severe anemia,
leukopenia, thrombocytopenia, and bone marrow hypoplasia have been reported.
Therefore, periodic blood counts are recommended during the first 12 months of LOPID
administration.
8. Liver Function – Abnormal liver function tests have been observed occasionally
during LOPID administration, including elevations of AST, ALT, LDH, bilirubin, and
alkaline phosphatase. These are usually reversible when LOPID is discontinued.
Therefore, periodic liver function studies are recommended and LOPID therapy should
be terminated if abnormalities persist.
9. Kidney Function – There have been reports of worsening renal insufficiency upon the
addition of LOPID therapy in individuals with baseline plasma creatinine >2.0 mg/dL. In
Reference ID: 3399646
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such patients, the use of alternative therapy should be considered against the risks and
benefits of a lower dose of LOPID.
10. Pediatric Use – Safety and efficacy in pediatric patients have not been established.
ADVERSE REACTIONS
In the double-blind controlled phase of the primary prevention component of the Helsinki
Heart Study, 2046 patients received LOPID for up to five years. In that study, the
following adverse reactions were statistically more frequent in subjects in the LOPID
group:
LOPID
PLACEBO
(N = 2046)
(N = 2035)
Frequency in
percent of subjects
Gastrointestinal reactions
34.2
23.8
Dyspepsia
19.6
11.9
Abdominal pain
9.8
5.6
Acute appendicitis
1.2
0.6
(histologically confirmed in most
cases where data were available)
Atrial fibrillation
0.7
0.1
Adverse events reported by more than 1% of subjects, but without a significant
difference between groups:
Diarrhea
7.2
6.5
Fatigue
3.8
3.5
Nausea/Vomiting
2.5
2.1
Eczema
1.9
1.2
Rash
1.7
1.3
Vertigo
1.5
1.3
Constipation
1.4
1.3
Headache
1.2
1.1
Gallbladder surgery was performed in 0.9% of LOPID and 0.5% of placebo subjects in
the primary prevention component, a 64% excess, which is not statistically different from
the excess of gallbladder surgery observed in the clofibrate group compared to the
placebo group of the WHO study. Gallbladder surgery was also performed more
frequently in the LOPID group compared to the placebo group (1.9% versus 0.3%,
p=0.07) in the secondary prevention component. A statistically significant increase in
appendectomy in the gemfibrozil group was seen also in the secondary prevention
component (6 on gemfibrozil versus 0 on placebo, p=0.014).
Reference ID: 3399646
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Nervous system and special senses adverse reactions were more common in the LOPID
group. These included hypesthesia, paresthesias, and taste perversion. Other adverse
reactions that were more common among LOPID treatment group subjects but where a
causal relationship was not established include cataracts, peripheral vascular disease, and
intracerebral hemorrhage.
From other studies it seems probable that LOPID is causally related to the occurrence of
MUSCULOSKELETAL SYMPTOMS (see WARNINGS), and to ABNORMAL LIVER
FUNCTION TESTS and HEMATOLOGIC CHANGES (see PRECAUTIONS).
Reports of viral and bacterial infections (common cold, cough, urinary tract infections)
were more common in gemfibrozil treated patients in other controlled clinical trials of
805 patients. Additional adverse reactions that have been reported for gemfibrozil are
listed below by system. These are categorized according to whether a causal relationship
to treatment with LOPID is probable or not established:
CAUSAL RELATIONSHIP
CAUSAL RELATIONSHIP
PROBABLE
NOT ESTABLISHED
General:
weight loss
Cardiac:
extrasystoles
Gastrointestinal:
cholestatic jaundice
pancreatitis
hepatoma
colitis
Central Nervous System: dizziness
confusion
somnolence
convulsions
paresthesia
syncope
peripheral neuritis
decreased libido
depression
headache
Eye:
blurred vision
retinal edema
Genitourinary:
impotence
decreased male fertility
renal dysfunction
Musculoskeletal:
myopathy
myasthenia
myalgia
painful extremities
arthralgia
synovitis
rhabdomyolysis (see
WARNINGS and Drug
Interactions under
PRECAUTIONS)
Clinical Laboratory:
increased creatine phosphokinase positive antinuclear antibody
increased bilirubin
Reference ID: 3399646
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Hematopoietic:
Immunologic:
Integumentary:
increased liver transaminases
(AST, ALT)
increased alkaline phosphatase
anemia
leukopenia
bone marrow hypoplasia
eosinophilia
angioedema
laryngeal edema
urticaria
exfoliative dermatitis
rash
dermatitis
pruritus
thrombocytopenia
anaphylaxis
Lupus-like syndrome
vasculitis
alopecia
photosensitivity
Additional adverse reactions that have been reported include cholecystitis and
cholelithiasis (see WARNINGS).
DOSAGE AND ADMINISTRATION
The recommended dose for adults is 1200 mg administered in two divided doses 30
minutes before the morning and evening meals (see CLINICAL PHARMACOLOGY).
OVERDOSAGE
There have been reported cases of overdosage with LOPID. In one case, a 7-year-old
child recovered after ingesting up to 9 grams of LOPID. Symptoms reported with
overdosage were abdominal cramps, abnormal liver function tests, diarrhea, increased
CPK, joint and muscle pain, nausea and vomiting. Symptomatic supportive measures
should be taken, should an overdose occur.
HOW SUPPLIED
LOPID (Tablet 737), white, elliptical, film-coated, scored tablets, each containing 600
mg gemfibrozil, are available as follows:
NDC 0071-0737-20: Bottles of 60
NDC 0071-0737-30: Bottles of 500
Store at controlled room temperature 20° – 25°C (68° – 77°F) [see USP]. Protect
from light and humidity.
Rx only company logo
Reference ID: 3399646
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LAB-0107-9.x
Revised October 2013
Reference ID: 3399646
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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This label may not be the latest approved by FDA.
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/017376s058,017598s040,018452s025lbl.pdf', 'application_number': 18452, 'submission_type': 'SUPPL ', 'submission_number': 25}
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NDA 18-449/S-039
NDA 17-643/S-072
Page 3
Intralipid® 20%
A 20% I.V. Fat Emulsion
In Excel® Container
DESCRIPTION
INTRALIPID® 20% (A 20% INTRAVENOUS FAT EMULSION) IS A STERILE, NON-PYROGENIC FAT EMULSION
PREPARED FOR INTRAVENOUS ADMINISTRATION AS A SOURCE OF CALORIES AND ESSENTIAL FATTY ACIDS. IT IS
MADE UP OF 20% SOYBEAN OIL, 1.2% EGG YOLK PHOSPHOLIPIDS, 2.25% GLYCERIN, AND WATER FOR
INJECTION. IN ADDITION, SODIUM HYDROXIDE HAS BEEN ADDED TO ADJUST THE PH SO THAT THE FINAL
PRODUCT PH IS 8. PH RANGE IS 6 TO 8.9.
The soybean oil is a refined natural product consisting of a mixture of neutral triglycerides of
predominantly unsaturated fatty acids with the following structure:
WHERE R1C-, R2C- AND R3C- ARE SATURATED AND UNSATURATED FATTY ACID RESIDUES.
The major component fatty acids are linoleic (44-62%), oleic (19-30%), palmitic (7-14%), linolenic (4-
11%) and stearic (1.4-5.5%)1. These fatty acids have the following chemical and structural formulas:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-449/S-039
NDA 17-643/S-072
Page 4
PURIFIED EGG PHOSPHATIDES ARE A MIXTURE OF NATURALLY OCCURRING PHOSPHOLIPIDS WHICH ARE
ISOLATED FROM THE EGG YOLK. THESE PHOSPHOLIPIDS HAVE THE FOLLOWING GENERAL STRUCTURE:
R1C- AND R2C- CONTAIN SATURATED AND UNSATURATED FATTY ACIDS THAT ABOUND IN NEUTRAL FATS. R3 IS
PRIMARILY EITHER THE CHOLINE OR ETHANOLAMINE ESTER OF PHOSPHORIC ACID.
GLYCERIN IS CHEMICALLY DESIGNATED C3H8O3 AND IS A CLEAR COLORLESS, HYGROSCOPIC SYRUPY LIQUID. IT
HAS THE FOLLOWING STRUCTURAL FORMULA:
INTRALIPID® 20% (A 20% INTRAVENOUSA FAT EMULSION) HAS AN OSMOLALITY OF APPROXIMATELY 350
MOSMOL/KG WATER (WHICH REPRESENTS 260 MOSMOL/LITER OF EMULSION) AND CONTAINS EMULSIFIED FAT
PARTICLES OF APPROXIMATELY 0.5 MICRON SIZE.
THE TOTAL CALORIC VALUE, INCLUDING FAT, PHOSPHOLIPID AND GLYCERIN, IS 2.0 KCAL PER ML OF
INTRALIPID® 20%. THE PHOSPHOLIPIDS PRESENT CONTRIBUTE 47 MILLIGRAMS OR APPROXIMATELY 1.5 MMOL
OF PHOSPHORUS PER 100 ML OF THE EMULSION.
THE PRIMARY CONTAINER IS MANUFACTURED FROM EXCEL® FILM, A POLYPROPYLENE BASED MATERIAL
COMPRISED OF THREE CO-EXTRUDED LAYERS.
THE PLASTIC CONTAINER IS MADE FROM MULTILAYERED FILM SPECIFICALLY DESIGNED FOR PARENTERAL
DRUGS. IT CONTAINS NO PLASTICIZERS AND EXHIBITS VIRTUALLY NO LEACHABLES. THE SOLUTION CONTACT
LAYER IS A RUBBERIZED COPOLYMER OF ETHYLENE AND PROPYLENE. THE CONTAINER IS NONTOXIC AND
BIOLOGICALLY INERT. THE CONTAINER-SOLUTION UNIT IS A CLOSED SYSTEM AND IS NOT DEPENDENT UPON
ENTRY OF EXTERNAL AIR DURING ADMINISTRATION. THE CONTAINER IS OVERWRAPPED TO PROVIDE
PROTECTION FROM THE PHYSICAL ENVIRONMENT AND TO PROVIDE AN ADDITIONAL MOISTURE BARRIER WHEN
NECESSARY.
CLINICAL PHARMACOLOGY
INTRALIPID® 20% IS METABOLIZED AND UTILIZED AS A SOURCE OF ENERGY CAUSING AN INCREASE IN HEAT
PRODUCTION, DECREASE IN RESPIRATORY QUOTIENT AND INCREASE IN OXYGEN CONSUMPTION. THE INFUSED
FAT PARTICLES ARE CLEARED FROM THE BLOOD STREAM IN A MANNER THOUGHT TO BE COMPARABLE TO THE
CLEARING OF CHYLOMICRONS.
INTRALIPID® 20% WILL PREVENT THE BIOCHEMICAL LESIONS OF ESSENTIAL FATTY ACID DEFICIENCY (EFAD),
AND CORRECT THE CLINICAL MANI-FESTATIONS OF THE EFAD SYNDROME.
INDICATIONS AND USAGE
INTRALIPID® 20% IS INDICATED AS A SOURCE OF CALORIES AND ESSENTIAL FATTY ACIDS FOR PATIENTS
REQUIRING PARENTERAL NUTRITION FOR EXTENDED PERIODS OF TIME (USUALLY FOR MORE THAN 5 DAYS) AND
AS A SOURCE OF ESSENTIAL FATTY ACIDS FOR PREVENTION OF EFAD.
CONTRAINDICATIONS
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-449/S-039
NDA 17-643/S-072
Page 5
THE ADMINISTRATION OF INTRALIPID® 20% IS CONTRAINDICATED IN PATIENTS WITH DISTURBANCES OF
NORMAL FAT METABOLISM SUCH AS PATHOLOGIC HYPERLIPEMIA, LIPOID NEPHROSIS OR ACUTE PANCREATITIS
IF ACCOMPANIED BY HYPERLIPIDEMIA.
WARNINGS
DEATHS IN PRETERM INFANTS AFTER INFUSION OF INTRAVENOUS FAT EMULSION HAVE BEEN REPORTED IN THE
MEDICAL LITERATURE.2 AUTOPSY FINDINGS INCLUDED INTRAVASCULAR FAT ACCUMULATION IN THE LUNGS.
TREATMENT OF PREMATURE AND LOW BIRTH WEIGHT INFANTS WITH INTRAVENOUS FAT EMULSION MUST BE
BASED UPON CAREFUL BENEFIT-RISK ASSESSMENT. STRICT ADHERENCE TO THE RECOMMENDED TOTAL DAILY
DOSE IS MANDATORY; HOURLY INFUSION RATE SHOULD BE AS SLOW AS POSSIBLE IN EACH CASE AND SHOULD
NOT IN ANY CASE EXCEED 1 G FAT/KG IN FOUR HOURS. PREMATURE AND SMALL FOR GESTATIONAL AGE
INFANTS HAVE POOR CLEARANCE OF INTRAVENOUS FAT EMULSION AND INCREASED FREE FATTY ACID PLASMA
LEVELS FOLLOWING FAT EMULSION INFUSION; THEREFORE, SERIOUS CONSIDERATION MUST BE GIVEN TO
ADMINISTRATION OF LESS THAN THE MAXIMUM RECOMMENDED DOSES IN THESE PATIENTS IN ORDER TO
DECREASE THE LIKELIHOOD OF INTRAVENOUS FAT OVERLOAD. THE INFANT’S ABILITY TO ELIMINATE THE
INFUSED FAT FROM THE CIRCULATION MUST BE CAREFULLY MONITORED (SUCH AS SERUM TRIGLYCERIDES
AND/OR PLASMA FREE FATTY ACID LEVELS). THE LIPEMIA MUST CLEAR BETWEEN DAILY INFUSIONS.
CAUTION SHOULD BE EXERCISED IN ADMINISTERING OF INTRALIPID® 20% (A 20% INTRAVENOUS FAT
EMULSION) TO PATIENTS WITH SEVERE LIVER DAMAGE, PULMONARY DISEASE, ANEMIA OR BLOOD
COAGULATION DISORDERS, OR WHEN THERE IS DANGER OF FAT EMBOLISM.
WARNING: THIS PRODUCT CONTAINS ALUMINUM THAT MAY BE TOXIC. ALUMINUM MAY REACH TOXIC
LEVELS WITH PROLONGED PARENTERAL ADMINISTRATION IF KIDNEY FUNCTION IS IMPAIRED. PREMATURE
NEONATES ARE PARTICULARLY AT RISK BECAUSE THEIR KIDNEYS ARE IMMATURE, AND THEY REQUIRE LARGE
AMOUNTS OF CALCIUM AND PHOSPHATE SOLUTIONS, WHICH CONTAIN ALUMINUM.
RESEARCH INDICATES THAT PATIENTS WITH IMPAIRED KIDNEY FUNCTION, INCLUDING PREMATURE NEONATES,
WHO RECEIVE PARENTERAL LEVELS OF ALUMINUM AT GREATER THAN 4 TO 5 MCG/KG/DAY ACCUMULATE
ALUMINUM AT LEVELS ASSOCIATED WITH CENTRAL NERVOUS SYSTEM AND BONE TOXICITY. TISSUE LOADING
MAY OCCUR AT EVEN LOWER RATES OF ADMINISTRATION.
PRECAUTIONS
WHEN INTRALIPID® 20% IS ADMINISTERED, THE PATIENTS CAPACITY TO ELIMINATE THE INFUSED FAT FROM THE
CIRCULATION MUST BE MONITORED BY USE OF AN APPROPRIATE LABORATORY DETERMINATION OF SERUM
TRIGLYCERIDES. OVERDOSAGE MUST BE AVOIDED.
DURING LONG TERM INTRAVENOUS NUTRITION WITH INTRALIPID® 20%, LIVER FUNCTION TESTS SHOULD BE
PERFORMED. IF THESE TESTS INDICATE THAT LIVER FUNCTION IS IMPAIRED, THE THERAPY SHOULD BE
WITHDRAWN.
FREQUENT (SOME ADVISE DAILY) PLATELET COUNTS SHOULD BE DONE IN NEONATAL PATIENTS RECEIVING
PARENTERAL NUTRITION WITH INTRALIPID® 20%.
DRUG PRODUCT CONTAINS NO MORE THAN 25 MCG/L OF ALUMINUM.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies with Intralipid® have not been
performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy Category C: Animal reproduction studies have not been conducted with Intralipid®. It is
also not known whether Intralipid® can cause fetal harm when administered to a pregnant woman or
can affect reproduction capacity. Intralipid® should be given to a pregnant woman only if clearly
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-449/S-039
NDA 17-643/S-072
Page 6
needed.
Nursing Mothers: Caution should be exercised when Intralipid® is administered to a nursing woman.
Pediatric Use: See DOSAGE AND ADMINISTRATION.
AVOID OVERDOSAGE ABSOLUTELY.
ADVERSE REACTIONS
THE ADVERSE REACTIONS OBSERVED CAN BE SEPARATED INTO TWO CLASSES:
1. THOSE MORE FREQUENTLY ENCOUNTERED ARE DUE: EITHER TO CONTAMINATION OF THE INTRAVENOUS
CATHETER AND RESULT IN SEPSIS, OR TO VEIN IRRITATION BY CONCURRENTLY INFUSED HYPERTONIC
SOLUTIONS AND MAY RESULT IN THROMBOPHLEBITIS. THESE ADVERSE REACTIONS ARE INSEPARABLE FROM
THE HYPERALIMENTATION PROCEDURE WITH OR WITHOUT INTRALIPID® 20% (A 20% I.V. FAT EMULSION).
2. LESS FREQUENT REACTIONS MORE DIRECTLY RELATED TO INTRALIPID® 20% ARE: A) IMMEDIATE OR EARLY
ADVERSE REACTIONS, EACH OF WHICH HAS BEEN REPORTED TO OCCUR IN CLINICAL TRIALS, IN AN INCIDENCE
OF LESS THAN 1%; DYSPNEA, CYANOSIS, ALLERGIC REACTIONS, HYPERLIPEMIA, HYPERCOAGULABILITY,
NAUSEA, VOMITING, HEADACHE, FLUSHING, INCREASE IN TEMPERATURE, SWEATING, SLEEPINESS, PAIN IN THE
CHEST AND BACK, SLIGHT PRESSURE OVER THE EYES, DIZZINESS, AND IRRITATION AT THE SITE OF INFUSION,
AND, RARELY, THROMBOCYTOPENIA IN NEONATES; B) DELAYED ADVERSE REACTIONS SUCH AS
HEPATOMEGALY, JAUNDICE DUE TO CENTRAL LOBULAR CHOLESTASIS, SPLENOMEGALY,
THROMBOCYTOPENIA, LEUKOPENIA, TRANSIENT INCREASES IN LIVER FUNCTION TESTS, AND OVERLOADING
SYNDROME (FOCAL SEIZURES, FEVER, LEUKOCYTOSIS, HEPATOMEGALY. SPLENOMEGALY AND SHOCK).
THE DEPOSITION OF A BROWN PIGMENTATION IN THE RETICULOEN-DOTHELIAL SYSTEM, THE SO CALLED
“INTRAVENOUS FAT PIGMENT,” HAS BEEN REPORTED IN PATIENTS INFUSED WITH INTRALIPID® 20%. THE CAUSES
AND SIGNIFICANCE OF THIS PHENOMENON ARE UNKNOWN.
OVERDOSAGE
IN THE EVENT OF FAT OVERLOAD DURING THERAPY, STOP THE INFUSION OF INTRALIPID® 20% UNTIL VISUAL
INSPECTION OF THE PLASMA, DETERMINATION OF TRIGLYCERIDE CONCENTRATIONS, OR MEASUREMENT OF
PLASMA LIGHT-SCATTERING ACTIVITY BY NEPHELOMETRY INDICATES THE LIPID HAS CLEARED. RE-EVALUATE
THE PATIENT AND INSTITUTE APPROPRIATE CORRECTIVE MEASURES. SEE WARNINGS AND PRECAUTIONS.
DOSAGE AND ADMINISTRATION
INTRALIPID® 20% SHOULD BE ADMINISTERED AS A PART OF INTRAVENOUS NUTRITION VIA PERPHERAL VEIN OR
BY CENTRAL VENOUS INFUSION.
Adult Patients
THE INITIAL RATE OF INFUSION IN ADULTS SHOULD BE 0.5 ML/MINUTE FOR THE FIRST 15 TO 30 MINUTES OF
INFUSION. IF NO UNTOWARD REACTIONS OCCUR (SEE ADVERSE REACTIONS SECTION), THE INFUSION RATE
CAN BE INCREASED TO 1 ML/MINUTE. NOT MORE THAN 500 ML OF INTRALIPID® 20% SHOULD BE INFUSED INTO
ADULTS ON THE FIRST DAY OF THERAPY. IF THE PATIENT HAS NO UNTOWARD REACTIONS, THE DOSE CAN BE
INCREASED ON THE FOLLOWING DAY. THE DAILY DOSAGE SHOULD NOT EXCEED 2.5 G OF FAT/KG OF BODY
WEIGHT (12.5 ML OF INTRALIPID® 20% PER KG). INTRALIPID® 20% (A 20% I.V. FAT EMULSION) SHOULD MAKE
UP NO MORE THAN 60% OF THE TOTAL CALORIC INPUT TO THE PATIENT. CARBOHYDRATE AND A SOURCE OF
AMINO ACIDS SHOULD COMPRISE THE REMAINING CALORIC INPUT.
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Pediatric Patients
THE DOSAGE FOR PREMATURE INFANTS STARTS AT 0.5 G FAT/KG BODY WEIGHT/24 HOURS (2.5 ML INTRALIPID®
20%) AND MAY BE INCREASED IN RELATION TO THE INFANT’S ABILITY TO ELIMINATE FAT. THE MAXIMUM
DOSAGE RECOMMENDED BY THE AMERICAN ACADEMY OF PEDIATRICS IS 3 G FAT/KG/24 HOURS3
THE INITIAL RATE OF INFUSION IN OLDER PEDIATRIC PATIENTS SHOULD BE NO MORE THAN 0.05 ML/MINUTE FOR
THE FIRST 10 TO 15 MINUTES. IF NO UNTOWARD REACTIONS OCCUR, THE RATE CAN BE CHANGED TO PERMIT
INFUSION OF 0.5 ML OF INTRALIPID® 20%/KG/HOUR. THE DAILY DOSAGE SHOULD NOT EXCEED 3 G OF FAT/KG
OF BODY WEIGHT3 INTRALIPID® 20% SHOULD MAKE UP NO MORE THAN 60% OF THE TOTAL CALORIC INPUT TO
THE PATIENT. CARBOHYDRATE AND A SOURCE OF AMINO ACIDS SHOULD COMPRISE THE REMAINING CALORIC
INPUT.
Essential Fatty Acid Deficiency
WHEN INTRALIPID® 20% IS ADMINISTERED TO CORRECT ESSENTIAL FATTY ACID DEFICIENCY, EIGHT TO TEN
PERCENT OF THE CALORIC INPUT SHOULD BE SUPPLIED BY INTRALIPID® 20% IN ORDER TO PROVIDE ADEQUATE
AMOUNTS OF LINOLEIC AND LINOLENIC ACIDS. WHEN EFAD OCCURS TOGETHER WITH STRESS, THE AMOUNT OF
INTRALIPID® 20% NEEDED TO CORRECT THE DEFICIENCY MAY BE INCREASED.
Administration
SEE MIXING GUIDELINES AND LIMITATIONS SECTION FOR INFORMATION REGARDING MIXING THIS FAT
EMULSION WITH OTHER PARENTERAL FLUIDS.
INTRALIPID® 20% CAN BE INFUSED INTO THE SAME CENTRAL OR PERIPHERAL VEIN AS CARBOHYDRATE/AMINO
ACIDS SOLUTIONS BY MEANS OF A Y-CONNECTOR NEAR THE INFUSION SITE. THIS ALLOWS FOR MIXING OF THE
EMULSION IMMEDIATELY BEFORE ENTERING THE VEIN OR FOR ALTERNATION OF EACH PARENTERAL FLUID. IF
INFUSION PUMPS ARE USED, FLOW RATES OF EACH PARENTERAL FLUID SHOULD BE CONTROLLED WITH A
SEPARATE PUMP. FAT EMULSION MAY ALSO BE INFUSED THROUGH A SEPARATE PERIPHERAL SITE. FILTERS OF
LESS THAN 1.2 MICRON PORE SIZE MUST NOT BE USED WITH INTRALIPID® 20%.
CONVENTIONAL ADMINISTRATION SETS AND TPN POOLING BAGS CONTAIN POLYVINYL CHLORIDE (PVC)
COMPONENTS THAT HAVE DEHP (DIETHYL HEXYL PHTHALATE) AS A PLASTICIZER. FAT-CONTAINING FLUIDS
SUCH AS INTRALIPID® 20% EXTRACT DEHP FROM THESE PVC COMPONENTS AND IT MAY BE ADVISABLE TO
CONSIDER INFUSION OF INTRALIPID® 20% THROUGH A NON-DEHP ADMINISTRATION SET.
DO NOT USE ANY BAG IN WHICH THERE APPEARS TO BE AN OILING OUT ON THE SURFACE OF THE EMULSION.
PARENTERAL DRUG PRODUCTS SHOULD BE INSPECTED VISUALLY FOR PARTICULATE MATTER AND
DISCOLORATION PRIOR TO ADMINISTRATION. WHENEVER SOLUTION AND CONTAINER PERMIT.
MIXING GUIDELINES AND LIMITATIONS
INVESTIGATIONS HAVE BEEN CONDUCTED WHICH DEMONSTRATE THE COMPATIBILITY OF INTRALIPID® 20% (A
20% I.V. FAT EMULSION) WHEN PROPERLY MIXED WITH EITHER NOVAMINE® OR 8.5% TRAVASOL® OR 10%
TRAVASOL® AMINO ACID INJECTIONS WITHOUT ELECTROLYTES FOR USE IN TPN THERAPY.
THE FOLLOWING PROPER MIXING SEQUENCE MUST BE FOLLOWED TO MINIMIZE PH RELATED PROBLEMS BY
ENSURING THAT TYPICALLY ACIDIC DEXTROSE INJECTIONS ARE NOT MIXED WITH LIPID EMULSIONS ALONE:
1. TRANSFER DEXTROSE INJECTION TO THE TPN ADMIXTURE CONTAINER
2. TRANSFER AMINO ACID INJECTION
3. TRANSFER INTRALIPID® 20% (A 20% INTRAVENOUS FAT EMULSION)
NOTE:
AMINO ACID INJECTION, DEXTROSE INJECTION AND INTRALIPID® 20% MAY BE SIMULTANEOUSLY
TRANSFERRED TO THE ADMIXTURE CONTAINER. ADMIXING SHOULD BE ACCOMPANIED BY GENTLE
AGITATION TO AVOID LOCALIZED CONCENTRATION EFFECTS.
THESE ADMIXTURES SHOULD BE USED PROMPTLY WITH STORAGE UNDER REFRIGERATION (2-8°C) NOT TO
EXCEED 24 HOURS AND MUST BE COMPLETELY USED WITHIN 24 HOURS AFTER REMOVAL FROM REFRIGERATION.
IT IS ESSENTIAL THAT THE ADMIXTURE BE PREPARED USING STRICT ASEPTIC TECHNIQUES AS THIS NUTRIENT
MIXTURE IS A GOOD GROWTH MEDIUM FOR MICROORGANISMS.
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ADDITIVES OTHER THAN THOSE NAMED ABOVE MAY BE INCOMPATIBLE. COMPLETE INFORMATION IS NOT
AVAILABLE. THOSE ADDITIVES KNOWN TO BE INCOMPATIBLE SHOULD NOT BE USED. CONSULT WITH
PHARMACIST, IF AVAILABLE. IF, IN THE INFORMED JUDGMENT OF THE PHYSICIAN, IT IS DEEMED ADVISABLE TO
INTRODUCE ADDITIVES, USE ASEPTIC TECHNIQUE. MIX THOROUGHLY WHEN ADDITIVES HAVE BEEN
INTRODUCED. DO NOT STORE SOLUTIONS CONTAINING ADDITIVES (E.G., VITAMINS AND MINERALS).
ADDITIVES MUST NOT BE ADDED DIRECTLY TO INTRALIPID® 20% AND IN NO CASE SHOULD INTRALIPID® 20% BE
ADDED TO THE TPN CONTAINER FIRST. BAGS SHOULD BE SHAKEN GENTLY AFTER EACH ADDITION TO MINIMIZE
LOCALIZED CONCENTRATION.
SUPPLEMENTAL ELECTROLYTES, TRACE METALS OR MULTIVITAMINS MAY BE REQUIRED IN ACCORDANCE WITH
THE PRESCRIPTION OF THE ATTENDING PHYSICIAN.
THE PRIME DESTABILIZERS OF EMULSIONS ARE EXCESSIVE ACIDITY (LOW PH) AND INAPPROPRIATE ELECTROLYTE
CONTENT. CAREFUL CONSIDERATION SHOULD BE GIVEN TO ADDITIONS OF DIVALENT CATIONS (CA++ AND MG++)
WHICH HAVE BEEN SHOWN TO CAUSE EMULSION INSTABILITY. AMINO ACID SOLUTIONS EXERT A BUFFERING
EFFECT PROTECTING THE EMULSION.
THE ADMIXTURE SHOULD BE INSPECTED CAREFULLY FOR “BREAKING OR OILING OUT“ OF THE EMULSION.
“BREAKING OR OILING OUT” IS DESCRIBED AS THE SEPARATION OF THE EMULSION AND CAN BE VISIBLY
IDENTIFIED BY A YELLOWISH STREAKING OR THE ACCUMULATION OF YELLOWISH DROPLETS IN THE ADMIXED
EMULSION. THE ADMIXTURE SHOULD ALSO BE EXAMINED FOR PARTICULATES. THE ADMIXTURE MUST BE
DISCARDED IF ANY OF THE ABOVE IS OBSERVED.
HOW SUPPLIED
INTRALIPID® 20% IS SUPPLIED AS A STERILE EMULSION IN THE FOLLOWING FILL SIZES: 100 ML, 250 ML, 500 ML
AND 1000 ML.
100 ML: 0338-0519-48
250 ML: 0338-0519-02
500 ML: 0338 0519-03
1000 ML:
0338-0519-04
STORAGE
INTRALIPID® 20% SHOULD NOT BE STORED ABOVE 25°C (77°F). DO NOT FREEZE INTRALIPID® 20%. IF
ACCIDENTALLY FROZEN, DISCARD THE BAG.
REFERENCES
1. PADLEY FB: “MAJOR VEGETABLE FATS,“ THE LIPID HANDBOOK
(GUNSTONE FD, HARWOOD JL, PADLEY FB, EDS.), CHAPMAN AND HALL LTD., CAMBRIDGE, UK (1986), PP.
88-9.
2. LEVENE MI, WIGGLESWORTH JS, DESAI R: PULMONARY FAT ACCUMULATION AFTER INTRALIPID® INFUSION
IN THE
PRETERM INFANT.
LANCET 1980; 2(8199):815-8.
3. AMERICAN ACADEMY OF PEDIATRICS: USE OF INTRAVENOUS FAT EMULSION IN PEDIATRIC PATIENTS.
PEDIATRICS 1981; 68:5(NOV) 738-43.
(REV JUNE 2006)
MANUFACTURED FOR
Baxter Healthcare Corporation
CLINTEC NUTRITION DIVISION
DEERFIELD, IL 60015 USA
MANUFACTURED BY
Fresenius Kabi,
UPPSALA, SWEDEN
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INTRALIPID® IS A REGISTERED TRADEMARK OF
FRESENIUS KABI AB.
NOVAMINE® IS A REGISTERED TRADEMARK OF
FRESENIUS KABI AB.
TRAVASOL® IS A REGISTERED TRADEMARK OF
BAXTER HEALTHCARE CORPORATION.
Instructions for Use – Intralipid® 20% Container
1. The integrity indicator (Oxalert™) A should be inspected before
removing the overpouch.
If the indicator is black the overpouch is damaged and the product
should be discarded.
2. REMOVE THE OVERWRAP BY TEARING AT THE NOTCH AND PULLING DOWN
ALONG THE CONTAINER. THE OXALERT™ SACHET A AND THE OXYGEN
ABSORBER B SHOULD BE DISPOSED.
3. Remove set port cover lifting ring with thumb and forefinger and
pulling upwards.
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4. Use a non-vented infusion set or close the air vent on a vented set.
Follow the instructions for use for the infusion set. Use a spike
conforming to ISO 8536-4, diameter 5.6 ± 0.1 mm.
5. The bag should be port side up when the infusion set is attached. Insert
the spike straight into the set port. Twist and push the spike through the
diaphragm.
Do not spike bag while the bag is hanging on the IV pole.
6. The step of the spike (shown by the arrow) should not be inserted into
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the port.
7. To hang the bag, invert and place hanger through container notch.
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Intralipid® 10%
A 10% I.V. Fat Emulsion
In Excel® Container
DESCRIPTION
INTRALIPID® 10% (A 10% INTRAVENOUS FAT EMULSION) IS A STERILE, NON-PYROGENIC FAT EMULSION
PREPARED FOR INTRAVENOUS ADMINISTRATION AS A SOURCE OF CALORIES AND ESSENTIAL FATTY ACIDS. IT IS
MADE UP OF 10% SOYBEAN OIL, 1.2% EGG YOLK PHOSPHOLIPIDS, 2.25% GLYCERIN, AND WATER FOR
INJECTION. IN ADDITION, SODIUM HYDROXIDE HAS BEEN ADDED TO ADJUST THE PH SO THAT THE FINAL
PRODUCT PH IS 8. PH RANGE IS 6 TO 8.9.
THE SOYBEAN OIL IS A REFINED NATURAL PRODUCT CONSISTING OF A MIXTURE OF NEUTRAL TRIGLYCERIDES OF
PREDOMINANTLY UNSATURATED FATTY ACIDS WITH THE FOLLOWING STRUCTURE:
WHERE R1C-, R2C- AND R3C- ARE SATURATED AND UNSATURATED FATTY ACID RESIDUES.
THE MAJOR COMPONENT FATTY ACIDS ARE LINOLEIC (44-62%), OLEIC (19-30%), PALMITIC (7-14%), LINOLENIC
(4-11%) AND STEARIC (1.4-5.5%)1. THESE FATTY ACIDS HAVE THE FOLLOWING CHEMICAL AND STRUCTURAL
FORMULAS:
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PURIFIED EGG PHOSPHATIDES ARE A MIXTURE OF NATURALLY OCCURRING PHOSPHOLIPIDS WHICH ARE
ISOLATED FROM THE EGG YOLK. THESE PHOSPHOLIPIDS HAVE THE FOLLOWING GENERAL STRUCTURE:
R1C- AND R2C-CONTAIN SATURATED AND UNSATURATED FATTY ACIDS THAT ABOUND IN NEUTRAL FATS. R3
PRIMARILY EITHER THE CHOLINE OR THE ETHANOLAMINE ESTER OF PHOSPHORIC ACID.
GLYCERIN IS CHEMICALLY DESIGNATED C3H8O3 AND IS A CLEAR COLORLESS, HYGROSCOPIC SYRUPY LIQUID. IT
HAS THE FOLLOWING STRUCTURAL FORMULA:
INTRALIPID® 10% (A 10% INTRAVENOUS FAT EMULSION) HAS AN OSMOLALITY OF APPROXIMATELY 300
MOSMOL/KG WATER (WHICH REPRESENTS 260 MOSMOL/LITER OF EMULSION) AND CONTAINS EMULSIFIED FAT
PARTICLES OF APPROXIMATELY 0.5 MICRON SIZE.
THE TOTAL CALORIC VALUE, INCLUDING FAT, PHOSPHOLIPID AND GLYCERIN, IS 1.1 KCAL PER ML OF INTRALIPID
10%. THE PHOSPHOLIPIDS PRESENT CONTRIBUTE 47 MILLIGRAMS OR APPROXIMATELY 1.5 MMOL OF
PHOSPHORUS PER 100 ML, OF THE EMULSION.
THE PRIMARY CONTAINER IS MANUFACTURED FROM EXCEL® FILM, A POLYPROPYLENE BASED MATERIAL
COMPRISED OF THREE CO-EXTRUDED LAYERS.
THE PLASTIC CONTAINER IS MADE FROM MULTILAYERED FILM SPECIFICALLY DESIGNED FOR PARENTERAL
DRUGS. IT CONTAINS NO PLASTICIZERS AND EXHIBITS VIRTUALLY NO LEACHABLES. THE SOLUTION CONTACT
LAYER IS A RUBBERIZED COPOLYMER OF ETHYLENE AND PROPYLENE. THE CONTAINER IS NONTOXIC AND
BIOLOGICALLY INERT. THE CONTAINER-SOLUTION UNIT IS A CLOSED SYSTEM AND IS NOT DEPENDENT UPON
ENTRY OF EXTERNAL AIR DURING ADMINISTRATION. THE CONTAINER IS OVERWRAPPED TO PROVIDE
PROTECTION FROM THE PHYSICAL ENVIRONMENT AND TO PROVIDE AN ADDITIONAL MOISTURE BARRIER WHEN
NECESSARY.
CLINICAL PHARMACOLOGY
INTRALIPID® 10% IS METABOLIZED AND UTILIZED AS A SOURCE OF ENERGY CAUSING AN INCREASE IN HEAT
PRODUCTION, DECREASE IN RESPIRATORY QUOTIENT AND INCREASE IN OXYGEN CONSUMPTION. THE INFUSED
FAT PARTICLES ARE CLEARED FROM THE BLOOD STREAM IN A MANNER THOUGHT TO BE COMPARABLE TO THE
CLEARING OF CHYLOMICRONS.
INTRALIPID® 10% WILL PREVENT THE BIOCHEMICAL LESIONS OF ESSENTIAL FATTY ACID DEFICIENCY (EFAD),
AND CORRECT THE CLINICAL MANIFESTATIONS OF THE EFAD SYNDROME.
INDICATIONS AND USAGE
INTRALIPID® 10% IS INDICATED AS A SOURCE OF CALORIES AND ESSENTIAL FATTY ACIDS FOR PATIENTS
REQUIRING PARENTERAL NUTRITION FOR EXTENDED PERIODS OF TIME (USUALLY FOR MORE THAN 5 DAYS) AND
AS A SOURCE OF ESSENTIAL FATTY ACIDS FOR PREVENTION OF EFAD.
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CONTRAINDICATIONS
THE ADMINISTRATION OF INTRALIPID® 10% IS CONTRAINDICATED IN PATIENTS WITH DISTURBANCES OF
NORMAL FAT METABOLISM SUCH AS PATHOLOGIC HYPERLIPEMIA, LIPOID NEPHROSIS OR ACUTE PANCREATITIS
IF ACCOMPANIED BY HYPERLIPIDEMIA.
WARNINGS
DEATHS IN PRETERM INFANTS AFTER INFUSION OF INTRAVENOUS FAT EMULSION HAVE BEEN REPORTED IN THE
MEDICAL LITERATURE.2 AUTOPSY FINDINGS INCLUDED INTRAVASCULAR FAT ACCUMULATION IN THE LUNGS.
TREATMENT OF PREMATURE AND LOW BIRTH WEIGHT INFANTS WITH INTRAVENOUS FAT EMULSION MUST BE
BASED UPON CAREFUL BENEFIT-RISK ASSESSMENT.
STRICT ADHERENCE TO THE RECOMMENDED TOTAL DAILY DOSE IS MANDATORY; HOURLY INFUSION RATE
SHOULD BE AS SLOW AS POSSIBLE IN EACH CASE AND FAT SHOULD NOT IN ANY CASE EXCEED 1 G FAT/KG IN
FOUR HOURS. PREMATURE AND SMALL FOR GESTATIONAL AGE INFANTS HAVE POOR CLEARANCE OF
INTRAVENOUS FAT EMULSION AND INCREASED FREE FATTY ACID PLASMA LEVELS FOLLOWING FAT EMULSION
INFUSION; THEREFORE, SERIOUS CONSIDERATION MUST BE GIVEN TO ADMINISTRATION OF LESS THAN THE
MAXIMUM RECOMMENDED DOSES IN THESE PATIENTS IN ORDER TO DECREASE THE LIKELIHOOD OF
INTRAVENOUS FAT OVERLOAD. THE INFANT’S ABILITY TO ELIMINATE THE INFUSED FAT FROM THE CIRCULATION
MUST BE CAREFULLY MONITORED (SUCH AS SERUM TRIGLYCERIDES AND/OR PLASMA FREE FATTY ACID
LEVELS). THE LIPEMIA MUST CLEAR BETWEEN DAILY INFUSIONS.
CAUTION SHOULD BE EXERCISED IN ADMINISTERING INTRALIPID® 10% (A 10% INTRAVENOUS FAT EMULSION)
TO PATIENTS WITH SEVERE LIVER DAMAGE, PULMONARY DISEASE, ANEMIA OR BLOOD COAGULATION
DISORDERS, OR WHEN THERE IS DANGER OF FAT EMBOLISM.
WARNING: THIS PRODUCT CONTAINS ALUMINUM THAT MAY BE TOXIC. ALUMINUM MAY REACH TOXIC
LEVELS WITH PROLONGED PARENTERAL ADMINISTRATION IF KIDNEY FUNCTION IS IMPAIRED. PREMATURE
NEONATES ARE PARTICULARLY AT RISK BECAUSE THEIR KIDNEYS ARE IMMATURE, AND THEY REQUIRE LARGE
AMOUNTS OF CALCIUM AND PHOSPHATE SOLUTIONS, WHICH CONTAIN ALUMINUM.
RESEARCH INDICATES THAT PATIENTS WITH IMPAIRED KIDNEY FUNCTION, INCLUDING PREMATURE NEONATES,
WHO RECEIVE PARENTERAL LEVELS OF ALUMINUM AT GREATER THAN 4 TO 5 MCG/KG/DAY ACCUMULATE
ALUMINUM AT LEVELS ASSOCIATED WITH CENTRAL NERVOUS SYSTEM AND BONE TOXICITY. TISSUE LOADING
MAY OCCUR AT EVEN LOWER RATES OF ADMINISTRATION.
PRECAUTIONS
WHEN INTRALIPID® 10% IS ADMINISTERED, THE PATIENTS CAPACITY TO ELIMINATE THE INFUSED FAT FROM THE
CIRCULATION MUST BE MONITORED BY USE OF AN APPROPRIATE LABORATORY DETERMINATION OF SERUM
TRIGLYCERIDES. OVERDOSAGE MUST BE AVOIDED.
DURING LONG TERM INTRAVENOUS NUTRITION WITH INTRALIPID® 10%, LIVER FUNCTION TESTS SHOULD BE
PERFORMED. IF THESE TESTS INDICATE THAT LIVER FUNCTION IS IMPAIRED, THE THERAPY SHOULD BE
WITHDRAWN.
FREQUENT (SOME ADVISE DAILY) PLATELET COUNTS SHOULD BE DONE IN NEONATAL PATIENTS RECEIVING
PARENTERAL NUTRITION WITH INTRALIPID® 10%.
DRUG PRODUCT CONTAINS NO MORE THAN 25 MCG/L OF ALUMINUM.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies with Intralipid® have not been
performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.
PREGNANCY CATEGORY C: ANIMAL REPRODUCTION STUDIES HAVE NOT BEEN CONDUCTED WITH
INTRALIPID®. IT IS ALSO NOT KNOWN WHETHER INTRALIPID® CAN CAUSE FETAL HARM WHEN ADMINISTERED TO
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A PREGNANT WOMAN OR CAN AFFECT REPRODUCTION CAPACITY. INTRALIPID® SHOULD BE GIVEN TO A
PREGNANT WOMAN ONLY IF CLEARLY NEEDED.
NURSING MOTHERS: CAUTION SHOULD BE EXERCISED WHEN INTRALIPID® IS ADMINISTERED TO A NURSING
WOMAN.
PEDIATRIC USE: SEE DOSAGE AND ADMINISTRATION.
AVOID OVERDOSAGE ABSOLUTELY.
ADVERSE REACTIONS
THE ADVERSE REACTIONS OBSERVED CAN BE SEPARATED INTO TWO CLASSES:
1.THOSE MORE FREQUENTLY ENCOUNTERED ARE DUE: EITHER TO CONTAMINATION OF THE INTRAVENOUS
CATHETER AND RESULT IN SEPSIS, OR TO VEIN IRRITATION BY CONCURRENTLY INFUSED HYPERTONIC
SOLUTIONS AND MAY RESULT IN THROMBOPHLEBITIS. THESE ADVERSE REACTIONS ARE INSEPARABLE FROM
THE HYPER-ALIMENTATION PROCEDURE WITH OR WITHOUT INTRALIPID® 10% (A 10% I.V. FAT EMULSION).
2.LESS FREQUENT REACTIONS MORE DIRECTLY RELATED TO INTRALIPID® 10% ARE: A) IMMEDIATE OR EARLY
ADVERSE REACTIONS, EACH OF WHICH HAS BEEN REPORTED TO OCCUR IN CLINICAL TRIALS, IN AN INCIDENCE
OF LESS THAN 1 %; DYSPNEA, CYANOSIS, ALLERGIC REACTIONS, HYPERLIPEMIA, HYPERCOAGULABILITY,
NAUSEA, VOMITING, HEADACHE, FLUSH-ING, INCREASE IN TEMPERATURE, SWEATING, SLEEPINESS, PAIN IN THE
CHEST AND BACK, SLIGHT PRESSURE OVER THE EYES, DIZZINESS, AND IRRITATION AT THE SITE OF INFUSION,
AND, RARELY, THROMBOCYTOPENIA IN NEONATES; B) DELAYED ADVERSE REACTIONS SUCH AS
HEPATOMEGALY, JAUNDICE DUE TO CENTRAL LOBULAR CHOLESTASIS, SPLENOMEGALY,
THROMBOCYTOPENIA, LEUKOPENIA, TRANSIENT INCREASES IN LIVER FUNCTION TESTS, AND OVERLOADING
SYNDROME (FOCAL SEIZURES, FEVER, LEUKOCYTOSIS, HEPATOMEGALY, SPLENOMEGALY AND SHOCK).
THE DEPOSITION OF A BROWN PIGMENTATION IN THE RETICULOEN-DOTHELIAL SYSTEM, THE SO-CALLED
“INTRAVENOUS FAT PIGMENT,” HAS BEEN REPORTED IN PATIENTS INFUSED WITH INTRALIPID® 10%. THE
CAUSES AND SIGNIFICANCE OF THIS PHENOMENON ARE UNKNOWN.
OVERDOSAGE
IN THE EVENT OF FAT OVERLOAD DURING THERAPY, STOP THE INFUSION OF INTRALIPID® 10% UNTIL VISUAL
INSPECTION OF THE PLASMA, DETERMINATION OF TRIGLYCERIDE CONCENTRATIONS, OR MEASUREMENT OF
PLASMA LIGHT-SCATTERING ACTIVITY BY NEPHELOMETRY INDICATES THE LIPID HAS CLEARED. RE-EVALUATE
THE PATIENT AND INSTITUTE APPROPRIATE CORRECTIVE MEASURES. SEE WARNINGS AND PRECAUTIONS.
DOSAGE AND ADMINISTRATION
INTRALIPID® 10% SHOULD BE ADMINISTERED AS A PART OF INTRAVENOUS NUTRITION VIA PERIPHERAL VEIN OR
BY CENTRAL VENOUS INFUSION.
Adult Patients
THE INITIAL RATE OF INFUSION IN ADULTS SHOULD BE 1 ML/MINUTE FOR THE FIRST 15 TO 30 MINUTES OF
INFUSION. IF NO UNTOWARD REACTIONS OCCUR (SEE ADVERSE REACTIONS SECTION), THE INFUSION RATE
CAN BE INCREASED TO 2 ML/MINUTE. NOT MORE THAN 500 ML OF INTRALIPID® 10% (A 10% INTRAVENOUS
FAT EMULSION) SHOULD BE INFUSED INTO ADULTS ON THE FIRST DAY OF THERAPY. IF THE PATIENT HAS NO
UNTOWARD REACTIONS, THE DOSE CAN BE INCREASED ON THE FOLLOWING DAY. THE DAILY DOSAGE SHOULD
NOT EXCEED 2.5 G OF FAT/KG OF BODY WEIGHT (25 ML OF INTRALIPID® 10% PER KG). INTRALIPID® 10%
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SHOULD MAKE UP NO MORE THAN 60% OF THE TOTAL CALORIC INPUT TO THE PATIENT. CARBOHYDRATE AND A
SOURCE OF AMINO ACIDS SHOULD COMPRISE THE REMAINING CALORIC INPUT.
Pediatric Patients
THE DOSAGE FOR PREMATURE INFANTS STARTS AT 0.5 G FAT/KG BODY WEIGHT/24 HOURS (5 ML INTRALIPID®
10%) AND MAY BE INCREASED IN RELATION TO THE INFANT’S ABILITY TO ELIMINATE FAT. THE MAXIMUM
DOSAGE RECOMMENDED BY THE AMERICAN ACADEMY OF PEDIATRICS IS 3 G FAT/KG/24 HOURS3.
THE INITIAL RATE OF INFUSION IN OLDER PEDIATRIC PATIENTS SHOULD BE NO MORE THAN 0.1 ML/MINUTE FOR
THE FIRST 10 TO 15 MINUTES. IF NO UNTOWARD REACTIONS OCCUR, THE RATE CAN BE CHANGED TO PERMIT
INFUSION OF 1 ML OF INTRALIPID® 10%/KG/HOUR. THE DAILY DOSAGE SHOULD NOT EXCEED 3 G OF FAT/KG OF
BODY WEIGHT3. INTRALIPID® 10% SHOULD MAKE UP NO MORE THAN 60% OF THE TOTAL CALORIC INPUT TO THE
PATIENT. CARBOHYDRATE AND A SOURCE OF AMINO ACIDS SHOULD COMPRISE THE REMAINING CALORIC INPUT.
Essential Fatty Acid Deficiency
WHEN INTRALIPID® 10% (A 10% I.V. FAT EMULSION) IS ADMINISTERED TO CORRECT ESSENTIAL FATTY ACID
DEFICIENCY, EIGHT TO TEN PERCENT OF THE CALORIC INPUT SHOULD BE SUPPLIED BY INTRALIPID® 10% IN
ORDER TO PROVIDE ADEQUATE AMOUNTS OF LINOLEIC AND LINOLENIC ACIDS. WHEN EFAD OCCURS TOGETHER
WITH STRESS, THE AMOUNT OF INTRALIPID® 10% NEEDED TO CORRECT THE DEFICIENCY MAY BE INCREASED.
Administration
SEE MIXING GUIDELINES AND LIMITATIONS SECTION FOR INFORMATION REGARDING MIXING THIS FAT
EMULSION WITH OTHER PARENTERAL FLUIDS.
INTRALIPID® 10% CAN BE INFUSED INTO THE SAME CENTRAL OR PERIPHERAL VEIN AS CARBOHYDRATE/AMINO
ACIDS SOLUTIONS BY MEANS OF A Y-CONNECTOR NEAR THE INFUSION SITE. THIS ALLOWS FOR MIXING OF THE
EMULSION IMMEDIATELY BEFORE ENTERING THE VEIN OR FOR ALTERNATION OF EACH PARENTERAL FLUID. IF
INFUSION PUMPS ARE USED, FLOW RATES OF EACH PARENTERAL FLUID SHOULD BE CONTROLLED WITH A
SEPARATE PUMP. FAT EMULSION MAY ALSO BE INFUSED THROUGH A SEPARATE PERIPHERAL SITE. FILTERS OF
LESS THAN 1.2 MICRON PORE SIZE MUST NOT BE USED WITH INTRALIPID® 10%.
CONVENTIONAL ADMINISTRATION SETS AND TPN POOLING BAGS CONTAIN POLYVINYL CHLORIDE (PVC)
COMPONENTS THAT HAVE DEHP (DIETHYL HEXYL PHTHALATE) AS A PLASTICIZER. FAT-CONTAINING FLUIDS
SUCH AS INTRALIPID® 10% EXTRACT DEHP FROM THESE PVC COMPONENTS AND IT MAY BE ADVISABLE TO
CONSIDER INFUSION OF INTRALIPID® 10% THROUGH A NON-DEHP ADMINISTRATION SET.
DO NOT USE ANY BAG IN WHICH THERE APPEARS TO BE AN OILING OUT ON THE SURFACE OF THE EMULSION.
PARENTERAL DRUG PRODUCTS SHOULD BE INSPECTED VISUALLY FOR PARTICULATE MATTER AND
DISCOLORATION PRIOR TO ADMINISTRATION, WHENEVER SOLUTION AND CONTAINER PERMIT.
MIXING GUIDELINES AND LIMITATIONS
INVESTIGATIONS HAVE BEEN CONDUCTED WHICH DEMONSTRATE THE COMPATIBILITY OF INTRALIPID® 10%
WHEN PROPERLY MIXED WITH EITHER NOVAMINE® OR 8.5% TRAVASOL® OR 10% TRAVASOL® AMINO ACID
INJECTIONS WITHOUT ELECTROLYTES FOR USE IN TPN THERAPY. THE FOLLOWING PROPER MIXING SEQUENCE
MUST BE FOLLOWED TO MINIMIZE PH RELATED PROBLEMS BY ENSURING THAT TYPICALLY ACIDIC
DEXTROSE INJECTIONS ARE NOT MIXED WITH LIPID EMULSIONS ALONE:
1. TRANSFER DEXTROSE INJECTION TO THE TPN ADMIXTURE CONTAINER
2. TRANSFER AMINO ACID INJECTION
3. TRANSFER INTRALIPID® 10% (A 10% INTRAVENOUS FAT EMULSION)
NOTE:
AMINO ACID INJECTION, DEXTROSE INJECTION AND INTRALIPID® 10% MAY BE SIMULTANEOUSLY
TRANSFERRED TO THE ADMIXTURE CONTAINER. ADMIXING SHOULD BE ACCOMPANIED BY GENTLE
AGITATION TO AVOID LOCALIZED CONCENTRATION EFFECTS.
THESE ADMIXTURES SHOULD BE USED PROMPTLY WITH STORAGE UNDER REFRIGERATION (2-8°C) NOT TO
EXCEED 24 HOURS AND MUST BE COMPLETELY USED WITHIN 24 HOURS AFTER REMOVAL FROM REFRIGERATION.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-449/S-039
NDA 17-643/S-072
Page 17
IT IS ESSENTIAL THAT THE ADMIXTURE BE PREPARED USING STRICT ASEPTIC TECHNIQUES AS THIS NUTRIENT
MIXTURE IS A GOOD GROWTH MEDIUM FOR MICROORGANISMS.
ADDITIVES OTHER THAN THOSE NAMED ABOVE MAY BE INCOMPATIBLE. COMPLETE INFORMATION IS NOT
AVAILABLE. THOSE ADDITIVES KNOWN TO BE INCOMPATIBLE SHOULD NOT BE USED. CONSULT WITH
PHARMACIST, IF AVAILABLE. IF, IN THE INFORMED JUDGMENT OF THE PHYSICIAN, IT IS DEEMED ADVISABLE TO
INTRODUCE ADDITIVES, USE ASEPTIC TECHNIQUE. MIX THOROUGHLY WHEN ADDITIVES HAVE BEEN
INTRODUCED. DO NOT STORE SOLUTIONS CONTAINING ADDITIVES (E.G., VITAMINS AND MINERALS).
ADDITIVES MUST NOT BE ADDED DIRECTLY TO INTRALIPID® 10% AND IN NO CASE SHOULD INTRALIPID® 10% BE
ADDED TO THE TPN CONTAINER FIRST. BAGS SHOULD BE SHAKEN GENTLY AFTER EACH ADDITION TO MINIMIZE
LOCALIZED CONCENTRATION.
SUPPLEMENTAL ELECTROLYTES, TRACE METALS OR MULTIVITAMINS MAY BE REQUIRED IN ACCORDANCE WITH
THE PRESCRIPTION OF THE ATTENDING PHYSICIAN.
THE PRIME DESTABILIZERS OF EMULSIONS ARE EXCESSIVE ACIDITY (LOW PH) AND INAPPROPRIATE
ELECTROLYTE CONTENT. CAREFUL CONSIDERATION SHOULD BE GIVEN TO ADDITIONS OF DIVALENT CATIONS
(CA++ AND MG++) WHICH HAVE BEEN SHOWN TO CAUSE EMULSION INSTABILITY. AMINO ACID SOLUTIONS EXERT
A BUFFERING EFFECT PROTECTING THE EMULSION.
THE ADMIXTURE SHOULD BE INSPECTED CAREFULLY FOR “BREAKING OR OILING OUT“ OF THE EMULSION.
“BREAKING OR OILING OUT” IS DESCRIBED AS THE SEPARATION OF THE EMULSION AND CAN BE VISIBLY
IDENTIFIED BY A YELLOWISH STREAKING OR THE ACCUMULATION OF YELLOWISH DROPLETS IN THE ADMIXED
EMULSION. THE ADMIXTURE SHOULD ALSO BE EXAMINED FOR PARTICULATES. THE ADMIXTURE MUST BE
DISCARDED IF ANY OF THE ABOVE IS OBSERVED.
HOW SUPPLIED
INTRALIPID® 10% IS SUPPLIED AS A STERILE EMULSION IN THE FOLLOWING FILL SIZES: 100 ML, 250 ML, AND
500 ML.
100 ML: 0338-0518-48
250 ML: 0338-0518-02
500 ML: 0338-0518-03
STORAGE
INTRALIPID® 10% SHOULD NOT BE STORED ABOVE 25°C (77°F). DO NOT FREEZE INTRALIPID® 10%. IF
ACCIDENTALLY FROZEN, DISCARD THE BAG.
REFERENCES
1.
PADLEY FB: “MAJOR VEGETABLE FATS,“ THE LIPID HANDBOOK (GUNSTONE FD, HARWOOD JL, PADLEY
FB, EDS.), CHAPMAN AND HALL LTD., CAMBRIDGE, UK (1986), PP. 88-9.
2.
LEVENE MI, WIGGLESWORTH JS, DESAI R: PULMONARY FAT ACCUMULATION AFTER INTRALIPID® INFUSION
IN THE PRETERM INFANT. LANCET 1980; 2(8199):815-8.
3.
AMERICAN ACADEMY OF PEDIATRICS: USE OF INTRAVENOUS FAT EMULSION IN PEDIATRIC PATIENTS.
PEDIATRICS 1981; 68:5(NOV) 738-43.
(REV JUNE 2006)
MANUFACTURED FOR
Baxter Healthcare Corporation
CLINTEC NUTRITION DIVISION
DEERFIELD, IL 60015 USA
MANUFACTURED BY
Fresenius Kabi,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-449/S-039
NDA 17-643/S-072
Page 18
UPPSALA, SWEDEN
INTRALIPID® IS A REGISTERED TRADEMARK OF
FRESENIUS KABI AB.
NOVAMINE® IS A REGISTERED TRADEMARK OF
FRESENIUS KABI AB.
TRAVASOL® IS A REGISTERED TRADEMARK OF
BAXTER HEALTHCARE CORPORATION.
Instructions for Use – Intralipid® 10% Container
1. The integrity indicator (Oxalert™) A should be inspected before
removing the overpouch.
If the indicator is black the overpouch is damaged and the product
should be discarded.
2. REMOVE THE OVERWRAP BY TEARING AT THE NOTCH AND PULLING DOWN
ALONG THE CONTAINER. THE OXALERT™ SACHET A AND THE OXYGEN
ABSORBER B SHOULD BE DISPOSED.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-449/S-039
NDA 17-643/S-072
Page 19
3. Remove set port cover lifting ring with thumb and forefinger and pulling upwards.
4. Use a non-vented infusion set or close the air vent on a vented set.
Follow the instructions for use for the infusion set. Use a spike
conforming to ISO 8536-4, diameter 5.6 ± 0.1 mm.
5. The bag should be port side up when the infusion set is attached. Insert
the spike straight into the set port. Twist and push the spike through the
diaphragm.
Do not spike bag while the bag is hanging on the IV pole.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-449/S-039
NDA 17-643/S-072
Page 20
6. The step of the spike (shown by the arrow) should not be inserted into the port.
7. To hang the bag, invert and place hanger through container notch.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/017643s072,018449s039lbl.pdf', 'application_number': 18449, 'submission_type': 'SUPPL ', 'submission_number': 39}
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/18-461S050_Lidocaine.pdf', 'application_number': 18461, 'submission_type': 'SUPPL ', 'submission_number': 50}
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CIV
TALACEN®
Pentazocine hydrochloride, USP,
and acetaminophen, USP
Hepatotoxicity
TALACEN contains pentazocine hydrochloride and acetaminophen. Acetaminophen has been
associated with cases of acute liver failure, at times resulting in liver transplant and death. Most
of the cases of liver injury are associated with the use of acetaminophen at doses that exceed
4000 milligrams per day, and often involve more than one acetaminophen-containing product.
DESCRIPTION
TALACEN is a combination of pentazocine hydrochloride, USP, equivalent to 25 mg base and
acetaminophen, USP, 650 mg.
Pentazocine is a member of the benzazocine series (also known as the benzomorphan series).
Chemically, pentazocine is (2R*,6R*,11R*)1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2
butenyl)-2,6-methano-3-benzazocin-8-ol, a white, crystalline substance soluble in acidic aqueous
solutions, and has the following structural formula:
Chemically, acetaminophen is Acetamide, N-(4-hydroxyphenyl)-, and has the following
structural formula:
Pentazocine is an analgesic and acetaminophen is an analgesic and antipyretic.
Reference ID: 2964236
1
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Inactive Ingredients: Colloidal Silicon Dioxide, FD&C Blue #1, Gelatin, Microcrystalline
Cellulose, Potassium Sorbate, Pregelatinized Starch, Sodium Lauryl Sulfate, Sodium
Metabisulfite, Sodium Starch Glycolate, Stearic Acid.
CLINICAL PHARMACOLOGY
Pentazocine is a Schedule IV opioid analgesic with agonist/antagonist action which when
administered orally is approximately equivalent on a mg for mg basis in analgesic effect to
codeine.
Acetaminophen is an analgesic and antipyretic.
Pentazocine weakly antagonizes the analgesic effects of morphine, meperidine, and phenazocine;
in addition, it produces incomplete reversal of cardiovascular, respiratory, and behavioral
depression induced by morphine and meperidine. Pentazocine has about 1/50 the antagonistic
activity of nalorphine. It also has sedative activity.
Onset of significant analgesia with pentazocine usually occurs between 15 and 30 minutes after
oral administration, and duration of action is usually three hours or longer.
Pentazocine is well absorbed from the gastrointestinal tract. Plasma levels closely correspond to
the onset, duration, and intensity of analgesia. The time to mean peak concentration in 24
normal volunteers was 1.7 hours (range 0.5 to 4 hours) after oral administration and the mean
plasma elimination half-life was 3.6 hours (range 1.5 to 10 hours).
The action of pentazocine is terminated for the most part by biotransformation in the liver with
some free pentazocine excreted in the urine. The products of the oxidation of the terminal
methyl groups and glucuronide conjugates are excreted by the kidney. Elimination of
approximately 60% of the total dose occurs within 24 hours. Pentazocine passes into fetal
circulation.
Onset of significant analgesic and antipyretic activity of acetaminophen when administered
orally occurs within 30 minutes and is maximal at approximately 2 1/2 hours. The
pharmacological mode of action of acetaminophen is unknown at this time.
Acetaminophen is rapidly and almost completely absorbed from the gastrointestinal tract. In 24
normal volunteers the time to mean peak plasma concentration was 1 hour (range 0.25 to 3
hours) after oral administration and the mean plasma elimination half-life was 2.8 hours (range 2
to 4 hours).
The effect of pentazocine on acetaminophen plasma protein binding or vice versa has not been
established. For acetaminophen there is little or no plasma protein binding at normal therapeutic
doses. When toxic doses of acetaminophen are ingested and drug plasma levels exceed
90 mcg/mL, plasma binding may vary from 8% to 43%.
Acetaminophen is conjugated in the liver with glucuronic acid and to a lesser extent with sulfuric
acid. Approximately 80% of acetaminophen is excreted in the urine after conjugation and about
2
Reference ID: 2964236
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For current labeling information, please visit https://www.fda.gov/drugsatfda
3% is excreted unchanged. The drug is also conjugated to a lesser extent with cysteine and
additionally metabolized by hydroxylation.
If TALACEN is taken every 4 hours over an extended period of time, accumulation of
pentazocine and to a lesser extent, acetaminophen, may occur.
INDICATIONS AND USAGE
TALACEN is indicated for the relief of mild to moderate pain.
CONTRAINDICATIONS
TALACEN is contraindicated in patients who are hypersensitive to either pentazocine or
acetaminophen.
TALACEN is contraindicated in patients with sulfite allergy.
WARNINGS
Hepatotoxicity
TALACEN contains pentazocine hydrochloride and acetaminophen. Acetaminophen has been
associated with cases of acute liver failure, at times resulting in liver transplant and death. Most
of the cases of liver injury are associated with the use of acetaminophen at doses that exceed
4000 milligrams per day, often involve more than one acetaminophen-containing product. The
excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as
patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing
products.
The risk of acute liver failure is higher in individuals with underlying liver disease and in
individuals who ingest alcohol while taking acetaminophen.
Instruct patients to look for acetaminophen or APAP on package labels and not to use more than
one product that contains acetaminophen. Instruct patients to seek medical attention immediately
upon ingestion of more than 4000 milligrams of acetaminophen per day, even if they feel well.
Hypersensitivity/anaphylaxis
There have been post-marketing reports of hypersensitivity and anaphylaxis associated with the
use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory
distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening
anaphylaxis requiring emergency medical attention. Instruct patients to discontinue TALACEN
immediately and seek medical care if they experience these symptoms. Do not prescribe
TALACEN for patients with acetaminophen allergy.
TALACEN contains sodium metabisulfite, a sulfite that may cause allergic-type reactions
including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain
susceptible people. The overall prevalence of sulfite sensitivity in the general population is
unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in
nonasthmatic people.
Reference ID: 2964236
3
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For current labeling information, please visit https://www.fda.gov/drugsatfda
There have been post-marketing reports of hypersensitivity and anaphylaxis associated with use
of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory
distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening
anaphylaxis requiring emergent medical attention. Instruct patients to discontinue TALACEN
immediately and seek medical care if they experience these symptoms. Do not prescribe
TALACEN for patients with acetaminophen allergy.
Drug Dependence
Pentazocine can cause a physical and psychological dependence. (See DRUG ABUSE AND
DEPENDENCE.)
Use In Head Injury and Increased Intracranial Pressure
In the presence of head injury, intracranial lesions or a preexisting increase in intracranial
pressure, the possible respiratory depressant effects of pentazocine and its potential to
elevate cerebrospinal fluid pressure (resulting from vasodilation following CO2 retention)
may be markedly increased. Furthermore, pentazocine can produce effects on pupillary
response and consciousness, which may obscure neurologic signs of further increases in
intracranial pressure in patients with head injuries. In such patients, TALACEN must be
used with extreme caution and only if its use is deemed essential.
Interactions with Alcohol and Drugs of Abuse
Pentazocine may be expected to have additive effects when used in conjunction with alcohol,
other opioids, or illicit drugs that cause central nervous system depression because respiratory
depression, hypotension, profound sedation, coma or death may result.
Patients Receiving Narcotics
Pentazocine is a mild narcotic antagonist. Some patients previously given narcotics, including
methadone for the daily treatment of narcotic dependence, have experienced withdrawal
symptoms after receiving pentazocine.
Respiratory Depression
Respiratory depression occurs more frequently in elderly or debilitated patients and in those
suffering from conditions accompanied by hypoxia, hypercapnia, or upper airway obstruction, in
whom even moderate therapeutic doses may significantly decrease pulmonary ventilation. Use
TALACEN with extreme caution in patients with chronic obstructive pulmonary disease or cor
pulmonale and in patients having a substantially decreased respiratory reserve (e.g., severe
kyphoscoliosis), hypoxia, hypercapnia, or pre-existing respiratory depression. Alternative non-
opioid analgesics should be considered, and TALACEN should be employed only under careful
medical supervision at the lowest effective dose in such patients.
Acute CNS Manifestations
Patients receiving therapeutic doses of TALACEN have experienced hallucinations (usually
visual), disorientation, and confusion which have cleared spontaneously within a period of hours.
The mechanism of this reaction is not known. Such patients should be closely observed and vital
signs checked. If the drug is reinstituted, it should be done with caution since these acute CNS
manifestations may recur.
Reference ID: 2964236
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRECAUTIONS
Drug Abuse and Dependence
TALACEN is a Schedule IV controlled substance.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is
characterized by misuse of a drug for non-medical purposes, often in combination with other
psychoactive substances. Addiction is a disease of repeated drug abuse. Addiction is a primary,
chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors
influencing its development and manifestations. Addiction is characterized by behaviors that
include one or more of the following: impaired control over drug use, compulsive use, continued
use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary
approach, but relapse is common. Physical dependence is a state of adaptation that is manifested
by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose
reduction, decreasing blood level of the drug, and/or administration of an antagonist. Tolerance
is a state of adaptation in which exposure to a drug induces changes that result in a diminution of
one or more of the drug’s effects over time. Tolerance may occur to both the desired and
undesired effects of drugs, and may develop at different rates for different effects.
Physicians should be aware that addiction may not be accompanied by concurrent tolerance and
symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the
absence of addiction and is characterized by misuse of the drug for non-medical purposes, and
often in combination with other psychoactive substances.
There have been some reports of dependence and of withdrawal symptoms with TALACEN.
Patients with a history of drug dependence should be under close supervision while receiving
pentazocine orally. There have been rare reports of possible abstinence syndromes in newborns
after prolonged use of pentazocine during pregnancy.
There have been reports of development of addiction and physical dependence in patients
receiving parenteral pentazocine. People with a history of drug abuse or alcohol abuse may have
a higher chance of becoming addicted to opioid medicines.
Abrupt dose cessation or rapid dose reduction following the extended use of parenteral
pentazocine has resulted in withdrawal symptoms such as abdominal cramps, nausea, vomiting,
elevated temperature, chills, rhinorrhea, restlessness, anxiety, or lacrimation. In general opioid
therapy should not be abruptly discontinued. When the patient no longer requires treatment with
TALACEN, the drug should be tapered gradually to prevent signs and symptoms of withdrawal
in patients who have been receiving opioids for an extended period of time and might have
become physically dependent.
In prescribing TALACEN for chronic use, the physician should take under consideration that
proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy,
and proper dispensing and storage are appropriate measures that help to identify and decrease
misuse and abuse of opioid drugs.
Reference ID: 2964236
5
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Severe, even lethal, consequences may result from misuse of tablets by injection either alone or
in combination with other substances, such as pulmonary emboli, vascular occlusion, ulceration
and abscesses, and withdrawal symptoms in narcotic dependent individuals.
CNS Effect
Caution should be used when TALACEN is administered to patients prone to seizures; seizures
have occurred in a few such patients in association with the use of pentazocine although no cause
and effect relationship has been established.
Porphyria
Particular caution should be exercised in administering pentazocine to patients with porphyria
since it may provoke an acute attack in susceptible individuals.
Cardiovascular Disease
Pentazocine can elevate blood pressure, possibly through the release of endogenous
catecholamines. Particular caution should be exercised in conditions where alterations in
vascular resistance and blood pressure might be particularly undesirable, such as in the acute
phase of myocardial infarction.
TALACEN should be used with caution in patients with myocardial infarction who have nausea
or vomiting.
Impaired Renal or Hepatic Function
Decreased metabolism of the drug by the liver in extensive liver disease may predispose to
accentuation of side effects. Although laboratory tests have not indicated that pentazocine causes
or increases renal or hepatic impairment, the drug should be administered with caution to
patients with such impairment.
Acetaminophen is metabolized by the liver, and has been associated with cases of acute liver
failure, at times resulting in liver transplant and death. Therefore, TALACEN should be
administered with caution to patients with hepatic impairment and in individuals who ingest
alcohol (See BOXED WARNING and WARNINGS, Hepatotoxicity).
Other
Caution should also be observed when administering TALACEN in patients with
hypothyroidism, adrenocortical insufficiency, prostate hypertrophy, inflammatory or obstructive
bowel disease, acute abdominal syndromes of unknown etiology, cholecystitis, pancreatitis, or
acute alcohol intoxication and delirium tremens.
Biliary Surgery
Narcotic drug products are generally considered to elevate biliary tract pressure for varying
periods following their administration. Some evidence suggests that pentazocine may differ
from other marketed narcotics in this respect (i.e., it causes little or no elevation in biliary tract
pressures). The clinical significance of these findings, however, is not yet known.
Information for Patients.
Reference ID: 2964236
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients receiving TALACEN should be given the following instructions by the physician:
• Do not take TALACEN if you are allergic to any of its ingredients.
• If you develop signs/symptoms of allergy such as a rash, hives, itching, vomiting, swelling of
the face or mouth, or difficulty breathing, stop taking TALACEN and contact your healthcare
provider immediately.
• Do not take more than 4000 milligrams of acetaminophen (alone or in combination with
other products containing acetaminophen). Seek medical attention immediately upon
ingestion of more than 4000 milligrams of acetaminophen per day, even if you feel well.
Look for acetaminophen or APAP on package labels. Do not use more than one product that
contains acetaminophen.
• Contact your healthcare provider if you took more than the recommended dose.
• Patients should be advised that TALACEN is a narcotic pain reliever, and should be taken
only as directed.
• The dose of TALACEN should not be adjusted without consulting with a physician or other
healthcare professional.
• Patients should be advised that TALACEN may cause drowsiness, dizziness, or
lightheadedness and may impair mental and/or physical ability required for the performance
of potentially hazardous tasks (e.g., driving, operating machinery). Patients started on
TALACEN or patients whose dose has been adjusted should refrain from any potentially
dangerous activity until it is established that they are not adversely affected.
• TALACEN will add to the effect of alcohol and other CNS depressants (such as
antihistamines, sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other
opioids, and monoamine oxidase [MAO]inhibitors).
• Patients should not combine TALACEN with alcohol or other central nervous system
depressants (sleep aids, tranquilizers) except by the orders of the prescribing physician,
because dangerous additive effects may occur, resulting in serious injury or death.
• Women of childbearing potential who become or are planning to become pregnant should
consult a physician prior to initiating or continuing therapy with TALACEN.
• Safe use in pregnancy has not been established. Prolonged use of opioid analgesics during
pregnancy may cause neonatal physical dependence, and neonatal withdrawal may occur.
• If patients have been receiving treatment with TALACEN for more than a few weeks and
cessation of therapy is indicated, they should be counseled on the importance of safely
tapering the dose and that abruptly discontinuing the medication could precipitate withdrawal
symptoms. The physician should provide a dose schedule to accomplish a gradual
discontinuation of the medication.
• Patients should be advised that TALACEN is a potential drug of abuse. They should protect
it from theft. It should never be given to anyone other than the individual for whom it was
prescribed.
• Patients should be instructed to keep TALACEN in a secure place out of the reach of
children. When TALACEN is no longer needed, please consult your pharmacist for proper
disposal instructions.
• As with other opioids, patients taking TALACEN should be advised of the potential for
severe constipation; appropriate laxatives and/or stool softeners as well as other appropriate
treatments should be initiated from the onset of opioid therapy.
7
Reference ID: 2964236
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For current labeling information, please visit https://www.fda.gov/drugsatfda
• Patients should be advised of the most common adverse events that may occur while taking
TALACEN: constipation, nausea, somnolence, lightheadedness, dizziness, sedation,
vomiting, and sweating.
Drug Interactions.
CNS Depressants
Other central nervous system (CNS) depressants including sedatives, hypnotics, general
anesthetics, antiemetics, phenothiazines, or other tranquilizers or alcohol increases the risk of
respiratory depression, hypotension, profound sedation, or coma. Use morphine sulfate with
caution and in reduced dosages in patients taking these agents.
Opioid Agonist Analgesics
TALACEN can antagonize the effects of a pure opioid agonist analgesic and/or may precipitate
withdrawal symptoms.
Monoamine Oxidase Inhibitors (MAOIs)
Concomitant use of monoamine oxidase inhibitors (MAOIs) with TALACEN may cause CNS
excitation and hypertension through their respective effects on catecholamines. Caution should
therefore be observed in administering TALACEN to patients who are currently receiving
MAOIs or who have received them within the preceding 14 days.
Anticholinergics
Anticholinergics or other medications with anticholinergic activity when used concurrently with
opioid analgesics may result in increased risk of urinary retention and/or severe constipation,
which may lead to paralytic ileus.
Tobacco
Smoking tobacco could enhance the metabolic clearance rate of pentazocine reducing the clinical
effectiveness of a standard dose of pentazocine.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis, mutagenesis, and impairment of fertility studies have not been done with this
combination product.
Studies to evaluate the mutagenic potential of the components of TALACEN have not been
conducted.
Pentazocine, when administered orally or parenterally, had no adverse effect on either the
reproductive capabilities or the course of pregnancy in rabbits and rats. Embryotoxic effects on
the fetuses were not shown.
The daily administration of 4 mg/kg to 20 mg/kg pentazocine subcutaneously to female rats
during a 14 day pre-mating period and until the 13th day of pregnancy did not have any adverse
effects on the fertility rate.
Pregnancy
Reference ID: 2964236
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Teratogenic Effects
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. TALACEN should be
used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Animal studies with the combination of pentazocine and acetaminophen have not been
completed.
In a published report, a single dose of pentazocine administered to pregnant hamsters on
gestation day 8 increased the incidence of exencephaly and cranioschisis at a dose of 196 mg/kg,
SC (0.2-times the maximum daily human dose of pentazocine via 6 caplets on a mg/m2 basis).
Nonteratogenic Effects
There has been no experience in this regard with the combination pentazocine and
acetaminophen. However, there have been rare reports of possible abstinence syndromes in
newborns after prolonged use of pentazocine during pregnancy. Frequent use of acetaminophen
(defined as most days or daily use) in late pregnancy may be associated with an increased risk of
persistent wheezing in the infant which may persist into childhood.
Labor and Delivery
Patients receiving pentazocine during labor have experienced no adverse effects other than those
that occur with commonly used analgesics. However, pentazocine can cross the placental barrier
and cause central nervous system depression in the newborn and, if used regularly throughout
pregnancy, may lead to symptoms of withdrawal in the newborn. TALACEN should be used
with caution in women delivering premature infants. The effect of TALACEN on the mother
and fetus, the duration of labor or delivery, the possibility that forceps delivery or other
intervention or resuscitation of the newborn may be necessary, or the effect of TALACEN, on
the later growth, development, and functional maturation of the child are unknown at the present
time.
Nursing Mothers
Pentazocine and acetaminophen are excreted in human milk. Caution should be exercised when
TALACEN is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients below the age of 12 have not been established.
Geriatric Use
Clinical studies of TALACEN did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end
of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy.
Reference ID: 2964236
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ADVERSE REACTIONS
Clinical experience with TALACEN has been insufficient to define all possible adverse reactions
with this combination. However, reactions reported after oral administration of pentazocine
hydrochloride in 50 mg dosage include the following:
Cardiovascular: hypertension, hypotension, circulatory depression, tachycardia.
Respiratory: rarely respiratory depression,
Acute CNS Manifestations: Hallucinations (usually visual), disorientation, and confusion
Other CNS effects: grand mal convulsions, increase in intracranial pressure, dizziness,
lightheadedness, hallucinations, sedation, euphoria, headache, confusion, disorientation;
infrequently weakness, disturbed dreams, insomnia, syncope, and depression; and rarely tremor,
irritability, excitement, tinnitus.
Autonomic: sweating; infrequently flushing; and rarely chills.
Gastrointestinal: nausea, vomiting, constipation; diarrhea, anorexia, dry mouth, Biliary tract
spasm, and rarely abdominal distress.
Allergic: edema of the face, anaphylactic shock, dermatitis including pruritus, flushed skin
including plethora, infrequently rash; and rarely urticaria.
Ophthalmic: visual blurring and focusing difficulty, miosis.
Hematologic: depression of white blood cells (especially granulocytes) with rare cases of
agranulocytosis, which is usually reversible, moderate transient eosinophilia.
Dependence and Withdrawal Symptoms: (See WARNINGS, PRECAUTIONS, and DRUG
ABUSE AND DEPENDENCE Sections).
Other: urinary retention, paresthesia, serious skin reactions, including erythema multiforme,
Stevens-Johnson Syndrome, toxic epidermal necrolysis, and alterations in rate or strength of
uterine contractions during labor.
A few cases of hypersensitivity to acetaminophen have been reported, as manifested by
anaphylaxis, angioneurotic edema, thrombocytopenic purpura, skin rashes, and rarely hemolytic
anemia and agranulocytosis. Occasionally individuals respond to ordinary doses with nausea
and vomiting and diarrhea.
OVERDOSAGE
Signs and Symptoms
For pentazocine alone in single doses above 60 mg there have been reports of the occurrence of
nalorphine-like psychotomimetic effects such as anxiety, nightmares, strange thoughts, and
hallucinations. Somnolence, marked respiratory depression associated with increased blood
10
Reference ID: 2964236
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
pressure and tachycardia have also resulted as have seizures, hypotension, dizziness, nausea,
vomiting, lethargy, and paresthesias. The respiratory depression is antagonized by naloxone (see
Treatment). Circulatory failure and deepening coma may occur in more severe cases, particularly
in patients who have also ingested other CNS depressants such as alcohol, sedative/hypnotics, or
antihistamines.
In acetaminophen overdosage: dose-dependent, potentially fatal hepatic necrosis is the most
serious adverse effect. Renal tubular necrosis, hypoglycemic coma, and coagulation defects may
also occur. Early symptoms following a potentially hepatotoxic overdose may include: nausea,
vomiting, diaphoresis, and general malaise. Clinical and laboratory evidence of hepatic toxicity
may not be apparent until 48-72 hours post-ingestion
Treatment
Adequate measures to maintain ventilation and general circulatory support should be employed.
Assisted or controlled ventilation, intravenous fluids, vasopressors, and other supportive
measures should be employed as indicated. Consideration should be given to gastric lavage and
gastric aspiration to reduce drug absorption.
Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as
indicated. Assisted or controlled ventilation should also be considered. For respiratory
depression due to overdosage or unusual sensitivity to TALACEN, parenteral naloxone is a
specific and effective antagonist.
Gastric decontamination with activated charcoal should be administered just prior to N
acetylcysteine (NAC) to decrease systemic absorption if acetaminophen ingestion is known or
suspected to have occurred within a few hours of presentation. Serum acetaminophen levels
should be obtained immediately if the patient presents 4 hours or more after ingestion to assess
potential risk of hepatotoxicity; acetaminophen levels drawn less then 4 hours post-ingestion
may be misleading. To obtain the best possible outcome, NAC should be administered as soon
as possible where impending or evolving liver injury is suspected. Intravenous NAC may be
administered when circumstances preclude oral administration.
Vigorous supportive therapy is required in severe intoxication. Procedures to limit the continuing
absorption of the drug must be readily performed since the hepatic injury is dose dependent and
occurs early in the course of intoxication.
DOSAGE AND ADMINISTRATION
Adult
The usual adult dose is 1 caplet every 4 hours as needed for pain relief, up to a maximum of 6
caplets per day.
Discontinuation
Due to the potential for withdrawal symptoms associated with abrupt discontinuation,
consideration should be given to tapering patients off TALACEN after prolonged periods of
treatment with TALACEN (See PRECAUTIONS, Drug Abuse and Dependence).
Reference ID: 2964236
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HOW SUPPLIED
TALACEN is available for oral administration as a pale blue, scored caplet embossed with
“Winthrop” on one side and “T37” on the other side.
Bottles of 100 (NDC 0024-1937-04).
Store at 25° C (77° F); excursions permitted between 15° - 30° C (59° - 86° F).
Rx Only
Revised May 2011
Manufactured for:
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
©2011 sanofi-aventis U.S. LLC
12
Reference ID: 2964236
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:44:43.664681
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018458s016lbl.pdf', 'application_number': 18458, 'submission_type': 'SUPPL ', 'submission_number': 16}
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NDA 18-469/S-052
Page 3
BSS PLUS®
STERILE IRRIGATING SOLUTION
(balanced salt solution enriched with bicarbonate, dextrose, and glutathione)
DESCRIPTION: BSS PLUS® is a sterile intraocular irrigating solution for use during all
intraocular surgical procedures, including those requiring a relatively long intraocular perfusion
time (e.g., pars plana vitrectomy, phacoemulsification, extra capsular cataract extraction/lens
aspiration, anterior segment reconstruction, etc.). The solution does not contain a preservative
and should be prepared just prior to use in surgery.
Part I: Part I is a sterile 480 mL solution in a 500 mL single-dose bag to which the Part II
concentrate is added. Each mL of Part I contains: sodium chloride 7.44 mg, potassium chloride
0.395 mg, dibasic sodium phosphate 0.433 mg, sodium bicarbonate 2.19 mg, hydrochloric acid
and/or sodium hydroxide (to adjust pH), in water for injection.
Part II: Part II is a sterile concentrate in a 20 mL single-dose vial for addition to Part I. Each mL
of Part II contains: calcium chloride dehydrate 3.85 mg, magnesium chloride hexahydrate 5 mg,
dextrose 23 mg, glutathione disulfide (oxidized glutathione) 4.6 mg, in water for injection.
After addition of BSS PLUS® solution Part II to the Part I bag, each mL of the reconstituted
product contains: sodium chloride 7.14 mg, potassium chloride 0.38 mg, calcium chloride
dehydrate 0.154 mg, magnesium chloride hexahydrate 0.2 mg, dibasic sodium phosphate 0.42
mg, sodium bicarbonate 2.1 mg, dextrose 0.92 mg, glutathione disulfide (oxidized glutathione)
0.184 mg, hydrochloric acid and/or sodium hydroxide (to adjust pH), in water for injection.
The reconstituted product has a pH of approximately 7.4. Osmolality is approximately 305
mOsm.
CLINICAL PHARMACOLOGY: None of the components of BSS PLUS solution are foreign
to the eye, and BSS PLUS solution has no pharmacological action. Human perfused cornea
studies have shown BSS PLUS solution to be an effective irrigation solution for providing
corneal detumescence and maintaining corneal endothelial integrity during intraocular perfusion.
An in vivo study in rabbits has shown the BSS PLUS solution is more suitable than normal
saline or Balanced Salt Solution for intravitreal irrigation because BSS PLUS solution contains
the appropriate bicarbonate, pH, and ionic composition necessary for the maintenance of normal
retinal electrical activity. Human in vivo studies have demonstrated BSS PLUS solution to be
safe and effective when used during surgical procedures such as pars plan vitrectomy,
phacoemulsification, cataract extraction/lens aspiration, anterior segment reconstruction. No
differences have been observed between adults and pediatric patients following use of this drug
product.
INDICATIONS AND USAGE: BSS PLUS solution is indicated for use as an intraocular
irrigating solution during intraocular surgical procedures involving perfusion of the eye.
CONTRAINDICATIONS: There are no specific contraindications to the use of BSS PLUS
solution; however, contraindications for the surgical procedure during which BSS PLUS solution
is to be used should be strictly adhered to.
Reference ID: 3316062
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-469/S-052
Page 4
WARNINGS: For IRRIGATION during ophthalmic surgery only. Not for injection or
intravenous infusion. Do not use unless product is clear, seal is intact and container is
undamaged. Do not use if product is discolored or contains a precipitate.
PRECAUTIONS: DO NOT USE BSS PLUS solution UNTIL PART I IS FULLY
RECONSTITUTED WITH PART II. Discard unused contents. BSS PLUS does not contain a
preservative; therefore, do not use this container for more than one patient. DISCARD ANY
UNUSED PORTION SIX HOURS AFTER PREPARATION. Studies suggest that intraocular
irrigating solutions which are iso-osmotic with normal aqueous fluids should be used with
caution in diabetic patients undergoing vitrectomy since intraoperative lens changes have been
observed.
There have been reports of corneal clouding or edema following ocular surgery in which BSS
PLUS solution was used as an irrigating solution. As in all surgical procedures appropriate
measures should be taken to minimize trauma to the cornea and other ocular tissues.
Preparation: Reconstitute BSS PLUS Intraocular Irrigating Solution just prior to use in surgery.
Follow the same strict aseptic procedures in the reconstitution of BSS PLUS solution as used for
intravenous additives. Remove the BSS PLUS solution Part I (480 mL) bag from the clear
overwrap. Remove the blue flip-off seal from the BSS PLUS solution Part II (20 mL) vial.
Clean and disinfect the rubber stoppers on both containers by using sterile alcohol wipes.
Transfer the contents of the Part II vial to the Part I bag using a BSS PLUS solution Dual-Spike
Transfer Device (provided). An alternative method of solution transfer may be accomplished by
using a 20 mL syringe to remove the Part II solution from the vial and transferring exactly 20 mL
to the Part I container through the outer target area of the rubber stopper. An excess volume of
Part II is provided in each vial. Gently agitate the contents to mix the solution. Place a sterile cap
on the bag. Record the time and date of reconstitution and the patient’s name on the bag label.
Geriatric Use: No overall differences in safety or effectiveness have been observed between
elderly and younger patients.
ADVERSE REACTIONS: Postoperative inflammatory reactions as well as incidents of corneal
edema and corneal decompensation have been reported. Their relationship to the use of BSS
PLUS solution has not been established.
OVERDOSAGE: The solution has no pharmacological action and thus no potential for
overdosage. However, as with any intraocular surgical procedure, the duration of intraocular
manipulation should be kept to a minimum.
DOSAGE AND ADMINISTRATION: The solution should be used according to the standard
technique employed by the operating surgeon. For non-active irrigating system, use an
administration set with an air-inlet in the plastic spike since the bag does not contain a separate
airway tube. Follow the directions for the particular administration set to be used. Insert the spike
aseptically into the bag through the center target area of the rubber stopper. Allow the fluid to
flow to remove air from the tubing before intraocular irrigation begins.
Reference ID: 3316062
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-469/S-052
Page 5
HOW SUPPLIED: BSS PLUS Solution is supplied in two packages for reconstitution prior to
use: a 500 mL bag containing 480 mL (Part I) and a 20 mL glass vial (Part II); both using grey
butyl stoppers and aluminum seals. See the PRECAUTIONS section regarding reconstitution of
the solution.
NDC 0065-0800-XX
Storage: Store Part I and Part II at 2° - 25°C (36° - 77°F). DO NOT FREEZE. Discard prepared
solution after six hours.
Rx Only
Reference ID: 3316062
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-469/S-052
Page 6
RECONSTITUTION INSTRUCTIONS
DIRECTIONS: Use Aseptic Technique
1. Remove the BSS PLUS® solution Part I (480 mL) bag from the clear overwrap. Remove the
blue flip- off seal from the BSS PLUS® solution Part II (20 mL) vial. Prepare the stoppers on
both parts by using sterile alcohol wipes.
2. Peel open a BSS PLUS® solution Dual-Spike Transfer Device package (supplied) and remove
the sterile transfer spike. NOTE: This device is vented permitting air to enter vial during solution
transfer, thereby preventing the creation of a vacuum inside the vial.
3. Remove protector from the white plastic piercing pin of the Dual-Spike Transfer Device.
4. Firmly grasp device from behind the flange and insert the white plastic piercing pin into the
upright rubber stopper of the BSS PLUS® solution Part II (20 mL) vial.
5. Remove guard from filter needle. Firmly grasp vial in the palm of one hand and with thumb
and index finger, hold plastic flange against top of vial.
6. Hold the vial in the upright position, incline and immediately insert the transfer device into the
center target of rubber stopper of the BSS PLUS® solution Part I (480 mL) bag. (See
illustration.) Note: Do not invert Part II (20 ml) vial before or during spiking of the BSS PLUS®
solution Part I bag rubber stopper, until ready to initiate transfer.
7. Invert vial to initiate the transfer of Part II into Part I. If transfer does not occur immediately,
gentle manipulation of the bag can initiate transfer. NOTE: An excess amount of BSS PLUS®
solution Part II is provided in each vial. A non-transferred solution residual of approximately 0.3
mL can be expected to remain in the vial.
8. Immediately remove vial (with spike attached) from the BSS PLUS® solution Part I container
and discard it after solution transfer has been completed.
9. Place a sterile safety cap over the rubber stopper of Part I if the solution is not going to be used
immediately. Mix the solution gently until uniform. Record the patient’s name and the date and
time of reconstitution. BSS PLUS® solution is now ready for use.
CAUTION: Reconstituted BSS PLUS® solution must be used within six hours of mixing.
Discard any solution which has aged beyond that time. Never use the same bag of BSS PLUS®
solution on more than one patient.
Alternative Transfer Method
If preferred, the contents of the BSS PLUS® Part II component may be aspirated with an 18
gauge cannula attached to a 20 mL syringe and then transferred into the Part I bag.
Reference ID: 3316062
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-469/S-052
Page 7 usage illustration
Reference ID: 3316062
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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custom-source
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018469s052lbl.pdf', 'application_number': 18469, 'submission_type': 'SUPPL ', 'submission_number': 52}
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NDA 018469/S-056
Page 4
Labeling for BSS PLUS 250 mL (Part I) and 10 mL (Part II) Bottle kit
BSS PLUS 250 mL (Part 1) container label
250mL
Single Patient Use
NDC 0065-0800-25
BSS PLUS*
STERILE INTRAOCULAR IRRIGATING SOLUTION
(balanced salt solution enriched with bicarbonate, dextrose and glutathione)
After addition of BSS PLUS*- Part II (10 mL), each mL contains: sodium chloride 7.14 mg, potassium
chloride 0.38 mg, calcium chloride dihydrate 0.154 mg, magnesium chloride hexahydrate 0.2 mg, dibasic
sodium phosphate 0.42 mg, sodium bicarbonate 2.1 mg, dextrose 0.92 mg, glutathione disulfide (oxidized
glutathione) 0.184 mg, hydrochloric acid and/or sodium hydroxide (to adjust pH), in water for injection.
pH Approx. 7.4 - Osmolality Approx. 305 mOsm/kg
Rx Only
WARNINGS: FOR IRRIGATION DURING OPHTHALMIC SURGERY ONLY. NOT FOR
INJECTION OR INTRAVENOUS INFUSION. DO NOT USE UNLESS PRODUCT IS CLEAR, SEAL
IS INTACT, VACUUM IS PRESENT AND CONTAINER IS UNDAMAGED. DO NOT USE IF
PRODUCT IS DISCOLORED OR CONTAINS A PRECIPITATE.
PRECAUTIONS: DO NOT USE BSS PLUS UNTIL PART I IS FULLY RECONSTITUTED WITH
PART II.
DISCARD UNUSED CONTENTS SIX HOURS AFTER PREPARATION.
DO NOT USE THIS CONTAINER FOR MORE THAN ONE PATIENT.
Reconstitute just prior to use in surgery
* a trademark of Novartis
Alcon®
a Novartis company
Alcon Laboratories, Inc.
Fort Worth, Texas 76134 USA
Patient:
Reconstituted at
AM/PM on
SINGLE USE ONLY
Reference ID: 3922596
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018469/S-056
Page 5
LOT:
EXP:
240mL
NDC 0065-0800-25
BSS PLUS* PART I
STERILE SOLUTION
(For Reconstitution by Addition of BSS PLUS* Concentrate Part II, 10 mL)**
Each mL contains: sodium chloride 7.44 mg, potassium chloride 0.395 mg, dibasic sodium phosphate
0.433 mg, sodium bicarbonate 2.19 mg, hydrochloric acid and/or sodium hydroxide (to adjust pH), in
water for injection.
Rx Only
Storage: Store at 2° - 25°C (36° - 77° F).
WARNINGS: FOR IRRIGATION DURING OPHTHALMIC SURGERY ONLY AFTER
RECONSITUTION. DO NOT USE UNLESS PRODUCT IS CLEAR, SEAL IS INTACT, VACUUM IS
PRESENT AND CONTAINER IS UNDAMAGED.
NOT FOR INJECTION OR INTRAVENOUS INFUSION.
**Reconstitute just prior to use in surgery. Remove this part of label after reconstitution. Read the
Preparation and Administration sections of the package insert before reconstitution for important
directions and precautions.
Alcon®
Alcon Laboratories, Inc.
Fort Worth, Texas 76134 USA
© 2002-2003, 2015 Novartis
A170511-0915
Reference ID: 3922596
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018469/S-056
Page 6
Labeling for BSS PLUS 500 mL (Part I) and 20 mL (Part II) Bottle kit
BSS PLUS 500 mL (Part 1) container label
500mL
Single Patient Use
NDC 0065-0800-50
BSS PLUS*
STERILE INTRAOCULAR IRRIGATING SOLUTION
(balanced salt solution enriched with bicarbonate, dextrose and glutathione)
After addition of BSS PLUS*- Part II (20 mL), each mL contains: sodium chloride 7.14 mg, potassium
chloride 0.38 mg, calcium chloride dihydrate 0.154 mg, magnesium chloride hexahydrate 0.2 mg, dibasic
sodium phosphate 0.42 mg, sodium bicarbonate 2.1 mg, dextrose 0.92 mg, glutathione disulfide (oxidized
glutathione) 0.184 mg, hydrochloric acid and/or sodium hydroxide (to adjust pH), in water for injection.
pH Approx. 7.4 - Osmolality Approx. 305 mOsm/kg
Rx Only
WARNINGS: FOR IRRIGATION DURING OPHTHALMIC SURGERY ONLY. NOT FOR
INJECTION OR INTRAVENOUS INFUSION. DO NOT USE UNLESS PRODUCT IS CLEAR, SEAL
IS INTACT, VACUUM IS PRESENT AND CONTAINER IS UNDAMAGED. DO NOT USE IF
PRODUCT IS DISCOLORED OR CONTAINS A PRECIPITATE.
PRECAUTIONS: DO NOT USE BSS PLUS UNTIL PART I IS FULLY RECONSTITUTED WITH
PART II.
DISCARD UNUSED CONTENTS SIX HOURS AFTER PREPARATION.
DO NOT USE THIS CONTAINER FOR MORE THAN ONE PATIENT.
Reconstitute just prior to use in surgery
* a trademark of Novartis
Alcon®
a Novartis company
Alcon Laboratories, Inc.
Fort Worth, Texas 76134 USA
© 2002-2003, 2015 Novartis
Patient:
Reconstituted at
AM/PM on
SINGLE USE ONLY
Reference ID: 3922596
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018469/S-056
Page 7
LOT:
EXP:
480mL
NDC 0065-0800-50
BSS PLUS* PART I
STERILE SOLUTION
(For Reconstitution by Addition of BSS PLUS* Concentrate Part II, 20 mL)**
Each mL contains: sodium chloride 7.44 mg, potassium chloride 0.395 mg, dibasic sodium phosphate
0.433 mg, sodium bicarbonate 2.19 mg, hydrochloric acid and/or sodium hydroxide (to adjust pH), in
water for injection.
Rx Only
Storage: Store at 2° - 25°C (36° - 77° F).
WARNINGS: FOR IRRIGATION DURING OPHTHALMIC SURGERY ONLY AFTER
RECONSITUTION. DO NOT USE UNLESS PRODUCT IS CLEAR, SEAL IS INTACT, VACUUM IS
PRESENT AND CONTAINER IS UNDAMAGED.
NOT FOR INJECTION OR INTRAVENOUS INFUSION.
**Reconstitute just prior to use in surgery. Remove this part of label after reconstitution. Read the
Preparation and Administration sections of the package insert before reconstitution for important
directions and precautions.
A170509-0915
Reference ID: 3922596
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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2025-02-12T13:44:43.974332
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/018469s056lbl.pdf', 'application_number': 18469, 'submission_type': 'SUPPL ', 'submission_number': 56}
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NDA 18-469/S-040 & S-041
Page 3
Package Insert (for combined 250mL and 500 mL sizes)
BSS PLUS® STERILE INTRAOCULAR IRRIGATING SOLUTION
(balanced salt solution enriched with bicarbonate, dextrose, and glutathione)
DESCRIPTION: BSS PLUS ® is a sterile intraocular irrigating solution for use during all intraocular
surgical procedures, including those requiring a relatively long intraocular
perfusion time (e.g., pars plana vitrectomy, phacoemulsification, extracapsular cataract
extraction/lens aspiration, anterior segment reconstruction, etc.). The solution does not contain a
preservative and should be prepared just prior to use in surgery.
Part I: Part I is a sterile 240 mL or 480 mL solution in a 250 mL or 500 mL single-dose bottle to
which the Part II concentrate is added. Each mL of Part I contains: Sodium Chloride 7.44 mg,
Potassium Chloride 0.395 mg, Dibasic Sodium Phosphate 0.433 mg, Sodium Bicarbonate 2.19 mg,
Hydrochloric Acid and/or Sodium Hydroxide (to adjust pH), in Water for Injection.
Part II: Part II is a sterile concentrate in a 10 mL or 20 mL single-dose vial for addition to Part I. Each
mL of Part II contains: Calcium Chloride Dihydrate 3.85 mg, Magnesium Chloride Hexahydrate 5 mg,
Dextrose 23 mg, Glutathione Disulfide (Oxidized Glutathione) 4.6 mg, in Water for Injection.
After addition of BSS PLUS Part II to the Part I bottle, each mL of the reconstituted product contains:
sodium chloride 7.14 mg, potassium chloride 0.38 mg, calcium chloride dihydrate 0.154 mg,
magnesium chloride hexahydrate 0.2 mg, dibasic sodium phosphate 0.42 mg, sodium bicarbonate 2.1
mg, dextrose 0.92 mg, glutathione disulfide (oxidized glutathione) 0.184 mg, hydrochloric acid and/or
sodium hydroxide (to adjust pH), in water for injection.
The reconstituted product has a pH of approximately 7.4. Osmolality is approximately 305 mOsm.
CLINICAL PHARMACOLOGY: None of the components of BSS PLUS are foreign to the eye, and
BSS PLUS has no pharmacological action. Human perfused cornea studies have shown BSS PLUS to
be an effective irrigation solution for providing corneal detumescence and maintaining corneal
endothelial integrity during intraocular perfusion. An in vivo study in rabbits has shown that BSS
PLUS is more suitable than normal saline or Balanced Salt Solution for intravitreal irrigation because
BSS PLUS contains the appropriate bicarbonate, pH, and ionic composition necessary for the
maintenance of normal retinal electrical activity. Human in vivo studies have demonstrated BSS PLUS
to be safe and effective when used during surgical procedures such as pars plana vitrectomy,
phacoemulsification, cataract extraction/lens aspiration and anterior segment reconstruction. No
differences have been observed between adults and pediatric patients following use of this drug
product.
INDICATIONS AND USAGE: BSS PLUS is indicated for use as an intraocular irrigating solution
during intraocular surgical procedures involving perfusion of the eye.
CONTRAINDICATIONS: There are no specific contraindications to the use of BSS PLUS; however,
contraindications for the surgical procedure during which BSS PLUS is to be used should be strictly
adhered to.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-469/S-040 & S-041
Page 4
WARNINGS: For IRRIGATION during ophthalmic surgery only. Not for injection or intravenous
infusion. Do not use unless product is clear, seal is intact, vacuum is present and container is
undamaged. Do not use if product is discolored or contains a precipitate.
PRECAUTIONS: DO NOT USE BSS PLUS UNTIL PART I IS FULLY RECONSTITUTED WITH
PART II. Discard unused contents. BSS PLUS does not contain a preservative; therefore, do not use
this container for more than one patient. Do not use additives other than BSS PLUS Concentrate Part
II (10 mL or 20 mL) with this product. Tissue damage could result if other drugs are added to product.
DISCARD ANY UNUSED PORTION SIX HOURS AFTER PREPARATION. Studies suggest that
intraocular irrigating solutions which are iso-osmotic with normal aqueous fluids should be used with
caution in diabetic patients undergoing vitrectomy since intraoperative lens changes have been
observed.
There have been reports of corneal clouding or edema following ocular surgery in which BSS PLUS
was used as an irrigating solution. As in all surgical procedures appropriate measures should be taken
to minimize trauma to the cornea and other ocular tissues.
Preparation: Reconstitute BSS PLUS® Intraocular Irrigating Solution just prior to use in surgery.
Follow the same strict aseptic procedures in the reconstitution of BSS PLUS as is used for intravenous
additives. Remove the blue flip-off seal from the BSS PLUS Part I (240 mL or 480 mL) bottle.
Remove the BSS PLUS Part II overcap and invert the assembly. Insert the transfer spike by holding
the vial/collar (to prevent premature activation) into the outer target area of the rubber stopper on the
BSS PLUS Part I bottle. Activate fluid transfer by pushing down on the bottom of the Part II vial to
actuate the transfer assembly. An excess volume of Part II is provided in each vial. After transfer,
remove the Part II vial system from the Part I bottle. Gently agitate the contents to mix the solution.
Place a sterile cap over the rubber stopper if the solution is not going to be used immediately. Remove
the tear-off portion of the label. Remove the tear-off portion of the label. Record the time and date of
reconstitution and the patient's name on the bottle label.
Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly
and younger patients.
ADVERSE REACTIONS: Postoperative inflammatory reactions as well as incidents of
corneal edema and corneal decompensation have been reported. Their relationship to the
use of BSS PLUS has not been established.
OVERDOSAGE: The solution has no pharmacological action and thus no potential for
overdosage. However, as with any intraocular surgical procedure, the duration of intraocular
manipulation should be kept to a minimum.
DOSAGE AND ADMINISTRATION: The solution should be used according to the standard
technique employed by the operating surgeon. Use an administration set with an air-inlet in the plastic
spike since the bottle does not contain a separate airway tube. Follow the directions for the particular
administration set to be used. Insert the spike aseptically into the bottle through the center target area
of the rubber stopper. Allow the fluid to flow to remove air from the tubing before intraocular
irrigation begins. If a second bottle is necessary to complete the surgical procedure, insure that the
vacuum is vented from the second bottle BEFORE attachment to the administration set.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-469/S-040 & S-041
Page 5
HOW SUPPLIED: BSS PLUS Solution is supplied in two sizes, 250 mL and 500 mL. BSS PLUS
250 mL is supplied in two packages for reconstitution prior to use: a 250 mL glass bottle, grey butyl
stopper and aluminum seal with blue polypropylene flip-off cap containing 240 mL (Part I) and a 24
mL glass vial, grey butyl stopper and plastic transfer spike/overcap assembly containing 10 mL (Part
II).
BSS PLUS 500 mL is supplied in two packages for reconstitution prior to use: a 500 mL glass bottle,
grey butyl stopper and aluminum seal with blue polypropylene flip-off cap containing 480 mL (Part I)
and a 24 mL glass vial, grey butyl stopper and plastic transfer spike/overcap assembly containing 20
mL (Part II).
See the PRECAUTIONS section regarding reconstitution of the solution.
250 mL – NDC 0065-0800-25
500 mL - NDC 0065-0800-50
Storage: Store Part I and Part II at 2° - 25°C (36° - 77°F). DO NOT FREEZE. Discard prepared
solution after six hours.
Rx Only
Alcon Laboratories, Inc.
Fort Worth, Texas 76134 USA
© 2002-2003 Alcon, Inc.
Reconstitution instructions for 250 mL and 500 mL sizes:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-469/S-040 & S-041
Page 6
RECONSTITUTION INSTRUCTIONS
BSS PLUS®
STERILE INTRAOCULAR IRRIGATING SOLUTION
(balanced salt solution enriched with bicarbonate, dextrose, and glutathione)
RECONSTITUTION INSTRUCTIONS
DIRECTIONS: Use Aseptic Technique
1. Remove the blue flip-off seal from the BSS PLUS Part I (240 mL or 480 mL) bottle. Prepare the
stoppers on the bottle by using a sterile alcohol wipe.
2. Open the BSS PLUS Part II vial/transfer assembly by twisting the overcap at the indicated “Rotate
at Arrows”. Place thumb and forefinger above the “Rotate at Arrows” instruction. Squeeze the
overcap and lift to remove.
3. Do not touch the transfer spike to avoid contaminating it.
4. Invert the BSS PLUS Part II (10 mL or 20 mL) vial. While holding the vial/collar (to prevent
premature activation), insert the transfer spike into the outer target of the rubber stopper of the BSS
PLUS Part I (240 mL or 480 mL) bottle. Do not twist the Part II vial while inserting it into the Part
I bottle. (See Illustration.)
5. Push down on the BSS PLUS Part II vial and fluid will automatically transfer from the vial into the
large Part I bottle. If product flow does not start within a few seconds, grasp the Part 1 bottle and
rotate it in a circular motion. NOTE: An excess amount of BSS PLUS Part II is provided in each
vial. A non-transferred solution residual of approximately 0.1 to 0.3 mL can be expected to remain
in the vial.
6. Immediately remove transfer assembly from the BSS PLUS Part I container and discard it after
solution transfer has been completed.
7. Place a sterile safety cap over the rubber stopper of Part I if the solution is not going to be used
immediately. Mix the solution gently until uniform. Peel off the right-hand side of Part I bottle
label (fully reconstituted BSS PLUS Solution). Record the patient’s name and the date and time of
reconstitution. BSS PLUS Solution is now ready for use.
CAUTION: Reconstituted BSS PLUS Solution must be used within six hours of mixing. Discard any
solution which has aged beyond that time. Never use the same bottle of BSS PLUS Solution on more
than one patient.
[diagram]
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:44.040748
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/18469s040,041lbl.pdf', 'application_number': 18469, 'submission_type': 'SUPPL ', 'submission_number': 41}
|
11,226
|
NDA 18469
S-054
S-055
Page 4
I.
Labeling for BSS PLUS 500 mL (Part I) and 20 mL (Part II) Bottle kit
BSS PLUS 500 mL (Part 1) /20 mL (Part II) package insert
BSS PLUS*
STERILE INTRAOCULAR IRRIGATING SOLUTION
(balanced salt solution enriched with bicarbonate, dextrose, and glutathione)
DESCRIPTION: BSS PLUS* is a sterile intraocular irrigating solution for use during all intraocular
surgical procedures, including those requiring a relatively long intraocular perfusion time (e.g., pars plana
vitrectomy, phacoemulsification, extracapsular cataract extraction/lens aspiration, anterior segment
reconstruction, etc.). The solution does not contain a preservative and should be prepared just prior to use
in surgery.
Part I: Part I is a sterile 480 mL solution in a 500 mL single-dose bottle to which the Part II concentrate
is added. Each mL of Part I contains: sodium chloride 7.44 mg, potassium chloride 0.395 mg, dibasic
sodium phosphate 0.433 mg, sodium bicarbonate 2.19 mg, hydrochloric acid and/or sodium hydroxide (to
adjust pH), in water for injection.
Part II: Part II is a sterile concentrate in a 20 mL single-dose vial for addition to Part I. Each mL of Part
II contains: calcium chloride dihydrate 3.85 mg, magnesium chloride hexahydrate 5 mg, dextrose 23 mg,
glutathione disulfide (oxidized glutathione) 4.6 mg, in water for injection.
After addition of BSS PLUS Part II to the Part I bottle, each mL of the reconstituted product contains:
sodium chloride 7.14 mg, potassium chloride 0.38 mg, calcium chloride dihydrate 0.154 mg, magnesium
chloride hexahydrate 0.2 mg, dibasic sodium phosphate 0.42 mg, sodium bicarbonate 2.1 mg, dextrose
0.92 mg, glutathione disulfide (oxidized glutathione) 0.184 mg, hydrochloric acid and/or sodium
hydroxide (to adjust pH), in water for injection.
The reconstituted product has a pH of approximately 7.4. Osmolality is approximately 305 mOsm.
CLINICAL PHARMACOLOGY: None of the components of BSS PLUS are foreign to the eye, and
BSS PLUS has no pharmacological action. Human perfused cornea studies have shown BSS PLUS to be
an effective irrigation solution for providing corneal detumescence and maintaining corneal endothelial
integrity during intraocular perfusion. An in vivo study in rabbits has shown that BSS PLUS is more
suitable than normal saline or Balanced Salt Solution for intravitreal irrigation because BSS PLUS
contains the appropriate bicarbonate, pH, and ionic composition necessary for the maintenance of normal
retinal electrical activity. Human in vivo studies have demonstrated BSS PLUS to be safe and effective
when used during surgical procedures such as pars plana vitrectomy, phacoemulsification, cataract
extraction/lens aspiration, anterior segment reconstruction. No differences have been observed between
adults and pediatric patients following use of this drug product.
INDICATIONS AND USAGE: BSS PLUS is indicated for use as an intraocular irrigating solution
during intraocular surgical procedures involving perfusion of the eye.
CONTRAINDICATIONS: There are no specific contraindications to the use of BSS PLUS; however,
contraindications for the surgical procedure during which BSS PLUS is to be used should be strictly
adhered to.
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 5
WARNINGS: For IRRIGATION during ophthalmic surgery only. Not for injection or intravenous
infusion. Do not use unless product is clear, seal is intact, vacuum is present and container is undamaged.
Do not use if product is discolored or contains a precipitate.
PRECAUTIONS: DO NOT USE BSS PLUS UNTIL PART I IS FULLY RECONSTITUTED WITH
PART II. Discard unused contents. BSS PLUS does not contain a preservative; therefore, do not use this
container for more than one patient. DISCARD ANY UNUSED PORTION SIX HOURS AFTER
PREPARATION. Studies suggest that intraocular irrigating solutions which are iso-osmotic with normal
aqueous fluids should be used with caution in diabetic patients undergoing vitrectomy since intraoperative
lens changes have been observed.
There have been reports of corneal clouding or edema following ocular surgery in which BSS PLUS was
used as an irrigating solution. As in all surgical procedures appropriate measures should be taken to
minimize trauma to the cornea and other ocular tissues.
Preparation: Reconstitute BSS PLUS Intraocular Irrigating Solution just prior to use in surgery.
Follow the same strict aseptic procedures in the reconstitution of BSS PLUS as is used for intravenous
additives. Remove the blue flip-off seal from the BSS PLUS Part I (480 mL) bottle. Remove the blue
flip-off seal from the BSS PLUS Part II (20 mL) vial. Clean and disinfect the rubber stoppers on both
containers by using sterile alcohol wipes. Transfer the contents of the Part II vial to the Part I bottle using
a BSS PLUS Vacuum Transfer Device (provided). An alternative method of solution transfer may be
accomplished by using a 20 mL syringe to remove the Part II solution from the vial and transferring
exactly 20 mL to the Part I container through the outer target area of the rubber stopper. An excess
volume of Part II is provided in each vial. Gently agitate the contents to mix the solution. Place a sterile
cap on the bottle. Remove the tear-off portion of the label. Record the time and date of reconstitution and
the patient's name on the bottle label.
Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and
younger patients.
ADVERSE REACTIONS: Postoperative inflammatory reactions as well as incidents of corneal edema
and corneal decompensation have been reported. Their relationship to the use of BSS PLUS has not been
established.
OVERDOSAGE: The solution has no pharmacological action and thus no potential for overdosage.
However, as with any intraocular surgical procedure, the duration of intraocular manipulation should be
kept to a minimum.
DOSAGE AND ADMINISTRATION: The solution should be used according to the standard technique
employed by the operating surgeon. Use an administration set with an air-inlet in the plastic spike since
the bottle does not contain a separate airway tube. Follow the directions for the particular administration
set to be used. Insert the spike aseptically into the bottle through the center target area of the rubber
stopper. Allow the fluid to flow to remove air from the tubing before intraocular irrigation begins. If a
second bottle is necessary to complete the surgical procedure, ensure that the vacuum is vented from the
second bottle BEFORE attachment to the administration set.
HOW SUPPLIED: BSS PLUS is supplied in two packages for reconstitution prior to use: a 500 mL
glass bottle containing 480 mL (Part I) and a 20 mL glass vial (Part II); both using grey butyl stoppers
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 6
and aluminum seals with polypropylene flip-off caps. See the PRECAUTIONS section regarding
reconstitution of the solution.
NDC 0065-0800-50.
Storage: Store Part I and Part II at 2° - 25°C (36° - 77°F). Discard prepared solution after six hours.
* a trademark of Novartis
Alcon®
a Novartis company
Distributed by:
Alcon Laboratories , Inc.
Fort Worth, Texas 76134 USA
©2002-2003, 2015 Novartis
BSS PLUS*
STERILE INTRAOCULAR IRRIGATING SOLUTION
(balanced salt solution enriched with bicarbonate, dextrose, and glutathione)
RECONSTITUTION INSTRUCTIONS
DIRECTIONS: Use Aseptic Technique usage illustration
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 7
1. Remove the blue flip-off seal from the BSS PLUS* Part I (480 mL) bottle. Remove the blue flipoff seal
from the BSS PLUS Part II (20 mL) vial. Prepare the stoppers on both parts by using sterile alcohol
wipes.
2. Peel open a BSS PLUS Vacuum Transfer Device package (supplied) and remove the sterile transfer
spike.
NOTE: This device is vented permitting air to enter vial during solution transfer, thereby preventing the
creation of a vacuum inside the vial. An air-inlet filter is provided to protect the system. Do not remove
the air-inlet filter.
3. Remove protector from the white plastic piercing pin.
4. Firmly grasp device from behind the flange and insert the white plastic piercing pin into the upright
rubber stopper of the BSS PLUS Part II (20 mL) vial.
5. Remove guard from filter needle. Firmly grasp vial in the palm of one hand and with thumb and index
finger, hold plastic flange against top of vial.
6. Invert vial and immediately insert filter needle into the outer target of the rubber stopper of the BSS
PLUS Part I (480 mL) bottle.
(See illustration.)
7. Fluid will automatically transfer from the vial into the large vacuum bottle unless filter becomes
occluded or loss of vacuum occurs. NOTE: An excess amount of BSS PLUS Part II is provided in each
vial. A non-transferred solution residual of approximately 0.3 mL can be expected to remain in the vial.
8. Immediately remove needle from the BSS PLUS Part I container and discard it after solution transfer
has been completed.
9. Place a sterile safety cap over the rubber stopper of Part I if the solution is not going to be used
immediately. Mix the solution gently until uniform. Peel off the right-hand side of Part I bottle label (fully
reconstituted BSS PLUS Solution). Record the patient’s name and the date and time of reconstitution.
BSS PLUS Solution is now ready for use.
CAUTION: Reconstituted BSS PLUS Solution must be used within six hours of mixing. Discard any
solution which has aged beyond that time. Never use the same bottle of BSS PLUS Solution on more than
one patient.
Alternative Transfer Method
If preferred, the contents of the BSS PLUS Part II component may be aspirated with an 18-gauge cannula
attached to a 20 mL syringe and then transferred into the Part I bottle.
Alcon®
a Novartis company
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 8
Distributed by:
Alcon Laboratories, Inc.
Fort Worth, Texas 76134 USA
Revised: XXXX2015
A171796-0915
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 9
II.
Labeling for BSS PLUS 500 mL (Part I) and 20 mL (Part II) Bottle kit
BSS PLUS 500 mL (Part 1) container label
500mL
Single Patient Use
NDC 0065-0800-50
BSS PLUS*
STERILE INTRAOCULAR IRRIGATING SOLUTION
(balanced salt solution enriched with bicarbonate, dextrose and glutathione)
After addition of BSS PLUS*- Part II (20 mL), each mL contains: sodium chloride 7.14 mg, potassium
chloride 0.38 mg, calcium chloride dihydrate 0.154 mg, magnesium chloride hexahydrate 0.2 mg, dibasic
sodium phosphate 0.42 mg, sodium bicarbonate 2.1 mg, dextrose 0.92 mg, glutathione disulfide (oxidized
glutathione) 0.184 mg, hydrochloric acid and/or sodium hydroxide (to adjust pH), in water for injection.
pH Approx. 7.4 - Osmolality Approx. 305 mOsm/kg
Rx Only
WARNINGS: FOR IRRIGATION DURING OPHTHALMIC SURGERY ONLY. NOT FOR
INJECTION OR INTRAVENOUS INFUSION. DO NOT USE UNLESS PRODUCT IS CLEAR, SEAL
IS INTACT, VACUUM IS PRESENT AND CONTAINER IS UNDAMAGED. DO NOT USE IF
PRODUCT IS DISCOLORED OR CONTAINS A PRECIPITATE.
PRECAUTIONS: DO NOT USE BSS PLUS UNTIL PART I IS FULLY RECONSTITUTED WITH
PART II.
DISCARD UNUSED CONTENTS SIX HOURS AFTER PREPARATION.
DO NOT USE THIS CONTAINER FOR MORE THAN ONE PATIENT.
Reconstitute just prior to use in surgery
* a trademark of Novartis
Alcon®
a Novartis company
Alcon Laboratories, Inc.
Fort Worth, Texas 76134 USA
© 2002-2003, 2015 Novartis
Patient:
Reconstituted at
AM/PM on
SINGLE USE ONLY
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 10
LOT:
EXP:
480mL
NDC 0065-0800-50
BSS PLUS* PART I
STERILE SOLUTION
(For Reconstitution by Addition of BSS PLUS* Concentrate Part II, 20 mL)**
Each mL contains: sodium chloride 7.44 mg, potassium chloride 0.395 mg, dibasic sodium phosphate
0.433 mg, sodium bicarbonate 2.19 mg, hydrochloric acid and/or sodium hydroxide (to adjust pH), in
water for injection.
Rx Only
Storage: Store at 2° - 25°C (36° - 77° F).
WARNINGS: FOR IRRIGATION DURING OPHTHALMIC SURGERY ONLY AFTER
RECONSITUTION. DO NOT USE UNLESS PRODUCT IS CLEAR, SEAL IS INTACT, VACUUM IS
PRESENT AND CONTAINER IS UNDAMAGED.
NOT FOR INJECTION OR INTRAVENOUS INFUSION.
**Reconstitute just prior to use in surgery. Do not use additives other than the BSS PLUS
Concentrate Part II (20 mL) provided with this bottle. Remove this part of label after
reconstitution. Read the Preparation and Administration sections of the package insert before
reconstitution for important directions and precautions.
A170509-0915
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 11
III.
Labeling for BSS PLUS 500 mL (Part I) and 20 mL (Part II) Bottle kit
BSS PLUS 20 mL (Part II) container label
LOT:
EXP:
A171400-0915
Each mL contains: calcium chloride dihydrate 3.85 mg, magnesium chloride hexahydrate 5 mg, dextrose
23 mg, glutathione disulfide (oxidized glutathione) 4.6 mg, in water for injection.
For Addition to BSS PLUS* – Part I (480 mL) only. See Preparation section of package insert.
WARNINGS: Not for injection or intravenous infusion – for reconstitution of irrigation solution only.
Do not use unless product is clear, seal is intact and container is undamaged. Do not use if product is
discolored or contains precipitate.
PRECAUTIONS: Discard unused contents. Do not use this container for more than one patient.
Storage: Store at 2°-25°C (36°-77°F).
Rx Only
© 2002-2003, 2015 Novartis
* a trademark of Novartis
NDC 0065-0800-50
20 mL
BSS PLUS*
CONCENTRATE PART II
(Sterile Solution for Reconstitution)
Alcon®
Alcon Laboratories, Inc.
Fort Worth, Texas 76134 USA
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 12
IV.
Labeling for BSS PLUS 500 mL (Part I) and 20 mL (Part II) Bottle kit
BSS PLUS 20 mL (Part II) carton
BSS PLUS*
STERILE IRRIGATING SOLUTION
(balanced salt solution enriched with bicarbonate, dextrose and glutathione)
Carton Contents:
1 Vial BSS PLUS* Concentrate Part II Sterile Solution for Reconstitution with BSS PLUS® PART I Only
1 BSS PLUS Vacuum Transfer Device
1 BSS PLUS Product Package Insert
WARNINGS: For IRRIGATION during ophthalmic surgery only. Not for injection or intravenous
infusion. Do not use unless product is clear, seal is intact, vacuum is present and container is undamaged.
Do not use if product is discolored or contains a precipitate.
Store at 2°-25°C (36°-77° F).
Discard prepared solution after six hours.
Alcon®
a Novartis company
Alcon Laboratories, Inc. Fort Worth, Texas 76134 USA
© 2002, 2013, 2015 Novartis
* a trademark of Novartis
PRECAUTIONS: DO NOT USE BSS PLUS* solution UNTIL PART I IS FULLY RECONSTITUTED
WITH PART II. Discard unused contents. BSS PLUS does not contain a preservative; therefore, do not
use this container for more than one patient. DISCARD ANY UNUSED PORTION SIX HOURS AFTER
PREPARATION. Studies suggest that intraocular irrigating solutions which are iso-osmotic with normal
aqueous fluids should be used with caution in diabetic patients undergoing vitrectomy since intraoperative
lens changes have been observed. There have been reports of corneal clouding or edema following ocular
surgery in which BSS PLUS solution was used as an irrigating solution. As in all surgical procedures,
appropriate measures should be taken to minimize trauma to the cornea and other ocular tissues.
A171557-0915
BSS PLUS*
STERILE IRRIGATING SOLUTION
(balanced salt solution enriched with bicarbonate, dextrose and glutathione)
Carton Contents:
1 Vial BSS PLUS* Concentrate Part II Sterile Solution for Reconstitution with BSS PLUS® PART I Only
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 13
1 BSS PLUS Vacuum Transfer Device
1 BSS PLUS Product Package Insert
WARNINGS: For IRRIGATION during ophthalmic surgery only. Not for injection or intravenous
infusion. Do not use unless product is clear, seal is intact, vacuum is present and container is undamaged.
Do not use if product is discolored or contains a precipitate.
Store at 2°-25°C (36°-77° F).
Alcon®
a Novartis company
Alcon Laboratories, Inc. Fort Worth, Texas 76134 USA
PRECAUTIONS: DO NOT USE BSS PLUS* solution UNTIL PART I IS FULLY RECONSTITUTED
WITH PART II. Discard unused contents. BSS PLUS does not contain a preservative; therefore, do not
use this container for more than one patient. DISCARD ANY UNUSED PORTION SIX HOURS AFTER
PREPARATION. Studies suggest that intraocular irrigating solutions which are iso-osmotic with normal
aqueous fluids should be used with caution in diabetic patients undergoing vitrectomy since intraoperative
lens changes have been observed. There have been reports of corneal clouding or edema following ocular
surgery in which BSS PLUS solution was used as an irrigating solution. As in all surgical procedures,
appropriate measures should be taken to minimize trauma to the cornea and other ocular tissues.
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 14
V.
Labeling for BSS PLUS 250 mL (Part I) and 10 mL (Part II) Bottle kit
BSS PLUS 500 mL (Part 1) /20 mL (Part II) package insert
BSS PLUS*
STERILE INTRAOCULAR IRRIGATING SOLUTION
(balanced salt solution enriched with bicarbonate, dextrose, and glutathione)
DESCRIPTION: BSS PLUS* is a sterile intraocular irrigating solution for use during all intraocular
surgical procedures, including those requiring a relatively long intraocular perfusion time (e.g., pars plana
vitrectomy, phacoemulsification, extracapsular cataract extraction/lens aspiration, anterior segment
reconstruction, etc.). The solution does not contain a preservative and should be prepared just prior to use
in surgery.
Part I: Part I is a sterile 240 mL solution in a 250 mL single-dose bottle to which the Part II concentrate
is added. Each mL of Part I contains: sodium chloride 7.44 mg, potassium chloride 0.395 mg, dibasic
sodium phosphate 0.433 mg, sodium bicarbonate 2.19 mg, hydrochloric acid and/or sodium hydroxide (to
adjust pH), in water for injection.
Part II: Part II is a sterile concentrate in a 10 mL single-dose vial for addition to Part I. Each mL of Part
II contains: calcium chloride dihydrate 3.85 mg, magnesium chloride hexahydrate 5 mg, dextrose 23 mg,
glutathione disulfide (oxidized glutathione) 4.6 mg, in water for injection.
After addition of BSS PLUS Part II to the Part I bottle, each mL of the reconstituted product contains:
sodium chloride 7.14 mg, potassium chloride 0.38 mg, calcium chloride dihydrate 0.154 mg, magnesium
chloride hexahydrate 0.2 mg, dibasic sodium phosphate 0.42 mg, sodium bicarbonate 2.1 mg, dextrose
0.92 mg, glutathione disulfide (oxidized glutathione) 0.184 mg, hydrochloric acid and/or sodium
hydroxide (to adjust pH), in water for injection.
The reconstituted product has a pH of approximately 7.4. Osmolality is approximately 305 mOsm.
CLINICAL PHARMACOLOGY: None of the components of BSS PLUS are foreign to the eye, and
BSS PLUS has no pharmacological action. Human perfused cornea studies have shown BSS PLUS to be
an effective irrigation solution for providing corneal detumescence and maintaining corneal endothelial
integrity during intraocular perfusion. An in vivo study in rabbits has shown that BSS PLUS is more
suitable than normal saline or Balanced Salt Solution for intravitreal irrigation because BSS PLUS
contains the appropriate bicarbonate, pH, and ionic composition necessary for the maintenance of normal
retinal electrical activity. Human in vivo studies have demonstrated BSS PLUS to be safe and effective
when used during surgical procedures such as pars plana vitrectomy, phacoemulsification, cataract
extraction/lens aspiration, anterior segment reconstruction. No differences have been observed between
adults and pediatric patients following use of this drug product.
INDICATIONS AND USAGE: BSS PLUS is indicated for use as an intraocular irrigating solution
during intraocular surgical procedures involving perfusion of the eye.
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 15
CONTRAINDICATIONS: There are no specific contraindications to the use of BSS PLUS; however,
contraindications for the surgical procedure during which BSS PLUS is to be used should be strictly
adhered to.
WARNINGS: For IRRIGATION during ophthalmic surgery only. Not for injection or intravenous
infusion. Do not use unless product is clear, seal is intact, vacuum is present and container is undamaged.
Do not use if product is discolored or contains a precipitate.
PRECAUTIONS: DO NOT USE BSS PLUS UNTIL PART I IS FULLY RECONSTITUTED WITH
PART II. Discard unused contents. BSS PLUS does not contain a preservative; therefore, do not use this
container for more than one patient.. DISCARD ANY UNUSED PORTION SIX HOURS AFTER
PREPARATION. Studies suggest that intraocular irrigating solutions which are iso-osmotic with normal
aqueous fluids should be used with caution in diabetic patients undergoing vitrectomy since intraoperative
lens changes have been observed.
There have been reports of corneal clouding or edema following ocular surgery in which BSS PLUS was
used as an irrigating solution. As in all surgical procedures appropriate measures should be taken to
minimize trauma to the cornea and other ocular tissues.
Preparation: Reconstitute BSS PLUS* Intraocular Irrigating Solution just prior to use in surgery.
Follow the same strict aseptic procedures in the reconstitution of BSS PLUS as is used for intravenous
additives. Remove the blue flip-off seal from the BSS PLUS Part I (240 mL) bottle. Remove the blue
flip-off seal from the BSS PLUS Part II (10 mL) vial. Clean and disinfect the rubber stoppers on both
containers by using sterile alcohol wipes. Transfer the contents of the Part II vial to the Part I bottle using
a BSS PLUS Vacuum Transfer Device (provided). An alternative method of solution transfer may be
accomplished by using a 10 mL syringe to remove the Part II solution from the vial and transferring
exactly 10 mL to the Part I container through the outer target area of the rubber stopper. An excess
volume of Part II is provided in each vial. Gently agitate the contents to mix the solution. Place a sterile
cap on the bottle. Remove the tear-off portion of the label. Record the time and date of reconstitution and
the patient's name on the bottle label.
Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and
younger patients.
ADVERSE REACTIONS: Postoperative inflammatory reactions as well as incidents of corneal edema
and corneal decompensation have been reported. Their relationship to the use of BSS PLUS has not been
established.
OVERDOSAGE: The solution has no pharmacological action and thus no potential for overdosage.
However, as with any intraocular surgical procedure, the duration of intraocular manipulation should be
kept to a minimum.
DOSAGE AND ADMINISTRATION: The solution should be used according to the standard technique
employed by the operating surgeon. Use an administration set with an air-inlet in the plastic spike since
the bottle does not contain a separate airway tube. Follow the directions for the particular administration
set to be used. Insert the spike aseptically into the bottle through the center target area of the rubber
stopper. Allow the fluid to flow to remove air from the tubing before intraocular irrigation begins. If a
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 16
second bottle is necessary to complete the surgical procedure, ensure that the vacuum is vented from the
second bottle BEFORE attachment to the administration set.
HOW SUPPLIED: BSS PLUS is supplied in two packages for reconstitution prior to use: a 250 mL
glass bottle containing 240 mL (Part I) and a 10 mL glass vial (Part II); both using grey butyl stoppers
and aluminum seals with polypropylene flip-off caps. See the PRECAUTIONS section regarding
reconstitution of the solution.
NDC 0065-0800-25.
Storage: Store Part I and Part II at 2° - 25°C (36° - 77°F). Discard prepared solution after six hours.
Alcon®
a Novartis company
Distributed by:
Alcon Laboratories, Inc.
Fort Worth, Texas 76134 USA
©2002-2003, 2015 Novartis
* a trademark of Novartis
A171608-0915
BSS PLUS*
STERILE INTRAOCULAR IRRIGATING SOLUTION
(balanced salt solution enriched with bicarbonate, dextrose, and glutathione)
RECONSTITUTION INSTRUCTIONS
DIRECTIONS: Use Aseptic Technique
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 17 usage illustration
1. Remove the blue flip-off seal from the BSS PLUS* Part I (240 mL) bottle. Remove the blue flipoff seal
from the BSS PLUS Part II (10 mL) vial. Prepare the stoppers on both parts by using sterile alcohol
wipes.
2. Peel open a BSS PLUS Vacuum Transfer Device package (supplied) and remove the sterile transfer
spike.
NOTE: This device is vented permitting air to enter vial during solution transfer, thereby preventing the
creation of a vacuum inside the vial. An air-inlet filter is provided to protect the system. Do not remove
the air-inlet filter.
3. Remove protector from the white plastic piercing pin.
4. Firmly grasp device from behind the flange and insert the white plastic piercing pin into the upright
rubber stopper of the BSS PLUS Part II (10 mL) vial.
5. Remove guard from filter needle. Firmly grasp vial in the palm of one hand and with thumb and index
finger, hold plastic flange against top of vial.
6. Invert vial and immediately insert filter needle into the outer target of the rubber stopper of the BSS
PLUS Part I (240 mL) bottle. (See illustration.)
7. Fluid will automatically transfer from the vial into the large vacuum bottle unless filter becomes
occluded or loss of vacuum occurs. NOTE: An excess amount of BSS PLUS Part II is provided in each
vial. A non-transferred solution residual of approximately 0.1 mL can be expected to remain in the vial.
8. Immediately remove needle from the BSS PLUS Part I container and discard it after solution transfer
has been completed.
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 18
9. Place a sterile safety cap over the rubber stopper of Part I if the solution is not going to be used
immediately. Mix the solution gently until uniform. Peel off the right-hand side of Part I bottle label (fully
reconstituted BSS PLUS Solution). Record the patient’s name and the date and time of reconstitution.
BSS PLUS Solution is now ready for use.
CAUTION: Reconstituted BSS PLUS Solution must be used within six hours of mixing. Discard any
solution which has aged beyond that time. Never use the same bottle of BSS PLUS Solution on more than
one patient.
Alternative Transfer Method
If preferred, the contents of the BSS PLUS Part II component may be aspirated with an 18-gauge cannula
attached to a 10 mL syringe and then transferred into the Part I bottle.
Alcon®
a Novartis company
Distributed by:
Alcon Laboratories, Inc.
Fort Worth, Texas 76134 USA
Revised: XXXX2015
* a trademark of Novartis
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 19
VI.
Labeling for BSS PLUS 250 mL (Part I) and 10 mL (Part II) Bottle kit
BSS PLUS 250 mL (Part 1) container label
250mL
Single Patient Use
NDC 0065-0800-25
BSS PLUS*
STERILE INTRAOCULAR IRRIGATING SOLUTION
(balanced salt solution enriched with bicarbonate, dextrose and glutathione)
After addition of BSS PLUS*- Part II (10 mL), each mL contains: sodium chloride 7.14 mg, potassium
chloride 0.38 mg, calcium chloride dihydrate 0.154 mg, magnesium chloride hexahydrate 0.2 mg, dibasic
sodium phosphate 0.42 mg, sodium bicarbonate 2.1 mg, dextrose 0.92 mg, glutathione disulfide (oxidized
glutathione) 0.184 mg, hydrochloric acid and/or sodium hydroxide (to adjust pH), in water for injection.
pH Approx. 7.4 - Osmolality Approx. 305 mOsm/kg
Rx Only
WARNINGS: FOR IRRIGATION DURING OPHTHALMIC SURGERY ONLY. NOT FOR
INJECTION OR INTRAVENOUS INFUSION. DO NOT USE UNLESS PRODUCT IS CLEAR, SEAL
IS INTACT, VACUUM IS PRESENT AND CONTAINER IS UNDAMAGED. DO NOT USE IF
PRODUCT IS DISCOLORED OR CONTAINS A PRECIPITATE.
PRECAUTIONS: DO NOT USE BSS PLUS UNTIL PART I IS FULLY RECONSTITUTED WITH
PART II.
DISCARD UNUSED CONTENTS SIX HOURS AFTER PREPARATION.
DO NOT USE THIS CONTAINER FOR MORE THAN ONE PATIENT.
Reconstitute just prior to use in surgery
* a trademark of Novartis
Alcon®
a Novartis company
Alcon Laboratories, Inc.
Fort Worth, Texas 76134 USA
Patient:
Reconstituted at
AM/PM on
SINGLE USE ONLY
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 20
LOT:
EXP:
240mL
NDC 0065-0800-25
BSS PLUS* PART I
STERILE SOLUTION
(For Reconstitution by Addition of BSS PLUS* Concentrate Part II, 10 mL)**
Each mL contains: sodium chloride 7.44 mg, potassium chloride 0.395 mg, dibasic sodium phosphate
0.433 mg, sodium bicarbonate 2.19 mg, hydrochloric acid and/or sodium hydroxide (to adjust pH), in
water for injection.
Rx Only
Storage: Store at 2° - 25°C (36° - 77° F).
WARNINGS: FOR IRRIGATION DURING OPHTHALMIC SURGERY ONLY AFTER
RECONSITUTION. DO NOT USE UNLESS PRODUCT IS CLEAR, SEAL IS INTACT, VACUUM IS
PRESENT AND CONTAINER IS UNDAMAGED.
NOT FOR INJECTION OR INTRAVENOUS INFUSION.
**Reconstitute just prior to use in surgery. Do not use additives other than the BSS PLUS
Concentrate Part II (10 mL) provided with this bottle. Remove this part of label after
reconstitution. Read the Preparation and Administration sections of the package insert before
reconstitution for important directions and precautions.
Alcon®
Alcon Laboratories, Inc.
Fort Worth, Texas 76134 USA
© 2002-2003, 2015 Novartis
A170511-0915
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 21
VII.
Labeling for BSS PLUS 250 mL (Part I) and 10 mL (Part II) Bottle kit
BSS PLUS 10 mL (Part II) container label
LOT:
EXP:
A171399-0915
Rx Only Each mL contains: calcium chloride dihydrate 3.85 mg, magnesium chloride hexahydrate 5 mg,
dextrose 23 mg, glutathione disulfide (oxidized glutathione) 4.6 mg, in water for injection.
For Addition to BSS PLUS* – Part I (240 mL) only. See Preparation section of package insert.
WARNINGS and PRECAUTIONS: Read enclosed insert.
Storage: Store at 2°-25°C (36°-77°F).
© 2002-2003, 2015 Novartis
* a trademark of Novartis
NDC 0065-0800-25
10 mL
BSS PLUS*
CONCENTRATE PART II
(Sterile Solution for Reconstitution)
Alcon®
Alcon Laboratories, Inc.
Fort Worth, Texas 76134 USA
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 22
VIII.
Labeling for BSS PLUS 250 mL (Part I) and 10 mL (Part II) Bottle kit
BSS PLUS 10 mL (Part II) carton
BSS PLUS*
STERILE IRRIGATING SOLUTION
(balanced salt solution enriched with bicarbonate, dextrose and glutathione)
Carton Contents:
1 Vial BSS PLUS* Concentrate Part II Sterile Solution for Reconstitution with BSS PLUS® PART I Only
1 BSS PLUS Vacuum Transfer Device
1 BSS PLUS Product Package Insert
WARNINGS: For IRRIGATION during ophthalmic surgery only. Not for injection or intravenous
infusion. Do not use unless product is clear, seal is intact, vacuum is present and container is undamaged.
Do not use if product is discolored or contains a precipitate.
Store at 2°-25°C (36°-77° F).
Discard prepared solution after six hours.
Alcon®
a Novartis company
Alcon Laboratories, Inc. Fort Worth, Texas 76134 USA
© 2002, 2013, 2015 Novartis
* a trademark of Novartis
PRECAUTIONS: DO NOT USE BSS PLUS* solution UNTIL PART I IS FULLY RECONSTITUTED
WITH PART II. Discard unused contents. BSS PLUS does not contain a preservative; therefore, do not
use this container for more than one patient. DISCARD ANY UNUSED PORTION SIX HOURS AFTER
PREPARATION. Studies suggest that intraocular irrigating solutions which are iso-osmotic with normal
aqueous fluids should be used with caution in diabetic patients undergoing vitrectomy since intraoperative
lens changes have been observed. There have been reports of corneal clouding or edema following ocular
surgery in which BSS PLUS solution was used as an irrigating solution. As in all surgical procedures,
appropriate measures should be taken to minimize trauma to the cornea and other ocular tissues.
A171557-0915
BSS PLUS*
STERILE IRRIGATING SOLUTION
(balanced salt solution enriched with bicarbonate, dextrose and glutathione)
Carton Contents:
1 Vial BSS PLUS* Concentrate Part II Sterile Solution for Reconstitution with BSS PLUS® PART I Only
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 23
1 BSS PLUS Vacuum Transfer Device
1 BSS PLUS Product Package Insert
WARNINGS: For IRRIGATION during ophthalmic surgery only. Not for injection or intravenous
infusion. Do not use unless product is clear, seal is intact, vacuum is present and container is undamaged.
Do not use if product is discolored or contains a precipitate.
Store at 2°-25°C (36°-77° F).
Alcon®
a Novartis company
Alcon Laboratories, Inc. Fort Worth, Texas 76134 USA
PRECAUTIONS: DO NOT USE BSS PLUS* solution UNTIL PART I IS FULLY RECONSTITUTED
WITH PART II. Discard unused contents. BSS PLUS does not contain a preservative; therefore, do not
use this container for more than one patient. DISCARD ANY UNUSED PORTION SIX HOURS AFTER
PREPARATION. Studies suggest that intraocular irrigating solutions which are iso-osmotic with normal
aqueous fluids should be used with caution in diabetic patients undergoing vitrectomy since intraoperative
lens changes have been observed. There have been reports of corneal clouding or edema following ocular
surgery in which BSS PLUS solution was used as an irrigating solution. As in all surgical procedures,
appropriate measures should be taken to minimize trauma to the cornea and other ocular tissues.
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 24
IX.
Labeling for BSS PLUS 500 mL bag presentation (Part I) + 20 mL bottle (Part II) kit
BSS PLUS Bag Presentation package insert
BSS PLUS*
STERILE IRRIGATING SOLUTION
(balanced salt solution enriched with bicarbonate, dextrose, and glutathione)
DESCRIPTION: BSS PLUS* is a sterile intraocular irrigating solution for use during all intraocular
surgical procedures, including those requiring a relatively long intraocular perfusion time (e.g., pars plana
vitrectomy, phacoemulsification, extra capsular cataract extraction/lens aspiration, anterior segment
reconstruction, etc.). The solution does not contain a preservative and should be prepared just prior to use
in surgery.
Part I: Part I is a sterile 480 mL solution in a 500 mL single-dose bag to which the Part II concentrate is
added. Each mL of Part I contains: sodium chloride 7.44 mg, potassium chloride 0.395 mg, dibasic
sodium phosphate 0.433 mg, sodium bicarbonate 2.19 mg, hydrochloric acid and/or sodium hydroxide (to
adjust pH), in water for injection.
Part II: Part II is a sterile concentrate in a 20 mL single-dose vial for addition to Part I. Each mL of Part
II contains: calcium chloride dihydrate 3.85 mg, magnesium chloride hexahydrate 5 mg, dextrose 23 mg,
glutathione disulfide (oxidized glutathione) 4.6 mg, in water for injection.
After addition of BSS PLUS solution Part II to the Part I bag, each mL of the reconstituted product
contains: sodium chloride 7.14 mg, potassium chloride 0.38 mg, calcium chloride dihydrate 0.154 mg,
magnesium chloride hexahydrate 0.2 mg, dibasic sodium phosphate 0.42 mg, sodium bicarbonate 2.1mg,
dextrose 0.92 mg, glutathione disulfide (oxidized glutathione) 0.184 mg, hydrochloric acid and/or sodium
hydroxide (to adjust pH), in water for injection.
The reconstituted product has a pH of approximately 7.4. Osmolality is approximately 305 mOsm.
CLINICAL PHARMACOLOGY: None of the components of BSS PLUS solution are foreign to the
eye, and BSS PLUS solution has no pharmacological action. Human perfused cornea studies have shown
BSS PLUS solution to be an effective irrigation solution for providing corneal detumescence and
maintaining corneal endothelial integrity during intraocular perfusion. An in vivo study in rabbits has
shown the BSS PLUS solution is more suitable than normal saline or balanced salt solution for
intravitreal irrigation because BSS PLUS solution contains the appropriate bicarbonate, pH, and ionic
composition necessary for the maintenance of normal retinal electrical activity. Human in vivo studies
have demonstrated BSS PLUS solution to be safe and effective when used during surgical procedures
such as pars plana vitrectomy, phacoemulsification, cataract extraction/lens aspiration, anterior segment
reconstruction. No differences have been observed between adults and pediatric patients following use of
this drug product.
INDICATIONS & USAGE: BSS PLUS solution is indicated for use as an intraocular irrigating solution
during intraocular surgical procedures involving perfusion of the eye.
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 25
CONTRAINDICATIONS: There are no specific contraindications to the use of BSS PLUS solution;
however, contraindications for the surgical procedure during which BSS PLUS solution is to be used
should be strictly adhered to.
WARNINGS: For IRRIGATION during ophthalmic surgery only. Not for injection or intravenous
infusion. Do not use unless product is clear, seal is intact and container is undamaged. Do not use if
product is discolored or contains a precipitate.
PRECAUTIONS: DO NOT USE BSS PLUS solution UNTIL PART I IS FULLY RECONSTITUTED
WITH PART II. Discard unused contents. BSS PLUS does not contain a preservative; therefore, do not
use this container for more than one patient. DISCARD ANY UNUSED PORTION SIX HOURS AFTER
PREPARATION. Studies suggest that intraocular irrigating solutions which are iso-osmotic with normal
aqueous fluids should be used with caution in diabetic patients undergoing vitrectomy since intraoperative
lens changes have been observed.
There have been reports of corneal clouding or edema following ocular surgery in which BSS PLUS
solution was used as an irrigating solution. As in all surgical procedures appropriate measures should be
taken to minimize trauma to the cornea and other ocular tissues.
Preparation: Reconstitute BSS PLUS Intraocular Irrigating Solution just prior to use in surgery. Follow
the same strict aseptic procedures in the reconstitution of BSS PLUS solution as is used for intravenous
additives. Remove the BSS PLUS solution Part I (480 mL) bag from the clear overwrap. Remove the
blue flip-off seal from the BSS PLUS solution Part II (20 mL) vial. Clean and disinfect the rubber
stoppers on both containers by using sterile alcohol wipes. Transfer the contents of the Part II vial to the
Part I bag using a BSS PLUS solution Dual-Spike Transfer Device (provided). An alternative method of
solution transfer may be accomplished by using a 20 mL syringe to remove the Part II solution from the
vial and transferring exactly 20 mL to the Part I container through the outer target area of the rubber
stopper. An excess volume of Part II is provided in each vial. Gently agitate the contents to mix the
solution. Place a sterile cap on the bag. Record the time and date of reconstitution and the patient's name
on the bag label.
GERIATRIC USE: No overall differences in safety or effectiveness have been observed between elderly
and younger patients.
ADVERSE REACTIONS: Postoperative inflammatory reactions as well as incidents of corneal edema
and corneal decompensation have been reported. Their relationship to the use of BSS PLUS solution has
not been established.
OVERDOSAGE: The solution has no pharmacological action and thus no potential for overdosage.
However, as with any intraocular surgical procedure, the duration of intraocular manipulation should be
kept to a minimum.
DOSAGE & ADMINISTRATION: The solution should be used according to the standard technique
employed by the operating surgeon. For non-active irrigating system, use an administration set with an
air-inlet in the plastic spike since the bag does not contain a separate airway tube. Follow the directions
for the particular administration set to be used. Insert the spike aseptically into the bag through the center
target area of the rubber stopper. Allow the fluid to flow to remove air from the tubing before intraocular
irrigation begins.
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 26
HOW SUPPLIED: BSS PLUS solution is supplied in two packages for reconstitution prior to use: a 500
mL bag containing 480 mL (Part I) and a 20 mL glass vial (Part II); both using grey butyl stoppers and
aluminum seals. See the PRECAUTIONS section regarding reconstitution of the solution.
NDC 0065-0800-94
STORAGE: Store Part I and Part II at 2° - 25°C (36° - 77°F). Discard prepared solution after six hours.
RECONSTITUTION INSTRUCTIONS
DIRECTIONS: Use Aseptic Technique
1.
Remove the BSS PLUS* solution Part I (480 mL) bag from the clear overwrap. Remove the blue
flip-off seal from the BSS PLUS solution Part II (20 mL) vial. Prepare the stoppers on both parts by using
sterile alcohol wipes.
2.
Peel open a BSS PLUS solution Dual-Spike Transfer Device package (supplied) and remove the
sterile transfer spike. NOTE: This device is vented permitting air to enter vial during solution transfer,
thereby preventing the creation of a vacuum inside the vial.
3.
Remove protector from the white plastic piercing pin of the Dual-Spike Transfer Device.
4.
Firmly grasp device from behind the flange and insert the white plastic piercing pin into the
upright rubber stopper of the BSS PLUS solution Part II (20 mL) vial.
5.
Remove guard from filter needle. Firmly grasp vial in the palm of one hand and with thumb and
index finger, hold plastic flange against top of vial.
6.
Hold the vial in the upright position, incline and immediately insert the transfer device into the
center target of rubber stopper of the BSS PLUS solution Part I (480 mL) bag. (See illustration.) NOTE:
Do not invert Part II (20mL) vial before or during spiking of the BSS PLUS solution Part I bag rubber
stopper, until ready to initiate transfer.
7.
Invert vial to initiate the transfer of Part II into Part I. If transfer does not occur immediately,
gentle manipulation of the bag can initiate transfer. NOTE: An excess amount of BSS PLUS solution Part
II is provided in each vial. A non-transferred solution residual of approximately 0.3 mL can be expected
to remain in the vial.
8.
Immediately remove vial (with spike attached) from the BSS PLUS solution Part I container and
discard it after solution transfer has been completed.
9.
Place a sterile safety cap over the rubber stopper of Part I if the solution is not going to be used
immediately. Mix the solution gently until uniform. Record the patient’s name and the date and time of
reconstitution. BSS PLUS solution is now ready for use.
CAUTION: Reconstituted BSS PLUS solution must be used within six hours of mixing.
Discard any solution which has aged beyond that time. Never use the same bag of BSS PLUS solution on
more than one patient.
Alternative Transfer Method
If preferred, the contents of the BSS PLUS Part II component may be aspirated with an 18-gauge cannula
attached to a 20 mL syringe and then transferred into the Part I bag.
A172589-0915
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 27 usage illustration
STEP 6 usage illustration
Alcon®
a Novartis company
Alcon Laboratories, Inc.
Fort Worth, Texas 76134 USA
© 2013, 2015 Novartis
* a trademark of Novartis
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 28
X.
Labeling for BSS PLUS 500 mL bag presentation (Part I) + 20 mL bottle (Part II) kit
BSS PLUS 500 mL Bag Presentation Part I container label
LOT:
EXP:
MFD:
A171396-0915
NDC 0065-0800-94
BSS PLUS* PART I
480 mL
STERILE SOLUTION
(For Reconstitution by Addition of BSS PLUS® Concentrate Part II, 20 mL)**
SINGLE PATIENT USE ONLY
**Reconstitute just prior to use in Surgery.
BSS PLUS*
500 mL
STERILE INTRAOCULAR IRRIGATING SOLUTION
(balanced salt solution enriched with bicarbonate, dextrose, and glutathione)
After addition of BSS PLUS- Part II (20 mL), each mL contains: sodium chloride 7.14 mg, potassium
chloride 0.38 mg, calcium chloride dihydrate 0.154 mg, magnesium chloride hexahydrate 0.2 mg, dibasic
sodium phosphate 0.42 mg, sodium bicarbonate 2.1 mg, dextrose 0.92 mg, glutathione disulfide (oxidized
glutathione) 0.184 mg, hydrochloric acid and/or sodium hydroxide (to adjust pH), in water for injection.
pH Approx. 7.4 . Osmolality Approx. 305 mOsm/kg
Rx Only
NOT FOR INJECTION OR INTRAVENOUS INFUSION
STORAGE: Store at 36° - 77°F (2° - 25°C)
See Warnings, Precautions and Preparation sections of package insert.
Alcon®
a Novartis company
Alcon Laboratories, Inc.
Fort Worth, Texas 76134 USA
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 29
© 2013, 2015 Novartis
* a trademark of Novartis
Patient _______________
Reconstituted at AM/PM on _____________
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18469
S-054
S-055
Page 30
XI.
`Labeling for BSS PLUS 500 mL bag presentation (Part I) + 20 mL bottle (Part II) kit
BSS PLUS Bag Presentation Part II (20 mL) container label
LOT:
EXP:
MFD:
A171397-0915
Each mL contains: calcium chloride dihydrate 3.85 mg, magnesium chloride hexahydrate 5 mg, dextrose
23 mg, glutathione disulfide (oxidized glutathione) 4.6 mg, in water for injection.
For Addition to BSS PLUS* – Part I (480 mL) only. See Preparation section of package insert.
WARNINGS: Not for injection or intravenous infusion – for reconstitution of irrigation solution only.
Do not use unless product is clear, seal is intact and container is undamaged. Do not use if product is
discolored or contains precipitate.
PRECAUTIONS: Discard unused contents. Do not use this container for more than one patient.
Storage: Store at 2-25°C (36-77°F).
Rx Only
© 2002-2003, 2013, 2015 Novartis
*a trademark of Novartis
NDC 0065-0800-94
20 mL
BSS PLUS*
CONCENTRATE PART II
(Sterile Solution for Reconstitution)
Alcon®
Alcon Laboratories, Inc.
Fort Worth, Texas 76134 USA
Reference ID: 3843569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:44.174394
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/018469s054s055lbl.pdf', 'application_number': 18469, 'submission_type': 'SUPPL ', 'submission_number': 55}
|
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PROCARDIA®
(nifedipine)
CAPSULES
For Oral Use
DESCRIPTION
PROCARDIA® (nifedipine) is an antianginal drug belonging to a class of pharmacological
agents, the calcium channel blockers. Nifedipine is 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,
6-dimethyl-4-(2-nitrophenyl)-, dimethyl ester, C17H18N2O6, and has the structural formula:
Nifedipine is a yellow crystalline substance, practically insoluble in water but soluble in ethanol.
It has a molecular weight of 346.3. PROCARDIA capsules are formulated as soft gelatin
capsules for oral administration, each containing 10 mg nifedipine.
Inert ingredients in the formulation are: glycerin; peppermint oil; polyethylene glycol; soft gelatin
capsules (which contain Yellow 6, and may contain Red Ferric Oxide and other inert
ingredients); and water. The 10 mg capsules also contain saccharin sodium.
Reference ID: 3346888
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINICAL PHARMACOLOGY
PROCARDIA is a calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist)
and inhibits the transmembrane influx of calcium ions into cardiac muscle and smooth muscle.
The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the
movement of extracellular calcium ions into these cells through specific ion channels.
PROCARDIA selectively inhibits calcium ion influx across the cell membrane of cardiac muscle
and vascular smooth muscle without changing serum calcium concentrations.
Mechanism of Action
The precise means by which this inhibition relieves angina has not been fully determined, but
includes at least the following two mechanisms:
1) Relaxation and Prevention of Coronary Artery Spasm
PROCARDIA dilates the main coronary arteries and coronary arterioles, both in normal and
ischemic regions, and is a potent inhibitor of coronary artery spasm, whether spontaneous or
ergonovine-induced. This property increases myocardial oxygen delivery in patients with
coronary artery spasm, and is responsible for the effectiveness of PROCARDIA in vasospastic
(Prinzmetal’s or variant) angina. Whether this effect plays any role in classical angina is not
clear, but studies of exercise tolerance have not shown an increase in the maximum exercise
rate-pressure product, a widely accepted measure of oxygen utilization. This suggests that, in
general, relief of spasm or dilation of coronary arteries is not an important factor in classical
angina.
2) Reduction of Oxygen Utilization
PROCARDIA regularly reduces arterial pressure at rest and at a given level of exercise by
dilating peripheral arterioles and reducing the total peripheral resistance (afterload) against which
the heart works. This unloading of the heart reduces myocardial energy consumption and oxygen
requirements and probably accounts for the effectiveness of PROCARDIA in chronic stable
angina.
Pharmacokinetics and Metabolism
PROCARDIA is rapidly and fully absorbed after oral administration. The drug is detectable in
serum 10 minutes after oral administration, and peak blood levels occur in approximately
30 minutes. Bioavailability is proportional to dose from 10 to 30 mg; half-life does not change
significantly with dose. There is little difference in relative bioavailability when PROCARDIA
capsules are given orally and either swallowed whole, bitten and swallowed, or bitten and held
sublingually. However, biting through the capsule prior to swallowing does result in slightly
earlier plasma concentrations (27 ng/mL 10 minutes after 10 mg) than if capsules are swallowed
intact. PROCARDIA is highly bound by serum proteins. PROCARDIA is extensively converted
to inactive metabolites and approximately 80 percent of PROCARDIA and metabolites are
eliminated via the kidneys. The elimination half-life of nifedipine is approximately two hours.
Since hepatic biotransformation is the predominant route for the disposition of nifedipine, the
pharmacokinetics may be altered in patients with chronic liver disease. Patients with hepatic
impairment (liver cirrhosis) have a longer disposition half-life and higher bioavailability of
Reference ID: 3346888
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nifedipine than healthy volunteers. The degree of serum protein binding of nifedipine is high
(92–98%). Protein binding may be greatly reduced in patients with renal or hepatic impairment.
Following intravenous administration, clearance of nifedipine was decreased by 33% in elderly
healthy subjects relative to young healthy subjects.
Hemodynamics
Like other slow-channel blockers, PROCARDIA exerts a negative inotropic effect on isolated
myocardial tissue. This is rarely, if ever, seen in intact animals or man, probably because of
reflex responses to its vasodilating effects. In man, PROCARDIA causes decreased peripheral
vascular resistance and a fall in systolic and diastolic pressure, usually modest (5–10 mm Hg
systolic), but sometimes larger. There is usually a small increase in heart rate, a reflex response to
vasodilation. Measurements of cardiac function in patients with normal ventricular function have
generally found a small increase in cardiac index without major effects on ejection fraction, left
ventricular end diastolic pressure (LVEDP), or volume (LVEDV). In patients with impaired
ventricular function, most acute studies have shown some increase in ejection fraction and
reduction in left ventricular filling pressure.
Electrophysiologic Effects
Although, like other members of its class, PROCARDIA decreases sinoatrial node function and
atrioventricular conduction in isolated myocardial preparations, such effects have not been seen
in studies in intact animals or in man. In formal electrophysiologic studies, predominantly in
patients with normal conduction systems, PROCARDIA has had no tendency to prolong
atrioventricular conduction, prolong sinus node recovery time, or slow sinus rate.
INDICATIONS AND USAGE
I. Vasospastic Angina
PROCARDIA (nifedipine) is indicated for the management of vasospastic angina confirmed by
any of the following criteria: 1) classical pattern of angina at rest accompanied by ST segment
elevation, 2) angina or coronary artery spasm provoked by ergonovine, or 3) angiographically
demonstrated coronary artery spasm. In those patients who have had angiography, the presence of
significant fixed obstructive disease is not incompatible with the diagnosis of vasospastic angina,
provided that the above criteria are satisfied. PROCARDIA may also be used where the clinical
presentation suggests a possible vasospastic component but where vasospasm has not been
confirmed, e.g., where pain has a variable threshold on exertion or when angina is refractory to
nitrates and/or adequate doses of beta blockers.
II. Chronic Stable Angina
(Classical Effort-Associated Angina)
PROCARDIA is indicated for the management of chronic stable angina (effort-associated
angina) without evidence of vasospasm in patients who remain symptomatic despite adequate
doses of beta blockers and/or organic nitrates or who cannot tolerate those agents.
Reference ID: 3346888
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In chronic stable angina (effort-associated angina), PROCARDIA has been effective in
controlled trials of up to eight weeks duration in reducing angina frequency and increasing
exercise tolerance, but confirmation of sustained effectiveness and evaluation of long-term safety
in these patients are incomplete.
Controlled studies in small numbers of patients suggest concomitant use of PROCARDIA and
beta-blocking agents may be beneficial in patients with chronic stable angina, but available
information is not sufficient to predict with confidence the effects of concurrent treatment,
especially in patients with compromised left ventricular function or cardiac conduction
abnormalities. When introducing such concomitant therapy, care must be taken to monitor blood
pressure closely since severe hypotension can occur from the combined effects of the drugs. (See
WARNINGS.)
CONTRAINDICATIONS
Known hypersensitivity reaction to PROCARDIA.
WARNINGS
Excessive Hypotension
Although, in most patients, the hypotensive effect of PROCARDIA is modest and well tolerated,
occasional patients have had excessive and poorly tolerated hypotension. These responses have
usually occurred during initial titration or at the time of subsequent upward dosage adjustment.
Although patients have rarely experienced excessive hypotension on PROCARDIA alone, this
may be more common in patients on concomitant beta blocker therapy. Although not approved
for this purpose, PROCARDIA and other immediate-release nifedipine capsules have been used
(orally and sublingually) for acute reduction of blood pressure. Several well-documented reports
describe cases of profound hypotension, myocardial infarction, and death when
immediate-release nifedipine was used in this way. PROCARDIA capsules should not be used
for the acute reduction of blood pressure.
Severe hypotension and/or increased fluid volume requirements have been reported in patients
receiving PROCARDIA together with a beta-blocking agent who underwent coronary artery
bypass surgery using high dose fentanyl anesthesia. The interaction with high dose fentanyl
appears to be due to the combination of PROCARDIA and a beta blocker, but the possibility that
it may occur with PROCARDIA alone, with low doses of fentanyl, in other surgical procedures,
or with other narcotic analgesics cannot be ruled out. In PROCARDIA treated patients where
surgery using high dose fentanyl anesthesia is contemplated, the physician should be aware of
these potential problems and, if the patient’s condition permits, sufficient time (at least 36 hours)
should be allowed for PROCARDIA to be washed out of the body prior to surgery.
Increased Angina and/or Myocardial Infarction
Rarely, patients, particularly those who have severe obstructive coronary artery disease, have
developed well documented increased frequency, duration, and/or severity of angina or acute
Reference ID: 3346888
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myocardial infarction on starting PROCARDIA or at the time of dosage increase. The
mechanism of this effect is not established.
Several well-controlled, randomized trials studied the use of immediate-release nifedipine in
patients who had just sustained myocardial infarctions. In none of these trials did
immediate-release nifedipine appear to provide any benefit. In some of the trials, patients who
received immediate-release nifedipine had significantly worse outcomes than patients who
received placebo. PROCARDIA capsules should not be administered within the first week
or two after myocardial infarction, and they should also be avoided in the setting of acute
coronary syndrome (when infarction may be imminent).
Use in Essential Hypertension
PROCARDIA and other immediate-release nifedipine capsules have also been used for the
long-term control of essential hypertension, although PROCARDIA capsules have not been
approved for this purpose and no properly controlled studies have been conducted to define an
appropriate dose or dose interval for such treatment. PROCARDIA capsules should not be
used for the control of essential hypertension.
Beta Blocker Withdrawal
Patients recently withdrawn from beta blockers may develop a withdrawal syndrome with
increased angina, probably related to increased sensitivity to catecholamines. Initiation of
PROCARDIA treatment will not prevent this occurrence and might be expected to exacerbate it
by provoking reflex catecholamine release. There have been occasional reports of increased
angina in a setting of beta blocker withdrawal and PROCARDIA initiation. It is important to
taper beta blockers if possible, rather than stopping them abruptly before beginning
PROCARDIA.
Congestive Heart Failure
Rarely, patients, usually those receiving a beta blocker, have developed heart failure after
beginning PROCARDIA. Patients with tight aortic stenosis may be at greater risk for such an
event, as the unloading effect of PROCARDIA would be expected to be of less benefit to these
patients, owing to their fixed impedance to flow across the aortic valve.
PRECAUTIONS
General:
Hypotension: Because PROCARDIA decreases peripheral vascular resistance, careful
monitoring of blood pressure during the initial administration and titration of PROCARDIA is
suggested. Close observation is especially recommended for patients already taking medications
that are known to lower blood pressure. (See WARNINGS.)
Peripheral Edema: Mild to moderate peripheral edema, typically associated with arterial
vasodilation and not due to left ventricular dysfunction, occurs in about one in ten patients
treated with PROCARDIA (nifedipine). This edema occurs primarily in the lower extremities
and usually responds to diuretic therapy. With patients whose angina is complicated by
Reference ID: 3346888
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congestive heart failure, care should be taken to differentiate this peripheral edema from the
effects of increasing left ventricular dysfunction.
Laboratory Tests: Rare, usually transient, but occasionally significant elevations of enzymes
such as alkaline phosphatase, CPK, LDH, SGOT, and SGPT have been noted. The relationship to
PROCARDIA therapy is uncertain in most cases, but probable in some. These laboratory
abnormalities have rarely been associated with clinical symptoms; however, cholestasis with or
without jaundice has been reported. Rare instances of allergic hepatitis have been reported.
PROCARDIA, like other calcium channel blockers, decreases platelet aggregation in vitro.
Limited clinical studies have demonstrated a moderate but statistically significant decrease in
platelet aggregation and an increase in bleeding time in some PROCARDIA patients. This is
thought to be a function of inhibition of calcium transport across the platelet membrane. No
clinical significance for these findings has been demonstrated.
Positive direct Coombs Test with/without hemolytic anemia has been reported but a causal
relationship between PROCARDIA administration and positivity of this laboratory test,
including hemolysis, could not be determined.
Although PROCARDIA has been used safely in patients with renal dysfunction and has been
reported to exert a beneficial effect, in certain cases, rare, reversible elevations in BUN and
serum creatinine have been reported in patients with pre-existing chronic renal insufficiency. The
relationship to PROCARDIA therapy is uncertain in most cases but probable in some.
Drug Interactions: Beta-adrenergic blocking agents: (See INDICATIONS AND USAGE and
WARNINGS.) Experience in over 1400 patients in a non-comparative clinical trial has shown
that concomitant administration of PROCARDIA and beta-blocking agents is usually well
tolerated, but there have been occasional literature reports suggesting that the combination may
increase the likelihood of congestive heart failure, severe hypotension, or exacerbation of angina.
Long-acting nitrates: PROCARDIA may be safely co-administered with nitrates, but there have
been no controlled studies to evaluate the antianginal effectiveness of this combination.
Digitalis: Since there have been isolated reports of patients with elevated digoxin levels, and
since there is a possible interaction between digoxin and nifedipine, it is recommended that
digoxin levels be monitored when initiating, adjusting, and discontinuing nifedipine to avoid
possible over- or under-digitalization.
Quinidine: There have been rare reports of an interaction between quinidine and nifedipine (with
a decreased plasma level of quinidine).
Coumarin anticoagulants: There have been rare reports of increased prothrombin time in patients
taking coumarin anticoagulants to whom PROCARDIA was administered. However, the
relationship to PROCARDIA therapy is uncertain.
Reference ID: 3346888
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Cimetidine: A study in six healthy volunteers has shown a significant increase in peak nifedipine
plasma levels (80%) and area-under-the-curve (74%) after a one week course of cimetidine at
1000 mg per day and nifedipine at 40 mg per day. Ranitidine produced smaller, non-significant
increases. The effect may be mediated by the known inhibition of cimetidine on hepatic
cytochrome P-450, the enzyme system probably responsible for the first-pass metabolism of
nifedipine. If nifedipine therapy is initiated in a patient currently receiving cimetidine, cautious
titration is advised.
Nifedipine is metabolized by CYP3A4. Co-administration of nifedipine with phenytoin, an
inducer of CYP3A4, lowers the systemic exposure to nifedipine by approximately 70%. Avoid
co-administration of nifedipine with phenytoin or any known CYP3A4 inducer or consider an
alternative antihypertensive therapy.
Other Interactions
Grapefruit Juice: Co-administration of nifedipine with grapefruit juice resulted in
approximately a doubling in nifedipine AUC and Cmax with no change in half-life. The
increased plasma concentrations most likely result from inhibition of CYP 3A4-related first-pass
metabolism. Avoid ingestion of grapefruit and grapefruit juice while taking nifedipine.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Nifedipine was administered
orally to rats for two years and was not shown to be carcinogenic. When given to rats prior to
mating, nifedipine caused reduced fertility at a dose approximately 5 times the maximum
recommended human dose. There is a literature report of reversible reduction in the ability of
human sperm obtained from a limited number of infertile men taking recommended doses of
nifedipine to bind to and fertilize an ovum in vitro. In vivo mutagenicity studies were negative.
Pregnancy: Pregnancy Category C: Nifedipine has been shown to produce teratogenic
findings in rats and rabbits, including digital anomalies similar to those reported for phenytoin.
Digital anomalies have been reported to occur with other members of the dihydropyridine class
and are possibly a result of compromised uterine blood flow. Nifedipine administration was
associated with a variety of embryotoxic, placentotoxic, and fetotoxic effects, including stunted
fetuses (rats, mice, rabbits), rib deformities (mice), cleft palate (mice), small placentas and
underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice, rabbits), and
prolonged pregnancy/decreased neonatal survival (rats; not evaluated in other species). On a
mg/kg basis, all of the doses associated with the teratogenic embryotoxic or fetotoxic effects in
animals were higher (5 to 50 times) than the maximum recommended human dose of
120 mg/day. On a mg/m2 basis, some doses were higher and some were lower than the maximum
recommended human dose but all were within an order of magnitude of it. The doses associated
with placentotoxic effects in monkeys were equivalent to or lower than the maximum
recommended human dose on a mg/m2 basis.
There are no adequate and well-controlled studies in pregnant women. PROCARDIA should be
used during pregnancy only if the potential benefit justifies the potential risk.
Reference ID: 3346888
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Lactation: Nifedipine is transferred through breast milk. PROCARDIA should be used during
breastfeeding only if the potential benefit justifies the potential risk.
Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Use in
pediatric population is not recommended.
Geriatric Use: Age appears to have a significant effect on the pharmacokinetics of nifedipine.
The clearance is decreased resulting in a higher AUC in the elderly. These changes are not due to
changes in renal function (see CLINICAL PHARMACOLOGY, Pharmacokinetics).
ADVERSE REACTIONS
In multiple-dose United States and foreign controlled studies in which adverse reactions were
reported spontaneously, adverse effects were frequent but generally not serious and rarely
required discontinuation of therapy or dosage adjustment. Most were expected consequences of
the vasodilator effects of PROCARDIA.
PROCARDIA (%)
Placebo (%)
Adverse Effect
(N=226)
(N=235)
Dizziness, lightheadedness, giddiness
27
15
Flushing, heat sensation
25
8
Headache
23
20
Weakness
12
10
Nausea, heartburn
11
8
Muscle cramps, tremor
8
3
Peripheral edema
7
1
Nervousness, mood changes
7
4
Palpitation
7
5
Dyspnea, cough, wheezing
6
3
Nasal congestion, sore throat
6
8
There is also a large uncontrolled experience in over 2100 patients in the United States. Most of
the patients had vasospastic or resistant angina pectoris, and about half had concomitant
treatment with beta-adrenergic blocking agents. The most common adverse events were:
Incidence Approximately 10%
Cardiovascular: peripheral edema
Central Nervous System: dizziness or lightheadedness
Gastrointestinal: nausea
Systemic: headache and flushing, weakness
Incidence Approximately 5%
Cardiovascular: transient hypotension
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Incidence 2% or Less
Cardiovascular: palpitation
Respiratory: nasal and chest congestion, shortness of breath
Gastrointestinal: diarrhea, constipation, cramps, flatulence
Musculoskeletal: inflammation, joint stiffness, muscle cramps
Central Nervous System: shakiness, nervousness, jitteriness, sleep disturbances, blurred
vision, difficulties in balance
Other: dermatitis, pruritus, urticaria, fever, sweating, chills, sexual difficulties
Incidence Approximately 0.5%
Cardiovascular: syncope (mostly with initial dosing and/or an increase in dose),
erythromelalgia
Incidence Less Than 0.5%
Hematologic: thrombocytopenia, anemia, leukopenia, purpura
Gastrointestinal: allergic hepatitis
Face and Throat: angioedema (mostly oropharyngeal edema with breathing difficulty in a few
patients), gingival hyperplasia
CNS: depression, paranoid syndrome
Special Senses: transient blindness at the peak of plasma level, tinnitus
Urogenital: nocturia, polyuria
Other: arthritis with ANA (+), exfoliative dermatitis, gynecomastia
Musculoskeletal: myalgia
Several of these side effects appear to be dose related. Peripheral edema occurred in about one in
25 patients at doses less than 60 mg per day and in about one patient in eight at 120 mg per day
or more. Transient hypotension, generally of mild to moderate severity and seldom requiring
discontinuation of therapy, occurred in one of 50 patients at less than 60 mg per day and in one of
20 patients at 120 mg per day or more.
Very rarely, introduction of PROCARDIA therapy was associated with an increase in anginal
pain, possibly due to associated hypotension. Transient unilateral loss of vision has also
occurred.
In addition, more serious adverse events were observed, not readily distinguishable from the
natural history of the disease in these patients. It remains possible, however, that some or many
of these events were drug related. Myocardial infarction occurred in about 4% of patients and
congestive heart failure or pulmonary edema in about 2%. Ventricular arrhythmias or conduction
disturbances each occurred in fewer than 0.5% of patients.
In a subgroup of over 1000 patients receiving PROCARDIA with concomitant beta blocker
therapy, the pattern and incidence of adverse experiences were not different from that of the
entire group of PROCARDIA (nifedipine) treated patients. (See PRECAUTIONS.)
Reference ID: 3346888
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In a subgroup of approximately 250 patients with a diagnosis of congestive heart failure as well
as angina pectoris (about 10% of the total patient population), dizziness or lightheadedness,
peripheral edema, headache, or flushing each occurred in one in eight patients. Hypotension
occurred in about one in 20 patients. Syncope occurred in approximately one patient in 250.
Myocardial infarction or symptoms of congestive heart failure each occurred in about one patient
in 15. Atrial or ventricular dysrhythmias each occurred in about one patient in 150.
In post-marketing experience, there have been rare reports of exfoliative dermatitis caused by
nifedipine. There have been rare reports of exfoliative or bullous skin adverse events (such as
erythema multiforme, Stevens-Johnson Syndrome, and toxic epidermal necrolysis) and
photosensitivity reactions. Acute generalized exanthematous pustulosis also has been reported.
OVERDOSAGE
Experience with nifedipine overdosage is limited. Generally, overdosage with nifedipine leading
to pronounced hypotension calls for active cardiovascular support including monitoring of
cardiovascular and respiratory function, elevation of extremities, and judicious use of calcium
infusion, pressor agents, and fluids. Clearance of nifedipine would be expected to be prolonged
in patients with impaired liver function. Since nifedipine is highly protein bound, dialysis is not
likely to be of any benefit; however, plasmapheresis may be beneficial.
DOSAGE AND ADMINISTRATION
The dosage of PROCARDIA needed to suppress angina and that can be tolerated by the
patient must be established by titration. Excessive doses can result in hypotension.
Therapy should be initiated with the 10 mg capsule. The starting dose is one 10 mg capsule,
swallowed whole, 3 times/day. The usual effective dose range is 10–20 mg three times daily.
Some patients, especially those with evidence of coronary artery spasm, respond only to higher
doses, more frequent administration, or both. In such patients, doses of 20–30 mg three or four
times daily may be effective. Doses above 120 mg daily are rarely necessary. More than 180 mg
per day is not recommended.
In most cases, PROCARDIA titration should proceed over a 7–14 day period so that the
physician can assess the response to each dose level and monitor the blood pressure before
proceeding to higher doses.
If symptoms so warrant, titration may proceed more rapidly provided that the patient is assessed
frequently. Based on the patient’s physical activity level, attack frequency, and sublingual
nitroglycerin consumption, the dose of PROCARDIA may be increased from 10 mg t.i.d. to
20 mg t.i.d. and then to 30 mg t.i.d. over a three-day period.
Reference ID: 3346888
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In hospitalized patients under close observation, the dose may be increased in 10 mg increments
over four- to six-hour periods as required to control pain and arrhythmias due to ischemia. A
single dose should rarely exceed 30 mg.
Avoid co-administration of nifedipine with grapefruit juice (see CLINICAL PHARMACOLOGY
and PRECAUTIONS: Other Interactions).
No “rebound effect” has been observed upon discontinuation of PROCARDIA. However, if
discontinuation of PROCARDIA is necessary, sound clinical practice suggests that the dosage
should be decreased gradually with close physician supervision.
Co-Administration with Other Antianginal Drugs
Sublingual nitroglycerin may be taken as required for the control of acute manifestations of
angina, particularly during PROCARDIA titration. See PRECAUTIONS, Drug Interactions, for
information on co-administration of PROCARDIA with beta blockers or long-acting nitrates.
HOW SUPPLIED
PROCARDIA soft gelatin capsules are supplied in:
Bottles of 100: 10 mg (NDC 0069-2600-66)
The capsules should be protected from light and moisture and stored at controlled room
temperature, 59° to 77°F (15° to 25°C) in the manufacturer’s original container. company logo
LAB-0178-4.x
Revised July 2013
Reference ID: 3346888
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018482s051lbl.pdf', 'application_number': 18482, 'submission_type': 'SUPPL ', 'submission_number': 51}
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NDA 18-469/S-052
Page 3
BSS PLUS®
STERILE IRRIGATING SOLUTION
(balanced salt solution enriched with bicarbonate, dextrose, and glutathione)
DESCRIPTION: BSS PLUS® is a sterile intraocular irrigating solution for use during all
intraocular surgical procedures, including those requiring a relatively long intraocular perfusion
time (e.g., pars plana vitrectomy, phacoemulsification, extra capsular cataract extraction/lens
aspiration, anterior segment reconstruction, etc.). The solution does not contain a preservative
and should be prepared just prior to use in surgery.
Part I: Part I is a sterile 480 mL solution in a 500 mL single-dose bag to which the Part II
concentrate is added. Each mL of Part I contains: sodium chloride 7.44 mg, potassium chloride
0.395 mg, dibasic sodium phosphate 0.433 mg, sodium bicarbonate 2.19 mg, hydrochloric acid
and/or sodium hydroxide (to adjust pH), in water for injection.
Part II: Part II is a sterile concentrate in a 20 mL single-dose vial for addition to Part I. Each mL
of Part II contains: calcium chloride dehydrate 3.85 mg, magnesium chloride hexahydrate 5 mg,
dextrose 23 mg, glutathione disulfide (oxidized glutathione) 4.6 mg, in water for injection.
After addition of BSS PLUS® solution Part II to the Part I bag, each mL of the reconstituted
product contains: sodium chloride 7.14 mg, potassium chloride 0.38 mg, calcium chloride
dehydrate 0.154 mg, magnesium chloride hexahydrate 0.2 mg, dibasic sodium phosphate 0.42
mg, sodium bicarbonate 2.1 mg, dextrose 0.92 mg, glutathione disulfide (oxidized glutathione)
0.184 mg, hydrochloric acid and/or sodium hydroxide (to adjust pH), in water for injection.
The reconstituted product has a pH of approximately 7.4. Osmolality is approximately 305
mOsm.
CLINICAL PHARMACOLOGY: None of the components of BSS PLUS solution are foreign
to the eye, and BSS PLUS solution has no pharmacological action. Human perfused cornea
studies have shown BSS PLUS solution to be an effective irrigation solution for providing
corneal detumescence and maintaining corneal endothelial integrity during intraocular perfusion.
An in vivo study in rabbits has shown the BSS PLUS solution is more suitable than normal
saline or Balanced Salt Solution for intravitreal irrigation because BSS PLUS solution contains
the appropriate bicarbonate, pH, and ionic composition necessary for the maintenance of normal
retinal electrical activity. Human in vivo studies have demonstrated BSS PLUS solution to be
safe and effective when used during surgical procedures such as pars plan vitrectomy,
phacoemulsification, cataract extraction/lens aspiration, anterior segment reconstruction. No
differences have been observed between adults and pediatric patients following use of this drug
product.
INDICATIONS AND USAGE: BSS PLUS solution is indicated for use as an intraocular
irrigating solution during intraocular surgical procedures involving perfusion of the eye.
CONTRAINDICATIONS: There are no specific contraindications to the use of BSS PLUS
solution; however, contraindications for the surgical procedure during which BSS PLUS solution
is to be used should be strictly adhered to.
Reference ID: 3316062
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-469/S-052
Page 4
WARNINGS: For IRRIGATION during ophthalmic surgery only. Not for injection or
intravenous infusion. Do not use unless product is clear, seal is intact and container is
undamaged. Do not use if product is discolored or contains a precipitate.
PRECAUTIONS: DO NOT USE BSS PLUS solution UNTIL PART I IS FULLY
RECONSTITUTED WITH PART II. Discard unused contents. BSS PLUS does not contain a
preservative; therefore, do not use this container for more than one patient. DISCARD ANY
UNUSED PORTION SIX HOURS AFTER PREPARATION. Studies suggest that intraocular
irrigating solutions which are iso-osmotic with normal aqueous fluids should be used with
caution in diabetic patients undergoing vitrectomy since intraoperative lens changes have been
observed.
There have been reports of corneal clouding or edema following ocular surgery in which BSS
PLUS solution was used as an irrigating solution. As in all surgical procedures appropriate
measures should be taken to minimize trauma to the cornea and other ocular tissues.
Preparation: Reconstitute BSS PLUS Intraocular Irrigating Solution just prior to use in surgery.
Follow the same strict aseptic procedures in the reconstitution of BSS PLUS solution as used for
intravenous additives. Remove the BSS PLUS solution Part I (480 mL) bag from the clear
overwrap. Remove the blue flip-off seal from the BSS PLUS solution Part II (20 mL) vial.
Clean and disinfect the rubber stoppers on both containers by using sterile alcohol wipes.
Transfer the contents of the Part II vial to the Part I bag using a BSS PLUS solution Dual-Spike
Transfer Device (provided). An alternative method of solution transfer may be accomplished by
using a 20 mL syringe to remove the Part II solution from the vial and transferring exactly 20 mL
to the Part I container through the outer target area of the rubber stopper. An excess volume of
Part II is provided in each vial. Gently agitate the contents to mix the solution. Place a sterile cap
on the bag. Record the time and date of reconstitution and the patient’s name on the bag label.
Geriatric Use: No overall differences in safety or effectiveness have been observed between
elderly and younger patients.
ADVERSE REACTIONS: Postoperative inflammatory reactions as well as incidents of corneal
edema and corneal decompensation have been reported. Their relationship to the use of BSS
PLUS solution has not been established.
OVERDOSAGE: The solution has no pharmacological action and thus no potential for
overdosage. However, as with any intraocular surgical procedure, the duration of intraocular
manipulation should be kept to a minimum.
DOSAGE AND ADMINISTRATION: The solution should be used according to the standard
technique employed by the operating surgeon. For non-active irrigating system, use an
administration set with an air-inlet in the plastic spike since the bag does not contain a separate
airway tube. Follow the directions for the particular administration set to be used. Insert the spike
aseptically into the bag through the center target area of the rubber stopper. Allow the fluid to
flow to remove air from the tubing before intraocular irrigation begins.
Reference ID: 3316062
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NDA 18-469/S-052
Page 5
HOW SUPPLIED: BSS PLUS Solution is supplied in two packages for reconstitution prior to
use: a 500 mL bag containing 480 mL (Part I) and a 20 mL glass vial (Part II); both using grey
butyl stoppers and aluminum seals. See the PRECAUTIONS section regarding reconstitution of
the solution.
NDC 0065-0800-XX
Storage: Store Part I and Part II at 2° - 25°C (36° - 77°F). DO NOT FREEZE. Discard prepared
solution after six hours.
Rx Only
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NDA 18-469/S-052
Page 6
RECONSTITUTION INSTRUCTIONS
DIRECTIONS: Use Aseptic Technique
1. Remove the BSS PLUS® solution Part I (480 mL) bag from the clear overwrap. Remove the
blue flip- off seal from the BSS PLUS® solution Part II (20 mL) vial. Prepare the stoppers on
both parts by using sterile alcohol wipes.
2. Peel open a BSS PLUS® solution Dual-Spike Transfer Device package (supplied) and remove
the sterile transfer spike. NOTE: This device is vented permitting air to enter vial during solution
transfer, thereby preventing the creation of a vacuum inside the vial.
3. Remove protector from the white plastic piercing pin of the Dual-Spike Transfer Device.
4. Firmly grasp device from behind the flange and insert the white plastic piercing pin into the
upright rubber stopper of the BSS PLUS® solution Part II (20 mL) vial.
5. Remove guard from filter needle. Firmly grasp vial in the palm of one hand and with thumb
and index finger, hold plastic flange against top of vial.
6. Hold the vial in the upright position, incline and immediately insert the transfer device into the
center target of rubber stopper of the BSS PLUS® solution Part I (480 mL) bag. (See
illustration.) Note: Do not invert Part II (20 ml) vial before or during spiking of the BSS PLUS®
solution Part I bag rubber stopper, until ready to initiate transfer.
7. Invert vial to initiate the transfer of Part II into Part I. If transfer does not occur immediately,
gentle manipulation of the bag can initiate transfer. NOTE: An excess amount of BSS PLUS®
solution Part II is provided in each vial. A non-transferred solution residual of approximately 0.3
mL can be expected to remain in the vial.
8. Immediately remove vial (with spike attached) from the BSS PLUS® solution Part I container
and discard it after solution transfer has been completed.
9. Place a sterile safety cap over the rubber stopper of Part I if the solution is not going to be used
immediately. Mix the solution gently until uniform. Record the patient’s name and the date and
time of reconstitution. BSS PLUS® solution is now ready for use.
CAUTION: Reconstituted BSS PLUS® solution must be used within six hours of mixing.
Discard any solution which has aged beyond that time. Never use the same bag of BSS PLUS®
solution on more than one patient.
Alternative Transfer Method
If preferred, the contents of the BSS PLUS® Part II component may be aspirated with an 18
gauge cannula attached to a 20 mL syringe and then transferred into the Part I bag.
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NDA 18-469/S-052
Page 7 usage illustration
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|
custom-source
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2025-02-12T13:44:44.267397
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018469s052lbl.pdf', 'application_number': 18489, 'submission_type': 'SUPPL ', 'submission_number': 52}
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FUR:R27
FUROSEMIDE
TABLETS, USP
20 mg, 40 mg and 80 mg
Rx only
WARNING: Furosemide is a potent diuretic which, if given in excessive amounts, can
lead to a profound diuresis with water and electrolyte depletion. Therefore, careful
medical supervision is required and dose and dose schedule must be adjusted to the
individual patient’s needs. (See DOSAGE AND ADMINISTRATION.)
DESCRIPTION: Furosemide is a diuretic which is an anthranilic acid derivative.
Chemically, it is 4-chloro-N-furfuryl-5-sulfamoylanthranilic acid. Furosemide, USP is a
white to slightly yellow odorless, crystalline powder. It is practically insoluble in water,
sparingly soluble in alcohol, freely soluble in dilute alkali solutions and insoluble in dilute
acids.
The structural formula is as follows:
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structural formula
C12H11CIN2O5S
M.W. 330.75
Each tablet for oral administration contains 20 mg, 40 mg or 80 mg of furosemide,
USP and the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate,
microcrystalline cellulose, pregelatinized starch (corn) and stearic acid.
CLINICAL PHARMACOLOGY: Investigations into the mode of action of furosemide
have utilized micropuncture studies in rats, stop flow experiments in dogs and various
clearance studies in both humans and experimental animals. It has been demonstrated that
furosemide inhibits primarily the absorption of sodium and chloride not only in the
proximal and distal tubules but also in the loop of Henle. The high degree of efficacy is
largely due to the unique site of action. The action on the distal tubule is independent of any
inhibitory effect on carbonic anhydrase and aldosterone.
Recent evidence suggests that furosemide glucuronide is the only or at least the
major biotransformation product of furosemide in man. Furosemide is extensively bound to
plasma proteins, mainly to albumin. Plasma concentrations ranging from 1 to 400 mcg/mL
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are 91% to 99% bound in healthy individuals. The unbound fraction averages 2.3% to 4.1%
at therapeutic concentrations.
The onset of diuresis following oral administration is within one hour. The peak
effect occurs within the first or second hour. The duration of diuretic effect is 6 to 8 hours.
In fasted normal men, the mean bioavailability of furosemide from furosemide
tablets and furosemide oral solution is 64% to 60%, respectively, of that from an
intravenous injection of the drug. Although furosemide is more rapidly absorbed from the
oral solution (50 minutes) than from the tablet (87 minutes), peak plasma levels and area
under the plasma concentration-time curves do not differ significantly. Peak plasma
concentrations increase with increasing dose but times-to-peak do not differ among doses.
The terminal half-life of furosemide is approximately 2 hours.
Significantly more furosemide is excreted in urine following the IV injection than
after the tablet or oral solution. There are no significant differences between the two oral
formulations in the amount of unchanged drug excreted in urine.
Geriatric Population: Furosemide binding to albumin may be reduced in elderly patients.
Furosemide is predominantly excreted unchanged in the urine. The renal clearance of
furosemide after intravenous administration in older healthy male subjects (60 to 70 years
of age) is statistically significantly smaller than in younger healthy male subjects (20 to 35
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years of age). The initial diuretic effect of furosemide in older subjects is decreased relative
to younger subjects. (See PRECAUTIONS: Geriatric Use.)
INDICATIONS AND USAGE: Edema: Furosemide is indicated in adults and pediatric
patients for the treatment of edema associated with congestive heart failure, cirrhosis of the
liver, and renal disease, including the nephrotic syndrome. Furosemide is particularly useful
when an agent with greater diuretic potential is desired.
Hypertension: Oral furosemide may be used in adults for the treatment of hypertension
alone or in combination with other antihypertensive agents. Hypertensive patients who
cannot be adequately controlled with thiazides will probably also not be adequately
controlled with furosemide alone.
CONTRAINDICATIONS: Furosemide is contraindicated in patients with anuria and in
patients with a history of hypersensitivity to furosemide.
WARNINGS: In patients with hepatic cirrhosis and ascites, furosemide therapy is best
initiated in the hospital. In hepatic coma and in states of electrolyte depletion, therapy
should not be instituted until the basic condition is improved. Sudden alterations of fluid
and electrolyte balance in patients with cirrhosis may precipitate hepatic coma; therefore,
strict observation is necessary during the period of diuresis. Supplemental potassium
chloride and, if required, an aldosterone antagonist are helpful in preventing hypokalemia
and metabolic alkalosis.
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If increasing azotemia and oliguria occur during treatment of severe progressive
renal disease, furosemide should be discontinued.
Cases of tinnitus and reversible or irreversible hearing impairment and deafness
have been reported. Reports usually indicate that furosemide ototoxicity is associated with
rapid injection, severe renal impairment, the use of higher than recommended doses,
hypoproteinemia or concomitant therapy with aminoglycoside antibiotics, ethacrynic acid,
or other ototoxic drugs. If the physician elects to use high dose parenteral therapy,
controlled intravenous infusion is advisable (for adults, an infusion rate not exceeding 4 mg
furosemide per minute has been used). (See PRECAUTIONS: Drug Interactions)
PRECAUTIONS: General: Excessive diuresis may cause dehydration and blood volume
reduction with circulatory collapse and possibly vascular thrombosis and embolism,
particularly in elderly patients. As with any effective diuretic, electrolyte depletion may
occur during furosemide therapy, especially in patients receiving higher doses and a
restricted salt intake. Hypokalemia may develop with furosemide, especially with brisk
diuresis, inadequate oral electrolyte intake, when cirrhosis is present, or during concomitant
use of corticosteroids, ACTH, licorice in large amounts, or prolonged use of laxatives.
Digitalis therapy may exaggerate metabolic effects of hypokalemia, especially myocardial
effects.
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All patients receiving furosemide therapy should be observed for these signs or
symptoms of fluid or electrolyte imbalance (hyponatremia, hypochloremic alkalosis,
hypokalemia, hypomagnesemia or hypocalcemia): dryness of mouth, thirst, weakness,
lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension,
oliguria, tachycardia, arrhythmia, or gastrointestinal disturbances such as nausea and
vomiting. Increases in blood glucose and alterations in glucose tolerance tests (with
abnormalities of the fasting and 2-hour postprandial sugar) have been observed, and rarely,
precipitation of diabetes mellitus has been reported.
In patients with severe symptoms of urinary retention (because of bladder emptying
disorders, prostatic hyperplasia, urethral narrowing), the administration of furosemide can
cause acute urinary retention related to increased production and retention of urine. Thus,
these patients require careful monitoring, especially during the initial stages of treatment.
In patients at high risk for radiocontrast nephropathy, furosemide can lead to a
higher incidence of deterioration in renal function after receiving radiocontrast compared to
high-risk patients who received only intravenous hydration prior to receiving radiocontrast.
In patients with hypoproteinemia (e.g., associated with nephrotic syndrome) the
effect of furosemide may be weakened and its ototoxicity potentiated.
Asymptomatic hyperuricemia can occur and gout may rarely be precipitated.
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Patients allergic to sulfonamides may also be allergic to furosemide. The possibility
exists of exacerbation or activation of systemic lupus erythematosus.
As with many other drugs, patients should be observed regularly for the possible
occurrence of blood dyscrasias, liver or kidney damage or other idiosyncratic reactions.
Information for Patients: Patients receiving furosemide should be advised that they may
experience symptoms from excessive fluid and/or electrolyte losses. The postural
hypotension that sometimes occurs can usually be managed by getting up slowly. Potassium
supplements and/or dietary measures may be needed to control or avoid hypokalemia.
Patients with diabetes mellitus should be told that furosemide may increase blood
glucose levels and thereby affect urine glucose tests. The skin of some patients may be more
sensitive to the effects of sunlight while taking furosemide.
Hypertensive patients should avoid medications that may increase blood pressure,
including over-the-counter products for appetite suppression and cold symptoms.
Laboratory Tests: Serum electrolytes, (particularly potassium), CO2, creatinine and BUN
should be determined frequently during the first few months of furosemide therapy and
periodically thereafter. Serum and urine electrolyte determinations are particularly
important when the patient is vomiting profusely or receiving parenteral fluids.
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Abnormalities should be corrected or the drug temporarily withdrawn. Other medications
may also influence serum electrolytes.
Reversible elevations of BUN may occur and are associated with dehydration, which
should be avoided, particularly in patients with renal insufficiency.
Urine and blood glucose should be checked periodically in diabetics receiving
furosemide, even in those suspected of latent diabetes.
Furosemide may lower serum levels of calcium (rarely cases of tetany have been
reported) and magnesium. Accordingly, serum levels of these electrolytes should be
determined periodically.
In premature infants furosemide may precipitate nephrocalcinosis/nephrolithiasis,
therefore renal function must be monitored and renal ultrasonography performed. (See
PRECAUTIONS: Pediatric Use)
Drug Interactions: Furosemide may increase the ototoxic potential of aminoglycoside
antibiotics, especially in the presence of impaired renal function. Except in life threatening
situations, avoid this combination.
Furosemide should not be used concomitantly with ethacrynic acid because of the
possibility of ototoxicity. Patients receiving high doses of salicylates concomitantly with
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furosemide, as in rheumatic disease, may experience salicylate toxicity at lower doses
because of competitive renal excretory sites.
There is a risk of ototoxic effects if cisplatin and furosemide are given
concomitantly. In addition, nephrotoxicity of nephrotoxic drugs such as cisplatin may be
enhanced if furosemide is not given in lower doses and with positive fluid balance when
used to achieve forced diuresis during cisplatin treatment.
Furosemide has a tendency to antagonize the skeletal muscle relaxing effect of
tubocurarine and may potentiate the action of succinylcholine.
Lithium generally should not be given with diuretics because they reduce lithium’s
renal clearance and add a high risk of lithium toxicity.
Furosemide combined with angiotensin converting enzyme inhibitors or angiotensin
II receptor blockers may lead to severe hypotension and deterioration in renal function,
including renal failure. An interruption or reduction in the dosage of furosemide,
angiotensin converting enzyme inhibitors, or angiotensin receptor blockers may be
necessary.
Potentiation occurs with ganglionic or peripheral adrenergic blocking drugs.
Reference ID: 3898381
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Furosemide may decrease arterial responsiveness to norepinephrine. However,
norepinephrine may still be used effectively.
Simultaneous administration of sucralfate and furosemide tablets may reduce the
natriuretic and antihypertensive effects of furosemide. Patients receiving both drugs should
be observed closely to determine if the desired diuretic and/or antihypertensive effect of
furosemide is achieved. The intake of furosemide and sucralfate should be separated by at
least 2 hours.
In isolated cases, intravenous administration of furosemide within 24 hours of taking
chloral hydrate may lead to flushing, sweating attacks, restlessness, nausea, increase in
blood pressure, and tachycardia. Use of furosemide concomitantly with chloral hydrate is
therefore not recommended.
Phenytoin interferes directly with renal action of furosemide. There is evidence that
treatment with phenytoin leads to decrease intestinal absorption of furosemide, and
consequently to lower peak serum furosemide concentrations.
Methotrexate and other drugs that, like furosemide, undergo significant renal tubular
secretion may reduce the effect of furosemide. Conversely, furosemide may decrease renal
elimination of other drugs that undergo tubular secretion. High-dose treatment of both
furosemide and these other drugs may result in elevated serum levels of these drugs and
may potentiate their toxicity as well as the toxicity of furosemide.
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Furosemide can increase the risk of cephalosporin-induced nephrotoxicity even in
the setting of minor or transient renal impairment.
Concomitant use of cyclosporine and furosemide is associated with increased risk of
gouty arthritis secondary to furosemide -induced hyperurecemia and cyclosporine
impairment of renal urate excretion.
High doses (> 80 mg) of furosemide may inhibit the binding of thyroid hormones to
carrier proteins and result in transient increase in free thyroid hormones, followed by an
overall decrease in total thyroid hormone levels.
One study in six subjects demonstrated that the combination of furosemide and
acetylsalicylic acid temporarily reduced creatinine clearance in patients with chronic renal
insufficiency. There are case reports of patients who developed increased BUN, serum
creatinine and serum potassium levels, and weight gain when furosemide was used in
conjunction with NSAIDs.
Literature reports indicate that coadministration of indomethacin may reduce the
natriuretic and antihypertensive effects of furosemide in some patients by inhibiting
prostaglandin synthesis. Indomethacin may also affect plasma renin levels, aldosterone
excretion, and renin profile evaluation. Patients receiving both indomethacin and
furosemide should be observed closely to determine if the desired diuretic and/or
antihypertensive effect of furosemide is achieved.
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Carcinogenesis, Mutagenesis, Impairment of Fertility: Furosemide was tested for
carcinogenicity by oral administration in one strain of mice and one strain of rats. A small
but significantly increased incidence of mammary gland carcinomas occurred in female
mice at a dose 17.5 times the maximum human dose of 600 mg. There were marginal
increases in uncommon tumors in male rats at a dose of 15 mg/kg (slightly greater than the
maximum human dose) but not at 30 mg/kg.
Furosemide was devoid of mutagenic activity in various strains of Salmonella
typhimurium when tested in the presence or absence of an in vitro metabolic activation
system, and questionably positive for gene mutation in mouse lymphoma cells in the
presence of rat liver S9 at the highest dose tested. Furosemide did not induce sister
chromatid exchange in human cells in vitro, but other studies on chromosomal aberrations
in human cells in vitro gave conflicting results. In Chinese hamster cells it induced
chromosomal damage but was questionably positive for sister chromatid exchange. Studies
on the induction by furosemide of chromosomal aberrations in mice were inconclusive. The
urine of rats treated with this drug did not induce gene conversion in Saccharomyces
cerevisiae.
Furosemide produced no impairment of fertility in male or female rats at 100
mg/kg/day (the maximum effective diuretic dose in the rat and 8 times the maximal human
dose of 600 mg/day).
Reference ID: 3898381
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Pregnancy: Teratogenic Effects. Pregnancy Category C: Furosemide has been shown to
cause unexplained maternal deaths and abortions in rabbits at 2, 4 and 8 times the maximal
recommended human dose. There are no adequate and well controlled studies in pregnant
women. Furosemide should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
Treatment during pregnancy requires monitoring of fetal growth because of the
potential for higher birth weights.
The effects of furosemide on embryonic and fetal development and on pregnant
dams were studied in mice, rats and rabbits.
Furosemide caused unexplained maternal deaths and abortions in the rabbit at the
lowest dose of 25 mg/kg (two times the maximal recommended human dose of 600
mg/day). In another study, a dose of 50 mg/kg (four times the maximal recommended
human dose of 600 mg/day) also caused maternal deaths and abortions when administered
to rabbits between Days 12 and 17 of gestation. In a third study, none of the pregnant
rabbits survived a dose of 100 mg/kg. Data from the above studies indicate fetal lethality
that can precede maternal deaths.
The results of the mouse study and one of the three rabbit studies also showed an
increased incidence and severity of hydronephrosis (distention of the renal pelvis and, in
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some cases, of the ureters) in fetuses derived from the treated dams as compared with the
incidence in fetuses from the control group.
Nursing Mothers: Because it appears in breast milk, caution should be exercised when
furosemide is administered to a nursing mother.
Furosemide may inhibit lactation.
Pediatric Use: In premature infants furosemide may precipitate
nephrocalcinosis/nephrolithiasis. Nephrocalcinosis/nephrolithiasis has also been observed in
children under 4 years of age with no history of prematurity who have been treated
chronically with furosemide. Monitor renal function, and renal ultrasonography should be
considered, in pediatric patients receiving furosemide.
If furosemide is administered to premature infants during the first weeks of life, it
may increase the risk of persistence of patent ductus arteriosus.
Geriatric Use: Controlled clinical studies of furosemide did not include sufficient numbers
of subjects aged 65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience has not identified differences in responses
between the elderly and younger patients. In general, dose selection for the elderly patient
should be cautious, usually starting at the low end of the dosing range, reflecting the greater
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frequency of decreased hepatic, renal or cardiac function and of concomitant disease or
other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic
reactions to this drug may be greater in patients with impaired renal function. Because
elderly patients are more likely to have decreased renal function, care should be taken in
dose selection and it may be useful to monitor renal function. (See PRECAUTIONS:
General and DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS: Adverse reactions are categorized below by organ system and
listed by decreasing severity.
Gastrointestinal System Reactions
1.
hepatic encephalopathy in patients with hepatocellular insufficiency
2.
pancreatitis
3.
jaundice (intrahepatic cholestatic jaundice)
4.
increased liver enzymes
5.
anorexia
6.
oral and gastric irritation
7.
cramping
8.
diarrhea
9.
constipation
10.
nausea
Reference ID: 3898381
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11.
vomiting
Systemic Hypersensitivity Reactions
1.
severe anaphylactic or anaphylactoid reactions (e.g., with shock)
2.
systemic vasculitis
3.
interstitial nephritis
4.
necrotizing angiitis
Central Nervous System Reactions
1.
tinnitus and hearing loss
2.
paresthesias
3.
vertigo
4.
dizziness
5.
headache
6.
blurred vision
7.
xanthopsia
Hematologic Reactions
1.
aplastic anemia
2.
thrombocytopenia
3.
agranulocytosis
4.
hemolytic anemia
5.
leukopenia
Reference ID: 3898381
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6.
anemia
7.
eosinophilia
Dermatologic-Hypersensitivity Reactions
1.
toxic epidermal necrolysis
2.
Stevens-Johnson Syndrome
3.
erythema multiforme
4.
drug rash with eosinophilia and systemic symptoms
5.
acute generalized exanthematous pustulosis
6.
exfoliative dermatitis
7.
bullous pemphigoid
8.
purpura
9.
photosensitivity
10.
rash
11.
pruritus
12.
urticaria
Cardiovascular Reaction
1.
Orthostatic hypotension may occur and be aggravated by alcohol,
barbiturates or narcotics.
2.
Increase in cholesterol and triglyceride serum levels.
Other Reactions
Reference ID: 3898381
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1.
hyperglycemia
2.
glycosuria
3.
hyperuricemia
4.
muscle spasm
5.
weakness
6.
restlessness
7.
urinary bladder spasm
8.
thrombophlebitis
9.
fever
Whenever adverse reactions are moderate or severe, furosemide dosage should be
reduced or therapy withdrawn.
OVERDOSAGE: The principal signs and symptoms of overdosage with furosemide are
dehydration, blood volume reduction, hypotension, electrolyte imbalance, hypokalemia and
hypochloremic alkalosis, and are extensions of its diuretic action.
The acute toxicity of furosemide has been determined in mice, rats and dogs. In all
three, the oral LD50 exceeded 1000 mg/kg body weight, while the intravenous LD50 ranged
from 300 to 680 mg/kg. The acute intragastric toxicity in neonatal rats is 7 to 10 times that
of adult rats.
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The concentration of furosemide in biological fluids associated with toxicity or
death is not known.
Treatment of overdosage is supportive and consists of replacement of excessive
fluid and electrolyte losses. Serum electrolytes, carbon dioxide level and blood pressure
should be determined frequently. Adequate drainage must be assured in patients with
urinary bladder outlet obstruction (such as prostatic hypertrophy).
Hemodialysis does not accelerate furosemide elimination.
DOSAGE AND ADMINISTRATION: Edema: Therapy should be individualized
according to patient response to gain maximal therapeutic response and to determine the
minimal dose needed to maintain that response.
Adults: The usual initial dose of furosemide is 20 mg to 80 mg given as a single dose.
Ordinarily a prompt diuresis ensues. If needed, the same dose can be administered 6 to 8
hours later or the dose may be increased. The dose may be raised by 20 mg or 40 mg and
given not sooner than 6 to 8 hours after the previous dose until the desired diuretic effect
has been obtained. The individually determined single dose should then be given once or
twice daily (e.g., at 8 am and 2 pm). The dose of furosemide may be carefully titrated up to
600 mg/day in patients with clinically severe edematous states.
Reference ID: 3898381
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Edema may be most efficiently and safely mobilized by giving furosemide on 2 to 4
consecutive days each week.
When doses exceeding 80 mg/day are given for prolonged periods, careful clinical
observation and laboratory monitoring are particularly advisable. (See PRECAUTIONS:
Laboratory Tests.)
Geriatric Patients: In general, dose selection for the elderly patient should be cautious,
usually starting at the low end of the dosing range (see PRECAUTIONS: Geriatric Use).
Pediatric Patients: The usual initial dose of oral furosemide in pediatric patients is 2 mg/kg
body weight, given as a single dose. If the diuretic response is not satisfactory after the
initial dose, dosage may be increased by 1 or 2 mg/kg no sooner than 6 to 8 hours after the
previous dose. Doses greater than 6 mg/kg body weight are not recommended. For
maintenance therapy in pediatric patients, the dose should be adjusted to the minimum
effective level.
Hypertension: Therapy should be individualized according to the patient’s response to gain
maximal therapeutic response and to determine the minimal dose needed to maintain the
therapeutic response.
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Adults: The usual initial dose of furosemide for hypertension is 80 mg, usually divided into
40 mg twice a day. Dosage should then be adjusted according to response. If response is not
satisfactory, add other antihypertensive agents.
Changes in blood pressure must be carefully monitored when furosemide is used
with other antihypertensive drugs, especially during initial therapy. To prevent excessive
drop in blood pressure, the dosage of other agents should be reduced by at least 50 percent
when furosemide is added to the regimen. As the blood pressure falls under the potentiating
effect of furosemide, a further reduction in dosage or even discontinuation of other
antihypertensive drugs may be necessary.
Geriatric Patients: In general, dose selection and dose adjustment for the elderly patient
should be cautious, usually starting at the low end of the dosing range (see
PRECAUTIONS: Geriatric Use).
HOW SUPPLIED: Furosemide Tablets, USP are available as tablets for oral
administration. Each tablet for oral administration contains 20 mg, 40 mg or 80 mg of
furosemide, USP.
The 20 mg tablets are white, round, unscored tablets debossed with M2. They are
available as follows:
NDC 0378-0208-01
Reference ID: 3898381
21
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For current labeling information, please visit https://www.fda.gov/drugsatfda
bottles of 100 tablets
NDC 0378-0208-10
bottles of 1000 tablets
The 40 mg tablets are white, round, scored tablets debossed with MYLAN over 216
on one side of the tablet and 40 on the other side. They are available as follows:
NDC 0378-0216-01
bottles of 100 tablets
NDC 0378-0216-10
bottles of 1000 tablets
The 80 mg tablets are white, round, scored tablets debossed with MYLAN over 232
on one side of the tablet and 80 on the other side. They are available as follows:
NDC 0378-0232-01
bottles of 100 tablets
NDC 0378-0232-05
bottles of 500 tablets
Reference ID: 3898381
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]
Protect from light.
Dispense in a tight, light-resistant container as defined in the USP using a child-
resistant closure. Exposure to light may cause slight discoloration. Discolored tablets should
not be dispensed. company logo
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.
REVISED MARCH 2016
FUR:R27
Reference ID: 3898381
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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custom-source
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2025-02-12T13:44:44.495263
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/018487s043lbl.pdf', 'application_number': 18487, 'submission_type': 'SUPPL ', 'submission_number': 43}
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11,233
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s
tructural formula
Propranolol hydrochloride extended-release capsules
Rx only
DESCRIPTION
Propranolol hydrochloride is a synthetic beta-adrenergic receptor-blocking agent chemically
described as 2-Propanol, 1-[(1-methylethyl)amino]-3-(1-naphthalenyloxy)-, hydrochloride,(±)-.
Its molecular and structural formulae are:
Propranolol hydrochloride is a stable, white, crystalline solid which is readily soluble in water
and ethanol. Its molecular weight is 295.80.
Propranolol hydrochloride extended-release capsules are formulated to provide a sustained
release of propranolol hydrochloride. Propranolol hydrochloride extended-release capsules are
available as 60 mg, 80 mg, 120 mg, and 160 mg capsules for oral administration.
The inactive ingredients contained in propranolol hydrochloride extended-release capsules are:
cellulose, ethylcellulose, gelatin capsules, hypromellose, and titanium dioxide. In addition,
propranolol hydrochloride extended-release capsules 60 mg, 80 mg, and 120 mg capsules contain
D&C Red No. 28 and FD&C Blue No. 1; propranolol hydrochloride extended-release capsules
160 mg capsules contain FD&C Blue No. 1.
These capsules comply with USP Dissolution Test 1.
CLINICAL PHARMACOLOGY
General
Propranolol is a nonselective, beta-adrenergic receptor-blocking agent possessing no other
autonomic nervous system activity. It specifically competes with beta-adrenergic receptor-
stimulating agents for available receptor sites. When access to beta-receptor sites is blocked by
propranolol, the chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation
are decreased proportionately. At dosages greater than required for beta blockade, propranolol
also exerts a quinidine-like or anesthetic-like membrane action, which affects the cardiac action
potential. The significance of the membrane action in the treatment of arrhythmias is uncertain.
Propranolol hydrochloride extended-release capsules should not be considered a simple mg-for
mg substitute for conventional propranolol and the blood levels achieved do not match (are lower
than) those of two to four times daily dosing with the same dose (see DOSAGE AND
ADMINISTRATION). When changing to propranolol hydrochloride extended-release capsules
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Reference ID: 2919382
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from conventional propranolol, a possible need for retitration upwards should be considered,
especially to maintain effectiveness at the end of the dosing interval. In most clinical settings,
however, such as hypertension or angina where there is little correlation between plasma levels
and clinical effect, propranolol hydrochloride extended-release capsules have been
therapeutically equivalent to the same mg dose of conventional propranolol hydrochloride
extended-release capsules as assessed by 24-hour effects on blood pressure and on 24-hour
exercise responses of heart rate, systolic pressure, and rate pressure product.
Mechanism of Action
The mechanism of the antihypertensive effect of propranolol has not been established. Among
the factors that may be involved in contributing to the antihypertensive action include:
(1) decreased cardiac output, (2) inhibition of renin release by the kidneys, and (3) diminution of
tonic sympathetic nerve outflow from vasomotor centers in the brain. Although total peripheral
resistance may increase initially, it readjusts to or below the pretreatment level with chronic use
of propranolol. Effects of propranolol on plasma volume appear to be minor and somewhat
variable.
In angina pectoris, propranolol generally reduces the oxygen requirement of the heart at any
given level of effort by blocking the catecholamine-induced increases in the heart rate, systolic
blood pressure, and the velocity and extent of myocardial contraction. Propranolol may increase
oxygen requirements by increasing left ventricular fiber length, end diastolic pressure, and
systolic ejection period. The net physiologic effect of beta-adrenergic blockade is usually
advantageous and is manifested during exercise by delayed onset of pain and increased work
capacity.
Propranolol exerts its antiarrhythmic effects in concentrations associated with beta-adrenergic
blockade, and this appears to be its principal antiarrhythmic mechanism of action. In dosages
greater than required for beta blockade, propranolol also exerts a quinidine-like or anesthetic-like
membrane action which affects the cardiac action potential. The significance of the membrane
action in the treatment of arrhythmias is uncertain.
The mechanism of the anti-migraine effect of propranolol has not been established.
Beta-adrenergic receptors have been demonstrated in the pial vessels of the brain.
PHARMACOKINETICS AND DRUG METABOLISM
Absorption
Propranolol is highly lipophilic and almost completely absorbed after oral administration.
However, it undergoes high first pass metabolism by the liver and on average, only about 25% of
propranolol reaches the systemic circulation. Propranolol hydrochloride extended-release
capsules (60, 80, 120, and 160 mg) release propranolol HCl at a controlled and predictable rate.
Peak blood levels following dosing with propranolol hydrochloride extended-release capsules
occur at about 6 hours.
The effect of food on propranolol hydrochloride extended-release capsules bioavailability has
not been investigated.
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Distribution
Approximately 90% of circulating propranolol is bound to plasma proteins (albumin and
alpha-1-acid glycoprotein). The binding is enantiomer-selective. The S(–)-enantiomer is
preferentially bound to alpha-1-glycoprotein and the R(+)-enantiomer preferentially bound to
albumin. The volume of distribution of propranolol is approximately 4 liters/kg.
Propranolol crosses the blood-brain barrier and the placenta, and is distributed into breast milk.
Metabolism and Elimination
Propranolol is extensively metabolized with most metabolites appearing in the urine. Propranolol
is metabolized through three primary routes: aromatic hydroxylation (mainly 4-hydroxylation),
N-dealkylation followed by further side-chain oxidation, and direct glucuronidation. It has been
estimated that the percentage contributions of these routes to total metabolism are 42%, 41% and
17%, respectively, but with considerable variability between individuals. The four major
metabolites are propranolol glucuronide, naphthyloxylactic acid and glucuronic acid, and sulfate
conjugates of 4-hydroxy propranolol.
In-vitro studies have indicated that the aromatic hydroxylation of propranolol is catalyzed mainly
by polymorphic CYP2D6. Side-chain oxidation is mediated mainly by CYP1A2 and to some
extent by CYP2D6. 4-hydroxy propranolol is a weak inhibitor of CYP2D6.
Propranolol is also a substrate of CYP2C19 and a substrate for the intestinal efflux transporter,
p-glycoprotein (p-gp). Studies suggest however that p-gp is not dose-limiting for intestinal
absorption of propranolol in the usual therapeutic dose range.
In healthy subjects, no difference was observed between CYP2D6 extensive metabolizers (EMs)
and poor metabolizers (PMs) with respect to oral clearance or elimination half-life. Partial
clearance of 4-hydroxy propranolol was significantly higher and naphthyloxyactic acid was
significantly lower in EMs than PMs.
When measured at steady state over a 24-hour period the areas under the propranolol plasma
concentration-time curve (AUCs) for the propranolol hydrochloride extended-release capsules
are approximately 60% to 65% of the AUCs for a comparable divided daily dose of propranolol
hydrochloride extended-release capsules. The lower AUCs for the propranolol hydrochloride
extended-release capsules are due to greater hepatic metabolism of propranolol, resulting from
the slower rate of absorption of propranolol. Over a twenty-four (24) hour period, blood levels
are fairly constant for about twelve (12) hours, then decline exponentially. The apparent plasma
half-life is about 10 hours.
Enantiomers
Propranolol is a racemic mixture of two enantiomers, R(+) and S(–). The S(–)-enantiomer is
approximately 100 times as potent as the R(+)-enantiomer in blocking beta adrenergic receptors.
In normal subjects receiving oral doses of racemic propranolol, S(–)-enantiomer concentrations
exceeded those of the R(+)-enantiomer by 40-90% as a result of stereoselective hepatic
metabolism. Clearance of the pharmacologically active S(–)-propranolol is lower than R(+)
propranolol after intravenous and oral doses.
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Reference ID: 2919382
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Special Population
Geriatric
The pharmacokinetics of propranolol hydrochloride extended-release capsules have not been
investigated in patients over 65 years of age.
In a study of 12 elderly (62-79 years old) and 12 young (25-33 years old) healthy subjects, the
clearance of S-enantiomer of propranolol was decreased in the elderly. Additionally, the half-life
of both the R- and S-propranolol were prolonged in the elderly compared with the young
(11 hours vs. 5 hours).
Clearance of propranolol is reduced with aging due to decline in oxidation capacity (ring
oxidation and side chain oxidation). Conjugation capacity remains unchanged. In a study of 32
patients age 30 to 84 years given a single 20-mg dose of propranolol, an inverse correlation was
found between age and the partial metabolic clearances to 4-hydroxypropranolol (40HP ring
oxidation) and to naphthoxylactic acid (NLA-side chain oxidation). No correlation was found
between age and the partial metabolic clearance to propranolol glucuronide (PPLG conjugation).
Gender
In a study of 9 healthy women and 12 healthy men, neither the administration of testosterone nor
the regular course of the menstrual cycle affected the plasma binding of the propranolol
enantiomers. In contrast, there was a significant, although non-enantioselective diminution of the
binding of propranolol after treatment with ethinyl estradiol. These findings are inconsistent with
another study, in which administration of testosterone cypionate confirmed the stimulatory role
of this hormone on propranolol metabolism and concluded that the clearance of propranolol in
men is dependent on circulating concentrations of testosterone. In women, none of the metabolic
clearances for propranolol showed any significant association with either estradiol or
testosterone.
Race
A study conducted in 12 Caucasian and 13 African-American male subjects taking propranolol,
showed that at steady state, the clearance of R(+)- and S(–)-propranolol were about 76% and
53% higher in African-Americans than in Caucasians, respectively.
Chinese subjects had a greater proportion (18% to 45% higher) of unbound propranolol in
plasma compared to Caucasians, which was associated with a lower plasma concentration of
alpha-1-acid glycoprotein.
Renal Insufficiency
The pharmacokinetics of propranolol hydrochloride extended-release capsules have not been
investigated in patients with renal insufficiency.
In a study conducted in 5 patients with chronic renal failure, 6 patients on regular dialysis, and 5
healthy subjects, who received a single oral dose of 40 mg of propranolol, the peak plasma
concentrations (Cmax) of propranolol in the chronic renal failure group were 2 to 3-fold higher
(161±41 ng/mL) than those observed in the dialysis patients (47±9 ng/mL) and in the healthy
subjects (26±1 ng/mL). Propranolol plasma clearance was also reduced in the patients with
chronic renal failure.
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Reference ID: 2919382
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Studies have reported a delayed absorption rate and a reduced half-life of propranolol in patients
with renal failure of varying severity. Despite this shorter plasma half-life, propranolol peak
plasma levels were 3-4 times higher and total plasma levels of metabolites were up to 3 times
higher in these patients than in subjects with normal renal function.
Chronic renal failure has been associated with a decrease in drug metabolism via down
regulation of hepatic cytochrome P450 activity resulting in a lower “first-pass” clearance.
Propranolol is not significantly dialyzable.
Hepatic Insufficiency
The pharmacokinetics of propranolol hydrochloride extended-release capsules have not been
investigated in patients with hepatic insufficiency.
Propranolol is extensively metabolized by the liver. In a study conducted in 6 patients with
cirrhosis and 7 healthy subjects receiving 160 mg of a long-acting preparation of propranolol
once a day for 7 days, the steady-state propranolol concentration in patients with cirrhosis was
increased 2.5-fold in comparison to controls. In the patients with cirrhosis, the half-life obtained
after a single intravenous dose of 10 mg propranolol increased to 7.2 hours compared to
2.9 hours in control (see PRECAUTIONS).
Drug Interactions
All drug interaction studies were conducted with propranolol. There are no data on drug
interactions with propranolol hydrochloride extended-release capsules capsules.
Interactions with Substrates, Inhibitors or Inducers of Cytochrome P-450 Enzymes
Because propranolol’s metabolism involves multiple pathways in the Cytochrome P-450 system
(CYP2D6, 1A2, 2C19), co-administration with drugs that are metabolized by, or affect the
activity (induction or inhibition) of one or more of these pathways may lead to clinically relevant
drug interactions (see Drug Interactions under PRECAUTIONS).
Substrates or Inhibitors of CYP2D6
Blood levels and/or toxicity of propranolol may be increased by co-administration with
substrates or inhibitors of CYP2D6, such as amiodarone, cimetidine, delavudin, fluoxetine,
paroxetine, quinidine, and ritonavir. No interactions were observed with either ranitidine or
lansoprazole.
Substrates or Inhibitors of CYP1A2
Blood levels and/or toxicity of propranolol may be increased by co-administration with
substrates or inhibitors of CYP1A2, such as imipramine, cimetidine, ciprofloxacin, fluvoxamine,
isoniazid, ritonavir, theophylline, zileuton, zolmitriptan, and rizatriptan.
Substrates or Inhibitors of CYP2C19
Blood levels and/or toxicity of propranolol may be increased by co-administration with
substrates or inhibitors of CYP2C19, such as fluconazole, cimetidine, fluoxetine, fluvoxamine,
tenioposide, and tolbutamide. No interaction was observed with omeprazole.
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Reference ID: 2919382
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Inducers of Hepatic Drug Metabolism
Blood levels of propranolol may be decreased by co-administration with inducers such as
rifampin, ethanol, phenytoin, and phenobarbital. Cigarette smoking also induces hepatic
metabolism and has been shown to increase up to 77% the clearance of propranolol, resulting in
decreased plasma concentrations.
Cardiovascular Drugs
Antiarrhythmics
The AUC of propafenone is increased by more than 200% by co-administration of propranolol.
The metabolism of propranolol is reduced by co-administration of quinidine, leading to a two to
three fold increased blood concentration and greater degrees of clinical beta-blockade.
The metabolism of lidocaine is inhibited by co-administration of propranolol, resulting in a 25%
increase in lidocaine concentrations.
Calcium Channel Blockers
The mean Cmax and AUC of propranolol are increased respectively, by 50% and 30% by
co-administration of nisoldipine and by 80% and 47%, by co-administration of nicardipine.
The mean Cmax and AUC of nifedipine are increased by 64% and 79%, respectively, by
co-administration of propranolol.
Propranolol does not affect the pharmacokinetics of verapamil and norverapamil. Verapamil
does not affect the pharmacokinetics of propranolol.
Non-Cardiovascular Drugs
Migraine Drugs
Administration of zolmitriptan or rizatriptan with propranolol resulted in increased
concentrations of zolmitriptan (AUC increased by 56% and Cmax by 37%) or rizatriptan (the
AUC and Cmax were increased by 67% and 75%, respectively).
Theophylline
Co-administration of theophylline with propranolol decreases theophylline oral clearance by
30% to 52%.
Benzodiazepines
Propranolol can inhibit the metabolism of diazepam, resulting in increased concentrations of
diazepam and its metabolites. Diazepam does not alter the pharmacokinetics of propranolol.
The pharmacokinetics of oxazepam, triazolam, lorazepam, and alprazolam are not affected by
co-administration of propranolol.
Neuroleptic Drugs
Co-administration of long-acting propranolol at doses greater than or equal to 160 mg/day
resulted in increased thioridazine plasma concentrations ranging from 55% to 369% and
increased thioridazine metabolite (mesoridazine) concentrations ranging from 33% to 209%.
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Reference ID: 2919382
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Co-administration of chlorpromazine with propranolol resulted in a 70% increase in propranolol
plasma level.
Anti-Ulcer Drugs
Co-administration of propranolol with cimetidine, a non-specific CYP450 inhibitor, increased
propranolol AUC and Cmax by 46% and 35%, respectively. Co-administration with aluminum
hydroxide gel (1200 mg) may result in a decrease in propranolol concentrations.
Co-administration of metoclopramide with the long-acting propranolol did not have a significant
effect on propranolol’s pharmacokinetics.
Lipid Lowering Drugs
Co-administration of cholestyramine or colestipol with propranolol resulted in up to 50%
decrease in propranolol concentrations.
Co-administration of propranolol with lovastatin or pravastatin, decreased 18% to 23% the AUC
of both, but did not alter their pharmacodynamics. Propranolol did not have an effect on the
pharmacokinetics of fluvastatin.
Warfarin
Concomitant administration of propranolol and warfarin has been shown to increase warfarin
bioavailability and increase prothrombin time.
PHARMACODYNAMICS AND CLINICAL EFFECTS
Hypertension
In a retrospective, uncontrolled study, 107 patients with diastolic blood pressure
110 to 150 mmHg received propranolol 120 mg t.i.d. for at least 6 months, in addition to
diuretics and potassium, but with no other hypertensive agent. Propranolol contributed to control
of diastolic blood pressure, but the magnitude of the effect of propranolol on blood pressure
cannot be ascertained.
Four double-blind, randomized, crossover studies were conducted in a total of 74 patients with
mild or moderately severe hypertension treated with propranolol hydrochloride extended-release
capsules 160 mg once daily or propranolol 160 mg given either once daily or in two 80 mg
doses. Three of these studies were conducted over a 4-week treatment period. One study was
assessed after a 24-hour period. Propranolol hydrochloride extended-release capsules were as
effective as propranolol in controlling hypertension (pulse rate, systolic and diastolic blood
pressure) in each of these trials.
Angina Pectoris
In a double-blind, placebo-controlled study of 32 patients of both sexes, aged 32 to 69 years,
with stable angina, propranolol 100 mg t.i.d. was administered for 4 weeks and shown to be more
effective than placebo in reducing the rate of angina episodes and in prolonging total exercise
time.
Twelve male patients with moderately severe angina pectoris were studied in a double-blind,
crossover study. Patients were randomized to either Propranolol hydrochloride extended-release
capsules 160 mg daily or conventional propranolol 40 mg four times a day for 2 weeks.
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Nitroglycerine tablets were allowed during the study. Blood pressure, heart rate and ECG's were
recorded during serial exercise treadmill testing. Propranolol hydrochloride extended-release
capsules were as effective as conventional propranolol for exercise heart rate, systolic and
diastolic blood pressure, duration of anginal pain and ST-segment depression before or after
exercise, exercise duration, angina attack rate and nitroglycerine consumption.
In another double-blind, randomized, crossover trial, the effectiveness of propranolol
hydrochloride extended-release capsules 160 mg daily and conventional propranolol 40 mg four
times a day were evaluated in 13 patients with angina. ECG's were recorded while patients
exercised until angina developed. Propranolol hydrochloride extended-release capsules were as
effective as conventional propranolol for amount of exercise performed, ST-segment depression,
number of anginal attacks, amount of nitroglycerine consumed, systolic and diastolic blood
pressures and heart rate at rest and after exercise.
Migraine
In a 34-week, placebo-controlled, 4-period, dose-finding crossover study with a double-blind
randomized treatment sequence, 62 patients with migraine received propranolol 20 to 80 mg 3 or
4 times daily. The headache unit index, a composite of the number of days with headache and the
associated severity of the headache, was significantly reduced for patients receiving propranolol
as compared to those on placebo.
Hypertrophic Subaortic Stenosis
In an uncontrolled series of 13 patients with New York Heart Association (NYHA) class 2 or 3
symptoms and hypertrophic subaortic stenosis diagnosed at cardiac catheterization, oral
propranolol 40-80 mg t.i.d. was administered and patients were followed for up to 17 months.
Propranolol was associated with improved NYHA class for most patients.
INDICATIONS AND USAGE
Hypertension
Propranolol hydrochloride extended-release capsules are indicated in the management of
hypertension. It may be used alone or used in combination with other antihypertensive agents,
particularly a thiazide diuretic. Propranolol hydrochloride extended-release capsules is not
indicated in the management of hypertensive emergencies.
Angina Pectoris Due to Coronary Atherosclerosis
Propranolol hydrochloride extended-release capsules are indicated to decrease angina frequency
and increase exercise tolerance in patients with angina pectoris.
Migraine
Propranolol hydrochloride extended-release capsules are indicated for the prophylaxis of
common migraine headache. The efficacy of propranolol in the treatment of a migraine attack
that has started has not been established, and propranolol is not indicated for such use.
Hypertrophic Subaortic Stenosis
Propranolol hydrochloride extended-release capsules improve NYHA functional class in
symptomatic patients with hypertrophic subaortic stenosis.
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Reference ID: 2919382
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CONTRAINDICATIONS
Propranolol is contraindicated in 1) cardiogenic shock; 2) sinus bradycardia and greater than
first-degree block; 3) bronchial asthma; and 4) in patients with known hypersensitivity to
propranolol hydrochloride.
WARNINGS
Angina Pectoris
There have been reports of exacerbation of angina and, in some cases, myocardial
infarction, following abrupt discontinuance of propranolol therapy. Therefore, when
discontinuance of propranolol is planned, the dosage should be gradually reduced over at
least a few weeks, and the patient should be cautioned against interruption or cessation of
therapy without the physician's advice. If propranolol therapy is interrupted and
exacerbation of angina occurs, it usually is advisable to reinstitute propranolol therapy and
take other measures appropriate for the management of unstable angina pectoris. Since
coronary artery disease may be unrecognized, it may be prudent to follow the above advice
in patients considered at risk of having occult atherosclerotic heart disease who are given
propranolol for other indications.
Hypersensitivity and Skin Reactions
Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, have been associated
with the administration of propranolol (see ADVERSE REACTIONS).
Cutaneous reactions, including Stevens-Johnson Syndrome, toxic epidermal necrolysis,
exfoliative dermatitis, erythema multiforme, and urticaria, have been reported with use of
propranolol (see ADVERSE REACTIONS).
Cardiac Failure
Sympathetic stimulation may be a vital component supporting circulatory function in patients
with congestive heart failure, and its inhibition by beta blockade may precipitate more severe
failure. Although beta blockers should be avoided in overt congestive heart failure, some have
been shown to be highly beneficial when used with close follow-up in patients with a history of
failure who are well compensated and are receiving diuretics as needed. Beta-adrenergic
blocking agents do not abolish the inotropic action of digitalis on heart muscle.
In Patients without a History of Heart Failure, continued use of beta blockers can, in some
cases, lead to cardiac failure.
Nonallergic Bronchospasm (e.g., Chronic Bronchitis, Emphysema)
In general, patients with bronchospastic lung disease should not receive beta-blockers.
Propranolol should be administered with caution in this setting since it may provoke a bronchial
asthmatic attack by blocking bronchodilation produced by endogenous and exogenous
catecholamine stimulation of beta-receptors.
Major Surgery
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major
surgery, however the impaired ability of the heart to respond to reflex adrenergic stimuli may augment
the risks of general anesthesia and surgical procedures.
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Reference ID: 2919382
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Diabetes and Hypoglycemia
Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and
symptoms (pulse rate and pressure changes) of acute hypoglycemia, especially in labile insulin-
dependent diabetics. In these patients, it may be more difficult to adjust the dosage of insulin.
Propranolol therapy, particularly when given to infants and children, diabetic or not, has been
associated with hypoglycemia especially during fasting as in preparation for surgery.
Hypoglycemia has been reported in patients taking propranolol after prolonged physical exertion
and in patients with renal insufficiency.
Thyrotoxicosis
Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism. Therefore, abrupt
withdrawal of propranolol may be followed by an exacerbation of symptoms of hyperthyroidism,
including thyroid storm. Propranolol may change thyroid-function tests, increasing T4 and
reverse T3, and decreasing T3.
Wolff-Parkinson-White Syndrome
Beta-adrenergic blockade in patients with Wolff-Parkinson-White syndrome and tachycardia has
been associated with severe bradycardia requiring treatment with a pacemaker. In one case, this
result was reported after an initial dose of 5 mg propranolol.
PRECAUTIONS
General
Propranolol should be used with caution in patients with impaired hepatic or renal function.
Propranolol hydrochloride extended-release capsules are not indicated for the treatment of
hypertensive emergencies.
Beta-adrenergic receptor blockade can cause reduction of intraocular pressure. Patients should be
told that propranolol hydrochloride extended-release capsules may interfere with the glaucoma
screening test. Withdrawal may lead to a return of increased intraocular pressure.
While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of
allergens may be more reactive to repeated challenge, either accidental, diagnostic, or
therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat
allergic reaction.
Clinical Laboratory Tests
In patients with hypertension, use of propranolol has been associated with elevated levels of
serum potassium, serum transaminases, and alkaline phosphatase. In severe heart failure, the use
of propranolol has been associated with increases in Blood Urea Nitrogen.
Drug Interactions
Caution should be exercised when propranolol hydrochloride extended-release capsules are
administered with drugs that have an affect on CYP2D6, 1A2, or 2C19 metabolic pathways. Co
administration of such drugs with propranolol may lead to clinically relevant drug interactions
and changes on its efficacy and/or toxicity (see Drug Interactions in PHARMACOKINETICS
AND DRUG METABOLISM).
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Reference ID: 2919382
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Alcohol when used concomitantly with propranolol, may increase plasma levels of propranolol.
Cardiovascular Drugs
Antiarrhythmics
Propafenone has negative inotropic and beta-blocking properties that can be additive to those of
propranolol.
Quinidine increases the concentration of propranolol and produces greater degrees of clinical
beta-blockade and may cause postural hypotension.
Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be
additive to those seen with β-blockers such as propranolol.
The clearance of lidocaine is reduced with administration of propranolol. Lidocaine toxicity has
been reported following co-administration with propranolol.
Caution should be exercised when administering propranolol hydrochloride extended-release
capsules with drugs that slow A-V nodal conduction, e.g., lidocaine and calcium channel
blockers.
Digitalis Glycosides
Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart
rate. Concomitant use can increase the risk of bradycardia.
Calcium Channel Blockers
Caution should be exercised when patients receiving a beta-blocker are administered a calcium-
channel-blocking drug with negative inotropic and/or chronotropic effects. Both agents may
depress myocardial contractility or atrioventricular conduction.
There have been reports of significant bradycardia, heart failure, and cardiovascular collapse
with concurrent use of verapamil and beta-blockers.
Co-administration of propranolol and diltiazem in patients with cardiac disease has been
associated with bradycardia, hypotension, high degree heart block, and heart failure.
ACE Inhibitors
When combined with beta-blockers, ACE inhibitors can cause hypotension, particularly in the
setting of acute myocardial infarction.
The antihypertensive effects of clonidine may be antagonized by beta-blockers. Propranolol
hydrochloride extended-release capsules should be administered cautiously to patients
withdrawing from clonidine.
Alpha Blockers
Prazosin has been associated with prolongation of first dose hypotension in the presence of
beta-blockers.
11
Reference ID: 2919382
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Postural hypotension has been reported in patients taking both beta-blockers and terazosin or
doxazosin.
Reserpine
Patients receiving catecholamine-depleting drugs, such as reserpine should be closely observed
for excessive reduction of resting sympathetic nervous activity, which may result in hypotension,
marked bradycardia, vertigo, syncopal attacks, or orthostatic hypotension.
Inotropic Agents
Patients on long-term therapy with propranolol may experience uncontrolled hypertension if
administered epinephrine as a consequence of unopposed alpha-receptor stimulation.
Epinephrine is therefore not indicated in the treatment of propranolol overdose (see
OVERDOSAGE).
Isoproterenol and Dobutamine
Propranolol is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by
administration of such agents, e.g., dobutamine or isoproterenol. Also, propranolol may reduce
sensitivity to dobutamine stress echocardiography in patients undergoing evaluation for
myocardial ischemia.
Non-Cardiovascular Drugs
Nonsteroidal Anti-Inflammatory Drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to blunt the
antihypertensive effect of beta-adrenoreceptor blocking agents.
Administration of indomethacin with propranolol may reduce the efficacy of propranolol in
reducing blood pressure and heart rate.
Antidepressants
The hypotensive effects of MAO inhibitors or tricyclic antidepressants may be exacerbated when
administered with beta-blockers by interfering with the beta blocking activity of propranolol.
Anesthetic Agents
Methoxyflurane and trichloroethylene may depress myocardial contractility when administered
with propranolol.
Warfarin
Propranolol when administered with warfarin increases the concentration of warfarin.
Prothrombin time, therefore, should be monitored.
Neuroleptic Drugs
Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and
haloperidol.
Thyroxine
Thyroxine may result in a lower than expected T3 concentration when used concomitantly with
propranolol.
12
Reference ID: 2919382
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Carcinogenesis, Mutagenesis, Impairment of Fertility
In dietary administration studies in which mice and rats were treated with propranolol
hydrochloride for up to 18 months at doses of up to 150 mg/kg/day, there was no evidence of
drug-related tumorigenesis. On a body surface area basis, this dose in the mouse and rat is,
respectively, about equal to and about twice the maximum recommended human oral daily dose
(MRHD) of 640 mg propranolol hydrochloride. In a study in which both male and female rats
were exposed to propranolol hydrochloride in their diets at concentrations of up to 0.05% (about
50 mg/kg body weight and less than the MRHD), from 60 days prior to mating and throughout
pregnancy and lactation for two generations, there were no effects on fertility. Based on differing
results from Ames Tests performed by different laboratories, there is equivocal evidence for a
genotoxic effect of propranolol in bacteria (S. typhimurium strain TA 1538).
Pregnancy: Pregnancy Category C
In a series of reproductive and developmental toxicology studies, propranolol was given to rats
by gavage or in the diet throughout pregnancy and lactation. At doses of 150 mg/kg/day, but not
at doses of 80 mg/kg/day (equivalent to the MRHD on a body surface area basis), treatment was
associated with embryotoxicity (reduced litter size and increased resorption rates) as well as
neonatal toxicity (deaths). Propranolol hydrochloride also was administered (in the feed) to
rabbits (throughout pregnancy and lactation) at doses as high as 150 mg/kg/day (about 5 times
the maximum recommended human oral daily dose). No evidence of embryo or neonatal toxicity
was noted.
There are no adequate and well-controlled studies in pregnant women. Intrauterine growth
retardation, small placentas, and congenital abnormalities have been reported in neonates whose
mothers received propranolol during pregnancy. Neonates whose mothers are receiving
propranolol at parturition have exhibited bradycardia, hypoglycemia and/or respiratory
depression. Adequate facilities for monitoring such infants at birth should be available.
Propranolol hydrochloride extended-release capsules should be used during pregnancy only if
the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Propranolol is excreted in human milk. Caution should be exercised when propranolol
hydrochloride extended-release capsules are administered to a nursing woman.
Pediatric Use
Safety and effectiveness of propranolol in pediatric patients have not been established.
Bronchospasm and congestive heart failure have been reported coincident with the
administration of propranolol therapy in pediatric patients.
Geriatric Use
Clinical studies of propranolol hydrochloride extended-release capsules did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond differently from
younger subjects. Other reported clinical experience has not identified differences in responses
between the elderly and younger patients. In general, dose selection for an elderly patient should
be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency
13
Reference ID: 2919382
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
of the decreased hepatic, renal or cardiac function, and of concomitant disease or other drug
therapy.
ADVERSE REACTIONS
The following adverse events were observed and have been reported in patients using
propranolol.
Cardiovascular: Bradycardia; congestive heart failure; intensification of AV block;
hypotension; paresthesia of hands; thrombocytopenic purpura; arterial insufficiency, usually of
the Raynaud type.
Central Nervous System: Light-headedness; mental depression manifested by insomnia,
lassitude, weakness, fatigue; catatonia; visual disturbances; hallucinations; vivid dreams; an
acute reversible syndrome characterized by disorientation for time and place, short-term memory
loss, emotional lability, slightly clouded sensorium, and decreased performance on
neuropsychometrics. For immediate release formulations, fatigue, lethargy, and vivid dreams
appear dose related.
Gastrointestinal: Nausea, vomiting, epigastric distress, abdominal cramping, diarrhea,
constipation, mesenteric arterial thrombosis, ischemic colitis.
Allergic: Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions; pharyngitis
and agranulocytosis; erythematous rash; fever combined with aching and sore throat;
laryngospasm; respiratory distress.
Respiratory: Bronchospasm.
Hematologic: Agranulocytosis, nonthrombocytopenic purpura, and thrombocytopenic purpura.
Autoimmune: Systemic lupus erythematosus (SLE).
Skin and mucous membranes: Stevens-Johnson Syndrome, toxic epidermal necrolysis, dry
eyes, exfoliative dermatitis, erythema multiforme, urticaria, alopecia, SLE-like reactions, and
psoriasisiform rashes. Oculomucocutaneous syndrome involving the skin, serous membranes,
and conjunctivae reported for a beta-blocker (practolol) have not been associated with
propranolol.
Genitourinary: Male impotence; Peyronie's disease.
OVERDOSAGE
Propranolol is not significantly dialyzable. In the event of overdosage or exaggerated response,
the following measures should be employed:
General: If ingestion is or may have been recent, evacuate gastric contents, taking care to
prevent pulmonary aspiration.
Supportive Therapy: Hypotension and bradycardia have been reported following propranolol
overdose and should be treated appropriately. Glucagon can exert potent inotropic and
14
Reference ID: 2919382
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
chronotropic effects and may be particularly useful for the treatment of hypotension or depressed
myocardial function after a propranolol overdose. Glucagon should be administered as
50-150 mcg/kg intravenously followed by continuous drip of 1-5 mg/hour for positive
chronotropic effect. Isoproterenol, dopamine or phosphodiesterase inhibitors may also be useful.
Epinephrine, however, may provoke uncontrolled hypertension. Bradycardia can be treated with
atropine or isoproterenol. Serious bradycardia may require temporary cardiac pacing.
The electrocardiogram, pulse, blood pressure, neurobehavioral status and intake and output
balance must be monitored. Isoproterenol and aminophylline may be used for bronchospasm.
DOSAGE AND ADMINISTRATION
General
Propranolol hydrochloride extended-release capsules provide propranolol hydrochloride in a
sustained-release capsule for administration once daily. If patients are switched from propranolol
hydrochloride tablets to propranolol hydrochloride extended-release capsules, care should be
taken to assure that the desired therapeutic effect is maintained. Propranolol hydrochloride
extended-release capsules should not be considered a simple mg-for-mg substitute for
propranolol hydrochloride tablets. Propranolol hydrochloride extended-release capsules have
different kinetics and produces lower blood levels. Retitration may be necessary, especially to
maintain effectiveness at the end of the 24-hour dosing interval.
Hypertension
The usual initial dosage is 80 mg propranolol hydrochloride extended-release capsules once
daily, whether used alone or added to a diuretic. The dosage may be increased to 120 mg once
daily or higher until adequate blood pressure control is achieved. The usual maintenance dosage
is 120 to 160 mg once daily. In some instances a dosage of 640 mg may be required. The time
needed for full hypertensive response to a given dosage is variable and may range from a few
days to several weeks.
Angina Pectoris
Starting with 80 mg propranolol hydrochloride extended-release capsules once daily, dosage
should be gradually increased at three- to seven-day intervals until optimal response is obtained.
Although individual patients may respond at any dosage level, the average optimal dosage
appears to be 160 mg once daily. In angina pectoris, the value and safety of dosage exceeding
320 mg per day have not been established.
If treatment is to be discontinued, reduce dosage gradually over a period of a few weeks
(see “WARNINGS”).
Migraine
The initial oral dose is 80 mg propranolol hydrochloride extended-release capsules once daily.
The usual effective dose range is 160 to 240 mg once daily. The dosage may be increased
gradually to achieve optimal migraine prophylaxis. If a satisfactory response is not obtained
within four to six weeks after reaching the maximal dose, propranolol hydrochloride extended-
release capsules therapy should be discontinued. It may be advisable to withdraw the drug
gradually over a period of several weeks depending on the patient's age, comorbidity, and dose
of propranolol hydrochloride extended-release capsules.
15
Reference ID: 2919382
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For current labeling information, please visit https://www.fda.gov/drugsatfda
c
ompany logo
Hypertrophic Subaortic Stenosis
The usual dosage is 80 to 160 mg propranolol hydrochloride extended-release capsules once
daily.
HOW SUPPLIED
Propranolol hydrochloride extended-release capsules
Each white capsule, identified by 3 narrow bands, 1 wide band, and “AK 60,” contains 60 mg of
propranolol hydrochloride in bottles of 100 (NDC 43478-900-88).
Each white/light blue capsule, identified by 3 narrow bands, 1 wide band, and “AK 80,” contains
80 mg of propranolol hydrochloride in bottles of 100 (NDC 43478-901-88).
Each white/dark blue capsule, identified by 3 narrow bands, 1 wide band, and “AK 120,”
contains 120 mg of propranolol hydrochloride in bottles of 100 (NDC 43478-902-88).
Each dark blue/light blue capsule, identified by 3 narrow bands, 1 wide band, and “AK 160,”
contains 160 mg of propranolol hydrochloride in bottles of 100 (NDC 43478-903-88).
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).
[See USP Controlled Room Temperature]
Protect from light, moisture, freezing, and excessive heat.
Dispense in a tight, light-resistant container as defined in the USP.
This product’s label may have been updated. For current package insert and
further product information, please call our medical communications
department toll-free at 1-877-567-0862
490F001
Rev 12/10
16
Reference ID: 2919382
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|
custom-source
|
2025-02-12T13:44:44.688134
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018553s037lbl.pdf', 'application_number': 18553, 'submission_type': 'SUPPL ', 'submission_number': 37}
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11,232
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Rev. July 2005
Lozol®
(indapamide)
1.25 mg tablets
Rx only
DESCRIPTION
Lozol® (indapamide) is an oral antihypertensive/diuretic. Its molecule contains both a polar
sulfamoyl chlorobenzamide moiety and a lipid-soluble methylindoline moiety. It differs
chemically from the thiazides in that it does not possess the thiazide ring system and contains
only
one
sulfonamide
group.
The
chemical
name
of
Lozol
is
1-(4-chloro-3
sulfamoylbenzamido)-2-methylindoline, and its molecular weight is 365.84. The compound is a
weak acid, pKa=8.8, and is soluble in aqueous solutions of strong bases. It is a white to yellow-
white crystalline (tetragonal) powder. chemical structure of indapamide
The tablets also contain microcrystalline cellulose, coloring agent, corn starch, pregelatinized
starch, hypromellose, lactose, magnesium stearate, polyethylene glycol, and talc.
CLINICAL PHARMACOLOGY
Indapamide is the first of a new class of antihypertensive/diuretics, the indolines. The oral
administration of 2.5 mg (two 1.25 mg tablets) of indapamide to male subjects produced peak
concentrations of approximately 115 ng/mL of the drug in blood within two hours. The oral
administration of 5 mg (two 2.5 mg tablets) of indapamide to healthy male subjects produced
peak concentrations of approximately 260 ng/mL of the drug in the blood within two hours. A
minimum of 70% of a single oral dose is eliminated by the kidneys and an additional 23% by the
gastrointestinal tract, probably including the biliary route. The half-life of Lozol in whole blood
is approximately 14 hours.
Lozol is preferentially and reversibly taken up by the erythrocytes in the peripheral blood. The
whole blood/plasma ratio is approximately 6:1 at the time of peak concentration and decreases to
3.5:1 at eight hours. From 71 to 79% of the Lozol in plasma is reversibly bound to plasma
proteins.
Lozol is an extensively metabolized drug, with only about 7% of the total dose administered,
recovered in the urine as unchanged drug during the first 48 hours after administration. The
urinary elimination of 14C-labeled indapamide and metabolites is biphasic with a terminal half-
life of excretion of total radioactivity of 26 hours.
In a parallel design double-blind, placebo controlled trial in hypertension, daily doses of
indapamide between 1.25 mg and 10.0 mg produced dose-related antihypertensive effects. Doses
of 5.0 and 10.0 mg were not distinguishable from each other although each was differentiated
from placebo and 1.25 mg indapamide. At daily doses of 1.25 mg, 5.0 mg and 10.0 mg, a mean
This label may not be the latest approved by FDA.
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decrease of serum potassium of 0.28, 0.61 and 0.76 mEq/L, respectively, was observed and uric
acid increased by about 0.69 mg/100 mL.
In other parallel design, dose-ranging clinical trials in hypertension and edema, daily doses of
indapamide between 0.5 and 5.0 mg produced dose-related effects. Generally, doses of 2.5 and
5.0 mg were not distinguishable from each other although each was differentiated from placebo
and from 0.5 or 1.0 mg indapamide. At daily doses of 2.5 and 5.0 mg a mean decrease of serum
potassium of 0.5 and 0.6 mEq/Liter, respectively, was observed and uric acid increased by about
1.0 mg/100 mL.
At these doses, the effects of indapamide on blood pressure and edema are approximately equal
to those obtained with conventional doses of other antihypertensive/diuretics.
In hypertensive patients, daily doses of 1.25, 2.5 and 5.0 mg of indapamide have no appreciable
cardiac inotropic or chronotropic effect. The drug decreases peripheral resistance, with little or
no effect on cardiac output, rate or rhythm. Chronic administration of indapamide to
hypertensive patients has little or no effect on glomerular filtration rate or renal plasma flow.
Lozol had an antihypertensive effect in patients with varying degrees of renal impairment,
although in general, diuretic effects declined as renal function decreased.
In a small number of controlled studies, Indapamide taken with other antihypertensive drugs
such as hydralazine, propranolol, guanethidine and methyldopa, appeared to have the additive
effect typical of thiazide-type diuretics.
INDICATIONS
Lozol is indicated for the treatment of hypertension, alone or in combination with other
antihypertensive drugs.
Lozol is also indicated for the treatment of salt and fluid retention associated with congestive
heart failure.
Usage in Pregnancy: The routine use of diuretics in an otherwise healthy woman is
inappropriate and exposes mother and fetus to unnecessary hazard (see PRECAUTIONS
below).
Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory
evidence that they are useful in the treatment of developed toxemia.
Edema during pregnancy may arise from pathological causes or from the physiologic and
mechanical consequences of pregnancy. Indapamide is indicated in pregnancy when edema is
due to pathologic causes, just as it is in the absence of pregnancy (however, see
PRECAUTIONS below). Dependent edema in pregnancy, resulting from restriction of venous
return by the expanded uterus, is properly treated through elevation of the lower extremities and
use of support hose; use of diuretics to lower intravascular volume in this case is illogical and
unnecessary. There is hypervolemia during normal pregnancy which is not harmful to either the
fetus or the mother (in the absence of cardiovascular disease), but which is associated with
edema, including generalized edema in the majority of pregnant women. If this edema produces
discomfort, increased recumbency will often provide relief. In rare instances, this edema may
cause extreme discomfort which is not relieved by rest. In these cases, a short course of diuretics
may provide relief and may be appropriate.
CONTRAINDICATIONS
Anuria.
Known hypersensitivity to indapamide or to other sulfonamide-derived drugs.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
WARNINGS
Severe cases of hyponatremia, accompanied by hypokalemia have been reported with
recommended doses of indapamide. This occurred primarily in elderly females. (See
PRECAUTIONS, Geriatric Use.) This appears to be dose related. Also, a large case-controlled
pharmacoepidemiology study indicates that there is an increased risk of hyponatremia with
indapamide 2.5 mg and 5 mg doses. Hyponatremia considered possibly clinically significant (<
125 mEq/L) has not been observed in clinical trials with the 1.25 mg dosage (see
PRECAUTIONS). Thus, patients should be started at the 1.25 mg dose and maintained at the
lowest possible dose. (See DOSAGE AND ADMINISTRATION.)
Hypokalemia occurs commonly with diuretics (see ADVERSE REACTIONS, hypokalemia),
and electrolyte monitoring is essential, particularly in patients who would be at increased risk
from hypokalemia, such as those with cardiac arrhythmias or who are receiving concomitant
cardiac glycosides.
In general, diuretics should not be given concomitantly with lithium because they reduce its renal
clearance and add a high risk of lithium toxicity. Read prescribing information for lithium
preparations before use of such concomitant therapy.
PRECAUTIONS
General: Hypokalemia, Hyponatremia, and Other Fluid and Electrolyte Imbalances: Periodic
determinations of serum electrolytes should be performed at appropriate intervals. In addition,
patients should be observed for clinical signs of fluid or electrolyte imbalance, such as
hyponatremia, hypochloremic alkalosis, or hypokalemia. Warning signs include dry mouth,
thirst, weakness, fatigue, lethargy, drowsiness, restlessness, muscle pains or cramps,
hypotension, oliguria, tachycardia, and gastrointestinal disturbance. Electrolyte determinations
are particularly important in patients who are vomiting excessively or receiving parenteral fluids,
in patients subject to electrolyte imbalance (including those with heart failure, kidney disease,
and cirrhosis), and in patients on a salt-restricted diet.
The risk of hypokalemia secondary to diuresis and natriuresis is increased when larger doses are
used, when the diuresis is brisk, when severe cirrhosis is present and during concomitant use of
corticosteroids or ACTH. Interference with adequate oral intake of electrolytes will also
contribute to hypokalemia. Hypokalemia can sensitize or exaggerate the response of the heart to
the toxic effects of digitalis, such as increased ventricular irritability.
Dilutional hyponatremia may occur in edematous patients; the appropriate treatment is restriction
of water rather than administration of salt, except in rare instances when the hyponatremia is life
threatening. However, in actual salt depletion, appropriate replacement is the treatment of choice.
Any chloride deficit that may occur during treatment is generally mild and usually does not
require specific treatment except in extraordinary circumstances as in liver or renal disease.
Thiazide-like diuretics have been shown to increase the urinary excretion of magnesium; this
may result in hypomagnesemia.
Hyperuricemia and Gout: Serum concentrations of uric acid increased by an average of 0.69
mg/100 mL in patients treated with indapamide 1.25 mg, and by an average of 1.0 mg/100 mL in
patients treated with indapamide 2.5 mg and 5.0 mg, and frank gout may be precipitated in
certain patients receiving indapamide (see ADVERSE REACTIONS below). Serum
concentrations of uric acid should, therefore, be monitored periodically during treatment.
Renal Impairment: Indapamide, like the thiazides, should be used with caution in patients with
severe renal disease, as reduced plasma volume may exacerbate or precipitate azotemia. If
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progressive renal impairment is observed in a patient receiving indapamide, withholding or
discontinuing diuretic therapy should be considered. Renal function tests should be performed
periodically during treatment with indapamide.
Impaired Hepatic Function: Indapamide, like the thiazides, should be used with caution in
patients with impaired hepatic function or progressive liver disease, since minor alterations of
fluid and electrolyte balance may precipitate hepatic coma.
Glucose Tolerance: Latent diabetes may become manifest and insulin requirements in diabetic
patients may be altered during thiazide administration. A mean increase in glucose of 6.47
mg/dL was observed in patients treated with indapamide 1.25 mg, which was not considered
clinically significant in these trials. Serum concentrations of glucose should be monitored
routinely during treatment with Lozol.
Calcium Excretion: Calcium excretion is decreased by diuretics pharmacologically related to
indapamide. After six to eight weeks of indapamide 1.25 mg treatment and in long-term studies
of hypertensive patients with higher doses of indapamide, however, serum concentrations of
calcium increased only slightly with indapamide. Prolonged treatment with drugs
pharmacologically related to indapamide may in rare instances be associated with hypercalcemia
and hypophosphatemia secondary to physiologic changes in the parathyroid gland; however, the
common complications of hyperparathyroidism, such as renal lithiasis, bone resorption, and
peptic ulcer, have not been seen. Treatment should be discontinued before tests for parathyroid
function are performed. Like the thiazides, indapamide may decrease serum PBI levels without
signs of thyroid disturbance.
Interaction With Systemic Lupus Erythematosus: Thiazides have exacerbated or activated
systemic lupus erythematosus and this possibility should be considered with indapamide as well.
Drug Interactions
Other Antihypertensives: Lozol may add to or potentiate the action of other antihypertensive
drugs. In limited controlled trials that compared the effect of indapamide combined with other
antihypertensive drugs with the effect of the other drugs administered alone, there was no
notable change in the nature or frequency of adverse reactions associated with the combined
therapy.
Lithium: See WARNINGS.
Post-Sympathectomy Patient: The antihypertensive effect of the drug may be enhanced in the
post-sympathectomized patient.
Norepinephrine: Indapamide, like the thiazides, may decrease arterial responsiveness to
norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent
for therapeutic use.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Both mouse and rat lifetime
carcinogenicity studies were conducted. There was no significant difference in the incidence of
tumors between the indapamide-treated animals and the control groups.
Pregnancy: Teratogenic Effects: Pregnancy Category B. Reproduction studies have been
performed in rats, mice and rabbits at doses up to 6,250 times the therapeutic human dose and
have revealed no evidence of impaired fertility or harm to the fetus due to Lozol® (indapamide).
Postnatal development in rats and mice was unaffected by pretreatment of parent animals during
gestation. There are, however, no adequate and well-controlled studies in pregnant women.
Moreover, diuretics are known to cross the placental barrier and appear in cord blood. Because
animal reproduction studies are not always predictive of human response, this drug should be
used during pregnancy only if clearly needed. There may be hazards associated with this use
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such as fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that
have occurred in the adult.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because most
drugs are excreted in human milk, if use of this drug is deemed essential, the patient should stop
nursing.
Pediatric Use: Safety and effectiveness of indapamide in pediatric patients have not been
established.
Geriatric Use:
Clinical studies of indapamide did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end
of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy.
Severe cases of hyponatremia, accompanied by hypokalemia have been reported with
recommended doses of indapamide in elderly females (see WARNINGS).
ADVERSE REACTIONS
Most adverse effects have been mild and transient.
The Clinical Adverse Reactions listed in Table 1 represent data from Phase II/III placebo-
controlled studies (306 patients given indapamide 1.25 mg). The Clinical Adverse Reactions
listed in Table 2 represent data from Phase II placebo-controlled studies and long-term controlled
clinical trials (426 patients given Lozol 2.5 mg or 5.0 mg). The reactions are arranged into two
groups: 1) a cumulative incidence equal to or greater than 5%; 2) a cumulative incidence less
than 5%. Reactions are counted regardless of relation to drug.
TABLE 1: Adverse Reactions from Studies of 1.25 mg
Incidence ≥ 5%
Incidence < 5%*
BODY AS A WHOLE
Headache
Infection
Pain
Back Pain
GASTROINTESTINAL SYSTEM
METABOLIC SYSTEM
CENTRAL NERVOUS SYSTEM
Dizziness
RESPIRATORY SYSTEM
Rhinitis
SPECIAL SENSES
Asthenia
Flu Syndrome
Abdominal Pain
Chest Pain
Constipation
Diarrhea
Dyspepsia
Nausea
Peripheral Edema
Nervousness
Hypertonia
Cough
Pharyngitis
Sinusitis
Conjunctivitis
*OTHER
All other clinical adverse reactions occurred at an incidence of <1%.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Approximately 4% of patients given indapamide 1.25 mg compared to 5% of the patients given
placebo discontinued treatment in the trials of up to eight weeks because of adverse reactions.
In controlled clinical trials of six to eight weeks in duration, 20% of patients receiving
indapamide 1.25 mg, 61% of patients receiving indapamide 5.0 mg, and 80% of patients
receiving indapamide 10.0 mg had at least one potassium value below 3.4 mEq/L. In the
indapamide 1.25 mg group, about 40% of those patients who reported hypokalemia as a
laboratory adverse event returned to normal serum potassium values without intervention.
Hypokalemia with concomitant clinical signs or symptoms occurred in 2% of patients receiving
indapamide 1.25 mg.
TABLE 2: Adverse Reactions from Studies of 2.5 mg and 5.0 mg
Incidence ≥ 5%
Incidence < 5%
CENTRAL NERVOUS SYSTEM/NEUROMUSCULAR
Headache
Dizziness
Fatigue, weakness, loss
of energy, lethargy, tiredness, or malaise
Muscle cramps or
spasm, or numbness of the extremities
Nervousness, tension,
anxiety, irritability, or agitation
GASTROINTESTINAL SYSTEM
CARDIOVASCULAR SYSTEM
GENITOURINARY SYSTEM
DERMATOLOGIC/ HYPERSENSITIVITY
OTHER
Lightheadedness
Drowsiness
Vertigo
Insomnia
Depression
Blurred Vision
Constipation
Nausea
Vomiting
Diarrhea
Gastric irritation
Abdominal pain or cramps
Anorexia
Orthostatic hypotension
Premature ventricular contractions
Irregular heart beat
Palpitations
Frequency of urination
Nocturia
Polyuria
Rash
Hives
Pruritus
Vasculitis
Impotence or reduced libido
Rhinorrhea
Flushing
Hyperuricemia
Hyperglycemia
Hyponatremia
Hypochloremia
Increase in serum urea nitrogen
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(BUN) or creatinine
Glycosuria
Weight loss
Dry mouth
Tingling of extremities
Because most of these data are from long-term studies (up to 40 weeks of treatment), it is
probable that many of the adverse experiences reported are due to causes other than the drug.
Approximately 10% of patients given indapamide discontinued treatment in long-term trials
because of reactions either related or unrelated to the drug.
Hypokalemia with concomitant clinical signs or symptoms occurred in 3% of patients receiving
indapamide 2.5 mg q.d. and 7% of patients receiving indapamide 5 mg q.d. In long-term
controlled clinical trials comparing the hypokalemic effects of daily doses of indapamide and
hydrochlorothiazide, however, 47% of patients receiving indapamide 2.5 mg, 72% of patients
receiving indapamide 5 mg, and 44% of patients receiving hydrochlorothiazide 50 mg had at
least one potassium value (out of a total of 11 taken during the study) below 3.5 mEq/L. In the
indapamide 2.5 mg group, over 50% of those patients returned to normal serum potassium values
without intervention.
In clinical trials of six to eight weeks, the mean changes in selected values were as shown in the
tables below.
Mean Changes from Baseline after 8 Weeks of Treatment – 1.25 mg
Indapamide
1.25 mg
(n=255-257)
Serum Electrolytes (mEq/L)
Potassium Sodium Chloride
Serum Uric Acid
(mg/dL)
BUN
(mg/dL)
– 0.28
– 0.63
– 2.60
0.69
1.46
Placebo
(n=263-266)
0.00
– 0.11
– 0.21
0.06
0.06
No patients receiving indapamide 1.25 mg experienced hyponatremia considered possibly
clinically significant (<125 mEq/L).
Indapamide had no adverse effects on lipids.
Mean Changes from Baseline after 40 Weeks of Treatment – 2.5 mg and 5.0 mg
Serum Electrolytes (mEq/L)
Potassium Sodium Chloride
Serum Uric Acid
(mg/dL)
BUN
(mg/dL)
Indapamide
2.5 mg (n=76)
Indapamide
5.0 mg (n=81)
– 0.4
– 0.6
– 3.6
– 0.6
– 0.7
– 5.1
0.7
1.1
– 0.1
1.4
The following reactions have been reported with clinical usage of Lozol: jaundice (intrahepatic
cholestatic jaundice), hepatitis, pancreatitis and abnormal liver function tests. These reactions
were reversible with discontinuance of the drug.
Also reported are erythema multiforme, Stevens-Johnson Syndrome, bullous eruptions, purpura,
photosensitivity, fever, pneumonitis, anaphylactic reactions, agranulocytosis, leukopenia,
thrombocytopenia
and
aplastic
anemia.
Other
adverse
reactions
reported
with
antihypertensive/diuretics are necrotizing angiitis, respiratory distress, sialadenitis, xanthopsia.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
OVERDOSAGE
Symptoms of overdosage include nausea, vomiting, weakness, gastrointestinal disorders and
disturbances of electrolyte balance. In severe instances, hypotension and depressed respiration
may be observed. If this occurs, support of respiration and cardiac circulation should be
instituted. There is no specific antidote. An evacuation of the stomach is recommended by
emesis and gastric lavage after which the electrolyte and fluid balance should be evaluated
carefully.
DOSAGE AND ADMINISTRATION
Hypertension: The adult starting indapamide dose for hypertension is 1.25 mg as a single daily
dose taken in the morning. If the response to 1.25 mg is not satisfactory after four weeks, the
daily dose may be increased to 2.5 mg taken once daily. If the response to 2.5 mg is not
satisfactory after four weeks, the daily dose may be increased to 5.0 mg taken once daily, but
adding another antihypertensive should be considered.
Edema of Congestive Heart Failure: The adult starting indapamide dose for edema of
congestive heart failure is 2.5 mg as a single daily dose taken in the morning. If the response to
2.5 mg is not satisfactory after one week, the daily dose may be increased to 5.0 mg taken once
daily.
If the antihypertensive response to indapamide is insufficient, Lozol may be combined with other
antihypertensive drugs, with careful monitoring of blood pressure. It is recommended that the
usual dose of other agents be reduced by 50% during initial combination therapy. As the blood
pressure response becomes evident, further dosage adjustments may be necessary.
In general, doses of 5.0 mg and larger have not appeared to provide additional effects on blood
pressure or heart failure, but are associated with a greater degree of hypokalemia. There is
minimal clinical trial experience in patients with doses greater than 5.0 mg once a day.
HOW SUPPLIED
Strength
Size
NDC 0075-
Color
Shape
Markings
1.25 mg
Bottles of 100
Bottles of 1000
0700-00
0700-99
Orange,
film-
coated
Octagon
Shaped
R
and
7
U.S. Pat. No. Des. 300,673.
Keep out of the reach of children.
Keep tightly closed. Store at Controlled Room Temperature 20 to 25°C (68 to 77°F) [see USP].
Avoid excessive heat. This product should be dispensed in a container with a child resistant cap.
Rev. July 2005
Aventis Pharmaceuticals Inc.
Bridgewater, NJ 08807 USA
©2005 Aventis Pharmaceuticals Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:44.721296
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018538s028lbl.pdf', 'application_number': 18538, 'submission_type': 'SUPPL ', 'submission_number': 28}
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11,231
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JANSSEN
PHARMACEUTICALS
NIZORAL
(KETOCONAZOLE)
TABLETS
WARNING:
NIZORAL® Tablets should be used only when other effective antifungal therapy is not
available or tolerated and the potential benefits are considered to outweigh the potential
risks.
Hepatotoxicity
Serious hepatotoxicity, including cases with a fatal outcome or requiring liver
transplantation has occurred with the use of oral ketoconazole. Some patients had no
obvious risk factors for liver disease. Patients receiving this drug should be informed by
the physician of the risk and should be closely monitored. See WARNINGS section.
QT Prolongation and Drug Interactions Leading to QT Prolongation
Co-administration of the following drugs with ketoconazole is contraindicated: dofetilide,
quinidine, pimozide, cisapride, methadone, disopyramide, dronedarone, ranolazine.
Ketoconazole can cause elevated plasma concentrations of these drugs and may prolong
QT intervals, sometimes resulting in life-threatening ventricular dysrhythmias such as
torsades de pointes. See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS:
Drug Interactions sections.
DESCRIPTION
NIZORAL is a synthetic broad-spectrum antifungal agent available in scored white
tablets, each containing 200 mg ketoconazole base for oral administration. Inactive
ingredients are colloidal silicon dioxide, corn starch, lactose, magnesium stearate,
microcrystalline cellulose, and povidone. Ketoconazole is cis-1- acetyl-4-[4-[[2-(2,4-
dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxyl]phenyl]
piperazine and has the following structural formula:
Reference ID: 3458324
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Ketoconazole is a white to slightly beige, odorless powder, soluble in acids, with a
molecular weight of 531.44.
CLINICAL PHARMACOLOGY
Pharmacokinetics
Absorption
Ketoconazole is a weak dibasic agent and thus requires acidity for dissolution and
absorption.
Mean peak plasma concentrations of approximately 3.5 µg/mL are reached within 1 to 2
hours, following oral administration of a single 200 mg dose taken with a meal. Oral
bioavailability is maximal when the tablets are taken with a meal.
Absorption of NIZORAL Tablets is reduced in subjects with reduced gastric acidity,
such as subjects taking medications known as acid neutralizing medicines (e.g. aluminum
hydroxide) and gastric acid secretion suppressors (e.g. H2-receptor antagonists, proton
pump inhibitors) or subjects with achlorhydria caused by certain diseases. (See Section
PRECAUTIONS: Drug Interactions.) Absorption of ketoconazole under fasted conditions
in these subjects is increased when NIZORAL Tablets are administered with an acidic
beverage (such as non-diet cola). After pretreatment with omeprazole, a proton pump
inhibitor, the bioavailability of a single 200-mg dose of ketoconazole under fasted
conditions was decreased to 17% of the bioavailability of ketoconazole administered
alone. When ketoconazole was administered with non-diet cola after pretreatment with
omeprazole, the bioavailability was 65% of that after administration of ketoconazole
alone.
Distribution
In vitro, the plasma protein binding is about 99% mainly to the albumin fraction.
Ketoconazole is widely distributed into tissues; however, only a negligible proportion
reaches the cerebrospinal fluid.
Metabolism
Following absorption from the gastrointestinal tract, NIZORAL is converted into several
inactive metabolites. In vitro studies have shown that CYP3A4 is the major enzyme
involved in the metabolism of ketoconazole. The major identified metabolic pathways are
oxidation and degradation of the imidazole and piperazine rings, by hepatic microsomal
enzymes. In addition, oxidative O-dealkylation and aromatic hydroxylation does occur.
Ketoconazole has not been demonstrated to induce its own metabolism.
Reference ID: 3458324
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Elimination
Elimination from plasma is biphasic with a half-life of 2 hours during the first 10 hours
and 8 hours thereafter.
Approximately 13% of the dose is excreted in the urine, of which 2 to 4% is unchanged
drug. The major route of excretion is through the bile into the intestinal tract with about
57% being excreted in the feces.
Special Populations
Patients with Hepatic or Renal Impairment
In patients with hepatic or renal impairment, the overall pharmacokinetics of
ketoconazole was not significantly different when compared with healthy subjects.
Pediatric Patients
Limited pharmacokinetic data are available on the use of NIZORAL Tablets in the
pediatric population.
Measurable ketoconazole plasma concentrations have been observed in pre-term infants
(single or daily doses of 3 to 10 mg/kg) and in pediatric patients 5 months of age and
older (daily doses of 3 to 13 mg/kg) when the drug was administered as a suspension,
tablet or crushed tablet. Limited data suggest that absorption may be greater when the
drug is administered as a suspension compared to a crushed tablet. Conditions that raise
gastric pH may lower or prevent absorption (See Section PRECAUTIONS: Drug
Interactions). Maximum plasma concentrations occurred 1 to 2 hours after dosing and
were in the same general range as those seen in adults who received a 200-400 mg dose.
Electrocardiogram
Pre-clinical electrophysiological studies have shown that ketoconazole inhibits the
rapidly activating component of the cardiac delayed rectifier potassium current, prolongs
the action potential duration, and may prolong the QTc interval. Data from some clinical
PK/PD studies and drug interaction studies suggest that oral dosing with ketoconazole at
200 mg twice daily for 3-7 days can result in an increase of the QTc interval: a mean
maximum increase of about 6 to 12 msec was seen at ketoconazole peak plasma
concentrations about 1-4 hours after ketoconazole administration.
MICROBIOLOGY
Mechanism of Action
Ketoconazole blocks the synthesis of ergosterol, a key component of the fungal cell
membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol
14α-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal
cell membrane. This results in an accumulation of methylated sterol precursors and a
Reference ID: 3458324
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depletion of ergosterol within the cell membrane thus weakening the structure and
function of the fungal cell membrane.
Activity In Vitro & In Vivo
NIZORAL Tablets are active against clinical infections with Blastomyces dermatitidis,
Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis.
INDICATIONS AND USAGE
NIZORAL® Tablets should be used only when other effective antifungal therapy is not
available or tolerated and the potential benefits are considered to outweigh the potential
risks.
NIZORAL (ketoconazole) Tablets are indicated for the treatment of the following
systemic fungal infections in patients who have failed or who are intolerant to other
therapies: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and
paracoccidioidomycosis. NIZORAL Tablets should not be used for fungal meningitis
because it penetrates poorly into the cerebrospinal fluid.
CONTRAINDICATIONS
Drug Interactions
Coadministration of a number of CYP3A4 substrates such as dofetilide, quinidine
cisapride and pimozide is contraindicated with NIZORAL Tablets. Coadministration
with ketoconazole can cause elevated plasma concentrations of these drugs and may
increase or prolong both therapeutic and adverse effects to such an extent that a
potentially serious adverse reaction may occur. For example, increased plasma
concentrations of some of these drugs can lead to QT prolongation and sometimes
resulting in life-threatening ventricular tachyarrhythmias including occurrences of
torsades de pointes, a potentially fatal arrhythmia. (See PRECAUTIONS: Drug
Interactions.)
Additionally, the following other drugs are contraindicated with NIZORAL® Tablets:
methadone, disopyramide, dronedarone, ergot alkaloids such as dihydroergotamine,
ergometrine, ergotamine, methylergometrine, irinotecan, lurasidone, oral midazolam,
alprazolam, triazolam, felodipine, nisoldipine, ranolazine, tolvaptan, eplerenone,
lovastatin, simvastatin and colchicine. (See PRECAUTIONS: Drug Interactions.)
Enhanced Sedation
Coadministration of NIZORAL® Tablets with oral midazolam, oral triazolam or
alprazolam has resulted in elevated plasma concentrations of these drugs. This may
potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or
chronic administration of these agents. Concomitant administration of NIZORAL®
Reference ID: 3458324
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Tablets with oral triazolam, oral midazolam or alprazolam is contraindicated. (See
PRECAUTIONS: Drug Interactions.)
Myopathy
Coadministration of CYP3A4 metabolized HMG-CoA reductase inhibitors such as
simvastatin, and lovastatin is contraindicated with NIZORAL® Tablets. (See
PRECAUTIONS: Drug Interactions.)
Ergotism
Concomitant administration of ergot alkaloids such as dihydroergotamine and ergotamine
with NIZORAL® Tablets is contraindicated. (See PRECAUTIONS: Drug Interactions.)
Liver Disease
The use of NIZORAL® Tablets is contraindicated in patients with acute or chronic liver
disease.
Hypersensitivity
NIZORAL is contraindicated in patients who have shown hypersensitivity to the drug.
WARNINGS
NIZORAL® Tablets should be used only when other effective antifungal therapy is not
available or tolerated and the potential benefits are considered to outweigh the potential
risks.
Hepatotoxicity
Serious hepatotoxicity, including cases with a fatal outcome or requiring liver
transplantation, has occurred with the use of oral ketoconazole. Some patients had no
obvious risk factors for liver disease. Serious hepatotoxicity was reported both by
patients receiving high doses for short treatment durations and by patients receiving low
doses for long durations.
The hepatic injury has usually, but not always, been reversible upon discontinuation of
NIZORAL® Tablets treatment. Cases of hepatitis have been reported in children.
At baseline, obtain laboratory tests (such as SGGT, alkaline phosphatase, ALT, AST,
total bilirubin (TBL), Prothrombin Time (PT), International Normalization Ratio (INR),
and testing for viral hepatitides). Patients should be advised against alcohol consumption
while on treatment. If possible, use of other potentially hepatotoxic drugs should be
avoided in patients receiving NIZORAL® Tablets.
Prompt recognition of liver injury is essential. During the course of treatment, serum
ALT should be monitored weekly for the duration of treatment. If ALT values increase to
Reference ID: 3458324
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For current labeling information, please visit https://www.fda.gov/drugsatfda
a level above the upper limit of normal or 30 percent above baseline, or if the patient
develops symptoms, ketoconazole treatment should be interrupted and a full set of liver
tests should be obtained. Liver tests should be repeated to ensure normalization of values.
Hepatotoxicity has been reported with restarting oral ketoconazole (rechallenge). If it is
decided to restart oral ketoconazole, monitor the patient frequently to detect any recurring
liver injury from the drug.
QT Prolongation and Drug Interactions Leading to QT Prolongation
Ketoconazole can prolong the QT interval. Co-administration of the following drugs with
ketoconazole is contraindicated: dofetilide, quinidine, pimozide, cisapride, methadone,
disopyramide, dronedarone, ranolazine. Ketoconazole can cause elevated plasma
concentrations of these drugs which may prolong the QT interval, sometimes resulting in
life-threatening ventricular dysrhythmias such as torsades de pointes.
Adrenal Insufficiency
NIZORAL® Tablets decrease adrenal corticosteroid secretion at doses of 400 mg and
higher. This effect is not shared with other azoles. The recommended dose of 200 mg -
400 mg daily should not be exceeded.
Adrenal function should be monitored in patients with adrenal insufficiency or with
borderline adrenal function and in patients under prolonged periods of stress (major
surgery, intensive care, etc.).
Adverse Reactions Associated with Unapproved Uses
Ketoconazole has been used in high doses for the treatment of advanced prostate cancer
and for Cushing’s syndrome when other treatment options have failed. The safety and
effectiveness of ketoconazole have not been established in these settings and the use of
ketoconazole for these indications is not approved by FDA.
In a clinical trial involving 350 patients with metastatic prostatic cancer, eleven deaths
were reported within two weeks of starting treatment with high doses of ketoconazole
tablets (1200 mg/day). It is not possible to ascertain from the information available
whether death was related to ketoconazole therapy or adrenal insufficiency in these
patients with serious underlying disease.
Hypersensitivity
Anaphylaxis has been reported after the first dose. Several cases of hypersensitivity
reactions including urticaria have also been reported.
Reference ID: 3458324
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PRECAUTIONS
General
NIZORAL Tablets have been demonstrated to lower serum testosterone. Once therapy
with NIZORAL Tablets has been discontinued, serum testosterone levels return to
baseline values. Testosterone levels are impaired with doses of 800 mg per day and
abolished by 1600 mg per day. Clinical manifestations of decreased testosterone
concentrations may include gynecomastia, impotence and oligospermia.
Information for Patients
Patients should be instructed to report any signs and symptoms which may suggest liver
dysfunction so that appropriate biochemical testing can be done. Such signs and
symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, abdominal
pain, jaundice, dark urine or pale stools (see WARNINGS section).
Drug Interactions
Ketoconazole is mainly metabolized through CYP3A4. Other substances that either share
this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics
of ketoconazole. Similarly, ketoconazole may modify the pharmacokinetics of other
substances that share this metabolic pathway. Ketoconazole is a potent CYP3A4 inhibitor
and a P-glycoprotein inhibitor. When using concomitant medication, the corresponding
label should be consulted for information on the route of metabolism and the possible
need to adjust dosages.
Interaction studies have only been performed in adults. The relevance of the results from
these studies in pediatric patients is unknown.
Drugs that may decrease ketoconazole plasma concentrations
Drugs that reduce the gastric acidity (e.g. acid neutralizing medicines such as aluminum
hydroxide, or acid secretion suppressors such as H2-receptor antagonists and proton pump
inhibitors) impair the absorption of ketoconazole from NIZORAL® Tablets. These drugs
should be used with caution when coadministered with NIZORAL® Tablets:
NIZORAL® Tablets should be administered with an acidic beverage (such as non-diet
cola) upon co-treatment with drugs reducing gastric acidity.
Acid neutralizing medicines (e.g. aluminum hydroxide) should be administered at
least 1 hour before or 2 hours after the intake of NIZORAL® Tablets.
Upon coadministration, the antifungal activity should be monitored and the
NIZORAL® Tablets dose increased as deemed necessary.
Reference ID: 3458324
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8
Coadministration of NIZORAL® Tablets with potent enzyme inducers of CYP3A4 may
decrease the bioavailability of ketoconazole to such an extent that efficacy may be
reduced. Examples include:
Antibacterials: isoniazid, rifabutin (see also under ‘Drugs that may have their plasma
concentrations increased’), rifampicin.
Anticonvulsants: carbamazepine (see also under ‘Drugs that may have their plasma
concentrations increased’), phenytoin.
Antivirals: efavirenz, nevirapine.
Therefore, administration of potent enzyme inducers of CYP3A4 with NIZORAL®
Tablets is not recommended. The use of these drugs should be avoided from 2 weeks
before and during treatment with NIZORAL® Tablets, unless the benefits outweigh the
risk of potentially reduced ketoconazole efficacy. Upon coadministration, the antifungal
activity should be monitored and the NIZORAL® Tablets dose increased as deemed
necessary.
Drugs that may increase ketoconazole plasma concentrations
Potent inhibitors of CYP3A4 (e.g. antivirals such as ritonavir, ritonavir-boosted darunavir
and ritonavir-boosted fosamprenavir) may increase the bioavailability of ketoconazole.
These drugs should be used with caution when coadministered with NIZORAL® Tablets.
Patients who must take NIZORAL® Tablets concomitantly with potent inhibitors of
CYP3A4 should be monitored closely for signs or symptoms of increased or prolonged
pharmacologic effects of ketoconazole, and the NIZORAL® Tablets dose should be
decreased as deemed necessary. When appropriate, ketoconazole plasma concentrations
should be measured.
Drugs that may have their plasma concentrations increased by ketoconazole
Ketoconazole can inhibit the metabolism of drugs metabolized by CYP3A4 and can
inhibit the drug transport by P-glycoprotein, which may result in increased plasma
concentrations of these drugs and/or their active metabolite(s) when they are
administered with ketoconazole. These elevated plasma concentrations may increase or
prolong both therapeutic and adverse effects of these drugs. CYP3A4-metabolized drugs
known to prolong the QT interval may be contraindicated with NIZORAL® Tablets, since
the combination may lead to ventricular tachyarrhythmias, including occurrences of
torsade de pointes, a potentially fatal arrhythmia.
Examples of drugs that may have their plasma concentrations increased by ketoconazole
presented by drug class with advice regarding coadministration with NIZORAL® Tablets:
Reference ID: 3458324
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Drug Class
Contraindicated
Not Recommended
Use with Caution
Comments
Under no circumstances
should
the
drug
be
coadministered
with
NIZORAL® Tablets, and up
to
one
week
after
discontinuation
of
treatment
with
ketoconazole.
The use of the drug should
be avoided during and up
to
one
week
after
discontinuation
of
treatment with NIZORAL®
Tablets, unless the benefits
outweigh the potentially
increased risks of side
effects. If coadministration
cannot be avoided, clinical
monitoring for signs or
symptoms of increased or
prolonged effects or side
effects of the interacting
drug is recommended, and
its
dosage
should
be
reduced or interrupted as
deemed necessary. When
appropriate,
plasma
concentrations should be
measured. The label of the
coadministered
drug
should be consulted for
information
on
dose
adjustment
and
adverse
effects.
Careful
monitoring
is
recommended
when
the
drug is coadministered with
NIZORAL® Tablets. Upon
coadministration, patients
should
be
monitored
closely
for
signs
or
symptoms of increased or
prolonged effects or side
effects of the interacting
drug, and its dosage should
be reduced as deemed
necessary.
When
appropriate,
plasma
concentrations should be
measured. The label of the
coadministered
drug
should be consulted for
information
on
dose
adjustment
and
adverse
effects.
Alpha Blockers
tamsulosin
Reference ID: 3458324
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Drug Class
Contraindicated
Not Recommended
Use with Caution
Comments
Analgesics
methadone
alfentanil,
buprenorphine IV and
sublingual,
fentanyl,
oxycodone,
sufentanil
Methadone: The potential increase in plasma concentrations
of methadone when coadministered with NIZORAL® Tablets
may increase the risk of serious cardiovascular events
including QT prolongation and torsade de pointes, or
respiratory
or
CNS
depression.
[See
CONTRAINDICATIONS.]
Fentanyl: The potential increase in plasma concentrations of
fentanyl when coadministered with NIZORAL® Tablets may
increase the risk of potentially fatal respiratory depression.
Sufentanil: No human pharmacokinetic data of an interaction
with ketoconazole are available. In vitro data suggest that
sufentanil is metabolized by CYP3A4 and so potentially
increased sufentanil plasma concentrations would be
expected when coadministered with NIZORAL® Tablets.
Antiarrhythmics
disopyramide,
dofetilide,
dronedarone,
quinidine
digoxin
Disopyramide, dofetilide, dronedarone, quinidine: The
potential increase in plasma concentrations of these drugs
when coadministered with ketoconazole may increase the
risk of serious cardiovascular events including QT
prolongation.
Digoxin: Rare cases of elevated plasma concentrations of
digoxin have been reported. It is not clear whether this was
due to the combination of therapy. It is, therefore, advisable
to monitor digoxin concentrations in patients receiving
ketoconazole.
Antibacterials
rifabutin
telithromycin
Rifabutin: see also under ‘Drugs that may decrease
ketoconazole plasma concentrations’.
Telithromycin: A multiple-dose interaction study with
ketoconazole showed that Cmax of telithromycin was
increased by 51% and AUC by 95%.
Reference ID: 3458324
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Drug Class
Contraindicated
Not Recommended
Use with Caution
Comments
Anticoagulants and
Antiplatelet Drugs
rivaroxaban
cilostazol,
coumarins,
dabigatran
Cilostazol: Concomitant administration of single doses of
cilostazol 100 mg and ketoconazole 400 mg approximately
doubled
cilostazol
concentrations
and
altered
(increase/decrease)
the
concentrations
of
the
active
metabolites of cilostazol.
Coumarins: Ketoconazole may enhance the anticoagulant
effect of coumarin-like drugs, thus the anticoagulant effect
should be carefully titrated and monitored.
Dabigatran: In patients with moderate renal impairment
(CrCL 50 mL/min to ≤ 80 mL/min), consider reducing the
dose of dabigatran to 75 mg twice daily when it is
coadministered with ketoconazole.
Anticonvulsants
carbamazepine
Carbamazepine: In vivo studies have demonstrated an
increase in plasma carbamazepine concentrations in subjects
concomitantly receiving ketoconazole. In addition, the
bioavailability of ketoconazole may be reduced by
carbamazepine.
Antidiabetics
repaglinide,
saxagliptin
Antihelmintics and
Antiprotozoals
praziquantel
Antimigraine Drugs
ergot alkaloids, such
as
dihydroergotamine,
ergometrine
(ergonovine),
ergotamine,
methylergometrine
(methylergonovine)
eletriptan
Ergot
alkaloids:
The
potential
increase
in
plasma
concentrations of ergot alkaloids when coadministered with
NIZORAL® Tablets may increase the risk of ergotism, i.e., a
risk for vasospasm potentially leading to cerebral ischemia
and/or ischemia of the extremities.
Eletriptan: Eletriptan should be used with caution with
ketoconazole, and specifically, should not be used within at
least 72 hours of treatment with ketoconazole.
Reference ID: 3458324
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Drug Class
Contraindicated
Not Recommended
Use with Caution
Comments
Antineoplastics
irinotecan
dasatinib,
lapatinib,
nilotinib
bortezomib,
busulphan,
docetaxel,
erlotinib,
imatinib,
ixabepilone,
paclitaxel,
trimetrexate,
vinca alkaloids
Irinotecan: The potential increase in plasma concentrations of
irinotecan when coadministered with NIZORAL® Tablets may
increase the risk of potentially fatal adverse events.
Docetaxel: In the presence of ketoconazole, the clearance of
docetaxel in cancer patients was shown to decrease by 50%.
Reference ID: 3458324
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Drug Class
Contraindicated
Not Recommended
Use with Caution
Comments
Antipsychotics,
Anxiolytics and
Hypnotics
alprazolam,
lurasidone,
oral midazolam,
pimozide,
triazolam
aripiprazole,
buspirone,
haloperidol,
midazolam IV,
quetiapine,
ramelteon,
risperidone
Alprazolam, midazolam, triazolam: Coadministration of
NIZORAL® Tablets with oral midazolam or triazolam, or
alprazolam may cause several-fold increases in plasma
concentrations of these drugs. This may potentiate and
prolong hypnotic and sedative effects, especially with
repeated dosing or chronic administration of these agents.
Pimozide: The potential increase in plasma concentrations of
pimozide when coadministered with NIZORAL® Tablets
may increase the risk of serious cardiovascular events
including QT prolongation and torsade de pointes.
Aripiprazole: Coadministration of ketoconazole (200 mg/day
for 14 days) with a 15 mg single dose of aripiprazole
increased the AUC of aripiprazole and its active metabolite
by 63% and 77%, respectively. The effect of a higher
ketoconazole dose (400 mg/day) has not been studied. When
ketoconazole is given concomitantly with aripiprazole, the
aripiprazole dose should be reduced to one-half of the
recommended dose.
Buspirone: Ketoconazole is expected to inhibit buspirone
metabolism and increase plasma concentrations of buspirone.
If a patient has been titrated to a stable dosage on buspirone,
a dose reduction of buspirone may be necessary to avoid
adverse events attributable to buspirone or diminished
anxiolytic activity.
Antivirals
indinavir,
maraviroc,
saquinavir
Beta Blockers
nadolol
Reference ID: 3458324
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Drug Class
Contraindicated
Not Recommended
Use with Caution
Comments
Calcium Channel
Blockers
felodipine,
nisoldipine
other
dihydropyridines,
verapamil
Calcium channel blockers can have a negative inotropic effect
which may be additive to those of ketoconazole. The potential
increase in plasma concentrations of calcium channel blockers
when co-administered with NIZORAL® Tablets may increase
the risk of edema and congestive heart failure.
Dihydropyridines:
Concomitant
administration
of
NIZORAL® Tablets may cause several-fold increases in
plasma concentrations of dihydropyridines.
Cardiovascular
Drugs, Miscellaneous
ranolazine
aliskiren,
bosentan
Ranolazine: The potential increase in plasma concentrations
of ranolazine when coadministered with NIZORAL® Tablets
may increase the risk of serious cardiovascular events
including QT prolongation.
Bosentan: Coadministration of bosentan 125 mg twice daily
and ketoconazole, increased the plasma concentrations of
bosentan by approximately 2-fold in normal volunteers. No
dose adjustment of bosentan is necessary, but patients should
be monitored for increased pharmacologic effects and
adverse reactions of bosentan.
Diuretics
eplerenone
The potential increase in plasma concentrations of eplerenone
when coadministered with NIZORAL® Tablets may increase
the risk of hyperkalemia and hypotension.
Gastrointestinal
Drugs
cisapride
aprepitant
Cisapride:
Oral
ketoconazole
potently
inhibits
the
metabolism of cisapride resulting in a mean eight-fold
increase in AUC of cisapride, which can lead to serious
cardiovascular events including QT prolongation.
Immunosuppressants
everolimus,
rapamycin (also
known as sirolimus),
temsirolimus
budesonide,
ciclesonide,
cyclosporine,
dexamethasone,
fluticasone,
methylprednisolone,
tacrolimus
Rapamycin (sirolimus): NIZORAL® Tablets 200 mg daily for
10 days increased the Cmax and AUC of a single 5-mg dose of
sirolimus by 4.3-fold and 10.9-fold, respectively in 23
healthy subjects.
Fluticasone: Coadministration of fluticasone propionate and
ketoconazole is not recommended unless the potential benefit
to the patient outweighs the risk of systemic corticosteroid
side effects.
Reference ID: 3458324
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
Drug Class
Contraindicated
Not Recommended
Use with Caution
Comments
Lipid Regulating
Drugs
lovastatin,
simvastatin
atorvastatin
The potential increase in plasma concentrations of
atorvastatin, lovastatin and simvastatin when coadministered
with NIZORAL® Tablets may increase the risk of skeletal
muscle toxicity, including rhabdomyolysis.
Respiratory Drugs
salmeterol
Urological Drugs
fesoterodine,
sildenafil,
solifenacin,
tadalafil,
tolterodine,
vardenafil
Vardenafil: A single dose of 5 mg of vardenafil should not be
exceeded when coadministered with ketoconazole.
Other
colchicine, in subjects
with renal or hepatic
impairment;
tolvaptan
colchicine
alcohol,
cinacalcet
Colchicine: The potential increase in plasma concentrations
of colchicine when coadministered with NIZORAL® Tablets
may increase the risk of potentially fatal adverse events.
Tolvaptan: Ketoconazole 200 mg administered with tolvaptan
increased tolvaptan exposure by 5-fold. Larger doses would
be expected to produce larger increases in tolvaptan
exposure. There is not adequate experience to define the dose
adjustment that would be needed to allow safe use of
tolvaptan
with
strong
CYP3A
inhibitors
such
as
ketoconazole.
Alcohol: Exceptional cases have been reported of a
disulfiram-like reaction to alcohol, characterized by flushing,
rash, peripheral edema, nausea and headache. All symptoms
completely resolved within a few hours.
Reference ID: 3458324
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Carcinogenesis, Mutagenesis, Impairment of Fertility
Ketoconazole did not show any signs of mutagenic potential when evaluated using the
dominant lethal mutation test or the Ames Salmonella microsomal activator assay.
Ketoconazole was not carcinogenic in an 18-month, oral study in Swiss albino mice or a
24-month oral carcinogenicity study in Wistar rats at dose levels of 5, 20 and 80
mg/kg/day. The high dose in these studies was approximately 1x (mouse) or 2x (rat) the
clinical dose in humans based on a mg/m2 comparison.
Pregnancy
Teratogenic effects: Pregnancy Category C: Ketoconazole has been shown to be
teratogenic (syndactylia and oligodactylia) in the rat when given in the diet at
80 mg/kg/day (2 times the maximum recommended human dose, based on body surface
area comparisons). However, these effects may be related to maternal toxicity, evidence
of which also was seen at this and higher dose levels.
There are no adequate and well controlled studies in pregnant women. NIZORAL
Tablets should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
Nonteratogenic Effects
Ketoconazole has also been found to be embryotoxic in the rat when given in the diet at
doses higher than 80 mg/kg during the first trimester of gestation.
In addition, dystocia (difficult labor) was noted in rats administered oral ketoconazole
during the third trimester of gestation. This occurred when ketoconazole was
administered at doses higher than 10 mg/kg (about one fourth the maximum human dose,
based on body surface area comparison).
Nursing Mothers
Ketoconazole has been shown to be excreted in the milk. Mothers who are under
treatment with NIZORAL® Tablets should not breast feed.
Pediatric Use
NIZORAL Tablets have not been systematically studied in children of any age, and
essentially no information is available on children under 2 years. NIZORAL Tablets
should not be used in pediatric patients unless the potential benefit outweighs the risks.
Reference ID: 3458324
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ADVERSE REACTIONS
Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates observed in practice.
The following adverse reactions were reported in clinical trials:
Immune System Disorders: anaphylactoid reaction
Endocrine Disorders: gynecomastia
Metabolism and Nutrition Disorders: alcohol intolerance, anorexia, hyperlipidemia,
increased appetite
Psychiatric Disorders: insomnia, nervousness
Nervous System Disorders: headache, dizziness, paresthesia, somnolence
Eye Disorders: photophobia
Vascular Disorders: orthostatic hypotension
Respiratory, Thoracic and Mediastinal Disorders: epistaxis
Gastrointestinal Disorders: vomiting, diarrhea, nausea, constipation, abdominal pain,
abdominal pain upper, dry mouth, dysgeusia, dyspepsia, flatulence, tongue discoloration
Hepatobiliary Disorders: hepatitis, jaundice, hepatic function abnormal
Skin and Subcutaneous Tissues Disorders: erythema multiforme, rash, dermatitis,
erythema, urticaria, pruritus, alopecia, xeroderma
Musculoskeletal and Connective Tissue Disorders: myalgia
Reproductive System and Breast Disorders: menstrual disorder
General Disorders and Administration Site Conditions: asthenia, fatigue, hot flush,
malaise, edema peripheral, pyrexia, chills
Investigations: platelet count decreased.
Post-Marketing Experience
The following adverse reactions have been identified during postapproval use of
NIZORAL® Tablets. Because these reactions are reported voluntarily from a population
of uncertain size, it is not always possible to reliably estimate their frequency or establish
a causal relationship to drug exposure.
Reference ID: 3458324
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The following adverse reactions were reported during post-marketing experience:
Blood and Lymphatic System Disorders: thrombocytopenia
Immune System Disorders: allergic conditions including anaphylactic shock, anaphylactic
reaction, angioneurotic edema
Endocrine Disorders: adrenocortical insufficiency
Nervous System Disorders: reversible intracranial pressure increased (e.g. papilloedema,
fontanelle bulging in infants)
Hepatobiliary Disorders: serious hepatotoxicity including hepatitis cholestatic, biopsy-
confirmed hepatic necrosis, cirrhosis, hepatic failure including cases resulting in
transplantation or death
Skin and Subcutaneous Tissue Disorders: acute generalized exanthematous pustulosis,
photosensitivity
Musculoskeletal and Connective Tissue Disorders: arthralgia
Reproductive System and Breast Disorders: erectile dysfunction; with doses higher than
the recommended therapeutic dose of 200 or 400mg daily, azoospermia.
OVERDOSAGE
In the event of acute accidental overdose, treatment consists of supportive and
symptomatic measures. Within the first hour after ingestion, activated charcoal may be
administered.
DOSAGE AND ADMINISTRATION
There should be laboratory as well as clinical documentation of infection prior to starting
ketoconazole therapy. The usual duration of therapy for systemic infection is 6 months.
Treatment should be continued until active fungal infection has subsided.
Adults
The recommended starting dose of NIZORAL (ketoconazole) Tablets is a single daily
administration of 200 mg (one tablet). If clinical responsiveness is insufficient within the
expected time, the dose of NIZORAL Tablets may be increased to 400 mg (two tablets)
once daily.
Reference ID: 3458324
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Children
In small numbers of children over 2 years of age, a single daily dose of 3.3 to 6.6 mg/kg
has been used. NIZORAL Tablets have not been studied in children under 2 years of
age.
HOW SUPPLIED
NIZORAL (ketoconazole) is available as white, scored tablets containing 200 mg of
ketoconazole debossed “JANSSEN” and on the reverse side debossed “NIZORAL”.
They are supplied in bottles of 100 tablets (NDC 50458-220-10).
Store at controlled room temperature 15°-25°C (59°-77°F).
Protect from moisture.
Keep out of reach of children.
Rev. PENDING
Janssen Pharmaceuticals, Inc,
Titusville, New Jersey 08560
Janssen Pharmaceuticals, Inc, 2014
___________________________
Reference ID: 3458324
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEDICATION GUIDE
NIZORAL®
(ketoconazole)
Tablets
What is the most important information I should know about NIZORAL® Tablets?
NIZORAL® Tablets is not the only medicine available to treat fungal infections and
should only be used when other medicines are not right for you. Talk to your healthcare
provider to find out if NIZORAL® Tablets are right for you.
NIZORAL® Tablets can cause serious side effects, including:
liver problems (hepatotoxicity). Some people who were treated with
ketoconazole the active ingredient in NIZORAL® Tablets, had serious liver
problems that led to death or the need for a liver transplant. Call your healthcare
provider right away if you have any of the following symptoms:
o loss of appetite or start losing weight (anorexia)
o nausea or vomiting
o feel tired
o stomach pain or tenderness
o dark urine or light colored stools
o yellowing of your skin or the whites of your eyes
o fever or rash
changes in the electrical activity of your heart called QT prolongation. QT
prolongation can cause irregular heart beats that can be life threatening. This
can happen when NIZORAL® Tablets are taken with certain medicines, such as
dofetilide, quinidine, pimozide, cisapride, methadone, disopyramide, dronedarone,
and ranolazine. Talk to your healthcare provider about other medicines you are taking
before you start taking NIZORAL® Tablets. Tell your healthcare provider right away
if you feel faint, lightheaded, dizzy, or feel your heart beating irregularly or fast.
These may be symptoms related to QT prolongation.
Reference ID: 3458324
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For current labeling information, please visit https://www.fda.gov/drugsatfda
What are NIZORAL® Tablets?
NIZORAL® Tablets are prescription medicine used to treat serious fungal infections
including: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and
paracoccidioidomycosis.
NIZORAL® Tablets are not for people with fungal nail infections.
NIZORAL® Tablets have not been approved for the treatment of advanced prostate
cancer or Cushing’s syndrome. The safety and efficacy have not been established.
NIZORAL® Tablets should only be used in children if prescribed by the healthcare
provider who has determined that the benefits outweigh the risks.
Who should not take NIZORAL® Tablets?
Do not take NIZORAL® Tablets if you:
o have liver problems
o take simvastatin, or lovastatin. NIZORAL® Tablets when taken with these
medicines may cause muscle problems.
o take eplerenone, dihydroergotamine, ergotamine, ergometrine (ergonovine),
methylergometrine (methylergonovine) or nisoldipine.
o take triazolam, midazolam, or alprazolam. Taking NIZORAL® Tablets with these
medicines may make you very drowsy and make your drowsiness last longer.
o are allergic to ketoconazole or any of the ingredients in NIZORAL® Tablets. See
the end of this Medication Guide for a complete list of ingredients in NIZORAL®
Tablets.
Before you take NIZORAL® Tablets, tell your healthcare provider if you:
have had an abnormal heart rhythm tracing (ECG) or anyone in your family have or
have had a heart problem called “congenital long QT syndrome”.
have adrenal insufficiency.
are pregnant or plan to become pregnant. It is not known if NIZORAL® Tablets will
harm your unborn baby.
are breastfeeding or plan to breastfeed. NIZORAL® Tablets can pass into your breast
milk. You and your healthcare provider should decide if you will take NIZORAL®
Reference ID: 3458324
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
22
Tablets or breastfeed. You should NOT do both.
Tell your healthcare provider about all the medicines you take, including prescription and
over-the-counter medicines, vitamins, and herbal supplements.
Using NIZORAL® Tablets with certain other medicines may affect each other. Using
NIZORAL® Tablets with other medicines can cause serious side effects.
How should I take NIZORAL® Tablets?
Take NIZORAL® 1 time each day.
Do not stop taking NIZORAL® Tablets without first talking to your healthcare
provider.
What should I avoid while taking NIZORAL® Tablets?
Do not drink alcohol while taking NIZORAL® Tablets.
What are the possible side effects of NIZORAL® Tablets?
NIZORAL® Tablets may cause serious side effects, including:
See “What is the most important information I should know about NIZORAL®
Tablets?”
adrenal insufficiency. Adrenal insufficiency is a condition in which the adrenal
glands do not make enough steroid hormones. NIZORAL® Tablets may cause adrenal
insufficiency if you take a high dose. Your healthcare provider will follow you
closely if you have adrenal insufficiency or if you are taking prednisone or other
similar medicines for long periods of time. Call your healthcare provider right away if
you have symptoms of adrenal insufficiency such as tiredness, weakness, dizziness,
nausea, and vomiting.
serious allergic reactions. Some people can have a serious allergic reaction to
NIZORAL® Tablets. Stop taking NIZORAL® Tablets and go to the nearest hospital
emergency room right away if you get a rash, itching, hives, fever, swelling of the
lips or tongue, chest pain, or have trouble breathing. These could be signs of a serious
allergic reaction.
muscle problems. Taking certain medicines with NIZORAL® Tablets may cause
muscle problems. See “Who should not take NIZORAL® Tablets?”
The most common side effects of NIZORAL® Tablets include nausea, headache,
Reference ID: 3458324
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
diarrhea, stomach pain, and abnormal liver function tests.
These are not all the possible side effects of NIZORAL® Tablets. For more information,
ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to
FDA at 1-800-FDA-1088.
How should I store NIZORAL® Tablets?
Store NIZORAL® Tablets at room temperature between 59°F to 77°F (15°C to 25°C).
Keep NIZORAL® Tablets dry.
General information about the safe and effective use of NIZORAL® Tablets.
Medications are sometimes prescribed for purposes other than those listed in a
Medication Guide. Do not use NIZORAL® Tablets for a condition for which it was not
prescribed. Do not give NIZORAL® Tablets to other people, even if they have the same
symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about NIZORAL®
Tablets.
If you would like more information, talk to your healthcare provider. You can ask your
pharmacist or healthcare provider for information about NIZORAL® Tablets that is
written for health professionals.
What are the ingredients in NIZORAL® Tablets?
Active ingredient: ketoconazole.
Inactive ingredients: colloidal silicon dioxide, corn starch, lactose, magnesium stearate,
microcrystalline cellulose, and povidone.
Janssen Pharmaceuticals, Inc., Titusville, New Jersey 08560, ©Janssen Pharmaceuticals, Inc. 2014
Issued: PENDING
This Medication Guide has been approved by the U.S. Food and Drug Administration
Reference ID: 3458324
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:44.767570
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018533s041lbl.pdf', 'application_number': 18533, 'submission_type': 'SUPPL ', 'submission_number': 41}
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HLR 052803
FANSIDAR
brand of
sulfadoxine and pyrimethamine
TABLETS
Rx only
WARNING: FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF
FANSIDAR HAVE OCCURRED DUE TO SEVERE REACTIONS, INCLUDING
STEVENS-JOHNSON SYNDROME AND TOXIC EPIDERMAL NECROLYSIS.
FANSIDAR PROPHYLAXIS MUST BE DISCONTINUED AT THE FIRST
APPEARANCE OF SKIN RASH, IF A SIGNIFICANT REDUCTION IN THE
COUNT OF ANY FORMED BLOOD ELEMENTS IS NOTED, OR UPON THE
OCCURRENCE OF ACTIVE BACTERIAL OR FUNGAL INFECTIONS.
DESCRIPTION
Fansidar is an antimalarial agent, each tablet containing 500 mg N1-(5,6-dimethoxy-4-
pyrimidinyl) sulfanilamide (sulfadoxine) and 25 mg 2,4-diamino-5-(p-chlorophenyl)-6-
ethylpyrimidine (pyrimethamine). Each tablet also contains cornstarch, gelatin, lactose,
magnesium stearate and talc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 052803
FANSIDAR (sulfadoxine and pyrimethamine)
CLINICAL PHARMACOLOGY
Microbiology
Mechanism of Action: Sulfadoxine and pyrimethamine, the constituents of Fansidar, are
folic acid antagonists. Sulfadoxine inhibits the activity of dihydropteroate synthase
whereas pyrimethamine inhibits dihydrofolate reductase.
Activity in vitro: Sulfadoxine and pyrimethamine are active against the asexual
erythrocytic stages of Plasmodium falciparum. Fansidar may also be effective against
strains of P. falciparum resistant to chloroquine.
Drug Resistance: Strains of P. falciparum with decreased susceptibility to sulfadoxine
and /or pyrimethamine can be selected in vitro or in vivo. P. falciparum malaria that is
clinically resistant to Fansidar occurs frequently in parts of Southeast Asia and South
America, and is also prevalent in East and Central Africa. Therefore, Fansidar should be
used with caution in these areas. Likewise, Fansidar may not be effective for treatment of
recrudescent malaria that develops after prior therapy (or prophylaxis) with Fansidar.
PHARMACOKINETICS
Absorption
After administration of 1 tablet, peak plasma levels for pyrimethamine (approximately
0.2 mg/L) and for sulfadoxine (approximately 60 mg/L) are reached after about 4 hours.
Distribution
The volume of distribution for sulfadoxine and pyrimethamine is 0.14 L/kg and 2.3 L/kg,
respectively.
Patients taking 1 tablet a week (recommended adult dose for malaria prophylaxis) can be
expected to have mean steady state plasma concentrations of about 0.15 mg/L for
pyrimethamine after about four weeks and about 98 mg/L for sulfadoxine after about
seven weeks. Plasma protein binding is about 90% for both pyrimethamine and
sulfadoxine. Both pyrimethamine and sulfadoxine cross the placental barrier and pass
into breast milk.
Metabolism
About 5% of sulfadoxine appears in the plasma as acetylated metabolite, about 2 to 3% as
the glucuronide. Pyrimethamine is transformed to several unidentified metabolites.
Elimination
A relatively long elimination half-life is characteristic of both components. The mean
values are about 100 hours for pyrimethamine and about 200 hours for sulfadoxine. Both
pyrimethamine and sulfadoxine are eliminated mainly via the kidneys.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 052803
FANSIDAR (sulfadoxine and pyrimethamine)
Characteristics in Patients
In malaria patients, single pharmacokinetic parameters may differ from those in healthy
subjects, depending on the population concerned. In patients with renal insufficiency,
delayed elimination of the components of Fansidar must be anticipated.
INDICATIONS AND USAGE
Treatment of Acute Malaria
Fansidar is indicated for the treatment of acute, uncomplicated P. falciparum malaria for
those patients in whom chloroquine resistance is suspected. However, strains of P.
falciparum (see CLINICAL PHARMACOLOGY: Microbiology) may be encountered
which have developed resistance to Fansidar, in which case alternative treatment should
be administered.
Prevention of Malaria
Malaria prophylaxis with Fansidar is not routinely recommended and should only be
considered for travelers to areas where chloroquine-resistant P. falciparum malaria is
endemic and sensitive to Fansidar, and when alternative drugs are not available or are
contraindicated (see CONTRAINDICATIONS). However, strains of P. falciparum may
be encountered which have developed resistance to Fansidar.
CONTRAINDICATIONS
• Repeated prophylactic use of Fansidar is contraindicated in patients with renal or
hepatic failure or with blood dyscrasias;
• Hypersensitivity to pyrimethamine, sulfonamides, or any other ingredient of Fansidar;
• Patients with documented megaloblastic anemia due to folate deficiency;
• Infants less than 2 months of age;
• Prophylactic use of Fansidar in pregnancy at term and during the nursing period.
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 052803
FANSIDAR (sulfadoxine and pyrimethamine)
WARNINGS
FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF FANSIDAR
HAVE OCCURRED DUE TO SEVERE REACTIONS, INCLUDING STEVENS-
JOHNSON SYNDROME AND TOXIC EPIDERMAL NECROLYSIS. FANSIDAR
PROPHYLAXIS MUST BE DISCONTINUED AT THE FIRST APPEARANCE
OF SKIN RASH, IF A SIGNIFICANT REDUCTION IN THE COUNT OF ANY
FORMED BLOOD ELEMENTS IS NOTED, OR UPON THE OCCURRENCE OF
ACTIVE BACTERIAL OR FUNGAL INFECTIONS.
Fatalities associated with the administration of sulfonamides, although rare, have
occurred due to severe reactions, including fulminant hepatic necrosis, agranulocytosis,
aplastic anemia and other blood dyscrasias. Fansidar prophylactic regimen has been
reported to cause leukopenia during a treatment of 2 months or longer. This leukopenia is
generally mild and reversible.
PRECAUTIONS
General
Oral Fansidar has not been evaluated for the treatment of cerebral malaria or other severe
manifestations of complicated malaria, including hyperparasitemia, pulmonary edema or
renal failure. Patients with severe malaria are not candidates for oral therapy. In the event
of recrudescent P. falciparum infections after treatment with Fansidar or failure of
chemoprophylaxis with Fansidar, patients should be treated with a different blood
schizonticide.
Fansidar should be given with caution to patients with impaired renal or hepatic function,
to those with possible folate deficiency and to those with severe allergy or bronchial
asthma. As with some sulfonamide drugs, in glucose-6-phosphate dehydrogenase-
deficient individuals, hemolysis may occur. Urinalysis with microscopic examination and
renal function tests should be performed during therapy of those patients who have
impaired renal function. Excessive sun exposure should be avoided.
Information for the Patient
Patients should be warned that at the first appearance of a skin rash, they should stop use
of Fansidar and seek medical attention immediately. Adequate fluid intake must be
maintained in order to prevent crystalluria and stone formation.
Patients should also be warned that the appearance of sore throat, fever, arthralgia, cough,
shortness of breath, pallor, purpura, jaundice or glossitis may be early indications of
serious disorders which require prophylactic treatment to be stopped and medical
treatment to be sought.
Females should be cautioned against becoming pregnant and should not breastfeed their
infants during Fansidar therapy or prophylactic treatment.
Patients should be warned to keep Fansidar out of reach of children.
Patients also should be advised:
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 052803
FANSIDAR (sulfadoxine and pyrimethamine)
• that malaria can be a life-threatening infection;
• that Fansidar is being prescribed to help prevent or treat this serious infection;
• that no chemoprophylactic regimen is 100% effective, and protective clothing, insect
repellents, and bednets are important components of malaria prophylaxis;
• to seek medical attention for any febrile illness that occurs after return from a
malarious area and inform their physician that they may have been exposed to
malaria;
• that in a small percentage of cases, patients are unable to take this medication because
of side effects, and it may be necessary to change medications;
• that when used as prophylaxis, the first dose of Fansidar should be taken 1 or 2 days
prior to arrival in an endemic area;
• that if the patient experiences any symptom that may affect the patient’s ability to
take this drug as prescribed, the physician should be contacted and alternative
antimalarial medication should be considered.
Laboratory Tests
Regularly scheduled complete blood counts, liver enzyme tests and analysis of urine for
crystalluria should be performed whenever Fansidar is administered for more than three
months.
Drug Interactions
There have been reports which may indicate an increase in incidence and severity of
adverse reactions when chloroquine is used with Fansidar as compared to the use of
Fansidar alone. Fansidar is compatible with quinine and with antibiotics. However,
antifolic drugs such as sulfonamides, trimethoprim, or trimethoprim-sulfamethoxazole
combinations should not be used while the patient is receiving Fansidar for antimalarial
prophylaxis. Fansidar has not been reported to interfere with antidiabetic agents.
If signs of folic acid deficiency develop, Fansidar should be discontinued. When recovery
of depressed platelets or white blood cell counts in patients with drug-induced folic acid
deficiency is too slow, folinic acid (leucovorin) may be administered in doses of 5-15 mg
intramuscularly daily for 3 days or longer.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Pyrimethamine was not found carcinogenic in female mice or in male and female rats.
The carcinogenic potential of pyrimethamine in male mice could not be assessed from the
study because of markedly reduced life-span. Pyrimethamine was found to be mutagenic
in laboratory animals and also in human bone marrow following 3 or 4 consecutive daily
doses totaling 200 mg to 300 mg. Pyrimethamine was not found mutagenic in the Ames
test. Testicular changes have been observed in rats treated with 105 mg/kg/day of
Fansidar and with 15 mg/kg/day of pyrimethamine alone. Fertility of male rats and the
ability of male or female rats to mate were not adversely affected at dosages of up to 210
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 052803
FANSIDAR (sulfadoxine and pyrimethamine)
mg/kg/day of Fansidar. The pregnancy rate of female rats was not affected following
their treatment with 10.5 mg/kg/day, but was significantly reduced at dosages of 31.5
mg/kg/day or higher, a dosage approximately 30 times the weekly human prophylactic
dose or higher.
Pregnancy
Teratogenic Effects: Pregnancy Category C. Fansidar has been shown to be teratogenic in
rats when given in weekly doses approximately 12 times the weekly human prophylactic
dose. Teratology studies with pyrimethamine plus sulfadoxine (1:20) in rats showed the
minimum oral teratogenic dose to be approximately 0.9 mg/kg pyrimethamine plus 18
mg/kg sulfadoxine. In rabbits, no teratogenic effects were noted at oral doses as high as
20 mg/kg pyrimethamine plus 400 mg/kg sulfadoxine.
There are no adequate and well-controlled studies in pregnant women. However, due to
the teratogenic effect shown in animals and because pyrimethamine plus sulfadoxine may
interfere with folic acid metabolism, Fansidar therapy should be used during pregnancy
only if the potential benefit justifies the potential risk to the fetus. Women of childbearing
potential who are traveling to areas where malaria is endemic should be warned against
becoming pregnant, and should be advised to practice contraception during prophylaxis
with Fansidar and for three months after the last dose.
Nonteratogenic Effects
See CONTRAINDICATIONS.
Nursing Mothers
See CONTRAINDICATIONS.
Pediatric Use
Fansidar should not be given to infants less than 2 months of age because of inadequate
development of the glucuronide-forming enzyme system.
Geriatric Use
Clinical studies of Fansidar did not include sufficient numbers of subjects aged 65 and
over to determine whether they respond differently from younger subjects. Other reported
clinical experience has not identified differences in responses between the elderly and
younger patients. In general, dose selection for an elderly patient should be cautious,
usually starting at the low end of the dosing range, reflecting the greater frequency of
decreased hepatic, renal or cardiac function, and of concomitant disease or other drug
therapy. This drug is known to be substantially excreted by the kidney, and the risk of
toxic reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care should be
taken in dose selection, and it may be useful to monitor renal function.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 052803
FANSIDAR (sulfadoxine and pyrimethamine)
ADVERSE REACTIONS
For completeness, all major reactions to sulfonamides and to pyrimethamine are included
below, even though they may not have been reported with Fansidar (see WARNINGS
and PRECAUTIONS: Information for the Patient).
Hematological Changes
Agranulocytosis, aplastic anemia, megaloblastic anemia, thrombocytopenia, leukopenia,
hemolytic
anemia,
purpura,
hypoprothrombinemia,
methemoglobinemia,
and
eosinophilia.
Skin and Miscellaneous Sites Allergic Reactions
Erythema multiforme, Stevens-Johnson syndrome, generalized skin eruptions, toxic
epidermal necrolysis, urticaria, serum sickness, pruritus, exfoliative dermatitis,
anaphylactoid reactions, periorbital edema, conjunctival and scleral injection,
photosensitization, arthralgia, allergic myocarditis, slight hair loss, Lyell’s syndrome, and
allergic pericarditis.
Gastrointestinal Reactions
Glossitis, stomatitis, nausea, emesis, abdominal pains, hepatitis, hepatocellular necrosis,
diarrhea, pancreatitis, feeling of fullness, and transient rise of liver enzymes.
Central Nervous System Reactions
Headache, peripheral neuritis, mental depression, convulsions, ataxia, hallucinations,
tinnitus, vertigo, insomnia, apathy, fatigue, muscle weakness, nervousness, and
polyneuritis.
Respiratory Reactions
Pulmonary infiltrates resembling eosinophilic or allergic alveolitis.
Genitourinary
Renal failure, interstitial nephritis, BUN and serum creatinine elevation, toxic nephrosis
with oliguria and anuria, and crystalluria.
Miscellaneous Reactions
Drug fever, chills, periarteritis nodosa and LE phenomenon have occurred.
The sulfonamides bear certain chemical similarities to some goitrogens, diuretics
(acetazolamide and the thiazides), and oral hypoglycemic agents. Diuresis and
hypoglycemia have occurred rarely in patients receiving sulfonamides. Cross-sensitivity
may exist with these agents. Rats appear to be especially susceptible to the goitrogenic
effects of sulfonamides, and long-term administration has produced thyroid malignancies
in the species.
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 052803
FANSIDAR (sulfadoxine and pyrimethamine)
OVERDOSAGE
Acute intoxication may be manifested by headache, nausea, anorexia, vomiting and
central nervous system stimulation (including convulsions), followed by megaloblastic
anemia, leukopenia, thrombocytopenia, glossitis and crystalluria. In acute intoxication,
emesis and gastric lavage followed by purges may be of benefit. The patient should be
adequately hydrated to prevent renal damage. The renal, hepatic, and hematopoietic
systems should be monitored for at least 1 month after an overdosage. If the patient is
having convulsions, the use of parenteral diazepam or a barbiturate is indicated. For
depressed platelet or white blood cell counts, folinic acid (leucovorin) should be
administered in a dosage of 5 mg to 15 mg intramuscularly daily for 3 days or longer.
DOSAGE AND ADMINISTRATION (See INDICATIONS AND USAGE)
The dosage should be swallowed whole, and not chewed, with plenty of fluids after a
meal.
Treatment of Acute Malaria
Adults
2 to 3 tablets taken as a single dose.
Pediatric patients
The dosage for treatment of malaria in
(>2 months to 18 years)
children is based upon body weight:
Weight (kg)
Number of Tablets Taken
as a Single Dose
>45
3
31 to 45
2
21 to 30
1 ½
11 to 20
1
5 to 10
½
Prevention of Malaria
The malaria risk must be carefully weighed against the risk of serious adverse drug
reactions (see INDICATIONS AND USAGE). If Fansidar is prescribed for prophylaxis,
it is important that the physician inquires about sulfonamide intolerance and points out
the risk and the need for immediate drug withdrawal if skin reactions do occur.
The first dose of Fansidar should be taken 1 or 2 days before arrival in an endemic area;
administration should be continued during the stay and for 4 to 6 weeks after return.
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 052803
FANSIDAR (sulfadoxine and pyrimethamine)
Once Every
Once Weekly
2 Weeks
Adults
1 tablet
2 tablets
Pediatric patients
The dosage for prevention of malaria in
(>2 months to 18 years)
children is based upon body weight:
Weight (kg)
Number of Tablets Taken
Once Weekly
>45
1 ½
31 to 45
1
21 to 30
¾
11 to 20
½
5 to 10
¼
Prophylaxis with Fansidar should not be continued for more than two years, since no
experience of more prolonged administration is available to date.
HOW SUPPLIED
Scored tablets, containing 500 mg sulfadoxine and 25 mg pyrimethamine — unit dose
packages of 25 (NDC-0004-0161-03). Imprint on tablets: FANSIDAR ((ROCHE LOGO))
ROCHE.
Manufactured by:
F. Hoffmann-La Roche Ltd.
Basel, Switzerland
Distributed by:
XXXXXXXX
Revised: XXXX XXXX
Copyright 1996-200X by Roche Laboratories Inc. All rights reserved.
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:44:44.908841
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/18557slr015_fansidar_lbl.pdf', 'application_number': 18557, 'submission_type': 'SUPPL ', 'submission_number': 15}
|
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
DEXTROSE INJECTION 20%, 30%, 40%, 50% and 70% safely and
effectively. See full prescribing information for DEXTROSE
INJECTION 20%, 30%, 40%, 50% and 70%.
DEXTROSE injection, for intravenous use
Initial U.S. Approval: 1940
----------------------------INDICATIONS AND USAGE---------------------------
Dextrose Injection 20%, 30%, 40%, 50% and 70%, mixed with amino acids or
other compatible intravenous fluids, is indicated as a source of calories for
patients requiring parenteral nutrition when oral or enteral nutrition is not
possible, insufficient or contraindicated (1)
----------------------DOSAGE AND ADMINISTRATION-----------------------
• Must be diluted with compatible intravenous fluids or used as admixture,
prior to administration. Not for direct intravenous infusion. (2.1)
• Only for slow intravenous infusion only into a: (2.1)
Central vein, if final dextrose concentration is greater than 5% or
osmolality is greater than 900 mOsm/L
Peripheral vein, if final dextrose concentration 5% or less and osmolality
is less than 900 mOsm/L
• Individualize dosage based on the patient’s clinical condition, body
weight, nutritional/fluid requirements, as well as additional energy given
orally/enterally (2.2)
• Discontinue infusion of concentrated dextrose solutions slowly and/or
administer 5% dextrose (2.3)
---------------------DOSAGE FORMS AND STRENGTHS----------------------
Injection: Single-dose, partial-fill, flexible containers with (3):
500 mL fill volume in 1000 mL flexible container:
• 20% (0.2 grams/mL): 20 grams of dextrose hydrous per 100 mL
• 30% (0.3 grams/mL): 30 grams of dextrose hydrous per 100 mL
• 40% (0.4 grams/mL): 40 grams of dextrose hydrous per 100 mL
• 50% (0.5 grams/mL): 50 grams of dextrose hydrous per 100 mL
• 70% (0.5 grams/mL): 70 grams of dextrose hydrous per 100 mL
1000 mL fill volume in 2000 mL flexible container:
• 50% (0.5 grams/mL): 50 grams of dextrose hydrous per 100 mL
---------------------------CONTRAINDICATIONS------------------------------
• Severe dehydration (4)
• Known allergy to corn or corn products (4)
-----------------------WARNINGS AND PRECAUTIONS------------------------
• Hyperglycemia or Hyperosmolar Hyperglycemic State: Monitor blood
glucose and administer insulin as needed (5.1)
• Hypersensitivity Reactions: monitor for signs and symptoms and
discontinue infusion if reactions occur (5.2)
• Risk of Infection: Monitor for signs and symptoms and laboratory
parameters (5.3)
• Refeeding Syndrome: monitory laboratory parameters (5.4)
• Vein Damage and Thrombosis: Administer solutions containing more than
5% dextrose as the final concentration or solutions with an osmolarity ≥
900 mOsm/L through a central vein (2.1, 5.5)
• Aluminum Toxicity: Dextrose Injection contains aluminum that may be
toxic. Patients with impaired renal function, and preterm infants, at higher
risk. Limit aluminum to less than 4 mcg/kg/day (5.6, 8.4)
• Parenteral Nutrition Associated Liver Disease: increased risk in patients
who receive parenteral nutrition for extended periods of time, especially
preterm infants; monitor liver function tests, if abnormalities occur
consider discontinuation or dosage reduction. (5.7, 8.4)
• Electrolyte Imbalance and Fluid Overload: monitor daily fluid balance,
blood electrolyte levels, correct as needed. (5.8, 8.4)
------------------------------ADVERSE REACTIONS-------------------------------
The most common adverse reactions are hyperosmolar syndrome, infection
both systemic and at the injection site, vein thrombosis or phlebitis, and
hypervolemia. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Hospira Inc.
at 1-800-441-4100, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
-----------------------USE IN SPECIFIC POPULATIONS------------------------
Pediatric Use: Increased risk of hypoglycemia/hyperglycemia; monitor serum
glucose concentrations. (8.4)
See 17 for PATIENT COUNSELING INFORMATION
Revised: 2/2016
_______________________________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1 Important Preparation and Administration Instructions
2.2 Dosing Considerations
2.3 Discontinuation of Dextrose Injection
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Hyperglycemia and Hyperosmolar Hyperglycemic State
5.2 Hypersensitivity Reactions
5.3 Risk of Infection
5.4 Refeeding Syndrome
5.5 Vein Damage and Thrombosis
5.6 Aluminum Toxicity
5.7 Risk of Parenteral Nutrition Associated Liver Disease
5.8 Fluid Overload and Electrolyte Imbalance
6
ADVERSE REACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
_______________________________________________________________________________________________________________________________________
Reference ID: 3888634
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
Dextrose Injection 20%, 30%, 40%, 50% and 70%, mixed with amino acids or other compatible
intravenous fluids, is indicated as a source of calories for patients requiring parenteral nutrition
when oral or enteral nutrition is not possible, insufficient, or contraindicated.
2
DOSAGE AND ADMINISTRATION
2.1
Important Preparation and Administration Instructions
Dextrose Injection is supplied in the following five strengths: 20%, 30%, 40%, 50% and 70%
[see How Supplied/Storage and Handling (16)]. Prior to administration, Dextrose Injection must
be diluted with other compatible intravenous fluids or used as an admixture with amino acids. It
is not for direct intravenous infusion.
Preparation Prior to Administration
• Because additives may be incompatible, evaluate all additions to the plastic container for
compatibility and stability of the resulting preparation. Consult with a pharmacist, if
available. If it is deemed advisable to introduce additives, use aseptic technique and mix
thoroughly.
• Inspect Dextrose Injection to ensure precipitates have not formed during the mixing or
addition of additives. Discard the bag if precipitates are observed. Some opacity of the
plastic container (due to moisture absorption during sterilization process) may be observed.
This is normal and does not affect the solution quality or safety. The opacity will diminish
gradually.
• Use promptly after admixing or dilution.
• For single use only; discard unused portion
Important Administration Instructions
• Set the vent to the closed position on a vented intravenous administration set to prevent air
embolism.
• Use a dedicated line without any connections to avoid air embolism.
• Prior to infusion, visually inspect the diluted dextrose solution for particulate matter. The
solution should be clear and there should be no precipitates. Do not administer unless
solution is clear and container is undamaged.
• The choice of a central or peripheral venous route of infusion should depend on the
osmolarity of the final infusate. Solutions with greater than 5% dextrose or with osmolarity
of greater than or equal to 900 mOsm/L must be infused through a central catheter [see
Warnings and Precautions (5.5)].
2.2
Dosing Information
Caution: Dextrose Injection is not for direct intravenous infusion. Prior to administration,
Dextrose Injection must be diluted with other compatible intravenous fluids or used as an
admixture with amino acids.
Individualize the dosage of Dextrose Injection based on the patient’s clinical condition (ability to
Reference ID: 3888634
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
adequately metabolize dextrose), body weight, nutritional and fluid requirements, as well as
additional energy given orally or enterally to the patient.
The administration rate should be governed, especially during the first few day of therapy, by the
patient’s tolerance to dextrose. Daily intake of amino acids and dextrose should be increased
gradually to the maximum required dose as indicated by frequent determinations of blood
glucose levels.
2.3 Discontinuation of Dextrose Injection
To reduce the risk of hypoglycemia, a gradual decrease in flow rate in the last hour of infusion
should be considered.
3
DOSAGE FORMS AND STRENGTHS
Dextrose Injection 20%, 30%, 40%, 50%, and 70% USP are sterile, non-pyrogenic, hypertonic
solutions of dextrose in single-dose, partial-fill, flexible containers.
500 mL fill volume in 1000 mL flexible container
• 20% (0.2 grams/mL): 20 grams of dextrose hydrous per 100 mL
• 30% (0.3 grams/mL): 30 grams of dextrose hydrous per 100 mL
• 40% (0.4 grams/mL): 40 grams of dextrose hydrous per 100 mL
• 50% (0.5 grams/mL): 50 grams of dextrose hydrous per 100 mL
• 70% (0.7 grams/mL): 70 grams of dextrose hydrous per 100 mL
1000 mL fill volume in 2000 mL flexible container
• 50% (0.5 grams/mL): 50 grams of dextrose hydrous per 100 mL
4
CONTRAINDICATIONS
The use of Dextrose Injection is contraindicated in patients:
• who are severely dehydrated as hypertonic dextrose solution can worsen the patient’s
hyperosmolar state.
• with known allergy to corn or corn products.
5
WARNINGS AND PRECAUTIONS
5.1 Hyperglycemia and Hyperosmolar Hyperglycemic State
The use of dextrose infusions in patients with diabetes mellitus or impaired glucose tolerance
may worsen hyperglycemia. Administration of dextrose at a rate exceeding the patient’s
utilization rate may lead to hyperglycemia, coma, and death. Patients with underlying confusion
and renal impairment who receive dextrose infusions, may be at greater risk of developing
hyperosmolar hyperglycemic state. Monitor blood glucose levels and treat hyperglycemia to
maintain optimum levels while administering Dextrose Injection. Insulin may be administered
or adjusted to maintain optimal blood glucose levels during Dextrose Injection administration.
5.2 Hypersensitivity Reactions
Hypersensitivity reactions including anaphylaxis have been reported with dextrose infusions.
Stop infusion immediately and treat patient accordingly if signs or symptoms of a
Reference ID: 3888634
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
hypersensitivity reaction develop. Signs or symptoms may include: tachypnea, dyspnea, hypoxia,
bronchospasm, tachycardia, hypotension, cyanosis, vomiting, nausea, headache, sweating,
dizziness, altered mentation, flushing, rash, urticaria, erythema, pyrexia, and chills.
Since the dextrose in Dextrose Injection is derived from corn, the product should not be used in
patients with known allergy to corn or corn products [see Contraindications (4)].
5.3 Risk of Infections
Patients who require parenteral nutrition are at high risk of infections because the nutritional
components of these solutions can support microbial growth. The risk of infection is increased
in patients with malnutrition-associated immunosuppression, hyperglycemia exacerbated by
dextrose infusion, long-term use and poor maintenance of intravenous catheters, or
immunosuppressive effects of other concomitant conditions, drugs, or other components of the
parenteral formulation (e.g., lipid emulsion).
To decrease the risk of infectious complications, ensure aseptic technique in catheter placement
and maintenance, as well as aseptic technique in the preparation and administration of the
nutritional formula.
Monitor for signs and symptoms (including fever and chills) of early infections, including
laboratory test results (including leukocytosis and hyperglycemia) and frequent checks of the
parenteral access device and insertion site for edema, redness and discharge.
5.4 Refeeding Syndrome
Refeeding severely undernourished patients may result in refeeding syndrome, characterized by
the intracellular shift of potassium, phosphorus, and magnesium as the patient becomes anabolic.
Thiamine deficiency and fluid retention may also develop. To prevent these complications,
monitor severely undernourished patients and slowly increase nutrient intakes.
5.5 Vein Damage and Thrombosis
Dextrose Injection is for admixture with amino acids or dilution with other compatible
intravenous fluids. It is not for direct intravenous infusion. Administer solutions containing
more than 5% dextrose or with an osmolarity of ≥ 900 mOsm/L through a central vein [see
Dosage and Administration (2.1)]. The infusion of hypertonic solutions into a peripheral vein
may result in vein irritation, vein damage, and/or thrombosis. The primary complication of
peripheral access is venous thrombophlebitis, which manifests as pain, erythema, tenderness or a
palpable cord. Remove the catheter as soon as possible, if thrombophlebitis develops.
5.6 Aluminum Toxicity
Dextrose Injection contains no more than 25 mcg/L of aluminum. However, with prolonged
parenteral administration in patients with renal impairment, the aluminum contained in Dextrose
Injection may reach toxic levels. Preterm infants are at greater risk because their kidneys are
immature, and they require large amounts of concomitant calcium and phosphate solutions that
contain aluminum. Patients with renal impairment, including preterm infants, who receive
parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day, accumulate aluminum at levels
Reference ID: 3888634
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
associated with central nervous system and bone toxicity. Tissue loading may occur at even
lower rates of administration of total parenteral nutrition products.
5. 7
Risk of Parenteral Nutrition Associated Liver Disease
Parenteral Nutrition Associated Liver Disease (PNALD) has been reported in patients who
receive parenteral nutrition for extended periods of time, especially preterm infants, and can
present as cholestasis or steatohepatitis. The exact etiology is not entirely clear and is likely
multifactorial. If Dextrose Injection-treated patients develop abnormal liver function tests
consider discontinuation or dosage reduction.
5.8
Electrolyte Imbalance and Fluid Overload
Electrolyte deficits, particularly in serum potassium and phosphate, may occur during prolonged
use of concentrated dextrose solutions.
Depending on the volume and rate of infusion, the intravenous administration of concentrated
dextrose solutions can cause fluid and/or solute overloading resulting in dilution of serum
electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of
dilutional states is inversely proportional to the electrolyte concentrations in the administered
solution. The risk of solute overload causing congested states with peripheral and pulmonary
edema is directly proportional to the electrolyte concentrations in the solution.
Monitor blood electrolyte levels, correct fluid and electrolyte imbalances, and administer
essential vitamins and minerals as needed.Monitor daily fluid balance.
6
ADVERSE REACTIONS
The following adverse reactions from voluntary reports or clinical studies have been reported
with Dextrose Injection. Because many of these reactions were reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure.
• Hyperglycemia and hyperosmolar hyperglycemic state [see Warnings and Precautions
(5.1)].
• Hypersensitivity reactions [see Warnings and Precautions (5.2)].
• Risk of infections [see Warnings and Precautions (5.3)].
• Refeeding syndrome [see Warnings and Precautions (5.4)].
• Vein damage and thrombosis [see Warnings and Precautions (5.5)].
• Aluminum toxicity [see Warnings and Precautions (5.6)].
• Risk of parenteral nutrition associated liver disease [see Warnings and Precautions
(5.7)].
• Electrolyte imbalance and fluid overload [see Warnings and Precautions (5.8)].
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
There are no data with Dextrose Injection in pregnant women. In addition, animal reproduction
studies have not been conducted with dextrose. In the U.S. general population, the estimated
Reference ID: 3888634
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2
to 4% and 15 to 20%, respectively.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
Consider parenteral nutrition in cases of severe maternal malnutrition where nutritional
requirements cannot be fulfilled by the enteral route because of the risks to the fetus
associated with severe malnutrition, including preterm delivery, low birth weight,
intrauterine growth restriction, congenital malformations, and perinatal mortality.
8.2
Lactation
There are no data regarding the presence of dextrose in human milk, the effects on a breastfed
infant, or the effects on milk production. The developmental and health benefits of breastfeeding
should be considered along with the mother’s clinical need for Dextrose Injection and any
potential adverse effects on the breastfed infant from Dextrose Injection or from the underlying
maternal condition.
8.4
Pediatric Use
Neonates, especially those born premature and with low birth weight are at increased risk of
developing hypo – or hyperglycemia and therefore need close monitoring during treatment with
intravenous glucose infusions to ensure adequate glycemic control in order to avoid potential
long term adverse effects. Hypoglycemia in the newborn can cause prolonged seizures, coma
and brain damage. Hyperglycemia has been associated with intraventricular hemorrhage, late
onset bacterial and fungal infection, retinopathy of prematurity, necrotizing enterocolitis,
bronchopulmonary dysplasia, prolonged length of hospital stay, and death. Plasma electrolyte
concentrations should be closely monitored in the pediatric population as this population may
have impaired ability to regulate fluids and electrolytes. In very low birth weight infants,
excessive or rapid administration of Dextrose Injection may result in increased serum osmolality
and possible intracerebral hemorrhage.
Because of immature renal function, preterm infants receiving prolonged treatment with
Dextrose Injection, may be at risk aluminum toxicity [see Warnings and Precautions (5.6)].
Patients, including pediatric patients, may be at risk for Parenteral Nutrition Associated Liver
Disease (PNALD) [see Warnings and Precautions (5.7)].
8.5
Geriatric Use
Clinical studies of Dextrose Injection did not include sufficient numbers of patients aged 65 and
over to determine whether they respond differently from other younger patients. Other reported
clinical experience has not identified differences in responses between the elderly and younger
patients.
10
OVERDOSAGE
An increased infusion rate of Dextrose Injection or administration of a concentrated dextrose
solution can cause hyperglycemia, hyperosmolality, and adverse effects on water and electrolyte
balance [see Warnings and Precautions (5.1, 5.8)].
Reference ID: 3888634
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Severe hyperglycemia and severe dilutional hyponatremia, and their complications, can be fatal.
Discontinue infusion and institute appropriate corrective measures in the event of overhydration
or solute overload during therapy, with particular attention to respiratory and cardiovascular
systems.
For current information on the management of poisoning or overdosage, contact the National
Poison Control Center at 1-800-222-1222 or www.poison.org.
11
DESCRIPTION
Dextrose Injection, USP 20%, 30%, 40%, 50% and 70% are sterile, nonpyrogenic, hypertonic
solutions of Dextrose, USP in Water for Injection in a polyvinylchloride flexible plastic
container for intravenous administration after appropriate admixture or dilution [see Dosage and
Administration (2.1)].
Partial-fill containers, designed to facilitate admixture or dilution to provide dextrose in various
concentrations, are available in various sizes. See Table 1 for the content and characteristics of
these concentrated solutions. The solutions contain no bacteriostatic, antimicrobial agent or
added buffer and are intended only for use as a single-dose injection following admixture or
dilution. The pH (range is 4.3 (3.2 to 6.5).
Water can permeate from inside the container into the overwrap but not in amounts sufficient to
affect the solution significantly.
Table 1. Contents and Characteristics of Dextrose Injection 20%, 30%, 40%, 50%, and
70%
Strength
Fill Volume
Amount of
Dextrose Hydrous
per Container
kcal*
per
Container
mOsmol
per liter
20% (0.2 grams/mL)
500 mL
100 grams
340
1009
30% (0.3 grams/mL)
500 mL
150 grams
510
1514
40% (0.4 grams/mL)
500 mL
200 grams
680
2018
50% (0.5 grams/mL)
500 mL
250 grams
850
2523
1000 mL
500 grams
1700
2523
70% (0.7 grams/mL)
500 mL
350 grams
1190
3532
*Caloric value calculated on the basis of 3.4 kcal/g of dextrose, hydrous.
Dextrose, USP is chemically designated D-glucose, monohydrate (C6H12O6 • H2O), a hexose
sugar freely soluble in water. The molecular weight of dextrose (D-glucose) monohydrate is
198.17. It has the following structural formula:
O
OH
CH2OH
OH
OH
OH
H2O
Reference ID: 3888634
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Water for Injection, USP is chemically designated H2O.
Dextrose Injection contains no more than 25 mcg/L of aluminum.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Dextrose Injection is used to supplement nutrition by providing glucose parenterally. Dextrose is
oxidized to carbon dioxide and water, yielding energy.
16
HOW SUPPLIED/STORAGE AND HANDLING
Dextrose Injection, 20%, 30%, 40%, 50%, and 70% USP are sterile hypertonic solutions of
dextrose supplied in single-dose, partial-fill flexible containers (see Tables 1 and 2) for
intravenous administration after appropriate admixture or dilution [see Dosage and
Administration (2.1)].
Do not remove container from the overwrap until intended for use.
Table 2: Strengths, Fill Volume, and NDC # of Dextrose Injection 20%, 30%, 40%, 50%,
and 70%
Strength
Fill
Volume
NDC#
20% (0.2 grams/mL)
500 mL
0409-7935-19
30% (0.3 grams/mL)
500 mL
0409-8004-15
40% (0.4 grams/mL)
500 mL
0409-7937-19
50% (0.5 grams/mL)
500 mL
0409-7936-19
1000 mL
0409-7936-29
70% (0.7 grams/mL)
500 mL
0409-7918-19
Use the product immediately after mixing and the introduction of additives.
Store between 20º C to 25° C (68º F to 77°F). [See USP controlled room temperature.]
Do not freeze.
17
PATIENT COUNSELING INFORMATION
Inform patients, caregivers, or home healthcare providers of the following risks of Dextrose
Injection:
• Hyperglycemia and hyperosmolar hyperglycemic state [see Warnings and Precautions
(5.1)]
• Hypersensitivity reactions [see Warnings and Precautions (5.2)]
• Risk of infection [see Warnings and Precautions (5.3)]
• Vein damage and thrombosis [see Warnings and Precautions (5.5)]
Reference ID: 3888634
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Aluminum toxicity [see Warnings and Precautions (5.6)]
• Risk of parenteral nutrition associated liver disease [see Warnings and Precautions (5.7)]
• Fluid overload and electrolyte imbalance [see Warnings and Precautions (5.8)]
EN-4133
Hospira, Inc., Lake Forest, IL 60045 USA
Reference ID: 3888634
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:45.174083
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/018561s057,018562s056,018563s057,018564s059,019345s044lbl.pdf', 'application_number': 18563, 'submission_type': 'SUPPL ', 'submission_number': 57}
|
11,237
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
DEXTROSE INJECTION 20%, 30%, 40%, 50% and 70% safely and
effectively. See full prescribing information for DEXTROSE
INJECTION 20%, 30%, 40%, 50% and 70%.
DEXTROSE injection, for intravenous use
Initial U.S. Approval: 1940
----------------------------INDICATIONS AND USAGE---------------------------
Dextrose Injection 20%, 30%, 40%, 50% and 70%, mixed with amino acids or
other compatible intravenous fluids, is indicated as a source of calories for
patients requiring parenteral nutrition when oral or enteral nutrition is not
possible, insufficient or contraindicated (1)
----------------------DOSAGE AND ADMINISTRATION-----------------------
• Must be diluted with compatible intravenous fluids or used as admixture,
prior to administration. Not for direct intravenous infusion. (2.1)
• Only for slow intravenous infusion only into a: (2.1)
Central vein, if final dextrose concentration is greater than 5% or
osmolality is greater than 900 mOsm/L
Peripheral vein, if final dextrose concentration 5% or less and osmolality
is less than 900 mOsm/L
• Individualize dosage based on the patient’s clinical condition, body
weight, nutritional/fluid requirements, as well as additional energy given
orally/enterally (2.2)
• Discontinue infusion of concentrated dextrose solutions slowly and/or
administer 5% dextrose (2.3)
---------------------DOSAGE FORMS AND STRENGTHS----------------------
Injection: Single-dose, partial-fill, flexible containers with (3):
500 mL fill volume in 1000 mL flexible container:
• 20% (0.2 grams/mL): 20 grams of dextrose hydrous per 100 mL
• 30% (0.3 grams/mL): 30 grams of dextrose hydrous per 100 mL
• 40% (0.4 grams/mL): 40 grams of dextrose hydrous per 100 mL
• 50% (0.5 grams/mL): 50 grams of dextrose hydrous per 100 mL
• 70% (0.5 grams/mL): 70 grams of dextrose hydrous per 100 mL
1000 mL fill volume in 2000 mL flexible container:
• 50% (0.5 grams/mL): 50 grams of dextrose hydrous per 100 mL
---------------------------CONTRAINDICATIONS------------------------------
• Severe dehydration (4)
• Known allergy to corn or corn products (4)
-----------------------WARNINGS AND PRECAUTIONS------------------------
• Hyperglycemia or Hyperosmolar Hyperglycemic State: Monitor blood
glucose and administer insulin as needed (5.1)
• Hypersensitivity Reactions: monitor for signs and symptoms and
discontinue infusion if reactions occur (5.2)
• Risk of Infection: Monitor for signs and symptoms and laboratory
parameters (5.3)
• Refeeding Syndrome: monitory laboratory parameters (5.4)
• Vein Damage and Thrombosis: Administer solutions containing more than
5% dextrose as the final concentration or solutions with an osmolarity ≥
900 mOsm/L through a central vein (2.1, 5.5)
• Aluminum Toxicity: Dextrose Injection contains aluminum that may be
toxic. Patients with impaired renal function, and preterm infants, at higher
risk. Limit aluminum to less than 4 mcg/kg/day (5.6, 8.4)
• Parenteral Nutrition Associated Liver Disease: increased risk in patients
who receive parenteral nutrition for extended periods of time, especially
preterm infants; monitor liver function tests, if abnormalities occur
consider discontinuation or dosage reduction. (5.7, 8.4)
• Electrolyte Imbalance and Fluid Overload: monitor daily fluid balance,
blood electrolyte levels, correct as needed. (5.8, 8.4)
------------------------------ADVERSE REACTIONS-------------------------------
The most common adverse reactions are hyperosmolar syndrome, infection
both systemic and at the injection site, vein thrombosis or phlebitis, and
hypervolemia. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Hospira Inc.
at 1-800-441-4100, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
-----------------------USE IN SPECIFIC POPULATIONS------------------------
Pediatric Use: Increased risk of hypoglycemia/hyperglycemia; monitor serum
glucose concentrations. (8.4)
See 17 for PATIENT COUNSELING INFORMATION
Revised: 2/2016
_______________________________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1 Important Preparation and Administration Instructions
2.2 Dosing Considerations
2.3 Discontinuation of Dextrose Injection
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Hyperglycemia and Hyperosmolar Hyperglycemic State
5.2 Hypersensitivity Reactions
5.3 Risk of Infection
5.4 Refeeding Syndrome
5.5 Vein Damage and Thrombosis
5.6 Aluminum Toxicity
5.7 Risk of Parenteral Nutrition Associated Liver Disease
5.8 Fluid Overload and Electrolyte Imbalance
6
ADVERSE REACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
_______________________________________________________________________________________________________________________________________
Reference ID: 3888634
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
Dextrose Injection 20%, 30%, 40%, 50% and 70%, mixed with amino acids or other compatible
intravenous fluids, is indicated as a source of calories for patients requiring parenteral nutrition
when oral or enteral nutrition is not possible, insufficient, or contraindicated.
2
DOSAGE AND ADMINISTRATION
2.1
Important Preparation and Administration Instructions
Dextrose Injection is supplied in the following five strengths: 20%, 30%, 40%, 50% and 70%
[see How Supplied/Storage and Handling (16)]. Prior to administration, Dextrose Injection must
be diluted with other compatible intravenous fluids or used as an admixture with amino acids. It
is not for direct intravenous infusion.
Preparation Prior to Administration
• Because additives may be incompatible, evaluate all additions to the plastic container for
compatibility and stability of the resulting preparation. Consult with a pharmacist, if
available. If it is deemed advisable to introduce additives, use aseptic technique and mix
thoroughly.
• Inspect Dextrose Injection to ensure precipitates have not formed during the mixing or
addition of additives. Discard the bag if precipitates are observed. Some opacity of the
plastic container (due to moisture absorption during sterilization process) may be observed.
This is normal and does not affect the solution quality or safety. The opacity will diminish
gradually.
• Use promptly after admixing or dilution.
• For single use only; discard unused portion
Important Administration Instructions
• Set the vent to the closed position on a vented intravenous administration set to prevent air
embolism.
• Use a dedicated line without any connections to avoid air embolism.
• Prior to infusion, visually inspect the diluted dextrose solution for particulate matter. The
solution should be clear and there should be no precipitates. Do not administer unless
solution is clear and container is undamaged.
• The choice of a central or peripheral venous route of infusion should depend on the
osmolarity of the final infusate. Solutions with greater than 5% dextrose or with osmolarity
of greater than or equal to 900 mOsm/L must be infused through a central catheter [see
Warnings and Precautions (5.5)].
2.2
Dosing Information
Caution: Dextrose Injection is not for direct intravenous infusion. Prior to administration,
Dextrose Injection must be diluted with other compatible intravenous fluids or used as an
admixture with amino acids.
Individualize the dosage of Dextrose Injection based on the patient’s clinical condition (ability to
Reference ID: 3888634
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
adequately metabolize dextrose), body weight, nutritional and fluid requirements, as well as
additional energy given orally or enterally to the patient.
The administration rate should be governed, especially during the first few day of therapy, by the
patient’s tolerance to dextrose. Daily intake of amino acids and dextrose should be increased
gradually to the maximum required dose as indicated by frequent determinations of blood
glucose levels.
2.3 Discontinuation of Dextrose Injection
To reduce the risk of hypoglycemia, a gradual decrease in flow rate in the last hour of infusion
should be considered.
3
DOSAGE FORMS AND STRENGTHS
Dextrose Injection 20%, 30%, 40%, 50%, and 70% USP are sterile, non-pyrogenic, hypertonic
solutions of dextrose in single-dose, partial-fill, flexible containers.
500 mL fill volume in 1000 mL flexible container
• 20% (0.2 grams/mL): 20 grams of dextrose hydrous per 100 mL
• 30% (0.3 grams/mL): 30 grams of dextrose hydrous per 100 mL
• 40% (0.4 grams/mL): 40 grams of dextrose hydrous per 100 mL
• 50% (0.5 grams/mL): 50 grams of dextrose hydrous per 100 mL
• 70% (0.7 grams/mL): 70 grams of dextrose hydrous per 100 mL
1000 mL fill volume in 2000 mL flexible container
• 50% (0.5 grams/mL): 50 grams of dextrose hydrous per 100 mL
4
CONTRAINDICATIONS
The use of Dextrose Injection is contraindicated in patients:
• who are severely dehydrated as hypertonic dextrose solution can worsen the patient’s
hyperosmolar state.
• with known allergy to corn or corn products.
5
WARNINGS AND PRECAUTIONS
5.1 Hyperglycemia and Hyperosmolar Hyperglycemic State
The use of dextrose infusions in patients with diabetes mellitus or impaired glucose tolerance
may worsen hyperglycemia. Administration of dextrose at a rate exceeding the patient’s
utilization rate may lead to hyperglycemia, coma, and death. Patients with underlying confusion
and renal impairment who receive dextrose infusions, may be at greater risk of developing
hyperosmolar hyperglycemic state. Monitor blood glucose levels and treat hyperglycemia to
maintain optimum levels while administering Dextrose Injection. Insulin may be administered
or adjusted to maintain optimal blood glucose levels during Dextrose Injection administration.
5.2 Hypersensitivity Reactions
Hypersensitivity reactions including anaphylaxis have been reported with dextrose infusions.
Stop infusion immediately and treat patient accordingly if signs or symptoms of a
Reference ID: 3888634
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
hypersensitivity reaction develop. Signs or symptoms may include: tachypnea, dyspnea, hypoxia,
bronchospasm, tachycardia, hypotension, cyanosis, vomiting, nausea, headache, sweating,
dizziness, altered mentation, flushing, rash, urticaria, erythema, pyrexia, and chills.
Since the dextrose in Dextrose Injection is derived from corn, the product should not be used in
patients with known allergy to corn or corn products [see Contraindications (4)].
5.3 Risk of Infections
Patients who require parenteral nutrition are at high risk of infections because the nutritional
components of these solutions can support microbial growth. The risk of infection is increased
in patients with malnutrition-associated immunosuppression, hyperglycemia exacerbated by
dextrose infusion, long-term use and poor maintenance of intravenous catheters, or
immunosuppressive effects of other concomitant conditions, drugs, or other components of the
parenteral formulation (e.g., lipid emulsion).
To decrease the risk of infectious complications, ensure aseptic technique in catheter placement
and maintenance, as well as aseptic technique in the preparation and administration of the
nutritional formula.
Monitor for signs and symptoms (including fever and chills) of early infections, including
laboratory test results (including leukocytosis and hyperglycemia) and frequent checks of the
parenteral access device and insertion site for edema, redness and discharge.
5.4 Refeeding Syndrome
Refeeding severely undernourished patients may result in refeeding syndrome, characterized by
the intracellular shift of potassium, phosphorus, and magnesium as the patient becomes anabolic.
Thiamine deficiency and fluid retention may also develop. To prevent these complications,
monitor severely undernourished patients and slowly increase nutrient intakes.
5.5 Vein Damage and Thrombosis
Dextrose Injection is for admixture with amino acids or dilution with other compatible
intravenous fluids. It is not for direct intravenous infusion. Administer solutions containing
more than 5% dextrose or with an osmolarity of ≥ 900 mOsm/L through a central vein [see
Dosage and Administration (2.1)]. The infusion of hypertonic solutions into a peripheral vein
may result in vein irritation, vein damage, and/or thrombosis. The primary complication of
peripheral access is venous thrombophlebitis, which manifests as pain, erythema, tenderness or a
palpable cord. Remove the catheter as soon as possible, if thrombophlebitis develops.
5.6 Aluminum Toxicity
Dextrose Injection contains no more than 25 mcg/L of aluminum. However, with prolonged
parenteral administration in patients with renal impairment, the aluminum contained in Dextrose
Injection may reach toxic levels. Preterm infants are at greater risk because their kidneys are
immature, and they require large amounts of concomitant calcium and phosphate solutions that
contain aluminum. Patients with renal impairment, including preterm infants, who receive
parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day, accumulate aluminum at levels
Reference ID: 3888634
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
associated with central nervous system and bone toxicity. Tissue loading may occur at even
lower rates of administration of total parenteral nutrition products.
5. 7
Risk of Parenteral Nutrition Associated Liver Disease
Parenteral Nutrition Associated Liver Disease (PNALD) has been reported in patients who
receive parenteral nutrition for extended periods of time, especially preterm infants, and can
present as cholestasis or steatohepatitis. The exact etiology is not entirely clear and is likely
multifactorial. If Dextrose Injection-treated patients develop abnormal liver function tests
consider discontinuation or dosage reduction.
5.8
Electrolyte Imbalance and Fluid Overload
Electrolyte deficits, particularly in serum potassium and phosphate, may occur during prolonged
use of concentrated dextrose solutions.
Depending on the volume and rate of infusion, the intravenous administration of concentrated
dextrose solutions can cause fluid and/or solute overloading resulting in dilution of serum
electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of
dilutional states is inversely proportional to the electrolyte concentrations in the administered
solution. The risk of solute overload causing congested states with peripheral and pulmonary
edema is directly proportional to the electrolyte concentrations in the solution.
Monitor blood electrolyte levels, correct fluid and electrolyte imbalances, and administer
essential vitamins and minerals as needed.Monitor daily fluid balance.
6
ADVERSE REACTIONS
The following adverse reactions from voluntary reports or clinical studies have been reported
with Dextrose Injection. Because many of these reactions were reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure.
• Hyperglycemia and hyperosmolar hyperglycemic state [see Warnings and Precautions
(5.1)].
• Hypersensitivity reactions [see Warnings and Precautions (5.2)].
• Risk of infections [see Warnings and Precautions (5.3)].
• Refeeding syndrome [see Warnings and Precautions (5.4)].
• Vein damage and thrombosis [see Warnings and Precautions (5.5)].
• Aluminum toxicity [see Warnings and Precautions (5.6)].
• Risk of parenteral nutrition associated liver disease [see Warnings and Precautions
(5.7)].
• Electrolyte imbalance and fluid overload [see Warnings and Precautions (5.8)].
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
There are no data with Dextrose Injection in pregnant women. In addition, animal reproduction
studies have not been conducted with dextrose. In the U.S. general population, the estimated
Reference ID: 3888634
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2
to 4% and 15 to 20%, respectively.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
Consider parenteral nutrition in cases of severe maternal malnutrition where nutritional
requirements cannot be fulfilled by the enteral route because of the risks to the fetus
associated with severe malnutrition, including preterm delivery, low birth weight,
intrauterine growth restriction, congenital malformations, and perinatal mortality.
8.2
Lactation
There are no data regarding the presence of dextrose in human milk, the effects on a breastfed
infant, or the effects on milk production. The developmental and health benefits of breastfeeding
should be considered along with the mother’s clinical need for Dextrose Injection and any
potential adverse effects on the breastfed infant from Dextrose Injection or from the underlying
maternal condition.
8.4
Pediatric Use
Neonates, especially those born premature and with low birth weight are at increased risk of
developing hypo – or hyperglycemia and therefore need close monitoring during treatment with
intravenous glucose infusions to ensure adequate glycemic control in order to avoid potential
long term adverse effects. Hypoglycemia in the newborn can cause prolonged seizures, coma
and brain damage. Hyperglycemia has been associated with intraventricular hemorrhage, late
onset bacterial and fungal infection, retinopathy of prematurity, necrotizing enterocolitis,
bronchopulmonary dysplasia, prolonged length of hospital stay, and death. Plasma electrolyte
concentrations should be closely monitored in the pediatric population as this population may
have impaired ability to regulate fluids and electrolytes. In very low birth weight infants,
excessive or rapid administration of Dextrose Injection may result in increased serum osmolality
and possible intracerebral hemorrhage.
Because of immature renal function, preterm infants receiving prolonged treatment with
Dextrose Injection, may be at risk aluminum toxicity [see Warnings and Precautions (5.6)].
Patients, including pediatric patients, may be at risk for Parenteral Nutrition Associated Liver
Disease (PNALD) [see Warnings and Precautions (5.7)].
8.5
Geriatric Use
Clinical studies of Dextrose Injection did not include sufficient numbers of patients aged 65 and
over to determine whether they respond differently from other younger patients. Other reported
clinical experience has not identified differences in responses between the elderly and younger
patients.
10
OVERDOSAGE
An increased infusion rate of Dextrose Injection or administration of a concentrated dextrose
solution can cause hyperglycemia, hyperosmolality, and adverse effects on water and electrolyte
balance [see Warnings and Precautions (5.1, 5.8)].
Reference ID: 3888634
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Severe hyperglycemia and severe dilutional hyponatremia, and their complications, can be fatal.
Discontinue infusion and institute appropriate corrective measures in the event of overhydration
or solute overload during therapy, with particular attention to respiratory and cardiovascular
systems.
For current information on the management of poisoning or overdosage, contact the National
Poison Control Center at 1-800-222-1222 or www.poison.org.
11
DESCRIPTION
Dextrose Injection, USP 20%, 30%, 40%, 50% and 70% are sterile, nonpyrogenic, hypertonic
solutions of Dextrose, USP in Water for Injection in a polyvinylchloride flexible plastic
container for intravenous administration after appropriate admixture or dilution [see Dosage and
Administration (2.1)].
Partial-fill containers, designed to facilitate admixture or dilution to provide dextrose in various
concentrations, are available in various sizes. See Table 1 for the content and characteristics of
these concentrated solutions. The solutions contain no bacteriostatic, antimicrobial agent or
added buffer and are intended only for use as a single-dose injection following admixture or
dilution. The pH (range is 4.3 (3.2 to 6.5).
Water can permeate from inside the container into the overwrap but not in amounts sufficient to
affect the solution significantly.
Table 1. Contents and Characteristics of Dextrose Injection 20%, 30%, 40%, 50%, and
70%
Strength
Fill Volume
Amount of
Dextrose Hydrous
per Container
kcal*
per
Container
mOsmol
per liter
20% (0.2 grams/mL)
500 mL
100 grams
340
1009
30% (0.3 grams/mL)
500 mL
150 grams
510
1514
40% (0.4 grams/mL)
500 mL
200 grams
680
2018
50% (0.5 grams/mL)
500 mL
250 grams
850
2523
1000 mL
500 grams
1700
2523
70% (0.7 grams/mL)
500 mL
350 grams
1190
3532
*Caloric value calculated on the basis of 3.4 kcal/g of dextrose, hydrous.
Dextrose, USP is chemically designated D-glucose, monohydrate (C6H12O6 • H2O), a hexose
sugar freely soluble in water. The molecular weight of dextrose (D-glucose) monohydrate is
198.17. It has the following structural formula:
O
OH
CH2OH
OH
OH
OH
H2O
Reference ID: 3888634
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Water for Injection, USP is chemically designated H2O.
Dextrose Injection contains no more than 25 mcg/L of aluminum.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Dextrose Injection is used to supplement nutrition by providing glucose parenterally. Dextrose is
oxidized to carbon dioxide and water, yielding energy.
16
HOW SUPPLIED/STORAGE AND HANDLING
Dextrose Injection, 20%, 30%, 40%, 50%, and 70% USP are sterile hypertonic solutions of
dextrose supplied in single-dose, partial-fill flexible containers (see Tables 1 and 2) for
intravenous administration after appropriate admixture or dilution [see Dosage and
Administration (2.1)].
Do not remove container from the overwrap until intended for use.
Table 2: Strengths, Fill Volume, and NDC # of Dextrose Injection 20%, 30%, 40%, 50%,
and 70%
Strength
Fill
Volume
NDC#
20% (0.2 grams/mL)
500 mL
0409-7935-19
30% (0.3 grams/mL)
500 mL
0409-8004-15
40% (0.4 grams/mL)
500 mL
0409-7937-19
50% (0.5 grams/mL)
500 mL
0409-7936-19
1000 mL
0409-7936-29
70% (0.7 grams/mL)
500 mL
0409-7918-19
Use the product immediately after mixing and the introduction of additives.
Store between 20º C to 25° C (68º F to 77°F). [See USP controlled room temperature.]
Do not freeze.
17
PATIENT COUNSELING INFORMATION
Inform patients, caregivers, or home healthcare providers of the following risks of Dextrose
Injection:
• Hyperglycemia and hyperosmolar hyperglycemic state [see Warnings and Precautions
(5.1)]
• Hypersensitivity reactions [see Warnings and Precautions (5.2)]
• Risk of infection [see Warnings and Precautions (5.3)]
• Vein damage and thrombosis [see Warnings and Precautions (5.5)]
Reference ID: 3888634
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Aluminum toxicity [see Warnings and Precautions (5.6)]
• Risk of parenteral nutrition associated liver disease [see Warnings and Precautions (5.7)]
• Fluid overload and electrolyte imbalance [see Warnings and Precautions (5.8)]
EN-4133
Hospira, Inc., Lake Forest, IL 60045 USA
Reference ID: 3888634
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:45.208190
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/018561s057,018562s056,018563s057,018564s059,019345s044lbl.pdf', 'application_number': 18564, 'submission_type': 'SUPPL ', 'submission_number': 59}
|
11,235
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
DEXTROSE INJECTION 20%, 30%, 40%, 50% and 70% safely and
effectively. See full prescribing information for DEXTROSE
INJECTION 20%, 30%, 40%, 50% and 70%.
DEXTROSE injection, for intravenous use
Initial U.S. Approval: 1940
----------------------------INDICATIONS AND USAGE---------------------------
Dextrose Injection 20%, 30%, 40%, 50% and 70%, mixed with amino acids or
other compatible intravenous fluids, is indicated as a source of calories for
patients requiring parenteral nutrition when oral or enteral nutrition is not
possible, insufficient or contraindicated (1)
----------------------DOSAGE AND ADMINISTRATION-----------------------
• Must be diluted with compatible intravenous fluids or used as admixture,
prior to administration. Not for direct intravenous infusion. (2.1)
• Only for slow intravenous infusion only into a: (2.1)
Central vein, if final dextrose concentration is greater than 5% or
osmolality is greater than 900 mOsm/L
Peripheral vein, if final dextrose concentration 5% or less and osmolality
is less than 900 mOsm/L
• Individualize dosage based on the patient’s clinical condition, body
weight, nutritional/fluid requirements, as well as additional energy given
orally/enterally (2.2)
• Discontinue infusion of concentrated dextrose solutions slowly and/or
administer 5% dextrose (2.3)
---------------------DOSAGE FORMS AND STRENGTHS----------------------
Injection: Single-dose, partial-fill, flexible containers with (3):
500 mL fill volume in 1000 mL flexible container:
• 20% (0.2 grams/mL): 20 grams of dextrose hydrous per 100 mL
• 30% (0.3 grams/mL): 30 grams of dextrose hydrous per 100 mL
• 40% (0.4 grams/mL): 40 grams of dextrose hydrous per 100 mL
• 50% (0.5 grams/mL): 50 grams of dextrose hydrous per 100 mL
• 70% (0.5 grams/mL): 70 grams of dextrose hydrous per 100 mL
1000 mL fill volume in 2000 mL flexible container:
• 50% (0.5 grams/mL): 50 grams of dextrose hydrous per 100 mL
---------------------------CONTRAINDICATIONS------------------------------
• Severe dehydration (4)
• Known allergy to corn or corn products (4)
-----------------------WARNINGS AND PRECAUTIONS------------------------
• Hyperglycemia or Hyperosmolar Hyperglycemic State: Monitor blood
glucose and administer insulin as needed (5.1)
• Hypersensitivity Reactions: monitor for signs and symptoms and
discontinue infusion if reactions occur (5.2)
• Risk of Infection: Monitor for signs and symptoms and laboratory
parameters (5.3)
• Refeeding Syndrome: monitory laboratory parameters (5.4)
• Vein Damage and Thrombosis: Administer solutions containing more than
5% dextrose as the final concentration or solutions with an osmolarity ≥
900 mOsm/L through a central vein (2.1, 5.5)
• Aluminum Toxicity: Dextrose Injection contains aluminum that may be
toxic. Patients with impaired renal function, and preterm infants, at higher
risk. Limit aluminum to less than 4 mcg/kg/day (5.6, 8.4)
• Parenteral Nutrition Associated Liver Disease: increased risk in patients
who receive parenteral nutrition for extended periods of time, especially
preterm infants; monitor liver function tests, if abnormalities occur
consider discontinuation or dosage reduction. (5.7, 8.4)
• Electrolyte Imbalance and Fluid Overload: monitor daily fluid balance,
blood electrolyte levels, correct as needed. (5.8, 8.4)
------------------------------ADVERSE REACTIONS-------------------------------
The most common adverse reactions are hyperosmolar syndrome, infection
both systemic and at the injection site, vein thrombosis or phlebitis, and
hypervolemia. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Hospira Inc.
at 1-800-441-4100, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
-----------------------USE IN SPECIFIC POPULATIONS------------------------
Pediatric Use: Increased risk of hypoglycemia/hyperglycemia; monitor serum
glucose concentrations. (8.4)
See 17 for PATIENT COUNSELING INFORMATION
Revised: 2/2016
_______________________________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1 Important Preparation and Administration Instructions
2.2 Dosing Considerations
2.3 Discontinuation of Dextrose Injection
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Hyperglycemia and Hyperosmolar Hyperglycemic State
5.2 Hypersensitivity Reactions
5.3 Risk of Infection
5.4 Refeeding Syndrome
5.5 Vein Damage and Thrombosis
5.6 Aluminum Toxicity
5.7 Risk of Parenteral Nutrition Associated Liver Disease
5.8 Fluid Overload and Electrolyte Imbalance
6
ADVERSE REACTIONS
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
_______________________________________________________________________________________________________________________________________
Reference ID: 3888634
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For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
Dextrose Injection 20%, 30%, 40%, 50% and 70%, mixed with amino acids or other compatible
intravenous fluids, is indicated as a source of calories for patients requiring parenteral nutrition
when oral or enteral nutrition is not possible, insufficient, or contraindicated.
2
DOSAGE AND ADMINISTRATION
2.1
Important Preparation and Administration Instructions
Dextrose Injection is supplied in the following five strengths: 20%, 30%, 40%, 50% and 70%
[see How Supplied/Storage and Handling (16)]. Prior to administration, Dextrose Injection must
be diluted with other compatible intravenous fluids or used as an admixture with amino acids. It
is not for direct intravenous infusion.
Preparation Prior to Administration
• Because additives may be incompatible, evaluate all additions to the plastic container for
compatibility and stability of the resulting preparation. Consult with a pharmacist, if
available. If it is deemed advisable to introduce additives, use aseptic technique and mix
thoroughly.
• Inspect Dextrose Injection to ensure precipitates have not formed during the mixing or
addition of additives. Discard the bag if precipitates are observed. Some opacity of the
plastic container (due to moisture absorption during sterilization process) may be observed.
This is normal and does not affect the solution quality or safety. The opacity will diminish
gradually.
• Use promptly after admixing or dilution.
• For single use only; discard unused portion
Important Administration Instructions
• Set the vent to the closed position on a vented intravenous administration set to prevent air
embolism.
• Use a dedicated line without any connections to avoid air embolism.
• Prior to infusion, visually inspect the diluted dextrose solution for particulate matter. The
solution should be clear and there should be no precipitates. Do not administer unless
solution is clear and container is undamaged.
• The choice of a central or peripheral venous route of infusion should depend on the
osmolarity of the final infusate. Solutions with greater than 5% dextrose or with osmolarity
of greater than or equal to 900 mOsm/L must be infused through a central catheter [see
Warnings and Precautions (5.5)].
2.2
Dosing Information
Caution: Dextrose Injection is not for direct intravenous infusion. Prior to administration,
Dextrose Injection must be diluted with other compatible intravenous fluids or used as an
admixture with amino acids.
Individualize the dosage of Dextrose Injection based on the patient’s clinical condition (ability to
Reference ID: 3888634
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adequately metabolize dextrose), body weight, nutritional and fluid requirements, as well as
additional energy given orally or enterally to the patient.
The administration rate should be governed, especially during the first few day of therapy, by the
patient’s tolerance to dextrose. Daily intake of amino acids and dextrose should be increased
gradually to the maximum required dose as indicated by frequent determinations of blood
glucose levels.
2.3 Discontinuation of Dextrose Injection
To reduce the risk of hypoglycemia, a gradual decrease in flow rate in the last hour of infusion
should be considered.
3
DOSAGE FORMS AND STRENGTHS
Dextrose Injection 20%, 30%, 40%, 50%, and 70% USP are sterile, non-pyrogenic, hypertonic
solutions of dextrose in single-dose, partial-fill, flexible containers.
500 mL fill volume in 1000 mL flexible container
• 20% (0.2 grams/mL): 20 grams of dextrose hydrous per 100 mL
• 30% (0.3 grams/mL): 30 grams of dextrose hydrous per 100 mL
• 40% (0.4 grams/mL): 40 grams of dextrose hydrous per 100 mL
• 50% (0.5 grams/mL): 50 grams of dextrose hydrous per 100 mL
• 70% (0.7 grams/mL): 70 grams of dextrose hydrous per 100 mL
1000 mL fill volume in 2000 mL flexible container
• 50% (0.5 grams/mL): 50 grams of dextrose hydrous per 100 mL
4
CONTRAINDICATIONS
The use of Dextrose Injection is contraindicated in patients:
• who are severely dehydrated as hypertonic dextrose solution can worsen the patient’s
hyperosmolar state.
• with known allergy to corn or corn products.
5
WARNINGS AND PRECAUTIONS
5.1 Hyperglycemia and Hyperosmolar Hyperglycemic State
The use of dextrose infusions in patients with diabetes mellitus or impaired glucose tolerance
may worsen hyperglycemia. Administration of dextrose at a rate exceeding the patient’s
utilization rate may lead to hyperglycemia, coma, and death. Patients with underlying confusion
and renal impairment who receive dextrose infusions, may be at greater risk of developing
hyperosmolar hyperglycemic state. Monitor blood glucose levels and treat hyperglycemia to
maintain optimum levels while administering Dextrose Injection. Insulin may be administered
or adjusted to maintain optimal blood glucose levels during Dextrose Injection administration.
5.2 Hypersensitivity Reactions
Hypersensitivity reactions including anaphylaxis have been reported with dextrose infusions.
Stop infusion immediately and treat patient accordingly if signs or symptoms of a
Reference ID: 3888634
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hypersensitivity reaction develop. Signs or symptoms may include: tachypnea, dyspnea, hypoxia,
bronchospasm, tachycardia, hypotension, cyanosis, vomiting, nausea, headache, sweating,
dizziness, altered mentation, flushing, rash, urticaria, erythema, pyrexia, and chills.
Since the dextrose in Dextrose Injection is derived from corn, the product should not be used in
patients with known allergy to corn or corn products [see Contraindications (4)].
5.3 Risk of Infections
Patients who require parenteral nutrition are at high risk of infections because the nutritional
components of these solutions can support microbial growth. The risk of infection is increased
in patients with malnutrition-associated immunosuppression, hyperglycemia exacerbated by
dextrose infusion, long-term use and poor maintenance of intravenous catheters, or
immunosuppressive effects of other concomitant conditions, drugs, or other components of the
parenteral formulation (e.g., lipid emulsion).
To decrease the risk of infectious complications, ensure aseptic technique in catheter placement
and maintenance, as well as aseptic technique in the preparation and administration of the
nutritional formula.
Monitor for signs and symptoms (including fever and chills) of early infections, including
laboratory test results (including leukocytosis and hyperglycemia) and frequent checks of the
parenteral access device and insertion site for edema, redness and discharge.
5.4 Refeeding Syndrome
Refeeding severely undernourished patients may result in refeeding syndrome, characterized by
the intracellular shift of potassium, phosphorus, and magnesium as the patient becomes anabolic.
Thiamine deficiency and fluid retention may also develop. To prevent these complications,
monitor severely undernourished patients and slowly increase nutrient intakes.
5.5 Vein Damage and Thrombosis
Dextrose Injection is for admixture with amino acids or dilution with other compatible
intravenous fluids. It is not for direct intravenous infusion. Administer solutions containing
more than 5% dextrose or with an osmolarity of ≥ 900 mOsm/L through a central vein [see
Dosage and Administration (2.1)]. The infusion of hypertonic solutions into a peripheral vein
may result in vein irritation, vein damage, and/or thrombosis. The primary complication of
peripheral access is venous thrombophlebitis, which manifests as pain, erythema, tenderness or a
palpable cord. Remove the catheter as soon as possible, if thrombophlebitis develops.
5.6 Aluminum Toxicity
Dextrose Injection contains no more than 25 mcg/L of aluminum. However, with prolonged
parenteral administration in patients with renal impairment, the aluminum contained in Dextrose
Injection may reach toxic levels. Preterm infants are at greater risk because their kidneys are
immature, and they require large amounts of concomitant calcium and phosphate solutions that
contain aluminum. Patients with renal impairment, including preterm infants, who receive
parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day, accumulate aluminum at levels
Reference ID: 3888634
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associated with central nervous system and bone toxicity. Tissue loading may occur at even
lower rates of administration of total parenteral nutrition products.
5. 7
Risk of Parenteral Nutrition Associated Liver Disease
Parenteral Nutrition Associated Liver Disease (PNALD) has been reported in patients who
receive parenteral nutrition for extended periods of time, especially preterm infants, and can
present as cholestasis or steatohepatitis. The exact etiology is not entirely clear and is likely
multifactorial. If Dextrose Injection-treated patients develop abnormal liver function tests
consider discontinuation or dosage reduction.
5.8
Electrolyte Imbalance and Fluid Overload
Electrolyte deficits, particularly in serum potassium and phosphate, may occur during prolonged
use of concentrated dextrose solutions.
Depending on the volume and rate of infusion, the intravenous administration of concentrated
dextrose solutions can cause fluid and/or solute overloading resulting in dilution of serum
electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of
dilutional states is inversely proportional to the electrolyte concentrations in the administered
solution. The risk of solute overload causing congested states with peripheral and pulmonary
edema is directly proportional to the electrolyte concentrations in the solution.
Monitor blood electrolyte levels, correct fluid and electrolyte imbalances, and administer
essential vitamins and minerals as needed.Monitor daily fluid balance.
6
ADVERSE REACTIONS
The following adverse reactions from voluntary reports or clinical studies have been reported
with Dextrose Injection. Because many of these reactions were reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure.
• Hyperglycemia and hyperosmolar hyperglycemic state [see Warnings and Precautions
(5.1)].
• Hypersensitivity reactions [see Warnings and Precautions (5.2)].
• Risk of infections [see Warnings and Precautions (5.3)].
• Refeeding syndrome [see Warnings and Precautions (5.4)].
• Vein damage and thrombosis [see Warnings and Precautions (5.5)].
• Aluminum toxicity [see Warnings and Precautions (5.6)].
• Risk of parenteral nutrition associated liver disease [see Warnings and Precautions
(5.7)].
• Electrolyte imbalance and fluid overload [see Warnings and Precautions (5.8)].
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Risk Summary
There are no data with Dextrose Injection in pregnant women. In addition, animal reproduction
studies have not been conducted with dextrose. In the U.S. general population, the estimated
Reference ID: 3888634
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background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2
to 4% and 15 to 20%, respectively.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
Consider parenteral nutrition in cases of severe maternal malnutrition where nutritional
requirements cannot be fulfilled by the enteral route because of the risks to the fetus
associated with severe malnutrition, including preterm delivery, low birth weight,
intrauterine growth restriction, congenital malformations, and perinatal mortality.
8.2
Lactation
There are no data regarding the presence of dextrose in human milk, the effects on a breastfed
infant, or the effects on milk production. The developmental and health benefits of breastfeeding
should be considered along with the mother’s clinical need for Dextrose Injection and any
potential adverse effects on the breastfed infant from Dextrose Injection or from the underlying
maternal condition.
8.4
Pediatric Use
Neonates, especially those born premature and with low birth weight are at increased risk of
developing hypo – or hyperglycemia and therefore need close monitoring during treatment with
intravenous glucose infusions to ensure adequate glycemic control in order to avoid potential
long term adverse effects. Hypoglycemia in the newborn can cause prolonged seizures, coma
and brain damage. Hyperglycemia has been associated with intraventricular hemorrhage, late
onset bacterial and fungal infection, retinopathy of prematurity, necrotizing enterocolitis,
bronchopulmonary dysplasia, prolonged length of hospital stay, and death. Plasma electrolyte
concentrations should be closely monitored in the pediatric population as this population may
have impaired ability to regulate fluids and electrolytes. In very low birth weight infants,
excessive or rapid administration of Dextrose Injection may result in increased serum osmolality
and possible intracerebral hemorrhage.
Because of immature renal function, preterm infants receiving prolonged treatment with
Dextrose Injection, may be at risk aluminum toxicity [see Warnings and Precautions (5.6)].
Patients, including pediatric patients, may be at risk for Parenteral Nutrition Associated Liver
Disease (PNALD) [see Warnings and Precautions (5.7)].
8.5
Geriatric Use
Clinical studies of Dextrose Injection did not include sufficient numbers of patients aged 65 and
over to determine whether they respond differently from other younger patients. Other reported
clinical experience has not identified differences in responses between the elderly and younger
patients.
10
OVERDOSAGE
An increased infusion rate of Dextrose Injection or administration of a concentrated dextrose
solution can cause hyperglycemia, hyperosmolality, and adverse effects on water and electrolyte
balance [see Warnings and Precautions (5.1, 5.8)].
Reference ID: 3888634
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Severe hyperglycemia and severe dilutional hyponatremia, and their complications, can be fatal.
Discontinue infusion and institute appropriate corrective measures in the event of overhydration
or solute overload during therapy, with particular attention to respiratory and cardiovascular
systems.
For current information on the management of poisoning or overdosage, contact the National
Poison Control Center at 1-800-222-1222 or www.poison.org.
11
DESCRIPTION
Dextrose Injection, USP 20%, 30%, 40%, 50% and 70% are sterile, nonpyrogenic, hypertonic
solutions of Dextrose, USP in Water for Injection in a polyvinylchloride flexible plastic
container for intravenous administration after appropriate admixture or dilution [see Dosage and
Administration (2.1)].
Partial-fill containers, designed to facilitate admixture or dilution to provide dextrose in various
concentrations, are available in various sizes. See Table 1 for the content and characteristics of
these concentrated solutions. The solutions contain no bacteriostatic, antimicrobial agent or
added buffer and are intended only for use as a single-dose injection following admixture or
dilution. The pH (range is 4.3 (3.2 to 6.5).
Water can permeate from inside the container into the overwrap but not in amounts sufficient to
affect the solution significantly.
Table 1. Contents and Characteristics of Dextrose Injection 20%, 30%, 40%, 50%, and
70%
Strength
Fill Volume
Amount of
Dextrose Hydrous
per Container
kcal*
per
Container
mOsmol
per liter
20% (0.2 grams/mL)
500 mL
100 grams
340
1009
30% (0.3 grams/mL)
500 mL
150 grams
510
1514
40% (0.4 grams/mL)
500 mL
200 grams
680
2018
50% (0.5 grams/mL)
500 mL
250 grams
850
2523
1000 mL
500 grams
1700
2523
70% (0.7 grams/mL)
500 mL
350 grams
1190
3532
*Caloric value calculated on the basis of 3.4 kcal/g of dextrose, hydrous.
Dextrose, USP is chemically designated D-glucose, monohydrate (C6H12O6 • H2O), a hexose
sugar freely soluble in water. The molecular weight of dextrose (D-glucose) monohydrate is
198.17. It has the following structural formula:
O
OH
CH2OH
OH
OH
OH
H2O
Reference ID: 3888634
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Water for Injection, USP is chemically designated H2O.
Dextrose Injection contains no more than 25 mcg/L of aluminum.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Dextrose Injection is used to supplement nutrition by providing glucose parenterally. Dextrose is
oxidized to carbon dioxide and water, yielding energy.
16
HOW SUPPLIED/STORAGE AND HANDLING
Dextrose Injection, 20%, 30%, 40%, 50%, and 70% USP are sterile hypertonic solutions of
dextrose supplied in single-dose, partial-fill flexible containers (see Tables 1 and 2) for
intravenous administration after appropriate admixture or dilution [see Dosage and
Administration (2.1)].
Do not remove container from the overwrap until intended for use.
Table 2: Strengths, Fill Volume, and NDC # of Dextrose Injection 20%, 30%, 40%, 50%,
and 70%
Strength
Fill
Volume
NDC#
20% (0.2 grams/mL)
500 mL
0409-7935-19
30% (0.3 grams/mL)
500 mL
0409-8004-15
40% (0.4 grams/mL)
500 mL
0409-7937-19
50% (0.5 grams/mL)
500 mL
0409-7936-19
1000 mL
0409-7936-29
70% (0.7 grams/mL)
500 mL
0409-7918-19
Use the product immediately after mixing and the introduction of additives.
Store between 20º C to 25° C (68º F to 77°F). [See USP controlled room temperature.]
Do not freeze.
17
PATIENT COUNSELING INFORMATION
Inform patients, caregivers, or home healthcare providers of the following risks of Dextrose
Injection:
• Hyperglycemia and hyperosmolar hyperglycemic state [see Warnings and Precautions
(5.1)]
• Hypersensitivity reactions [see Warnings and Precautions (5.2)]
• Risk of infection [see Warnings and Precautions (5.3)]
• Vein damage and thrombosis [see Warnings and Precautions (5.5)]
Reference ID: 3888634
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Aluminum toxicity [see Warnings and Precautions (5.6)]
• Risk of parenteral nutrition associated liver disease [see Warnings and Precautions (5.7)]
• Fluid overload and electrolyte imbalance [see Warnings and Precautions (5.8)]
EN-4133
Hospira, Inc., Lake Forest, IL 60045 USA
Reference ID: 3888634
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:45.223246
|
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|
11,241
|
Topicort®
(Desoximetasone) Ointment USP 0.05%
For topical use only. Not for oral, ophthalmic, or intravaginal use.
Rx only
DESCRIPTION
Topicort® (desoximetasone) Ointment USP, 0.05% contains the active synthetic corticosteroid
desoximetasone. The topical corticosteroids constitute a class of primarily synthetic steroids used
as anti-inflammatory and antipruritic agents.
Each gram of Topicort® (desoximetasone) Ointment USP, 0.05% contains 0.5 mg of
desoximetasone in an ointment base consisting of mineral oil and white petrolatum.
The chemical name of desoximetasone is Pregna-1, 4-diene-3, 20-dione, 9-fluoro-11, 21
dihydroxy- 16-methyl-,(11ß,16α)-.
Desoximetasone has the molecular formula C22H29FO4 and a molecular weight of 376.47. The
CAS Registry Number is 382-67-2.
The structural formula is: Structural Formula
CLINICAL PHARMACOLOGY
Topical corticosteroids share anti-inflammatory, antipruritic and vasoconstrictive actions.
The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various
laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies
and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a
recognizable correlation exists between vasoconstrictor potency and therapeutic efficacy in man.
Pharmacokinetics
The extent of percutaneous absorption of topical corticosteroids is determined by many factors
including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings.
Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other
disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially
increase the percutaneous absorption of topical corticosteroids. Thus, occlusive dressings may be
a valuable therapeutic adjunct for treatment of resistant dermatoses.
Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic
pathways similar to systemically administered corticosteroids. Corticosteroids are bound to
plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are
then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also
excreted into the bile.
Pharmacokinetic studies in men with Topicort® (desoximetasone) Ointment 0.25% with tagged
desoximetasone showed no detectable level (limit of sensitivity: 0.003 µg/mL) in 1 subject and
0.004 and 0.006 µg/mL in the remaining 2 subjects in the blood when it was applied topically on
the back followed by occlusion for 24 hours. The extent of absorption for the ointment was 7%
based on radioactivity recovered from urine and feces. Seven days after application, no further
radioactivity was detected in urine or feces. Studies with other similarly structured steroids have
shown that predominant metabolite reaction occurs through conjugation to form the glucuronide
and sulfate ester.
INDICATIONS AND USAGE
Topicort® (desoximetasone) Ointment USP, 0.05% is indicated for the relief of the inflammatory
and pruritic manifestations of corticosteroid-responsive dermatoses.
CONTRAINDICATIONS
Topical corticosteroids are contraindicated in those patients with a history of hypersensitivity to
any of the components of the preparation.
WARNINGS
Keep out of reach of children.
PRECAUTIONS
General
Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary
adrenal (HPA) axis suppression with the potential for clinical glucocorticosteroid insufficiency.
This may occur during treatment or upon withdrawal of the topical corticosteroid.
Because of the potential for systemic absorption, use of topical corticosteroids may require that
patients be periodically evaluated for HPA axis suppression. Factors that predispose a patient
using a topical corticosteroid to HPA axis suppression include the use of more potent steroids,
use over large surface areas, use over prolonged periods, use under occlusion, use on an altered
skin barrier, and use in patients with liver failure.
An ACTH stimulation test may be helpful in evaluating patients for HPA axis suppression. If
HPA axis suppression is documented, an attempt should be made to gradually withdraw the drug,
to reduce the frequency of application, or to substitute a less potent steroid. Manifestations of
adrenal insufficiency may require supplemental systemic corticosteroids. Recovery of HPA axis
function is generally prompt and complete upon discontinuation of topical corticosteroids.
Cushing’s syndrome, hyperglycemia, and unmasking of latent diabetes mellitus can also result
from systemic absorption of topical corticosteroids.
Use of more than one corticosteroid-containing product at the same time may increase the total
systemic corticosteroid exposure.
Pediatric patients may be more susceptible to systemic toxicity from use of topical
corticosteroids.
Local Adverse Reactions with Topical Corticosteroids
Local adverse reactions may be more likely to occur with occlusive use, prolonged use or use of
higher potency corticosteroids. Reactions may include atrophy, striae, telangiectasias, burning,
itching, irritation, dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral
dermatitis, allergic contact dermatitis, secondary infection, and miliaria. Some local adverse
reactions may be irreversible.
Allergic Contact Dermatitis with Topical Corticosteroids
Allergic contact dermatitis to any component of topical corticosteroids is usually diagnosed by a
failure to heal rather than a clinical exacerbation. Clinical diagnosis of allergic contact dermatitis
can be confirmed by patch testing.
Concomitant Skin Infections
Concomitant skin infections should be treated with an appropriate antimicrobial agent. If the
infection persists, Topicort® (desoximetasone) Ointment USP, 0.05% should be discontinued
until the infection has been adequately treated.
Information for the Patient
Patients using topical corticosteroids should receive the following information and instructions:
1. This medication is to be used as directed by the physician. It is for external use only. Avoid
contact with the eyes.
2. Patients should be advised not to use this medication for any disorder other than for which it
was prescribed.
3. The treated skin area should not be bandaged or otherwise covered or wrapped as to be
occlusive unless directed by the physician.
4. Patients should report any signs of local adverse reactions, especially under occlusive
dressings.
5. Other
corticosteroid-containing
products
should
not
be
used
with
Topicort®
(desoximetasone) Ointment USP, 0.05% without first consulting with the physician. As with
other corticosteroids, therapy should be discontinued when control is achieved. If no
improvement is seen within 4 weeks, contact the physician.
Laboratory Tests
The following tests may be helpful in evaluating the hypothalamic-pituitary-adrenal (HPA) axis
suppression:
Urinary free cortisol test
ACTH stimulation test
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term animal studies have not been performed to evaluate the carcinogenic potential or the
effect on fertility of topical corticosteroids.
Desoximetasone was nonmutagenic in the Ames test.
Pregnancy. Teratogenic Effects. Pregnancy Category C
Corticosteroids have been shown to be teratogenic in laboratory animals when administered
systemically at relatively low dosage levels. Some corticosteroids have been shown to be
teratogenic after dermal application in laboratory animals.
Desoximetasone has been shown to be teratogenic and embryotoxic in mice, rats, and rabbits
when given by subcutaneous or dermal routes of administration in doses 15 to 150 times the
human dose of Topicort® (desoximetasone) Ointment USP, 0.05%.
There are no adequate and well-controlled studies in pregnant women on teratogenic effects from
topically applied corticosteroids. Therefore, Topicort® (desoximetasone) Ointment USP, 0.05%
should be used during pregnancy only if the potential benefit justifies the potential risk to the
fetus. Drugs of this class should not be used extensively on pregnant patients, in large amounts,
or for prolonged periods of time.
Nursing Mothers
It is not known whether topical administration of corticosteroids could result in sufficient
systemic absorption to produce detectable quantities in breast milk. Systemically administered
corticosteroids are secreted into breast milk in quantities not likely to have a deleterious effect on
the infant. Nevertheless, caution should be exercised when topical corticosteroids are
administered to a nursing woman.
Pediatric Use
Pediatric patients may demonstrate greater susceptibility to topical corticosteroid- induced
HPA axis suppression and Cushing’s syndrome than mature patients because of a larger
skin surface area to body weight ratio.
Hypothalmic-pituitary-adrenal (HPA) axis suppression, Cushing’s syndrome, and intracranial
hypertension have been reported in pediatric patients receiving topical corticosteroids.
Manifestations of adrenal suppression in pediatric patients include linear growth retardation,
delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation.
Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral
papilledema.
Administration of topical corticosteroids to pediatric patients should be limited to the least
amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may
interfere with the growth and development of pediatric patients.
ADVERSE REACTIONS
The following local adverse reactions are reported infrequently with topical corticosteroids, but
may occur more frequently with the use of occlusive dressings. These reactions are listed in an
approximate decreasing order of occurrence:
Burning, itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions,
hypopigmentation, perioral dermatitis, allergic contact dermatitis, maceration of the skin,
secondary infection, skin atrophy, striae, and miliaria.
In controlled clinical studies the incidence of adverse reactions was low (0.2%) for Topicort®
(desoximetasone) Ointment USP, 0.05% and included mild burning sensation at the site of
application.
OVERDOSAGE
Topically applied corticosteroids can be absorbed in sufficient amounts to produce systemic
effects (see PRECAUTIONS).
DOSAGE AND ADMINISTRATION
Apply a thin film of Topicort® (desoximetasone) Ointment USP, 0.05% to the affected skin areas
twice daily. Rub in gently.
HOW SUPPLIED
Topicort® (desoximetasone) Ointment USP, 0.05% is supplied in:
15 gram tubes (NDC 51672-5263-1), and 60 gram tubes (NDC 51672-5263-3).
Store at controlled room temperature between 20 to 25°C(68 to 77°F), excursions permitted to 15
to 30°C(59 to 86°F). [See USP Controlled Room Temperature]
Mfd. by: Taro Pharmaceuticals Inc., Brampton, Ontario, Canada L6T 1C1
Dist. by: TaroPharma a division of Taro Pharmaceuticals U.S.A., Inc., Hawthorne, NY 10532
Topicort® and TaroPharma® are trademarks of Taro Pharmaceuticals U.S.A., Inc. and/or its
affiliates.
Revised: May, 2010
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custom-source
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2025-02-12T13:44:45.617773
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018594s007lbl.pdf', 'application_number': 18594, 'submission_type': 'SUPPL ', 'submission_number': 7}
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FUROSEMIDE
FUROSEMIDE
INJECTION, USP
INJECTION, USP
10 mg/mL
10 mg/mL
Rx Only
Rx Only bar code
WARNING
Furosemide is a potent diuretic which, if given in excessive amounts, can lead to a profound diuresis with water and
electrolyte depletion. Therefore, careful medical supervision is required and dose and dose schedule must be
adjusted to the individual patient's needs. (See DOSAGE AND ADMINISTRATION.)
DESCRIPTION
Furosemide is a diuretic which is an anthranilic acid derivative.
Chemically, it is 4chloroNfurfuryl5sulfamoylanthranilic acid.
Furosemide Injection 10 mg/mL is a sterile, nonpyrogenic solution in vials for intravenous and intramuscular injection.
Furosemide is a white to offwhite odorless crystalline powder. It is practically insoluble in water, sparingly soluble in
alcohol, freely soluble in dilute alkali solutions and insoluble in dilute acids.
The structural formula is as follows:
structural formula
Each mL contains: Furosemide 10 mg, Water for Injection q.s., Sodium Chloride for isotonicity, Sodium Hydroxide and, if
necessary, Hydrochloric Acid to adjust pH between 8.0 and 9.3.
CLINICAL PHARMACOLOGY
Investigations into the mode of action of furosemide have utilized micropuncture studies in rats, stop flow experiments in
dogs and various clearance studies in both humans and experimental animals. It has been demonstrated that furosemide
inhibits primarily the reabsorption of sodium and chloride not only in the proximal and distal tubules but also in the loop
of Henle. The high degree of efficacy is largely due to this unique site of action. The action on the distal tubule is
independent of any inhibitory effect on carbonic anhydrase and aldosterone.
Recent evidence suggests that furosemide glucuronide is the only or at least the major biotransformation product of
furosemide in man. Furosemide is extensively bound to plasma proteins, mainly to albumin. Plasma concentrations
ranging from 1 to 400 µg/mL are 91 to 99% bound in healthy individuals. The unbound fraction averages 2.3 to 4.1% at
therapeutic concentrations.
The onset of diuresis following intravenous administration is within 5 minutes and somewhat later after intramuscular
administration. The peak effect occurs within the first half hour. The duration of diuretic effect is approximately 2 hours.
In fasted normal men, the mean bioavailability of furosemide from furosemide tablets and furosemide oral solution is 64%
and 60%, respectively, of that from an intravenous injection of the drug. Although furosemide is more rapidly absorbed
from the oral solution (50 minutes) than from the tablet (87 minutes), peak plasma levels and area under the plasma
concentrationtime curves do not differ significantly. Peak plasma concentrations increase with increasing dose but times
topeak do not differ among doses. The terminal halflife of furosemide is approximately 2 hours.
Significantly more furosemide is excreted in urine following the intravenous injection than after the tablet or oral solution.
There are no significant differences between the two oral formulations in the amount of unchanged drug excreted in urine.
Geriatric Population
Furosemide binding to albumin may be reduced in elderly patients. Furosemide is predominantly excreted unchanged in
the urine. The renal clearance of furosemide after intravenous administration in older healthy male subjects (6070 years
of age) is statistically significantly smaller than in younger healthy male subjects (2035 years of age). The initial diuretic
effect of furosemide in older subjects is decreased relative to younger subjects. (See PRECAUTIONS: Geriatric Use.)
INDICATIONS AND USAGE
Parenteral therapy should be reserved for patients unable to take oral medication or for patients in emergency clinical
situations.
Edema: Furosemide is indicated in adults and pediatric patients for the treatment of edema associated with congestive
heart failure, cirrhosis of the liver, and renal disease, including the nephrotic syndrome. Furosemide is particularly useful
when an agent with greater diuretic potential is desired.
Furosemide is indicated as adjunctive therapy in acute pulmonary edema. The intravenous administration of furosemide
is indicated when a rapid onset of diuresis is desired, e.g., in acute pulmonary edema.
If gastrointestinal absorption is impaired or oral medication is not practical for any reason, furosemide is indicated by the
intravenous or intramuscular route. Parenteral use should be replaced with oral furosemide as soon as practical.
CONTRAINDICATIONS
Furosemide is contraindicated in patients with anuria and in patients with a history of hypersensitivity to furosemide.
WARNINGS
In patients with hepatic cirrhosis and ascites, furosemide therapy is best initiated in the hospital. In hepatic coma and in
states of electrolyte depletion, therapy should not be instituted until the basic condition is improved. Sudden alterations
of fluid and electrolyte balance in patients with cirrhosis may precipitate hepatic coma; therefore, strict observation is
necessary during the period of diuresis. Supplemental potassium chloride and, if required, an aldosterone antagonist are
helpful in preventing hypokalemia and metabolic alkalosis.
If increasing azotemia and oliguria occur during treatment of severe progressive renal disease, furosemide should be
discontinued.
Cases of tinnitus and reversible or irreversible hearing impairment and deafness have been reported. Reports usually
indicate that furosemide ototoxicity is associated with rapid injection, severe renal impairment, the use of higher than
recommended doses, hypoproteinemia or concomitant therapy with aminoglycoside antibiotics, ethacrynic acid, or other
ototoxic drugs. If the physician elects to use high dose parenteral therapy, controlled intravenous infusion is advisable (for
adults, an infusion rate not exceeding 4 mg furosemide per minute has been used). (See PRECAUTIONS, Drug
Interactions.)
Pediatric Use: In premature neonates with respiratory distress syndrome, diuretic treatment with furosemide in the first
few weeks of life may increase the risk of persistent patent ductus arteriosus (PDA), possibly through a prostaglandinE
mediated process.
Literature reports indicate that premature infants with post conceptual age (gestational plus postnatal) less than 31 weeks
receiving doses exceeding 1 mg/kg/24 hours may develop plasma levels which could be associated with potential toxic
effects including ototoxicity.
Hearing loss in neonates has been associated with the use of furosemide injection (see WARNINGS, above).
PRECAUTIONS
General: Excessive diuresis may cause dehydration and blood volume reduction with circulatory collapse and possibly
vascular thrombosis and embolism, particularly in elderly patients. As with any effective diuretic, electrolyte depletion may
occur during furosemide therapy, especially in patients receiving higher doses and a restricted salt intake. Hypokalemia
may develop with furosemide, especially with brisk diuresis, inadequate oral electrolyte intake, when cirrhosis is present,
or during concomitant use of corticosteroids, ACTH, licorice in large amounts, or prolonged use of laxatives. Digitalis
therapy may exaggerate metabolic effects of hypokalemia, especially myocardial effects.
All patients receiving furosemide therapy should be observed for these signs or symptoms of fluid or electrolyte imbalance
(hyponatremia, hypochloremic alkalosis, hypokalemia, hypomagnesemia or hypocalcemia): dryness of mouth, thirst,
weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria,
tachycardia, arrhythmia or gastrointestinal disturbances such as nausea and vomiting.
Increases in blood glucose and alterations in glucose tolerance tests (with abnormalities of the fasting and 2hour
postprandial sugar) have been observed, and rarely, precipitation of diabetes mellitus has been reported.
In patients with severe symptoms of urinary retention (because of bladder emptying disorders, prostatic hyperplasia,
urethral narrowing), the administration of furosemide can cause acute urinary retention related to increased production
and retention of urine. Thus, these patients require careful monitoring, especially during the initial stages of treatment.
In patients at high risk for radiocontrast nephropathy, furosemide can lead to a higher incidence of deterioration in renal
function after receiving radiocontrast compared to highrisk patients who received only intravenous hydration prior to
receiving radiocontrast.
In patients with hypoproteinemia (e.g., associated with nephrotic syndrome) the effect of furosemide may be weakened
and its ototoxicity potentiated.
Asymptomatic hyperuricemia can occur and gout may rarely be precipitated.
Patients allergic to sulfonamides may also be allergic to furosemide. The possibility exists of exacerbation or activation
of systemic lupus erythematosus.
As with many other drugs, patients should be observed regularly for the possible occurrence of blood dyscrasias, liver or
kidney damage, or other idiosyncratic reactions.
Information for Patients: Patients receiving furosemide should be advised that they may experience symptoms from
excessive fluid and/or electrolyte losses. The postural hypotension that sometimes occurs can usually be managed by
getting up slowly. Potassium supplements and/or dietary measures may be needed to control or avoid hypokalemia.
Patients with diabetes mellitus should be told that furosemide may increase blood glucose levels and thereby affect urine
glucose tests. The skin of some patients may be more sensitive to the effects of sunlight while taking furosemide.
Hypertensive patients should avoid medications that may increase blood pressure, including overthecounter products
for appetite suppression and cold symptoms.
Laboratory Tests: Serum electrolytes, (particularly potassium), CO2, creatinine and BUN should be determined frequently
during the first few months of furosemide therapy and periodically thereafter. Serum and urine electrolyte determinations
are particularly important when the patient is vomiting profusely or receiving parenteral fluids. Abnormalities should be
corrected or the drug temporarily withdrawn. Other medications may also influence serum electrolytes.
Reversible elevations of BUN may occur and are associated with dehydration, which should be avoided, particularly in
patients with renal insufficiency.
Urine and blood glucose should be checked periodically in diabetics receiving furosemide, even in those suspected of
latent diabetes.
Furosemide may lower serum levels of calcium (rarely cases of tetany have been reported) and magnesium. Accordingly,
serum levels of these electrolytes should be determined periodically.
In premature infants furosemide may precipitate nephrocalcinosis/nephrolithiasis, therefore renal function must be
monitored and renal ultrasonography performed. (See PRECAUTIONS, Pediatric Use.)
Drug Interactions: Furosemide may increase the ototoxic potential of aminoglycoside antibiotics, especially in the
presence of impaired renal function. Except in lifethreatening situations, avoid this combination.
Furosemide should not be used concomitantly with ethacrynic acid because of the possibility of ototoxicity. Patients
receiving high doses of salicylates concomitantly with furosemide, as in rheumatic diseases, may experience salicylate
toxicity at lower doses because of competitive renal excretory sites.
There is a risk of ototoxic effects if cisplatin and furosemide are given concomitantly. In addition, nephrotoxicity of
nephrotoxic drugs such as cisplatin may be enhanced if furosemide is not given in lower doses and with positive fluid
balance when used to achieve forced diuresis during cisplatin treatment.
Furosemide has a tendency to antagonize the skeletal muscle relaxing effect of tubocurarine and may potentiate the action
of succinylcholine.
Lithium generally should not be given with diuretics because they reduce lithium's renal clearance and add a high risk of
lithium toxicity.
Furosemide combined with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers may lead to
severe hypotension and deterioration in renal function, including renal failure. An interruption or reduction in the dosage
of furosemide, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers may be necessary.
Furosemide may add to or potentiate the therapeutic effect of other antihypertensive drugs. Potentiation occurs with
ganglionic or peripheral adrenergic blocking drugs.
Furosemide may decrease arterial responsiveness to norepinephrine. However, norepinephrine may still be used
effectively.
In isolated cases, intravenous administration of furosemide within 24 hours of taking chloral hydrate may lead to flushing,
sweating attacks, restlessness, nausea, increase in blood pressure, and tachycardia. Use of furosemide concomitantly
with chloral hydrate is therefore not recommended.
Phenytoin interferes directly with renal action of furosemide.
Methotrexate and other drugs that, like furosemide, undergo significant renal tubular secretion may reduce the effect of
furosemide. Conversely, furosemide may decrease renal elimination of other drugs that undergo tubular secretion. High
dose treatment of both furosemide and these other drugs may result in elevated serum levels of these drugs and may
potentiate their toxicity as well as the toxicity of furosemide.
Furosemide can increase the risk of cephalosporininduced nephrotoxicity even in the setting of minor or transient renal
impairment.
Concomitant use of cyclosporine and furosemide is associated with increased risk of gouty arthritis secondary to
furosemideinduced hyperuricemia and cyclosporine impairment of renal urate excretion.
One study in six subjects demonstrated that the combination of furosemide and acetylsalicylic acid temporarily reduced
creatinine clearance in patients with chronic renal insufficiency. There are case reports of patients who developed
increased BUN, serum creatinine and serum potassium levels, and weight gain when furosemide was used in conjunction
with NSAIDs.
Literature reports indicate that coadministration of indomethacin may reduce the natriuretic and antihypertensive effects
of furosemide in some patients by inhibiting prostaglandin synthesis. Indomethacin may also affect plasma renin levels,
aldosterone excretion, and renin profile evaluation. Patients receiving both indomethacin and furosemide should be
observed closely to determine if the desired diuretic and/or antihypertensive effect of furosemide is achieved.
Reference ID: 2999360
(1)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FUROSEMIDE
FUROSEMIDE
INJECTION, USP
INJECTION, USP
10 mg/mL
10 mg/mL
Rx Only
Rx Only bar code
Carcinogenesis, Mutagenesis, Impairment of Fertility: Furosemide was tested for carcinogenicity by oral administration
in one strain of mice and one strain of rats. A small but significantly increased incidence of mammary gland carcinomas
occurred in female mice at a dose 17.5 times the maximum human dose of 600 mg. There were marginal increases in
uncommon tumors in male rats at a dose of 15 mg/kg (slightly greater than the maximum human dose) but not at
30 mg/kg.
Furosemide was devoid of mutagenic activity in various strains of Salmonella typhimurium when tested in the presence
or absence of an in vitro metabolic activation system, and questionably positive for gene mutation in mouse lymphoma
cells in the presence of rat liver S9 at the highest dose tested. Furosemide did not induce sister chromatid exchange in
human cells in vitro, but other studies on chromosomal aberrations in human cells in vitro gave conflicting results. In
Chinese hamster cells it induced chromosomal damage but was questionably positive for sister chromatid exchange.
Studies on the induction by furosemide of chromosomal aberrations in mice were inconclusive. The urine of rats treated
with this drug did not induce gene conversion in Saccharomyces cerevisiae.
Furosemide produced no impairment of fertility in male or female rats, at 100 mg/kg/day (the maximum effective diuretic
dose in the rat and 8 times the maximal human dose of 600 mg/day).
Pregnancy: Teratogenic Effects: Pregnancy Category C. Furosemide has been shown to cause unexplained maternal
deaths and abortions in rabbits at 2, 4, and 8 times the maximal recommended human oral dose. There are no adequate
and wellcontrolled studies in pregnant women. Furosemide should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
Treatment during pregnancy requires monitoring of fetal growth because of the potential for higher fetal birth weights.
The effects of furosemide on embryonic and fetal development and on pregnant dams were studied in mice, rats and
rabbits.
Furosemide caused unexplained maternal deaths and abortions in the rabbit at the lowest dose of 25 mg/kg (2 times the
maximal recommended human oral dose of 600 mg/day). In another study, a dose of 50 mg/kg (4 times the maximal
recommended human oral dose of 600 mg/day) also caused maternal deaths and abortions when administered to rabbits
between Days 12 and 17 of gestation. In a third study, none of the pregnant rabbits survived an oral dose of 100 mg/kg.
Data from the above studies indicate fetal lethality that can precede maternal deaths.
The results of the mouse study and one of the three rabbit studies also showed an increased incidence and severity of
hydronephrosis (distention of the renal pelvis and, in some cases, of the ureters) in fetuses derived from the treated dams
as compared with the incidence of fetuses from the control group.
Nursing Mothers: Because it appears in breast milk, caution should be exercised when furosemide is administered to a
nursing mother.
Furosemide may inhibit lactation.
Pediatric
Use:
In
premature
infants
furosemide
may
precipitate
nephrocalcinosis/nephrolithiasis.
Nephrocalcinosis/nephrolithiasis has also been observed in children under 4 years of age with no history of prematurity
who have been treated chronically with furosemide. Monitor renal function, and renal ultrasonography should be
considered, in pediatric patients receiving furosemide.
If furosemide is administered to premature infants during the first weeks of life, it may increase the risk of persistence of
patent ductus arteriosus.
Renal calcifications (from barely visible on xray to staghorn) have occurred in some severely premature infants treated
with intravenous furosemide for edema due to patent ductus arteriosus and hyaline membrane disease. The concurrent
use of chlorothiazide has been reported to decrease hypercalcinuria and dissolve some calculi.
Geriatric Use: Controlled clinical studies of furosemide did not include sufficient numbers of subjects aged 65 and over
to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified
differences in responses between the elderly and younger patients. In general, dose selection for the elderly patient should
be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic,
renal or cardiac function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater
in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care
should be taken in dose selection and it may be useful to monitor renal function. (See PRECAUTIONS: General and
DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
Adverse reactions are categorized below by organ system and listed by decreasing severity.
Gastrointestinal System Reactions
1. Hepatic encephalopathy in patients with
6. Oral and gastric irritation
hepatocellular insufficiency
7. Cramping
2. Pancreatitis
8. Diarrhea
3. Jaundice (intrahepatic cholestatic jaundice)
9. Constipation
4. Increased liver enzymes
10. Nausea
5. Anorexia
11. Vomiting
Systemic Hypersensitivity Reactions
1. Severe anaphylactic or anaphylactoid reactions
3. Interstitial nephritis
(e.g. with shock)
4. Necrotizing angiitis
2. Systemic vasculitis
Central Nervous System Reactions
1. Tinnitus and hearing loss
5. Headache
2. Paresthesias
6. Blurred vision
3. Vertigo
7. Xanthopsia
4. Dizziness
Hematologic Reactions
1. Aplastic anemia
5. Leukopenia
2. Thrombocytopenia
6. Anemia
3. Agranulocytosis
7. Eosinophilia
4. Hemolytic anemia
DermatologicHypersensitivity Reactions
1. Exfoliative dermatitis
6. Urticaria
2. Bullous pemphigoid
7. Rash
3. Erythema multiforme
8. Pruritus
4. Purpura
9. StevensJohnson Syndrome
5. Photosensitivity
10. Toxic epidermal necrolysis
Cardiovascular Reaction
Other Reactions
1. Hyperglycemia
7. Urinary bladder spasm
2. Glycosuria
8. Thrombophlebitis
3. Hyperuricemia
9. Transient injection site pain following intramuscular
4. Muscle spasms
injection
5. Weakness
10. Fever
6. Restlessness
Whenever adverse reactions are moderate or severe, furosemide dosage should be reduced or therapy withdrawn.
OVERDOSAGE
The principal signs and symptoms of overdose with furosemide are dehydration, blood volume reduction, hypotension,
electrolyte imbalance, hypokalemia and hypochloremic alkalosis, and are extensions of its diuretic action.
The acute toxicity of furosemide has been determined in mice, rats and dogs. In all three, the oral LD50 exceeded
1000 mg/kg body weight, while the intravenous LD50 ranged from 300 to 680 mg/kg. The acute intragastric toxicity in
neonatal rats is 7 to 10 times that of adult rats.
The concentration of furosemide in biological fluids associated with toxicity or death is not known.
Treatment of overdosage is supportive and consists of replacement of excessive fluid and electrolyte losses. Serum
electrolytes, carbon dioxide level and blood pressure should be determined frequently. Adequate drainage must be
assured in patients with urinary bladder outlet obstruction (such as prostatic hypertrophy).
Hemodialysis does not accelerate furosemide elimination.
DOSAGE AND ADMINISTRATION
Adults
Parenteral therapy with Furosemide Injection should be used only in patients unable to take oral medication or in
emergency situations and should be replaced with oral therapy as soon as practical.
Edema
The usual initial dose of furosemide is 20 to 40 mg given as a single dose, injected intramuscularly or intravenously. The
intravenous dose should be given slowly (1 to 2 minutes). Ordinarily a prompt diuresis ensues. If needed, another dose
may be administered in the same manner 2 hours later or the dose may be increased. The dose may be raised by 20 mg
and given not sooner than 2 hours after the previous dose until the desired diuretic effect has been obtained. This
individually determined single dose should then be given once or twice daily.
Therapy should be individualized according to patient response to gain maximal therapeutic response and to determine
the minimal dose needed to maintain that response. Close medical supervision is necessary.
When furosemide is given for prolonged periods, careful clinical observation and laboratory monitoring are particularly
advisable. (See PRECAUTIONS: Laboratory Tests.)
If the physician elects to use high dose parenteral therapy, add the furosemide to either Sodium Chloride Injection USP,
Lactated Ringer's Injection USP, or Dextrose (5%) Injection USP after pH has been adjusted to above 5.5, and administer
as a controlled intravenous infusion at a rate not greater than 4 mg/min. Furosemide Injection is a buffered alkaline
solution with a pH of about 9 and drug may precipitate at pH values below 7. Care must be taken to ensure that the pH of
the prepared infusion solution is in the weakly alkaline to neutral range. Acid solutions, including other parenteral
medications (e.g., labetalol, ciprofloxacin, amrinone, milrinone) must not be administered concurrently in the same
infusion because they may cause precipitation of the furosemide. In addition, furosemide injection should not be added
to a running intravenous line containing any of these acidic products.
Acute Pulmonary Edema
The usual initial dose of furosemide is 40 mg injected slowly intravenously (over 1 to 2 minutes). If a satisfactory response
does not occur within 1 hour, the dose may be increased to 80 mg injected slowly intravenously (over 1 to 2 minutes).
If necessary, additional therapy (e.g., digitalis, oxygen) may be administered concomitantly.
Geriatric Patients
In general, dose selection for the elderly patient should be cautious, usually starting at the low end of the dosing range.
(See PRECAUTIONS: Geriatric Use.)
Pediatric Patients
Parenteral therapy should be used only in patients unable to take oral medication or in emergency situations and should
be replaced with oral therapy as soon as practical.
The usual initial dose of Furosemide Injection (intravenously or intramuscularly) in pediatric patients is 1 mg/kg body
weight and should be given slowly under close medical supervision. If the diuretic response to the initial dose is not
satisfactory, dosage may be increased by 1 mg/kg not sooner than 2 hours after the previous dose, until the desired
diuretic effect has been obtained. Doses greater than 6 mg/kg body weight are not recommended.
Literature reports suggest that the maximum dose for premature infants should not exceed 1 mg/kg/day. (See
WARNINGS, Pediatric Use.)
Furosemide Injection should be inspected visually for particulate matter and discoloration before administration.
HOW SUPPLIED: Furosemide Injection, USP (10 mg/mL)
NDC 0517570225
2 mL single dose amber colored vials
Boxes of 25
NDC 0517570425
4 mL single dose amber colored vials
Boxes of 25
NDC 0517571025
10 mL single dose amber colored vials
Boxes of 25
Do not use if solution is discolored.
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) (See USP Controlled Room
Temperature). Protect from light.
IN5702
Rev. 6/11
MG #7822
1. Orthostatic hypotension may occur and be aggravated by alcohol, barbiturates or narcotics.
AMERICAN
2. Increase in cholesterol and triglyceride serum levels.
REGENT, INC.
SHIRLEY, NY 11967
Reference ID: 2999360
(2)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018579s029lbl.pdf', 'application_number': 18579, 'submission_type': 'SUPPL ', 'submission_number': 29}
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NDA 018565/S-020
Page 4
PRESERVATIVE-FREE
DURAMORPH (morphine sulfate injection, USP)
Rx only
Not For Use in Continuous Microinfusion Devices
DESCRIPTION
Morphine is the most important alkaloid of opium and is a phenanthrene derivative. It is
available as the sulfate salt, having the following structural formula: structural formula
7,8-Didehydro-4,5-epoxy-17-methyl-(5α,6α)-morphinan-3,6-diol sulfate (2:1)
(salt), pentahydrate
(C17H19NO3)2 • H2SO4 • 5H2O
Molecular Weight is 758.83
Preservative-free DURAMORPH (morphine sulfate injection, USP) is a sterile, nonpyrogenic,
isobaric solution of morphine sulfate, free of antioxidants, preservatives or other potentially
neurotoxic additives and is intended for intravenous, epidural or intrathecal administration as a
narcotic analgesic. Each milliliter contains morphine sulfate 0.5 mg or 1 mg and sodium chloride
9 mg in Water for Injection. pH range is 2.5-6.5. Each 10 mL DOSETTE ampul of
DURAMORPH is intended for SINGLE USE ONLY. Discard any unused portion. DO NOT
HEAT-STERILIZE.
CLINICAL PHARMACOLOGY
Morphine produces a wide spectrum of pharmacologic effects including analgesia, dysphoria,
euphoria, somnolence, respiratory depression, diminished gastrointestinal motility and physical
dependence. Opiate analgesia involves at least three anatomical areas of the central nervous
system: the periaqueductal-periventricular gray matter, the ventromedial medulla and the spinal
cord. A systematically administered opiate may produce analgesia by acting at any, all or some
combination of these distinct regions. Morphine interacts predominantly with the µ-receptor. The
µ-binding sites of opioids are very discretely distributed in the human brain, with high densities
of sites found in the posterior amygdala, hypothalamus, thalamus, nucleus caudatus, putamen
and certain cortical areas. They are also found on the terminal axons of primary afferents within
laminae I and II (substantia gelatinosa) of the spinal cord and in the spinal nucleus of the
trigeminal nerve.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018565/S-020
Page 5
Morphine has an apparent volume of distribution ranging from 1.0 to 4.7 L/kg after intravenous
dosage. Protein binding is low, about 36%, and muscle tissue binding is reported as 54%. A
blood-brain barrier exists, and when morphine is introduced outside of the CNS (e.g.,
intravenously), plasma concentrations of morphine remain higher than the corresponding CSF
morphine levels. Conversely, when morphine is injected into the intrathecal space, it diffuses out
into the systemic circulation slowly, accounting for the long duration of action of morphine
administered by this route.
Morphine has a total plasma clearance which ranges from 0.9 to 1.2 L/kg/h (liters/kilogram/hour)
in postoperative patients, but shows considerable interindividual variation. The major pathway of
clearance is hepatic glucuronidation to morphine-3-glucuronide, which is pharmacologically
inactive. The major excretion path of the conjugate is through the kidneys, with about 10% in the
feces. Morphine is also eliminated by the kidneys, 2 to 12% being excreted unchanged in the
urine. Terminal half-life is commonly reported to vary from 1.5 to 4.5 hours, although the longer
half-lives were obtained when morphine levels were monitored over protracted periods with very
sensitive radioimmunoassay methods. The accepted elimination half-life in normal subjects is
1.5 to 2 hours.
“Selective” blockade of pain sensation is possible by neuraxial application of morphine. In
addition, duration of analgesia may be much longer by this route compared to systemic
administration. However, CNS effects, associated with systemic administration, are still seen.
These include respiratory depression, sedation, nausea and vomiting, pruritus and urinary
retention. In particular, both early and late respiratory depression (up to 24 hours post dosing)
have been reported following neuraxial administration. Circulation of the spinal fluid may also
result in high concentrations of morphine reaching the brain stem directly.
The incidence of unwanted CNS effects, including delayed respiratory depression, associated
with neuraxial application of morphine, is related to the circulatory dynamics of the epidural
venous plexus and the spinal fluid. The lipid solubility and degree of ionization of morphine
plays an important part in both the onset and duration of analgesia and the CNS effects.
Morphine has a pKa 7.9, with an octanol/water partition coefficient of 1.42 at pH 7.4. At this pH,
the tertiary amino group in each of the opioids is mostly ionized, making the molecule water
soluble. Morphine, with additional hydroxyl groups on the molecule, is significantly more water
soluble than any other opioid in clinical use.
Morphine, injected into the epidural space, is rapidly absorbed into the general circulation.
Absorption is so rapid that the plasma concentration-time profiles closely resemble those
obtained after intravenous or intramuscular administration. Peak plasma concentrations
averaging 33–40 ng/mL (range 5–62 ng/mL) are achieved within 10 to 15 minutes after
administration of 3 mg of morphine. Plasma concentrations decline in a multiexponential
fashion. The terminal half-life is reported to range from 39 to 249 minutes (mean of 90±34.3
min) and, though somewhat shorter, is similar in magnitude as values reported after intravenous
and intramuscular administration (1.5–4.5 h). CSF concentrations of morphine, after epidural
doses of 2 to 6 mg in postoperative patients, have been reported to be 50 to 250 times higher than
corresponding plasma concentrations. The CSF levels of morphine exceed those in plasma after
only 15 minutes and are detectable for as long as 20 hours after the injection of 2 mg of epidural
morphine. Approximately 4% of the dose injected epidurally reaches the CSF. This corresponds
to the relative minimum effective epidural and intrathecal doses of 5 mg and 0.25 mg,
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respectively. The disposition of morphine in the CSF follows a biphasic pattern, with an early
half-life of 1.5 h and a late phase half-life of about 6 h. Morphine crosses the dura slowly, with
an absorption half-life across the dura averaging 22 minutes. Maximum CSF concentrations are
seen 60–90 minutes after injection. Minimum effective CSF concentrations for postoperative
analgesia average 150 ng/mL (range < 1-380 ng/mL).
The intrathecal route of administration circumvents meningeal diffusion barriers and, therefore,
lower doses of morphine produce comparable analgesia to that induced by the epidural route.
After intrathecal bolus injection of morphine, there is a rapid initial distribution phase lasting 15–
30 minutes and a half-life in the CSF of 42–136 min (mean 90±16 min). Derived from limited
data, it appears that the disposition of morphine in the CSF, from 15 minutes postintrathecal
administration to the end of a six-hour observation period, represents a combination of the
distribution and elimination phases. Morphine concentrations in the CSF averaged
332±137 ng/mL at 6 hours, following a bolus dose of 0.3 mg of morphine. The apparent volume
of distribution of morphine in the intrathecal space is about 22±8 mL.
Time-to-peak plasma concentrations, however, are similar (5-10 min) after either epidural or
intrathecal bolus administration of morphine. Maximum plasma morphine concentrations after
0.3 mg intrathecal morphine have been reported from < 1 to 7.8 ng/mL. The minimum analgesic
morphine plasma concentration during Patient-Controlled Analgesia (PCA) has been reported as
20–40 ng/mL, suggesting that any analgesic contribution from systemic redistribution would be
minimal after the first 30–60 minutes with epidural administration and virtually absent with
intrathecal administration of morphine.
INDICATIONS AND USAGE
DURAMORPH is a systemic narcotic analgesic for administration by the intravenous, epidural
or intrathecal routes. It is used for the management of pain not responsive to non-narcotic
analgesics. DURAMORPH administered epidurally or intrathecally, provides pain relief for
extended periods without attendant loss of motor, sensory or sympathetic function.
Not For Use in Continuous Microinfusion Devices
CONTRAINDICATIONS
DURAMORPH is contraindicated in those medical conditions which would preclude the
administration of opioids by the intravenous route—allergy to morphine or other opiates, acute
bronchial asthma, upper airway obstruction.
DURAMORPH, like all opioid analgesics, may cause severe hypotension in an individual whose
ability to maintain blood pressure has already been compromised by a depleted blood volume or
a concurrent administration of drugs, such as phenothiazines or general anesthetics. (See also
PRECAUTIONS: Use with Other Central Nervous System Depressants.)
WARNINGS
Morphine sulfate may be habit forming. (See DRUG ABUSE AND DEPENDENCE.)
Overdoses may cause respiratory depression, coma and death.
DURAMORPH administration should be limited to use by those familiar with the management
of respiratory depression. Rapid intravenous administration may result in chest wall rigidity.
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Prior to any epidural or intrathecal drug administration, the physician should be familiar
with patient conditions (such as infection at the injection site, bleeding diathesis,
anticoagulant therapy, etc.) which call for special evaluation of the benefit versus risk
potential.
In the case of epidural or intrathecal administration, DURAMORPH should be administered by
or under the direction of a physician experienced in the techniques and familiar with the patient
management problems associated with epidural or intrathecal drug administration. Because
epidural administration has been associated with less potential for immediate or late adverse
effects than intrathecal administration, the epidural route should be used whenever possible.
SEVERE RESPIRATORY DEPRESSION UP TO 24 HOURS FOLLOWING EPIDURAL OR
INTRATHECAL ADMINISTRATION HAS BEEN REPORTED.
BECAUSE OF THE RISK OF SEVERE ADVERSE EFFECTS WHEN THE
EPIDURAL OR INTRATHECAL ROUTE OF ADMINISTRATION IS
EMPLOYED, PATIENTS MUST BE OBSERVED IN A FULLY EQUIPPED
AND STAFFED ENVIRONMENT FOR AT LEAST 24 HOURS AFTER THE
INITIAL DOSE.
THE FACILITY MUST BE EQUIPPED TO RESUSCITATE PATIENTS WITH SEVERE
OPIATE OVERDOSAGE, AND THE PERSONNEL MUST BE FAMILIAR WITH THE USE
AND LIMITATIONS OF SPECIFIC NARCOTIC ANTAGONISTS (NALOXONE,
NALTREXONE) IN SUCH CASES.
Tolerance and Myoclonic Activity
PATIENTS SOMETIMES MANIFEST UNUSUAL ACCELERATION OF NEURAXIAL
MORPHINE REQUIREMENTS, WHICH MAY CAUSE CONCERN REGARDING
SYSTEMIC ABSORPTION AND THE HAZARDS OF LARGE DOSES; THESE PATIENTS
MAY BENEFIT FROM HOSPITALIZATION AND DETOXIFICATION. TWO CASES OF
MYOCLONIC-LIKE SPASM OF THE LOWER EXTREMITIES HAVE BEEN REPORTED
IN PATIENTS RECEIVING MORE THAN 20 MG/DAY OF INTRATHECAL MORPHINE.
AFTER DETOXIFICATION, IT MIGHT BE POSSIBLE TO RESUME TREATMENT AT
LOWER DOSES, AND SOME PATIENTS HAVE BEEN SUCCESSFULLY CHANGED
FROM CONTINUOUS EPIDURAL MORPHINE TO CONTINUOUS INTRATHECAL
MORPHINE. REPEAT DETOXIFICATION MAY BE INDICATED AT A LATER DATE.
THE UPPER DAILY DOSAGE LIMIT FOR EACH PATIENT DURING CONTINUING
TREATMENT MUST BE INDIVIDUALIZED.
PRECAUTIONS
General
Control of pain by neuraxial opiate delivery is always accompanied by considerable risk to the
patients and requires a high level of skill to be successfully accomplished. The task of treating
these patients must be undertaken by experienced clinical teams, well-versed in patient selection,
evolving technology and emerging standards of care. For safety reasons, it is recommended that
administration of DURAMORPH by the epidural or intrathecal routes be limited to the lumbar
area. Intrathecal use has been associated with a higher incidence of respiratory depression than
epidural use.
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Seizures may result from high doses. Patients with known seizure disorders should be carefully
observed for evidence of morphine-induced seizure activity.
Use in Patients with Increased Intracranial Pressure or Head Injury
DURAMORPH should be used with extreme caution in patients with head injury or increased
intracranial pressure. Pupillary changes (miosis) from morphine may obscure the existence,
extent and course of intracranial pathology. High doses of neuraxial morphine may produce
myoclonic events (see WARNINGS and ADVERSE REACTIONS). Clinicians should
maintain a high index of suspicion for adverse drug reactions when evaluating altered mental
status or movement abnormalities in patients receiving this modality of treatment.
Use in Chronic Pulmonary Disease
Care is urged in using this drug in patients who have a decreased respiratory reserve (e.g.,
emphysema, severe obesity, kyphoscoliosis or paralysis of the phrenic nerve). DURAMORPH
should not be given in cases of chronic asthma, upper airway obstruction or in any other chronic
pulmonary disorder without due consideration of the known risk of acute respiratory failure
following morphine administration in such patients.
Use in Hepatic or Renal Disease
The elimination half-life of morphine may be prolonged in patients with reduced metabolic rates
and with hepatic and/or renal dysfunction. Hence, care should be exercised in administering
DURAMORPH epidurally to patients with these conditions, since high blood morphine levels,
due to reduced clearance, may take several days to develop.
Use in Biliary Surgery or Disorders of the Biliary Tract
As significant morphine is released into the systemic circulation from neuraxial administration,
the ensuing smooth muscle hypertonicity may result in biliary colic.
Use with Disorders of the Urinary System
Initiation of neuraxial opiate analgesia is frequently associated with disturbances of micturition,
especially in males with prostatic enlargement. Early recognition of difficulty in urination and
prompt intervention in cases of urinary retention is indicated.
Use in Ambulatory Patients
Patients with reduced circulating blood volume, impaired myocardial function or on
sympatholytic drugs should be monitored for the possible occurrence of orthostatic hypotension,
a frequent complication in single-dose neuraxial morphine analgesia.
Use with Other Central Nervous System Depressants
The depressant effects of morphine are potentiated by the presence of other CNS depressants
such as alcohol, sedatives, antihistaminics or psychotropic drugs. Use of neuroleptics in
conjunction with neuraxial morphine may increase the risk of respiratory depression.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Morphine is without known carcinogenic or mutagenic effects and is not known to impair
fertility at non-narcotic doses in animals, but studies of the carcinogenic and mutagenic potential
or the effect on fertility of DURAMORPH have not been conducted.
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Pregnancy
Teratogenic Effects—Pregnancy Category C
Morphine sulfate is not teratogenic in rats at 35 mg/kg/day (thirty-five times the usual human
dose) but does result in increased pup mortality and growth retardation at doses that narcotize the
animal (> 10 mg/kg/day, ten times the usual human dose). DURAMORPH should only be given
to pregnant women when no other method of controlling pain is available and means are at hand
to manage the delivery and perinatal care of the opiate-dependent infant.
Nonteratogenic Effects
Infants born to mothers who have been taking morphine chronically may exhibit withdrawal
symptoms.
Labor and Delivery
Intravenous morphine readily passes into the fetal circulation and may result in respiratory
depression in the neonate. Naloxone and resuscitative equipment should be available for reversal
of narcotic-induced respiratory depression in the neonate. In addition, intravenous morphine may
reduce the strength, duration and frequency of uterine contraction resulting in prolonged labor.
Epidurally and intrathecally administered morphine readily passes into the fetal circulation and
may result in respiratory depression of the neonate. Controlled clinical studies have shown that
epidural administration has little or no effect on the relief of labor pain.
Nursing Mothers
Morphine is excreted in maternal milk. Effects on the nursing infant are not known.
Pediatric Use
Adequate studies, to establish the safety and effectiveness of spinal morphine in pediatric
patients, have not been performed, and usage in this population is not recommended.
Geriatric Use
The pharmacodynamic effects of neuraxial morphine in the elderly are more variable than in the
younger population. Patients will vary widely in the effective initial dose, rate of development of
tolerance and the frequency and magnitude of associated adverse effects as the dose is increased.
Initial doses should be based on careful clinical observation following “test doses”, after making
due allowances for the effects of the patient’s age and infirmity on his/her ability to clear the
drug, particularly in patients receiving epidural morphine.
Elderly patients may be more susceptible to respiratory depression and/or respiratory arrest
following administration of morphine.
ADVERSE REACTIONS
The most serious adverse experience encountered during administration of DURAMORPH is
respiratory depression and/or respiratory arrest. This depression and/or respiratory arrest may be
severe and could require intervention. (See WARNINGS and OVERDOSAGE.) Because of
delay in maximum CNS effect with intravenously administered drug (30 min), rapid
administration may result in overdosing. Single-dose neuraxial administration may result in acute
or delayed respiratory depression for periods at least as long as 24 hours.
Tolerance and Myoclonus
See WARNINGS for discussion of these and related hazards.
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While low doses of intravenously administered morphine have little effect on cardiovascular
stability, high doses are excitatory, resulting from sympathetic hyperactivity and increase in
circulating catecholamines. Excitation of the central nervous system, resulting in convulsions,
may accompany high doses of morphine given intravenously. Dysphoric reactions may occur
after any size dose and toxic psychoses have been reported.
Pruritus
Single-dose epidural or intrathecal administration is accompanied by a high incidence of
pruritus that is dose-related but not confined to the site of administration. Pruritus, following
continuous infusion of epidural or intrathecal morphine, is occasionally reported in the literature;
these reactions are poorly understood as to their cause.
Urinary Retention
Urinary retention, which may persist 10 to 20 hours following single epidural or intrathecal
administration, is a frequent side effect and must be anticipated primarily in male patients, with a
somewhat lower incidence in females. Also frequently reported in the literature is the occurrence
of urinary retention during the first several days of hospitalization for the initiation of continuous
intrathecal or epidural morphine therapy. Patients who develop urinary retention have responded
to cholinomimetic treatment and/or judicious use of catheters (see PRECAUTIONS).
Constipation
Constipation is frequently encountered during continuous infusion of morphine; this can usually
be managed by conventional therapy.
Headache
Lumbar puncture-type headache is encountered in a significant minority of cases for several days
following intrathecal catheter implantation; this, generally, responds to bed rest and/or other
conventional therapy.
Other
Other adverse experiences reported following morphine therapy include—Dizziness, euphoria,
anxiety, hypotension, confusion, reduced male potency, decreased libido in men and
women, and menstrual irregularities including amenorrhea, depression of cough reflex,
interference with thermal regulation and oliguria. Evidence of histamine release such as
urticaria, wheals and/or local tissue irritation may occur. Nausea and vomiting are frequently
seen in patients following morphine administration.
Pruritus, nausea/vomiting and urinary retention, if associated with continuous infusion therapy,
may respond to intravenous administration of a low dose of naloxone (0.2 mg). The risks of
using narcotic antagonists in patients chronically receiving narcotic therapy should be
considered.
In general, side effects are amenable to reversal by narcotic antagonists.
NALOXONE INJECTION AND RESUSCITATIVE EQUIPMENT SHOULD
BE IMMEDIATELY AVAILABLE FOR ADMINISTRATION IN CASE OF
LIFE-THREATENING OR INTOLERABLE SIDE EFFECTS AND
WHENEVER DURAMORPH THERAPY IS BEING INITIATED.
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DRUG ABUSE AND DEPENDENCE
Controlled Substance
Morphine sulfate is a Schedule II narcotic under the United States Controlled Substance Act (21
U.S.C. 801-886).
Morphine is the most commonly cited prototype for narcotic substances that possess an
addiction-forming or addiction-sustaining liability. A patient may be at risk for developing a
dependence to morphine if used improperly or for overly long periods of time. As with all potent
opioids which are µ-agonists, tolerance as well as psychological and physical dependence to
morphine may develop irrespective of the route of administration (intravenous, intramuscular,
intrathecal, epidural or oral). Individuals with a prior history of opioid or other substance abuse
or dependence, being more apt to respond to the euphorogenic and reinforcing properties of
morphine, would be considered to be at greater risk.
Care must be taken to avert withdrawal in patients who have been maintained on parenteral/oral
narcotics when epidural or intrathecal administration is considered. Withdrawal symptoms may
occur when morphine is discontinued abruptly or upon administration of a narcotic antagonist.
OVERDOSAGE
PARENTERAL ADMINISTRATION OF NARCOTICS IN PATIENTS RECEIVING
EPIDURAL OR INTRATHECAL MORPHINE MAY RESULT IN OVERDOSAGE.
Overdosage of morphine is characterized by respiratory depression, with or without concomitant
CNS depression. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may
occur. Since respiratory arrest may result either through direct depression of the respiratory
center or as the result of hypoxia, primary attention should be given to the establishment of
adequate respiratory exchange through provision of a patent airway and institution of assisted, or
controlled, ventilation. The narcotic antagonist, naloxone, is a specific antidote. An initial dose
of 0.4 to 2 mg of naloxone should be administered intravenously, simultaneously with
respiratory resuscitation. If the desired degree of counteraction and improvement in respiratory
function is not obtained, naloxone may be repeated at 2- to 3-minute intervals. If no response is
observed after 10 mg of naloxone has been administered, the diagnosis of narcotic-induced, or
partial narcotic-induced, toxicity should be questioned. Intramuscular or subcutaneous
administration may be used if the intravenous route is not available.
As the duration of effect of naloxone is considerably shorter than that of epidural or intrathecal
morphine, repeated administration may be necessary. Patients should be closely observed for
evidence of renarcotization.
DOSAGE AND ADMINISTRATION
DURAMORPH is intended for intravenous, epidural or intrathecal administration.
Not For Use in Continuous Microinfusion Devices
Intravenous Administration
Dosage
The initial dose of morphine should be 2 mg to 10 mg/70 kg of body weight. No information is
available regarding the use of DURAMORPH in patients under the age of 18.
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NDA 018565/S-020
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Geriatric Use
Administer with extreme caution. (See PRECAUTIONS.)
Epidural Administration
DURAMORPH SHOULD BE ADMINISTERED EPIDURALLY BY OR UNDER THE
DIRECTION OF A PHYSICIAN EXPERIENCED IN THE TECHNIQUE OF EPIDURAL
ADMINISTRATION AND WHO IS THOROUGHLY FAMILIAR WITH THE LABELING. IT
SHOULD BE ADMINISTERED ONLY IN SETTINGS WHERE ADEQUATE PATIENT
MONITORING IS POSSIBLE. RESUSCITATIVE EQUIPMENT AND A SPECIFIC
ANTAGONIST (NALOXONE INJECTION) SHOULD BE IMMEDIATELY AVAILABLE
FOR THE MANAGEMENT OF RESPIRATORY DEPRESSION AS WELL AS
COMPLICATIONS WHICH MIGHT RESULT FROM INADVERTENT INTRATHECAL OR
INTRAVASCULAR INJECTION. (NOTE: INTRATHECAL DOSAGE IS USUALLY 1/10
THAT OF EPIDURAL DOSAGE.) PATIENT MONITORING SHOULD BE CONTINUED
FOR AT LEAST 24 HOURS AFTER EACH DOSE, SINCE DELAYED RESPIRATORY
DEPRESSION MAY OCCUR.
Proper placement of a needle or catheter in the epidural space should be verified before
DURAMORPH is injected.
Acceptable techniques for verifying proper placement include: a) aspiration to check for absence
of blood or cerebrospinal fluid, or b) administration of 5 mL (3 mL in obstetric patients) of 1.5%
PRESERVATIVE-FREE Lidocaine and Epinephrine (1:200,000) Injection and then observe the
patient for lack of tachycardia (this indicates that vascular injection has not been made) and lack
of sudden onset of segmental anesthesia (this indicates that intrathecal injection has not been
made).
Epidural Adult Dosage
Initial injection of 5 mg in the lumbar region may provide satisfactory pain relief for up to 24
hours. If adequate pain relief is not achieved within one hour, careful administration of
incremental doses of 1 to 2 mg at intervals sufficient to assess effectiveness may be given. No
more than 10 mg/24 hr should be administered.
Thoracic administration has been shown to dramatically increase the incidence of early and late
respiratory depression even at doses of 1 to 2 mg.
Geriatric Use
Administer with extreme caution. (See PRECAUTIONS.)
Epidural Pediatric Use
No information on use in pediatric patients is available. (See PRECAUTIONS.)
Intrathecal Administration
NOTE: INTRATHECAL DOSAGE IS USUALLY 1/10 THAT OF
EPIDURAL DOSAGE.
DURAMORPH SHOULD BE ADMINISTERED INTRATHECALLY BY OR UNDER THE
DIRECTION OF A PHYSICIAN EXPERIENCED IN THE TECHNIQUE OF INTRATHECAL
ADMINISTRATION AND WHO IS THOROUGHLY FAMILIAR WITH THE LABELING. IT
SHOULD BE ADMINISTERED ONLY IN SETTINGS WHERE ADEQUATE PATIENT
MONITORING IS POSSIBLE. RESUSCITATIVE EQUIPMENT AND A SPECIFIC
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ANTAGONIST (NALOXONE INJECTION) SHOULD BE IMMEDIATELY AVAILABLE
FOR THE MANAGEMENT OF RESPIRATORY DEPRESSION AS WELL AS
COMPLICATIONS WHICH MIGHT RESULT FROM INADVERTENT INTRAVASCULAR
INJECTION. PATIENT MONITORING SHOULD BE CONTINUED FOR AT LEAST 24
HOURS AFTER EACH DOSE, SINCE DELAYED RESPIRATORY DEPRESSION MAY
OCCUR. RESPIRATORY DEPRESSION (BOTH EARLY AND LATE ONSET) HAS
OCCURRED MORE FREQUENTLY FOLLOWING INTRATHECAL ADMINISTRATION
THAN EPIDURAL ADMINISTRATION.
Intrathecal Adult Dosage
A single injection of 0.2 to 1 mg may provide satisfactory pain relief for up to 24 hours.
(CAUTION: THIS IS ONLY 0.4 TO 2 ML OF THE 5 MG/10 ML AMPUL OR 0.2 TO 1 ML
OF THE 10 MG/10 ML AMPUL OF DURAMORPH). DO NOT INJECT INTRATHECALLY
MORE THAN 2 ML OF THE 5 MG/10 ML AMPUL OR 1 ML OF THE 10 MG/10 ML
AMPUL. USE IN THE LUMBAR AREA ONLY IS RECOMMENDED. Repeated intrathecal
injections of DURAMORPH are not recommended. A constant intravenous infusion of
naloxone, 0.6 mg/hr, for 24 hours after intrathecal injection may be used to reduce the incidence
of potential side effects.
Geriatric Use
Administer with extreme caution. (See PRECAUTIONS.)
Repeat Dosage
If pain recurs, alternative routes of administration should be considered, since experience with
repeated doses of morphine by the intrathecal route is limited.
Intrathecal Pediatric Use
No information on use in pediatric patients is available. (See PRECAUTIONS.)
SAFETY AND HANDLING INSTRUCTIONS
DURAMORPH is supplied in sealed ampuls. Accidental dermal exposure should be
treated by the removal of any contaminated clothing and rinsing the affected area
with water.
Each ampul of DURAMORPH contains a potent narcotic which has been associated
with abuse and dependence among health care providers. Due to the limited
indications for this product, the risk of overdosage and the risk of its diversion
and abuse, it is recommended that special measures be taken to control this
product within the hospital or clinic.
DURAMORPH should be subject to rigid accounting, rigorous control of wastage
and restricted access.
Parenteral drug products should be inspected for particulate matter and
discoloration prior to administration, whenever solution and container permit.
DO NOT USE IF COLOR IS DARKER THAN PALE YELLOW, IF IT IS
DISCOLORED IN ANY OTHER WAY OR IF IT CONTAINS A
PRECIPITATE.
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NDA 018565/S-020
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HOW SUPPLIED
Preservative-Free DURAMORPH (morphine sulfate injection, USP) is available in amber
DOSETTE ampuls for intravenous, epidural and intrathecal administration:
5 mg/10 mL (0.5 mg/mL) packaged in 10s (NDC 60977-016-02)
10 mg/10 mL (1 mg/mL) packaged in 10s (NDC 60977-017-01)
Also available from Baxter: INFUMORPH (Preservative-free Morphine Sulfate Sterile Solution)
200 mg/20 mL (10 mg/mL) and 500 mg/20 mL (25 mg/mL) for epidural and intrathecal
administration via a continuous microinfusion device.
Storage
PROTECT FROM LIGHT. Store in carton at 20°- 25°C (68°- 77°F), excursions permitted
to 15°- 30°C (59°- 86°F) [see USP Controlled Room Temperature] until ready to use. DO
NOT FREEZE. DURAMORPH contains no preservative or antioxidant. DISCARD ANY
UNUSED PORTION. DO NOT HEAT-STERILIZE.
Baxter, Dosette, Duramorph, and Infumorph are trademarks of Baxter International, Inc., or its
subsidiaries. company logo
Manufactured by
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
For Product Inquiry 1 800 ANA DRUG (1-800-262-3784)
MLT 01070,B
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018565s020lbl.pdf', 'application_number': 18565, 'submission_type': 'SUPPL ', 'submission_number': 20}
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1
PRESERVATIVE-FREE
DURAMORPH (morphine sulfate injection, USP)
CII
Rx only
DESCRIPTION
Morphine is the most important alkaloid of opium and is a phenanthrene derivative. It is
available as the sulfate salt, having the following structural formula:
7,8-Didehydro-4,5-epoxy-17-methyl-(5Į,6Į)-morphinan-3,6-diol sulfate (2:1)
(salt), pentahydrate
(C17H19NO3)2 • H2SO4 • 5H2O
Molecular Weight is 758.83
Preservative-free DURAMORPH (morphine sulfate injection, USP) is a sterile,
nonpyrogenic, isobaric solution of morphine sulfate, free of antioxidants, preservatives or
other potentially neurotoxic additives and is intended for intravenous, epidural or
intrathecal administration as a narcotic analgesic. Each milliliter contains morphine
sulfate 0.5 mg or 1 mg and sodium chloride 9 mg in Water for Injection. pH range is
2.5-6.5. Each 10 mL DOSETTE ampul of DURAMORPH is intended for SINGLE USE
ONLY. Discard any unused portion. DO NOT HEAT-STERILIZE.
CLINICAL PHARMACOLOGY
Morphine produces a wide spectrum of pharmacologic effects including analgesia,
dysphoria, euphoria, somnolence, respiratory depression, diminished gastrointestinal
motility and physical dependence. Opiate analgesia involves at least three anatomical
areas of the central nervous system: the periaqueductal-periventricular gray matter, the
ventromedial medulla and the spinal cord. A systematically administered opiate may
produce analgesia by acting at any, all or some combination of these distinct regions.
Morphine interacts predominantly with the P-receptor. The P-binding sites of opioids are
very discretely distributed in the human brain, with high densities of sites found in the
posterior amygdala, hypothalamus, thalamus, nucleus caudatus, putamen and certain
cortical areas. They are also found on the terminal axons of primary afferents within
laminae I and II (substantia gelatinosa) of the spinal cord and in the spinal nucleus of the
trigeminal nerve.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
2
Morphine has an apparent volume of distribution ranging from 1.0 to 4.7 L/kg after
intravenous dosage. Protein binding is low, about 36%, and muscle tissue binding is
reported as 54%. A blood-brain barrier exists, and when morphine is introduced outside
of the CNS (e.g., intravenously), plasma concentrations of morphine remain higher than
the corresponding CSF morphine levels. Conversely, when morphine is injected into the
intrathecal space, it diffuses out into the systemic circulation slowly, accounting for the
long duration of action of morphine administered by this route.
Morphine has a total plasma clearance which ranges from 0.9 to 1.2 L/kg/h
(liters/kilogram/hour) in postoperative patients, but shows considerable interindividual
variation. The major pathway of clearance is hepatic glucuronidation to
morphine-3-glucuronide, which is pharmacologically inactive. The major excretion path
of the conjugate is through the kidneys, with about 10% in the feces. Morphine is also
eliminated by the kidneys, 2 to 12% being excreted unchanged in the urine. Terminal
half-life is commonly reported to vary from 1.5 to 4.5 hours, although the longer
half-lives were obtained when morphine levels were monitored over protracted periods
with very sensitive radioimmunoassay methods. The accepted elimination half-life in
normal subjects is 1.5 to 2 hours.
“Selective” blockade of pain sensation is possible by neuraxial application of morphine.
In addition, duration of analgesia may be much longer by this route compared to systemic
administration. However, CNS effects, associated with systemic administration, are still
seen. These include respiratory depression, sedation, nausea and vomiting, pruritus and
urinary retention. In particular, both early and late respiratory depression (up to 24 hours
post dosing) have been reported following neuraxial administration. Circulation of the
spinal fluid may also result in high concentrations of morphine reaching the brain
stem directly.
The incidence of unwanted CNS effects, including delayed respiratory depression,
associated with neuraxial application of morphine, is related to the circulatory dynamics
of the epidural venous plexus and the spinal fluid. The lipid solubility and degree of
ionization of morphine plays an important part in both the onset and duration of analgesia
and the CNS effects. Morphine has a pKa 7.9, with an octanol/water partition coefficient
of 1.42 at pH 7.4. At this pH, the tertiary amino group in each of the opioids is mostly
ionized, making the molecule water soluble. Morphine, with additional hydroxyl groups
on the molecule, is significantly more water soluble than any other opioid in clinical use.
Morphine, injected into the epidural space, is rapidly absorbed into the general
circulation. Absorption is so rapid that the plasma concentration-time profiles closely
resemble those obtained after intravenous or intramuscular administration. Peak plasma
concentrations averaging 33–40 ng/mL (range 5–62 ng/mL) are achieved within 10 to 15
minutes after administration of 3 mg of morphine. Plasma concentrations decline in a
multiexponential fashion. The terminal half-life is reported to range from 39 to 249
minutes (mean of 90±34.3 min) and, though somewhat shorter, is similar in magnitude as
values reported after intravenous and intramuscular administration (1.5–4.5 h). CSF
concentrations of morphine, after epidural doses of 2 to 6 mg in postoperative patients,
have been reported to be 50 to 250 times higher than corresponding plasma
concentrations. The CSF levels of morphine exceed those in plasma after only 15 minutes
and are detectable for as long as 20 hours after the injection of 2 mg of epidural
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3
morphine. Approximately 4% of the dose injected epidurally reaches the CSF. This
corresponds to the relative minimum effective epidural and intrathecal doses of 5 mg and
0.25 mg, respectively. The disposition of morphine in the CSF follows a biphasic pattern,
with an early half-life of 1.5 h and a late phase half-life of about 6 h. Morphine crosses
the dura slowly, with an absorption half-life across the dura averaging 22 minutes.
Maximum CSF concentrations are seen 60–90 minutes after injection. Minimum
effective CSF concentrations for postoperative analgesia average 150 ng/mL
(range < 1-380 ng/mL).
The intrathecal route of administration circumvents meningeal diffusion barriers and,
therefore, lower doses of morphine produce comparable analgesia to that induced by the
epidural route. After intrathecal bolus injection of morphine, there is a rapid initial
distribution phase lasting 15–30 minutes and a half-life in the CSF of 42–136 min (mean
90±16 min). Derived from limited data, it appears that the disposition of morphine in the
CSF, from 15 minutes postintrathecal administration to the end of a six-hour observation
period, represents a combination of the distribution and elimination phases. Morphine
concentrations in the CSF averaged 332±137 ng/mL at 6 hours, following a bolus dose of
0.3 mg of morphine. The apparent volume of distribution of morphine in the intrathecal
space is about 22±8 mL.
Time-to-peak plasma concentrations, however, are similar (5-10 min) after either epidural
or intrathecal bolus administration of morphine. Maximum plasma morphine
concentrations after 0.3 mg intrathecal morphine have been reported from < 1 to
7.8 ng/mL. The minimum analgesic morphine plasma concentration during
Patient-Controlled Analgesia (PCA) has been reported as 20–40 ng/mL, suggesting that
any analgesic contribution from systemic redistribution would be minimal after the first
30–60 minutes with epidural administration and virtually absent with intrathecal
administration of morphine.
INDICATIONS AND USAGE
DURAMORPH is a systemic narcotic analgesic for administration by the intravenous,
epidural or intrathecal routes. It is used for the management of pain not responsive to
non-narcotic analgesics. DURAMORPH administered epidurally or intrathecally,
provides pain relief for extended periods without attendant loss of motor, sensory or
sympathetic function.
CONTRAINDICATIONS
DURAMORPH is contraindicated in those medical conditions which would preclude the
administration of opioids by the intravenous route—allergy to morphine or other opiates,
acute bronchial asthma, upper airway obstruction.
DURAMORPH, like all opioid analgesics, may cause severe hypotension in an individual
whose ability to maintain blood pressure has already been compromised by a depleted
blood volume or a concurrent administration of drugs, such as phenothiazines or general
anesthetics. (See also PRECAUTIONS: Use with Other Central Nervous System
Depressants.)
WARNINGS
Morphine sulfate may be habit forming. (See DRUG ABUSE AND DEPENDENCE.)
Overdoses may cause respiratory depression, coma and death.
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DURAMORPH administration should be limited to use by those familiar with the
management of respiratory depression. Rapid intravenous administration may result in
chest wall rigidity.
Prior to any epidural or intrathecal drug administration, the physician should be
familiar with patient conditions (such as infection at the injection site, bleeding
diathesis, anticoagulant therapy, etc.) which call for special evaluation of the benefit
versus risk potential.
In the case of epidural or intrathecal administration, DURAMORPH should be
administered by or under the direction of a physician experienced in the techniques and
familiar with the patient management problems associated with epidural or intrathecal
drug administration. Because epidural administration has been associated with less
potential for immediate or late adverse effects than intrathecal administration, the
epidural route should be used whenever possible.
SEVERE RESPIRATORY DEPRESSION UP TO 24 HOURS FOLLOWING
EPIDURAL OR INTRATHECAL ADMINISTRATION HAS BEEN REPORTED.
BECAUSE OF THE RISK OF SEVERE ADVERSE EFFECTS WHEN THE
EPIDURAL OR INTRATHECAL ROUTE OF ADMINISTRATION IS
EMPLOYED, PATIENTS MUST BE OBSERVED IN A FULLY EQUIPPED
AND STAFFED ENVIRONMENT FOR AT LEAST 24 HOURS AFTER THE
INITIAL DOSE.
THE FACILITY MUST BE EQUIPPED TO RESUSCITATE PATIENTS WITH
SEVERE OPIATE OVERDOSAGE, AND THE PERSONNEL MUST BE FAMILIAR
WITH THE USE AND LIMITATIONS OF SPECIFIC NARCOTIC ANTAGONISTS
(NALOXONE, NALTREXONE) IN SUCH CASES.
Tolerance and Myoclonic Activity
PATIENTS SOMETIMES MANIFEST UNUSUAL ACCELERATION OF
NEURAXIAL MORPHINE REQUIREMENTS, WHICH MAY CAUSE CONCERN
REGARDING SYSTEMIC ABSORPTION AND THE HAZARDS OF LARGE
DOSES; THESE PATIENTS MAY BENEFIT FROM HOSPITALIZATION AND
DETOXIFICATION. TWO CASES OF MYOCLONIC-LIKE SPASM OF THE
LOWER EXTREMITIES HAVE BEEN REPORTED IN PATIENTS RECEIVING
MORE THAN 20 MG/DAY OF INTRATHECAL MORPHINE. AFTER
DETOXIFICATION, IT MIGHT BE POSSIBLE TO RESUME TREATMENT AT
LOWER DOSES, AND SOME PATIENTS HAVE BEEN SUCCESSFULLY
CHANGED FROM CONTINUOUS EPIDURAL MORPHINE TO CONTINUOUS
INTRATHECAL MORPHINE. REPEAT DETOXIFICATION MAY BE INDICATED
AT A LATER DATE. THE UPPER DAILY DOSAGE LIMIT FOR EACH PATIENT
DURING CONTINUING TREATMENT MUST BE INDIVIDUALIZED.
PRECAUTIONS
General
Control of pain by neuraxial opiate delivery is always accompanied by considerable risk
to the patients and requires a high level of skill to be successfully accomplished. The task
of treating these patients must be undertaken by experienced clinical teams, well-versed
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5
in patient selection, evolving technology and emerging standards of care. For safety
reasons, it is recommended that administration of DURAMORPH by the epidural or
intrathecal routes be limited to the lumbar area. Intrathecal use has been associated with a
higher incidence of respiratory depression than epidural use.
Seizures may result from high doses. Patients with known seizure disorders should be
carefully observed for evidence of morphine-induced seizure activity.
Use in Patients with Increased Intracranial Pressure or Head Injury
DURAMORPH should be used with extreme caution in patients with head injury or
increased intracranial pressure. Pupillary changes (miosis) from morphine may obscure
the existence, extent and course of intracranial pathology. High doses of neuraxial
morphine may produce myoclonic events (see WARNINGS and ADVERSE
REACTIONS). Clinicians should maintain a high index of suspicion for adverse drug
reactions when evaluating altered mental status or movement abnormalities in patients
receiving this modality of treatment.
Use in Chronic Pulmonary Disease
Care is urged in using this drug in patients who have a decreased respiratory reserve (e.g.,
emphysema, severe obesity, kyphoscoliosis or paralysis of the phrenic nerve).
DURAMORPH should not be given in cases of chronic asthma, upper airway obstruction
or in any other chronic pulmonary disorder without due consideration of the known risk
of acute respiratory failure following morphine administration in such patients.
Use in Hepatic or Renal Disease
The elimination half-life of morphine may be prolonged in patients with reduced
metabolic rates and with hepatic and/or renal dysfunction. Hence, care should be
exercised in administering DURAMORPH epidurally to patients with these
conditions, since high blood morphine levels, due to reduced clearance, may take
several days to develop.
Use in Biliary Surgery or Disorders of the Biliary Tract
As significant morphine is released into the systemic circulation from neuraxial
administration, the ensuing smooth muscle hypertonicity may result in biliary colic.
Use with Disorders of the Urinary System
Initiation of neuraxial opiate analgesia is frequently associated with disturbances of
micturition, especially in males with prostatic enlargement. Early recognition of difficulty
in urination and prompt intervention in cases of urinary retention is indicated.
Use in Ambulatory Patients
Patients with reduced circulating blood volume, impaired myocardial function or on
sympatholytic drugs should be monitored for the possible occurrence of orthostatic
hypotension, a frequent complication in single-dose neuraxial morphine analgesia.
Use with Other Central Nervous System Depressants
The depressant effects of morphine are potentiated by the presence of other CNS
depressants such as alcohol, sedatives, antihistaminics or psychotropic drugs. Use of
neuroleptics in conjunction with neuraxial morphine may increase the risk of
respiratory depression.
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Carcinogenesis, Mutagenesis, Impairment of Fertility
Morphine is without known carcinogenic or mutagenic effects and is not known to impair
fertility at non-narcotic doses in animals, but studies of the carcinogenic and mutagenic
potential or the effect on fertility of DURAMORPH have not been conducted.
Pregnancy
Teratogenic Effects—Pregnancy Category C
Morphine sulfate is not teratogenic in rats at 35 mg/kg/day (thirty-five times the usual
human dose) but does result in increased pup mortality and growth retardation at doses
that narcotize the animal (> 10 mg/kg/day, ten times the usual human dose).
DURAMORPH should only be given to pregnant women when no other method of
controlling pain is available and means are at hand to manage the delivery and perinatal
care of the opiate-dependent infant.
Nonteratogenic Effects
Infants born to mothers who have been taking morphine chronically may exhibit
withdrawal symptoms.
Labor and Delivery
Intravenous morphine readily passes into the fetal circulation and may result in
respiratory depression in the neonate. Naloxone and resuscitative equipment should be
available for reversal of narcotic-induced respiratory depression in the neonate. In
addition, intravenous morphine may reduce the strength, duration and frequency of
uterine contraction resulting in prolonged labor.
Epidurally and intrathecally administered morphine readily passes into the fetal
circulation and may result in respiratory depression of the neonate. Controlled clinical
studies have shown that epidural administration has little or no effect on the relief of
labor pain.
Nursing Mothers
Morphine is excreted in maternal milk. Effects on the nursing infant are not known.
Pediatric Use
Adequate studies, to establish the safety and effectiveness of spinal morphine in pediatric
patients, have not been performed, and usage in this population is not recommended.
Geriatric Use
The pharmacodynamic effects of neuraxial morphine in the elderly are more variable than
in the younger population. Patients will vary widely in the effective initial dose, rate of
development of tolerance and the frequency and magnitude of associated adverse effects
as the dose is increased. Initial doses should be based on careful clinical observation
following “test doses”, after making due allowances for the effects of the patient’s age
and infirmity on his/her ability to clear the drug, particularly in patients receiving
epidural morphine.
Elderly patients may be more susceptible to respiratory depression and/or respiratory
arrest following administration of morphine.
ADVERSE REACTIONS
The most serious adverse experience encountered during administration of
DURAMORPH is respiratory depression and/or respiratory arrest. This depression and/or
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7
respiratory arrest may be severe and could require intervention. (See WARNINGS and
OVERDOSAGE.) Because of delay in maximum CNS effect with intravenously
administered drug (30 min), rapid administration may result in overdosing. Single-dose
neuraxial administration may result in acute or delayed respiratory depression for periods
at least as long as 24 hours.
Tolerance and Myoclonus
See WARNINGS for discussion of these and related hazards.
While low doses of intravenously administered morphine have little effect on
cardiovascular stability, high doses are excitatory, resulting from sympathetic
hyperactivity and increase in circulating catecholamines. Excitation of the central
nervous system, resulting in convulsions, may accompany high doses of morphine given
intravenously. Dysphoric reactions may occur after any size dose and toxic psychoses
have been reported.
Pruritus
Single-dose epidural or intrathecal administration is accompanied by a high incidence of
pruritus that is dose-related but not confined to the site of administration. Pruritus,
following continuous infusion of epidural or intrathecal morphine, is occasionally
reported in the literature; these reactions are poorly understood as to their cause.
Urinary Retention
Urinary retention, which may persist 10 to 20 hours following single epidural or
intrathecal administration, is a frequent side effect and must be anticipated primarily in
male patients, with a somewhat lower incidence in females. Also frequently reported in
the literature is the occurrence of urinary retention during the first several days of
hospitalization for the initiation of continuous intrathecal or epidural morphine therapy.
Patients who develop urinary retention have responded to cholinomimetic treatment
and/or judicious use of catheters (see PRECAUTIONS).
Constipation
Constipation is frequently encountered during continuous infusion of morphine; this can
usually be managed by conventional therapy.
Headache
Lumbar puncture-type headache is encountered in a significant minority of cases for
several days following intrathecal catheter implantation; this, generally, responds to bed
rest and/or other conventional therapy.
Other
Other adverse experiences reported following morphine therapy include—Dizziness,
euphoria, anxiety, hypotension, confusion, reduced male potency, decreased libido
in men and women, and menstrual irregularities including amenorrhea, depression
of cough reflex, interference with thermal regulation and oliguria. Evidence of
histamine release such as urticaria, wheals and/or local tissue irritation may occur.
Nausea and vomiting are frequently seen in patients following morphine administration.
Pruritus, nausea/vomiting and urinary retention, if associated with continuous infusion
therapy, may respond to intravenous administration of a low dose of naloxone (0.2 mg).
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8
The risks of using narcotic antagonists in patients chronically receiving narcotic therapy
should be considered.
In general, side effects are amenable to reversal by narcotic antagonists.
NALOXONE INJECTION AND RESUSCITATIVE EQUIPMENT SHOULD
BE IMMEDIATELY AVAILABLE FOR ADMINISTRATION IN CASE OF
LIFE-THREATENING OR INTOLERABLE SIDE EFFECTS AND
WHENEVER DURAMORPH THERAPY IS BEING INITIATED.
DRUG ABUSE AND DEPENDENCE
Controlled Substance
Morphine sulfate is a Schedule II narcotic under the United States Controlled Substance
Act (21 U.S.C. 801-886).
Morphine is the most commonly cited prototype for narcotic substances that possess an
addiction-forming or addiction-sustaining liability. A patient may be at risk for
developing a dependence to morphine if used improperly or for overly long periods of
time. As with all potent opioids which are P-agonists, tolerance as well as psychological
and physical dependence to morphine may develop irrespective of the route of
administration (intravenous, intramuscular, intrathecal, epidural or oral). Individuals with
a prior history of opioid or other substance abuse or dependence, being more apt to
respond to the euphorogenic and reinforcing properties of morphine, would be considered
to be at greater risk.
Care must be taken to avert withdrawal in patients who have been maintained on
parenteral/oral narcotics when epidural or intrathecal administration is considered.
Withdrawal symptoms may occur when morphine is discontinued abruptly or upon
administration of a narcotic antagonist.
OVERDOSAGE
PARENTERAL ADMINISTRATION OF NARCOTICS IN PATIENTS
RECEIVING EPIDURAL OR INTRATHECAL MORPHINE MAY RESULT IN
OVERDOSAGE.
Overdosage of morphine is characterized by respiratory depression, with or without
concomitant CNS depression. In severe overdosage, apnea, circulatory collapse, cardiac
arrest and death may occur. Since respiratory arrest may result either through direct
depression of the respiratory center or as the result of hypoxia, primary attention should
be given to the establishment of adequate respiratory exchange through provision of a
patent airway and institution of assisted, or controlled, ventilation. The narcotic
antagonist, naloxone, is a specific antidote. An initial dose of 0.4 to 2 mg of naloxone
should be administered intravenously, simultaneously with respiratory resuscitation. If
the desired degree of counteraction and improvement in respiratory function is not
obtained, naloxone may be repeated at 2- to 3-minute intervals. If no response is observed
after 10 mg of naloxone has been administered, the diagnosis of narcotic-induced, or
partial narcotic-induced, toxicity should be questioned. Intramuscular or subcutaneous
administration may be used if the intravenous route is not available.
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9
As the duration of effect of naloxone is considerably shorter than that of epidural or
intrathecal morphine, repeated administration may be necessary. Patients should be
closely observed for evidence of renarcotization.
DOSAGE AND ADMINISTRATION
DURAMORPH is intended for intravenous, epidural or intrathecal administration.
Intravenous Administration
Dosage
The initial dose of morphine should be 2 mg to 10 mg/70 kg of body weight. No
information is available regarding the use of DURAMORPH in patients under the
age of 18.
Geriatric Use
Administer with extreme caution. (See PRECAUTIONS.)
Epidural Administration
DURAMORPH SHOULD BE ADMINISTERED EPIDURALLY BY OR UNDER THE
DIRECTION OF A PHYSICIAN EXPERIENCED IN THE TECHNIQUE OF
EPIDURAL ADMINISTRATION AND WHO IS THOROUGHLY FAMILIAR WITH
THE LABELING. IT SHOULD BE ADMINISTERED ONLY IN SETTINGS WHERE
ADEQUATE PATIENT MONITORING IS POSSIBLE. RESUSCITATIVE
EQUIPMENT AND A SPECIFIC ANTAGONIST (NALOXONE INJECTION)
SHOULD BE IMMEDIATELY AVAILABLE FOR THE MANAGEMENT OF
RESPIRATORY DEPRESSION AS WELL AS COMPLICATIONS WHICH MIGHT
RESULT FROM INADVERTENT INTRATHECAL OR INTRAVASCULAR
INJECTION. (NOTE: INTRATHECAL DOSAGE IS USUALLY 1/10 THAT OF
EPIDURAL DOSAGE.) PATIENT MONITORING SHOULD BE CONTINUED
FOR AT LEAST 24 HOURS AFTER EACH DOSE, SINCE DELAYED
RESPIRATORY DEPRESSION MAY OCCUR.
Proper placement of a needle or catheter in the epidural space should be verified before
DURAMORPH is injected.
Acceptable techniques for verifying proper placement include: a) aspiration to check for
absence of blood or cerebrospinal fluid, or b) administration of 5 mL (3 mL in obstetric
patients) of 1.5% PRESERVATIVE-FREE Lidocaine and Epinephrine (1:200,000)
Injection and then observe the patient for lack of tachycardia (this indicates that vascular
injection has not been made) and lack of sudden onset of segmental anesthesia (this
indicates that intrathecal injection has not been made).
Epidural Adult Dosage
Initial injection of 5 mg in the lumbar region may provide satisfactory pain relief for up
to 24 hours. If adequate pain relief is not achieved within one hour, careful administration
of incremental doses of 1 to 2 mg at intervals sufficient to assess effectiveness may be
given. No more than 10 mg/24 hr should be administered.
Thoracic administration has been shown to dramatically increase the incidence of early
and late respiratory depression even at doses of 1 to 2 mg.
For continuous infusion, an initial dose of 2 to 4 mg/24 hours is recommended. Further
doses of 1 to 2 mg may be given if pain relief is not achieved initially.
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Geriatric Use
Administer with extreme caution. (See PRECAUTIONS.)
Epidural Pediatric Use
No information on use in pediatric patients is available. (See PRECAUTIONS.)
Intrathecal Administration
NOTE: INTRATHECAL DOSAGE IS USUALLY 1/10 THAT OF
EPIDURAL DOSAGE.
DURAMORPH SHOULD BE ADMINISTERED INTRATHECALLY BY OR UNDER
THE DIRECTION OF A PHYSICIAN EXPERIENCED IN THE TECHNIQUE OF
INTRATHECAL ADMINISTRATION AND WHO IS THOROUGHLY FAMILIAR
WITH THE LABELING. IT SHOULD BE ADMINISTERED ONLY IN SETTINGS
WHERE ADEQUATE PATIENT MONITORING IS POSSIBLE. RESUSCITATIVE
EQUIPMENT AND A SPECIFIC ANTAGONIST (NALOXONE INJECTION)
SHOULD BE IMMEDIATELY AVAILABLE FOR THE MANAGEMENT OF
RESPIRATORY DEPRESSION AS WELL AS COMPLICATIONS WHICH MIGHT
RESULT FROM INADVERTENT INTRAVASCULAR INJECTION. PATIENT
MONITORING SHOULD BE CONTINUED FOR AT LEAST 24 HOURS AFTER
EACH DOSE, SINCE DELAYED RESPIRATORY DEPRESSION MAY OCCUR.
RESPIRATORY DEPRESSION (BOTH EARLY AND LATE ONSET) HAS
OCCURRED MORE FREQUENTLY FOLLOWING INTRATHECAL
ADMINISTRATION THAN EPIDURAL ADMINISTRATION.
Intrathecal Adult Dosage
A single injection of 0.2 to 1 mg may provide satisfactory pain relief for up to 24 hours.
(CAUTION: THIS IS ONLY 0.4 TO 2 ML OF THE 5 MG/10 ML AMPUL OR 0.2 TO
1 ML OF THE 10 MG/10 ML AMPUL OF DURAMORPH). DO NOT INJECT
INTRATHECALLY MORE THAN 2 ML OF THE 5 MG/10 ML AMPUL OR 1 ML OF
THE 10 MG/10 ML AMPUL. USE IN THE LUMBAR AREA ONLY IS
RECOMMENDED. Repeated intrathecal injections of DURAMORPH are not
recommended. A constant intravenous infusion of naloxone, 0.6 mg/hr, for 24 hours after
intrathecal injection may be used to reduce the incidence of potential side effects.
Geriatric Use
Administer with extreme caution. (See PRECAUTIONS.)
Repeat Dosage
If pain recurs, alternative routes of administration should be considered, since experience
with repeated doses of morphine by the intrathecal route is limited.
Intrathecal Pediatric Use
No information on use in pediatric patients is available. (See PRECAUTIONS.)
SAFETY AND HANDLING INSTRUCTIONS
DURAMORPH is supplied in sealed ampuls. Accidental dermal exposure should be
treated by the removal of any contaminated clothing and rinsing the affected area
with water.
Each ampul of DURAMORPH contains a potent narcotic which has been associated
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11
with abuse and dependence among health care providers. Due to the limited
indications for this product, the risk of overdosage and the risk of its diversion
and abuse, it is recommended that special measures be taken to control this
product within the hospital or clinic.
DURAMORPH should be subject to rigid accounting, rigorous control of wastage
and restricted access.
Parenteral drug products should be inspected for particulate matter and
discoloration prior to administration, whenever solution and container permit.
DO NOT USE IF COLOR IS DARKER THAN PALE YELLOW, IF IT IS
DISCOLORED IN ANY OTHER WAY OR IF IT CONTAINS A
PRECIPITATE.
HOW SUPPLIED
Preservative-Free DURAMORPH (morphine sulfate injection, USP) is available in amber
DOSETTE ampuls for intravenous, epidural and intrathecal administration:
5 mg/10 mL (0.5 mg/mL) packaged in 10s (NDC 60977-016-02)
10 mg/10 mL (1 mg/mL) packaged in 10s (NDC 60977-017-01)
Also available from Baxter: INFUMORPH (Preservative-free Morphine Sulfate Sterile
Solution) 200 mg/20 mL (10 mg/mL) and 500 mg/20 mL (25 mg/mL) for epidural and
intrathecal administration via a continuous microinfusion device.
Storage
PROTECT FROM LIGHT. Store in carton at 20°- 25°C (68°- 77°F), excursions
permitted to 15°- 30°C (59°- 86°F) [see USP Controlled Room Temperature] until
ready to use. DO NOT FREEZE. DURAMORPH contains no preservative or
antioxidant. DISCARD ANY UNUSED PORTION. DO NOT HEAT-STERILIZE.
Baxter, Dosette, Duramorph, and Infumorph are trademarks of Baxter International, Inc.,
or its subsidiaries.
Manufactured by
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
For Product Inquiry 1 800 ANA DRUG (1-800-262-3784)
MLT-01070/2.0
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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2025-02-12T13:44:45.658525
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/018565s014lbl.pdf', 'application_number': 18565, 'submission_type': 'SUPPL ', 'submission_number': 14}
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CARDIZEM®
(diltiazem hydrochloride)
Direct Compression Tablets
Rx only
DESCRIPTION
Cardizem® (diltiazem hydrochloride) is a calcium ion cellular influx inhibitor (slow channel blocker or
calcium antagonist). Chemically, diltiazem hydrochloride is 1,5-Benzothiazepin-4(5H)-one, 3
(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-, monohydrochloride,(+)-cis-.
The chemical structure is: structural formula
Diltiazem hydrochloride is a white to off-white crystalline powder with a bitter taste. It is soluble in
water, methanol, and chloroform. It has a molecular weight of 450.98. Each tablet of Cardizem contains
30 mg, 60 mg, 90 mg, or 120 mg diltiazem hydrochloride.
Also contains: colloidal silicon dioxide, D&C Yellow #10 Aluminum Lake, FD&C Blue #1 Aluminum
Lake (30 mg and 90 mg), FD&C Yellow #6 Aluminum Lake (60 mg and 120 mg), hydroxypropyl
cellulose, hypromellose, lactose, magnesium stearate, methylparaben, microcrystalline cellulose, and
polyethylene glycol.
For oral administration.
CLINICAL PHARMACOLOGY
The therapeutic benefits achieved with Cardizem are believed to be related to its ability to inhibit the
influx of calcium ions during membrane depolarization of cardiac and vascular smooth muscle.
Mechanisms of Action
Although precise mechanisms of its antianginal action are still being delineated, Cardizem is believed to
act in the following ways:
1. Angina Due to Coronary Artery Spasm. Cardizem has been shown to be a potent dilator of coronary
arteries both epicardial and subendocardial. Spontaneous and ergonovine-induced coronary artery spasm
are inhibited by Cardizem.
Reference ID: 2868026
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For current labeling information, please visit https://www.fda.gov/drugsatfda
N18602/S-063
Page 3
2. Exertional Angina. Cardizem has been shown to produce increases in exercise tolerance, probably due
to its ability to reduce myocardial oxygen demand. This is accomplished via reductions in heart rate and
systemic blood pressure at submaximal and maximal exercise workloads.
In animal models, diltiazem interferes with the slow inward (depolarizing) current in excitable tissue. It
causes excitation-contraction uncoupling in various myocardial tissues without changes in the
configuration of the action potential. Diltiazem produces relaxation of coronary vascular smooth muscle
and dilation of both large and small coronary arteries at drug levels which cause little or no negative
inotropic effect. The resultant increases in coronary blood flow (epicardial and subendocardial) occur in
ischemic and nonischemic models and are accompanied by dose-dependent decreases in systemic blood
pressure and decreases in peripheral resistance.
Hemodynamic and Electrophysiologic Effects
Like other calcium antagonists, diltiazem decreases sinoatrial and atrioventricular conduction in isolated
tissues and has a negative inotropic effect in isolated preparations. In the intact animal, prolongation of
the AH interval can be seen at higher doses.
In man, diltiazem prevents spontaneous and ergonovine-provoked coronary artery spasm. It causes a
decrease in peripheral vascular resistance and a modest fall in blood pressure, and in exercise tolerance
studies in patients with ischemic heart disease, reduces the heart rate-blood pressure product for any given
workload. Studies to date, primarily in patients with good ventricular function, have not revealed
evidence of a negative inotropic effect; cardiac output, ejection fraction, and left ventricular end-diastolic
pressure have not been affected. There are as yet few data on the interaction of diltiazem and beta-
blockers. Resting heart rate is usually unchanged or slightly reduced by diltiazem.
Intravenous diltiazem in doses of 20 mg prolongs AH conduction time and AV node functional and
effective refractory periods approximately 20%. In a study involving single oral doses of 300 mg of
Cardizem in six normal volunteers, the average maximum PR prolongation was 14% with no instances of
greater than first-degree AV block. Diltiazem-associated prolongation of the AH interval is not more
pronounced in patients with first-degree heart block. In patients with sick sinus syndrome, diltiazem
significantly prolongs sinus cycle length (up to 50% in some cases).
Chronic oral administration of Cardizem in doses of up to 240 mg/day has resulted in small increases in
PR interval but has not usually produced abnormal prolongation.
Pharmacokinetics and Metabolism
Diltiazem is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass effect,
giving an absolute bioavailability (compared to intravenous dosing) of about 40%. Cardizem undergoes
extensive metabolism in which 2% to 4% of the unchanged drug appears in the urine. In vitro binding
studies show Cardizem is 70% to 80% bound to plasma proteins. Competitive in vitro ligand binding
studies have also shown Cardizem binding is not altered by therapeutic concentrations of digoxin,
hydrochlorothiazide, phenylbutazone, propranolol, salicylic acid, or warfarin. The plasma elimination
half-life following single or multiple drug administration is approximately 3.0 to 4.5 hours. Desacetyl
diltiazem is also present in the plasma at levels of 10% to 20% of the parent drug and is 25% to 50% as
potent as a coronary vasodilator as diltiazem. Minimum therapeutic plasma levels of Cardizem appear to
be in the range of 50 to 200 ng/mL. There is a departure from linearity when dose strengths are increased.
A study that compared patients with normal hepatic function to patients with cirrhosis found an increase
in half-life and a 69% increase in AUC (area-under-the-plasma concentration vs time curve) in the
hepatically impaired patients. A single study in nine patients with severely impaired renal functions
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showed no difference in the pharmacokinetic profile of diltiazem as compared to patients with normal
renal function.
Cardizem Tablets. Diltiazem is absorbed from the tablet formulation to about 98% of a reference
solution. Single oral doses of 30 to 120 mg of Cardizem tablets result in detectable plasma levels within
30 to 60 minutes and peak plasma levels 2 to 4 hours after drug administration. As the dose of Cardizem
tablets is increased from a daily dose of 120 mg (30 mg qid) to 240 mg (60 mg qid) daily, there is an
increase in area-under-the-curve of 2.3 times. When the dose is increased from 240 mg to 360 mg, daily,
there is an increase in area-under-the-curve of 1.8 times.
INDICATIONS AND USAGE
Cardizem is indicated for the management of chronic stable angina and angina due to coronary artery
spasm.
CONTRAINDICATIONS
Cardizem is contraindicated in (1) patients with sick sinus syndrome except in the presence of a
functioning ventricular pacemaker, (2) patients with second- or third-degree AV block except in the
presence of a functioning ventricular pacemaker, (3) patients with hypotension (less than 90 mm Hg
systolic), (4) patients who have demonstrated hypersensitivity to the drug, and (5) patients with acute
myocardial infarction and pulmonary congestion documented by x-ray on admission.
WARNINGS
1. Cardiac Conduction. Cardizem prolongs AV node refractory periods without significantly prolonging
sinus node recovery time, except in patients with sick sinus syndrome. This effect may rarely result in
abnormally slow heart rates (particularly in patients with sick sinus syndrome) or second- or third-degree
AV block (six of 1243 patients for 0.48%). Concomitant use of diltiazem with beta-blockers or digitalis
may result in additive effects on cardiac conduction. A patient with Prinzmetal's angina developed
periods of asystole (2 to 5 seconds) after a single dose of 60 mg of diltiazem (see ADVERSE
REACTIONS).
2. Congestive Heart Failure. Although diltiazem has a negative inotropic effect in isolated animal tissue
preparations, hemodynamic studies in humans with normal ventricular function have not shown a
reduction in cardiac index nor consistent negative effects on contractility (dp/dt). Experience with the use
of Cardizem alone or in combination with beta-blockers in patients with impaired ventricular function is
very limited. Caution should be exercised when using the drug in such patients.
3. Hypotension. Decreases in blood pressure associated with Cardizem therapy may occasionally result
in symptomatic hypotension.
4. Acute Hepatic Injury. In rare instances, significant elevations in enzymes such as alkaline
phosphatase, LDH, SGOT, SGPT, and other phenomena consistent with acute hepatic injury have been
noted. These reactions have been reversible upon discontinuation of drug therapy. The relationship to
Cardizem is uncertain in most cases, but probable in some (see PRECAUTIONS).
PRECAUTIONS
General
Cardizem (diltiazem hydrochloride) is extensively metabolized by the liver and excreted by the kidneys
and in bile. As with any drug given over prolonged periods, laboratory parameters of renal and hepatic
function should be monitored at regular intervals. The drug should be used with caution in patients with
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impaired renal or hepatic function. In subacute and chronic dog and rat studies designed to produce
toxicity, high doses of diltiazem were associated with hepatic damage. In special subacute hepatic
studies, oral doses of 125 mg/kg and higher in rats were associated with histological changes in the liver,
which were reversible when the drug was discontinued. In dogs, doses of 20 mg/kg were also associated
with hepatic changes; however, these changes were reversible with continued dosing. Dermatological
events (see ADVERSE REACTIONS) may be transient and may disappear despite continued use of
Cardizem. However, skin eruptions progressing to erythema multiforme and/or exfoliative dermatitis
have also been infrequently reported. Should a dermatologic reaction persist, the drug should be
discontinued.
Drug Interactions
Due to the potential for additive effects, caution and careful titration are warranted in patients receiving
Cardizem concomitantly with any agents known to affect cardiac contractility and/or conduction (see
WARNINGS).
Pharmacologic studies indicate that there may be additive effects in prolonging AV conduction when
using beta-blockers or digitalis concomitantly with Cardizem (see WARNINGS).
As with all drugs, care should be exercised when treating patients with multiple medications. Diltiazem is
both a substrate and an inhibitor of the cytochrome P-450 3A4 enzyme system. Other drugs that are
specific substrates, inhibitors, or inducers of this enzyme system may have a significant impact on the
efficacy and side effect profile of diltiazem. Patients taking other drugs that are substrates of CYP450
3A4, especially patients with renal and/or hepatic impairment, may require dosage adjustment when
starting or stopping concomitantly administered diltiazem in order to maintain optimum therapeutic blood
levels.
Anesthetics. The depression of cardiac contractility, conductivity, and automaticity, as well as the
vascular dilation associated with anesthetics, may be potentiated by calcium channel blockers. When
used concomitantly, anesthetics and calcium blockers should be titrated carefully.
Benzodiazepines. Studies showed that diltiazem increased the AUC of midazolam and triazolam by 3- to
4-fold and the Cmax by 2-fold, compared to placebo. The elimination half-life of midazolam and triazolam
also increased (1.5- to 2.5-fold) during coadministration with diltiazem. These pharmacokinetic effects
seen during diltiazem coadministration can result in increased clinical effects (e.g., prolonged sedation) of
both midazolam and triazolam.
Beta-blockers. Controlled and uncontrolled domestic studies suggest that concomitant use of Cardizem
and beta-blockers is usually well tolerated. Available data are not sufficient, however, to predict the
effects of concomitant treatment, particularly in patients with left ventricular dysfunction or cardiac
conduction abnormalities.
Administration of Cardizem (diltiazem hydrochloride) concomitantly with propranolol in five normal
volunteers resulted in increased propranolol levels in all subjects, and bioavailability of propranolol was
increased approximately 50%. In vitro, propranolol appears to be displaced from its binding sites by
diltiazem. If combination therapy is initiated or withdrawn in conjunction with propranolol, an
adjustment in the propranolol dose may be warranted (see WARNINGS).
Buspirone. In nine healthy subjects, diltiazem significantly increased the mean buspirone AUC 5.5-fold
and Cmax 4.1-fold compared to placebo. The T1/2 and Tmax of buspirone were not significantly affected by
diltiazem. Enhanced effects and increased toxicity of buspirone may be possible during concomitant
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administration with diltiazem. Subsequent dose adjustments may be necessary during coadministration,
and should be based on clinical assessment.
Carbamazepine. Concomitant administration of diltiazem with carbamazepine has been reported to
result in elevated serum levels of carbamazepine (40% to 72% increase) resulting in toxicity in some
cases. Patients receiving these drugs concurrently should be monitored for a potential drug interaction.
Cimetidine. A study in six healthy volunteers has shown a significant increase in peak diltiazem plasma
levels (58%) and area-under-the-curve (53%) after a 1-week course of cimetidine at 1200 mg per day and
a single dose of diltiazem 60 mg. Ranitidine produced smaller, nonsignificant increases. The effect may
be mediated by cimetidine's known inhibition of hepatic cytochrome P-450, the enzyme system
responsible for the first-pass metabolism of diltiazem. Patients currently receiving diltiazem therapy
should be carefully monitored for a change in pharmacological effect when initiating and discontinuing
therapy with cimetidine. An adjustment in the diltiazem dose may be warranted.
Clonidine. Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in
association with the use of clonidine concurrently with diltiazem. Monitor heart rate in patients receiving
concomitant diltiazem and clonidine.
Cyclosporine. A pharmacokinetic interaction between diltiazem and cyclosporine has been observed
during studies involving renal and cardiac transplant patients. In renal and cardiac transplant recipients, a
reduction of cyclosporine trough dose ranging from 15% to 48% was necessary to maintain
concentrations similar to those seen prior to the addition of diltiazem. If these agents are to be
administered concurrently, cyclosporine concentrations should be monitored, especially when diltiazem
therapy is initiated, adjusted, or discontinued. The effect of cyclosporine on diltiazem plasma
concentrations has not been evaluated.
Digitalis. Administration of Cardizem with digoxin in 24 healthy male subjects increased plasma digoxin
concentrations approximately 20%. Another investigator found no increase in digoxin levels in 12
patients with coronary artery disease. Since there have been conflicting results regarding the effect of
digoxin levels, it is recommended that digoxin levels be monitored when initiating, adjusting, and
discontinuing Cardizem therapy to avoid possible over- or under-digitalization (see WARNINGS).
Quinidine. Diltiazem significantly increases the AUC (0→∞) of quinidine by 51%, T1/2 by 36%, and
decreases its CLoral by 33%. Monitoring for quinidine adverse effects may be warranted and the dose
adjusted accordingly.
Rifampin. Coadministration of rifampin with diltiazem lowered the diltiazem plasma concentrations to
undetectable levels. Coadministration of diltiazem with rifampin or any known CYP3A4 inducer should
be avoided when possible, and alternative therapy considered.
Statins. Diltiazem is an inhibitor of CYP3A4 and has been shown to increase significantly the AUC of
some statins. The risk of myopathy and rhabdomyolysis with statins metabolized by CYP3A4 may be
increased with concomitant use of diltiazem. When possible, use a non-CYP3A4-metabolized statin
together with diltiazem; otherwise, dose adjustments for both diltiazem and the statin should be
considered along with close monitoring for signs and symptoms of any statin related adverse events.
In a healthy volunteer cross-over study (N=10), co-administration of a single 20 mg dose of simvastatin at
the end of a 14 day regimen with 120 mg BID diltiazem SR resulted in a 5-fold increase in mean
simvastatin AUC versus simvastatin alone. Subjects with increased average steady-state exposures of
Reference ID: 2868026
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diltiazem showed a greater fold increase in simvastatin exposure. Computer-based simulations showed
that at a daily dose of 480 mg of diltiazem, an 8- to 9-fold mean increase in simvastatin AUC can be
expected. If co-administration of simvastatin with diltiazem is required, limit the daily doses of
simvastatin to 10 mg and diltiazem to 240 mg.
In a ten-subject randomized, open label, 4-way cross-over study, co-administration of diltiazem (120 mg
BID diltiazem SR for 2 weeks) with a single 20 mg dose of lovastatin resulted in 3- to 4-fold increase in
mean lovastatin AUC and Cmax versus lovastatin alone. In the same study, there was no significant
change in 20 mg single dose pravastatin AUC and Cmax during diltiazem coadministration. Diltiazem
plasma levels were not significantly affected by lovastatin or pravastatin.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 24-month study in rats and a 21-month study in mice showed no evidence of carcinogenicity. There
was also no mutagenic response in in vitro bacterial tests. No intrinsic effect on fertility was observed in
rats.
Pregnancy
Category C. Reproduction studies have been conducted in mice, rats, and rabbits. Administration of
doses ranging from five to ten times greater (on a mg/kg basis) than the daily recommended therapeutic
dose has resulted in embryo and fetal lethality. These doses, in some studies, have been reported to cause
skeletal abnormalities. In the perinatal/postnatal studies, there was some reduction in early individual pup
weights and survival rates. There was an increased incidence of stillbirths at doses of 20 times the human
dose or greater.
There are no well-controlled studies in pregnant women; therefore, use Cardizem in pregnant women only
if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Diltiazem is excreted in human milk. One report suggests that concentrations in breast milk may
approximate serum levels. If use of Cardizem is deemed essential, an alternative method of infant feeding
should be instituted.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of diltiazem did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects. Other reported clinical experience has not
identified differences in responses between the elderly and younger patients. In general, dose selection
for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the
greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other
drug therapy.
ADVERSE REACTIONS
Serious adverse reactions have been rare in studies carried out to date, but it should be recognized that
patients with impaired ventricular function and cardiac conduction abnormalities usually have been
excluded.
In domestic placebo-controlled angina trials, the incidence of adverse reactions reported during Cardizem
therapy was not greater than that reported during placebo therapy.
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The following represent occurrences observed in clinical studies of angina patients. In many cases, the
relationship to Cardizem has not been established. The most common occurrences from these studies, as
well their frequency of presentation, are edema (2.4%), headache (2.1%), nausea (1.9%), dizziness
(1.5%), rash (1.3%), and asthenia (1.2%). In addition, the following events were reported infrequently
(less than 1%):
Cardiovascular: Angina, arrhythmia, AV block (first-degree), AV block (second- or third-degree – see
WARNINGS, Cardiac Conduction), bradycardia, bundle branch block, congestive heart failure, ECG
abnormality, flushing, hypotension, palpitations, syncope, tachycardia, ventricular extrasystoles.
Nervous System: Abnormal dreams, amnesia, depression, gait abnormality, hallucinations, insomnia,
nervousness, paresthesia, personality change, somnolence, tremor.
Gastrointestinal: Anorexia, constipation, diarrhea, dysgeusia, dyspepsia, mild elevations of alkaline
phosphatase, SGOT, SGPT, and LDH (see WARNINGS, Acute Hepatic Injury), thirst, vomiting,
weight increase.
Dermatological: Petechiae, photosensitivity, pruritus, urticaria.
Other: Amblyopia, CPK elevation, dry mouth, dyspnea, epistaxis, eye irritation, hyperglycemia,
hyperuricemia, impotence, muscle cramps, nasal congestion, nocturia, osteoarticular pain, polyuria,
sexual difficulties, tinnitus.
The following postmarketing events have been reported infrequently in patients receiving Cardizem:
acute generalized exanthematous pustulosis, allergic reactions, alopecia, angioedema (including facial or
periorbital edema), asystole, erythema multiforme (including Stevens-Johnson syndrome, toxic epidermal
necrolysis), extrapyramidal symptoms, gingival hyperplasia, hemolytic anemia, increased bleeding time,
leukopenia, photosensitivity (including lichenoid keratosis and hyperpigmentation at sun-exposed skin
areas), purpura, retinopathy, myopathy, and thrombocytopenia. There have been observed cases of a
generalized rash, some characterized as leukocytoclastic vasculitis. In addition, events such as
myocardial infarction have been observed, which are not readily distinguishable from the natural history
of the disease in these patients. A definitive cause and effect relationship between these events and
Cardizem therapy cannot yet be established. Exfoliative dermatitis (proven by rechallenge) has also been
reported.
OVERDOSAGE
The oral LD50s in mice and rats range from 415 to 740 mg/kg and from 560 to 810 mg/kg, respectively.
The intravenous LD50s in these species were 60 and 38 mg/kg, respectively. The oral LD50 in dogs is
considered to be in excess of 50 mg/kg, while lethality was seen in monkeys at 360 mg/kg.
The toxic dose in man is not known. Due to extensive metabolism, blood levels after a standard dose of
diltiazem can vary over tenfold, limiting the usefulness of blood levels in overdose cases.
There have been reports of diltiazem overdose in amounts ranging from <1 g to 18 g. Of cases with
known outcome, most patients recovered and in cases with a fatal outcome, the majority involved
multiple drug ingestion.
Events observed following diltiazem overdose included bradycardia, hypotension, heart block, and
cardiac failure. Most reports of overdose described some supportive medical measure and/or drug
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treatment. Bradycardia frequently responded favorably to atropine, as did heart block, although cardiac
pacing was also frequently utilized to treat heart block. Fluids and vasopressors were used to maintain
blood pressure, and in cases of cardiac failure, inotropic agents were administered. In addition, some
patients received treatment with ventilatory support, gastric lavage, activated charcoal, and/or intravenous
calcium.
The effectiveness of intravenous calcium administration to reverse the pharmacological effects of
diltiazem overdose has been inconsistent. In a few reported cases, overdose with calcium channel
blockers associated with hypotension and bradycardia that was initially refractory to atropine became
more responsive to atropine after the patients received intravenous calcium. In some cases intravenous
calcium has been administered (1 g calcium chloride or 3 g calcium gluconate) over 5 minutes and
repeated every 10 to 20 minutes as necessary. Calcium gluconate has also been administered as a
continuous infusion at a rate of 2 g per hour for 10 hours. Infusions of calcium for 24 hours or more may
be required. Patients should be monitored for signs of hypercalcemia.
In the event of overdose or exaggerated response, appropriate supportive measures should be employed in
addition to gastrointestinal decontamination. Diltiazem does not appear to be removed by peritoneal or
hemodialysis. Limited data suggest that plasmapheresis or charcoal hemoperfusion may hasten diltiazem
elimination following overdose. Based on the known pharmacological effects of diltiazem and/or
reported clinical experiences, the following measures may be considered:
Bradycardia: Administer atropine (0.60 to 1.0 mg). If there is no response to vagal blockade, administer
isoproterenol cautiously.
High-Degree AV Block: Treat as for bradycardia above. Fixed high-degree AV block should be treated
with cardiac pacing.
Cardiac Failure: Administer inotropic agents (isoproterenol, dopamine, or dobutamine) and diuretics.
Hypotension: Vasopressors (e.g., dopamine or norepinephrine).
Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and
experience of the treating physician.
DOSAGE AND ADMINISTRATION
Exertional Angina Pectoris Due to Atherosclerotic Coronary Artery Disease or Angina Pectoris at Rest
Due to Coronary Artery Spasm
Dosage must be adjusted to each patient's needs. Starting with 30 mg four times daily, before meals and
at bedtime, dosage should be increased gradually (given in divided doses three or four times daily) at 1- to
2-day intervals until optimum response is obtained. Although individual patients may respond to any
dosage level, the average optimum dosage range appears to be 180 to 360 mg/day. There are no available
data concerning dosage requirements in patients with impaired renal or hepatic function. If the drug must
be used in such patients, titration should be carried out with particular caution.
Concomitant Use With Other Cardiovascular Agents
1. Sublingual NTG may be taken as required to abort acute anginal attacks during Cardizem (diltiazem
hydrochloride) therapy.
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2. Prophylactic Nitrate Therapy. Cardizem may be safely coadministered with short- and long-acting
nitrates, but there have been no controlled studies to evaluate the antianginal effectiveness of this
combination.
3. Beta-blockers. (See WARNINGS and PRECAUTIONS).
HOW SUPPLIED
Cardizem 30-mg tablets are supplied in bottles of 100 (NDC 64455-771-47) and 500 (NDC 64455-771
55). Each green tablet is engraved with MARION on one side and 1771 on the other.
Cardizem 60-mg scored tablets are supplied in bottles of 100 (NDC 64455-772-47) and 500 (NDC 64455
772-55). Each yellow tablet is engraved with MARION on one side and 1772 on the other.
Cardizem 90-mg scored tablets are supplied in bottles of 100 (NDC 64455-791-47). Each green oblong
tablet is engraved with CARDIZEM on one side and 90 mg on the other.
Cardizem 120-mg scored tablets are supplied in bottles of 100 (NDC 64455-792-47). Each yellow
oblong tablet is engraved with CARDIZEM on one side and 120 mg on the other.
Store at 25°C (77°); excursions permitted to 15-30°C (59-86°) [see USP Controlled Room Temperature].
Avoid excessive humidity.
Caridizem® is a registered trademark of Biovail Laboratories International SRL
Manufactured by:
sanofi-aventis U.S. LLC
Kansas City, MO, 64137, USA
For:
BTA Pharmaceuticals, Inc.
(subsidiary of Biovail Corporation)
Bridgewater, NJ, 08807, USA
LB0078-01 Rev. 11/09
Reference ID: 2868026
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018602s063lbl.pdf', 'application_number': 18602, 'submission_type': 'SUPPL ', 'submission_number': 63}
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/18609s33s35lbl.pdf', 'application_number': 18609, 'submission_type': 'SUPPL ', 'submission_number': 33}
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3186262
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---------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
---------------------------------------------------------------------------------------------------------
/s/
----------------------------------------------------
THOMAS F OLIVER
09/07/2012
Reference ID: 3186262
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Heparin Sodium and 0.9% Sodium Chloride Injection
in Plastic Container
VIAFLEX Plus Container
DESCRIPTION
Heparin is a heterogenous group of straight-chain anionic mucopolysaccharides, called
glycosaminoglycans having anticoagulant properties. Although others may be present,
the main sugars occurring in heparin are: (1) α-L-iduronic acid 2-sulfate, (2) 2-deoxy-2
sulfamino-α-D-glucose 6-sulfate, (3) ß-D-glucuronic acid, (4) 2-acetamido-2-deoxy-α-D
glucose, and (5) α-L-iduronic acid. These sugars are present in decreasing amounts,
usually in the order (2) > (1) > (4) > (3) > (5), and are joined by glycosidic linkages,
forming polymers of varying sizes. Heparin is strongly acidic because of its content of
covalently linked sulfate and carboxylic acid groups. In heparin sodium, the acidic
protons of the sulfate units are partially replaced by sodium ions.
Structure of Heparin Sodium (representative subunits): Structure of heparin Sodium (representative subunits)
Heparin Sodium and 0.9% Sodium Chloride Injection is a buffered, sterile, nonpyrogenic
solution of Heparin Sodium, USP derived from porcine intestinal mucosa, standardized
for anticoagulant activity supplied in single dose containers for vascular administration. It
contains no antimicrobial agents. The potency is determined by a biological assay using a
USP reference standard based on units of heparin activity per milligram. Composition,
osmolarity, pH and ionic concentration are shown in Table 1.
1
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Table 1
Size (mL)
Composition
*Osmolarity (mOsmol/L) (actual)
pH
Ionic Concentration
(mEq/L)
Heparin Sodium, USP
(units/mL)
Sodium Chloride, USP
(NaCl) (g/L)
Dibasic Sodium Phosphate
Heptahydrate, USP
(Na2 HPO4 •7H2 O) (g/L)
Citric Acid Hydrous, USP
(C 6 H 8 0 7 •H 2 O) (g/L)
Sodium
Chloride
Phosphate
(as HPO4 = )
Citrate
1000 USP
Heparin
Units and
0.9%
Sodium
Chloride
Injection
500
2
9
4.34
0.4
322
7.0
(6.0 to 8.0)
186
154
32
(16 mmol/L)
6
2000 USP
Heparin
Units and
0.9%
Sodium
Chloride
Injection
1000
2
9
4.34
0.4
322
7.0
(6.0 to 8.0)
186
154
32
(16 mmol/L)
6
* Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L.
Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage.
This VIAFLEX Plus plastic container is fabricated from a specially formulated polyvinyl
chloride (PL 146 Plastic). VIAFLEX Plus on the container indicates the presence of a
drug additive in a drug vehicle. The VIAFLEX Plus plastic container system utilizes the
same container as the VIAFLEX plastic container system. The amount of water that can
permeate from inside the container into the overwrap is insufficient to affect the solution
significantly. Solutions in contact with the plastic container can leach out certain of its
chemical components in very small amounts within the expiration period, e.g., di-2
ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic
has been confirmed in tests in animals according to USP biological tests for plastic
containers as well as by tissue culture toxicity studies.
2
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CLINICAL PHARMACOLOGY
Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin
clots both in vitro and in vivo. Heparin acts at multiple sites in the normal coagulation
system. Small amounts of heparin in combination with antithrombin III (heparin cofactor)
can inhibit thrombosis by inactivating activated Factor X and inhibiting the conversion of
prothrombin to thrombin. Once active thrombosis has developed, larger amounts of
heparin can inhibit further coagulation by inactivating thrombin and preventing the
conversion of fibrinogen to fibrin. Heparin also prevents the formation of a stable fibrin
clot by inhibiting the activation of the fibrin stabilizing factor.
Bleeding time is usually unaffected by heparin. Clotting time is prolonged by full
therapeutic doses of heparin; in most cases, it is not measurably affected by low doses of
heparin.
Patients over 60 years of age, following similar doses of heparin, may have higher plasma
levels of heparin and longer activated partial thromboplastin times (APTTs) compared
with patients under 60 years of age.
Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots.
INDICATIONS AND USAGE
Heparin Sodium and 0.9% Sodium Chloride Injection at a concentration of 2 units/mL is
indicated as an aid in the maintenance of catheter patency.
CONTRAINDICATIONS
Heparin sodium should not be used in patients:
With severe thrombocytopenia;
In whom suitable blood coagulation tests - e.g., the whole-blood clotting time, partial
thromboplastin time, etc. - cannot be performed at appropriate intervals (this
contraindication refers to full-dose heparin; there is usually no need to monitor
coagulation parameters in patients receiving low-dose heparin);
With an uncontrollable active bleeding state (see Warnings), except when this is due to
disseminated intravascular coagulation.
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WARNINGS
Hypersensitivity
Patients with documented hypersensitivity to heparin should be given the drug only in
clearly life-threatening situations.
Hemorrhage
Hemorrhage can occur at virtually any site in patients receiving heparin. An unexplained
fall in hematocrit, fall in blood pressure, or any other unexplained symptom should lead
to serious consideration of hemorrhagic event.
Heparin sodium should be used with extreme caution in disease states in which there is
increased danger of hemorrhage. Some of the conditions in which increased danger of
hemorrhage exists are:
Cardiovascular - Subacute bacterial endocarditis. Severe hypertension.
Surgical - During and immediately following (a) spinal tap or spinal anesthesia or (b)
major surgery, especially involving the brain, spinal cord, or eye.
Hematologic - Conditions associated with increased bleeding tendencies, such as
hemophilia, thrombocytopenia, and some vascular purpuras.
Gastrointestinal - Ulcerative lesions and continuous tube drainage of the stomach or small
intestine.
Other - Menstruation, liver disease with impaired hemostasis.
Coagulation Testing
When heparin sodium is administered in therapeutic amounts, its dosage should be
regulated by frequent blood coagulation tests. If the coagulation test is unduly prolonged
or if hemorrhage occurs, heparin sodium should be discontinued promptly (see
Overdosage).
Thrombocytopenia
Thrombocytopenia has been reported to occur in patients receiving heparin with a
reported incidence of up to 30%. Platelet counts should be obtained at baseline and
periodically during heparin administration. Mild thrombocytopenia (count greater than
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
100,000/mm3) may remain stable or reverse even if heparin is continued. However,
thrombocytopenia of any degree should be monitored closely. If the count falls below
100,000/mm3 or if recurrent thrombosis develops (see Heparin-induced
Thrombocytopenia (HIT) With or Without Thrombosis), the heparin product should
be discontinued and, if necessary, an alternative anticoagulant administered.
Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis)
HIT is a serious immune-mediated reaction resulting from irreversible aggregation of
platelets. HIT may progress to the development of venous and arterial thromboses, a
condition referred to as HIT with thrombosis. Thrombotic events may also be the initial
presentation for HIT. These serious thromboembolic events include deep vein
thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke,
myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis,
gangrene of the extremities that may lead to amputation, and fatal outcomes.
Once HIT (with or without thrombosis) is diagnosed or strongly suspected, all heparin
sodium sources (including heparin flushes) should be discontinued and an alternative
anticoagulant used. Future use of heparin sodium, especially within 3 to 6 months
following the diagnosis of HIT (with or without thrombosis), and while patients test
positive for HIT antibodies, should be avoided.
Immune-mediated HIT is diagnosed based on clinical findings supplemented by
laboratory tests confirming the presence of antibodies to heparin sodium, or platelet
activation induced by heparin sodium. A drop in platelet count greater than 50% from
baseline is considered indicative of HIT. Platelet counts begin to fall 5 to 10 days after
exposure to heparin sodium in heparin sodium–naïve individuals, and reach a threshold
by days 7 to 14. In contrast, “rapid onset” HIT can occur very quickly (within 24 hours
following heparin sodium initiation), especially in patients with a recent exposure to
heparin sodium (i.e. previous 3 months). Thrombosis development shortly after
documenting thrombocytopenia is a characteristic finding in almost half of all patients
with HIT.
Thrombocytopenia of any degree should be monitored closely. If the platelet count falls
below 100,000/mm3 or if recurrent thrombosis develops, the heparin product should be
promptly discontinued and alternative anticoagulants considered if patients require
continued anticoagulation.
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Delayed Onset of HIT (With or Without Thrombosis)
Heparin-induced thrombocytopenia (with or without thrombosis) can occur up to several
weeks after the discontinuation of heparin therapy. Patients presenting with
thrombocytopenia or thrombosis after discontinuation of heparin sodium should be
evaluated for HIT (with or without thrombosis).
Other
Solutions containing sodium ion should be used with great care in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there
exists edema with sodium retention.
The intravenous administration of solutions can cause fluid and/or solute overloading
resulting in dilution of serum electrolyte concentrations, overhydration, congested states
or pulmonary edema. The risk of dilutional states is inversely proportional to the
electrolyte concentrations of the injections. The risk of solute overload causing congested
states with peripheral and pulmonary edema is directly proportional to the electrolyte
concentrations of the injections.
Excessive administration of potassium free solutions may result in significant
hypokalemia.
In patients with diminished renal function, administration may result in sodium retention.
PRECAUTIONS
General
Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) (With or Without
Thrombosis) and Delayed Onset of HIT (With or Without Thrombosis).
See WARNINGS.
Heparin Resistance
Increased resistance to heparin is frequently encountered in fever, thrombosis,
thrombophlebitis, infections with thrombosing tendencies, myocardial infarction,cancer
and in postsurgical patients.
Increased Risk in Older Patients, Especially Women
A higher incidence of bleeding has been reported in patients, particularly women, over 60
years of age.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Solutions Containing Sodium
These solutions should be used with caution in patients receiving corticosteroids or
corticotropin.
Laboratory Tests
Periodic platelet counts, hematocrits, and tests for occult blood in stool are recommended
during the entire course of heparin therapy, regardless of the route of administration (see
Dosage and Administration).
Drug Interactions
Oral anticoagulants: Heparin sodium may prolong the one-stage prothrombin time.
Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of
at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose
should elapse before blood is drawn if a valid prothrombin time is to be obtained.
Platelet inhibitors: Drugs such as acetylsalicylic acid, dextran, phenylbutazone,
ibuprofen, indomethacin, dipyridamole, hydroxychloroquine and others that interfere
with platelet-aggregation reactions (the main hemostatic defense of heparinized patients)
may induce bleeding and should be used with caution in patients receiving heparin
sodium.
Other interactions; Digitalis, tetracyclines, nicotine, or antihistamines may partially
counteract the anticoagulant action of heparin sodium.
Drug/Laboratory Tests Interactions
Hyperaminotransferasemia
Significant elevations of aminotransferase (SGOT [S-AST] and SGPT [S-ALT]) levels
have occurred in a high percentage of patients (and healthy subjects) who have received
heparin. Since aminotransferase determinations are important in the differential diagnosis
of myocardial infarction, liver disease, and pulmonary emboli, rises that might be caused
by drugs (like heparin) should be interpreted with caution.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term studies in animals have been performed to evaluate carcinogenic potential
of heparin. Also, no reproduction studies in animals have been performed concerning
mutagenesis or impairment of fertility.
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pregnancy
Teratogenic Effects
Pregnancy Category C
Animal reproduction studies have not been conducted with heparin sodium. It is not
known whether heparin sodium can cause fetal harm when administered to a pregnant
woman or can affect reproduction capacity. Heparin sodium should be given to a
pregnant woman only if clearly needed.
Nonteratogenic Effects: Heparin does not cross the placental barrier.
Nursing Mothers
Heparin is not excreted in human milk.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
See Dosage and Administration.
Geriatric Use
A higher incidence of bleeding has been reported in patients over 60 years of age,
especially women (see Precautions, General). Clinical studies indicate that lower doses
of heparin may be indicated in these patients (see Precautions, General and Clinical
Pharmacology).
Do not administer unless solution is clear and seal is intact.
ADVERSE REACTIONS
Hemorrhage
Hemorrhage is the chief complication that may result from heparin therapy (see
Warnings). An overly prolonged clotting time or minor bleeding during therapy can
usually be controlled by withdrawing the drug (see Overdosage). It should be
appreciated that gastrointestinal or urinary tract bleeding during anticoagulant
therapy may indicate the presence of an underlying occult lesion. Bleeding can occur
at any site but certain specific hemorrhage complications may be difficult to detect:
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Adrenal hemorrhage, with resultant acute adrenal insufficiency, has occurred during
anticoagulant therapy. Therefore, such treatment should be discontinued in patients who
develop signs and symptoms of acute adrenal hemorrhage and insufficiency. Initiation of
corrective therapy should not depend on laboratory confirmation of the diagnosis, since
any delay in an acute situation may result in the patient’s death.
Ovarian (corpus luteum) hemorrhage developed in a number of women of reproductive
age receiving short or long-term anticoagulant therapy. This complication if
unrecognized may be fatal.
Retroperitoneal hemorrhage.
Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) (With or
Without Thrombosis) and Delayed Onset of HIT (With or Without
Thrombosis).
See WARNINGS.
Local Irritation
Local irritation, erythema, mild pain, hematoma or ulceration may follow deep
subcutaneous (intrafat) injection of heparin sodium. These complications are much more
common after intramuscular use, and such use is not recommended.
Hypersensitivity
General hypersensitivity reactions have been reported, with chills, fever, and urticaria as
the most usual manifestations, and asthma, rhinitis, lacrimation, headache, nausea and
vomiting, and anaphylactoid reactions, including shock, occurring more rarely. Itching
and burning, especially on the plantar site of the feet, may occur. (See Warnings,
Precautions.)
Certain episodes of painful, ischemic, and cyanosed limbs have in the past been attributed
to allergic vasospastic reactions. Whether these are in fact identical to the
thrombocytopenia associated complications remains to be determined.
Miscellaneous
Osteoporosis following long-term administration of high-doses of heparin, cutaneous
necrosis after systemic administration, suppression of aldosterone synthesis, delayed
transient alopecia, priapism, and rebound hyperlipemia on discontinuation of heparin
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
sodium have also been reported. Significant elevations of aminotransferase (SGOT [S
AST] and SGPT [S-ALT]) levels have occurred in a high percentage of patients (and
healthy subjects) who have received heparin.
OVERDOSAGE
Symptoms
Bleeding is the chief sign of heparin overdosage. Nosebleeds, blood in urine or tarry
stools may be noted as the first sign of bleeding. Easy bruising or petechial formations
may precede frank bleeding.
Treatment
Neutralization of heparin effect.
When clinical circumstances (bleeding) require reversal of heparinization, protamine
sulfate (1% solution) by slow infusion will neutralize heparin sodium. No more than 50
mg should be administered, very slowly in any 10 minute period. Each mg of protamine
sulfate neutralizes approximately 100 USP heparin units. The amount of protamine
required decreases over time as heparin is metabolized. Although the metabolism of
heparin is complex, it may, for the purpose of choosing a protamine dose, be assumed to
have a half-life of about 1/2 hour after intravenous injection.
Administration of protamine sulfate can cause severe hypotensive and anaphylactoid
reactions. Because fatal reactions often resembling anaphylaxis have been reported, the
drug should be given only when resuscitation techniques and treatment of anaphylactoid
shock are readily available.
For additional information the labeling of Protamine Sulfate Injection, USP products
should be consulted.
DOSAGE AND ADMINISTRATION
Heparin sodium is not effective by oral administration and Heparin Sodium and 0.9%
Sodium Chloride Injection should not be given orally.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration whenever solution and container permit. Use of a
final filter is recommended during administration of all parenteral solutions, where
possible.
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Maintenance of Catheter Patency
Although the rate for infusion of the 2 units/mL formulation is dependent upon age,
weight, clinical condition of the patient and the procedure being employed, an infusion
rate of 3 mL/hour has been found to be satisfactory.
Periodic platelet counts, hematocrits, and tests for occult blood in stool are recommended
during the entire course of heparin therapy, regardless of the route of administration.
All injections in VIAFLEX Plus plastic containers are intended for administration using
sterile equipment.
Because dosages of this drug are titrated to response, no additives should be made to
Heparin Sodium and 0.9% Sodium Chloride Injection.
HOW SUPPLIED
Heparin Sodium and 0.9% Sodium Chloride Injection in VIAFLEX Plus plastic container
is supplied as follows:
Code
Size
NDC
Product Name
(mL)
2B0953
500
0338-0431-03
1000 USP Heparin Units and 0.9% Sodium Chloride
Injection
2B0944
1000
0338-0433-04
2000 USP Heparin Units and 0.9% Sodium Chloride
Injection
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat.
It is recommended the product be stored at room temperature (25°C); brief exposure up to
40°C does not adversely affect the product.
DIRECTION FOR USE OF VIAFLEX PLUS PLASTIC CONTAINER
Warning: Do not use plastic containers in series connections. Such use could result in air
embolism due to residual air being drawn from the primary container before
administration of the fluid from the secondary container is completed.
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
To Open
Tear overwrap down side at slit and remove solution container. Some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This
is normal and does not affect the solution quality or safety. The opacity will diminish
gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found
discard solution as sterility may be impaired. Do not add supplementary medication.
Preparation for Administration
1. Suspend container from eyelet support.
2. Remove plastic protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*Bar Code Position Only
071964111
©Copyright 1981, 1982, 1983, 1989, 1995,
Baxter Healthcare Corporation. All rights reserved.
07-19-64-111
Rev. July 2010
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:46.048635
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018609s044lbl.pdf', 'application_number': 18609, 'submission_type': 'SUPPL ', 'submission_number': 44}
|
11,246
|
nicotine polacrilex gum, 2mg
STOP SMOKING AID
®
FOR THOSE WHO
SMOKE LESS THAN
25 CIGARETTES A DAY
If you smoke 25 or more
cigarettes a day: use Nicorette 4mg
40 PIECES, 2mg EACH
GUM
GUM
2mg
2mg
COATED
COATED
Drug Facts
Active ingredient Purpose
(in each chewing piece)
Nicotine polacrilex (equal to 2mg nicotine)..Stop smoking aid
Use
• reduces withdrawal symptoms, including
nicotine craving, associated with quitting smoking
Warnings
If you are pregnant or breast-feeding, only use this
medicine on the advice of your health care provider.
Smoking can seriously harm your child. Try to stop smoking
without using any nicotine replacement medicine.
This medicine is believed to be safer than smoking. However,
the risks to your child from this medicine are not fully known.
Do not use
• if you continue to smoke, chew tobacco, use snuff, or use a
nicotine patch or other nicotine containing products
Ask a doctor before use if you have
• a sodium-restricted diet
• heart disease, recent heart attack, or irregular heartbeat.
Nicotine can increase your heart rate.
• high blood pressure not controlled with medication.
Nicotine can increase blood pressure.
• stomach ulcer or diabetes
Ask a doctor or pharmacist before use if you are
• using a non-nicotine stop smoking drug
• taking prescription medicine for depression or asthma.
Your prescription dose may need to be adjusted.
Stop use and ask a doctor if
• mouth, teeth or jaw problems occur
• irregular heartbeat or palpitations occur
• you get symptoms of nicotine overdose such as nausea,
vomiting, dizziness, diarrhea, weakness and rapid heartbeat
Keep out of reach of children and pets. Pieces of nicotine
gum may have enough nicotine to make children and pets
sick. Wrap used pieces of gum in paper and throw away in
the trash. In case of overdose, get medical help or contact
a Poison Control Center right away.
Directions
• if you are under 18 years of age, ask a doctor before use
• before using this product, read the enclosed User’s
Guide for complete directions and other important
information
• stop smoking completely when you begin using the gum
• if you smoke 25 or more cigarettes a day; use 4mg
nicotine gum
• if you smoke less than 25 cigarettes a day; use
according to the following 12 week schedule:
Weeks 1 to 6
1 piece every
1 to 2 hours
Weeks 7 to 9
1 piece every
2 to 4 hours
Weeks 10 to 12
1 piece every
4 to 8 hours
Drug Facts (continued)
• nicotine gum is a medicine and must be used
a certain way to get the best results
• chew the gum slowly until it tingles. Then
park it between your cheek and gum. When
the tingle is gone, begin chewing again, until
the tingle returns.
• repeat this process until most of the tingle is
gone (about 30 minutes)
• do not eat or drink for 15 minutes before
chewing the nicotine gum, or while chewing
a piece
• to improve your chances of quitting, use at
least 9 pieces per day for the first 6 weeks
• if you experience strong or frequent
cravings, you may use a second piece within
the hour. However, do not continuously use
one piece after another since this may cause
you hiccups, heartburn, nausea or other
side effects.
• do not use more than 24 pieces a day
• it is important to complete treatment. Stop
using the nicotine gum at the end of
12 weeks. If you still feel the need to use
nicotine gum, talk to your doctor.
Other information
• each piece contains: calcium 94mg, sodium
11mg
• store at 20 - 25°C (68 - 77°F)
• protect from light
Inactive ingredients acacia,
acesulfame potassium, carnauba wax, edible
ink, flavor, gum base, hypromellose,
magnesium oxide, menthol, peppermint oil,
polysorbate 80, sodium bicarbonate, sodium
carbonate, sucralose, titanium dioxide, xylitol
Questions or comments?
call 1-800-419-4766 weekdays
(10:00 a.m. - 4:30 p.m. EST)
© 2005 GlaxoSmithKline
Manufactured by Pfizer Health AB,
Helsingborg, Sweden for
GlaxoSmithKline
Consumer Healthcare, L.P.
Moon Township, PA 15108
■ not for sale to those under 18 years of age
■ proof of age required
■ not for sale in vending machines or from
any source where proof of age cannot be
verified
Theft surveillance tag area
32
29724XA
EAS Tagged
TO INCREASE YOUR SUCCESS IN QUITTING:
1. You must be motivated to quit.
2. Use Enough - Chew at least 9 pieces of
Nicorette per day during the first six weeks.
3. Use Long Enough - Use Nicorette for the full
12 weeks.
4. Use with a support program as directed in
the enclosed User's Guide.
INDIVIDUALIZED STOP
FREE
SMOKING PROGRAM
FREE
®
VISIT COMMITTEDQUITTERS.COM
(To Enroll See Details Inside)
OPEN HERE
This product is protected in sealed
blisters. Do not use if individual
blisters or printed backings are
broken, open, or torn.
Peel off backing,
starting at
corner with
loose edge.
To remove
the gum,
tear off
single unit.
Push gum
through
foil.
™
Free Audio CD upon request.
See inside.
816216
816216
™
816216
816216
3
6
0766-7857-30
Doc ID:
NDA Document Page:
NDA 18-612
Nicorette (nicotine polacrilex) fruit chill 2 mg Coated Gum
Supplemental New Drug Application
GlaxoSmithKline Consumer Healthcare
0900233c8038412c
1 of 1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Theft surveillance
tag area
EAS Tagged
31
29728XA
816219
816219
TO INCREASE YOUR SUCCESS IN QUITTING:
1. You must be motivated to quit.
2. Use Enough - Chew at least 9 pieces of Nicorette
per day during the first six weeks.
3. Use Long Enough - Use Nicorette for the
full 12 weeks.
4. Use with a support program as directed in the
enclosed User's Guide.
Peel off backing, starting
at corner with loose edge.
To remove the gum,
tear off single unit.
Push gum
through foil.
Includes Carrying Case
© 2005 GlaxoSmithKline
Manufactured by Pfizer Health AB, Helsingborg,
Sweden for
GlaxoSmithKline Consumer Healthcare, L.P.
Moon Township, PA 15108
®
INDIVIDUALIZED STOP
FREE
SMOKING PROGRAM
FREE
®
VISIT COMMITTEDQUITTERS.COM
(To Enroll See Details Inside)
™
®
Free Audio CD upon request.
See inside.
Active ingredient (in each chewing piece)
Purpose
Nicotine polacrilex (equal to 4mg nicotine).….….….….….….….….…..….….…..….….……... Stop smoking aid
Use
• reduces withdrawal symptoms, including nicotine craving, associated with quitting smoking
Warnings
If you are pregnant or breast-feeding, only use this medicine on the advice of your health care provider.
Smoking can seriously harm your child. Try to stop smoking without using any nicotine replacement medicine. This
medicine is believed to be safer than smoking. However, the risks to your child from this medicine are not fully known.
Do not use
• if you continue to smoke, chew tobacco, use snuff, or use a nicotine patch or other nicotine containing products
Ask a doctor before use if you have
• a sodium-restricted diet
• heart disease, recent heart attack, or irregular heartbeat. Nicotine can increase your heart rate.
• high blood pressure not controlled with medication. Nicotine can increase blood pressure.
• stomach ulcer or diabetes
Ask a doctor or pharmacist before use if you are
• using a non-nicotine stop smoking drug
• taking prescription medicine for depression or asthma. Your prescription dose may need to be adjusted.
Stop use and ask a doctor if
• mouth, teeth or jaw problems occur
• irregular heartbeat or palpitations occur
• you get symptoms of nicotine overdose such as nausea, vomiting, dizziness, diarrhea, weakness and rapid heartbeat
Keep out of reach of children and pets. Pieces of nicotine gum may have enough nicotine to make children and
pets sick. Wrap used pieces of gum in paper and throw away in the trash. In case of overdose, get medical help or
contact a Poison Control Center right away.
Directions
• if you are under 18 years of age, ask a doctor before use
• before using this product, read the enclosed User’s Guide for complete directions and other important information
• stop smoking completely when you begin using the gum
• if you smoke less than 25 cigarettes a day; use 2mg nicotine gum
• if you smoke 25 or more cigarettes a day; use according to the following 12 week schedule:
• nicotine gum is a medicine and must be used a certain way to get the best results
• chew the gum slowly until it tingles. Then park it between your cheek and gum. When the tingle is gone, begin
chewing again, until the tingle returns.
• repeat this process until most of the tingle is gone (about 30 minutes)
• do not eat or drink for 15 minutes before chewing the nicotine gum, or while chewing a piece
• to improve your chances of quitting, use at least 9 pieces per day for the first 6 weeks
• if you experience strong or frequent cravings, you may use a second piece within the hour. However, do not
continuously use one piece after another since this may cause you hiccups, heartburn, nausea or other side effects.
• do not use more than 24 pieces a day
• it is important to complete treatment. Stop using the nicotine gum at the end of 12 weeks. If you still feel the need
to use nicotine gum, talk to your doctor.
Other information
• each piece contains: calcium 94mg, sodium 13mg
• store at 20 - 25°C (68 - 77°F)
• protect from light
Drug Facts
Weeks 1 to 6
1 piece every 1 to 2 hours
Weeks 7 to 9
1 piece every 2 to 4 hours
Weeks 10 to 12
1 piece every 4 to 8 hours
■ not for sale to those under 18 years
of age
■ proof of age required
■ not for sale in vending machines or
from any source where proof of age
cannot be verified
This product is protected in sealed
blisters. Do not use if individual
blisters or printed backings are
broken, open, or torn.
Inactive ingredients acacia, acesulfame
potassium, carnauba wax, D&C yellow #10 Al.
lake, edible ink, flavor, gum base, hypromellose,
magnesium oxide, menthol, peppermint oil,
polysorbate 80, sodium carbonate, sucralose,
titanium dioxide, xylitol
Questions or comments?
call 1-800-419-4766 weekdays
(10:00 a.m. - 4:30 p.m. EST)
Drug Facts (continued)
TM
TM
®
TM
nicotine polacrilex gum, 4mg
STOP SMOKING AID
®
™
OPEN HERE
100 PIECES, 4mg EACH
FOR THOSE WHO
SMOKE 25 OR MORE
CIGARETTES A DAY
If you smoke less than 25
cigarettes a day: use Nicorette 2mg
COATED
COATED GUM
GUM
COATED GUM
4mg
mg
4mg
816219
816219
3
3
0766-7857-60
VARNISH
KO AREA
VARNISH
KO AREA
VARNISH
KO AREA
NO COPY
AREA
NO COPY
AREA
VARNISH KO
AREA
VARNISH KO
AREA
VARNISH KO
AREA
VARNISH KO
AREA
Doc ID:
NDA Document Page:
NDA 20-066
Nicorette (nicotine polacrilex) fruit chill 4mg Coated Gum
Supplemental NDA Application
GlaxoSmithKline Consumer Healthcare
0900233c8038415d
1 of 1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NICORETTE®
2mg FRUIT CHILL™ 10 pieces
58134XA
Chew Activated Release® Keep out of reach of children
NICORETTE® 2mg
nicotine polacrilex
FRUIT CHILL™
Distributed by:
GlaxoSmithKline
Moon Twp, PA 15108
1 piece
00000 00/0000
NICORETTE® 2mg
nicotine polacrilex
FRUIT CHILL™
Distributed by:
GlaxoSmithKline
Moon Twp, PA 15108
1 piece
00000 00/0000
NICORETTE® 2mg
nicotine polacrilex
FRUIT CHILL™
Distributed by:
GlaxoSmithKline
Moon Twp, PA 15108
1 piece
00000 00/0000
NICORETTE® 2mg
nicotine polacrilex
FRUIT CHILL™
Distributed by:
GlaxoSmithKline
Moon Twp, PA 15108
1 piece
00000 00/0000
NICORETTE® 2mg
nicotine polacrilex
FRUIT CHILL™
Distributed by:
GlaxoSmithKline
Moon Twp, PA 15108
1 piece
00000 00/0000
NICORETTE® 2mg
nicotine polacrilex
FRUIT CHILL™
Distributed by:
GlaxoSmithKline
Moon Twp, PA 15108
1 piece
00000 00/0000
NICORETTE® 2mg
nicotine polacrilex
FRUIT CHILL™
Distributed by:
GlaxoSmithKline
Moon Twp, PA 15108
1 piece
00000 00/0000
NICORETTE® 2mg
nicotine polacrilex
FRUIT CHILL™
Distributed by:
GlaxoSmithKline
Moon Twp, PA 15108
1 piece
00000 00/0000
NICORETTE® 2mg
nicotine polacrilex
FRUIT CHILL™
Distributed by:
GlaxoSmithKline
Moon Twp, PA 15108
1 piece
00000 00/0000
NICORETTE® 2mg
nicotine polacrilex
FRUIT CHILL™
Distributed by:
GlaxoSmithKline
Moon Twp, PA 15108
1 piece
00000 00/0000
Doc ID:
NDA Document Page:
NDA 18-612
Nicorette (nicotine polacrilex) fruit chill 2 mg Coated Gum
Supplemental New Drug Application
GlaxoSmithKline Consumer Healthcare
0900233c8038af04
1 of 1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NICORETTE®
4mg FRUIT CHILL™ 10 pieces
58135XA
Chew Activated Release® Keep out of reach of children
NICORETTE® 4mg
nicotine polacrilex
FRUIT CHILL™
Distributed by:
GlaxoSmithKline
Moon Twp, PA 15108
1 piece
00000 00/0000
NICORETTE® 4mg
nicotine polacrilex
FRUIT CHILL™
Distributed by:
GlaxoSmithKline
Moon Twp, PA 15108
1 piece
00000 00/0000
NICORETTE® 4mg
nicotine polacrilex
FRUIT CHILL™
Distributed by:
GlaxoSmithKline
Moon Twp, PA 15108
1 piece
00000 00/0000
NICORETTE® 4mg
nicotine polacrilex
FRUIT CHILL™
Distributed by:
GlaxoSmithKline
Moon Twp, PA 15108
1 piece
00000 00/0000
NICORETTE® 4mg
nicotine polacrilex
FRUIT CHILL™
Distributed by:
GlaxoSmithKline
Moon Twp, PA 15108
1 piece
00000 00/0000
NICORETTE® 4mg
nicotine polacrilex
FRUIT CHILL™
Distributed by:
GlaxoSmithKline
Moon Twp, PA 15108
1 piece
00000 00/0000
NICORETTE® 4mg
nicotine polacrilex
FRUIT CHILL™
Distributed by:
GlaxoSmithKline
Moon Twp, PA 15108
1 piece
00000 00/0000
NICORETTE® 4mg
nicotine polacrilex
FRUIT CHILL™
Distributed by:
GlaxoSmithKline
Moon Twp, PA 15108
1 piece
00000 00/0000
NICORETTE® 4mg
nicotine polacrilex
FRUIT CHILL™
Distributed by:
GlaxoSmithKline
Moon Twp, PA 15108
1 piece
00000 00/0000
NICORETTE® 4mg
nicotine polacrilex
FRUIT CHILL™
Distributed by:
GlaxoSmithKline
Moon Twp, PA 15108
1 piece
00000 00/0000
Doc ID:
NDA Document Page:
NDA 20-066
Nicorette (nicotine polacrilex) fruit chill 4mg Coated Gum
Supplemental NDA Application
GlaxoSmithKline Consumer Healthcare
0900233c8038af0c
1 of 1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
®
88721XA
™
GLUE FLAP - NO VARNISH / NO COPY
Doc ID:
NDA Document Page:
NDA 20-066
Nicorette (nicotine polacrilex) fruit chill 4mg Coated Gum
Supplemental NDA Application
GlaxoSmithKline Consumer Healthcare
0900233c8038af05
1 of 1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:46.453334
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/018612s042,020066s023lbl.pdf', 'application_number': 18612, 'submission_type': 'SUPPL ', 'submission_number': 42}
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11,249
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NDA 18-613/S-011
Page 3
3
OVIDE®
(malathion)
Lotion, 0.5%
NDC 99207-650-02
Ovide® (malathion) Lotion, 0.5%
Rx Only
For topical use only. Not for oral or ophthalmic use.
DESCRIPTION
OVIDE Lotion contains 0.005 g of malathion per mL in a vehicle of isopropyl alcohol (78%),
terpineol, dipentene, and pine needle oil. The chemical name of malathion is (+)-
[(dimethoxyphosphinothioyl)-thio] butanedioic acid diethyl ester. Malathion has a molecular weight of
330.36, represented by C10H19O6PS2, and has the following chemical structure:
CLINICAL PHARMACOLOGY
Malathion is an organophosphate agent which acts as a pediculocide by inhibiting cholinesterase
activity in vivo. Inadvertent transdermal absorption of malathion has occurred from its agricultural use.
In such cases, acute toxicity was manifested by excessive cholinergic activity, i.e., increased sweating,
salivary and gastric secretion, gastrointestinal and uterine motility, and bradycardia (see
OVERDOSAGE). Because the potential for transdermal absorption of malathion from OVIDE
Lotion is not known at this time, strict adherence to the dosing instructions regarding its use in
children, method of application, duration of exposure, and frequency of application is required.
INDICATIONS AND USAGE
OVIDE Lotion is indicated for patients infected with Pediculus humanus capitis (head lice and their
ova) of the scalp hair.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-613/S-011
Page 4
4
CONTRAINDICATIONS
OVIDE Lotion is contraindicated for neonates and infants because their scalps are more permeable and
may have increased absorption of malathion. OVIDE Lotion should also not be used on individuals
known to be sensitive to malathion or any of the ingredients in the vehicle.
WARNINGS
1. OVIDE Lotion is flammable. The lotion and wet hair should not be exposed to open flames or
electric heat sources, including hair dryers and electric curlers. Do not smoke while applying lotion
or while hair is wet. Allow hair to dry naturally and to remain uncovered after application of
OVIDE Lotion.
2. OVIDE Lotion should only be used on children under the direct supervision of an adult.
3. If OVIDE Lotion comes into contact with the eyes, flush immediately with water. Consult a
physician if eye irritation persists.
4. If skin irritation occurs, discontinue use of product until irritation clears. Reapply the OVIDE
Lotion, and if irritation reoccurs, consult a physician.
5. Slight stinging sensations may occur with the use of OVIDE Lotion.
General: Keep out of reach of children. Close eyes tightly during product application. If accidentally
placed in the eye, flush immediately with water. Use only on scalp hair.
Information to Patients
1. OVIDE Lotion is flammable. The lotion and hair wet with lotion should not be exposed to open
flames or electric heat sources, including hair dryers and electric curlers. Do not smoke while
applying lotion or while hair is wet. The person applying OVIDE Lotion should wash hands after
application. Allow hair to dry naturally and to remain uncovered after application of OVIDE
Lotion.
2. OVIDE Lotion should only be used on children under the direct supervision of an adult. Children
should be warned to stay away from lighted cigarettes, open flames, and electric heat sources while
the hair is wet.
3. In case of accidental ingestion of OVIDE Lotion by mouth, seek medical attention immediately.
4. If you are pregnant or nursing, you should contact your physician before using OVIDE Lotion.
5. If OVIDE Lotion comes into contact with the eyes, flush immediately with water. Consult a
physician if eye irritation persists or if visual changes occur.
6. If skin irritation occurs, wash scalp and hair immediately. If the irritation clears, OVIDE Lotion
may be reapplied. If irritation reoccurs, consult a physician.
7. Slight stinging sensations may be produced when using OVIDE Lotion.
8. Apply OVIDE Lotion on the scalp hair in an amount just sufficient to thoroughly wet hair and
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-613/S-011
Page 5
5
scalp. Pay particular attention to the back of the head and neck when applying OVIDE Lotion.
Anyone applying OVIDE Lotion should wash hands immediately after the application process is
complete.
9. Allow hair to dry naturally and to remain uncovered. Shampoo hair after 8 to 12 hours, again
paying attention to the back of the head and neck while shampooing.
10. Rinse hair and use a fine-toothed (nit) comb to remove dead lice and eggs.
11. If lice are still present after 7-9 days, repeat with a second application of OVIDE Lotion.
12. Further treatment is generally not necessary. Other family members should be evaluated by a
physician to determine if infested, and if so, receive treatment.
Laboratory Tests: There are no special laboratory tests needed in order to use this medication.
Carcinogenesis, Mutagenesis, and Impairment of Fertility:
Carcinogenesis, mutagenesis, and impairment of fertility have not been studied with OVIDE Lotion
(0.5% pharmaceutical grade malathion). However, following long-term oral administration of
technical grade malathion to rodents via dietary supplementation, increase incidences of hepatocellular
neoplastic lesions were observed in B6C3F1 mice dosed for 18 months at malathion doses greater than
1500 mg/kg/day, and in female F344 rats dosed for 2 years at malathion doses greater than 400
mg/kg/day. These tumors occurred only in association with severe hepatic toxicity and chronic
suppression acethylcholinesterase activity, or at does causing excessive mortality. Based on body
surface area, doses at which carcinogenic effects were observed in rodents following life-time
exposures to malathion were approximately 14-to 26-fold greater than the maximum dose anticipated
in a 10 kg child following a single use of OVIDE Lotion, assuming 100% bioavailabilty. Actual
systemic exposures are expected to be less than 10% of the administered dose.
The malathion of greater than pharmaceutical-grade purity used in OVIDE Lotion has not been tested
for genotoxicity. The technical-grade malathion (95% pure) was found to be negative in Salmonella
typhimurium, equivocally positive in the mouse lymphoma cell assay, and positive in in vitro
chromosomal aberration and sister chromatid exchange assays. Fifteen separate in vitro mutation
studies with malathion of unknown purity have reported negative results, while three studies reported
malathion to be mutagenic in bacterial cells. Both technical grade (94-96,5%) and purified (98-99%)
malathion have been reported to cause chromosomal aberrations and sister chromatid exchanges in
vitro in human and hamster cell lines. In vivo chromosomal aberration and micronucleus studies of
technical-grade malathion are reported to be positive, whereas an in vivo chromosomal aberration study
of >99% pure malathion was reported to be negative. Furthermore, mice exposed to malathion in their
drinking water for 7 weeks demonstrated no evidence of chromosome damage in bone marrow cells,
spermatogonia, or primary spermatocytes. Lack of details makes independent evaluation of the results
of these assays impossible. Ashby and Purchase have suggested that impurities may be responsible for
some of the observed genetic activity of malathion.
Reproduction studies performed with malathion in rats at doses approximately 30 fold greater than
those anticipated in humans (based on body surface area and assuming 100% bioavailability) revealed
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-613/S-011
Page 6
6
no evidence of impaired fertility.
Pregnancy: Pregnancy Category B. There was no evidence of teratogenicity in studies in rats and
rabbits at doses up to 900 mg/kg/day and 100 mg/kg/day malathion, respectively. A study in rats failed
to show any gross fetal abnormalities attributable to feeding malathion up to 2,500 ppm (~ 200
mg/kg/day) in the diet during a three-generation evaluation period. These doses were approximately 2
to 10 times higher than the anticipated human dose (based on body surface area and assuming 100%
bioavailability). Because animal reproduction studies are not always predictive of human responses,
this drug should be used (or handled) during pregnancy only if clearly needed.
Nursing Mothers: Malathion in an acetone vehicle has been reported to be absorbed through human
skin to the extent of 8% of the applied dose. However, percutaneous absorption from the OVIDE®
(malathion) Lotion, 0.5% formulation has not been studied, and it is not known whether malathion is
excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised
when OVIDE Lotion is administered to (or handled by) a nursing mother.
Pediatric Use: The safety and effectiveness of OVIDE Lotion in children less than 6 years of age has
not been established via well-controlled trials.
ADVERSE REACTIONS
Malathion has been shown to be irritating to the skin and scalp. Accidental contact with the eyes can
result in mild conjunctivitis.
It is not known if OVIDE Lotion has the potential to cause contact allergic sensitization.
OVERDOSAGE
Consideration should be given, as part of the treatment program, to the high concentration of isopropyl
alcohol in the vehicle.
Malathion, although a weaker cholinesterase inhibitor than some other organophosphates, may be
expected to exhibit the same symptoms of cholinesterase depletion after accidental ingestion orally. If
accidentally swallowed, vomiting should be induced promptly or the stomach lavaged with 5% sodium
bicarbonate solution.
Severe respiratory distress is the major and most serious symptom of organophosphate poisoning
requiring artificial respiration, and atropine may be needed to counteract the symptoms of
cholinesterase depletion.
Repeat analyses of serum and RBC cholinesterase may assist in establishing the diagnosis and
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-613/S-011
Page 7
7
formulating a long - range prognosis.
DOSAGE AND ADMINISTRATION
1. Apply OVIDE Lotion on DRY hair in amount just sufficient to thoroughly wet the hair and scalp.
Pay particular attention to the back of the head and neck while applying OVIDE Lotion. Wash
hands after applying to scalp.
2. Allow hair to dry naturally - use no electric heat source, and allow hair to remain uncovered.
3. After 8 to 12 hours, the hair should be shampooed.
4. Rinse and use a fine-toothed (nit) comb to remove dead lice and eggs.
5. If lice are still present after 7-9 days, repeat with a second application of OVIDE Lotion.
Further treatment is generally not necessary. Other family members should be evaluated by a physician
to determine if infested, and if so, receive treatment.
Clinical Studies:
Two controlled clinical trials evaluated the pediculocidal activity of OVIDE Lotion. Patients applied
the lotion to the hair and scalp in quantities, up to a maximum of 2 fl. oz., sufficient to thoroughly wet
the hair and scalp. The lotion was allowed to air dry and was shampooed with Prell shampoo 8 to 12
hours after application. Patients in both the OVIDE Lotion group and in the vehicle group were
examined immediately after shampooing, 24 hours after, and 7 days after for the presence of live lice.
Results are shown in the following table:
Number of Patients Without Live Scalp Lice
Treatment
Immediately After
24 Hrs. After
7 Days After
OVIDE Lotion
129/129
122/129
114/126
OVIDE Vehicle
105/105
63/105
31/105
The presence or absence of ova at day 7 was not evaluated in these studies. The presence or absence of live
lice or ova at 14 days following treatment was not evaluated in these studies. The residual amount of
malathion on hair and scalp is unknown.
HOW SUPPLIED
OVIDE® (malathion) Lotion, 0.5%, is supplied in bottles of 2 fl. oz. (59 mL) NDC 99207-650-02.
Store at controlled room temperature 20°-25°C (68°-77°F).
Flammable. Keep away from heat and open flame.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-613/S-011
Page 8
8
The Dermatology Company®
Manufactured for:
MEDICIS, The Dermatology Company®
by: DPT Lakewood,
Lakewood, NJ 08701
65002-08B
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:46.535657
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/018613s011lbl.pdf', 'application_number': 18613, 'submission_type': 'SUPPL ', 'submission_number': 11}
|
11,250
|
company logo
NDC 51672-5276-4
Ovide® (malathion) Lotion, 0.5%
Rx Only
For topical use only. Not for oral or ophthalmic use.
DESCRIPTION
OVIDE Lotion contains 0.005 g of malathion per mL in a vehicle of isopropyl alcohol (78%), terpineol, dipentene,
and pine needle oil. The chemical name of malathion is (±) - [(dimethoxyphosphinothioyl) - thio] butanedioic acid
diethyl ester. Malathion has a molecular weight of 330.36, represented by C10H19O6PS2, and has the following
chemical structure: structural formula
CLINICAL PHARMACOLOGY
Malathion is an organophosphate agent which acts as a pediculicide by inhibiting cholinesterase activity in vivo.
Inadvertent transdermal absorption of malathion has occurred from its agricultural use. In such cases, acute toxicity
was manifested by excessive cholinergic activity, i.e., increased sweating, salivary and gastric secretion,
gastrointestinal and uterine motility, and bradycardia (see OVERDOSAGE). Because the potential for transdermal
absorption of malathion from OVIDE Lotion is not known at this time, strict adherence to the dosing instructions
regarding its use in children, method of application, duration of exposure, and frequency of application is required.
INDICATIONS AND USAGE
OVIDE Lotion is indicated for patients infected with Pediculus humanus capitis (head lice and their ova) of the
scalp hair.
CONTRAINDICATIONS
OVIDE Lotion is contraindicated for neonates and infants because their scalps are more permeable and may have
increased absorption of malathion. OVIDE Lotion should also not be used on individuals known to be sensitive to
malathion or any of the ingredients in the vehicle.
WARNINGS
1. OVIDE Lotion is flammable. The lotion and wet hair should not be exposed to open flames or electric heat
sources, including hair dryers and electric curlers.
Do not smoke while applying lotion or while hair is wet.
Allow hair to dry naturally and to remain uncovered after application of OVIDE Lotion.
2. OVIDE Lotion should only be used on children under the direct supervision of an adult.
3. If OVIDE Lotion comes into contact with the eyes, flush immediately with water. Consult a physician if eye
irritation persists.
4. If skin irritation occurs, discontinue use of product until irritation clears. Reapply the OVIDE Lotion, and if
irritation reoccurs, consult a physician.
5. Chemical burns including second-degree burns and stinging sensations may occur with the use of OVIDE
Lotion.
Reference ID: 3056658
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
General: Keep out of reach of children. Close eyes tightly during product application. If accidentally placed in the
eye, flush immediately with water. Use only on scalp hair.
Information to Patients
1. OVIDE Lotion is flammable. The lotion and hair wet with lotion should not be exposed to open flames or
electric heat sources, including hair dryers and electric curlers. Do not smoke while applying lotion or while
hair is wet. The person applying OVIDE Lotion should wash h ands after application. Allow hair to dry naturally
and to remain uncovered after application of OVIDE Lotion.
2. OVIDE Lotion should only be used on children under the direct supervision of an adult. Children should be
warned to stay away from lighted cigarettes, open flames, and electric heat sources while the hair is wet.
3. In case of accidental ingestion of OVIDE Lotion by mouth, seek medical attention immediately.
4. If you are pregnant or nursing, you should contact your physician before using OVIDE Lotion.
5. If OVIDE Lotion comes into contact with the eyes, fl ush immediately with water. Consult a physician if eye
irritation persists or if visual changes occur.
6. If skin irritation occurs, wash scalp and hair immediately. If th e irritation clears, OVIDE Lotion may be
reapplied. If irritation reoccurs, consult a physician.
7. Burns and stinging sensations may occur when using OVIDE Lotion.
8. Apply OVIDE Lotion on the scalp hair in an amount just sufficient to thoroughly wet hair and scalp. Pay
particular attention to the back of the head and neck when applying OVIDE Lotion. Anyone applying OVIDE
Lotion should wash hands immediately after the application process is complete.
9. Allow hair to dry naturally and to remain uncovere d. Shampoo hair after 8 to 12 hours, again paying attention to
the back of the head and neck while shampooing.
10. Rinse hair and use a fine - toothed (nit) comb to remove dead lice and eggs.
11. If lice are still present after 7 - 9 days, repeat with a second application of OVIDE Lotion.
12. Further treatment is generally not necessary. Other family members should be evaluated by a physician to
determine if infested, and if so, receive treatment.
Laboratory Tests: There are no special laboratory tests needed in order to use this medication.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: Carcinogenesis, mutagenesis and impairment of
fertility have not been studied with OVIDE Lotion (0.5% pharmaceutical grade malathion). However, followi ng
long-term oral administration of technical grade malathion to rodents via dietary supplementation, increased
incidences of hepatocellular neoplastic lesions were observed in B6C3F1 mice dosed for 18 months at malathion
doses greater than 1500 mg/kg/day, and in female F344 rats dosed for 2 years at malathion doses greater than 4 00
mg/kg/day. These tumors occurred only in association with severe hepatic toxicity and chronic suppression of
acetylcholinesterase activity, or at doses causing excessive mortality. Based on body surface area, doses at which
carcinogenic effects were observed in rodents following life-time exposures to malathion were approximately 14- to
26-fold greater than the maximum dose anticipated in a 10 kg child following a single use of OVIDE Lotion,
assumi ng 100% bioavailability. Actual systemic exposures are expected to be less than 10% of the administered
dose.
The malathion of greater than pharmaceutical-grade purity used in OVIDE Lotion has not been tested for
genotoxicity. The technical-grade malathion (95% pure) was found to be negative in Salmonella typhimurium,
equivocally positive in the mouse lymphoma cell assay, and positive in in vitro chromosomal aberration and sister
chromatid exchange assays. Fifteen separate in vitro gene mutation studies with malathion of unknown purity have
reported negative results, while three studies reported malathion to be mutagenic in bacterial cells. Both technical
grade (94–96.5%) and purified (98-99%) malathion have been reported to cause chromosomal aberrations and sist er
chromatid exchanges in vitro in human and hamster cell lines. In vivo chromosomal aberration and micronucleus
studies of technical-grade malathion are reported to be positive, whereas an in vivo chromosomal aberration study of
>99% pure malathion was reported to be negative. Furthermore, mice exposed to malathion in their drinking wate r
for 7 weeks demonstrated no evidence of chromosome damage in bone marrow cells, spermatogonia, or primary
spermatocytes. Lack of details makes independent evaluation of the results of these assays impossible. Ashby and
Purchase have suggested that impurities may be responsible for some of the observed genetic activity of malathion.
Reproduction studies performed with malathion in rats at doses over 180 fold greater than those anticipated in a 60
kg adult (based on body surface area and assuming 100% bioavailability) revealed no evidence of impaired fertility.
Reference ID: 3056658
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pregnancy: Pregnancy Category B. There was no evidence of teratogenicity in studies in rats and rabbits at doses
up to 900 mg/kg/day and 100 mg/kg/day malathion, respectively. A study in rats failed to show any gross fetal
abnormalities attributable to feeding malathion up to 2,500 ppm (~ 200 mg/kg/day) in the diet during a three -
generation evaluation period. These doses were approximately 40 to 180 times higher than the dose anticipated in a
60 kg adult (based on body surface area and assuming 100% bioavailability). Because animal reproduction studies
are not always predictive of human responses, this drug should be used (or handled) during pregnancy only if clearly
needed.
Nursing Mothers: Malathion in an acetone vehicle has been reported to be absorbed through human skin to the
extent of 8% of the applied dose. However, percutaneous absorption from the OVIDE® (malathion) Lotion, 0.5%
formulation has not been studied, and it is not known whether malathion is excreted in human milk. Because many
drugs are excreted in h uman milk, caution should be exercised when OVIDE Lotion is administered to (or handled
by) a nursing mother.
Pediatric Use: The safety and effectiv eness of OVIDE Lotion in children less than 6 years of age has not been
established via well-controlled trials.
ADVERSE REACTIONS
Malathion has been shown to be irritating to the skin and scalp. Other adverse reactions reported ar e chemical burns
including second-degree burns. Accidental contact with the eyes can result in mild conjun ctivitis.
It is not known if OVIDE Lotion has the potential to cause contact allergic sensitization.
OVERDOSAGE
Consideratio n should be given, as part of the treatment program, to the high concentration of isopropyl alcohol in
the vehicle.
Malathion, although a weaker cholinesterase inhibitor than some other organophosphates, may be expected to
exhibit the same symptoms of cholinesterase depletion after accidental ingestion orally. If accidentall y swallowed,
vomiting should be induced promptly or the stomach lavaged with 5% sodium bicarbonate solution.
Severe respiratory distress is the major and most serious symptom of organophosphate poisoning re quiring artificial
respiration, and atropine may be needed to counteract the symptoms of cholinesterase depletion.
Repeat analyses o f serum and RBC cholinesterase may assist in establishing the diagnosis and formulating a long -
ra nge prognosis.
DOSAGE AND ADMINISTRATION
1. Apply OVIDE Lotion on DRY hair in amount just sufficient to thoroughly wet the hair and scalp. Pay particular
attention to the back of the head and neck while applying OVIDE Lotion. Wash hands after appl ying to scalp.
2. Allow hair to dry naturally - use no electric heat sou rce, and allow hair to remain uncovered.
3. After 8 to 12 hours, the hair should be shampooed.
4. Rinse and use a fine - toothed (nit) comb to remove dead lice and eggs.
5. If lice are still present after 7 - 9 days, repeat with a second application of OVIDE Lotion.
Further treatment is generally not necess ary. Other family members should be evaluated by a physician to determine
if infested, and if so, receive treatment.
Clinical Studies:
Two controlled clinical trials evaluated the pediculicidal activity of OVIDE Lotion. Patients applied the lotion to the
hair and scalp in quantities, up to a maximum of 2 fl. oz., sufficient to thoroughly wet the hair and scalp. The lotion
was allowed to air dry and was shampooed with Prell shampoo 8 to 12 hours after application. Patients in both the
OVIDE Lotion group and in the vehicle group were examined immediately after shampooing, 24 hours after, and 7
days after for the presence of live lice. Results are shown in the following table:
Number of Patients Without Li ve Scalp Lice
Treatment
Imm
fter
ediately A
24
r
Hrs. Afte
7 Days After
OVIDE Lotion
129/129
122/129
114/126
OVIDE Vehicle
105/105
63/105
31/105
Reference ID: 3056658
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The presence or absence of ova at day 7 was not evaluated in these studies. The presence or absence of live lice or
ova at 14 days following treatment was not evaluated in these studies. The residual amount of malathion on hair and
scalp is unknown.
HOW SUPPLIED
OVIDE® (malathion) Lotion, 0.5%, is supplied in bottles of 2 fl. oz. (59 mL) NDC 51672-5276-4.
Store at controlled room temperature 20° - 25°C (68° - 77°F).
Flammable. Keep away from heat and open flame.
Manufactured for:
company logo
Manufactured by: Taro Pharmaceutical Industries Ltd., Haifa Bay, Israel, 26110
Revised: December, 2011
Ovide® and TaroPharma™ ®are trademarks of Taro Pharmaceuticals U.S.A., Inc. and/or its affiliates.
70205--0611-1
Reference ID: 3056658
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:46.780327
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018613s017lbl.pdf', 'application_number': 18613, 'submission_type': 'SUPPL ', 'submission_number': 17}
|
11,251
|
TRENTAL®
(pentoxifylline)
Extended-Release Tablets, 400 mg
DESCRIPTION
TRENTAL® (pentoxifylline) extended-release tablets for oral administration contain 400 mg of
the active drug and the following inactive ingredients: FD&C Red No. 3, hypromellose USP,
magnesium stearate NF, polyethylene glycol NF, povidone USP, talc USP, titanium dioxide
USP, and hydroxyethyl cellulose USP in an extended-release formulation. TRENTAL is a
tri-substituted xanthine derivative designated chemically as 1-(5-oxohexyl)-3, 7
dimethylxanthine that, unlike theophylline, is a hemorrheologic agent, i.e. an agent that affects
blood viscosity. Pentoxifylline is soluble in water and ethanol, and sparingly soluble in toluene.
The CAS Registry Number is 6493-05-6.
The chemical structure is: structural formula
CLINICAL PHARMACOLOGY
Mode of Action
Pentoxifylline and its metabolites improve the flow properties of blood by decreasing its
viscosity. In patients with chronic peripheral arterial disease, this increases blood flow to the
affected microcirculation and enhances tissue oxygenation. The precise mode of action of
pentoxifylline and the sequence of events leading to clinical improvement are still to be defined.
Pentoxifylline administration has been shown to produce dose-related hemorrheologic effects,
lowering blood viscosity, and improving erythrocyte flexibility. Leukocyte properties of
hemorrheologic importance have been modified in animal and in vitro human studies.
Pentoxifylline has been shown to increase leukocyte deformability and to inhibit neutrophil
adhesion and activation. Tissue oxygen levels have been shown to be significantly increased by
therapeutic doses of pentoxifylline in patients with peripheral arterial disease.
Pharmacokinetics and Metabolism
After oral administration in aqueous solution pentoxifylline is almost completely absorbed. It
undergoes a first-pass effect and the various metabolites appear in plasma very soon after dosing.
Peak plasma levels of the parent compound and its metabolites are reached within 1 hour. The
major metabolites are Metabolite I (1-[5-hydroxyhexyl]-3,7-dimethylxanthine) and Metabolite V
(1-[3-carboxypropyl]-3,7-dimethylxanthine), and plasma levels of these metabolites are 5 and 8
times greater, respectively, than pentoxifylline.
Reference ID: 3873773
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Following oral administration of aqueous solutions containing 100 to 400 mg of pentoxifylline,
the pharmacokinetics of the parent compound and Metabolite I are dose-related and not
proportional (non-linear), with half-life and area under the blood-level time curve (AUC)
increasing with dose. The elimination kinetics of Metabolite V are not dose-dependent. The
apparent plasma half-life of pentoxifylline varies from 0.4 to 0.8 hours and the apparent plasma
half-lives of its metabolites vary from 1 to 1.6 hours. There is no evidence of accumulation or
enzyme induction (Cytochrome P450) following multiple oral doses.
Excretion is almost totally urinary; the main biotransformation product is Metabolite V.
Essentially no parent drug is found in the urine. Despite large variations in plasma levels of
parent compound and its metabolites, the urinary recovery of Metabolite V is consistent and
shows dose proportionality. Less than 4% of the administered dose is recovered in feces. Food
intake shortly before dosing delays absorption of an immediate-release dosage form but does not
affect total absorption. The pentoxifylline AUC was increased and elimination rate decreased in
an older population (60-68 years, n=6) compared to younger individuals (22-30 years, n=6) (see
PRECAUTIONS, Geriatric Use).
After administration of the 400 mg extended-release TRENTAL tablet, plasma levels of the
parent compound and its metabolites reach their maximum within 2 to 4 hours and remain
constant over an extended period of time. Coadministration of TRENTAL extended-release
tablets with meals resulted in an increase in mean AUC and Cmax of about 1.1 and 1.3 fold for
pentoxifylline, respectively. Cmax for Metabolite I also increased about1.2 fold. The extended
release of pentoxifylline from the tablet eliminates peaks and troughs in plasma levels for
improved gastrointestinal tolerance.
Patients with Hepatic Impairment
In patients with mild to moderate liver impairment AUC and Cmax of pentoxifylline increased
6.5 and 7.5 fold, respectively, after a single 400 mg dose of TRENTAL. AUC and Cmax of the
active Metabolite I also increased 6.9 and 8.2 fold, respectively, in hepatic impaired subjects.
TRENTAL has not been studied in patients with severe hepatic failure.
Patients with Renal Impairment
In patients with mild, moderate, or severe renal impairment the exposure to pentoxifylline and its
active Metabolite I are not increased. In contrast, AUC0-tss and Cmax of the active Metabolite V
in patients with mild to moderate renal impairment increased 2.4 and 2.1 fold, respectively, with
a 400 mg TID regimen of TRENTAL. In severe renal impairment AUC0-tss and Cmax of the
active Metabolite V increased 12.9 and 10.6 fold, respectively, with a 400 mg TRENTAL TID
regimen. The increase in exposure to Metabolite V is only slightly smaller in both renal
impairment groups if TRENTAL is administered BID.
2
Reference ID: 3873773
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INDICATIONS AND USAGE
TRENTAL is indicated for the treatment of patients with intermittent claudication on the basis of
chronic occlusive arterial disease of the limbs. TRENTAL can improve function and symptoms
but is not intended to replace more definitive therapy, such as surgical bypass, or removal of
arterial obstructions when treating peripheral vascular disease.
CONTRAINDICATIONS
TRENTAL should not be used in patients with recent cerebral and/or retinal hemorrhage or in
patients who have previously exhibited intolerance to this product or methylxanthines such as
caffeine, theophylline, and theobromine.
PRECAUTIONS
General
At the first sign of anaphylactic/anaphylactoid reaction, TRENTAL must be discontinued.
Patients with chronic occlusive arterial disease of the limbs frequently show other manifestations
of arteriosclerotic disease. TRENTAL has been used safely for treatment of peripheral arterial
disease in patients with concurrent coronary artery and cerebrovascular diseases, but there have
been occasional reports of angina, hypotension, and arrhythmia. Controlled trials do not show
that TRENTAL causes such adverse effects more often than placebo, but, as it is a
methylxanthine derivative, it is possible some individuals will experience such responses.
Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients
with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration,
cerebral and/or retinal bleeding) should have periodic examinations for bleeding including,
hematocrit and/or hemoglobin.
In patients with hepatic or renal impairment, the exposure to pentoxifylline and/or active
metabolites is increased. The consequences of the increase in drug exposure are not known (see
Pharmacokinetics and Metabolism and DOSAGE AND ADMINISTRATION).
Drug Interactions
Bleeding has been reported in patients treated with Trental with or without
concomitant NSAIDs, anticoagulants, or platelet aggregation inhibitors.
Increased prothrombin time has been reported in patients concomitantly treated with
pentoxifylline and vitamin K antagonists. Monitoring of anticoagulant activity in these patients is
recommended when pentoxifylline is introduced or the dose is changed.
Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased
theophylline levels and theophylline toxicity in some individuals. Monitor theophylline levels
when starting Trental or changing dose.
3
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Concomitant administration of strong CYP1A2 inhibitors (including e.g.
ciprofloxacin or fluvoxamine) may increase the exposure to pentoxifylline (see
ADVERSE REACTIONS).
.
TRENTAL has been used concurrently with antihypertensive drugs, beta blockers, digitalis,
diuretics, and antiarrhythmics, without observed problems. Small decreases in blood pressure
have been observed in some patients treated with TRENTAL; periodic systemic blood pressure
monitoring is recommended for patients receiving concomitant antihypertensive therapy. If
indicated, dosage of the antihypertensive agents should be reduced.
Postmarketing cases of increased anticoagulant activity have been reported in patients
concomitantly treated with pentoxifylline and vitamin K antagonists. Monitoring of
anticoagulant activity in these patients is recommended when pentoxifylline is introduced or the
dose is changed.
Concomitant administration with cimetidine is reported to increase the average steady state
plasma concentration of pentoxifylline (~25%) and the Metabolite I (~30%).
.
Carcinogenesis, Mutagenesis and Impairment of Fertility
Long-term studies of the carcinogenic potential of pentoxifylline were conducted in mice and
rats by dietary administration of the drug at doses up to 450 mg/kg (approximately 19 times the
maximum recommended human daily dose (MRHD) in both species when based on body
weight; 1.5 times the MRHD in the mouse and 3.3 times the MRHD in the rat when based on
body surface area). In mice, the drug was administered for 18 months, whereas in rats, the drug
was administered for 18 months followed by an additional 6 months without drug exposure. In
the rat study, there was a statistically significant increase in benign mammary fibroadenomas in
females of the 450 mg/kg group. The relevance of this finding to human use is uncertain.
Pentoxifylline was devoid of mutagenic activity in various strains of Salmonella (Ames test) and
in cultured mammalian cells (unscheduled DNA synthesis test) when tested in the presence and
absence of metabolic activation. It was also negative in the in vivo mouse micronucleus test.
Pregnancy
Category C. Teratogenicity studies have been performed in rats and rabbits using oral doses up to
576 and 264 mg/kg, respectively. On a weight basis, these doses are 24 and 11 times the
maximum recommended human daily dose (MRHD); on a body-surface-area basis, they are 4.2
and 3.5 times the MRHD. No evidence of fetal malformation was observed. Increased resorption
was seen in rats of the 576 mg/kg group. There are no adequate and well controlled studies in
pregnant women. TRENTAL (pentoxifylline) should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
4
Reference ID: 3873773
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Nursing Mothers
Pentoxifylline and its metabolites are excreted in human milk. Because of the potential for
tumorigenicity shown for pentoxifylline in rats, a decision should be made whether to
discontinue nursing or discontinue the drug, taking into account the importance of the drug to the
mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of TRENTAL did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end
of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy.
The active Metabolite V is known to be substantially excreted by the kidney, and the risk
of toxic reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care should be
taken in dose selection, and it may be useful to monitor renal function.
ADVERSE REACTIONS
Clinical trials were conducted using either extended-release TRENTAL tablets for up to 60
weeks or immediate-release TRENTAL capsules for up to 24 weeks. Dosage ranges in the tablet
studies were 400 mg bid to tid and in the capsule studies, 200-400 mg tid. The table summarizes
the incidence (in percent) of adverse reactions considered drug related, as well as the numbers of
patients who received extended-release TRENTAL tablets, immediate-release TRENTAL
capsules, or the corresponding placebos. The incidence of adverse reactions was higher in the
capsule studies (where dose related increases were seen in digestive and nervous system side
effects) than in the tablet studies. Studies with the capsule include domestic experience, whereas
studies with the extended-release tablets were conducted outside the U.S.
The table indicates that in the tablet studies few patients discontinued because of adverse effects.
INCIDENCE (%) OF SIDE EFFECTS
Extended-Release Tablets
Immediate-Release Capsules
Commercially Available
Used only for Controlled Clinical
Trials
5
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TRENTAL
Placebo
TRENTAL
Placebo
(Numbers of Patients at Risk)
(321)
(128)
(177)
(138)
Discontinued for Side Effect
3.1
0
9.6
7.2
CARDIOVASCULAR SYSTEM
Angina/Chest Pain
0.3
-
1.1
2.2
Arrhythmia/Palpitation
-
-
1.7
0.7
Flushing
-
-
2.3
0.7
DIGESTIVE SYSTEM
Abdominal Discomfort
-
-
4.0
1.4
Belching/Flatus/Bloating
0.6
-
9.0
3.6
Diarrhea
-
-
3.4
2.9
Dyspepsia
2.8
4.7
9.6
2.9
Nausea
2.2
0.8
28.8
8.7
Vomiting
1.2
-
4.5
0.7
NERVOUS SYSTEM
Agitation/Nervousness
-
-
1.7
0.7
Dizziness
1.9
3.1
11.9
4.3
Drowsiness
-
-
1.1
5.8
Headache
1.2
1.6
6.2
5.8
Insomnia
-
-
2.3
2.2
Tremor
0.3
0.8
-
Blurred Vision
-
-
2.3
1.4
TRENTAL has been marketed in Europe and elsewhere since 1972. In addition to the above
symptoms, the following have been reported spontaneously since marketing or occurred in other
clinical trials with an incidence of less than 1%; the causal relationship was uncertain:
Cardiovascular - dyspnea, edema, hypotension.
Digestive - anorexia, cholecystitis, constipation, dry mouth/thirst.
Nervous - anxiety, confusion, depression, seizures, aseptic meningitis.
Respiratory - epistaxis, flu-like symptoms, laryngitis, nasal congestion.
Skin and Appendages - brittle fingernails, pruritus, rash, urticaria, angioedema.
Special Senses - blurred vision, conjunctivitis, earache, scotoma.
Miscellaneous - bad taste, excessive salivation, leukopenia, malaise, sore throat/swollen
neck glands, weight change.
A few rare events have been reported spontaneously worldwide since marketing in 1972.
Although they occurred under circumstances in which a causal relationship with pentoxifylline
could not be established, they are listed to serve as information for physicians. Cardiovascular
— angina, arrhythmia, tachycardia. Digestive — hepatitis, jaundice, cholestasis, increased liver
enzymes; and Hemic and Lymphatic — decreased serum fibrinogen, pancytopenia, aplastic
anemia, leukemia, purpura, thrombocytopenia. Immune system disorders — anaphylactic
reaction, anaphylactoid reaction, anaphylactic shock.
OVERDOSAGE
6
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Overdosage with TRENTAL has been reported in pediatric patients and adults. Symptoms
appear to be dose related. A report from a poison control center on 44 patients taking overdoses
of enteric-coated pentoxifylline extended-release tablets noted that symptoms usually occurred 4
5 hours after ingestion and lasted about 12 hours. The highest amount ingested was 80 mg/kg;
flushing, hypotension, convulsions, somnolence, loss of consciousness, fever, and agitation
occurred. All patients recovered. In addition to symptomatic treatment and gastric lavage, special
attention must be given to supporting respiration, maintaining systemic blood pressure, and
controlling convulsions. Activated charcoal has been used to absorb pentoxifylline in patients
who have overdosed.
DOSAGE AND ADMINISTRATION
The usual dosage of TRENTAL in extended-release tablet form is one tablet (400 mg) three
times a day with meals.
While the effect of TRENTAL may be seen within 2 to 4 weeks, it is recommended that
treatment be continued for at least 8 weeks. Efficacy has been demonstrated in double-blind
clinical studies of 6 months duration.
Digestive and central nervous system side effects are dose related. If patients develop these
effects it is recommended that the dosage be lowered to one tablet twice a day (800 mg/day). If
side effects persist at this lower dosage, the administration of TRENTAL should be discontinued.
In patients with severe renal impairment (creatinine clearance below 30 mL/min) reduce dose to
400 mg once a day.
Dosing information cannot be provided for patients with hepatic impairment.
HOW SUPPLIED
TRENTAL (pentoxifylline) is available for oral administration as 400-mg pink film-coated
oblong tablets imprinted Trental; supplied in bottles of 100 (NDC 0039-0078-10).
Store between 59 and 86° F (15 and 30° C).
Dispense in well-closed, light-resistant containers.
Rx only
Rev. January 2016
Validus Pharmaceuticals LLC
Parsippany, NJ 07054
7
Reference ID: 3873773
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1-866-9VALIDUS (1-866-982-5438)
info@validuspharma.com
©2016 Validus Pharmaceutials LLC
60028-00
8
Reference ID: 3873773
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/018631s041lbl.pdf', 'application_number': 18631, 'submission_type': 'SUPPL ', 'submission_number': 41}
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---------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
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/s/
----------------------------------------------------
THERESA M MICHELE
10/30/2014
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Attachment 1
Page 1
Class Suicidality Labeling Language for Antidepressants
[This section should be located at the beginning of the package insert with bolded font and
enclosed in a black box]
[Insert established name]
Suicidality in Children and Adolescents
Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term
studies in children and adolescents with Major Depressive Disorder (MDD) and other
psychiatric disorders. Anyone considering the use of [Insert established name] or any other
antidepressant in a child or adolescent must balance this risk with the clinical need. Patients
who are started on therapy should be observed closely for clinical worsening, suicidality, or
unusual changes in behavior. Families and caregivers should be advised of the need for close
observation and communication with the prescriber. [Insert established name] is not approved
for use in pediatric patients. (See Warnings and Precautions: Pediatric Use)
Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs
(SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive
compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over
4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or
behavior (suicidality) during the first few months of treatment in those receiving
antidepressants. The average risk of such events in patients receiving antidepressants was 4%,
twice the placebo risk of 2%. No suicides occurred in these trials.
[This section should be located under WARNINGS. Please note that the title of this
section should be bolded, and it should be the first paragraph in this section.]
WARNINGS-Clinical Worsening and Suicide Risk
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of
their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual
changes in behavior, whether or not they are taking antidepressant medications, and this risk may
persist until significant remission occurs. There has been a long-standing concern that antidepressants
may have a role in inducing worsening of depression and the emergence of suicidality in certain
patients. A causal role for antidepressants in inducing suicidality has been established in pediatric
patients.
Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in
children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving
over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or
thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 2
Page 2
average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%.
There was considerable variation in risk among drugs, but a tendency toward an increase for almost
all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there
were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive
disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is
unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond
several months. It is also unknown whether the suicidality risk extends to adults.
All pediatric patients being treated with antidepressants for any indication should be observed
closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the
initial few months of a course of drug therapy, or at times of dose changes, either increases or
decreases. Such observation would generally include at least weekly face-to-face contact with
patients or their family members or caregivers during the first 4 weeks of treatment, then every
other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12
weeks. Additional contact by telephone may be appropriate between face-to-face visits.
Adults with MDD or co-morbid depression in the setting of other psychiatric illness being
treated with antidepressants should be observed similarly for clinical worsening and suicidality,
especially during the initial few months of a course of drug therapy, or at times of dose changes,
either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been
reported in adult and pediatric patients being treated with antidepressants for major depressive disorder
as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between
the emergence of such symptoms and either the worsening of depression and/or the emergence of
suicidal impulses has not been established, there is concern that such symptoms may represent
precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing
the medication, in patients whose depression is persistently worse, or who are experiencing emergent
suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if
these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Families and caregivers of pediatric patients being treated with antidepressants for major
depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted
about the need to monitor patients for the emergence of agitation, irritability, unusual changes in
behavior, and the other symptoms described above, as well as the emergence of suicidality, and
to report such symptoms immediately to health care providers. Such monitoring should include
daily observation by families and caregivers. Prescriptions for [Insert established name] should be
written for the smallest quantity of tablets consistent with good patient management, in order to reduce
the risk of overdose. Families and caregivers of adults being treated for depression should be similarly
advised.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation
of bipolar disorder. It is generally believed (though not established in controlled trials) that treating
such an episode with an antidepressant alone may increase the likelihood of precipitation of a
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Attachment 2
Page 3
mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described
above represent such a conversion is unknown. However, prior to initiating treatment with an
antidepressant, patients with depressive symptoms should be adequately screened to determine if they
are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a
family history of suicide, bipolar disorder, and depression. It should be noted that [Insert established
name] is not approved for use in treating bipolar depression.
[This section should be located under PRECAUTIONS, Information for Patients.]
Prescribers or other health professionals should inform patients, their families, and their caregivers
about the benefits and risks associated with treatment with [Insert established name] and should
counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in
Children and Adolescents is available for [Insert established name]. The prescriber or health
professional should instruct patients, their families, and their caregivers to read the Medication Guide
and should assist them in understanding its contents. Patients should be given the opportunity to
discuss the contents of the Medication Guide and to obtain answers to any questions they may have.
The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur
while taking [Insert established name].
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be
encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability,
hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other
unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during
antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients
should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes
may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional,
especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior
and indicate a need for very close monitoring and possibly changes in the medication.
[This section should be located under PRECAUTIONS, Pediatric Use.]
Pediatric Use-Safety and effectiveness in the pediatric population have not been established (see BOX
WARNING and WARNINGS—Clinical Worsening and Suicide Risk). Anyone considering the use of
[Insert established name] in a child or adolescent must balance the potential risks with the clinical
need.
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Attachment 2
Page 1
Medication Guide
About Using Antidepressants in Children and Teenagers
What is the most important information I should know if my child is being prescribed an
antidepressant?
Parents or guardians need to think about 4 important things when their child is prescribed an
antidepressant:
1. There is a risk of suicidal thoughts or actions
2. How to try to prevent suicidal thoughts or actions in your child
3. You should watch for certain signs if your child is taking an antidepressant
4. There are benefits and risks when using antidepressants
1. There is a Risk of Suicidal Thoughts or Actions
Children and teenagers sometimes think about suicide, and many report trying to kill themselves.
Antidepressants increase suicidal thoughts and actions in some children and teenagers. But suicidal
thoughts and actions can also be caused by depression, a serious medical condition that is commonly
treated with antidepressants. Thinking about killing yourself or trying to kill yourself is called
suicidality or being suicidal.
A large study combined the results of 24 different studies of children and teenagers with depression or
other illnesses. In these studies, patients took either a placebo (sugar pill) or an antidepressant for 1 to
4 months. No one committed suicide in these studies, but some patients became suicidal. On sugar
pills, 2 out of every 100 became suicidal. On the antidepressants, 4 out of every 100 patients became
suicidal.
For some children and teenagers, the risks of suicidal actions may be especially high. These
include patients with
• Bipolar illness (sometimes called manic-depressive illness)
• A family history of bipolar illness
• A personal or family history of attempting suicide
If any of these are present, make sure you tell your healthcare provider before your child takes an
antidepressant.
2. How to Try to Prevent Suicidal Thoughts and Actions
To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in her or
his moods or actions, especially if the changes occur suddenly. Other important people in your child's
life can help by paying attention as well (e.g., your child, brothers and sisters, teachers, and other
important people). The changes to look out for are listed in Section 3, on what to watch for.
Whenever an antidepressant is started or its dose is changed, pay close attention to your child.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 2
Page 2
After starting an antidepressant, your child should generally see his or her healthcare provider:
• Once a week for the first 4 weeks
• Every 2 weeks for the next 4 weeks
• After taking the antidepressant for 12 weeks
• After 12 weeks, follow your healthcare provider's advice about how often to come back
• More often if problems or questions arise (see other side)
You should call your child's healthcare provider between visits if needed.
3. You Should Watch for Certain Signs If Your Child is Taking an Antidepressant
Contact your child's healthcare provider right away if your child exhibits any of the following signs for
the first time, or if they seem worse, or worry you, your child, or your child's teacher:
• Thoughts about suicide or dying
• Attempts to commit suicide
• New or worse depression
• New or worse anxiety
• Feeling very agitated or restless
• Panic attacks
• Difficulty sleeping (insomnia)
• New or worse irritability
• Acting aggressive, being angry, or violent
• Acting on dangerous impulses
• An extreme increase in activity and talking
• Other unusual changes in behavior or mood
Never let your child stop taking an antidepressant without first talking to his or her healthcare
provider. Stopping an antidepressant suddenly can cause other symptoms.
4. There are Benefits and Risks When Using Antidepressants
Antidepressants are used to treat depression and other illnesses. Depression and other illnesses can
lead to suicide. In some children and teenagers, treatment with an antidepressant increases suicidal
thinking or actions. It is important to discuss all the risks of treating depression and also the risks of
not treating it. You and your child should discuss all treatment choices with your healthcare provider,
not just the use of antidepressants.
Other side effects can occur with antidepressants (see section below).
Of all the antidepressants, only fluoxetine (ProzacTM) has been FDA approved to treat pediatric
depression.
For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine
(ProzacTM), sertraline (ZoloftTM), fluvoxamine, and clomipramine (AnafranilTM) .
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Attachment 2
Page 3
Your healthcare provider may suggest other antidepressants based on the past experience of your child
or other family members.
Is this all I need to know if my child is being prescribed an antidepressant?
No. This is a warning about the risk for suicidality. Other side effects can occur with antidepressants.
Be sure to ask your healthcare provider to explain all the side effects of the particular drug he or she is
prescribing. Also ask about drugs to avoid when taking an antidepressant. Ask your healthcare
provider or pharmacist where to find more information.
This Medication Guide has been approved by the U.S. Food and Drug Administration for all
antidepressants.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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0000-0000-00
Reference ID: 3522999
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3522999
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3522999
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3522999
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10 PIECES,
2mg EACH
Reference ID: 3522999
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3522999
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
OPEN HERE
Peel off backing,
starting at
corner with
loose edge.
To remove
the gum,
tear off
single unit.
Push gum
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foil.
10 PIECES,
4mg EACH
Reference ID: 3522999
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3522999
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3522999
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3522999
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3522999
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3522999
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3522999
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3522999
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3522999
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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1
PRESCRIBING INFORMATION
1
WELLBUTRIN®
2
(bupropion hydrochloride)
3
Tablets
4
5
Suicidality in Children and Adolescents
6
Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in
7
short-term studies in children and adolescents with Major Depressive Disorder (MDD) and
8
other psychiatric disorders. Anyone considering the use of WELLBUTRIN or any other
9
antidepressant in a child or adolescent must balance this risk with the clinical need.
10
Patients who are started on therapy should be observed closely for clinical worsening,
11
suicidality, or unusual changes in behavior. Families and caregivers should be advised of
12
the need for close observation and communication with the prescriber. WELLBUTRIN is
13
not approved for use in pediatric patients. (See WARNINGS and PRECAUTIONS:
14
Pediatric Use.)
15
Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of
16
9 antidepressant drugs (SSRIs and others) in children and adolescents with major
17
depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric
18
disorders (a total of 24 trials involving over 4,400 patients) have revealed a greater risk of
19
adverse events representing suicidal thinking or behavior (suicidality) during the first few
20
months of treatment in those receiving antidepressants. The average risk of such events in
21
patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides
22
occurred in these trials.
23
DESCRIPTION
24
WELLBUTRIN (bupropion hydrochloride), an antidepressant of the aminoketone class, is
25
chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other
26
known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related
27
to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-
28
propanone hydrochloride. The molecular weight is 276.2. The empirical formula is
29
C13H18ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in
30
water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The
31
structural formula is:
32
33
34
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
WELLBUTRIN is supplied for oral administration as 75-mg (yellow-gold) and 100-mg (red)
35
film-coated tablets. Each tablet contains the labeled amount of bupropion hydrochloride and the
36
inactive ingredients: 75-mg tablet – D&C Yellow No. 10 Lake, FD&C Yellow No. 6 Lake,
37
hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and
38
titanium dioxide; 100-mg tablet – FD&C Red No. 40 Lake, FD&C Yellow No. 6 Lake,
39
hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and
40
titanium dioxide.
41
CLINICAL PHARMACOLOGY
42
Pharmacodynamics: The neurochemical mechanism of the antidepressant effect of
43
bupropion is not known. Bupropion is a relatively weak inhibitor of the neuronal uptake of
44
norepinephrine, serotonin, and dopamine, and does not inhibit monoamine oxidase.
45
Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals,
46
as evidenced by increased locomotor activity, increased rates of responding in various
47
schedule-controlled operant behavior tasks, and, at high doses, induction of mild stereotyped
48
behavior.
49
Bupropion causes convulsions in rodents and dogs at doses approximately tenfold the dose
50
recommended as the human antidepressant dose.
51
Pharmacokinetics: Bupropion is a racemic mixture. The pharmacological activity and
52
pharmacokinetics of the individual enantiomers have not been studied. In humans, following oral
53
administration of WELLBUTRIN, peak plasma bupropion concentrations are usually achieved
54
within 2 hours, followed by a biphasic decline. The terminal phase has a mean half-life of
55
14 hours, with a range of 8 to 24 hours. The distribution phase has a mean half-life of 3 to
56
4 hours. The mean elimination half-life (±SD) of bupropion after chronic dosing is 21 (±9)
57
hours, and steady-state plasma concentrations of bupropion are reached within 8 days. Plasma
58
bupropion concentrations are dose-proportional following single doses of 100 to 250 mg;
59
however, it is not known if the proportionality between dose and plasma level is maintained in
60
chronic use.
61
Absorption: The absolute bioavailability of WELLBUTRIN Tablets in humans has not been
62
determined because an intravenous formulation for human use is not available. However, it
63
appears likely that only a small proportion of any orally administered dose reaches the systemic
64
circulation intact.
65
Distribution: In vitro tests show that bupropion is 84% bound to human plasma protein at
66
concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion
67
metabolite is similar to that for bupropion, whereas the extent of protein binding of the
68
threohydrobupropion metabolite is about half that seen with bupropion.
69
Metabolism: Bupropion is extensively metabolized in humans. Three metabolites have been
70
shown to be active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group
71
of bupropion, and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion,
72
which are formed via reduction of the carbonyl group. In vitro findings suggest that cytochrome
73
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
P450IIB6 (CYP2B6) is the principal isoenzyme involved in the formation of hydroxybupropion,
74
while cytochrome P450 isoenzymes are not involved in the formation of threohydrobupropion.
75
Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-
76
chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and
77
toxicity of the metabolites relative to bupropion have not been fully characterized. However, it
78
has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one
79
half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold
80
less potent than bupropion. This may be of clinical importance because their plasma
81
concentrations are as high or higher than those of bupropion.
82
Because bupropion is extensively metabolized, there is the potential for drug-drug
83
interactions, particularly with those agents that are metabolized by the cytochrome P450IIB6
84
(CYP2B6) isoenzyme. Although bupropion is not metabolized by cytochrome P450IID6
85
(CYP2D6), there is the potential for drug-drug interactions when bupropion is co-administered
86
with drugs metabolized by this isoenzyme (see PRECAUTIONS: Drug Interactions).
87
Following a single dose in humans, peak plasma concentrations of hydroxybupropion occur
88
approximately 3 hours after administration of WELLBUTRIN Tablets. Peak plasma
89
concentrations of hydroxybupropion are approximately 10 times the peak level of the parent drug
90
at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours,
91
and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations
92
for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the
93
hydroxybupropion metabolite. However, their elimination half-lives are longer, 33 (±10) and
94
37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion,
95
respectively.
96
Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300
97
to 450 mg/day.
98
Elimination: Following oral administration of 200 mg of 14C-bupropion in humans, 87% and
99
10% of the radioactive dose were recovered in the urine and feces, respectively. However, the
100
fraction of the oral dose of WELLBUTRIN excreted unchanged was only 0.5%, a finding
101
consistent with the extensive metabolism of bupropion.
102
Populations Subgroups: Factors or conditions altering metabolic capacity (e.g., liver
103
disease, congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may
104
be expected to influence the degree and extent of accumulation of the active metabolites of
105
bupropion. The elimination of the major metabolites of bupropion may be affected by reduced
106
renal or hepatic function because they are moderately polar compounds and are likely to undergo
107
further metabolism or conjugation in the liver prior to urinary excretion.
108
Hepatic: The effect of hepatic impairment on the pharmacokinetics of bupropion was
109
characterized in 2 single-dose studies, one in patients with alcoholic liver disease and one in
110
patients with mild to severe cirrhosis. The first study showed that the half-life of
111
hydroxybupropion was significantly longer in 8 patients with alcoholic liver disease than in
112
8 healthy volunteers (32±14 hours versus 21±5 hours, respectively). Although not statistically
113
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be
114
greater (by 53% to 57%) in volunteers with alcoholic liver disease. The differences in half-life
115
for bupropion and the other metabolites in the 2 patient groups were minimal.
116
The second study showed that there were no statistically significant differences in the
117
pharmacokinetics of bupropion and its active metabolites in 9 patients with mild to moderate
118
hepatic cirrhosis compared to 8 healthy volunteers. However, more variability was observed in
119
some of the pharmacokinetic parameters for bupropion (AUC, Cmax, and Tmax) and its active
120
metabolites (t½) in patients with mild to moderate hepatic cirrhosis. In addition, in patients with
121
severe hepatic cirrhosis, the bupropion Cmax and AUC were substantially increased (mean
122
difference: by approximately 70% and 3-fold, respectively) and more variable when compared to
123
values in healthy volunteers; the mean bupropion half-life was also longer (29 hours in patients
124
with severe hepatic cirrhosis vs. 19 hours in healthy subjects). For the metabolite
125
hydroxybupropion, the mean Cmax was approximately 69% lower. For the combined amino-
126
alcohol isomers threohydrobupropion and erythrohydrobupropion, the mean Cmax was
127
approximately 31% lower. The mean AUC increased by about 1½-fold for hydroxybupropion
128
and about 2½-fold for threo/erythrohydrobupropion. The median Tmax was observed 19 hours
129
later for hydroxybupropion and 31 hours later for threo/erythrohydrobupropion. The mean
130
half-lives for hydroxybupropion and threo/erythrohydrobupropion were increased 5- and 2-fold,
131
respectively, in patients with severe hepatic cirrhosis compared to healthy volunteers (see
132
WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).
133
Renal: There is limited information on the pharmacokinetics of bupropion in patients with
134
renal impairment. The elimination of the major metabolites of bupropion may be reduced by
135
impaired renal function (see PRECAUTIONS: Renal Impairment).
136
Left Ventricular Dysfunction: During a chronic dosing study in 14 depressed patients
137
with left ventricular dysfunction (history of CHF or an enlarged heart on x-ray), no apparent
138
effect on the pharmacokinetics of bupropion or its metabolites was revealed, compared to healthy
139
volunteers.
140
Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have not
141
been fully characterized, but an exploration of steady-state bupropion concentrations from
142
several depression efficacy studies involving patients dosed in a range of 300 to 750 mg/day, on
143
a 3 times daily schedule, revealed no relationship between age (18 to 83 years) and plasma
144
concentration of bupropion. A single-dose pharmacokinetic study demonstrated that the
145
disposition of bupropion and its metabolites in elderly subjects was similar to that of younger
146
subjects. These data suggest there is no prominent effect of age on bupropion concentration;
147
however, another pharmacokinetic study, single and multiple dose, has suggested that the elderly
148
are at increased risk for accumulation of bupropion and its metabolites (see PRECAUTIONS:
149
Geriatric Use).
150
Gender: A single-dose study involving 12 healthy male and 12 healthy female volunteers
151
revealed no sex-related differences in the pharmacokinetic parameters of bupropion.
152
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion were
153
studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17
154
were nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there
155
were no statistically significant differences in Cmax, half-life, Tmax, AUC or clearance of
156
bupropion or its active metabolites between smokers and nonsmokers.
157
INDICATIONS AND USAGE
158
WELLBUTRIN is indicated for the treatment of major depressive disorder. A physician
159
considering WELLBUTRIN for the management of a patient’s first episode of depression should
160
be aware that the drug may cause generalized seizures in a dose-dependent manner with an
161
approximate incidence of 0.4% (4/1,000). This incidence of seizures may exceed that of other
162
marketed antidepressants by as much as 4-fold. This relative risk is only an approximate estimate
163
because no direct comparative studies have been conducted (see WARNINGS).
164
The efficacy of WELLBUTRIN has been established in 3 placebo-controlled trials, including
165
2 of approximately 3 weeks’ duration in depressed inpatients and one of approximately 6 weeks’
166
duration in depressed outpatients. The depressive disorder of the patients studied corresponds
167
most closely to the Major Depression category of the APA Diagnostic and Statistical Manual III.
168
Major Depression implies a prominent and relatively persistent depressed or dysphoric mood
169
that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should
170
include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor
171
agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased
172
fatigability, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and
173
suicidal ideation or attempts.
174
Effectiveness of WELLBUTRIN in long-term use, that is, for more than 6 weeks, has not
175
been systematically evaluated in controlled trials. Therefore, the physician who elects to use
176
WELLBUTRIN for extended periods should periodically reevaluate the long-term usefulness of
177
the drug for the individual patient.
178
CONTRAINDICATIONS
179
WELLBUTRIN is contraindicated in patients with a seizure disorder.
180
WELLBUTRIN is contraindicated in patients treated with ZYBAN® (bupropion
181
hydrochloride) Sustained-Release Tablets; WELLBUTRIN SR® (bupropion hydrochloride), the
182
sustained-release formulation; WELLBUTRIN XL® (bupropion hydrochloride), the extended-
183
release formulation; or any other medications that contain bupropion because the incidence of
184
seizure is dose dependent.
185
WELLBUTRIN is contraindicated in patients with a current or prior diagnosis of bulimia or
186
anorexia nervosa because of a higher incidence of seizures noted in such patients treated with
187
WELLBUTRIN.
188
WELLBUTRIN is contraindicated in patients undergoing abrupt discontinuation of alcohol or
189
sedatives (including benzodiazepines).
190
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
The concurrent administration of WELLBUTRIN and a monoamine oxidase (MAO) inhibitor
191
is contraindicated. At least 14 days should elapse between discontinuation of an MAO inhibitor
192
and initiation of treatment with WELLBUTRIN.
193
WELLBUTRIN is contraindicated in patients who have shown an allergic response to
194
bupropion or the other ingredients that make up WELLBUTRIN Tablets.
195
WARNINGS
196
Clinical Worsening and Suicide Risk: Patients with major depressive disorder (MDD),
197
both adult and pediatric, may experience worsening of their depression and/or the emergence of
198
suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they
199
are taking antidepressant medications, and this risk may persist until significant remission
200
occurs. There has been a long-standing concern that antidepressants may have a role in inducing
201
worsening of depression and the emergence of suicidality in certain patients. Antidepressants
202
increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children
203
and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders.
204
Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and
205
others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of
206
24 trials involving over 4,400 patients) have revealed a greater risk of adverse events
207
representing suicidal behavior or thinking (suicidality) during the first few months of treatment
208
in those receiving antidepressants. The average risk of such events in patients receiving
209
antidepressants was 4%, twice the placebo risk of 2%. There was considerable variation in risk
210
among drugs, but a tendency toward an increase for almost all drugs studied. The risk of
211
suicidality was most consistently observed in the MDD trials, but there were signals of risk
212
arising from some trials in other psychiatric indications (obsessive compulsive disorder and
213
social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown
214
whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond several
215
months. It is also unknown whether the suicidality risk extends to adults.
216
All pediatric patients being treated with antidepressants for any indication should be
217
observed closely for clinical worsening, suicidality, and unusual changes in behavior,
218
especially during the initial few months of a course of drug therapy, or at times of dose
219
changes, either increases or decreases. Such observation would generally include at least
220
weekly face-to-face contact with patients or their family members or caregivers during the
221
first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at
222
12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may
223
be appropriate between face-to-face visits.
224
Adults with MDD or co-morbid depression in the setting of other psychiatric illness
225
being treated with antidepressants should be observed similarly for clinical worsening and
226
suicidality, especially during the initial few months of a course of drug therapy, or at times
227
of dose changes, either increases or decreases.
228
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
In addition, patients with a history of suicidal behavior or thoughts, those patients
229
exhibiting a significant degree of suicidal ideation prior to commencement of treatment,
230
and young adults, are at an increased risk of suicidal thoughts or suicide attempts, and
231
should receive careful monitoring during treatment.
232
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
233
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
234
been reported in adult and pediatric patients being treated with antidepressants for major
235
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
236
Although a causal link between the emergence of such symptoms and either the worsening of
237
depression and/or the emergence of suicidal impulses has not been established, there is concern
238
that such symptoms may represent precursors to emerging suicidality.
239
Consideration should be given to changing the therapeutic regimen, including possibly
240
discontinuing the medication, in patients whose depression is persistently worse, or who are
241
experiencing emergent suicidality or symptoms that might be precursors to worsening depression
242
or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
243
patient’s presenting symptoms.
244
Families and caregivers of pediatric patients being treated with antidepressants for
245
major depressive disorder or other indications, both psychiatric and nonpsychiatric,
246
should be alerted about the need to monitor patients for the emergence of agitation,
247
irritability, unusual changes in behavior, and the other symptoms described above, as well
248
as the emergence of suicidality, and to report such symptoms immediately to health care
249
providers. Such monitoring should include daily observation by families and caregivers.
250
Prescriptions for WELLBUTRIN should be written for the smallest quantity of tablets consistent
251
with good patient management, in order to reduce the risk of overdose. Families and caregivers
252
of adults being treated for depression should be similarly advised.
253
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
254
presentation of bipolar disorder. It is generally believed (though not established in controlled
255
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
256
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
257
symptoms described above represent such a conversion is unknown. However, prior to initiating
258
treatment with an antidepressant, patients with depressive symptoms should be adequately
259
screened to determine if they are at risk for bipolar disorder; such screening should include a
260
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
261
depression. It should be noted that WELLBUTRIN is not approved for use in treating bipolar
262
depression.
263
Patients should be made aware that WELLBUTRIN contains the same active ingredient
264
found in ZYBAN, used as an aid to smoking cessation treatment, and that WELLBUTRIN
265
should not be used in combination with ZYBAN, or any other medications that contain
266
bupropion, such as WELLBUTRIN SR (bupropion hydrochloride), the sustained-release
267
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
formulation or WELLBUTRIN XL (bupropion hydrochloride), the extended-release
268
formulation.
269
270
Seizures: Bupropion is associated with seizures in approximately 0.4% (4/1,000) of
271
patients treated at doses up to 450 mg/day. This incidence of seizures may exceed that of
272
other marketed antidepressants by as much as 4-fold. This relative risk is only an
273
approximate estimate because no direct comparative studies have been conducted. The
274
estimated seizure incidence for WELLBUTRIN increases almost tenfold between 450 and
275
600 mg/day, which is twice the usually required daily dose (300 mg) and one and one-third
276
the maximum recommended daily dose (450 mg). Given the wide variability among
277
individuals and their capacity to metabolize and eliminate drugs this disproportionate
278
increase in seizure incidence with dose incrementation calls for caution in dosing.
279
During the initial development, 25 among approximately 2,400 patients treated with
280
WELLBUTRIN experienced seizures. At the time of seizure, 7 patients were receiving daily
281
doses of 450 mg or below for an incidence of 0.33% (3/1,000) within the recommended dose
282
range. Twelve patients experienced seizures at 600 mg/day (2.3% incidence); 6 additional
283
patients had seizures at daily doses between 600 and 900 mg (2.8% incidence).
284
A separate, prospective study was conducted to determine the incidence of seizure
285
during an 8-week treatment exposure in approximately 3,200 additional patients who
286
received daily doses of up to 450 mg. Patients were permitted to continue treatment beyond
287
8 weeks if clinically indicated. Eight seizures occurred during the initial 8-week treatment
288
period and 5 seizures were reported in patients continuing treatment beyond 8 weeks,
289
resulting in a total seizure incidence of 0.4%.
290
The risk of seizure appears to be strongly associated with dose. Sudden and large
291
increments in dose may contribute to increased risk. While many seizures occurred early in
292
the course of treatment, some seizures did occur after several weeks at fixed dose.
293
WELLBUTRIN should be discontinued and not restarted in patients who experience a
294
seizure while on treatment.
295
The risk of seizure is also related to patient factors, clinical situations, and concomitant
296
medications, which must be considered in selection of patients for therapy with
297
WELLBUTRIN.
298
• Patient factors: Predisposing factors that may increase the risk of seizure with
299
bupropion use include history of head trauma or prior seizure, central nervous system
300
(CNS) tumor, the presence of severe hepatic cirrhosis, and concomitant medications
301
that lower seizure threshold.
302
• Clinical situations: Circumstances associated with an increased seizure risk include,
303
among others, excessive use of alcohol or sedatives (including benzodiazepines);
304
addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and
305
anorectics; and diabetes treated with oral hypoglycemics or insulin.
306
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
• Concomitant medications: Many medications (e.g., antipsychotics, antidepressants,
307
theophylline, systemic steroids) are known to lower seizure threshold.
308
Recommendations for Reducing the Risk of Seizure: Retrospective analysis of
309
clinical experience gained during the development of WELLBUTRIN suggests that the risk
310
of seizure may be minimized if
311
• the total daily dose of WELLBUTRIN does not exceed 450 mg,
312
• the daily dose is administered 3 times daily, with each single dose not to exceed 150 mg
313
to avoid high peak concentrations of bupropion and/or its metabolites, and
314
• the rate of incrementation of dose is very gradual.
315
WELLBUTRIN should be administered with extreme caution to patients with a history
316
of seizure, cranial trauma, or other predisposition(s) toward seizure, or patients treated
317
with other agents (e.g., antipsychotics, other antidepressants, theophylline, systemic
318
steroids, etc.) that lower seizure threshold.
319
Hepatic Impairment: WELLBUTRIN should be used with extreme caution in patients
320
with severe hepatic cirrhosis. In these patients a reduced dose and/or frequency is required,
321
as peak bupropion, as well as AUC, levels are substantially increased and accumulation is
322
likely to occur in such patients to a greater extent than usual. The dose should not exceed
323
75 mg once a day in these patients (see CLINICAL PHARMACOLOGY, PRECAUTIONS,
324
and DOSAGE AND ADMINISTRATION).
325
Potential for Hepatotoxicity: In rats receiving large doses of bupropion chronically, there
326
was an increase in incidence of hepatic hyperplastic nodules and hepatocellular hypertrophy. In
327
dogs receiving large doses of bupropion chronically, various histologic changes were seen in the
328
liver, and laboratory tests suggesting mild hepatocellular injury were noted.
329
PRECAUTIONS
330
General: Agitation and Insomnia: A substantial proportion of patients treated with
331
WELLBUTRIN experience some degree of increased restlessness, agitation, anxiety, and
332
insomnia, especially shortly after initiation of treatment. In clinical studies, these symptoms were
333
sometimes of sufficient magnitude to require treatment with sedative/hypnotic drugs. In
334
approximately 2% of patients, symptoms were sufficiently severe to require discontinuation of
335
treatment with WELLBUTRIN.
336
Psychosis, Confusion, and Other Neuropsychiatric Phenomena: Depressed
337
patients treated with WELLBUTRIN have been reported to show a variety of neuropsychiatric
338
signs and symptoms including delusions, hallucinations, psychosis, concentration disturbance,
339
paranoia, and confusion. Because of the uncontrolled nature of many studies, it is impossible to
340
provide a precise estimate of the extent of risk imposed by treatment with WELLBUTRIN. In
341
several cases, neuropsychiatric phenomena abated upon dose reduction and/or withdrawal of
342
treatment.
343
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
Activation of Psychosis and/or Mania: Antidepressants can precipitate manic episodes
344
in bipolar disorder patients during the depressed phase of their illness and may activate latent
345
psychosis in other susceptible patients. WELLBUTRIN is expected to pose similar risks.
346
Altered Appetite and Weight: A weight loss of greater than 5 lbs occurred in 28% of
347
patients receiving WELLBUTRIN. This incidence is approximately double that seen in
348
comparable patients treated with tricyclics or placebo. Furthermore, while 35% of patients
349
receiving tricyclic antidepressants gained weight, only 9.4% of patients treated with
350
WELLBUTRIN did. Consequently, if weight loss is a major presenting sign of a patient’s
351
depressive illness, the anorectic and/or weight reducing potential of WELLBUTRIN should be
352
considered.
353
Allergic Reactions: Anaphylactoid/anaphylactic reactions characterized by symptoms such
354
as pruritus, urticaria, angioedema, and dyspnea requiring medical treatment have been reported
355
in clinical trials with bupropion. In addition, there have been rare spontaneous postmarketing
356
reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated
357
with bupropion. A patient should stop taking WELLBUTRIN and consult a doctor if
358
experiencing allergic or anaphylactoid/anaphylactic reactions (e.g., skin rash, pruritus, hives,
359
chest pain, edema, and shortness of breath) during treatment.
360
Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed
361
hypersensitivity have been reported in association with bupropion. These symptoms may
362
resemble serum sickness.
363
Cardiovascular Effects: In clinical practice, hypertension, in some cases severe, requiring
364
acute treatment, has been reported in patients receiving bupropion alone and in combination with
365
nicotine replacement therapy. These events have been observed in both patients with and without
366
evidence of preexisting hypertension.
367
Data from a comparative study of the sustained-release formulation of bupropion (ZYBAN®
368
Sustained-Release Tablets), nicotine transdermal system (NTS), the combination of sustained-
369
release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher
370
incidence of treatment-emergent hypertension in patients treated with the combination of
371
sustained-release bupropion and NTS. In this study, 6.1% of patients treated with the
372
combination of sustained-release bupropion and NTS had treatment-emergent hypertension
373
compared to 2.5%, 1.6%, and 3.1% of patients treated with sustained-release bupropion, NTS,
374
and placebo, respectively. The majority of these patients had evidence of preexisting
375
hypertension. Three patients (1.2%) treated with the combination of ZYBAN and NTS and 1
376
patient (0.4%) treated with NTS had study medication discontinued due to hypertension
377
compared to none of the patients treated with ZYBAN or placebo. Monitoring of blood pressure
378
is recommended in patients who receive the combination of bupropion and nicotine replacement.
379
There is no clinical experience establishing the safety of WELLBUTRIN in patients with a
380
recent history of myocardial infarction or unstable heart disease. Therefore, care should be
381
exercised if it is used in these groups. Bupropion was well tolerated in depressed patients who
382
had previously developed orthostatic hypotension while receiving tricyclic antidepressants and
383
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
was also generally well tolerated in a group of 36 depressed inpatients with stable congestive
384
heart failure (CHF). However, bupropion was associated with a rise in supine blood pressure in
385
the study of patients with CHF, resulting in discontinuation of treatment in 2 patients for
386
exacerbation of baseline hypertension.
387
Hepatic Impairment: WELLBUTRIN should be used with extreme caution in patients with
388
severe hepatic cirrhosis. In these patients, a reduced dose and frequency is required.
389
WELLBUTRIN should be used with caution in patients with hepatic impairment (including mild
390
to moderate hepatic cirrhosis) and a reduced frequency and/or dose should be considered in
391
patients with mild to moderate hepatic cirrhosis.
392
All patients with hepatic impairment should be closely monitored for possible adverse effects
393
that could indicate high drug and metabolite levels (see CLINICAL PHARMACOLOGY,
394
WARNINGS, and DOSAGE AND ADMINISTRATION).
395
Renal Impairment: There is limited information on the pharmacokinetics of bupropion in
396
patients with renal impairment. Bupropion is extensively metabolized in the liver to active
397
metabolites, which are further metabolized and subsequently excreted by the kidneys.
398
WELLBUTRIN should be used with caution in patients with renal impairment and a reduced
399
frequency and/or dose should be considered as the metabolites of bupropion may accumulate in
400
such patients to a greater extent than usual. The patient should be closely monitored for possible
401
adverse effects that could indicate high drug or metabolite levels.
402
Information for Patients: Prescribers or other health professionals should inform patients,
403
their families, and their caregivers about the benefits and risks associated with treatment with
404
WELLBUTRIN and should counsel them in its appropriate use. A patient Medication Guide
405
About Using Antidepressants in Children and Teenagers is available for WELLBUTRIN. The
406
prescriber or health professional should instruct patients, their families, and their caregivers to
407
read the Medication Guide and should assist them in understanding its contents. Patients should
408
be given the opportunity to discuss the contents of the Medication Guide and to obtain answers
409
to any questions they may have. The complete text of the Medication Guide is reprinted at the
410
end of this document. Additional important information concerning WELLBUTRIN is provided
411
in a tear-off leaflet entitled "Patient Information" at the end of this labeling.
412
Patients should be advised of the following issues and asked to alert their prescriber if these
413
occur while taking WELLBUTRIN.
414
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers
415
should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia,
416
irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
417
hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal
418
ideation, especially early during antidepressant treatment and when the dose is adjusted up or
419
down. Families and caregivers of patients should be advised to observe for the emergence of
420
such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be
421
reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in
422
onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be
423
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
associated with an increased risk for suicidal thinking and behavior and indicate a need for very
424
close monitoring and possibly changes in the medication.
425
Patients should be made aware that WELLBUTRIN contains the same active ingredient found
426
in ZYBAN, used as an aid to smoking cessation, and that WELLBUTRIN should not be used in
427
combination with ZYBAN or any other medications that contain bupropion hydrochloride (such
428
as WELLBUTRIN SR, the sustained-release formulation and WELLBUTRIN XL, the extended-
429
release formulation).
430
Patients should be instructed to take WELLBUTRIN in equally divided doses 3 or 4 times a
431
day to minimize the risk of seizure.
432
Patients should be told that WELLBUTRIN should be discontinued and not restarted if they
433
experience a seizure while on treatment.
434
Patients should be told that any CNS-active drug like WELLBUTRIN may impair their ability
435
to perform tasks requiring judgment or motor and cognitive skills. Consequently, until they are
436
reasonably certain that WELLBUTRIN does not adversely affect their performance, they should
437
refrain from driving an automobile or operating complex, hazardous machinery.
438
Patients should be told that the excessive use or abrupt discontinuation of alcohol or sedatives
439
(including benzodiazepines) may alter the seizure threshold. Some patients have reported lower
440
alcohol tolerance during treatment with WELLBUTRIN. Patients should be advised that the
441
consumption of alcohol should be minimized or avoided.
442
Patients should be advised to inform their physicians if they are taking or plan to take any
443
prescription or over-the-counter drugs. Concern is warranted because WELLBUTRIN and other
444
drugs may affect each other’s metabolism.
445
Patients should be advised to notify their physicians if they become pregnant or intend to
446
become pregnant during therapy.
447
Laboratory Tests: There are no specific laboratory tests recommended.
448
Drug Interactions: Few systemic data have been collected on the metabolism of bupropion
449
following concomitant administration with other drugs or, alternatively, the effect of
450
concomitant administration of bupropion on the metabolism of other drugs.
451
Because bupropion is extensively metabolized, the coadministration of other drugs may affect
452
its clinical activity. In vitro studies indicate that bupropion is primarily metabolized to
453
hydroxybupropion by the CYP2B6 isoenzyme. Therefore, the potential exists for a drug
454
interaction between WELLBUTRIN and drugs that are the substrates or inhibitors of the
455
CYP2B6 isoenzyme (e.g., orphenadrine, thiotepa, and cyclophosphamide). In addition, in vitro
456
studies suggest that paroxetine, sertraline, norfluoxetine, and fluvoxamine as well as nelfinavir,
457
ritonavir, and efavirenz inhibit the hydroxylation of bupropion. No clinical studies have been
458
performed to evaluate this finding. The threohydrobupropion metabolite of bupropion does not
459
appear to be produced by the cytochrome P450 isoenzymes. The effects of concomitant
460
administration of cimetidine on the pharmacokinetics of bupropion and its active metabolites
461
were studied in 24 healthy young male volunteers. Following oral administration of two 150-mg
462
sustained-release tablets with and without 800 mg of cimetidine, the pharmacokinetics of
463
bupropion and hydroxybupropion were unaffected. However, there were 16% and 32% increases
464
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
in the AUC and Cmax, respectively, of the combined moieties of threohydrobupropion and
465
erythrohydrobupropion.
466
While not systematically studied, certain drugs may induce the metabolism of bupropion (e.g.,
467
carbamazepine, phenobarbital, phenytoin).
468
Multiple oral doses of bupropion had no statistically significant effects on the single dose
469
pharmacokinetics of lamotrigine in 12 healthy volunteers and was associated with a slight
470
increase in the AUC (15%) of lamotrigine glucuronide.
471
Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in
472
humans. In one study, following chronic administration of bupropion, 100 mg 3 times daily to 8
473
healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism.
474
Nevertheless, there may be the potential for clinically important alterations of blood levels of
475
coadministered drugs.
476
Drugs Metabolized by Cytochrome P450IID6 (CYP2D6): Many drugs, including most
477
antidepressants (SSRIs, many tricyclics), beta-blockers, antiarrhythmics, and antipsychotics are
478
metabolized by the CYP2D6 isoenzyme. Although bupropion is not metabolized by this
479
isoenzyme, bupropion and hydroxybupropion are inhibitors of the CYP2D6 isoenzyme in vitro.
480
In a study of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of the
481
CYP2D6 isoenzyme, daily doses of bupropion given as 150 mg twice daily followed by a single
482
dose of 50 mg desipramine increased the Cmax, AUC, and t1/2 of desipramine by an average of
483
approximately 2-, 5- and 2-fold, respectively. The effect was present for at least 7 days after the
484
last dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6
485
has not been formally studied.
486
Therefore, co-administration of bupropion with drugs that are metabolized by CYP2D6
487
isoenzyme including certain antidepressants (e.g., nortriptyline, imipramine, desipramine,
488
paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine),
489
beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide),
490
should be approached with caution and should be initiated at the lower end of the dose range of
491
the concomitant medication. If bupropion is added to the treatment regimen of a patient already
492
receiving a drug metabolized by CYP2D6, the need to decrease the dose of the original
493
medication should be considered, particularly for those concomitant medications with a narrow
494
therapeutic index.
495
MAO Inhibitors: Studies in animals demonstrate that the acute toxicity of bupropion is
496
enhanced by the MAO inhibitor phenelzine (see CONTRAINDICATIONS).
497
Levodopa and Amantadine: Limited clinical data suggest a higher incidence of adverse
498
experiences in patients receiving bupropion concurrently with either levodopa or amantadine.
499
Administration of WELLBUTRIN Tablets to patients receiving either levodopa or amantadine
500
concurrently should be undertaken with caution, using small initial doses and small gradual dose
501
increases.
502
Drugs that Lower Seizure Threshold: Concurrent administration of WELLBUTRIN and
503
agents (e.g., antipsychotics, other antidepressants, theophylline, systemic steroids, etc.) that
504
lower seizure threshold should be undertaken only with extreme caution (see WARNINGS).
505
Low initial dosing and small gradual dose increases should be employed.
506
Nicotine Transdermal System: (see PRECAUTIONS: Cardiovascular Effects).
507
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
Alcohol: In postmarketing experience, there have been rare reports of adverse
508
neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol
509
during treatment with WELLBUTRIN. The consumption of alcohol during treatment with
510
WELLBUTRIN should be minimized or avoided (also see CONTRAINDICATIONS).
511
Carcinogenesis, Mutagenesis, Impairment of Fertility: Lifetime carcinogenicity studies
512
were performed in rats and mice at doses up to 300 and 150 mg/kg/day, respectively. In the rat
513
study there was an increase in nodular proliferative lesions of the liver at doses of 100 to
514
300 mg/kg/day; lower doses were not tested. The question of whether or not such lesions may be
515
precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen
516
in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in
517
either study.
518
Bupropion produced a borderline positive response (2 to 3 times control mutation rate) in
519
some strains in the Ames bacterial mutagenicity test, and a high oral dose (300 mg/kg, but not
520
100 or 200 mg/kg) produced a low incidence of chromosomal aberrations in rats. The relevance
521
of these results in estimating the risk of human exposure to therapeutic doses is unknown.
522
A fertility study was performed in rats; no evidence of impairment of fertility was
523
encountered at oral doses up to 300 mg/kg/day.
524
Pregnancy: Teratogenic Effects: Pregnancy Category C. In studies conducted in rats and
525
rabbits, bupropion was administered orally at doses up to 450 and 150 mg/kg/day, respectively
526
(approximately 11 and 7 times the maximum recommended human dose [MRHD], respectively,
527
on a mg/m2 basis), during the period of organogenesis. No clear evidence of teratogenic activity
528
was found in either species; however, in rabbits, slightly increased incidences of fetal
529
malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day,
530
approximately equal to the MRHD on a mg/m2 basis) and greater. Decreased fetal weights were
531
seen at 50 mg/kg and greater.
532
When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately
533
7 times the MRHD on a mg/m2 basis) prior to mating and throughout pregnancy and lactation,
534
there were no apparent adverse effects on offspring development.
535
One study has been conducted in pregnant women. This retrospective, managed-care database
536
study assessed the risk of congenital malformations overall, and cardiovascular malformations
537
specifically, following exposure to bupropion in the first trimester compared to the risk of these
538
malformations following exposure to other antidepressants in the first trimester and bupropion
539
outside of the first trimester. This study included 7,005 infants with antidepressant exposure
540
during pregnancy, 1,213 of whom were exposed to bupropion in the first trimester. The study
541
showed no greater risk for congenital malformations overall, or cardiovascular malformations
542
specifically, following first trimester bupropion exposure compared to exposure to all other
543
antidepressants in the first trimester, or bupropion outside of the first trimester. The results of
544
this study have not been corroborated. WELLBUTRIN should be used during pregnancy only if
545
the potential benefit justifies the potential risk to the fetus.
546
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
To monitor fetal outcomes of pregnant women exposed to WELLBUTRIN, GlaxoSmithKline
547
maintains a Bupropion Pregnancy Registry. Health care providers are encouraged to register
548
patients by calling (800) 336-2176.
549
Labor and Delivery: The effect of WELLBUTRIN on labor and delivery in humans is
550
unknown.
551
Nursing Mothers: Like many other drugs, bupropion and its metabolites are secreted in human
552
milk. Because of the potential for serious adverse reactions in nursing infants from
553
WELLBUTRIN, a decision should be made whether to discontinue nursing or to discontinue the
554
drug, taking into account the importance of the drug to the mother.
555
Pediatric Use: Safety and effectiveness in the pediatric population have not been established
556
(see BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk). Anyone
557
considering the use of WELLBUTRIN in a child or adolescent must balance the potential risks
558
with the clinical need.
559
Geriatric Use: Of the approximately 6,000 patients who participated in clinical trials with
560
bupropion sustained-release tablets (depression and smoking cessation studies), 275 were 65 and
561
over and 47 were 75 and over. In addition, several hundred patients 65 and over participated in
562
clinical trials using the immediate-release formulation of bupropion (depression studies). No
563
overall differences in safety or effectiveness were observed between these subjects and younger
564
subjects, and other reported clinical experience has not identified differences in responses
565
between the elderly and younger patients, but greater sensitivity of some older individuals cannot
566
be ruled out.
567
A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its
568
metabolites in elderly subjects was similar to that of younger subjects; however, another
569
pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased
570
risk for accumulation of bupropion and its metabolites (see CLINICAL PHARMACOLOGY).
571
Bupropion is extensively metabolized in the liver to active metabolites, which are further
572
metabolized and excreted by the kidneys. The risk of toxic reaction to this drug may be greater in
573
patients with impaired renal function. Because elderly patients are more likely to have decreased
574
renal function, care should be taken in dose selection, and it may be useful to monitor renal
575
function (see PRECAUTIONS: Renal Impairment and DOSAGE AND ADMINISTRATION).
576
577
ADVERSE REACTIONS (see also WARNINGS and PRECAUTIONS)
578
Adverse events commonly encountered in patients treated with WELLBUTRIN are agitation,
579
dry mouth, insomnia, headache/migraine, nausea/vomiting, constipation, and tremor.
580
Adverse events were sufficiently troublesome to cause discontinuation of treatment with
581
WELLBUTRIN in approximately 10% of the 2,400 patients and volunteers who participated in
582
clinical trials during the product’s initial development. The more common events causing
583
discontinuation include neuropsychiatric disturbances (3.0%), primarily agitation and
584
abnormalities in mental status; gastrointestinal disturbances (2.1%), primarily nausea and
585
vomiting; neurological disturbances (1.7%), primarily seizures, headaches, and sleep
586
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
disturbances; and dermatologic problems (1.4%), primarily rashes. It is important to note,
587
however, that many of these events occurred at doses that exceed the recommended daily dose.
588
Accurate estimates of the incidence of adverse events associated with the use of any drug are
589
difficult to obtain. Estimates are influenced by drug dose, detection technique, setting, physician
590
judgments, etc. Consequently, the table below is presented solely to indicate the relative
591
frequency of adverse events reported in representative controlled clinical studies conducted to
592
evaluate the safety and efficacy of WELLBUTRIN under relatively similar conditions of daily
593
dosage (300 to 600 mg), setting, and duration (3 to 4 weeks). The figures cited cannot be used to
594
predict precisely the incidence of untoward events in the course of usual medical practice where
595
patient characteristics and other factors must differ from those which prevailed in the clinical
596
trials. These incidence figures also cannot be compared with those obtained from other clinical
597
studies involving related drug products as each group of drug trials is conducted under a different
598
set of conditions.
599
Finally, it is important to emphasize that the tabulation does not reflect the relative severity
600
and/or clinical importance of the events. A better perspective on the serious adverse events
601
associated with the use of WELLBUTRIN is provided in WARNINGS and PRECAUTIONS.
602
603
Table 1. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled
604
Clinical Trials* (Percent of Patients Reporting)
605
Adverse Experience
WELLBUTRIN Patients
(n = 323)
Placebo Patients
(n = 185)
Cardiovascular
Cardiac arrhythmias
5.3
4.3
Dizziness
22.3
16.2
Hypertension
4.3
1.6
Hypotension
2.5
2.2
Palpitations
3.7
2.2
Syncope
1.2
0.5
Tachycardia
10.8
8.6
Dermatologic
Pruritus
2.2
0.0
Rash
8.0
6.5
Gastrointestinal
Anorexia
18.3
18.4
Appetite increase
3.7
2.2
Constipation
26.0
17.3
Diarrhea
6.8
8.6
Dyspepsia
3.1
2.2
Nausea/vomiting
22.9
18.9
Weight gain
13.6
22.7
Weight loss
23.2
23.2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
Genitourinary
Impotence
3.4
3.1
Menstrual complaints
4.7
1.1
Urinary frequency
2.5
2.2
Urinary retention
1.9
2.2
Musculoskeletal
Arthritis
3.1
2.7
Neurological
Akathisia
1.5
1.1
Akinesia/bradykinesia
8.0
8.6
Cutaneous temperature
disturbance
1.9
1.6
Dry mouth
27.6
18.4
Excessive sweating
22.3
14.6
Headache/migraine
25.7
22.2
Impaired sleep quality
4.0
1.6
Increased salivary flow
3.4
3.8
Insomnia
18.6
15.7
Muscle spasms
1.9
3.2
Pseudoparkinsonism
1.5
1.6
Sedation
19.8
19.5
Sensory disturbance
4.0
3.2
Tremor
21.1
7.6
Neuropsychiatric
Agitation
31.9
22.2
Anxiety
3.1
1.1
Confusion
8.4
4.9
Decreased libido
3.1
1.6
Delusions
1.2
1.1
Disturbed concentration
3.1
3.8
Euphoria
1.2
0.5
Hostility
5.6
3.8
Nonspecific
Fatigue
5.0
8.6
Fever/chills
1.2
0.5
Respiratory
Upper respiratory complaints
5.0
11.4
Special Senses
Auditory disturbance
5.3
3.2
Blurred vision
14.6
10.3
Gustatory disturbance
3.1
1.1
*Events reported by at least 1% of patients receiving WELLBUTRIN are included.
606
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18
607
Other Events Observed During the Development of WELLBUTRIN: The conditions
608
and duration of exposure to WELLBUTRIN varied greatly, and a substantial proportion of the
609
experience was gained in open and uncontrolled clinical settings. During this experience,
610
numerous adverse events were reported; however, without appropriate controls, it is impossible
611
to determine with certainty which events were or were not caused by WELLBUTRIN. The
612
following enumeration is organized by organ system and describes events in terms of their
613
relative frequency of reporting in the data base. Events of major clinical importance are also
614
described in WARNINGS and PRECAUTIONS.
615
The following definitions of frequency are used: Frequent adverse events are defined as those
616
occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to
617
1/1,000 patients, while rare events are those occurring in less than 1/1,000 patients.
618
Cardiovascular: Frequent was edema; infrequent were chest pain, electrocardiogram (ECG)
619
abnormalities (premature beats and nonspecific ST-T changes), and shortness of breath/dyspnea;
620
rare were flushing, pallor, phlebitis, and myocardial infarction.
621
Dermatologic: Frequent were nonspecific rashes; infrequent were alopecia and dry skin;
622
rare were change in hair color, hirsutism, and acne.
623
Endocrine: Infrequent was gynecomastia; rare were glycosuria and hormone level change.
624
Gastrointestinal: Infrequent were dysphagia, thirst disturbance, and liver damage/jaundice;
625
rare were rectal complaints, colitis, gastrointestinal bleeding, intestinal perforation, and stomach
626
ulcer.
627
Genitourinary: Frequent was nocturia; infrequent were vaginal irritation, testicular swelling,
628
urinary tract infection, painful erection, and retarded ejaculation; rare were dysuria, enuresis,
629
urinary incontinence, menopause, ovarian disorder, pelvic infection, cystitis, dyspareunia, and
630
painful ejaculation.
631
Hematologic/Oncologic: Rare were lymphadenopathy, anemia, and pancytopenia.
632
Musculoskeletal: Rare was musculoskeletal chest pain.
633
Neurological: (see WARNINGS) Frequent were ataxia/incoordination, seizure, myoclonus,
634
dyskinesia, and dystonia; infrequent were mydriasis, vertigo, and dysarthria; rare were
635
electroencephalogram (EEG) abnormality, abnormal neurological exam, impaired attention,
636
sciatica, and aphasia.
637
Neuropsychiatric: (see PRECAUTIONS) Frequent were mania/hypomania, increased
638
libido, hallucinations, decrease in sexual function, and depression; infrequent were memory
639
impairment, depersonalization, psychosis, dysphoria, mood instability, paranoia, formal thought
640
disorder, and frigidity; rare was suicidal ideation.
641
Oral Complaints: Frequent was stomatitis; infrequent were toothache, bruxism, gum
642
irritation, and oral edema; rare was glossitis.
643
Respiratory: Infrequent were bronchitis and shortness of breath/dyspnea; rare were
644
epistaxis, rate or rhythm disorder, pneumonia, and pulmonary embolism.
645
Special Senses: Infrequent was visual disturbance; rare was diplopia.
646
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19
Nonspecific: Frequent were flu-like symptoms; infrequent was nonspecific pain; rare were
647
body odor, surgically related pain, infection, medication reaction, and overdose.
648
Postintroduction Reports: Voluntary reports of adverse events temporally associated with
649
bupropion that have been received since market introduction and which may have no causal
650
relationship with the drug include the following:
651
Body (General): arthralgia, myalgia, and fever with rash and other symptoms suggestive of
652
delayed hypersensitivity. These symptoms may resemble serum sickness (see PRECAUTIONS).
653
Cardiovascular: hypertension (in some cases severe, see PRECAUTIONS), orthostatic
654
hypotension, third degree heart block
655
Endocrine: syndrome of inappropriate antidiuretic hormone secretion, hyperglycemia,
656
hypoglycemia
657
Gastrointestinal: esophagitis, hepatitis, liver damage
658
Hemic and Lymphatic: ecchymosis, leukocytosis, leukopenia, thrombocytopenia. Altered
659
PT and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were
660
observed when bupropion was coadministered with warfarin.
661
Musculoskeletal: arthralgia, myalgia, muscle rigidity/fever/rhabdomyolysis, muscle
662
weakness
663
Nervous: aggression, coma, delirium, dream abnormalities, paranoid ideation, paresthesia,
664
restlessness, unmasking of tardive dyskinesia
665
Skin and Appendages: Stevens-Johnson syndrome, angioedema, exfoliative dermatitis,
666
urticaria
667
Special Senses: tinnitus
668
DRUG ABUSE AND DEPENDENCE
669
Humans: Controlled clinical studies conducted in normal volunteers, in subjects with a history
670
of multiple drug abuse, and in depressed patients showed some increase in motor activity and
671
agitation/excitement.
672
In a population of individuals experienced with drugs of abuse, a single dose of 400 mg of
673
WELLBUTRIN produced mild amphetamine-like activity as compared to placebo on the
674
Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI) and a
675
score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These
676
scales measure general feelings of euphoria and drug desirability.
677
Findings in clinical trials, however, are not known to predict the abuse potential of drugs
678
reliably. Nonetheless, evidence from single-dose studies does suggest that the recommended
679
daily dosage of bupropion when administered in divided doses is not likely to be especially
680
reinforcing to amphetamine or stimulant abusers. However, higher doses that could not be tested
681
because of the risk of seizure might be modestly attractive to those who abuse stimulant drugs.
682
Animals: Studies in rodents have shown that bupropion exhibits some pharmacologic actions
683
common to psychostimulants including increases in locomotor activity and the production of a
684
mild stereotyped behavior and increases in rates of responding in several schedule-controlled
685
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
20
behavior paradigms. Drug discrimination studies in rats showed stimulus generalization between
686
bupropion and amphetamine and other psychostimulants. Rhesus monkeys have been shown to
687
self-administer bupropion intravenously.
688
OVERDOSAGE
689
Human Overdose Experience: Overdoses of up to 30 g or more of bupropion have been
690
reported. Seizure was reported in approximately one third of all cases. Other serious reactions
691
reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus
692
tachycardia, and ECG changes such as conduction disturbances or arrhythmias. Fever, muscle
693
rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported
694
mainly when bupropion was part of multiple drug overdoses.
695
Although most patients recovered without sequelae, deaths associated with overdoses of
696
bupropion alone have been reported in patients ingesting large doses of the drug. Multiple
697
uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported
698
in these patients.
699
Overdosage Management: Ensure an adequate airway, oxygenation, and ventilation.
700
Monitor cardiac rhythm and vital signs. EEG monitoring is also recommended for the first
701
48 hours post-ingestion. General supportive and symptomatic measures are also recommended.
702
Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with
703
appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in
704
symptomatic patients.
705
Activated charcoal should be administered. There is no experience with the use of forced
706
diuresis, dialysis, hemoperfusion, or exchange transfusion in the management of bupropion
707
overdoses. No specific antidotes for bupropion are known.
708
Due to the dose-related risk of seizures with WELLBUTRIN, hospitalization following
709
suspected overdose should be considered. Based on studies in animals, it is recommended that
710
seizures be treated with intravenous benzodiazepine administration and other supportive
711
measures, as appropriate.
712
In managing overdosage, consider the possibility of multiple drug involvement. The physician
713
should consider contacting a poison control center for additional information on the treatment of
714
any overdose. Telephone numbers for certified poison control centers are listed in the
715
Physicians’ Desk Reference (PDR).
716
DOSAGE AND ADMINISTRATION
717
General Dosing Considerations: It is particularly important to administer WELLBUTRIN
718
in a manner most likely to minimize the risk of seizure (see WARNINGS). Increases in dose
719
should not exceed 100 mg/day in a 3-day period. Gradual escalation in dosage is also important
720
if agitation, motor restlessness, and insomnia, often seen during the initial days of treatment, are
721
to be minimized. If necessary, these effects may be managed by temporary reduction of dose or
722
the short-term administration of an intermediate to long-acting sedative hypnotic. A sedative
723
hypnotic usually is not required beyond the first week of treatment. Insomnia may also be
724
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
21
minimized by avoiding bedtime doses. If distressing, untoward effects supervene, dose escalation
725
should be stopped.
726
No single dose of WELLBUTRIN should exceed 150 mg. WELLBUTRIN should be
727
administered 3 times daily, preferably with at least 6 hours between successive doses.
728
Usual Dosage for Adults: The usual adult dose is 300 mg/day, given 3 times daily. Dosing
729
should begin at 200 mg/day, given as 100 mg twice daily. Based on clinical response, this dose
730
may be increased to 300 mg/day, given as 100 mg 3 times daily, no sooner than 3 days after
731
beginning therapy (see table below).
732
733
Table 2. Dosing Regimen
734
Number of Tablets
Treatment Day
Total Daily Dose
Tablet Strength
Morning
Midday
Evening
1
200 mg
100 mg
1
0
1
4
300 mg
100 mg
1
1
1
735
Increasing the Dosage Above 300 mg/Day: As with other antidepressants, the full
736
antidepressant effect of WELLBUTRIN may not be evident until 4 weeks of treatment or longer.
737
An increase in dosage, up to a maximum of 450 mg/day, given in divided doses of not more than
738
150 mg each, may be considered for patients in whom no clinical improvement is noted after
739
several weeks of treatment at 300 mg/day. Dosing above 300 mg/day may be accomplished
740
using the 75- or 100-mg tablets. The 100-mg tablet must be administered 4 times daily with at
741
least 4 hours between successive doses, in order not to exceed the limit of 150 mg in a single
742
dose. WELLBUTRIN should be discontinued in patients who do not demonstrate an adequate
743
response after an appropriate period of treatment at 450 mg/day.
744
Maintenance Treatment: The lowest dose that maintains remission is recommended.
745
Although it is not known how long the patient should remain on WELLBUTRIN, it is generally
746
recognized that acute episodes of depression require several months or longer of antidepressant
747
drug treatment.
748
Dosage Adjustment for Patients with Impaired Hepatic Function: WELLBUTRIN
749
should be used with extreme caution in patients with severe hepatic cirrhosis. The dose should
750
not exceed 75 mg once a day in these patients. WELLBUTRIN should be used with caution in
751
patients with hepatic impairment (including mild to moderate hepatic cirrhosis) and a reduced
752
frequency and/or dose should be considered in patients with mild to moderate hepatic cirrhosis
753
(see CLINICAL PHARMACOLOGY, WARNINGS, and PRECAUTIONS).
754
Dosage Adjustment for Patients with Impaired Renal Function: WELLBUTRIN
755
should be used with caution in patients with renal impairment and a reduced frequency and/or
756
dose should be considered (see CLINICAL PHARMACOLOGY and PRECAUTIONS).
757
HOW SUPPLIED
758
WELLBUTRIN Tablets, 75 mg of bupropion hydrochloride, are yellow-gold, round, biconvex
759
tablets printed with “WELLBUTRIN 75” in bottles of 100 (NDC 0173-0177-55).
760
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
22
WELLBUTRIN Tablets, 100 mg of bupropion hydrochloride, are red, round, biconvex tablets
761
printed with “WELLBUTRIN 100” in bottles of 100 (NDC 0173-0178-55).
762
Store at 15° to 25°C (59° to 77°F). Protect from light and moisture.
763
764
Medication Guide
765
WELLBUTRIN® (WELL byu-trin)
766
(bupropion hydrochloride) Tablets
767
About Using Antidepressants in Children and Teenagers
768
769
What is the most important information I should know if my child is being prescribed an
770
antidepressant?
771
772
Parents or guardians need to think about 4 important things when their child is prescribed an
773
antidepressant:
774
1. There is a risk of suicidal thoughts or actions
775
2. How to try to prevent suicidal thoughts or actions in your child
776
3. You should watch for certain signs if your child is taking an antidepressant
777
4. There are benefits and risks when using antidepressants
778
779
1. There is a Risk of Suicidal Thoughts or Actions
780
781
Children and teenagers sometimes think about suicide, and many report trying to kill themselves.
782
783
Antidepressants increase suicidal thoughts and actions in some children and teenagers. But
784
suicidal thoughts and actions can also be caused by depression, a serious medical condition that
785
is commonly treated with antidepressants. Thinking about killing yourself or trying to kill
786
yourself is called suicidality or being suicidal.
787
788
A large study combined the results of 24 different studies of children and teenagers with
789
depression or other illnesses. In these studies, patients took either a placebo (sugar pill) or an
790
antidepressant for 1 to 4 months. No one committed suicide in these studies, but some patients
791
became suicidal. On sugar pills, 2 out of every 100 became suicidal. On the antidepressants, 4
792
out of every 100 patients became suicidal.
793
794
For some children and teenagers, the risks of suicidal actions may be especially high. These
795
include patients with
796
• Bipolar illness (sometimes called manic-depressive illness)
797
• A family history of bipolar illness
798
• A personal or family history of attempting suicide
799
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
If any of these are present, make sure you tell your healthcare provider before your child takes an
800
antidepressant.
801
802
2. How to Try to Prevent Suicidal Thoughts and Actions
803
804
To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in her
805
or his moods or actions, especially if the changes occur suddenly. Other important people in your
806
child’s life can help by paying attention as well (e.g., your child, brothers and sisters, teachers,
807
and other important people). The changes to look out for are listed in Section 3, on what to watch
808
for.
809
810
Whenever an antidepressant is started or its dose is changed, pay close attention to your child.
811
After starting an antidepressant, your child should generally see his or her healthcare provider:
812
• Once a week for the first 4 weeks
813
• Every 2 weeks for the next 4 weeks
814
• After taking the antidepressant for 12 weeks
815
• After 12 weeks, follow your healthcare provider’s advice about how often to come back
816
• More often if problems or questions arise (see Section 3)
817
818
You should call your child’s healthcare provider between visits if needed.
819
820
3. You Should Watch For Certain Signs if Your Child is Taking an Antidepressant
821
822
Contact your child’s healthcare provider right away if your child exhibits any of the following
823
signs for the first time, or they seem worse, or worry you, your child, or your child’s teacher:
824
• Thoughts about suicide or dying
825
• Attempts to commit suicide
826
• New or worse depression
827
• New or worse anxiety
828
• Feeling very agitated or restless
829
• Panic attacks
830
• Difficulty sleeping (insomnia)
831
• New or worse irritability
832
• Acting aggressive, being angry, or violent
833
• Acting on dangerous impulses
834
• An extreme increase in activity and talking
835
• Other unusual changes in behavior or mood
836
837
Never let your child stop taking an antidepressant without first talking to his or her healthcare
838
provider. Stopping an antidepressant suddenly can cause other symptoms.
839
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
24
840
4. There are Benefits and Risks When Using Antidepressants
841
842
Antidepressants are used to treat depression and other illnesses. Depression and other illnesses
843
can lead to suicide. In some children and teenagers, treatment with an antidepressant increases
844
suicidal thinking or actions. It is important to discuss all the risks of treating depression and also
845
the risks of not treating it. You and your child should discuss all treatment choices with your
846
healthcare provider, not just the use of antidepressants.
847
848
Other side effects can occur with antidepressants (see section below).
849
850
Of all antidepressants, only fluoxetine (Prozac®)* has been FDA approved to treat pediatric
851
depression.
852
853
For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine
854
(Prozac®)*, sertraline (Zoloft®)*, fluvoxamine, and clomipramine (Anafranil®)*.
855
856
Your healthcare provider may suggest other antidepressants based on the past experience of your
857
child or other family members.
858
859
Is this all I need to know if my child is being prescribed an antidepressant?
860
861
No. This is a warning about the risk of suicidality. Other side effects can occur with
862
antidepressants. Be sure to ask your healthcare provider to explain all the side effects of the
863
particular drug he or she is prescribing. Also ask about drugs to avoid when taking an
864
antidepressant. Ask your healthcare provider or pharmacist where to find more information.
865
866
*The following are registered trademarks of their respective manufacturers: Prozac®/Eli Lilly
867
and Company; Zoloft®/Pfizer Pharmaceuticals; Anafranil®/Mallinckrodt Inc.
868
869
This Medication Guide has been approved by the U.S. Food and Drug Administration for all
870
antidepressants.
871
872
January 2005
MG-WT:1
873
874
875
876
Manufactured by
877
DSM Pharmaceuticals, Inc.
878
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
25
Greenville, NC 27834 for
879
GlaxoSmithKline
880
Research Triangle Park, NC 27709
881
882
2006, GlaxoSmithKline. All rights reserved.
883
884
May 2006
RL-2281
885
886
887
PHARMACIST--DETACH HERE AND GIVE LEAFLET TO PATIENT. ALSO
PROVIDE AN APPROVED MEDICATION GUIDE ABOUT USING
ANTIDEPRESSANTS IN CHILDREN AND TEENAGERS.
888
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
889
Patient Information
890
WELLBUTRIN® (WELL byu-trin)
891
(bupropion hydrochloride) Tablets
892
893
Read the Patient Information that comes with WELLBUTRIN before you start taking
894
WELLBUTRIN and each time you get a refill. There may be new information. This leaflet
895
does not take the place of talking with your doctor about your medical condition or your
896
treatment.
897
898
What is the most important information I should know about WELLBUTRIN?
899
There is a chance of having a seizure (convulsion, fit) with WELLBUTRIN, especially in
900
people:
901
• with certain medical problems.
902
• who take certain medicines.
903
904
The chance of having seizures increases with higher doses of WELLBUTRIN. For more
905
information, see the sections “Who should not take WELLBUTRIN?” and “What should I tell
906
my doctor before using WELLBUTRIN?” Tell your doctor about all of your medical conditions
907
and all the medicines you take. Do not take any other medicines while you are using
908
WELLBUTRIN unless your doctor has said it is okay to take them.
909
910
If you have a seizure while taking WELLBUTRIN, stop taking the tablets and call your
911
doctor right away. Do not take WELLBUTRIN again if you have a seizure.
912
913
What is important information I should know and share with my family about taking
914
antidepressants?
915
Patients and their families should watch out for worsening depression or thoughts of suicide.
916
Also watch out for sudden or severe changes in feelings such as feeling anxious, agitated,
917
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
26
panicky, irritable, hostile, aggressive, impulsive, severely restless, overly excited and
918
hyperactive, not being able to sleep or other unusual changes in behavior. If this happens,
919
especially at the beginning of antidepressant treatment or after a change in dose, call your doctor.
920
A patient Medication Guide will be provided to you with each prescription of WELLBUTRIN
921
entitled "About Using Antidepressants in Children and Teenagers." WELLBUTRIN is not
922
approved for the use in children and teenagers.
923
924
What is WELLBUTRIN?
925
WELLBUTRIN is a prescription medicine used to treat adults with a certain type of depression
926
called major depressive disorder.
927
928
Who should not take WELLBUTRIN?
929
Do not take WELLBUTRIN if you
930
• have or had a seizure disorder or epilepsy.
931
• are taking ZYBAN (used to help people stop smoking) or any other medicines that
932
contain bupropion hydrochloride, such as WELLBUTRIN SR Sustained-Release
933
Tablets or WELLBUTRIN XL Extended-Release Tablets. Bupropion is the same
934
ingredient that is in WELLBUTRIN.
935
• drink a lot of alcohol and abruptly stop drinking, or use medicines called sedatives (these
936
make you sleepy) or benzodiazepines and you stop using them all of a sudden.
937
• have taken within the last 14 days medicine for depression called a monoamine oxidase
938
inhibitor (MAOI), such as NARDIL®* (phenelzine sulfate), PARNATE®(tranylcypromine
939
sulfate), or MARPLAN®* (isocarboxazid).
940
• have or had an eating disorder such as anorexia nervosa or bulimia.
941
• are allergic to the active ingredient in WELLBUTRIN, bupropion, or to any of the inactive
942
ingredients. See the end of this leaflet for a complete list of ingredients in WELLBUTRIN.
943
944
What should I tell my doctor before using WELLBUTRIN?
945
• Tell your doctor about your medical conditions. Tell your doctor if you:
946
• are pregnant or plan to become pregnant. It is not known if WELLBUTRIN can harm
947
your unborn baby. If you can use WELLBUTRIN while you are pregnant, talk to your
948
doctor about how you can be on the Bupropion Pregnancy Registry.
949
• are breastfeeding. WELLBUTRIN passes through your milk. It is not known if
950
WELLBUTRIN can harm your baby.
951
• have liver problems, especially cirrhosis of the liver.
952
• have kidney problems.
953
• have an eating disorder, such as anorexia nervosa or bulimia.
954
• have had a head injury.
955
• have had a seizure (convulsion, fit).
956
• have a tumor in your nervous system (brain or spine).
957
• have had a heart attack, heart problems, or high blood pressure.
958
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
27
• are a diabetic taking insulin or other medicines to control your blood sugar.
959
• drink a lot of alcohol.
960
• abuse prescription medicines or street drugs.
961
• Tell your doctor about all the medicines you take, including prescription and non-
962
prescription medicines, vitamins, and herbal supplements. Many medicines increase your
963
chances of having seizures or other serious side effects if you take them while you are using
964
WELLBUTRIN.
965
966
WELLBUTRIN has not been studied in children under the age of 18 years.
967
968
How should I take WELLBUTRIN?
969
• Take WELLBUTRIN exactly as prescribed by your doctor.
970
• Take WELLBUTRIN at the same time each day.
971
• Take your doses of WELLBUTRIN at least 6 hours apart.
972
• You may take WELLBUTRIN with or without food.
973
• If you miss a dose, do not take an extra tablet to make up for the dose you forgot. Wait and
974
take your next tablet at the regular time. This is very important. Too much WELLBUTRIN
975
can increase your chance of having a seizure.
976
• If you take too much WELLBUTRIN, or overdose, call your local emergency room or poison
977
control center right away.
978
• Do not take any other medicines while using WELLBUTRIN unless your doctor has
979
told you it is okay.
980
• It may take several weeks for you to feel that WELLBUTRIN is working. Once you feel
981
better, it is important to keep taking WELLBUTRIN exactly as directed by your doctor. Call
982
your doctor if you do not feel WELLBUTRIN is working for you.
983
• Do not change your dose or stop taking WELLBUTRIN without talking with your doctor
984
first.
985
986
What should I avoid while taking WELLBUTRIN?
987
• Do not drink a lot of alcohol while taking WELLBUTRIN. If you usually drink a lot of
988
alcohol, talk with your doctor before suddenly stopping. If you suddenly stop drinking
989
alcohol, you may increase your risk of having seizures.
990
• Do not drive a car or use heavy machinery until you know how WELLBUTRIN affects you.
991
WELLBUTRIN can impair your ability to perform these tasks.
992
993
What are possible side effects of WELLBUTRIN?
994
• Seizures. Some patients get seizures while taking WELLBUTRIN. If you have a seizure
995
while taking WELLBUTRIN, stop taking the tablets and call your doctor right away.
996
Do not take WELLBUTRIN again if you have a seizure.
997
• Hypertension (high blood pressure). Some patients get high blood pressure, sometimes
998
severe, while taking WELLBUTRIN. The chance of high blood pressure may be increased if
999
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
28
you also use nicotine replacement therapy (for example a nicotine patch) to help you stop
1000
smoking.
1001
• Severe allergic reactions. Stop taking WELLBUTRIN and call your doctor right away
1002
if you get a rash, itching, hives, fever, swollen lymph glands, painful sores in the mouth or
1003
around the eyes, swelling of the lips or tongue, chest pain, or have trouble breathing. These
1004
could be signs of a serious allergic reaction.
1005
• Unusual thoughts or behaviors. Some patients have unusual thoughts or behaviors while
1006
taking WELLBUTRIN, including delusions (believe you are someone else), hallucinations
1007
(seeing or hearing things that are not there), paranoia (feeling that people are against you), or
1008
feeling confused. If this happens to you, call your doctor.
1009
1010
The most common side effects of WELLBUTRIN are nervousness, constipation, trouble
1011
sleeping, dry mouth, headache, nausea, vomiting, and shakiness (tremor).
1012
1013
If you have nausea, you may want to take your medicine with food. If you have trouble sleeping,
1014
do not take your medicine too close to bedtime.
1015
1016
Tell your doctor right away about any side effects that bother you.
1017
1018
These are not all the side effects of WELLBUTRIN. For a complete list, ask your doctor or
1019
pharmacist.
1020
1021
How should I store WELLBUTRIN?
1022
• Store WELLBUTRIN at room temperature. Store out of direct sunlight. Keep
1023
WELLBUTRIN in its tightly closed bottle.
1024
1025
General Information about WELLBUTRIN.
1026
• Medicines are sometimes prescribed for conditions that are not mentioned in patient
1027
information leaflets. Do not use WELLBUTRIN for a condition for which it was not
1028
prescribed. Do not give WELLBUTRIN to other people, even if they have the same
1029
symptoms you have. It may harm them. Keep WELLBUTRIN out of the reach of children.
1030
1031
This leaflet summarizes important information about WELLBUTRIN. For more information,
1032
talk to your doctor. You can ask your doctor or pharmacist for information about
1033
WELLBUTRIN that is written for health professionals.
1034
1035
What are the ingredients in WELLBUTRIN?
1036
Active ingredient: bupropion hydrochloride.
1037
1038
Inactive ingredients: 75-mg tablet – D&C Yellow No. 10 Lake, FD&C Yellow No. 6 Lake,
1039
hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and
1040
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
29
titanium dioxide; 100-mg tablet – FD&C Red No. 40 Lake, FD&C Yellow No. 6 Lake,
1041
hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and
1042
titanium dioxide.
1043
1044
*The following are registered trademarks of their respective manufacturers: Nardil®/Warner
1045
Lambert Company; Marplan®/Oxford Pharmaceutical Services, Inc.
1046
1047
1048
1049
1050
Manufactured by DSM Pharmaceuticals, Inc.
1051
Greenville, NC 27834 for
1052
GlaxoSmithKline
1053
Research Triangle Park, NC 27709
1054
1055
©2006, GlaxoSmithKline. All rights reserved.
1056
1057
May 2006
RL-2281
1058
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
PRESCRIBING INFORMATION
1
WELLBUTRIN SR®
2
(bupropion hydrochloride)
3
Sustained-Release Tablets
4
5
Suicidality in Children and Adolescents
6
Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in
7
short-term studies in children and adolescents with Major Depressive Disorder (MDD) and
8
other psychiatric disorders. Anyone considering the use of WELLBUTRIN SR or any other
9
antidepressant in a child or adolescent must balance this risk with the clinical need.
10
Patients who are started on therapy should be observed closely for clinical worsening,
11
suicidality, or unusual changes in behavior. Families and caregivers should be advised of
12
the need for close observation and communication with the prescriber. WELLBUTRIN SR
13
is not approved for use in pediatric patients. (See WARNINGS and PRECAUTIONS:
14
Pediatric Use.)
15
Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of
16
9 antidepressant drugs (SSRIs and others) in children and adolescents with major
17
depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric
18
disorders (a total of 24 trials involving over 4,400 patients) have revealed a greater risk of
19
adverse events representing suicidal thinking or behavior (suicidality) during the first few
20
months of treatment in those receiving antidepressants. The average risk of such events in
21
patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides
22
occurred in these trials.
23
DESCRIPTION
24
WELLBUTRIN SR (bupropion hydrochloride), an antidepressant of the aminoketone class, is
25
chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other
26
known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related
27
to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-
28
propanone hydrochloride. The molecular weight is 276.2. The molecular formula is
29
C13H18ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in
30
water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The
31
structural formula is:
32
33
34
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
WELLBUTRIN SR Tablets are supplied for oral administration as 100-mg (blue), 150-mg
35
(purple), and 200-mg (light pink), film-coated, sustained-release tablets. Each tablet contains the
36
labeled amount of bupropion hydrochloride and the inactive ingredients: carnauba wax, cysteine
37
hydrochloride, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene
38
glycol, polysorbate 80, and titanium dioxide and is printed with edible black ink. In addition, the
39
100-mg tablet contains FD&C Blue No. 1 Lake, the 150-mg tablet contains FD&C Blue No. 2
40
Lake and FD&C Red No. 40 Lake, and the 200-mg tablet contains FD&C Red No. 40 Lake.
41
CLINICAL PHARMACOLOGY
42
Pharmacodynamics: Bupropion is a relatively weak inhibitor of the neuronal uptake of
43
norepinephrine, serotonin, and dopamine, and does not inhibit monoamine oxidase. While the
44
mechanism of action of bupropion, as with other antidepressants, is unknown, it is presumed that
45
this action is mediated by noradrenergic and/or dopaminergic mechanisms.
46
Pharmacokinetics: Bupropion is a racemic mixture. The pharmacologic activity and
47
pharmacokinetics of the individual enantiomers have not been studied. The mean elimination
48
half-life (±SD) of bupropion after chronic dosing is 21 (±9) hours, and steady-state plasma
49
concentrations of bupropion are reached within 8 days. In a study comparing chronic dosing with
50
WELLBUTRIN SR Tablets 150 mg twice daily to the immediate-release formulation of
51
bupropion at 100 mg 3 times daily, peak plasma concentrations of bupropion at steady state for
52
WELLBUTRIN SR Tablets were approximately 85% of those achieved with the
53
immediate-release formulation. There was equivalence for bupropion AUCs, as well as
54
equivalence for both peak plasma concentration and AUCs for all 3 of the detectable bupropion
55
metabolites. Thus, at steady state, WELLBUTRIN SR Tablets, given twice daily, and the
56
immediate-release formulation of bupropion, given 3 times daily, are essentially bioequivalent
57
for both bupropion and the 3 quantitatively important metabolites.
58
Absorption: Following oral administration of WELLBUTRIN SR Tablets to healthy
59
volunteers, peak plasma concentrations of bupropion are achieved within 3 hours. Food
60
increased Cmax and AUC of bupropion by 11% and 17%, respectively, indicating that there is no
61
clinically significant food effect.
62
Distribution: In vitro tests show that bupropion is 84% bound to human plasma proteins at
63
concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion
64
metabolite is similar to that for bupropion, whereas the extent of protein binding of the
65
threohydrobupropion metabolite is about half that seen with bupropion.
66
Metabolism: Bupropion is extensively metabolized in humans. Three metabolites have been
67
shown to be active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group
68
of bupropion, and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion,
69
which are formed via reduction of the carbonyl group. In vitro findings suggest that cytochrome
70
P450IIB6 (CYP2B6) is the principal isoenzyme involved in the formation of hydroxybupropion,
71
while cytochrome P450 isoenzymes are not involved in the formation of threohydrobupropion.
72
Oxidation of the bupropion side chain results in the formation of a glycine conjugate of
73
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency
74
and toxicity of the metabolites relative to bupropion have not been fully characterized. However,
75
it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is
76
one half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-
77
fold less potent than bupropion. This may be of clinical importance because the plasma
78
concentrations of the metabolites are as high or higher than those of bupropion.
79
Because bupropion is extensively metabolized, there is the potential for drug-drug
80
interactions, particularly with those agents that are metabolized by the cytochrome P450IIB6
81
(CYP2B6) isoenzyme. Although bupropion is not metabolized by cytochrome P450IID6
82
(CYP2D6), there is the potential for drug-drug interactions when bupropion is co-administered
83
with drugs metabolized by this isoenzyme (see PRECAUTIONS: Drug Interactions).
84
Following a single dose in humans, peak plasma concentrations of hydroxybupropion occur
85
approximately 6 hours after administration of WELLBUTRIN SR Tablets. Peak plasma
86
concentrations of hydroxybupropion are approximately 10 times the peak level of the parent drug
87
at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours,
88
and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations
89
for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the
90
hydroxybupropion metabolite. However, their elimination half-lives are longer, 33 (±10) and 37
91
(±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion,
92
respectively.
93
Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300
94
to 450 mg/day.
95
Elimination: Following oral administration of 200 mg of 14C-bupropion in humans, 87% and
96
10% of the radioactive dose were recovered in the urine and feces, respectively. However, the
97
fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent
98
with the extensive metabolism of bupropion.
99
Population Subgroups: Factors or conditions altering metabolic capacity (e.g., liver disease,
100
congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may be
101
expected to influence the degree and extent of accumulation of the active metabolites of
102
bupropion. The elimination of the major metabolites of bupropion may be affected by reduced
103
renal or hepatic function because they are moderately polar compounds and are likely to undergo
104
further metabolism or conjugation in the liver prior to urinary excretion.
105
Hepatic: The effect of hepatic impairment on the pharmacokinetics of bupropion was
106
characterized in 2 single-dose studies, one in patients with alcoholic liver disease and one in
107
patients with mild to severe cirrhosis. The first study showed that the half-life of
108
hydroxybupropion was significantly longer in 8 patients with alcoholic liver disease than in
109
8 healthy volunteers (32±14 hours versus 21±5 hours, respectively). Although not statistically
110
significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be
111
greater (by 53% to 57%) in patients with alcoholic liver disease. The differences in half-life for
112
bupropion and the other metabolites in the 2 patient groups were minimal.
113
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
The second study showed no statistically significant differences in the pharmacokinetics of
114
bupropion and its active metabolites in 9 patients with mild to moderate hepatic cirrhosis
115
compared to 8 healthy volunteers. However, more variability was observed in some of the
116
pharmacokinetic parameters for bupropion (AUC, Cmax, and Tmax) and its active metabolites (t½)
117
in patients with mild to moderate hepatic cirrhosis. In addition, in patients with severe hepatic
118
cirrhosis, the bupropion Cmax and AUC were substantially increased (mean difference: by
119
approximately 70% and 3-fold, respectively) and more variable when compared to values in
120
healthy volunteers; the mean bupropion half-life was also longer (29 hours in patients with
121
severe hepatic cirrhosis vs. 19 hours in healthy subjects). For the metabolite hydroxybupropion,
122
the mean Cmax was approximately 69% lower. For the combined amino-alcohol isomers
123
threohydrobupropion and erythrohydrobupropion, the mean Cmax was approximately 31% lower.
124
The mean AUC increased by about 1½-fold for hydroxybupropion and about 2½-fold for
125
threo/erythrohydrobupropion. The median Tmax was observed 19 hours later for
126
hydroxybupropion and 31 hours later for threo/erythrohydrobupropion. The mean half-lives for
127
hydroxybupropion and threo/erythrohydrobupropion were increased 5- and 2-fold, respectively,
128
in patients with severe hepatic cirrhosis compared to healthy volunteers (see WARNINGS,
129
PRECAUTIONS, and DOSAGE AND ADMINISTRATION).
130
Renal: There is limited information on the pharmacokinetics of bupropion in patients with
131
renal impairment. The elimination of the major metabolites of bupropion may be reduced by
132
impaired renal function (see PRECAUTIONS: Renal Impairment).
133
Left Ventricular Dysfunction: During a chronic dosing study with bupropion in
134
14 depressed patients with left ventricular dysfunction (history of CHF or an enlarged heart on
135
x-ray), no apparent effect on the pharmacokinetics of bupropion or its metabolites was revealed,
136
compared to healthy volunteers.
137
Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have not
138
been fully characterized, but an exploration of steady-state bupropion concentrations from
139
several depression efficacy studies involving patients dosed in a range of 300 to 750 mg/day, on
140
a 3 times daily schedule, revealed no relationship between age (18 to 83 years) and plasma
141
concentration of bupropion. A single-dose pharmacokinetic study demonstrated that the
142
disposition of bupropion and its metabolites in elderly subjects was similar to that of younger
143
subjects. These data suggest there is no prominent effect of age on bupropion concentration;
144
however, another pharmacokinetic study, single and multiple dose, has suggested that the elderly
145
are at increased risk for accumulation of bupropion and its metabolites (see PRECAUTIONS:
146
Geriatric Use).
147
Gender: A single-dose study involving 12 healthy male and 12 healthy female volunteers
148
revealed no sex-related differences in the pharmacokinetic parameters of bupropion.
149
Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion were
150
studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17
151
were nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there
152
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
was no statistically significant difference in Cmax, half-life, Tmax, AUC, or clearance of bupropion
153
or its active metabolites between smokers and nonsmokers.
154
CLINICAL TRIALS
155
The efficacy of the immediate-release formulation of bupropion as a treatment for depression
156
was established in two 4-week, placebo-controlled trials in adult inpatients with depression and
157
in one 6-week, placebo-controlled trial in adult outpatients with depression. In the first study,
158
patients were titrated in a bupropion dose range of 300 to 600 mg/day on a 3 times daily
159
schedule; 78% of patients received maximum doses of 450 mg/day or less. This trial
160
demonstrated the effectiveness of the immediate-release formulation of bupropion on the
161
Hamilton Depression Rating Scale (HDRS) total score, the depressed mood item (item 1) from
162
that scale, and the Clinical Global Impressions (CGI) severity score. A second study included
163
2 fixed doses of the immediate-release formulation of bupropion (300 and 450 mg/day) and
164
placebo. This trial demonstrated the effectiveness of the immediate-release formulation of
165
bupropion, but only at the 450-mg/day dose; the results were positive for the HDRS total score
166
and the CGI severity score, but not for HDRS item 1. In the third study, outpatients received
167
300 mg/day of the immediate-release formulation of bupropion. This study demonstrated the
168
effectiveness of the immediate-release formulation of bupropion on the HDRS total score, HDRS
169
item 1, the Montgomery-Asberg Depression Rating Scale, the CGI severity score, and the CGI
170
improvement score.
171
Although there are not as yet independent trials demonstrating the antidepressant effectiveness
172
of the sustained-release formulation of bupropion, studies have demonstrated the bioequivalence
173
of the immediate-release and sustained-release forms of bupropion under steady-state conditions,
174
i.e., bupropion sustained-release 150 mg twice daily was shown to be bioequivalent to 100 mg
175
3 times daily of the immediate-release formulation of bupropion, with regard to both rate and
176
extent of absorption, for parent drug and metabolites.
177
In a longer-term study, outpatients meeting DSM-IV criteria for major depressive disorder,
178
recurrent type, who had responded during an 8-week open trial on WELLBUTRIN SR (150 mg
179
twice daily) were randomized to continuation of their same WELLBUTRIN SR dose or placebo,
180
for up to 44 weeks of observation for relapse. Response during the open phase was defined as
181
CGI Improvement score of 1 (very much improved) or 2 (much improved) for each of the final
182
3 weeks. Relapse during the double-blind phase was defined as the investigator’s judgment that
183
drug treatment was needed for worsening depressive symptoms. Patients receiving continued
184
WELLBUTRIN SR treatment experienced significantly lower relapse rates over the subsequent
185
44 weeks compared to those receiving placebo.
186
INDICATIONS AND USAGE
187
WELLBUTRIN SR is indicated for the treatment of major depressive disorder.
188
The efficacy of bupropion in the treatment of a major depressive episode was established in
189
two 4-week controlled trials of depressed inpatients and in one 6-week controlled trial of
190
depressed outpatients whose diagnoses corresponded most closely to the Major Depression
191
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
category of the APA Diagnostic and Statistical Manual (DSM) (see CLINICAL
192
PHARMACOLOGY).
193
A major depressive episode (DSM-IV) implies the presence of 1) depressed mood or 2) loss
194
of interest or pleasure; in addition, at least 5 of the following symptoms have been present during
195
the same 2-week period and represent a change from previous functioning: depressed mood,
196
markedly diminished interest or pleasure in usual activities, significant change in weight and/or
197
appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue,
198
feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt
199
or suicidal ideation.
200
The efficacy of WELLBUTRIN SR in maintaining an antidepressant response for up to
201
44 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial
202
(see CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use
203
WELLBUTRIN SR for extended periods should periodically reevaluate the long-term usefulness
204
of the drug for the individual patient.
205
CONTRAINDICATIONS
206
WELLBUTRIN SR is contraindicated in patients with a seizure disorder.
207
WELLBUTRIN SR is contraindicated in patients treated with ZYBAN® (bupropion
208
hydrochloride) Sustained-Release Tablets; WELLBUTRIN® (bupropion hydrochloride), the
209
immediate-release formulation; WELLBUTRIN XL® (bupropion hydrochloride), the extended-
210
release formulation; or any other medications that contain bupropion because the incidence of
211
seizure is dose dependent.
212
WELLBUTRIN SR is contraindicated in patients with a current or prior diagnosis of bulimia
213
or anorexia nervosa because of a higher incidence of seizures noted in patients treated for
214
bulimia with the immediate-release formulation of bupropion.
215
WELLBUTRIN SR is contraindicated in patients undergoing abrupt discontinuation of
216
alcohol or sedatives (including benzodiazepines).
217
The concurrent administration of WELLBUTRIN SR Tablets and a monoamine oxidase
218
(MAO) inhibitor is contraindicated. At least 14 days should elapse between discontinuation of an
219
MAO inhibitor and initiation of treatment with WELLBUTRIN SR Tablets.
220
WELLBUTRIN SR is contraindicated in patients who have shown an allergic response to
221
bupropion or the other ingredients that make up WELLBUTRIN SR Tablets.
222
WARNINGS
223
Clinical Worsening and Suicide Risk: Patients with major depressive disorder (MDD),
224
both adult and pediatric, may experience worsening of their depression and/or the emergence of
225
suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they
226
are taking antidepressant medications, and this risk may persist until significant remission
227
occurs. There has been a long-standing concern that antidepressants may have a role in inducing
228
worsening of depression and the emergence of suicidality in certain patients. Antidepressants
229
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children
230
and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders.
231
Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and
232
others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of
233
24 trials involving over 4,400 patients) have revealed a greater risk of adverse events
234
representing suicidal behavior or thinking (suicidality) during the first few months of treatment
235
in those receiving antidepressants. The average risk of such events in patients receiving
236
antidepressants was 4%, twice the placebo risk of 2%. There was considerable variation in risk
237
among drugs, but a tendency toward an increase for almost all drugs studied. The risk of
238
suicidality was most consistently observed in the MDD trials, but there were signals of risk
239
arising from some trials in other psychiatric indications (obsessive compulsive disorder and
240
social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown
241
whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond several
242
months. It is also unknown whether the suicidality risk extends to adults.
243
All pediatric patients being treated with antidepressants for any indication should be
244
observed closely for clinical worsening, suicidality, and unusual changes in behavior,
245
especially during the initial few months of a course of drug therapy, or at times of dose
246
changes, either increases or decreases. Such observation would generally include at least
247
weekly face-to-face contact with patients or their family members or caregivers during the
248
first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at
249
12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may
250
be appropriate between face-to-face visits.
251
Adults with MDD or co-morbid depression in the setting of other psychiatric illness
252
being treated with antidepressants should be observed similarly for clinical worsening and
253
suicidality, especially during the initial few months of a course of drug therapy, or at times
254
of dose changes, either increases or decreases.
255
In addition, patients with a history of suicidal behavior or thoughts, those patients
256
exhibiting a significant degree of suicidal ideation prior to commencement of treatment,
257
and young adults, are at an increased risk of suicidal thoughts or suicide attempts, and
258
should receive careful monitoring during treatment.
259
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
260
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
261
been reported in adult and pediatric patients being treated with antidepressants for major
262
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
263
Although a causal link between the emergence of such symptoms and either the worsening of
264
depression and/or the emergence of suicidal impulses has not been established, there is concern
265
that such symptoms may represent precursors to emerging suicidality.
266
Consideration should be given to changing the therapeutic regimen, including possibly
267
discontinuing the medication, in patients whose depression is persistently worse, or who are
268
experiencing emergent suicidality or symptoms that might be precursors to worsening depression
269
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
270
patient’s presenting symptoms.
271
Families and caregivers of pediatric patients being treated with antidepressants for
272
major depressive disorder or other indications, both psychiatric and nonpsychiatric,
273
should be alerted about the need to monitor patients for the emergence of agitation,
274
irritability, unusual changes in behavior, and the other symptoms described above, as well
275
as the emergence of suicidality, and to report such symptoms immediately to health care
276
providers. Such monitoring should include daily observation by families and caregivers.
277
Prescriptions for WELLBUTRIN SR should be written for the smallest quantity of tablets
278
consistent with good patient management, in order to reduce the risk of overdose. Families and
279
caregivers of adults being treated for depression should be similarly advised.
280
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
281
presentation of bipolar disorder. It is generally believed (though not established in controlled
282
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
283
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
284
symptoms described above represent such a conversion is unknown. However, prior to initiating
285
treatment with an antidepressant, patients with depressive symptoms should be adequately
286
screened to determine if they are at risk for bipolar disorder; such screening should include a
287
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
288
depression. It should be noted that WELLBUTRIN SR is not approved for use in treating bipolar
289
depression.
290
Patients should be made aware that WELLBUTRIN SR contains the same active
291
ingredient found in ZYBAN, used as an aid to smoking cessation treatment, and that
292
WELLBUTRIN SR should not be used in combination with ZYBAN, or any other
293
medications that contain bupropion, such as WELLBUTRIN (bupropion hydrochloride),
294
the immediate-release formulation or WELLBUTRIN XL (bupropion hydrochloride), the
295
extended-release formulation.
296
297
Seizures: Bupropion is associated with a dose-related risk of seizures. The risk of seizures
298
is also related to patient factors, clinical situations, and concomitant medications, which
299
must be considered in selection of patients for therapy with WELLBUTRIN SR.
300
WELLBUTRIN SR should be discontinued and not restarted in patients who experience a
301
seizure while on treatment.
302
• Dose: At doses of WELLBUTRIN SR up to a dose of 300 mg/day, the incidence of
303
seizure is approximately 0.1% (1/1,000) and increases to approximately 0.4% (4/1,000)
304
at the maximum recommended dose of 400 mg/day.
305
Data for the immediate-release formulation of bupropion revealed a seizure incidence
306
of approximately 0.4% (i.e., 13 of 3,200 patients followed prospectively) in patients
307
treated at doses in a range of 300 to 450 mg/day. The 450-mg/day upper limit of this
308
dose range is close to the currently recommended maximum dose of 400 mg/day for
309
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
WELLBUTRIN SR Tablets. This seizure incidence (0.4%) may exceed that of other
310
marketed antidepressants and WELLBUTRIN SR Tablets up to 300 mg/day by as
311
much as 4-fold. This relative risk is only an approximate estimate because no direct
312
comparative studies have been conducted.
313
Additional data accumulated for the immediate-release formulation of bupropion
314
suggested that the estimated seizure incidence increases almost tenfold between 450 and
315
600 mg/day, which is twice the usual adult dose and one and one-half the maximum
316
recommended daily dose (400 mg) of WELLBUTRIN SR Tablets. This
317
disproportionate increase in seizure incidence with dose incrementation calls for
318
caution in dosing.
319
Data for WELLBUTRIN SR Tablets revealed a seizure incidence of approximately
320
0.1% (i.e., 3 of 3,100 patients followed prospectively) in patients treated at doses in a
321
range of 100 to 300 mg/day. It is not possible to know if the lower seizure incidence
322
observed in this study involving the sustained-release formulation of bupropion
323
resulted from the different formulation or the lower dose used. However, as noted
324
above, the immediate-release and sustained-release formulations are bioequivalent with
325
regard to both rate and extent of absorption during steady state (the most pertinent
326
condition to estimating seizure incidence), since most observed seizures occur under
327
steady-state conditions.
328
• Patient factors: Predisposing factors that may increase the risk of seizure with
329
bupropion use include history of head trauma or prior seizure, central nervous system
330
(CNS) tumor, the presence of severe hepatic cirrhosis, and concomitant medications
331
that lower seizure threshold.
332
• Clinical situations: Circumstances associated with an increased seizure risk include,
333
among others, excessive use of alcohol or sedatives (including benzodiazepines);
334
addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and
335
anorectics; and diabetes treated with oral hypoglycemics or insulin.
336
• Concomitant medications: Many medications (e.g., antipsychotics, antidepressants,
337
theophylline, systemic steroids) are known to lower seizure threshold.
338
Recommendations for Reducing the Risk of Seizure: Retrospective analysis of
339
clinical experience gained during the development of bupropion suggests that the risk of
340
seizure may be minimized if
341
• the total daily dose of WELLBUTRIN SR Tablets does not exceed 400 mg,
342
• the daily dose is administered twice daily, and
343
• the rate of incrementation of dose is gradual.
344
• No single dose should exceed 200 mg to avoid high peak concentrations of bupropion
345
and/or its metabolites.
346
WELLBUTRIN SR should be administered with extreme caution to patients with a
347
history of seizure, cranial trauma, or other predisposition(s) toward seizure, or patients
348
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
treated with other agents (e.g., antipsychotics, other antidepressants, theophylline, systemic
349
steroids, etc.) that lower seizure threshold.
350
Hepatic Impairment: WELLBUTRIN SR should be used with extreme caution in patients
351
with severe hepatic cirrhosis. In these patients a reduced frequency and/or dose is required,
352
as peak bupropion, as well as AUC, levels are substantially increased and accumulation is
353
likely to occur in such patients to a greater extent than usual. The dose should not exceed
354
100 mg every day or 150 mg every other day in these patients (see CLINICAL
355
PHARMACOLOGY, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).
356
Potential for Hepatotoxicity: In rats receiving large doses of bupropion chronically, there
357
was an increase in incidence of hepatic hyperplastic nodules and hepatocellular hypertrophy. In
358
dogs receiving large doses of bupropion chronically, various histologic changes were seen in the
359
liver, and laboratory tests suggesting mild hepatocellular injury were noted.
360
PRECAUTIONS
361
General: Agitation and Insomnia: Patients in placebo-controlled trials with
362
WELLBUTRIN SR Tablets experienced agitation, anxiety, and insomnia as shown in Table 1.
363
364
Table 1. Incidence of Agitation, Anxiety, and Insomnia in Placebo-Controlled Trials
365
Adverse Event Term
WELLBUTRIN SR
300 mg/day
(n = 376)
WELLBUTRIN SR
400 mg/day
(n = 114)
Placebo
(n = 385)
Agitation
3%
9%
2%
Anxiety
5%
6%
3%
Insomnia
11%
16%
6%
366
In clinical studies, these symptoms were sometimes of sufficient magnitude to require
367
treatment with sedative/hypnotic drugs.
368
Symptoms were sufficiently severe to require discontinuation of treatment in 1% and 2.6% of
369
patients treated with 300 and 400 mg/day, respectively, of WELLBUTRIN SR Tablets and 0.8%
370
of patients treated with placebo.
371
Psychosis, Confusion, and Other Neuropsychiatric Phenomena: Depressed
372
patients treated with an immediate-release formulation of bupropion or with WELLBUTRIN SR
373
Tablets have been reported to show a variety of neuropsychiatric signs and symptoms, including
374
delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. In some
375
cases, these symptoms abated upon dose reduction and/or withdrawal of treatment.
376
Activation of Psychosis and/or Mania: Antidepressants can precipitate manic episodes
377
in bipolar disorder patients during the depressed phase of their illness and may activate latent
378
psychosis in other susceptible patients. WELLBUTRIN SR is expected to pose similar risks.
379
Altered Appetite and Weight: In placebo-controlled studies, patients experienced weight
380
gain or weight loss as shown in Table 2.
381
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For current labeling information, please visit https://www.fda.gov/drugsatfda
11
382
Table 2. Incidence of Weight Gain and Weight Loss in Placebo-Controlled Trials
383
Weight Change
WELLBUTRIN SR
300 mg/day
(n = 339)
WELLBUTRIN SR
400 mg/day
(n = 112)
Placebo
(n = 347)
Gained >5 lbs
3%
2%
4%
Lost >5 lbs
14%
19%
6%
384
In studies conducted with the immediate-release formulation of bupropion, 35% of patients
385
receiving tricyclic antidepressants gained weight, compared to 9% of patients treated with the
386
immediate-release formulation of bupropion. If weight loss is a major presenting sign of a
387
patient’s depressive illness, the anorectic and/or weight-reducing potential of
388
WELLBUTRIN SR Tablets should be considered.
389
Allergic Reactions: Anaphylactoid/anaphylactic reactions characterized by symptoms such
390
as pruritus, urticaria, angioedema, and dyspnea requiring medical treatment have been reported
391
in clinical trials with bupropion. In addition, there have been rare spontaneous postmarketing
392
reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated
393
with bupropion. A patient should stop taking WELLBUTRIN SR and consult a doctor if
394
experiencing allergic or anaphylactoid/anaphylactic reactions (e.g., skin rash, pruritus, hives,
395
chest pain, edema, and shortness of breath) during treatment.
396
Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed
397
hypersensitivity have been reported in association with bupropion. These symptoms may
398
resemble serum sickness.
399
Cardiovascular Effects: In clinical practice, hypertension, in some cases severe, requiring
400
acute treatment, has been reported in patients receiving bupropion alone and in combination with
401
nicotine replacement therapy. These events have been observed in both patients with and without
402
evidence of preexisting hypertension.
403
Data from a comparative study of the sustained-release formulation of bupropion (ZYBAN
404
Sustained-Release Tablets), nicotine transdermal system (NTS), the combination of sustained-
405
release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher
406
incidence of treatment-emergent hypertension in patients treated with the combination of
407
sustained-release bupropion and NTS. In this study, 6.1% of patients treated with the
408
combination of sustained-release bupropion and NTS had treatment-emergent hypertension
409
compared to 2.5%, 1.6%, and 3.1% of patients treated with sustained-release bupropion, NTS,
410
and placebo, respectively. The majority of these patients had evidence of preexisting
411
hypertension. Three patients (1.2%) treated with the combination of ZYBAN and NTS and
412
1 patient (0.4%) treated with NTS had study medication discontinued due to hypertension
413
compared to none of the patients treated with ZYBAN or placebo. Monitoring of blood pressure
414
is recommended in patients who receive the combination of bupropion and nicotine replacement.
415
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
There is no clinical experience establishing the safety of WELLBUTRIN SR Tablets in
416
patients with a recent history of myocardial infarction or unstable heart disease. Therefore, care
417
should be exercised if it is used in these groups. Bupropion was well tolerated in depressed
418
patients who had previously developed orthostatic hypotension while receiving tricyclic
419
antidepressants, and was also generally well tolerated in a group of 36 depressed inpatients with
420
stable congestive heart failure (CHF). However, bupropion was associated with a rise in supine
421
blood pressure in the study of patients with CHF, resulting in discontinuation of treatment in
422
2 patients for exacerbation of baseline hypertension.
423
Hepatic Impairment: WELLBUTRIN SR should be used with extreme caution in patients
424
with severe hepatic cirrhosis. In these patients, a reduced frequency and/or dose is required.
425
WELLBUTRIN SR should be used with caution in patients with hepatic impairment (including
426
mild to moderate hepatic cirrhosis) and reduced frequency and/or dose should be considered in
427
patients with mild to moderate hepatic cirrhosis.
428
All patients with hepatic impairment should be closely monitored for possible adverse effects
429
that could indicate high drug and metabolite levels (see CLINICAL PHARMACOLOGY,
430
WARNINGS, and DOSAGE AND ADMINISTRATION).
431
Renal Impairment: There is limited information on the pharmacokinetics of bupropion in
432
patients with renal impairment. Bupropion is extensively metabolized in the liver to active
433
metabolites, which are further metabolized and subsequently excreted by the kidneys.
434
WELLBUTRIN SR should be used with caution in patients with renal impairment and a reduced
435
frequency and/or dose should be considered as the metabolites of bupropion may accumulate in
436
such patients to a greater extent than usual. The patient should be closely monitored for possible
437
adverse effects that could indicate high drug or metabolite levels.
438
Information for Patients: Prescribers or other health professionals should inform patients,
439
their families, and their caregivers about the benefits and risks associated with treatment with
440
WELLBUTRIN SR and should counsel them in its appropriate use. A patient Medication Guide
441
About Using Antidepressants in Children and Teenagers is available for WELLBUTRIN SR.
442
The prescriber or health professional should instruct patients, their families, and their caregivers
443
to read the Medication Guide and should assist them in understanding its contents. Patients
444
should be given the opportunity to discuss the contents of the Medication Guide and to obtain
445
answers to any questions they may have. The complete text of the Medication Guide is reprinted
446
at the end of this document. Additional important information concerning WELLBUTRIN SR is
447
provided in a tear-off leaflet entitled "Patient Information" at the end of this labeling.
448
Patients should be advised of the following issues and asked to alert their prescriber if these
449
occur while taking WELLBUTRIN SR.
450
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers
451
should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia,
452
irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
453
hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal
454
ideation, especially early during antidepressant treatment and when the dose is adjusted up or
455
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
down. Families and caregivers of patients should be advised to observe for the emergence of
456
such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be
457
reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in
458
onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be
459
associated with an increased risk for suicidal thinking and behavior and indicate a need for very
460
close monitoring and possibly changes in the medication.
461
Patients should be made aware that WELLBUTRIN SR contains the same active ingredient
462
found in ZYBAN, used as an aid to smoking cessation treatment, and that WELLBUTRIN SR
463
should not be used in combination with ZYBAN or any other medications that contain bupropion
464
hydrochloride (such as WELLBUTRIN, the immediate-release formulation and WELLBUTRIN
465
XL, the extended-release formulation).
466
As dose is increased during initial titration to doses above 150 mg/day, patients should be
467
instructed to take WELLBUTRIN SR Tablets in 2 divided doses, preferably with at least 8 hours
468
between successive doses, to minimize the risk of seizures.
469
Patients should be told that WELLBUTRIN SR should be discontinued and not restarted if
470
they experience a seizure while on treatment.
471
Patients should be told that any CNS-active drug like WELLBUTRIN SR Tablets may impair
472
their ability to perform tasks requiring judgment or motor and cognitive skills. Consequently,
473
until they are reasonably certain that WELLBUTRIN SR Tablets do not adversely affect their
474
performance, they should refrain from driving an automobile or operating complex, hazardous
475
machinery.
476
Patients should be told that the excessive use or abrupt discontinuation of alcohol or sedatives
477
(including benzodiazepines) may alter the seizure threshold. Some patients have reported lower
478
alcohol tolerance during treatment with WELLBUTRIN SR. Patients should be advised that the
479
consumption of alcohol should be minimized or avoided.
480
Patients should be advised to inform their physicians if they are taking or plan to take any
481
prescription or over-the-counter drugs. Concern is warranted because WELLBUTRIN SR
482
Tablets and other drugs may affect each other’s metabolism.
483
Patients should be advised to notify their physicians if they become pregnant or intend to
484
become pregnant during therapy.
485
Patients should be advised to swallow WELLBUTRIN SR Tablets whole so that the release
486
rate is not altered. Do not chew, divide, or crush tablets.
487
Laboratory Tests: There are no specific laboratory tests recommended.
488
Drug Interactions: Few systemic data have been collected on the metabolism of bupropion
489
following concomitant administration with other drugs or, alternatively, the effect of
490
concomitant administration of bupropion on the metabolism of other drugs.
491
Because bupropion is extensively metabolized, the coadministration of other drugs may affect
492
its clinical activity. In vitro studies indicate that bupropion is primarily metabolized to
493
hydroxybupropion by the CYP2B6 isoenzyme. Therefore, the potential exists for a drug
494
interaction between WELLBUTRIN SR and drugs that are substrates or inhibitors of the
495
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
CYP2B6 isoenzyme (e.g., orphenadrine, thiotepa, and cyclophosphamide). In addition, in vitro
496
studies suggest that paroxetine, sertraline, norfluoxetine, and fluvoxamine as well as nelfinavir,
497
ritonavir, and efavirenz inhibit the hydroxylation of bupropion. No clinical studies have been
498
performed to evaluate this finding. The threohydrobupropion metabolite of bupropion does not
499
appear to be produced by the cytochrome P450 isoenzymes. The effects of concomitant
500
administration of cimetidine on the pharmacokinetics of bupropion and its active metabolites
501
were studied in 24 healthy young male volunteers. Following oral administration of two 150-mg
502
WELLBUTRIN SR Tablets with and without 800 mg of cimetidine, the pharmacokinetics of
503
bupropion and hydroxybupropion were unaffected. However, there were 16% and 32% increases
504
in the AUC and Cmax, respectively, of the combined moieties of threohydrobupropion and
505
erythrohydrobupropion.
506
While not systematically studied, certain drugs may induce the metabolism of bupropion (e.g.,
507
carbamazepine, phenobarbital, phenytoin).
508
Multiple oral doses of bupropion had no statistically significant effects on the single dose
509
pharmacokinetics of lamotrigine in 12 healthy volunteers and was associated with a slight
510
increase in the AUC (15%) of lamotrigine glucuronide.
511
Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in
512
humans. In one study, following chronic administration of bupropion, 100 mg 3 times daily to
513
8 healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism.
514
Nevertheless, there may be the potential for clinically important alterations of blood levels of
515
coadministered drugs.
516
Drugs Metabolized By Cytochrome P450IID6 (CYP2D6): Many drugs, including most
517
antidepressants (SSRIs, many tricyclics), beta-blockers, antiarrhythmics, and antipsychotics are
518
metabolized by the CYP2D6 isoenzyme. Although bupropion is not metabolized by this
519
isoenzyme, bupropion and hydroxybupropion are inhibitors of CYP2D6 isoenzyme in vitro. In a
520
study of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of the CYP2D6
521
isoenzyme, daily doses of bupropion given as 150 mg twice daily followed by a single dose of
522
50 mg desipramine increased the Cmax, AUC, and t1/2 of desipramine by an average of
523
approximately 2-, 5-, and 2-fold, respectively. The effect was present for at least 7 days after the
524
last dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6
525
has not been formally studied.
526
Therefore, co-administration of bupropion with drugs that are metabolized by CYP2D6
527
isoenzyme including certain antidepressants (e.g., nortriptyline, imipramine, desipramine,
528
paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine),
529
beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide),
530
should be approached with caution and should be initiated at the lower end of the dose range of
531
the concomitant medication. If bupropion is added to the treatment regimen of a patient already
532
receiving a drug metabolized by CYP2D6, the need to decrease the dose of the original
533
medication should be considered, particularly for those concomitant medications with a narrow
534
therapeutic index.
535
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
MAO Inhibitors: Studies in animals demonstrate that the acute toxicity of bupropion is
536
enhanced by the MAO inhibitor phenelzine (see CONTRAINDICATIONS).
537
Levodopa and Amantadine: Limited clinical data suggest a higher incidence of adverse
538
experiences in patients receiving bupropion concurrently with either levodopa or amantadine.
539
Administration of WELLBUTRIN SR Tablets to patients receiving either levodopa or
540
amantadine concurrently should be undertaken with caution, using small initial doses and
541
gradual dose increases.
542
Drugs That Lower Seizure Threshold: Concurrent administration of
543
WELLBUTRIN SR Tablets and agents (e.g., antipsychotics, other antidepressants, theophylline,
544
systemic steroids, etc.) that lower seizure threshold should be undertaken only with extreme
545
caution (see WARNINGS). Low initial dosing and gradual dose increases should be employed.
546
Nicotine Transdermal System: (see PRECAUTIONS: Cardiovascular Effects).
547
Alcohol: In postmarketing experience, there have been rare reports of adverse
548
neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol
549
during treatment with WELLBUTRIN SR. The consumption of alcohol during treatment with
550
WELLBUTRIN SR should be minimized or avoided (also see CONTRAINDICATIONS).
551
Carcinogenesis, Mutagenesis, Impairment of Fertility: Lifetime carcinogenicity studies
552
were performed in rats and mice at doses up to 300 and 150 mg/kg/day, respectively. These
553
doses are approximately 7 and 2 times the maximum recommended human dose (MRHD),
554
respectively, on a mg/m2 basis. In the rat study there was an increase in nodular proliferative
555
lesions of the liver at doses of 100 to 300 mg/kg/day (approximately 2 to 7 times the MRHD on a
556
mg/m2 basis); lower doses were not tested. The question of whether or not such lesions may be
557
precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen
558
in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in
559
either study.
560
Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of 5 strains in
561
the Ames bacterial mutagenicity test and an increase in chromosomal aberrations in 1 of 3 in
562
vivo rat bone marrow cytogenetic studies.
563
A fertility study in rats at doses up to 300 mg/kg/day revealed no evidence of impaired
564
fertility.
565
Pregnancy: Teratogenic Effects: Pregnancy Category C. In studies conducted in rats and
566
rabbits, bupropion was administered orally at doses up to 450 and 150 mg/kg/day, respectively
567
(approximately 11 and 7 times the maximum recommended human dose [MRHD], respectively,
568
on a mg/m2 basis), during the period of organogenesis. No clear evidence of teratogenic activity
569
was found in either species; however, in rabbits, slightly increased incidences of fetal
570
malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day,
571
approximately equal to the MRHD on a mg/m2 basis) and greater. Decreased fetal weights were
572
seen at 50 mg/kg and greater.
573
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately
574
7 times the MRHD on a mg/m2 basis) prior to mating and throughout pregnancy and lactation,
575
there were no apparent adverse effects on offspring development.
576
One study has been conducted in pregnant women. This retrospective, managed-care database
577
study assessed the risk of congenital malformations overall, and cardiovascular malformations
578
specifically, following exposure to bupropion in the first trimester compared to the risk of these
579
malformations following exposure to other antidepressants in the first trimester and bupropion
580
outside of the first trimester. This study included 7,005 infants with antidepressant exposure
581
during pregnancy, 1,213 of whom were exposed to bupropion in the first trimester. The study
582
showed no greater risk for congenital malformations overall, or cardiovascular malformations
583
specifically, following first trimester bupropion exposure compared to exposure to all other
584
antidepressants in the first trimester, or bupropion outside of the first trimester. The results of
585
this study have not been corroborated. WELLBUTRIN SR should be used during pregnancy only
586
if the potential benefit justifies the potential risk to the fetus.
587
To monitor fetal outcomes of pregnant women exposed to WELLBUTRIN SR,
588
GlaxoSmithKline maintains a Bupropion Pregnancy Registry. Health care providers are
589
encouraged to register patients by calling (800) 336-2176.
590
Labor and Delivery: The effect of WELLBUTRIN SR Tablets on labor and delivery in
591
humans is unknown.
592
Nursing Mothers: Like many other drugs, bupropion and its metabolites are secreted in human
593
milk. Because of the potential for serious adverse reactions in nursing infants from
594
WELLBUTRIN SR Tablets, a decision should be made whether to discontinue nursing or to
595
discontinue the drug, taking into account the importance of the drug to the mother.
596
Pediatric Use: Safety and effectiveness in the pediatric population have not been established
597
(see BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk). Anyone
598
considering the use of WELLBUTRIN SR in a child or adolescent must balance the potential
599
risks with the clinical need.
600
Geriatric Use: Of the approximately 6,000 patients who participated in clinical trials with
601
bupropion sustained-release tablets (depression and smoking cessation studies), 275 were 65 and
602
over and 47 were 75 and over. In addition, several hundred patients 65 and over participated in
603
clinical trials using the immediate-release formulation of bupropion (depression studies). No
604
overall differences in safety or effectiveness were observed between these subjects and younger
605
subjects, and other reported clinical experience has not identified differences in responses
606
between the elderly and younger patients, but greater sensitivity of some older individuals cannot
607
be ruled out.
608
A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its
609
metabolites in elderly subjects was similar to that of younger subjects; however, another
610
pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased
611
risk for accumulation of bupropion and its metabolites (see CLINICAL PHARMACOLOGY).
612
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
Bupropion is extensively metabolized in the liver to active metabolites, which are further
613
metabolized and excreted by the kidneys. The risk of toxic reaction to this drug may be greater in
614
patients with impaired renal function. Because elderly patients are more likely to have decreased
615
renal function, care should be taken in dose selection, and it may be useful to monitor renal
616
function (see PRECAUTIONS: Renal Impairment and DOSAGE AND ADMINISTRATION).
617
ADVERSE REACTIONS (See also WARNINGS and PRECAUTIONS.)
618
The information included under the Incidence in Controlled Trials subsection of ADVERSE
619
REACTIONS is based primarily on data from controlled clinical trials with WELLBUTRIN SR
620
Tablets. Information on additional adverse events associated with the sustained-release
621
formulation of bupropion in smoking cessation trials, as well as the immediate-release
622
formulation of bupropion, is included in a separate section (see Other Events Observed During
623
the Clinical Development and Postmarketing Experience of Bupropion).
624
Incidence in Controlled Trials With WELLBUTRIN SR: Adverse Events Associated
625
With Discontinuation of Treatment Among Patients Treated With
626
WELLBUTRIN SR Tablets: In placebo-controlled clinical trials, 9% and 11% of patients
627
treated with 300 and 400 mg/day, respectively, of WELLBUTRIN SR Tablets and 4% of patients
628
treated with placebo discontinued treatment due to adverse events. The specific adverse events in
629
these trials that led to discontinuation in at least 1% of patients treated with either 300 or
630
400 mg/day of WELLBUTRIN SR Tablets and at a rate at least twice the placebo rate are listed
631
in Table 3.
632
633
Table 3. Treatment Discontinuations Due to Adverse Events in Placebo-Controlled Trials
634
Adverse Event Term
WELLBUTRIN SR
300 mg/day
(n = 376)
WELLBUTRIN SR
400 mg/day
(n = 114)
Placebo
(n = 385)
Rash
2.4%
0.9%
0.0%
Nausea
0.8%
1.8%
0.3%
Agitation
0.3%
1.8%
0.3%
Migraine
0.0%
1.8%
0.3%
635
Adverse Events Occurring at an Incidence of 1% or More Among Patients
636
Treated With WELLBUTRIN SR Tablets: Table 4 enumerates treatment-emergent adverse
637
events that occurred among patients treated with 300 and 400 mg/day of WELLBUTRIN SR
638
Tablets and with placebo in placebo-controlled trials. Events that occurred in either the 300- or
639
400-mg/day group at an incidence of 1% or more and were more frequent than in the placebo
640
group are included. Reported adverse events were classified using a COSTART-based
641
Dictionary.
642
Accurate estimates of the incidence of adverse events associated with the use of any drug are
643
difficult to obtain. Estimates are influenced by drug dose, detection technique, setting, physician
644
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18
judgments, etc. The figures cited cannot be used to predict precisely the incidence of untoward
645
events in the course of usual medical practice where patient characteristics and other factors
646
differ from those that prevailed in the clinical trials. These incidence figures also cannot be
647
compared with those obtained from other clinical studies involving related drug products as each
648
group of drug trials is conducted under a different set of conditions.
649
Finally, it is important to emphasize that the tabulation does not reflect the relative severity
650
and/or clinical importance of the events. A better perspective on the serious adverse events
651
associated with the use of WELLBUTRIN SR Tablets is provided in the WARNINGS and
652
PRECAUTIONS sections.
653
654
Table 4. Treatment-Emergent Adverse Events in Placebo-Controlled Trials*
655
Body System/
Adverse Event
WELLBUTRIN SR
300 mg/day
(n = 376)
WELLBUTRIN SR
400 mg/day
(n = 114)
Placebo
(n = 385)
Body (General)
Headache
26%
25%
23%
Infection
8%
9%
6%
Abdominal pain
3%
9%
2%
Asthenia
2%
4%
2%
Chest pain
3%
4%
1%
Pain
2%
3%
2%
Fever
1%
2%
—
Cardiovascular
Palpitation
2%
6%
2%
Flushing
1%
4%
—
Migraine
1%
4%
1%
Hot flashes
1%
3%
1%
Digestive
Dry mouth
17%
24%
7%
Nausea
13%
18%
8%
Constipation
10%
5%
7%
Diarrhea
5%
7%
6%
Anorexia
5%
3%
2%
Vomiting
4%
2%
2%
Dysphagia
0%
2%
0%
Musculoskeletal
Myalgia
2%
6%
3%
Arthralgia
1%
4%
1%
Arthritis
0%
2%
0%
Twitch
1%
2%
—
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19
Nervous system
Insomnia
11%
16%
6%
Dizziness
7%
11%
5%
Agitation
3%
9%
2%
Anxiety
5%
6%
3%
Tremor
6%
3%
1%
Nervousness
5%
3%
3%
Somnolence
2%
3%
2%
Irritability
3%
2%
2%
Memory decreased
—
3%
1%
Paresthesia
1%
2%
1%
Central nervous
system stimulation
2%
1%
1%
Respiratory
Pharyngitis
3%
11%
2%
Sinusitis
3%
1%
2%
Increased cough
1%
2%
1%
Skin
Sweating
6%
5%
2%
Rash
5%
4%
1%
Pruritus
2%
4%
2%
Urticaria
2%
1%
0%
Special senses
Tinnitus
6%
6%
2%
Taste perversion
2%
4%
—
Amblyopia
3%
2%
2%
Urogenital
Urinary frequency
2%
5%
2%
Urinary urgency
—
2%
0%
Vaginal hemorrhage†
0%
2%
—
Urinary tract
infection
1%
0%
—
* Adverse events that occurred in at least 1% of patients treated with either 300 or 400 mg/day
656
of WELLBUTRIN SR Tablets, but equally or more frequently in the placebo group, were:
657
abnormal dreams, accidental injury, acne, appetite increased, back pain, bronchitis,
658
dysmenorrhea, dyspepsia, flatulence, flu syndrome, hypertension, neck pain, respiratory
659
disorder, rhinitis, and tooth disorder.
660
† Incidence based on the number of female patients.
661
— Hyphen denotes adverse events occurring in greater than 0 but less than 0.5% of patients.
662
663
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
20
Incidence of Commonly Observed Adverse Events in Controlled Clinical Trials:
664
Adverse events from Table 4 occurring in at least 5% of patients treated with
665
WELLBUTRIN SR Tablets and at a rate at least twice the placebo rate are listed below for the
666
300- and 400-mg/day dose groups.
667
WELLBUTRIN SR 300 mg/day: Anorexia, dry mouth, rash, sweating, tinnitus, and
668
tremor.
669
WELLBUTRIN SR 400 mg/day: Abdominal pain, agitation, anxiety, dizziness, dry
670
mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary
671
frequency.
672
Other Events Observed During the Clinical Development and Postmarketing
673
Experience of Bupropion: In addition to the adverse events noted above, the following
674
events have been reported in clinical trials and postmarketing experience with the
675
sustained-release formulation of bupropion in depressed patients and in nondepressed smokers,
676
as well as in clinical trials and postmarketing clinical experience with the immediate-release
677
formulation of bupropion.
678
Adverse events for which frequencies are provided below occurred in clinical trials with the
679
sustained-release formulation of bupropion. The frequencies represent the proportion of patients
680
who experienced a treatment-emergent adverse event on at least one occasion in
681
placebo-controlled studies for depression (n = 987) or smoking cessation (n = 1,013), or patients
682
who experienced an adverse event requiring discontinuation of treatment in an open-label
683
surveillance study with WELLBUTRIN SR Tablets (n = 3,100). All treatment-emergent adverse
684
events are included except those listed in Tables 1 through 4, those events listed in other
685
safety-related sections, those adverse events subsumed under COSTART terms that are either
686
overly general or excessively specific so as to be uninformative, those events not reasonably
687
associated with the use of the drug, and those events that were not serious and occurred in fewer
688
than 2 patients. Events of major clinical importance are described in the WARNINGS and
689
PRECAUTIONS sections of the labeling.
690
Events are further categorized by body system and listed in order of decreasing frequency
691
according to the following definitions of frequency: Frequent adverse events are defined as those
692
occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to
693
1/1,000 patients, while rare events are those occurring in less than 1/1,000 patients.
694
Adverse events for which frequencies are not provided occurred in clinical trials or
695
postmarketing experience with bupropion. Only those adverse events not previously listed for
696
sustained-release bupropion are included. The extent to which these events may be associated
697
with WELLBUTRIN SR is unknown.
698
Body (General): Infrequent were chills, facial edema, musculoskeletal chest pain, and
699
photosensitivity. Rare was malaise. Also observed were arthralgia, myalgia, and fever with rash
700
and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble
701
serum sickness (see PRECAUTIONS).
702
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
21
Cardiovascular: Infrequent were postural hypotension, stroke, tachycardia, and
703
vasodilation. Rare was syncope. Also observed were complete atrioventricular block,
704
extrasystoles, hypotension, hypertension (in some cases severe, see PRECAUTIONS),
705
myocardial infarction, phlebitis, and pulmonary embolism.
706
Digestive: Infrequent were abnormal liver function, bruxism, gastric reflux, gingivitis,
707
glossitis, increased salivation, jaundice, mouth ulcers, stomatitis, and thirst. Rare was edema of
708
tongue. Also observed were colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage,
709
hepatitis, intestinal perforation, liver damage, pancreatitis, and stomach ulcer.
710
Endocrine: Also observed were hyperglycemia, hypoglycemia, and syndrome of
711
inappropriate antidiuretic hormone.
712
Hemic and Lymphatic: Infrequent was ecchymosis. Also observed were anemia,
713
leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered PT
714
and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were
715
observed when bupropion was coadministered with warfarin.
716
Metabolic and Nutritional: Infrequent were edema and peripheral edema. Also observed
717
was glycosuria.
718
Musculoskeletal: Infrequent were leg cramps. Also observed were muscle
719
rigidity/fever/rhabdomyolysis and muscle weakness.
720
Nervous System: Infrequent were abnormal coordination, decreased libido,
721
depersonalization, dysphoria, emotional lability, hostility, hyperkinesia, hypertonia, hypesthesia,
722
suicidal ideation, and vertigo. Rare were amnesia, ataxia, derealization, and hypomania. Also
723
observed were abnormal electroencephalogram (EEG), akinesia, aggression, aphasia, coma,
724
delirium, delusions, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal syndrome,
725
hallucinations, hypokinesia, increased libido, manic reaction, neuralgia, neuropathy, paranoid
726
ideation, restlessness, and unmasking tardive dyskinesia.
727
Respiratory: Rare was bronchospasm. Also observed was pneumonia.
728
Skin: Rare was maculopapular rash. Also observed were alopecia, angioedema, exfoliative
729
dermatitis, and hirsutism.
730
Special Senses: Infrequent were accommodation abnormality and dry eye. Also observed
731
were deafness, diplopia, and mydriasis.
732
Urogenital: Infrequent were impotence, polyuria, and prostate disorder. Also observed were
733
abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection,
734
salpingitis, urinary incontinence, urinary retention, and vaginitis.
735
DRUG ABUSE AND DEPENDENCE
736
Controlled Substance Class: Bupropion is not a controlled substance.
737
Humans: Controlled clinical studies of bupropion (immediate-release formulation) conducted
738
in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed patients
739
showed some increase in motor activity and agitation/excitement.
740
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
22
In a population of individuals experienced with drugs of abuse, a single dose of 400 mg of
741
bupropion produced mild amphetamine-like activity as compared to placebo on the
742
Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI), and a
743
score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These
744
scales measure general feelings of euphoria and drug desirability.
745
Findings in clinical trials, however, are not known to reliably predict the abuse potential of
746
drugs. Nonetheless, evidence from single-dose studies does suggest that the recommended daily
747
dosage of bupropion when administered in divided doses is not likely to be especially reinforcing
748
to amphetamine or stimulant abusers. However, higher doses that could not be tested because of
749
the risk of seizure might be modestly attractive to those who abuse stimulant drugs.
750
Animals: Studies in rodents and primates have shown that bupropion exhibits some
751
pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase
752
locomotor activity, elicit a mild stereotyped behavioral response, and increase rates of
753
responding in several schedule-controlled behavior paradigms. In primate models to assess the
754
positive reinforcing effects of psychoactive drugs, bupropion was self-administered
755
intravenously. In rats, bupropion produced amphetamine-like and cocaine-like discriminative
756
stimulus effects in drug discrimination paradigms used to characterize the subjective effects of
757
psychoactive drugs.
758
OVERDOSAGE
759
Human Overdose Experience: Overdoses of up to 30 g or more of bupropion have been
760
reported. Seizure was reported in approximately one third of all cases. Other serious reactions
761
reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus
762
tachycardia, and ECG changes such as conduction disturbances or arrhythmias. Fever, muscle
763
rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported
764
mainly when bupropion was part of multiple drug overdoses.
765
Although most patients recovered without sequelae, deaths associated with overdoses of
766
bupropion alone have been reported in patients ingesting large doses of the drug. Multiple
767
uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported
768
in these patients.
769
Overdosage Management: Ensure an adequate airway, oxygenation, and ventilation.
770
Monitor cardiac rhythm and vital signs. EEG monitoring is also recommended for the first
771
48 hours post-ingestion. General supportive and symptomatic measures are also recommended.
772
Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with
773
appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in
774
symptomatic patients.
775
Activated charcoal should be administered. There is no experience with the use of forced
776
diuresis, dialysis, hemoperfusion, or exchange transfusion in the management of bupropion
777
overdoses. No specific antidotes for bupropion are known.
778
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
Due to the dose-related risk of seizures with WELLBUTRIN SR, hospitalization following
779
suspected overdose should be considered. Based on studies in animals, it is recommended that
780
seizures be treated with intravenous benzodiazepine administration and other supportive
781
measures, as appropriate.
782
In managing overdosage, consider the possibility of multiple drug involvement. The physician
783
should consider contacting a poison control center for additional information on the treatment of
784
any overdose. Telephone numbers for certified poison control centers are listed in the
785
Physicians’ Desk Reference (PDR).
786
DOSAGE AND ADMINISTRATION
787
General Dosing Considerations: It is particularly important to administer
788
WELLBUTRIN SR Tablets in a manner most likely to minimize the risk of seizure (see
789
WARNINGS). Gradual escalation in dosage is also important if agitation, motor restlessness,
790
and insomnia, often seen during the initial days of treatment, are to be minimized. If necessary,
791
these effects may be managed by temporary reduction of dose or the short-term administration of
792
an intermediate to long-acting sedative hypnotic. A sedative hypnotic usually is not required
793
beyond the first week of treatment. Insomnia may also be minimized by avoiding bedtime doses.
794
If distressing, untoward effects supervene, dose escalation should be stopped.
795
WELLBUTRIN SR should be swallowed whole and not crushed, divided, or chewed.
796
Initial Treatment: The usual adult target dose for WELLBUTRIN SR Tablets is 300 mg/day,
797
given as 150 mg twice daily. Dosing with WELLBUTRIN SR Tablets should begin at
798
150 mg/day given as a single daily dose in the morning. If the 150-mg initial dose is adequately
799
tolerated, an increase to the 300-mg/day target dose, given as 150 mg twice daily, may be made
800
as early as day 4 of dosing. There should be an interval of at least 8 hours between successive
801
doses.
802
Increasing the Dosage Above 300 mg/day: As with other antidepressants, the full
803
antidepressant effect of WELLBUTRIN SR Tablets may not be evident until 4 weeks of
804
treatment or longer. An increase in dosage to the maximum of 400 mg/day, given as 200 mg
805
twice daily, may be considered for patients in whom no clinical improvement is noted after
806
several weeks of treatment at 300 mg/day.
807
Maintenance Treatment: It is generally agreed that acute episodes of depression require
808
several months or longer of sustained pharmacological therapy beyond response to the acute
809
episode. In a study in which patients with major depressive disorder, recurrent type, who had
810
responded during 8 weeks of acute treatment with WELLBUTRIN SR were assigned randomly
811
to placebo or to the same dose of WELLBUTRIN SR (150 mg twice daily) during 44 weeks of
812
maintenance treatment as they had received during the acute stabilization phase, longer-term
813
efficacy was demonstrated (see CLINICAL TRIALS under CLINICAL PHARMACOLOGY).
814
Based on these limited data, it is unknown whether or not the dose of WELLBUTRIN SR needed
815
for maintenance treatment is identical to the dose needed to achieve an initial response. Patients
816
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
24
should be periodically reassessed to determine the need for maintenance treatment and the
817
appropriate dose for such treatment.
818
Dosage Adjustment for Patients with Impaired Hepatic Function: WELLBUTRIN SR
819
should be used with extreme caution in patients with severe hepatic cirrhosis. The dose should
820
not exceed 100 mg every day or 150 mg every other day in these patients. WELLBUTRIN SR
821
should be used with caution in patients with hepatic impairment (including mild to moderate
822
hepatic cirrhosis) and a reduced frequency and/or dose should be considered in patients with
823
mild to moderate hepatic cirrhosis (see CLINICAL PHARMACOLOGY, WARNINGS, and
824
PRECAUTIONS).
825
Dosage Adjustment for Patients with Impaired Renal Function: WELLBUTRIN SR
826
should be used with caution in patients with renal impairment and a reduced frequency and/or
827
dose should be considered (see CLINICAL PHARMACOLOGY and PRECAUTIONS).
828
HOW SUPPLIED
829
WELLBUTRIN SR Sustained-Release Tablets, 100 mg of bupropion hydrochloride, are blue,
830
round, biconvex, film-coated tablets printed with “WELLBUTRIN SR 100” in bottles of 60
831
(NDC 0173-0947-55) tablets.
832
WELLBUTRIN SR Sustained-Release Tablets, 150 mg of bupropion hydrochloride, are
833
purple, round, biconvex, film-coated tablets printed with "WELLBUTRIN SR 150" in bottles of
834
60 (NDC 0173-0135-55) tablets.
835
WELLBUTRIN SR Sustained-Release Tablets, 200 mg of bupropion hydrochloride, are light
836
pink, round, biconvex, film-coated tablets printed with “WELLBUTRIN SR 200” in bottles of 60
837
(NDC 0173-0722-00) tablets.
838
Store at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP]. Dispense in a
839
tight, light-resistant container as defined in the USP.
840
841
Medication Guide
842
WELLBUTRIN SR® (WELL byu-trin)
843
(bupropion hydrochloride) Sustained-Release Tablets
844
About Using Antidepressants in Children and Teenagers
845
846
What is the most important information I should know if my child is being prescribed an
847
antidepressant?
848
849
Parents or guardians need to think about 4 important things when their child is prescribed an
850
antidepressant:
851
1. There is a risk of suicidal thoughts or actions
852
2. How to try to prevent suicidal thoughts or actions in your child
853
3. You should watch for certain signs if your child is taking an antidepressant
854
4. There are benefits and risks when using antidepressants
855
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
25
856
1. There is a Risk of Suicidal Thoughts or Actions
857
858
Children and teenager sometimes think about suicide, and many report trying to kill themselves.
859
860
Antidepressants increase suicidal thoughts and actions in some children and teenagers. But
861
suicidal thoughts and actions can also be caused by depression, a serious medical condition that
862
is commonly treated with antidepressants. Thinking about killing yourself or trying to kill
863
yourself is called suicidality or being suicidal.
864
865
A large study combined the results of 24 different studies of children and teenagers with
866
depression or other illnesses. In these studies, patients took either a placebo (sugar pill) or an
867
antidepressant for 1 to 4 months. No one committed suicide in these studies, but some patients
868
became suicidal. On sugar pills, 2 out of every 100 became suicidal. On the antidepressants, 4
869
out of every 100 patients became suicidal.
870
871
For some children and teenagers, the risks of suicidal actions may be especially high. These
872
include patients with
873
• Bipolar illness (sometimes called manic-depressive illness)
874
• A family history of bipolar illness
875
• A personal or family history of attempting suicide
876
If any of these are present, make sure you tell your healthcare provider before your child takes an
877
antidepressant.
878
879
2. How to Try to Prevent Suicidal Thoughts and Actions
880
881
To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in her
882
or his moods or actions, especially if the changes occur suddenly. Other important people in your
883
child’s life can help by paying attention as well (e.g., your child, brothers and sisters, teachers,
884
and other important people). The changes to look out for are listed in Section 3, on what to watch
885
for.
886
887
Whenever an antidepressant is started or its dose is changed, pay close attention to your child.
888
After starting an antidepressant, your child should generally see his or her healthcare provider:
889
• Once a week for the first 4 weeks
890
• Every 2 weeks for the next 4 weeks
891
• After taking the antidepressant for 12 weeks
892
• After 12 weeks, follow your healthcare provider’s advice about how often to come back
893
• More often if problems or questions arise (see Section 3)
894
895
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
26
You should call your child’s healthcare provider between visits if needed.
896
897
3. You Should Watch For Certain Signs if Your Child is Taking an Antidepressant
898
899
Contact your child’s healthcare provider right away if your child exhibits any of the following
900
signs for the first time, or they seem worse, or worry you, your child, or your child’s teacher:
901
• Thoughts about suicide or dying
902
• Attempts to commit suicide
903
• New or worse depression
904
• New or worse anxiety
905
• Feeling very agitated or restless
906
• Panic attacks
907
• Difficulty sleeping (insomnia)
908
• New or worse irritability
909
• Acting aggressive, being angry, or violent
910
• Acting on dangerous impulses
911
• An extreme increase in activity and talking
912
• Other unusual changes in behavior or mood
913
914
Never let your child stop taking an antidepressant without first talking to his or her healthcare
915
provider. Stopping an antidepressant suddenly can cause other symptoms.
916
917
4. There are Benefits and Risks When Using Antidepressants
918
919
Antidepressants are used to treat depression and other illnesses. Depression and other illnesses
920
can lead to suicide. In some children and teenagers, treatment with an antidepressant increases
921
suicidal thinking or actions. It is important to discuss all the risks of treating depression and also
922
the risks of not treating it. You and your child should discuss all treatment choices with your
923
healthcare provider, not just the use of antidepressants.
924
925
Other side effects can occur with antidepressants (see section below).
926
927
Of all antidepressants, only fluoxetine (Prozac®)* has been FDA approved to treat pediatric
928
depression.
929
930
For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine
931
(Prozac®)*, sertraline (Zoloft®)*, fluvoxamine, and clomipramine (Anafranil®)*.
932
933
Your healthcare provider may suggest other antidepressants based on the past experience of your
934
child or other family members.
935
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
27
936
Is this all I need to know if my child is being prescribed an antidepressant?
937
938
No. This is a warning about the risk of suicidality. Other side effects can occur with
939
antidepressants. Be sure to ask your healthcare provider to explain all the side effects of the
940
particular drug he or she is prescribing. Also ask about drugs to avoid when taking an
941
antidepressant. Ask your healthcare provider or pharmacist where to find more information.
942
943
*The following are registered trademarks of their respective manufacturers: Prozac®/Eli Lilly
944
and Company; Zoloft®/Pfizer Pharmaceuticals; Anafranil®/Mallinckrodt Inc.
945
946
This Medication Guide has been approved by the U.S. Food and Drug Administration for all
947
antidepressants.
948
949
January 2005
MG-MS:1
950
951
952
Distributed by:
953
GlaxoSmithKline, Research Triangle Park, NC 27709
954
955
Manufactured by:
956
GlaxoSmithKline
957
Research Triangle Park, NC 27709
958
or
959
DSM Pharmaceuticals, Inc.
960
Greenville, NC 27834
961
962
©2006, GlaxoSmithKline. All rights reserved.
963
964
May 2006
RL-2280
965
966
PHARMACIST--DETACH HERE AND GIVE LEAFLET TO PATIENT. ALSO
PROVIDE AN APPROVED MEDICATION GUIDE ABOUT USING
ANTIDEPRESSANTS IN CHILDREN AND TEENAGERS.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
967
Patient Information
968
WELLBUTRIN SR® (WELL byu-trin)
969
(bupropion hydrochloride) Sustained-Release Tablets
970
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
28
971
Read the Patient Information that comes with WELLBUTRIN SR before you start taking
972
WELLBUTRIN SR and each time you get a refill. There may be new information. This leaflet
973
does not take the place of talking with your doctor about your medical condition or your
974
treatment.
975
976
What is the most important information I should know about WELLBUTRIN SR?
977
There is a chance of having a seizure (convulsion, fit) with WELLBUTRIN SR, especially
978
in people:
979
• with certain medical problems.
980
• who take certain medicines.
981
982
The chance of having seizures increases with higher doses of WELLBUTRIN SR. For more
983
information, see the sections “Who should not take WELLBUTRIN SR?” and “What should I
984
tell my doctor before using WELLBUTRIN SR?” Tell your doctor about all of your medical
985
conditions and all the medicines you take. Do not take any other medicines while you are
986
using WELLBUTRIN SR unless your doctor has said it is okay to take them.
987
988
If you have a seizure while taking WELLBUTRIN SR, stop taking the tablets and call your
989
doctor right away. Do not take WELLBUTRIN SR again if you have a seizure.
990
991
What is important information I should know and share with my family about taking
992
antidepressants?
993
Patients and their families should watch out for worsening depression or thoughts of suicide.
994
Also watch out for sudden or severe changes in feelings such as feeling anxious, agitated,
995
panicky, irritable, hostile, aggressive, impulsive, severely restless, overly excited and
996
hyperactive, not being able to sleep, or other unusual changes in behavior. If this happens,
997
especially at the beginning of antidepressant treatment or after a change in dose, call your doctor.
998
A patient Medication Guide will be provided to you with each prescription of
999
WELLBUTRIN SR entitled "About Using Antidepressants in Children and Teenagers."
1000
WELLBUTRIN SR is not approved for use in children and teenagers.
1001
1002
What is WELLBUTRIN SR?
1003
WELLBUTRIN SR is a prescription medicine used to treat adults with a certain type of
1004
depression called major depressive disorder.
1005
1006
Who should not take WELLBUTRIN SR?
1007
Do not take WELLBUTRIN SR if you
1008
• have or had a seizure disorder or epilepsy.
1009
• are taking ZYBAN® (used to help people stop smoking) or any other medicines that
1010
contain bupropion hydrochloride, such as WELLBUTRIN® Tablets or WELLBUTRIN
1011
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
29
XL® Extended-Release Tablets. Bupropion is the same active ingredient that is in
1012
WELLBUTRIN SR.
1013
• drink a lot of alcohol and abruptly stop drinking, or use medicines called sedatives (these
1014
make you sleepy) or benzodiazepines and you stop using them all of a sudden.
1015
• have taken within the last 14 days medicine for depression called a monoamine oxidase
1016
inhibitor (MAOI), such as NARDIL®*(phenelzine sulfate), PARNATE®(tranylcypromine
1017
sulfate), or MARPLAN®*(isocarboxazid).
1018
• have or had an eating disorder such as anorexia nervosa or bulimia.
1019
• are allergic to the active ingredient in WELLBUTRIN SR, bupropion, or to any of the
1020
inactive ingredients. See the end of this leaflet for a complete list of ingredients in
1021
WELLBUTRIN SR.
1022
1023
What should I tell my doctor before using WELLBUTRIN SR?
1024
• Tell your doctor about your medical conditions. Tell your doctor if you:
1025
• are pregnant or plan to become pregnant. It is not known if WELLBUTRIN SR can
1026
harm your unborn baby. If you can use WELLBUTRIN SR while you are pregnant, talk
1027
to your doctor about how you can be on the Bupropion Pregnancy Registry.
1028
• are breastfeeding. WELLBUTRIN SR passes through your milk. It is not known if
1029
WELLBUTRIN SR can harm your baby.
1030
• have liver problems, especially cirrhosis of the liver.
1031
• have kidney problems.
1032
• have an eating disorder such as anorexia nervosa or bulimia.
1033
• have had a head injury.
1034
• have had a seizure (convulsion, fit).
1035
• have a tumor in your nervous system (brain or spine).
1036
• have had a heart attack, heart problems, or high blood pressure.
1037
• are a diabetic taking insulin or other medicines to control your blood sugar.
1038
• drink a lot of alcohol.
1039
• abuse prescription medicines or street drugs.
1040
1041
• Tell your doctor about all the medicines you take, including prescription and non-
1042
prescription medicines, vitamins, and herbal supplements. Many medicines increase your
1043
chances of having seizures or other serious side effects if you take them while you are using
1044
WELLBUTRIN SR.
1045
1046
WELLBUTRIN SR has not been studied in children under the age of 18 years.
1047
1048
How should I take WELLBUTRIN SR?
1049
• Take WELLBUTRIN SR exactly as prescribed by your doctor.
1050
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
30
• Do not chew, cut, or crush WELLBUTRIN SR Tablets. You must swallow the tablets
1051
whole. Tell your doctor if you cannot swallow medicine tablets.
1052
• Take WELLBUTRIN SR at the same time each day.
1053
• Take your doses of WELLBUTRIN SR at least 8 hours apart.
1054
• You may take WELLBUTRIN SR with or without food.
1055
• If you miss a dose, do not take an extra tablet to make up for the dose you forgot. Wait and
1056
take your next tablet at the regular time. This is very important. Too much
1057
WELLBUTRIN SR can increase your chance of having a seizure.
1058
• If you take too much WELLBUTRIN SR, or overdose, call your local emergency room or
1059
poison control center right away.
1060
• Do not take any other medicines while using WELLBUTRIN SR unless your doctor has
1061
told you it is okay.
1062
• It may take several weeks for you to feel that WELLBUTRIN SR is working. Once you feel
1063
better, it is important to keep taking WELLBUTRIN SR exactly as directed by your doctor.
1064
Call your doctor if you do not feel WELLBUTRIN SR is working for you.
1065
• Do not change your dose or stop taking WELLBUTRIN SR without talking with your doctor
1066
first.
1067
1068
What should I avoid while taking WELLBUTRIN SR?
1069
• Do not drink a lot of alcohol while taking WELLBUTRIN SR. If you usually drink a lot of
1070
alcohol, talk with your doctor before suddenly stopping. If you suddenly stop drinking
1071
alcohol, you may increase your chance of having seizures.
1072
• Do not drive a car or use heavy machinery until you know how WELLBUTRIN SR affects
1073
you. WELLBUTRIN SR can impair your ability to perform these tasks.
1074
1075
What are possible side effects of WELLBUTRIN SR?
1076
• Seizures. Some patients get seizures while taking WELLBUTRIN SR. If you have a seizure
1077
while taking WELLBUTRIN SR, stop taking the tablets and call your doctor right
1078
away. Do not take WELLBUTRIN SR again if you have a seizure.
1079
• Hypertension (high blood pressure). Some patients get high blood pressure, sometimes
1080
severe, while taking WELLBUTRIN SR. The chance of high blood pressure may be
1081
increased if you also use nicotine replacement therapy (for example, a nicotine patch) to help
1082
you stop smoking.
1083
• Severe allergic reactions: Stop taking WELLBUTRIN SR and call your doctor right
1084
away if you get a rash, itching, hives, fever, swollen lymph glands, painful sores in the
1085
mouth or around the eyes, swelling of the lips or tongue, chest pain, or have trouble
1086
breathing. These could be signs of a serious allergic reaction.
1087
• Unusual thoughts or behaviors. Some patients have unusual thoughts or behaviors while
1088
taking WELLBUTRIN SR, including delusions (believe you are someone else),
1089
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
31
hallucinations (seeing or hearing things that are not there), paranoia (feeling that people are
1090
against you), or feeling confused. If this happens to you, call your doctor.
1091
1092
The most common side effects of WELLBUTRIN SR are loss of appetite, dry mouth, skin rash,
1093
sweating, ringing in the ears, shakiness, stomach pain, agitation, anxiety, dizziness, trouble
1094
sleeping, muscle pain, nausea, fast heart beat, sore throat, and urinating more often.
1095
1096
If you have nausea, you may want to take your medicine with food. If you have trouble sleeping,
1097
do not take your medicine too close to bedtime.
1098
1099
Tell your doctor right away about any side effects that bother you.
1100
1101
These are not all the side effects of WELLBUTRIN SR. For a complete list, ask your doctor or
1102
pharmacist.
1103
1104
How should I store WELLBUTRIN SR?
1105
• Store WELLBUTRIN SR at room temperature. Store out of direct sunlight. Keep
1106
WELLBUTRIN SR in its tightly closed bottle.
1107
• WELLBUTRIN SR tablets may have an odor.
1108
1109
General Information about WELLBUTRIN SR.
1110
• Medicines are sometimes prescribed for conditions that are not mentioned in patient
1111
information leaflets. Do not use WELLBUTRIN SR for a condition for which it was not
1112
prescribed. Do not give WELLBUTRIN SR to other people, even if they have the same
1113
symptoms you have. It may harm them. Keep WELLBUTRIN SR out of the reach of
1114
children.
1115
1116
This leaflet summarizes important information about WELLBUTRIN SR. For more information,
1117
talk with your doctor. You can ask your doctor or pharmacist for information about
1118
WELLBUTRIN SR that is written for health professionals.
1119
1120
What are the ingredients in WELLBUTRIN SR?
1121
Active ingredient: bupropion hydrochloride.
1122
1123
Inactive ingredients: carnauba wax, cysteine hydrochloride, hypromellose, magnesium stearate,
1124
microcrystalline cellulose, polyethylene glycol, polysorbate 80, and titanium dioxide. In
1125
addition, the 100-mg tablet contains FD&C Blue No. 1 Lake, the 150-mg tablet contains FD&C
1126
Blue No. 2 Lake and FD&C Red No. 40 Lake, and the 200-mg tablet contains FD&C Red No. 40
1127
Lake. The tablets are printed with edible black ink.
1128
1129
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
32
*The following are registered trademarks of their respective manufacturers: Nardil®/Warner
1130
Lambert Company; Marplan®/Oxford Pharmaceutical Services, Inc.
1131
1132
1133
1134
1135
Distributed by:
1136
GlaxoSmithKline
1137
Research Triangle Park, NC 27709
1138
1139
Manufactured by:
1140
GlaxoSmithKline
1141
Research Triangle Park, NC 27709
1142
or
1143
DSM Pharmaceuticals, Inc.
1144
Greenville, NC 27834
1145
1146
©2006, GlaxoSmithKline. All rights reserved.
1147
1148
May 2006
RL-2280
1149
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:48.332920
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/018644s33s34,020358s37s40,021515s14lbl.pdf', 'application_number': 18644, 'submission_type': 'SUPPL ', 'submission_number': 33}
|
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|
NDA 18-644/S-039
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Page 4
PRESCRIBING INFORMATION
WELLBUTRIN®
(bupropion hydrochloride)
Tablets
WARNING
Suicidality and Antidepressant Drugs
Use in Treating Psychiatric Disorders: Antidepressants increased the risk compared
to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults
in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone
considering the use of WELLBUTRIN or any other antidepressant in a child, adolescent, or young
adult must balance this risk with the clinical need. Short-term studies did not show an increase in
the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was
a reduction in risk with antidepressants compared to placebo in adults aged 65 and older.
Depression and certain other psychiatric disorders are themselves associated with increases in the
risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored
appropriately and observed closely for clinical worsening, suicidality, or unusual changes in
behavior. Families and caregivers should be advised of the need for close observation and
communication with the prescriber. WELLBUTRIN is not approved for use in pediatric patients.
(See WARNINGS: Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders,
PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use.)
Use in Smoking Cessation Treatment: WELLBUTRIN®, WELLBUTRIN SR®, and
WELLBUTRIN XL® are not approved for smoking cessation treatment, but bupropion under the
name ZYBAN® is approved for this use. Serious neuropsychiatric events, including but not limited
to depression, suicidal ideation, suicide attempt, and completed suicide have been
reported in patients taking bupropion for smoking cessation. Some cases may have been
complicated by the symptoms of nicotine withdrawal in patients who stopped smoking.
Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal
ideation, has been reported in smokers undergoing a smoking cessation attempt without medication.
However, some of these symptoms have occurred in patients taking bupropion who
continued to smoke.
All patients being treated with bupropion for smoking cessation treatment should be
observed for neuropsychiatric symptoms including changes in behavior, hostility, agitation,
depressed mood, and suicide-related events, including ideation, behavior, and attempted suicide.
These symptoms, as well as worsening of pre-existing psychiatric illness and completed suicide
have been reported in some patients attempting to quit smoking while taking ZYBAN in the
postmarketing experience. When symptoms were reported, most were during treatment with
ZYBAN, but some were following discontinuation of treatment with ZYBAN. These events have
occurred in patients with and without pre-existing psychiatric disease; some have experienced
worsening of their psychiatric illnesses. Patients with serious psychiatric illness such as
schizophrenia, bipolar disorder, and major depressive disorder did not participate in the
premarketing studies of ZYBAN.
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Page 5
Advise patients and caregivers that the patient using bupropion for smoking
cessation should stop taking bupropion and contact a healthcare provider
immediately if agitation, hostility, depressed mood, or changes in thinking or
behavior that are not typical for the patient are observed, or if the patient develops
suicidal ideation or suicidal behavior. In many postmarketing cases, resolution of symptoms
after discontinuation of ZYBAN was reported, although in some cases the symptoms persisted;
therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.
The risks of using bupropion for smoking cessation should be weighed against the
benefits of its use. ZYBAN has been demonstrated to increase the likelihood of abstinence
from smoking for as long as 6 months compared to treatment with placebo. The health
benefits of quitting smoking are immediate and substantial. (See WARNINGS:
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment and
PRECAUTIONS: Information for Patients.)
DESCRIPTION
WELLBUTRIN (bupropion hydrochloride), an antidepressant of the aminoketone class, is
chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other known
antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to
phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1
propanone hydrochloride. The molecular weight is 276.2. The empirical formula is
C13H18ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in
water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The
structural formula is: chemical structure
WELLBUTRIN is supplied for oral administration as 75-mg (yellow-gold) and 100-mg
(red) film-coated tablets. Each tablet contains the labeled amount of bupropion hydrochloride and
the inactive ingredients: 75-mg tablet – D&C Yellow No. 10 Lake, FD&C Yellow No. 6 Lake,
hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and
titanium dioxide; 100-mg tablet – FD&C Red No. 40 Lake, FD&C Yellow No. 6 Lake,
hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and
titanium dioxide.
CLINICAL PHARMACOLOGY
Pharmacodynamics: The neurochemical mechanism of the antidepressant effect of bupropion is
not known. Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and
dopamine, and does not inhibit monoamine oxidase or the re-uptake of serotonin.
Bupropion produces dose-related central nervous system (CNS) stimulant effects in
animals, as evidenced by increased locomotor activity, increased rates of responding in various
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Page 6
schedule-controlled operant behavior tasks, and, at high doses, induction of mild stereotyped
behavior.
Bupropion causes convulsions in rodents and dogs at doses approximately tenfold the dose
recommended as the human antidepressant dose.
Pharmacokinetics: Bupropion is a racemic mixture. The pharmacological activity and
pharmacokinetics of the individual enantiomers have not been studied. In humans, following oral
administration of WELLBUTRIN, peak plasma bupropion concentrations are usually achieved
within 2 hours, followed by a biphasic decline. The terminal phase has a mean half-life of 14 hours,
with a range of 8 to 24 hours. The distribution phase has a mean half-life of 3 to 4 hours. The mean
elimination half-life (±SD) of bupropion after chronic dosing is 21 (±9) hours, and steady-state
plasma concentrations of bupropion are reached within 8 days. Plasma bupropion concentrations
are dose-proportional following single doses of 100 to 250 mg; however, it is not known if the
proportionality between dose and plasma level is maintained in chronic use.
Absorption: The absolute bioavailability of WELLBUTRIN Tablets in humans has not
been determined because an intravenous formulation for human use is not available. However, it
appears likely that only a small proportion of any orally administered dose reaches the systemic
circulation intact.
Distribution: In vitro tests show that bupropion is 84% bound to human plasma protein at
concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion
metabolite is similar to that for bupropion, whereas the extent of protein binding of the
threohydrobupropion metabolite is about half that seen with bupropion.
Metabolism: Bupropion is extensively metabolized in humans. Three metabolites have
been shown to be active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl
group of bupropion, and the amino-alcohol isomers threohydrobupropion and
erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings
suggest that cytochrome P450IIB6 (CYP2B6) is the principal isoenzyme involved in the formation
of hydroxybupropion, while cytochrome P450 isoenzymes are not involved in the formation of
threohydrobupropion. Oxidation of the bupropion side chain results in the formation of a glycine
conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The
potency and toxicity of the metabolites relative to bupropion have not been fully characterized.
However, it has been demonstrated in an antidepressant screening test in mice that
hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and
erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance
because their plasma concentrations are as high or higher than those of bupropion.
Because bupropion is extensively metabolized, there is the potential for drug-drug
interactions, particularly with those agents that are metabolized by the cytochrome P450IIB6
(CYP2B6) isoenzyme. Although bupropion is not metabolized by cytochrome P450IID6
(CYP2D6), there is the potential for drug-drug interactions when bupropion is coadministered with
drugs metabolized by this isoenzyme (see PRECAUTIONS: Drug Interactions).
Following a single dose in humans, peak plasma concentrations of hydroxybupropion occur
approximately 3 hours after administration of WELLBUTRIN Tablets. Peak plasma concentrations
of hydroxybupropion are approximately 10 times the peak level of the parent drug at steady state.
The elimination half-life of hydroxybupropion is approximately 20 (±5) hours, and its AUC at
steady state is about 17 times that of bupropion. The times to peak concentrations for the
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erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the
hydroxybupropion metabolite. However, their elimination half-lives are longer, 33 (±10) and
37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion,
respectively.
Bupropion and its metabolites exhibit linear kinetics following chronic administration of
300 to 450 mg/day.
Elimination: Following oral administration of 200 mg of 14C-bupropion in humans, 87%
and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the
fraction of the oral dose of WELLBUTRIN excreted unchanged was only 0.5%, a finding
consistent with the extensive metabolism of bupropion.
Populations Subgroups: Factors or conditions altering metabolic capacity (e.g., liver disease,
congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may be expected
to influence the degree and extent of accumulation of the active metabolites of bupropion. The
elimination of the major metabolites of bupropion may be affected by reduced renal or hepatic
function because they are moderately polar compounds and are likely to undergo further
metabolism or conjugation in the liver prior to urinary excretion.
Hepatic: The effect of hepatic impairment on the pharmacokinetics of bupropion was
characterized in 2 single-dose studies, one in patients with alcoholic liver disease and one in
patients with mild-to-severe cirrhosis. The first study showed that the half-life of
hydroxybupropion was significantly longer in 8 patients with alcoholic liver disease than in
8 healthy volunteers (32 ± 14 hours versus 21 ± 5 hours, respectively). Although not statistically
significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be
greater (by 53% to 57%) in volunteers with alcoholic liver disease. The differences in half-life for
bupropion and the other metabolites in the 2 patient groups were minimal.
The second study showed that there were no statistically significant differences in the
pharmacokinetics of bupropion and its active metabolites in 9 patients with mild-to-moderate
hepatic cirrhosis compared to 8 healthy volunteers. However, more variability was observed in
some of the pharmacokinetic parameters for bupropion (AUC, Cmax, and Tmax) and its active
metabolites (t½) in patients with mild-to-moderate hepatic cirrhosis. In addition, in patients with
severe hepatic cirrhosis, the bupropion Cmax and AUC were substantially increased (mean
difference: by approximately 70% and 3-fold, respectively) and more variable when compared to
values in healthy volunteers; the mean bupropion half-life was also longer (29 hours in patients
with severe hepatic cirrhosis vs. 19 hours in healthy subjects). For the metabolite
hydroxybupropion, the mean Cmax was approximately 69% lower. For the combined amino-alcohol
isomers threohydrobupropion and erythrohydrobupropion, the mean Cmax was approximately 31%
lower. The mean AUC increased by about 1½-fold for hydroxybupropion and about 2½-fold for
threo/erythrohydrobupropion. The median Tmax was observed 19 hours later for hydroxybupropion
and 31 hours later for threo/erythrohydrobupropion. The mean half-lives for hydroxybupropion and
threo/erythrohydrobupropion were increased 5- and 2-fold, respectively, in patients with severe
hepatic cirrhosis compared to healthy volunteers (see WARNINGS, PRECAUTIONS, and
DOSAGE AND ADMINISTRATION).
Renal: There is limited information on the pharmacokinetics of bupropion in patients with
renal impairment. An inter-study comparison between normal subjects and patients with end-stage
renal failure demonstrated that the parent drug Cmax and AUC values were comparable in the 2
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Page 8
groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3- and 2.8
fold increase, respectively, in AUC for patients with end-stage renal failure. A second study,
comparing normal subjects and patients with moderate-to-severe renal impairment (GFR 30.9 ±
10.8 mL/min) showed that exposure to a single 150-mg dose of sustained-release bupropion was
approximately 2-fold higher in patients with impaired renal function while levels of the
hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the 2
groups. The elimination of bupropion and/or the major metabolites of bupropion may be reduced
by impaired renal function (see PRECAUTIONS: Renal Impairment).
Left Ventricular Dysfunction: During a chronic dosing study in 14 depressed patients
with left ventricular dysfunction (history of CHF or an enlarged heart on x-ray), no apparent effect
on the pharmacokinetics of bupropion or its metabolites was revealed, compared to healthy
volunteers.
Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have not
been fully characterized, but an exploration of steady-state bupropion concentrations from several
depression efficacy studies involving patients dosed in a range of 300 to 750 mg/day, on a 3 times
daily schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of
bupropion. A single-dose pharmacokinetic study demonstrated that the disposition of bupropion
and its metabolites in elderly subjects was similar to that of younger subjects. These data suggest
there is no prominent effect of age on bupropion concentration; however, another pharmacokinetic
study, single and multiple dose, has suggested that the elderly are at increased risk for accumulation
of bupropion and its metabolites (see PRECAUTIONS: Geriatric Use).
Gender: A single-dose study involving 12 healthy male and 12 healthy female volunteers
revealed no sex-related differences in the pharmacokinetic parameters of bupropion.
Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion were
studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17 were
nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there were no
statistically significant differences in Cmax, half-life, Tmax, AUC or clearance of bupropion or its
active metabolites between smokers and nonsmokers.
INDICATIONS AND USAGE
WELLBUTRIN is indicated for the treatment of major depressive disorder. A physician
considering WELLBUTRIN for the management of a patient’s first episode of depression should
be aware that the drug may cause generalized seizures in a dose-dependent manner with an
approximate incidence of 0.4% (4/1,000). This incidence of seizures may exceed that of other
marketed antidepressants by as much as 4-fold. This relative risk is only an approximate estimate
because no direct comparative studies have been conducted (see WARNINGS).
The efficacy of WELLBUTRIN has been established in 3 placebo-controlled trials,
including 2 of approximately 3 weeks’ duration in depressed inpatients and one of approximately
6 weeks’ duration in depressed outpatients. The depressive disorder of the patients studied
corresponds most closely to the Major Depression category of the APA Diagnostic and Statistical
Manual III.
Major Depression implies a prominent and relatively persistent depressed or dysphoric
mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should
include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor
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agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased
fatigability, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and
suicidal ideation or attempts.
Effectiveness of WELLBUTRIN in long-term use, that is, for more than 6 weeks, has not
been systematically evaluated in controlled trials. Therefore, the physician who elects to use
WELLBUTRIN for extended periods should periodically reevaluate the long-term usefulness of the
drug for the individual patient.
CONTRAINDICATIONS
WELLBUTRIN is contraindicated in patients with a seizure disorder.
WELLBUTRIN is contraindicated in patients treated with ZYBAN® (bupropion
hydrochloride) Sustained-Release Tablets; WELLBUTRIN SR® (bupropion hydrochloride), the
sustained-release formulation; WELLBUTRIN XL® (bupropion hydrochloride), the extended-
release formulation; or any other medications that contain bupropion because the incidence of
seizure is dose dependent.
WELLBUTRIN is contraindicated in patients with a current or prior diagnosis of bulimia or
anorexia nervosa because of a higher incidence of seizures noted in such patients treated with
WELLBUTRIN.
WELLBUTRIN is contraindicated in patients undergoing abrupt discontinuation of alcohol
or sedatives (including benzodiazepines).
The concurrent administration of WELLBUTRIN and a monoamine oxidase (MAO)
inhibitor is contraindicated. At least 14 days should elapse between discontinuation of an MAO
inhibitor and initiation of treatment with WELLBUTRIN.
WELLBUTRIN is contraindicated in patients who have shown an allergic response to
bupropion or the other ingredients that make up WELLBUTRIN Tablets.
WARNINGS
Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders: Patients with
major depressive disorder (MDD), both adult and pediatric, may experience worsening of their
depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes
in behavior, whether or not they are taking antidepressant medications, and this risk may persist
until significant remission occurs. Suicide is a known risk of depression and certain other
psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There
has been a long-standing concern, however, that antidepressants may have a role in inducing
worsening of depression and the emergence of suicidality in certain patients during the early phases
of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs
and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality)
in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and
other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality
with antidepressants compared to placebo in adults beyond age 24; there was a reduction with
antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24
short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of
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placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295
short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
There was considerable variation in risk of suicidality among drugs, but a tendency toward an
increase in the younger patients for almost all drugs studied. There were differences in absolute risk
of suicidality across the different indications, with the highest incidence in MDD. The risk
differences (drug vs placebo), however, were relatively stable within age strata and across
indications. These risk differences (drug-placebo difference in the number of cases of suicidality
per 1,000 patients treated) are provided in Table 1.
Table 1
Age Range
Drug-Placebo Difference in Number of Cases
of Suicidality per 1,000 Patients Treated
Increases Compared to Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but
the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
months. However, there is substantial evidence from placebo-controlled maintenance trials in
adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored
appropriately and observed closely for clinical worsening, suicidality, and unusual changes in
behavior, especially during the initial few months of a course of drug therapy, or at times of
dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
been reported in adult and pediatric patients being treated with antidepressants for major depressive
disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal
link between the emergence of such symptoms and either the worsening of depression and/or the
emergence of suicidal impulses has not been established, there is concern that such symptoms may
represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly
discontinuing the medication, in patients whose depression is persistently worse, or who are
experiencing emergent suicidality or symptoms that might be precursors to worsening depression or
suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major
depressive disorder or other indications, both psychiatric and nonpsychiatric, should be
alerted about the need to monitor patients for the emergence of agitation, irritability, unusual
changes in behavior, and the other symptoms described above, as well as the emergence of
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suicidality, and to report such symptoms immediately to healthcare providers. Such
monitoring should include daily observation by families and caregivers. Prescriptions for
WELLBUTRIN should be written for the smallest quantity of tablets consistent with good patient
management, in order to reduce the risk of overdose.
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment:
WELLBUTRIN, WELLBUTRIN SR, and WELLBUTRIN XL are not approved for smoking
cessation treatment, but bupropion under the name ZYBAN is approved for this use. Serious
neuropsychiatric symptoms have been reported in patients taking bupropion for smoking cessation
(see BOXED WARNING, ADVERSE REACTIONS). These have included changes in mood
(including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal
ideation, hostility, agitation, aggression, anxiety, and panic, as well as suicidal ideation,
suicide attempt, and completed suicide. Some reported cases may have been complicated
by the symptoms of nicotine withdrawal in patients who stopped smoking. Depressed
mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal
ideation, has been reported in smokers undergoing a smoking cessation attempt without
medication. However, some of these symptoms have occurred in patients taking
bupropion who continued to smoke. When symptoms were reported, most were during
bupropion treatment, but some were following discontinuation of bupropion therapy.
These events have occurred in patients with and without pre-existing psychiatric
disease; some have experienced worsening of their psychiatric illnesses. All patients being
treated with bupropion as part of smoking cessation treatment should be observed for
neuropsychiatric symptoms or worsening of pre-existing psychiatric illness.
Patients with serious psychiatric illness such as schizophrenia, bipolar disorder,
and major depressive disorder did not participate in the pre-marketing studies of ZYBAN.
Advise patients and caregivers that the patient using bupropion for smoking
cessation should stop taking bupropion and contact a healthcare provider
immediately if agitation, depressed mood, or changes in behavior or thinking that
are not typical for the patient are observed, or if the patient develops suicidal
ideation or suicidal behavior. In many postmarketing cases, resolution of symptoms after
discontinuation of ZYBAN was reported, although in some cases the symptoms persisted,
therefore, ongoing monitoring and supportive care should be provided until symptoms
resolve.
The risks of using bupropion for smoking cessation should be weighed against the
benefits of its use. ZYBAN has been demonstrated to increase the likelihood of abstinence
from smoking for as long as six months compared to treatment with placebo. The health
benefits of quitting smoking are immediate and substantial.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
presentation of bipolar disorder. It is generally believed (though not established in controlled trials)
that treating such an episode with an antidepressant alone may increase the likelihood of
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
symptoms described above represent such a conversion is unknown. However, prior to initiating
treatment with an antidepressant, patients with depressive symptoms should be adequately screened
to determine if they are at risk for bipolar disorder; such screening should include a detailed
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psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should
be noted that WELLBUTRIN is not approved for use in treating bipolar depression.
Bupropion-Containing Products: Patients should be made aware that WELLBUTRIN
contains the same active ingredient found in ZYBAN, used as an aid to smoking cessation
treatment, and that WELLBUTRIN should not be used in combination with ZYBAN, or any other
medications that contain bupropion, such as WELLBUTRIN SR (bupropion hydrochloride), the
sustained-release formulation or WELLBUTRIN XL (bupropion hydrochloride), the extended-
release formulation.
Seizures: Bupropion is associated with seizures in approximately 0.4% (4/1,000) of patients
treated at doses up to 450 mg/day. This incidence of seizures may exceed that of other
marketed antidepressants by as much as 4-fold. This relative risk is only an approximate
estimate because no direct comparative studies have been conducted. The estimated seizure
incidence for WELLBUTRIN increases almost tenfold between 450 and 600 mg/day, which is
twice the usually required daily dose (300 mg) and one and one-third the maximum
recommended daily dose (450 mg). Given the wide variability among individuals and their
capacity to metabolize and eliminate drugs this disproportionate increase in seizure incidence
with dose incrementation calls for caution in dosing.
During the initial development, 25 among approximately 2,400 patients treated with
WELLBUTRIN experienced seizures. At the time of seizure, 7 patients were receiving daily
doses of 450 mg or below for an incidence of 0.33% (3/1,000) within the recommended dose
range. Twelve patients experienced seizures at 600 mg/day (2.3% incidence); 6 additional
patients had seizures at daily doses between 600 and 900 mg (2.8% incidence).
A separate, prospective study was conducted to determine the incidence of seizure
during an 8-week treatment exposure in approximately 3,200 additional patients who
received daily doses of up to 450 mg. Patients were permitted to continue treatment beyond
8 weeks if clinically indicated. Eight seizures occurred during the initial 8-week treatment
period and 5 seizures were reported in patients continuing treatment beyond 8 weeks,
resulting in a total seizure incidence of 0.4%.
The risk of seizure appears to be strongly associated with dose. Sudden and large
increments in dose may contribute to increased risk. While many seizures occurred early in
the course of treatment, some seizures did occur after several weeks at fixed dose.
WELLBUTRIN should be discontinued and not restarted in patients who experience a
seizure while on treatment.
The risk of seizure is also related to patient factors, clinical situations, and
concomitant medications, which must be considered in selection of patients for therapy with
WELLBUTRIN.
• Patient factors: Predisposing factors that may increase the risk of seizure with
bupropion use include history of head trauma or prior seizure, central nervous system
(CNS) tumor, the presence of severe hepatic cirrhosis, and concomitant medications that
lower seizure threshold.
• Clinical situations: Circumstances associated with an increased seizure risk include,
among others, excessive use of alcohol or sedatives (including benzodiazepines); addiction
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to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; and
diabetes treated with oral hypoglycemics or insulin.
• Concomitant medications: Many medications (e.g., antipsychotics, antidepressants,
theophylline, systemic steroids) are known to lower seizure threshold.
Recommendations for Reducing the Risk of Seizure: Retrospective analysis of
clinical experience gained during the development of WELLBUTRIN suggests that the risk of
seizure may be minimized if
• the total daily dose of WELLBUTRIN does not exceed 450 mg,
• the daily dose is administered 3 times daily, with each single dose not to exceed 150 mg to
avoid high peak concentrations of bupropion and/or its metabolites, and
• the rate of incrementation of dose is very gradual.
WELLBUTRIN should be administered with extreme caution to patients with a
history of seizure, cranial trauma, or other predisposition(s) toward seizure, or patients
treated with other agents (e.g., antipsychotics, other antidepressants, theophylline, systemic
steroids, etc.) that lower seizure threshold.
Hepatic Impairment: WELLBUTRIN should be used with extreme caution in patients with
severe hepatic cirrhosis. In these patients a reduced dose and/or frequency is required, as
peak bupropion, as well as AUC, levels are substantially increased and accumulation is likely
to occur in such patients to a greater extent than usual. The dose should not exceed 75 mg
once a day in these patients (see CLINICAL PHARMACOLOGY, PRECAUTIONS, and
DOSAGE AND ADMINISTRATION).
Potential for Hepatotoxicity: In rats receiving large doses of bupropion chronically, there was
an increase in incidence of hepatic hyperplastic nodules and hepatocellular hypertrophy. In dogs
receiving large doses of bupropion chronically, various histologic changes were seen in the liver,
and laboratory tests suggesting mild hepatocellular injury were noted.
PRECAUTIONS
General: Agitation and Insomnia: A substantial proportion of patients treated with
WELLBUTRIN experience some degree of increased restlessness, agitation, anxiety, and insomnia,
especially shortly after initiation of treatment. In clinical studies, these symptoms were sometimes
of sufficient magnitude to require treatment with sedative/hypnotic drugs. In approximately 2% of
patients, symptoms were sufficiently severe to require discontinuation of treatment with
WELLBUTRIN.
Psychosis, Confusion, and Other Neuropsychiatric Phenomena: Depressed
patients treated with WELLBUTRIN have been reported to show a variety of neuropsychiatric
signs and symptoms including delusions, hallucinations, psychosis, concentration disturbance,
paranoia, and confusion. Because of the uncontrolled nature of many studies, it is impossible to
provide a precise estimate of the extent of risk imposed by treatment with WELLBUTRIN. In
several cases, neuropsychiatric phenomena abated upon dose reduction and/or withdrawal of
treatment.
Activation of Psychosis and/or Mania: Antidepressants can precipitate manic
episodes in bipolar disorder patients during the depressed phase of their illness and may activate
latent psychosis in other susceptible patients. WELLBUTRIN is expected to pose similar risks.
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Altered Appetite and Weight: A weight loss of greater than 5 lbs occurred in 28% of
patients receiving WELLBUTRIN. This incidence is approximately double that seen in comparable
patients treated with tricyclics or placebo. Furthermore, while 35% of patients receiving tricyclic
antidepressants gained weight, only 9.4% of patients treated with WELLBUTRIN did.
Consequently, if weight loss is a major presenting sign of a patient’s depressive illness, the
anorectic and/or weight reducing potential of WELLBUTRIN should be considered.
Allergic Reactions: Anaphylactoid/anaphylactic reactions characterized by symptoms
such as pruritus, urticaria, angioedema, and dyspnea requiring medical treatment have been
reported in clinical trials with bupropion. In addition, there have been rare spontaneous
postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock
associated with bupropion. A patient should stop taking WELLBUTRIN and consult a doctor if
experiencing allergic or anaphylactoid/anaphylactic reactions (e.g., skin rash, pruritus, hives, chest
pain, edema, and shortness of breath) during treatment.
Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed
hypersensitivity have been reported in association with bupropion. These symptoms may resemble
serum sickness.
Cardiovascular Effects: In clinical practice, hypertension, in some cases severe,
requiring acute treatment, has been reported in patients receiving bupropion alone and in
combination with nicotine replacement therapy. These events have been observed in both patients
with and without evidence of preexisting hypertension.
Data from a comparative study of the sustained-release formulation of bupropion (ZYBAN®
Sustained-Release Tablets), nicotine transdermal system (NTS), the combination of sustained-
release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence
of treatment-emergent hypertension in patients treated with the combination of sustained-release
bupropion and NTS. In this study, 6.1% of patients treated with the combination of sustained-
release bupropion and NTS had treatment-emergent hypertension compared to 2.5%, 1.6%, and
3.1% of patients treated with sustained-release bupropion, NTS, and placebo, respectively. The
majority of these patients had evidence of preexisting hypertension. Three patients (1.2%) treated
with the combination of ZYBAN and NTS and 1 patient (0.4%) treated with NTS had study
medication discontinued due to hypertension compared to none of the patients treated with ZYBAN
or placebo. Monitoring of blood pressure is recommended in patients who receive the combination
of bupropion and nicotine replacement.
There is no clinical experience establishing the safety of WELLBUTRIN in patients with a
recent history of myocardial infarction or unstable heart disease. Therefore, care should be
exercised if it is used in these groups. Bupropion was well tolerated in depressed patients who had
previously developed orthostatic hypotension while receiving tricyclic antidepressants and was also
generally well tolerated in a group of 36 depressed inpatients with stable congestive heart failure
(CHF). However, bupropion was associated with a rise in supine blood pressure in the study of
patients with CHF, resulting in discontinuation of treatment in 2 patients for exacerbation of
baseline hypertension.
Hepatic Impairment: WELLBUTRIN should be used with extreme caution in patients
with severe hepatic cirrhosis. In these patients, a reduced dose and frequency is required.
WELLBUTRIN should be used with caution in patients with hepatic impairment (including mild
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to-moderate hepatic cirrhosis) and a reduced frequency and/or dose should be considered in
patients with mild-to-moderate hepatic cirrhosis.
All patients with hepatic impairment should be closely monitored for possible adverse
effects that could indicate high drug and metabolite levels (see CLINICAL PHARMACOLOGY,
WARNINGS, and DOSAGE AND ADMINISTRATION).
Renal Impairment: There is limited information on the pharmacokinetics of bupropion in
patients with renal impairment. An inter-study comparison between normal subjects and patients
with end-stage renal failure demonstrated that the parent drug Cmax and AUC values were
comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites
had a 2.3- and 2.8-fold increase, respectively, in AUC for patients with end-stage renal failure. A
second study, comparing normal subjects and patients with moderate-to-severe renal impairment
(GFR 30.9 ± 10.8 mL/min) showed that exposure to a single 150-mg dose of sustained-release
bupropion was approximately 2-fold higher in patients with impaired renal function while levels of
the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the
2 groups. Bupropion is extensively metabolized in the liver to active metabolites, which are further
metabolized and subsequently excreted by the kidneys. WELLBUTRIN should be used with
caution in patients with renal impairment and a reduced frequency and/or dose should be
considered as bupropion and the metabolites of bupropion may accumulate in such patients to a
greater extent than usual. The patient should be closely monitored for possible adverse effects that
could indicate high drug or metabolite levels.
Information for Patients: Prescribers or other health professionals should inform patients, their
families, and their caregivers about the benefits and risks associated with treatment with
WELLBUTRIN and should counsel them in its appropriate use. A patient Medication Guide about
“Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts
or Actions,” “Quitting Smoking, Quit-Smoking Medication, Changes in Thinking and Behavior,
Depression, and Suicidal Thoughts or Actions,” and What Other Important Information Should I
Know About WELLBUTRIN ?” is available for WELLBUTRIN. The prescriber or health
professional should instruct patients, their families, and their caregivers to read the Medication
Guide and should assist them in understanding its contents. Patients should be given the
opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions
they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these
occur while taking WELLBUTRIN.
Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders: Patients,
their families, and their caregivers should be encouraged to be alert to the emergence of anxiety,
agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia
(psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of
depression, and suicidal ideation, especially early during antidepressant treatment and when the
dose is adjusted up or down. Families and caregivers of patients should be advised to look for the
emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms
should be reported to the patient’s prescriber or health professional, especially if they are severe,
abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these
may be associated with an increased risk for suicidal thinking and behavior and indicate a need for
very close monitoring and possibly changes in the medication.
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Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation
Treatment: Although WELLBUTRIN is not indicated for smoking cessation treatment, it contains
the same active ingredient as ZYBAN which is approved for this use. Patients should be informed
that quitting smoking, with or without ZYBAN, may be associated with nicotine withdrawal
symptoms (including depression or agitation), or exacerbation of pre-existing psychiatric illness.
Furthermore, some patients have experienced changes in mood (including depression and mania),
psychosis, hallucinations, paranoia, delusions, homicidal ideation aggression, anxiety, and panic, as
well as suicidal ideation, suicide attempt, and completed suicide when attempting to quit smoking
while taking ZYBAN. If patients develop agitation, hostility, depressed mood, or changes in
thinking or behavior that are not typical for them, or if patients develop suicidal ideation or
behavior, they should be urged to report these symptoms to their healthcare provider immediately.
Bupropion-Containing Products: Patients should be made aware that WELLBUTRIN
contains the same active ingredient found in ZYBAN, used as an aid to smoking cessation, and that
WELLBUTRIN should not be used in combination with ZYBAN or any other medications that
contain bupropion hydrochloride (such as WELLBUTRIN SR, the sustained-release formulation
and WELLBUTRIN XL, the extended-release formulation).
Patients should be instructed to take WELLBUTRIN in equally divided doses 3 or 4 times a
day to minimize the risk of seizure.
Patients should be told that WELLBUTRIN should be discontinued and not restarted if they
experience a seizure while on treatment.
Patients should be told that any CNS-active drug like WELLBUTRIN may impair their
ability to perform tasks requiring judgment or motor and cognitive skills. Consequently, until they
are reasonably certain that WELLBUTRIN does not adversely affect their performance, they
should refrain from driving an automobile or operating complex, hazardous machinery.
Patients should be told that the excessive use or abrupt discontinuation of alcohol or
sedatives (including benzodiazepines) may alter the seizure threshold. Some patients have reported
lower alcohol tolerance during treatment with WELLBUTRIN. Patients should be advised that the
consumption of alcohol should be minimized or avoided.
Patients should be advised to inform their physicians if they are taking or plan to take any
prescription or over-the-counter drugs. Concern is warranted because WELLBUTRIN and other
drugs may affect each other’s metabolism.
Patients should be advised to notify their physicians if they become pregnant or intend to
become pregnant during therapy.
Laboratory Tests: There are no specific laboratory tests recommended.
Drug Interactions: Few systemic data have been collected on the metabolism of bupropion
following concomitant administration with other drugs or, alternatively, the effect of concomitant
administration of bupropion on the metabolism of other drugs.
Because bupropion is extensively metabolized, the coadministration of other drugs may
affect its clinical activity. In vitro studies indicate that bupropion is primarily metabolized to
hydroxybupropion by the CYP2B6 isoenzyme. Therefore, the potential exists for a drug interaction
between WELLBUTRIN and drugs that are the substrates or inhibitors of the CYP2B6 isoenzyme
(e.g., orphenadrine, thiotepa, and cyclophosphamide). In addition, in vitro studies suggest that
paroxetine, sertraline, norfluoxetine, and fluvoxamine as well as nelfinavir, ritonavir, and efavirenz
inhibit the hydroxylation of bupropion. No clinical studies have been performed to evaluate this
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finding. The threohydrobupropion metabolite of bupropion does not appear to be produced by the
cytochrome P450 isoenzymes. The effects of concomitant administration of cimetidine on the
pharmacokinetics of bupropion and its active metabolites were studied in 24 healthy young male
volunteers. Following oral administration of two 150-mg sustained-release tablets with and without
800 mg of cimetidine, the pharmacokinetics of bupropion and hydroxybupropion were unaffected.
However, there were 16% and 32% increases in the AUC and Cmax, respectively, of the combined
moieties of threohydrobupropion and erythrohydrobupropion.
While not systematically studied, certain drugs may induce the metabolism of bupropion
(e.g., carbamazepine, phenobarbital, phenytoin).
Multiple oral doses of bupropion had no statistically significant effects on the single dose
pharmacokinetics of lamotrigine in 12 healthy volunteers.
Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in
humans. In one study, following chronic administration of bupropion, 100 mg 3 times daily to 8
healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism.
Nevertheless, there may be the potential for clinically important alterations of blood levels of
coadministered drugs.
Drugs Metabolized by Cytochrome P450IID6 (CYP2D6): Many drugs, including
most antidepressants (SSRIs, many tricyclics), beta-blockers, antiarrhythmics, and antipsychotics
are metabolized by the CYP2D6 isoenzyme. Although bupropion is not metabolized by this
isoenzyme, bupropion and hydroxybupropion are inhibitors of the CYP2D6 isoenzyme in vitro. In
a study of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of the CYP2D6
isoenzyme, daily doses of bupropion given as 150 mg twice daily followed by a single dose of
50 mg desipramine increased the Cmax, AUC, and t1/2 of desipramine by an average of
approximately 2-, 5- and 2-fold, respectively. The effect was present for at least 7 days after the last
dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6 has
not been formally studied.
Therefore, coadministration of bupropion with drugs that are metabolized by CYP2D6
isoenzyme including certain antidepressants (e.g., nortriptyline, imipramine, desipramine,
paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-
blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be
approached with caution and should be initiated at the lower end of the dose range of the
concomitant medication. If bupropion is added to the treatment regimen of a patient already
receiving a drug metabolized by CYP2D6, the need to decrease the dose of the original medication
should be considered, particularly for those concomitant medications with a narrow therapeutic
index.
MAO Inhibitors: Studies in animals demonstrate that the acute toxicity of bupropion is
enhanced by the MAO inhibitor phenelzine (see CONTRAINDICATIONS).
Levodopa and Amantadine: Limited clinical data suggest a higher incidence of adverse
experiences in patients receiving bupropion concurrently with either levodopa or amantadine.
Administration of WELLBUTRIN Tablets to patients receiving either levodopa or amantadine
concurrently should be undertaken with caution, using small initial doses and small gradual dose
increases.
Drugs that Lower Seizure Threshold: Concurrent administration of WELLBUTRIN
and agents (e.g., antipsychotics, other antidepressants, theophylline, systemic steroids, etc.) that
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lower seizure threshold should be undertaken only with extreme caution (see WARNINGS). Low
initial dosing and small gradual dose increases should be employed.
Nicotine Transdermal System: (see PRECAUTIONS: Cardiovascular Effects).
Alcohol: In postmarketing experience, there have been rare reports of adverse
neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol during
treatment with WELLBUTRIN. The consumption of alcohol during treatment with WELLBUTRIN
should be minimized or avoided (also see CONTRAINDICATIONS).
Carcinogenesis, Mutagenesis, Impairment of Fertility: Lifetime carcinogenicity studies
were performed in rats and mice at doses up to 300 and 150 mg/kg/day, respectively. In the rat
study there was an increase in nodular proliferative lesions of the liver at doses of 100 to
300 mg/kg/day; lower doses were not tested. The question of whether or not such lesions may be
precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen in
the mouse study, and no increase in malignant tumors of the liver and other organs was seen in
either study.
Bupropion produced a borderline positive response (2 to 3 times control mutation rate) in
some strains in the Ames bacterial mutagenicity test, and a high oral dose (300 mg/kg, but not 100
or 200 mg/kg) produced a low incidence of chromosomal aberrations in rats. The relevance of these
results in estimating the risk of human exposure to therapeutic doses is unknown.
A fertility study was performed in rats; no evidence of impairment of fertility was
encountered at oral doses up to 300 mg/kg/day.
Pregnancy: Teratogenic Effects: Pregnancy Category C. In studies conducted in rats and
rabbits, bupropion was administered orally at doses up to 450 and 150 mg/kg/day, respectively
(approximately 11 and 7 times the MRHD, respectively, on a mg/m2 basis), during the period of
organogenesis. No clear evidence of teratogenic activity was found in either species; however, in
rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed
at the lowest dose tested (25 mg/kg/day, approximately equal to the MRHD on a mg/m2 basis) and
greater. Decreased fetal weights were seen at 50 mg/kg and greater.
When rats were administered bupropion at oral doses of up to 300 mg/kg/day
(approximately 7 times the MRHD on a mg/m2 basis) prior to mating and throughout pregnancy
and lactation, there were no apparent adverse effects on offspring development.
One study has been conducted in pregnant women. This retrospective, managed-care
database study assessed the risk of congenital malformations overall and cardiovascular
malformations specifically, following exposure to bupropion in the first trimester compared to the
risk of these malformations following exposure to other antidepressants in the first trimester and
bupropion outside of the first trimester. This study included 7,005 infants with antidepressant
exposure during pregnancy, 1,213 of whom were exposed to bupropion in the first trimester. The
study showed no greater risk for congenital malformations overall or cardiovascular malformations
specifically, following first trimester bupropion exposure compared to exposure to all other
antidepressants in the first trimester, or bupropion outside of the first trimester. The results of this
study have not been corroborated. WELLBUTRIN should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Labor and Delivery: The effect of WELLBUTRIN on labor and delivery in humans is unknown.
Nursing Mothers: Like many other drugs, bupropion and its metabolites are secreted in human
milk. Because of the potential for serious adverse reactions in nursing infants from
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WELLBUTRIN, a decision should be made whether to discontinue nursing or to discontinue the
drug, taking into account the importance of the drug to the mother.
Pediatric Use: Safety and effectiveness in the pediatric population have not been established (see
BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk in Treating Psychiatric
Disorders). Anyone considering the use of WELLBUTRIN in a child or adolescent must balance
the potential risks with the clinical need.
Geriatric Use: Of the approximately 6,000 patients who participated in clinical trials with
bupropion sustained-release tablets (depression and smoking cessation studies), 275 were 65 and
over and 47 were 75 and over. In addition, several hundred patients 65 and over participated in
clinical trials using the immediate-release formulation of bupropion (depression studies). No
overall differences in safety or effectiveness were observed between these subjects and younger
subjects, and other reported clinical experience has not identified differences in responses between
the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled
out.
A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its
metabolites in elderly subjects was similar to that of younger subjects; however, another
pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased risk
for accumulation of bupropion and its metabolites (see CLINICAL PHARMACOLOGY).
Bupropion is extensively metabolized in the liver to active metabolites, which are further
metabolized and excreted by the kidneys. The risk of toxic reaction to this drug may be greater in
patients with impaired renal function. Because elderly patients are more likely to have decreased
renal function, care should be taken in dose selection, and it may be useful to monitor renal
function (see PRECAUTIONS: Renal Impairment and DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS (See also WARNINGS and PRECAUTIONS.)
Adverse events commonly encountered in patients treated with WELLBUTRIN are
agitation, dry mouth, insomnia, headache/migraine, nausea/vomiting, constipation, and tremor.
Adverse events were sufficiently troublesome to cause discontinuation of treatment with
WELLBUTRIN in approximately 10% of the 2,400 patients and volunteers who participated in
clinical trials during the product’s initial development. The more common events causing
discontinuation include neuropsychiatric disturbances (3.0%), primarily agitation and abnormalities
in mental status; gastrointestinal disturbances (2.1%), primarily nausea and vomiting; neurological
disturbances (1.7%), primarily seizures, headaches, and sleep disturbances; and dermatologic
problems (1.4%), primarily rashes. It is important to note, however, that many of these events
occurred at doses that exceed the recommended daily dose.
Accurate estimates of the incidence of adverse events associated with the use of any drug
are difficult to obtain. Estimates are influenced by drug dose, detection technique, setting,
physician judgments, etc. Consequently, Table 2 is presented solely to indicate the relative
frequency of adverse events reported in representative controlled clinical studies conducted to
evaluate the safety and efficacy of WELLBUTRIN under relatively similar conditions of daily
dosage (300 to 600 mg), setting, and duration (3 to 4 weeks). The figures cited cannot be used to
predict precisely the incidence of untoward events in the course of usual medical practice where
patient characteristics and other factors must differ from those which prevailed in the clinical trials.
These incidence figures also cannot be compared with those obtained from other clinical studies
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involving related drug products as each group of drug trials is conducted under a different set of
conditions.
Finally, it is important to emphasize that the tabulation does not reflect the relative severity
and/or clinical importance of the events. A better perspective on the serious adverse events
associated with the use of WELLBUTRIN is provided in WARNINGS and PRECAUTIONS.
Table 2. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical
Trialsa (Percent of Patients Reporting)
Adverse Experience
WELLBUTRIN Patients
(n = 323)
Placebo Patients
(n = 185)
Cardiovascular
Cardiac arrhythmias
5.3
4.3
Dizziness
22.3
16.2
Hypertension
4.3
1.6
Hypotension
2.5
2.2
Palpitations
3.7
2.2
Syncope
1.2
0.5
Tachycardia
10.8
8.6
Dermatologic
Pruritus
Rash
2.2
8.0
0.0
6.5
Gastrointestinal
Anorexia
18.3
18.4
Appetite increase
3.7
2.2
Constipation
26.0
17.3
Diarrhea
6.8
8.6
Dyspepsia
3.1
2.2
Nausea/vomiting
22.9
18.9
Weight gain
13.6
22.7
Weight loss
23.2
23.2
Genitourinary
Impotence
3.4
3.1
Menstrual complaints
4.7
1.1
Urinary frequency
2.5
2.2
Urinary retention
1.9
2.2
Musculoskeletal
Arthritis
3.1
2.7
Neurological
Akathisia
1.5
1.1
Akinesia/bradykinesia
8.0
8.6
Cutaneous temperature
1.9
1.6
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disturbance
Dry mouth
27.6
18.4
Excessive sweating
22.3
14.6
Headache/migraine
25.7
22.2
Impaired sleep quality
4.0
1.6
Increased salivary flow
3.4
3.8
Insomnia
18.6
15.7
Muscle spasms
1.9
3.2
Pseudoparkinsonism
1.5
1.6
Sedation
19.8
19.5
Sensory disturbance
4.0
3.2
Tremor
21.1
7.6
Neuropsychiatric
Agitation
31.9
22.2
Anxiety
3.1
1.1
Confusion
8.4
4.9
Decreased libido
3.1
1.6
Delusions
1.2
1.1
Disturbed concentration
3.1
3.8
Euphoria
1.2
0.5
Hostility
5.6
3.8
Nonspecific
Fatigue
Fever/chills
5.0
1.2
8.6
0.5
Respiratory
Upper respiratory complaints
5.0
11.4
Special Senses
Auditory disturbance
5.3
3.2
Blurred vision
14.6
10.3
Gustatory disturbance
3.1
1.1
a Events reported by at least 1% of patients receiving WELLBUTRIN are included.
Other Events Observed During the Development of WELLBUTRIN: The conditions and
duration of exposure to WELLBUTRIN varied greatly, and a substantial proportion of the
experience was gained in open and uncontrolled clinical settings. During this experience, numerous
adverse events were reported; however, without appropriate controls, it is impossible to determine
with certainty which events were or were not caused by WELLBUTRIN. The following
enumeration is organized by organ system and describes events in terms of their relative frequency
of reporting in the data base. Events of major clinical importance are also described in
WARNINGS and PRECAUTIONS.
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The following definitions of frequency are used: Frequent adverse events are defined as
those occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to
1/1,000 patients, while rare events are those occurring in less than 1/1,000 patients.
Cardiovascular: Frequent was edema; infrequent were chest pain, electrocardiogram
(ECG) abnormalities (premature beats and nonspecific ST-T changes), and shortness of
breath/dyspnea; rare were flushing, pallor, phlebitis, and myocardial infarction.
Dermatologic: Frequent were nonspecific rashes; infrequent were alopecia and dry skin;
rare were change in hair color, hirsutism, and acne.
Endocrine: Infrequent was gynecomastia; rare were glycosuria and hormone level change.
Gastrointestinal: Infrequent were dysphagia, thirst disturbance, and liver
damage/jaundice; rare were rectal complaints, colitis, gastrointestinal bleeding, intestinal
perforation, and stomach ulcer.
Genitourinary: Frequent was nocturia; infrequent were vaginal irritation, testicular
swelling, urinary tract infection, painful erection, and retarded ejaculation; rare were dysuria,
enuresis, urinary incontinence, menopause, ovarian disorder, pelvic infection, cystitis, dyspareunia,
and painful ejaculation.
Hematologic/Oncologic: Rare were lymphadenopathy, anemia, and pancytopenia.
Musculoskeletal: Rare was musculoskeletal chest pain.
Neurological: (see WARNINGS) Frequent were ataxia/incoordination, seizure,
myoclonus, dyskinesia, and dystonia; infrequent were mydriasis, vertigo, and dysarthria; rare were
electroencephalogram (EEG) abnormality, abnormal neurological exam, impaired attention,
sciatica, and aphasia.
Neuropsychiatric: (see PRECAUTIONS) Frequent were mania/hypomania, increased
libido, hallucinations, decrease in sexual function, and depression; infrequent were memory
impairment, depersonalization, psychosis, dysphoria, mood instability, paranoia, formal thought
disorder, and frigidity; rare was suicidal ideation.
Oral Complaints: Frequent was stomatitis; infrequent were toothache, bruxism, gum
irritation, and oral edema; rare was glossitis.
Respiratory: Infrequent were bronchitis and shortness of breath/dyspnea; rare were
epistaxis, rate or rhythm disorder, pneumonia, and pulmonary embolism.
Special Senses: Infrequent was visual disturbance; rare was diplopia.
Nonspecific: Frequent were flu-like symptoms; infrequent was nonspecific pain; rare
were body odor, surgically related pain, infection, medication reaction, and overdose.
Postintroduction Reports: Voluntary reports of adverse events temporally associated with
bupropion that have been received since market introduction and which may have no causal
relationship with the drug include the following:
Body (General): arthralgia, myalgia, and fever with rash and other symptoms suggestive
of delayed hypersensitivity. These symptoms may resemble serum sickness (see PRECAUTIONS).
Cardiovascular: hypertension (in some cases severe, see PRECAUTIONS), orthostatic
hypotension, third degree heart block
Endocrine: syndrome of inappropriate antidiuretic hormone secretion, hyperglycemia,
hypoglycemia
Gastrointestinal: esophagitis, hepatitis, liver damage
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Hemic and Lymphatic: ecchymosis, leukocytosis, leukopenia, thrombocytopenia.
Altered PT and/or INR, infrequently associated with hemorrhagic or thrombotic complications,
were observed when bupropion was coadministered with warfarin.
Musculoskeletal: arthralgia, myalgia, muscle rigidity/fever/rhabdomyolysis, muscle
weakness
Nervous: aggression, coma, completed suicide, delirium, dream abnormalities, paranoid
ideation, paresthesia, restlessness, suicide attempt, unmasking of tardive dyskinesia
Skin and Appendages: Stevens-Johnson syndrome, angioedema, exfoliative dermatitis,
urticaria
Special Senses: tinnitus, increased intraocular pressure
DRUG ABUSE AND DEPENDENCE
Humans: Controlled clinical studies conducted in normal volunteers, in subjects with a history of
multiple drug abuse, and in depressed patients showed some increase in motor activity and
agitation/excitement.
In a population of individuals experienced with drugs of abuse, a single dose of 400 mg of
WELLBUTRIN produced mild amphetamine-like activity as compared to placebo on the
Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI) and a score
intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These scales
measure general feelings of euphoria and drug desirability.
Findings in clinical trials, however, are not known to predict the abuse potential of drugs
reliably. Nonetheless, evidence from single-dose studies does suggest that the recommended daily
dosage of bupropion when administered in divided doses is not likely to be especially reinforcing to
amphetamine or stimulant abusers. However, higher doses that could not be tested because of the
risk of seizure might be modestly attractive to those who abuse stimulant drugs.
Animals: Studies in rodents have shown that bupropion exhibits some pharmacologic actions
common to psychostimulants including increases in locomotor activity and the production of a mild
stereotyped behavior and increases in rates of responding in several schedule-controlled behavior
paradigms. Drug discrimination studies in rats showed stimulus generalization between bupropion
and amphetamine and other psychostimulants. Rhesus monkeys have been shown to self-administer
bupropion intravenously.
OVERDOSAGE
Human Overdose Experience: Overdoses of up to 30 g or more of bupropion have been
reported. Seizure was reported in approximately one-third of all cases. Other serious reactions
reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus
tachycardia, and ECG changes such as conduction disturbances (including QRS prolongation) or
arrhythmias. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory
failure have been reported mainly when bupropion was part of multiple drug overdoses.
Although most patients recovered without sequelae, deaths associated with overdoses of
bupropion alone have been reported in patients ingesting large doses of the drug. Multiple
uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported in
these patients.
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Overdosage Management: Ensure an adequate airway, oxygenation, and ventilation. Monitor
cardiac rhythm and vital signs. EEG monitoring is also recommended for the first 48 hours
post-ingestion. General supportive and symptomatic measures are also recommended. Induction of
emesis is not recommended.
Activated charcoal should be administered. There is no experience with the use of forced
diuresis, dialysis, hemoperfusion, or exchange transfusion in the management of bupropion
overdoses. No specific antidotes for bupropion are known.
Due to the dose-related risk of seizures with WELLBUTRIN, hospitalization following
suspected overdose should be considered. Based on studies in animals, it is recommended that
seizures be treated with intravenous benzodiazepine administration and other supportive measures,
as appropriate.
In managing overdosage, consider the possibility of multiple drug involvement. The
physician should consider contacting a poison control center for additional information on the
treatment of any overdose. Telephone numbers for certified poison control centers are listed in the
Physicians’ Desk Reference (PDR).
DOSAGE AND ADMINISTRATION
General Dosing Considerations: It is particularly important to administer WELLBUTRIN in
a manner most likely to minimize the risk of seizure (see WARNINGS). Increases in dose should
not exceed 100 mg/day in a 3-day period. Gradual escalation in dosage is also important if
agitation, motor restlessness, and insomnia, often seen during the initial days of treatment, are to be
minimized. If necessary, these effects may be managed by temporary reduction of dose or the
short-term administration of an intermediate to long-acting sedative hypnotic. A sedative hypnotic
usually is not required beyond the first week of treatment. Insomnia may also be minimized by
avoiding bedtime doses. If distressing, untoward effects supervene, dose escalation should be
stopped.
No single dose of WELLBUTRIN should exceed 150 mg. WELLBUTRIN should be
administered 3 times daily, preferably with at least 6 hours between successive doses.
Usual Dosage for Adults: The usual adult dose is 300 mg/day, given 3 times daily. Dosing
should begin at 200 mg/day, given as 100 mg twice daily. Based on clinical response, this dose may
be increased to 300 mg/day, given as 100 mg 3 times daily, no sooner than 3 days after beginning
therapy (see Table 3).
Table 3. Dosing Regimen
Treatment Day
Total Daily Dose
Tablet Strength
Number of Tablets
Morning Midday
Evening
1
4
200 mg
300 mg
100 mg
100 mg
1
1
0
1
1
1
Increasing the Dosage Above 300 mg/Day: As with other antidepressants, the full
antidepressant effect of WELLBUTRIN may not be evident until 4 weeks of treatment or longer.
An increase in dosage, up to a maximum of 450 mg/day, given in divided doses of not more than
150 mg each, may be considered for patients in whom no clinical improvement is noted after
several weeks of treatment at 300 mg/day. Dosing above 300 mg/day may be accomplished using
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the 75- or 100-mg tablets. The 100-mg tablet must be administered 4 times daily with at least
4 hours between successive doses, in order not to exceed the limit of 150 mg in a single dose.
WELLBUTRIN should be discontinued in patients who do not demonstrate an adequate response
after an appropriate period of treatment at 450 mg/day.
Maintenance Treatment: The lowest dose that maintains remission is recommended. Although
it is not known how long the patient should remain on WELLBUTRIN, it is generally recognized
that acute episodes of depression require several months or longer of antidepressant drug treatment.
Dosage Adjustment for Patients with Impaired Hepatic Function: WELLBUTRIN
should be used with extreme caution in patients with severe hepatic cirrhosis. The dose should not
exceed 75 mg once a day in these patients. WELLBUTRIN should be used with caution in patients
with hepatic impairment (including mild-to-moderate hepatic cirrhosis) and a reduced frequency
and/or dose should be considered in patients with mild-to-moderate hepatic cirrhosis (see
CLINICAL PHARMACOLOGY, WARNINGS, and PRECAUTIONS).
Dosage Adjustment for Patients with Impaired Renal Function: WELLBUTRIN should
be used with caution in patients with renal impairment and a reduced frequency and/or dose should
be considered (see CLINICAL PHARMACOLOGY and PRECAUTIONS).
HOW SUPPLIED
WELLBUTRIN Tablets, 75 mg of bupropion hydrochloride, are yellow-gold, round,
biconvex tablets printed with “WELLBUTRIN 75” in bottles of 100 (NDC 0173-0177-55).
WELLBUTRIN Tablets, 100 mg of bupropion hydrochloride, are red, round, biconvex
tablets printed with “WELLBUTRIN 100” in bottles of 100 (NDC 0173-0178-55).
Store at 15° to 25°C (59° to 77°F). Protect from light and moisture.
MEDICATION GUIDE
WELLBUTRIN® (WELL byu-trin)
(bupropion hydrochloride) Tablets
Read this Medication Guide carefully before you start using WELLBUTRIN and each time you get
a refill. There may be new information. This information does not take the place of talking with
your doctor about your medical condition or your treatment. If you have any questions about
WELLBUTRIN, ask your doctor or pharmacist.
IMPORTANT: Be sure to read the three sections of this Medication Guide. The first section
is about the risk of suicidal thoughts and actions with antidepressant medicines; the second
section is about the risk of changes in thinking and behavior, depression and suicidal
thoughts or actions with medicines used to quit smoking; and the third section is entitled
“What Other Important Information Should I Know About WELLBUTRIN?”
Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and
Suicidal Thoughts or Actions
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This section of the Medication Guide is only about the risk of suicidal thoughts and
actions with antidepressant medicines. Talk to your, or your family member’s,
healthcare provider about:
• all risks and benefits of treatment with antidepressant medicines
• all treatment choices for depression or other serious mental illness
What is the most important information I should know about antidepressant medicines,
depression and other serious mental illnesses, and suicidal thoughts or actions?
1. Antidepressant medicines may increase suicidal thoughts or actions in some children,
teenagers, and young adults within the first few months of treatment.
2. Depression and other serious mental illnesses are the most important causes of suicidal
thoughts and actions. Some people may have a particularly high risk of having suicidal
thoughts or actions. These include people who have (or have a family history of) bipolar
illness (also called manic-depressive illness) or suicidal thoughts or actions.
3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family
member?
• Pay close attention to any changes, especially sudden changes, in mood, behaviors,
thoughts, or feelings. This is very important when an antidepressant medicine is started or
when the dose is changed.
• Call the healthcare provider right away to report new or sudden changes in mood, behavior,
thoughts, or feelings.
• Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare
provider between visits as needed, especially if you have concerns about symptoms.
Call a healthcare provider right away if you or your family member has any of the following
symptoms, especially if they are new, worse, or worry you:
• thoughts about suicide or dying
• trouble sleeping (insomnia)
• attempts to commit suicide
• new or worse irritability
• new or worse depression
• acting aggressive, being angry, or violent
• new or worse anxiety
• acting on dangerous impulses
• feeling very agitated or restless
• an extreme increase in activity and talking (mania)
• panic attacks
• other unusual changes in behavior or mood
What else do I need to know about antidepressant medicines?
• Never stop an antidepressant medicine without first talking to a healthcare provider.
Stopping an antidepressant medicine suddenly can cause other symptoms.
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• Antidepressants are medicines used to treat depression and other illnesses. It is important
to discuss all the risks of treating depression and also the risks of not treating it. Patients and
their families or other caregivers should discuss all treatment choices with the healthcare
provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects. Talk to the healthcare provider about the
side effects of the medicine prescribed for you or your family member.
• Antidepressant medicines can interact with other medicines. Know all of the medicines that
you or your family member takes. Keep a list of all medicines to show the healthcare provider.
Do not start new medicines without first checking with your healthcare provider.
• Not all antidepressant medicines prescribed for children are FDA approved for use in
children. Talk to your child’s healthcare provider for more information.
WELLBUTRIN has not been studied in children under the age of 18 and is not approved for use in
children and teenagers.
Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior,
Depression, and Suicidal Thoughts or Actions
This section of the Medication Guide is only about the risk of changes in thinking and
behavior, depression and suicidal thoughts or actions with drugs used to quit smoking.
Although WELLBUTRIN is not a treatment for quitting smoking, it contains the same active
ingredient (bupropion hydrochloride) as ZYBAN® which is used to help patients quit smoking.
Some people have had changes in behavior, hostility, agitation, depression, suicidal thoughts or
actions while taking bupropion to help them quit smoking. These symptoms can develop during
treatment with bupropion or after stopping treatment with bupropion.
If you, your family member, or your caregiver notice agitation, hostility, depression, or
changes in thinking or behavior that are not typical for you, or you have any of the
following symptoms, stop taking bupropion and call your healthcare provider right away:
• thoughts about suicide or dying
• an extreme increase in activity and talking (mania)
• attempts to commit suicide
• abnormal thoughts or sensations
• new or worse depression
• seeing or hearing things that are not there
• new or worse anxiety
(hallucinations)
• panic attacks
• feeling people are against you (paranoia)
• feeling very agitated or restless
• feeling confused
• acting aggressive, being angry, or violent
• other unusual changes in behavior or mood
• acting on dangerous impulses
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When you try to quit smoking, with or without bupropion, you may have symptoms that may be
due to nicotine withdrawal, including urge to smoke, depressed mood, trouble sleeping, irritability,
frustration, anger, feeling anxious, difficulty concentrating, restlessness, decreased heart rate, and
increased appetite or weight gain. Some people have even experienced suicidal thoughts when
trying to quit smoking without medication. Sometimes quitting smoking can lead to worsening of
mental health problems that you already have, such as depression.
Before taking bupropion, tell your healthcare provider if you have ever had depression or
other mental illnesses. You should also tell your doctor about any symptoms you had
during other times you tried to quit smoking, with or without bupropion.
What Other Important Information Should I Know About WELLBUTRIN?
Seizures: There is a chance of having a seizure (convulsion, fit) with WELLBUTRIN,
especially in people:
• with certain medical problems.
• who take certain medicines.
The chance of having seizures increases with higher doses of WELLBUTRIN. For more
information, see the sections “Who should not take WELLBUTRIN?” and “What should I tell
my doctor before using WELLBUTRIN?” Tell your doctor about all of your medical conditions
and all the medicines you take. Do not take any other medicines while you are using
WELLBUTRIN unless your doctor has said it is okay to take them.
If you have a seizure while taking WELLBUTRIN, stop taking the tablets and call your
doctor right away. Do not take WELLBUTRIN again if you have a seizure.
• High blood pressure (hypertension). Some people get high blood pressure, that can be
severe, while taking WELLBUTRIN. The chance of high blood pressure may be higher if you
also use nicotine replacement therapy (such as a nicotine patch) to help you stop smoking.
• Severe allergic reactions. Some people have severe allergic reaction to WELLBUTRIN.
Stop taking WELLBUTRIN and call your doctor right away if you get a rash, itching,
hives, fever, swollen lymph glands, painful sores in the mouth or around the eyes, swelling of
the lips or tongue, chest pain, or have trouble breathing. These could be signs of a serious
allergic reaction.
• Unusual thoughts or behaviors. Some patients have unusual thoughts or behaviors while
taking WELLBUTRIN, including delusions (believe you are someone else), hallucinations
(seeing or hearing things that are not there), paranoia (feeling that people are against you), or
feeling confused. If this happens to you, call your doctor.
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What is WELLBUTRIN?
WELLBUTRIN is a prescription medicine used to treat adults with a certain type of depression
called major depressive disorder.
Who should not take WELLBUTRIN?
Do not take WELLBUTRIN if you
• have or had a seizure disorder or epilepsy.
• are taking ZYBAN (used to help people stop smoking) or any other medicines that contain
bupropion hydrochloride, such as WELLBUTRIN SR Sustained-Release Tablets or
WELLBUTRIN XL Extended-Release Tablets. Bupropion is the same ingredient that is in
WELLBUTRIN.
• drink a lot of alcohol and abruptly stop drinking, or use medicines called sedatives (these make
you sleepy) or benzodiazepines and you stop using them all of a sudden.
• have taken within the last 14 days medicine for depression called a monoamine oxidase
inhibitor (MAOI), such as NARDIL®* (phenelzine sulfate), PARNATE® (tranylcypromine
sulfate), or MARPLAN®* (isocarboxazid).
• have or had an eating disorder such as anorexia nervosa or bulimia.
• are allergic to the active ingredient in WELLBUTRIN, bupropion, or to any of the inactive
ingredients. See the end of this leaflet for a complete list of ingredients in WELLBUTRIN.
What should I tell my doctor before using WELLBUTRIN?
Tell your doctor if you have ever had depression, suicidal thoughts or actions, or other mental
health problems. See “Antidepressant Medicines, Depression and Other Serious Mental Illnesses,
and Suicidal Thoughts or Actions.”
• Tell your doctor about your other medical conditions including if you:
• are pregnant or plan to become pregnant. It is not known if WELLBUTRIN can harm
your unborn baby.
• are breastfeeding. WELLBUTRIN passes through your milk. It is not known if
WELLBUTRIN can harm your baby.
• have liver problems, especially cirrhosis of the liver.
• have kidney problems.
• have an eating disorder, such as anorexia nervosa or bulimia.
• have had a head injury.
• have had a seizure (convulsion, fit).
• have a tumor in your nervous system (brain or spine).
• have had a heart attack, heart problems, or high blood pressure.
• are a diabetic taking insulin or other medicines to control your blood sugar.
• drink a lot of alcohol.
NDA 18-644/S-039
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Page 30
• abuse prescription medicines or street drugs.
• Tell your doctor about all the medicines you take, including prescription and non
prescription medicines, vitamins, and herbal supplements. Many medicines increase your
chances of having seizures or other serious side effects if you take them while you are using
WELLBUTRIN.
How should I take WELLBUTRIN?
• Take WELLBUTRIN exactly as prescribed by your doctor.
• Take WELLBUTRIN at the same time each day.
• Take your doses of WELLBUTRIN at least 6 hours apart.
• You may take WELLBUTRIN with or without food.
• If you miss a dose, do not take an extra tablet to make up for the dose you forgot. Wait and take
your next tablet at the regular time. This is very important. Too much WELLBUTRIN can
increase your chance of having a seizure.
• If you take too much WELLBUTRIN, or overdose, call your local emergency room or poison
control center right away.
• Do not take any other medicines while using WELLBUTRIN unless your doctor has told
you it is okay.
• It may take several weeks for you to feel that WELLBUTRIN is working. Once you feel better,
it is important to keep taking WELLBUTRIN exactly as directed by your doctor. Call your
doctor if you do not feel WELLBUTRIN is working for you.
• Do not change your dose or stop taking WELLBUTRIN without talking with your doctor first.
What should I avoid while taking WELLBUTRIN?
• Do not drink a lot of alcohol while taking WELLBUTRIN. If you usually drink a lot of alcohol,
talk with your doctor before suddenly stopping. If you suddenly stop drinking alcohol, you may
increase your risk of having seizures.
• Do not drive a car or use heavy machinery until you know how WELLBUTRIN affects you.
WELLBUTRIN can impair your ability to perform these tasks.
What are possible side effects of WELLBUTRIN?
WELLBUTRIN can cause serious side effects. Read this entire Medication Guide for more
information about these serious side effects.
The most common side effects of WELLBUTRIN are nervousness, constipation, trouble sleeping,
dry mouth, headache, nausea, vomiting, and shakiness (tremor).
If you have nausea, take your medicine with food. If you have trouble sleeping, do not take your
medicine too close to bedtime.
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These are not all the side effects of WELLBUTRIN. For a complete list, ask your doctor or
pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at
1-800-FDA-1088.
How should I store WELLBUTRIN?
• Store WELLBUTRIN at room temperature. Store out of direct sunlight. Keep WELLBUTRIN
in its tightly closed bottle.
General Information about WELLBUTRIN.
• Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use WELLBUTRIN for a condition for which it was not prescribed. Do not give
WELLBUTRIN to other people, even if they have the same symptoms you have. It may harm
them. Keep WELLBUTRIN out of the reach of children.
This Medication Guide summarizes important information about WELLBUTRIN. For more
information, talk to your doctor. You can ask your doctor or pharmacist for information about
WELLBUTRIN that is written for health professionals.
What are the ingredients in WELLBUTRIN?
Active ingredient: bupropion hydrochloride.
Inactive ingredients: 75-mg tablet – D&C Yellow No. 10 Lake, FD&C Yellow No. 6 Lake,
hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and
titanium dioxide; 100-mg tablet – FD&C Red No. 40 Lake, FD&C Yellow No. 6 Lake,
hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and
titanium dioxide.
WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and PARNATE are registered
trademarks of GlaxoSmithKline.
*The following are registered trademarks of their respective manufacturers: NARDIL®/Warner
Lambert Company; MARPLAN®/Oxford Pharmaceutical Services, Inc. Rx Only
This Medication Guide has been approved by the U.S. Food and Drug Administration.
June 2009
WLT:5MG GSK logo
NDA 18-644/S-039
NDA 18-644/S-040
NDA 20-358/S-046
NDA 20-358/S-047
Page 32
Distributed by:
GlaxoSmithKline
Research Triangle Park, NC 27709
Manufactured by DSM Pharmaceuticals, Inc.
Greenville, NC 27834 for
GlaxoSmithKline
Research Triangle Park, NC 27709
©2009, GlaxoSmithKline. All rights reserved.
June 2009
WLT:4PI
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custom-source
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018644s039s040.pdf', 'application_number': 18644, 'submission_type': 'SUPPL ', 'submission_number': 39}
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PRESCRIBING INFORMATION
WELLBUTRIN®
(bupropion hydrochloride)
Tablets
WARNING
Suicidality and Antidepressant Drugs
Use in Treating Psychiatric Disorders: Antidepressants increased the risk compared to
placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults
in short-term studies of major depressive disorder (MDD) and other psychiatric disorders.
Anyone considering the use of WELLBUTRIN or any other antidepressant in a child, adolescent,
or young adult must balance this risk with the clinical need. Short-term studies did not show an
increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age
24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and
older. Depression and certain other psychiatric disorders are themselves associated with
increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy
should be monitored appropriately and observed closely for clinical worsening, suicidality, or
unusual changes in behavior. Families and caregivers should be advised of the need for close
observation and communication with the prescriber. WELLBUTRIN is not approved for use in
pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk in Treating
Psychiatric Disorders, PRECAUTIONS: Information for Patients, and PRECAUTIONS:
Pediatric Use.)
Use in Smoking Cessation Treatment: WELLBUTRIN®, WELLBUTRIN SR®, and
WELLBUTRIN XL® are not approved for smoking cessation treatment, but bupropion under the
name ZYBAN® is approved for this use. Serious neuropsychiatric events, including but not
limited to depression, suicidal ideation, suicide attempt, and completed suicide have been
reported in patients taking bupropion for smoking cessation. Some cases may have been
complicated by the symptoms of nicotine withdrawal in patients who stopped smoking.
Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including
suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without
medication. However, some of these symptoms have occurred in patients taking bupropion who
continued to smoke.
All patients being treated with bupropion for smoking cessation treatment should be observed
for neuropsychiatric symptoms including changes in behavior, hostility, agitation, depressed
mood, and suicide-related events, including ideation, behavior, and attempted suicide. These
symptoms, as well as worsening of pre-existing psychiatric illness and completed suicide have
been reported in some patients attempting to quit smoking while taking ZYBAN in the
postmarketing experience. When symptoms were reported, most were during treatment with
ZYBAN, but some were following discontinuation of treatment with ZYBAN. These events have
occurred in patients with and without pre-existing psychiatric disease; some have experienced
1
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41
worsening of their psychiatric illnesses. Patients with serious psychiatric illness such as
42
schizophrenia, bipolar disorder, and major depressive disorder did not participate in the
43
premarketing studies of ZYBAN.
44
Advise patients and caregivers that the patient using bupropion for smoking cessation
45
should stop taking bupropion and contact a healthcare provider immediately if agitation,
46
hostility, depressed mood, or changes in thinking or behavior that are not typical for the
47
patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In
48
many postmarketing cases, resolution of symptoms after discontinuation of ZYBAN was
49
reported, although in some cases the symptoms persisted; therefore, ongoing monitoring and
50
supportive care should be provided until symptoms resolve.
51
The risks of using bupropion for smoking cessation should be weighed against the benefits of
52
its use. ZYBAN has been demonstrated to increase the likelihood of abstinence from smoking
53
for as long as 6 months compared to treatment with placebo. The health benefits of quitting
54
smoking are immediate and substantial. (See WARNINGS: Neuropsychiatric Symptoms and
55
Suicide Risk in Smoking Cessation Treatment and PRECAUTIONS: Information for Patients.)
56
DESCRIPTION
57
WELLBUTRIN (bupropion hydrochloride), an antidepressant of the aminoketone class, is
58
chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other
59
known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related
60
to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1
61
propanone hydrochloride. The molecular weight is 276.2. The empirical formula is
62
C13H18ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in
63
water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The
64
structural formula is:
65 structural formula
66
67
WELLBUTRIN is supplied for oral administration as 75-mg (yellow-gold) and 100-mg (red)
68
film-coated tablets. Each tablet contains the labeled amount of bupropion hydrochloride and the
69
inactive ingredients: 75-mg tablet – D&C Yellow No. 10 Lake, FD&C Yellow No. 6 Lake,
70
hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and
71
titanium dioxide; 100-mg tablet – FD&C Red No. 40 Lake, FD&C Yellow No. 6 Lake,
72
hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and
73
titanium dioxide.
2
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74
CLINICAL PHARMACOLOGY
75
Pharmacodynamics: The neurochemical mechanism of the antidepressant effect of
76
bupropion is not known. Bupropion is a relatively weak inhibitor of the neuronal uptake of
77
norepinephrine and dopamine, and does not inhibit monoamine oxidase or the re-uptake of
78
serotonin.
79
Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals,
80
as evidenced by increased locomotor activity, increased rates of responding in various
81
schedule-controlled operant behavior tasks, and, at high doses, induction of mild stereotyped
82
behavior.
83
Bupropion causes convulsions in rodents and dogs at doses approximately tenfold the dose
84
recommended as the human antidepressant dose.
85
Pharmacokinetics: Bupropion is a racemic mixture. The pharmacological activity and
86
pharmacokinetics of the individual enantiomers have not been studied. In humans, following oral
87
administration of WELLBUTRIN, peak plasma bupropion concentrations are usually achieved
88
within 2 hours, followed by a biphasic decline. The terminal phase has a mean half-life of
89
14 hours, with a range of 8 to 24 hours. The distribution phase has a mean half-life of 3 to
90
4 hours. The mean elimination half-life (±SD) of bupropion after chronic dosing is 21 (±9)
91
hours, and steady-state plasma concentrations of bupropion are reached within 8 days. Plasma
92
bupropion concentrations are dose-proportional following single doses of 100 to 250 mg;
93
however, it is not known if the proportionality between dose and plasma level is maintained in
94
chronic use.
95
Absorption: The absolute bioavailability of WELLBUTRIN in humans has not been
96
determined because an intravenous formulation for human use is not available. However, it
97
appears likely that only a small proportion of any orally administered dose reaches the systemic
98
circulation intact.
99
Distribution: In vitro tests show that bupropion is 84% bound to human plasma protein at
100
concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion
101
metabolite is similar to that for bupropion, whereas the extent of protein binding of the
102
threohydrobupropion metabolite is about half that seen with bupropion.
103
Metabolism: Bupropion is extensively metabolized in humans. Three metabolites have been
104
shown to be active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group
105
of bupropion, and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion,
106
which are formed via reduction of the carbonyl group. In vitro findings suggest that cytochrome
107
P450IIB6 (CYP2B6) is the principal isoenzyme involved in the formation of hydroxybupropion,
108
while cytochrome P450 isoenzymes are not involved in the formation of threohydrobupropion.
109
Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta
110
chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and
111
toxicity of the metabolites relative to bupropion have not been fully characterized. However, it
112
has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is
113
one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5
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114
fold less potent than bupropion. This may be of clinical importance because their plasma
115
concentrations are as high or higher than those of bupropion.
116
Because bupropion is extensively metabolized, there is the potential for drug-drug
117
interactions, particularly with those agents that are metabolized by or which inhibit/induce the
118
cytochrome P450IIB6 (CYP2B6) isoenzyme, such as ritonavir. In a healthy volunteer study,
119
ritonavir at a dose of 100 mg twice daily reduced the AUC and Cmax of bupropion by 22% and
120
21%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 23%, the
121
threohydrobupropion decreased by 38%, and the erythrohydrobupropion decreased by 48%.
122
In a second healthy volunteer study, ritonavir at a dose of 600 mg twice daily decreased the
123
AUC and the Cmax of bupropion by 66% and 62%, respectively. The exposure of the
124
hydroxybupropion metabolite was decreased by 78%, the threohydrobupropion decreased by
125
50%, and the erythrohydrobupropion decreased by 68%.
126
In another healthy volunteer study, KALETRA®* (lopinavir 400 mg/ritonavir 100 mg twice
127
daily) decreased bupropion AUC and Cmax by 57%. The AUC and Cmax of hydroxybupropion
128
were decreased by 50% and 31%, respectively (see PRECAUTIONS: Drug Interactions).
129
Although bupropion is not metabolized by cytochrome P450IID6 (CYP2D6), there is the
130
potential for drug-drug interactions when bupropion is coadministered with drugs metabolized
131
by this isoenzyme (see PRECAUTIONS: Drug Interactions).
132
Following a single dose in humans, peak plasma concentrations of hydroxybupropion occur
133
approximately 3 hours after administration of WELLBUTRIN. Peak plasma concentrations of
134
hydroxybupropion are approximately 10 times the peak level of the parent drug at steady state.
135
The elimination half-life of hydroxybupropion is approximately 20 (±5) hours, and its AUC at
136
steady state is about 17 times that of bupropion. The times to peak concentrations for the
137
erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the
138
hydroxybupropion metabolite. However, their elimination half-lives are longer, 33 (±10) and
139
37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion,
140
respectively.
141
Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300
142
to 450 mg/day.
143
Elimination: Following oral administration of 200 mg of 14C-bupropion in humans, 87% and
144
10% of the radioactive dose were recovered in the urine and feces, respectively. However, the
145
fraction of the oral dose of WELLBUTRIN excreted unchanged was only 0.5%, a finding
146
consistent with the extensive metabolism of bupropion.
147
Populations Subgroups: Factors or conditions altering metabolic capacity (e.g., liver
148
disease, congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may
149
be expected to influence the degree and extent of accumulation of the active metabolites of
150
bupropion. The elimination of the major metabolites of bupropion may be affected by reduced
151
renal or hepatic function because they are moderately polar compounds and are likely to undergo
152
further metabolism or conjugation in the liver prior to urinary excretion.
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153
Hepatic: The effect of hepatic impairment on the pharmacokinetics of bupropion was
154
characterized in 2 single-dose studies, one in patients with alcoholic liver disease and one in
155
patients with mild-to-severe cirrhosis. The first study showed that the half-life of
156
hydroxybupropion was significantly longer in 8 patients with alcoholic liver disease than in
157
8 healthy volunteers (32 ± 14 hours versus 21 ± 5 hours, respectively). Although not statistically
158
significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be
159
greater (by 53% to 57%) in volunteers with alcoholic liver disease. The differences in half-life
160
for bupropion and the other metabolites in the 2 patient groups were minimal.
161
The second study showed that there were no statistically significant differences in the
162
pharmacokinetics of bupropion and its active metabolites in 9 patients with mild-to-moderate
163
hepatic cirrhosis compared to 8 healthy volunteers. However, more variability was observed in
164
some of the pharmacokinetic parameters for bupropion (AUC, Cmax, and Tmax) and its active
165
metabolites (t½) in patients with mild-to-moderate hepatic cirrhosis. In addition, in patients with
166
severe hepatic cirrhosis, the bupropion Cmax and AUC were substantially increased (mean
167
difference: by approximately 70% and 3-fold, respectively) and more variable when compared to
168
values in healthy volunteers; the mean bupropion half-life was also longer (29 hours in patients
169
with severe hepatic cirrhosis vs. 19 hours in healthy subjects). For the metabolite
170
hydroxybupropion, the mean Cmax was approximately 69% lower. For the combined amino
171
alcohol isomers threohydrobupropion and erythrohydrobupropion, the mean Cmax was
172
approximately 31% lower. The mean AUC increased by about 1½-fold for hydroxybupropion
173
and about 2½-fold for threo/erythrohydrobupropion. The median Tmax was observed 19 hours
174
later for hydroxybupropion and 31 hours later for threo/erythrohydrobupropion. The mean
175
half-lives for hydroxybupropion and threo/erythrohydrobupropion were increased 5- and 2-fold,
176
respectively, in patients with severe hepatic cirrhosis compared to healthy volunteers (see
177
WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).
178
Renal: There is limited information on the pharmacokinetics of bupropion in patients with
179
renal impairment. An inter-study comparison between normal subjects and patients with end
180
stage renal failure demonstrated that the parent drug Cmax and AUC values were comparable in
181
the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3-
182
and 2.8-fold increase, respectively, in AUC for patients with end-stage renal failure. A second
183
study, comparing normal subjects and patients with moderate-to-severe renal impairment (GFR
184
30.9 ± 10.8 mL/min) showed that exposure to a single 150-mg dose of sustained-release
185
bupropion was approximately 2-fold higher in patients with impaired renal function while levels
186
of the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar
187
in the 2 groups. The elimination of bupropion and/or the major metabolites of bupropion may be
188
reduced by impaired renal function (see PRECAUTIONS: Renal Impairment).
189
Left Ventricular Dysfunction: During a chronic dosing study in 14 depressed patients
190
with left ventricular dysfunction (history of CHF or an enlarged heart on x-ray), no apparent
191
effect on the pharmacokinetics of bupropion or its metabolites was revealed, compared to healthy
192
volunteers.
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193
Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have not
194
been fully characterized, but an exploration of steady-state bupropion concentrations from
195
several depression efficacy studies involving patients dosed in a range of 300 to 750 mg/day, on
196
a 3 times daily schedule, revealed no relationship between age (18 to 83 years) and plasma
197
concentration of bupropion. A single-dose pharmacokinetic study demonstrated that the
198
disposition of bupropion and its metabolites in elderly subjects was similar to that of younger
199
subjects. These data suggest there is no prominent effect of age on bupropion concentration;
200
however, another pharmacokinetic study, single and multiple dose, has suggested that the elderly
201
are at increased risk for accumulation of bupropion and its metabolites (see PRECAUTIONS:
202
Geriatric Use).
203
Gender: A single-dose study involving 12 healthy male and 12 healthy female volunteers
204
revealed no sex-related differences in the pharmacokinetic parameters of bupropion.
205
Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion were
206
studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17
207
were nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there
208
were no statistically significant differences in Cmax, half-life, Tmax, AUC or clearance of
209
bupropion or its active metabolites between smokers and nonsmokers.
210
INDICATIONS AND USAGE
211
WELLBUTRIN is indicated for the treatment of major depressive disorder. A physician
212
considering WELLBUTRIN for the management of a patient’s first episode of depression should
213
be aware that the drug may cause generalized seizures in a dose-dependent manner with an
214
approximate incidence of 0.4% (4/1,000). This incidence of seizures may exceed that of other
215
marketed antidepressants by as much as 4-fold. This relative risk is only an approximate estimate
216
because no direct comparative studies have been conducted (see WARNINGS).
217
The efficacy of WELLBUTRIN has been established in 3 placebo-controlled trials, including
218
2 of approximately 3 weeks’ duration in depressed inpatients and one of approximately 6 weeks’
219
duration in depressed outpatients. The depressive disorder of the patients studied corresponds
220
most closely to the Major Depression category of the APA Diagnostic and Statistical Manual III.
221
Major Depression implies a prominent and relatively persistent depressed or dysphoric mood
222
that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should
223
include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor
224
agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased
225
fatigability, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and
226
suicidal ideation or attempts.
227
Effectiveness of WELLBUTRIN in long-term use, that is, for more than 6 weeks, has not
228
been systematically evaluated in controlled trials. Therefore, the physician who elects to use
229
WELLBUTRIN for extended periods should periodically reevaluate the long-term usefulness of
230
the drug for the individual patient.
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231
CONTRAINDICATIONS
232
WELLBUTRIN is contraindicated in patients with a seizure disorder.
233
WELLBUTRIN is contraindicated in patients treated with ZYBAN® (bupropion
234
hydrochloride) Sustained-Release Tablets; WELLBUTRIN SR® (bupropion hydrochloride), the
235
sustained-release formulation; WELLBUTRIN XL® (bupropion hydrochloride), the extended
236
release formulation; or any other medications that contain bupropion because the incidence of
237
seizure is dose dependent.
238
WELLBUTRIN is contraindicated in patients with a current or prior diagnosis of bulimia or
239
anorexia nervosa because of a higher incidence of seizures noted in such patients treated with
240
WELLBUTRIN.
241
WELLBUTRIN is contraindicated in patients undergoing abrupt discontinuation of alcohol or
242
sedatives (including benzodiazepines).
243
The concurrent administration of WELLBUTRIN and a monoamine oxidase (MAO) inhibitor
244
is contraindicated. At least 14 days should elapse between discontinuation of an MAO inhibitor
245
and initiation of treatment with WELLBUTRIN.
246
WELLBUTRIN is contraindicated in patients who have shown an allergic response to
247
bupropion or the other ingredients that make up WELLBUTRIN.
248
WARNINGS
249
Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders: Patients
250
with major depressive disorder (MDD), both adult and pediatric, may experience worsening of
251
their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual
252
changes in behavior, whether or not they are taking antidepressant medications, and this risk may
253
persist until significant remission occurs. Suicide is a known risk of depression and certain other
254
psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.
255
There has been a long-standing concern, however, that antidepressants may have a role in
256
inducing worsening of depression and the emergence of suicidality in certain patients during the
257
early phases of treatment. Pooled analyses of short-term placebo-controlled trials of
258
antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal
259
thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with
260
major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not
261
show an increase in the risk of suicidality with antidepressants compared to placebo in adults
262
beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65
263
and older.
264
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
265
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24
266
short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of
267
placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of
268
295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000
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patients. There was considerable variation in risk of suicidality among drugs, but a tendency
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270
toward an increase in the younger patients for almost all drugs studied. There were differences in
271
absolute risk of suicidality across the different indications, with the highest incidence in MDD.
272
The risk differences (drug vs placebo), however, were relatively stable within age strata and
273
across indications. These risk differences (drug-placebo difference in the number of cases of
274
suicidality per 1,000 patients treated) are provided in Table 1.
275
276
Table 1
Age Range
Drug-Placebo Difference in Number of Cases
of Suicidality per 1,000 Patients Treated
Increases Compared to Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
277
278
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but
279
the number was not sufficient to reach any conclusion about drug effect on suicide.
280
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
281
months. However, there is substantial evidence from placebo-controlled maintenance trials in
282
adults with depression that the use of antidepressants can delay the recurrence of depression.
283
All patients being treated with antidepressants for any indication should be monitored
284
appropriately and observed closely for clinical worsening, suicidality, and unusual changes
285
in behavior, especially during the initial few months of a course of drug therapy, or at times
286
of dose changes, either increases or decreases.
287
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
288
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
289
been reported in adult and pediatric patients being treated with antidepressants for major
290
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
291
Although a causal link between the emergence of such symptoms and either the worsening of
292
depression and/or the emergence of suicidal impulses has not been established, there is concern
293
that such symptoms may represent precursors to emerging suicidality.
294
Consideration should be given to changing the therapeutic regimen, including possibly
295
discontinuing the medication, in patients whose depression is persistently worse, or who are
296
experiencing emergent suicidality or symptoms that might be precursors to worsening depression
297
or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
298
patient’s presenting symptoms.
299
Families and caregivers of patients being treated with antidepressants for major
300
depressive disorder or other indications, both psychiatric and nonpsychiatric, should be
301
alerted about the need to monitor patients for the emergence of agitation, irritability,
8
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302
unusual changes in behavior, and the other symptoms described above, as well as the
303
emergence of suicidality, and to report such symptoms immediately to healthcare
304
providers. Such monitoring should include daily observation by families and caregivers.
305
Prescriptions for WELLBUTRIN should be written for the smallest quantity of tablets consistent
306
with good patient management, in order to reduce the risk of overdose.
307
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment:
308
WELLBUTRIN, WELLBUTRIN SR, and WELLBUTRIN XL are not approved for smoking
309
cessation treatment, but bupropion under the name ZYBAN is approved for this use. Serious
310
neuropsychiatric symptoms have been reported in patients taking bupropion for smoking
311
cessation (see BOXED WARNING, ADVERSE REACTIONS). These have included
312
changes in mood (including depression and mania), psychosis, hallucinations, paranoia,
313
delusions, homicidal ideation, hostility, agitation, aggression, anxiety, and panic, as well as
314
suicidal ideation, suicide attempt, and completed suicide. Some reported cases may have been
315
complicated by the symptoms of nicotine withdrawal in patients who stopped smoking.
316
Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including
317
suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without
318
medication. However, some of these symptoms have occurred in patients taking bupropion who
319
continued to smoke. When symptoms were reported, most were during bupropion treatment, but
320
some were following discontinuation of bupropion therapy.
321
These events have occurred in patients with and without pre-existing psychiatric disease;
322
some have experienced worsening of their psychiatric illnesses. All patients being treated with
323
bupropion as part of smoking cessation treatment should be observed for neuropsychiatric
324
symptoms or worsening of pre-existing psychiatric illness.
325
Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major
326
depressive disorder did not participate in the pre-marketing studies of ZYBAN.
327
Advise patients and caregivers that the patient using bupropion for smoking cessation
328
should stop taking bupropion and contact a healthcare provider immediately if agitation,
329
depressed mood, or changes in behavior or thinking that are not typical for the patient are
330
observed, or if the patient develops suicidal ideation or suicidal behavior. In many
331
postmarketing cases, resolution of symptoms after discontinuation of ZYBAN was
332
reported, although in some cases the symptoms persisted, therefore, ongoing monitoring
333
and supportive care should be provided until symptoms resolve.
334
The risks of using bupropion for smoking cessation should be weighed against the benefits of
335
its use. ZYBAN has been demonstrated to increase the likelihood of abstinence from smoking
336
for as long as six months compared to treatment with placebo. The health benefits of quitting
337
smoking are immediate and substantial.
338
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
339
presentation of bipolar disorder. It is generally believed (though not established in controlled
340
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
341
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
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342
symptoms described above represent such a conversion is unknown. However, prior to initiating
343
treatment with an antidepressant, patients with depressive symptoms should be adequately
344
screened to determine if they are at risk for bipolar disorder; such screening should include a
345
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
346
depression. It should be noted that WELLBUTRIN is not approved for use in treating bipolar
347
depression.
348
Bupropion-Containing Products: Patients should be made aware that WELLBUTRIN
349
contains the same active ingredient found in ZYBAN, used as an aid to smoking cessation
350
treatment, and that WELLBUTRIN should not be used in combination with ZYBAN, or any
351
other medications that contain bupropion, such as WELLBUTRIN SR (bupropion
352
hydrochloride), the sustained-release formulation or WELLBUTRIN XL (bupropion
353
hydrochloride), the extended-release formulation.
354
355
Seizures: Bupropion is associated with seizures in approximately 0.4% (4/1,000) of
356
patients treated at doses up to 450 mg/day. This incidence of seizures may exceed that of
357
other marketed antidepressants by as much as 4-fold. This relative risk is only an
358
approximate estimate because no direct comparative studies have been conducted. The
359
estimated seizure incidence for WELLBUTRIN increases almost tenfold between 450 and
360
600 mg/day, which is twice the usually required daily dose (300 mg) and one and one-third
361
the maximum recommended daily dose (450 mg). Given the wide variability among
362
individuals and their capacity to metabolize and eliminate drugs this disproportionate
363
increase in seizure incidence with dose incrementation calls for caution in dosing.
364
During the initial development, 25 among approximately 2,400 patients treated with
365
WELLBUTRIN experienced seizures. At the time of seizure, 7 patients were receiving daily
366
doses of 450 mg or below for an incidence of 0.33% (3/1,000) within the recommended dose
367
range. Twelve patients experienced seizures at 600 mg/day (2.3% incidence); 6 additional
368
patients had seizures at daily doses between 600 and 900 mg (2.8% incidence).
369
A separate, prospective study was conducted to determine the incidence of seizure
370
during an 8-week treatment exposure in approximately 3,200 additional patients who
371
received daily doses of up to 450 mg. Patients were permitted to continue treatment beyond
372
8 weeks if clinically indicated. Eight seizures occurred during the initial 8-week treatment
373
period and 5 seizures were reported in patients continuing treatment beyond 8 weeks,
374
resulting in a total seizure incidence of 0.4%.
375
The risk of seizure appears to be strongly associated with dose. Sudden and large
376
increments in dose may contribute to increased risk. While many seizures occurred early in
377
the course of treatment, some seizures did occur after several weeks at fixed dose.
378
WELLBUTRIN should be discontinued and not restarted in patients who experience a
379
seizure while on treatment.
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380
The risk of seizure is also related to patient factors, clinical situations, and concomitant
381
medications, which must be considered in selection of patients for therapy with
382
WELLBUTRIN.
383
• Patient factors: Predisposing factors that may increase the risk of seizure with
384
bupropion use include history of head trauma or prior seizure, central nervous system
385
(CNS) tumor, the presence of severe hepatic cirrhosis, and concomitant medications
386
that lower seizure threshold.
387
• Clinical situations: Circumstances associated with an increased seizure risk include,
388
among others, excessive use of alcohol or sedatives (including benzodiazepines);
389
addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and
390
anorectics; and diabetes treated with oral hypoglycemics or insulin.
391
• Concomitant medications: Many medications (e.g., antipsychotics, antidepressants,
392
theophylline, systemic steroids) are known to lower seizure threshold.
393
Recommendations for Reducing the Risk of Seizure: Retrospective analysis of
394
clinical experience gained during the development of WELLBUTRIN suggests that the risk
395
of seizure may be minimized if
396
• the total daily dose of WELLBUTRIN does not exceed 450 mg,
397
• the daily dose is administered 3 times daily, with each single dose not to exceed 150 mg
398
to avoid high peak concentrations of bupropion and/or its metabolites, and
399
• the rate of incrementation of dose is very gradual.
400
WELLBUTRIN should be administered with extreme caution to patients with a history
401
of seizure, cranial trauma, or other predisposition(s) toward seizure, or patients treated
402
with other agents (e.g., antipsychotics, other antidepressants, theophylline, systemic
403
steroids, etc.) that lower seizure threshold.
404
Hepatic Impairment: WELLBUTRIN should be used with extreme caution in patients
405
with severe hepatic cirrhosis. In these patients a reduced dose and/or frequency is required,
406
as peak bupropion, as well as AUC, levels are substantially increased and accumulation is
407
likely to occur in such patients to a greater extent than usual. The dose should not exceed
408
75 mg once a day in these patients (see CLINICAL PHARMACOLOGY, PRECAUTIONS,
409
and DOSAGE AND ADMINISTRATION).
410
Potential for Hepatotoxicity: In rats receiving large doses of bupropion chronically, there
411
was an increase in incidence of hepatic hyperplastic nodules and hepatocellular hypertrophy. In
412
dogs receiving large doses of bupropion chronically, various histologic changes were seen in the
413
liver, and laboratory tests suggesting mild hepatocellular injury were noted.
414
PRECAUTIONS
415
General: Agitation and Insomnia: A substantial proportion of patients treated with
416
WELLBUTRIN experience some degree of increased restlessness, agitation, anxiety, and
417
insomnia, especially shortly after initiation of treatment. In clinical studies, these symptoms were
418
sometimes of sufficient magnitude to require treatment with sedative/hypnotic drugs. In
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
419
approximately 2% of patients, symptoms were sufficiently severe to require discontinuation of
420
treatment with WELLBUTRIN.
421
Psychosis, Confusion, and Other Neuropsychiatric Phenomena: Depressed
422
patients treated with WELLBUTRIN have been reported to show a variety of neuropsychiatric
423
signs and symptoms including delusions, hallucinations, psychosis, concentration disturbance,
424
paranoia, and confusion. Because of the uncontrolled nature of many studies, it is impossible to
425
provide a precise estimate of the extent of risk imposed by treatment with WELLBUTRIN. In
426
several cases, neuropsychiatric phenomena abated upon dose reduction and/or withdrawal of
427
treatment.
428
Activation of Psychosis and/or Mania: Antidepressants can precipitate manic episodes
429
in bipolar disorder patients during the depressed phase of their illness and may activate latent
430
psychosis in other susceptible patients. WELLBUTRIN is expected to pose similar risks.
431
Altered Appetite and Weight: A weight loss of greater than 5 lbs occurred in 28% of
432
patients receiving WELLBUTRIN. This incidence is approximately double that seen in
433
comparable patients treated with tricyclics or placebo. Furthermore, while 35% of patients
434
receiving tricyclic antidepressants gained weight, only 9.4% of patients treated with
435
WELLBUTRIN did. Consequently, if weight loss is a major presenting sign of a patient’s
436
depressive illness, the anorectic and/or weight reducing potential of WELLBUTRIN should be
437
considered.
438
Allergic Reactions: Anaphylactoid/anaphylactic reactions characterized by symptoms such
439
as pruritus, urticaria, angioedema, and dyspnea requiring medical treatment have been reported
440
in clinical trials with bupropion. In addition, there have been rare spontaneous postmarketing
441
reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated
442
with bupropion. A patient should stop taking WELLBUTRIN and consult a doctor if
443
experiencing allergic or anaphylactoid/anaphylactic reactions (e.g., skin rash, pruritus, hives,
444
chest pain, edema, and shortness of breath) during treatment.
445
Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed
446
hypersensitivity have been reported in association with bupropion. These symptoms may
447
resemble serum sickness.
448
Cardiovascular Effects: In clinical practice, hypertension, in some cases severe, requiring
449
acute treatment, has been reported in patients receiving bupropion alone and in combination with
450
nicotine replacement therapy. These events have been observed in both patients with and without
451
evidence of preexisting hypertension.
452
Data from a comparative study of the sustained-release formulation of bupropion (ZYBAN®
453
Sustained-Release Tablets), nicotine transdermal system (NTS), the combination of sustained
454
release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher
455
incidence of treatment-emergent hypertension in patients treated with the combination of
456
sustained-release bupropion and NTS. In this study, 6.1% of patients treated with the
457
combination of sustained-release bupropion and NTS had treatment-emergent hypertension
458
compared to 2.5%, 1.6%, and 3.1% of patients treated with sustained-release bupropion, NTS,
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
459
and placebo, respectively. The majority of these patients had evidence of preexisting
460
hypertension. Three patients (1.2%) treated with the combination of ZYBAN and NTS and 1
461
patient (0.4%) treated with NTS had study medication discontinued due to hypertension
462
compared to none of the patients treated with ZYBAN or placebo. Monitoring of blood pressure
463
is recommended in patients who receive the combination of bupropion and nicotine replacement.
464
There is no clinical experience establishing the safety of WELLBUTRIN in patients with a
465
recent history of myocardial infarction or unstable heart disease. Therefore, care should be
466
exercised if it is used in these groups. Bupropion was well tolerated in depressed patients who
467
had previously developed orthostatic hypotension while receiving tricyclic antidepressants and
468
was also generally well tolerated in a group of 36 depressed inpatients with stable congestive
469
heart failure (CHF). However, bupropion was associated with a rise in supine blood pressure in
470
the study of patients with CHF, resulting in discontinuation of treatment in 2 patients for
471
exacerbation of baseline hypertension.
472
Hepatic Impairment: WELLBUTRIN should be used with extreme caution in patients with
473
severe hepatic cirrhosis. In these patients, a reduced dose and frequency is required.
474
WELLBUTRIN should be used with caution in patients with hepatic impairment (including
475
mild-to-moderate hepatic cirrhosis) and a reduced frequency and/or dose should be considered in
476
patients with mild-to-moderate hepatic cirrhosis.
477
All patients with hepatic impairment should be closely monitored for possible adverse effects
478
that could indicate high drug and metabolite levels (see CLINICAL PHARMACOLOGY,
479
WARNINGS, and DOSAGE AND ADMINISTRATION).
480
Renal Impairment: There is limited information on the pharmacokinetics of bupropion in
481
patients with renal impairment. An inter-study comparison between normal subjects and patients
482
with end-stage renal failure demonstrated that the parent drug Cmax and AUC values were
483
comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion
484
metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for patients with end-stage
485
renal failure. A second study, comparing normal subjects and patients with moderate-to-severe
486
renal impairment (GFR 30.9 ± 10.8 mL/min) showed that exposure to a single 150-mg dose of
487
sustained-release bupropion was approximately 2-fold higher in patients with impaired renal
488
function while levels of the hydroxybupropion and threo/erythrohydrobupropion (combined)
489
metabolites were similar in the 2 groups. Bupropion is extensively metabolized in the liver to
490
active metabolites, which are further metabolized and subsequently excreted by the kidneys.
491
WELLBUTRIN should be used with caution in patients with renal impairment and a reduced
492
frequency and/or dose should be considered as bupropion and the metabolites of bupropion may
493
accumulate in such patients to a greater extent than usual. The patient should be closely
494
monitored for possible adverse effects that could indicate high drug or metabolite levels.
495
Information for Patients: Prescribers or other health professionals should inform patients,
496
their families, and their caregivers about the benefits and risks associated with treatment with
497
WELLBUTRIN and should counsel them in its appropriate use. A patient Medication Guide
498
about “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
499
Thoughts or Actions,” “Quitting Smoking, Quit-Smoking Medication, Changes in Thinking and
500
Behavior, Depression, and Suicidal Thoughts or Actions,” and “What Other Important
501
Information Should I Know About WELLBUTRIN ?” is available for WELLBUTRIN. The
502
prescriber or health professional should instruct patients, their families, and their caregivers to
503
read the Medication Guide and should assist them in understanding its contents. Patients should
504
be given the opportunity to discuss the contents of the Medication Guide and to obtain answers
505
to any questions they may have. The complete text of the Medication Guide is reprinted at the
506
end of this document.
507
Patients should be advised of the following issues and asked to alert their prescriber if these
508
occur while taking WELLBUTRIN.
509
Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders: Patients,
510
their families, and their caregivers should be encouraged to be alert to the emergence of anxiety,
511
agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia
512
(psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of
513
depression, and suicidal ideation, especially early during antidepressant treatment and when the
514
dose is adjusted up or down. Families and caregivers of patients should be advised to look for the
515
emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such
516
symptoms should be reported to the patient’s prescriber or health professional, especially if they
517
are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms
518
such as these may be associated with an increased risk for suicidal thinking and behavior and
519
indicate a need for very close monitoring and possibly changes in the medication.
520
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation
521
Treatment: Although WELLBUTRIN is not indicated for smoking cessation treatment, it
522
contains the same active ingredient as ZYBAN which is approved for this use. Patients should be
523
informed that quitting smoking, with or without ZYBAN, may be associated with nicotine
524
withdrawal symptoms (including depression or agitation), or exacerbation of pre-existing
525
psychiatric illness. Furthermore, some patients have experienced changes in mood (including
526
depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation
527
aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed
528
suicide when attempting to quit smoking while taking ZYBAN. If patients develop agitation,
529
hostility, depressed mood, or changes in thinking or behavior that are not typical for them, or if
530
patients develop suicidal ideation or behavior, they should be urged to report these symptoms to
531
their healthcare provider immediately.
532
Bupropion-Containing Products: Patients should be made aware that WELLBUTRIN
533
contains the same active ingredient found in ZYBAN, used as an aid to smoking cessation, and
534
that WELLBUTRIN should not be used in combination with ZYBAN or any other medications
535
that contain bupropion hydrochloride (such as WELLBUTRIN SR, the sustained-release
536
formulation and WELLBUTRIN XL, the extended-release formulation).
537
Patients should be instructed to take WELLBUTRIN in equally divided doses 3 or 4 times a
538
day to minimize the risk of seizure.
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
539
Patients should be told that WELLBUTRIN should be discontinued and not restarted if they
540
experience a seizure while on treatment.
541
Patients should be told that any CNS-active drug like WELLBUTRIN may impair their ability
542
to perform tasks requiring judgment or motor and cognitive skills. Consequently, until they are
543
reasonably certain that WELLBUTRIN does not adversely affect their performance, they should
544
refrain from driving an automobile or operating complex, hazardous machinery.
545
Patients should be told that the excessive use or abrupt discontinuation of alcohol or sedatives
546
(including benzodiazepines) may alter the seizure threshold. Some patients have reported lower
547
alcohol tolerance during treatment with WELLBUTRIN. Patients should be advised that the
548
consumption of alcohol should be minimized or avoided.
549
Patients should be advised to inform their physicians if they are taking or plan to take any
550
prescription or over-the-counter drugs. Concern is warranted because WELLBUTRIN and other
551
drugs may affect each other’s metabolism.
552
Patients should be advised to notify their physicians if they become pregnant or intend to
553
become pregnant during therapy.
554
Laboratory Tests: There are no specific laboratory tests recommended.
555
Drug Interactions: Few systemic data have been collected on the metabolism of bupropion
556
following concomitant administration with other drugs or, alternatively, the effect of
557
concomitant administration of bupropion on the metabolism of other drugs.
558
Because bupropion is extensively metabolized, the coadministration of other drugs may affect
559
its clinical activity. In vitro studies indicate that bupropion is primarily metabolized to
560
hydroxybupropion by the CYP2B6 isoenzyme. Therefore, the potential exists for a drug
561
interaction between WELLBUTRIN and drugs that are substrates of or inhibitors/inducers of the
562
CYP2B6 isoenzyme (e.g., orphenadrine, thiotepa, cyclophosphamide, ticlopidine, and
563
clopidogrel). In addition, in vitro studies suggest that paroxetine, sertraline, norfluoxetine, and
564
fluvoxamine as well as nelfinavir and efavirenz inhibit the hydroxylation of bupropion. No
565
clinical studies have been performed to evaluate this finding. The threohydrobupropion
566
metabolite of bupropion does not appear to be produced by the cytochrome P450 isoenzymes.
567
The effects of concomitant administration of cimetidine on the pharmacokinetics of bupropion
568
and its active metabolites were studied in 24 healthy young male volunteers. Following oral
569
administration of two 150-mg sustained-release tablets with and without 800 mg of cimetidine,
570
the pharmacokinetics of bupropion and hydroxybupropion were unaffected. However, there were
571
16% and 32% increases in the AUC and Cmax, respectively, of the combined moieties of
572
threohydrobupropion and erythrohydrobupropion.
573
In a series of studies in healthy volunteers, ritonavir (100 mg twice daily or 600 mg twice
574
daily) or ritonavir 100 mg plus lopinavir 400 mg (KALETRA) twice daily reduced the exposure
575
of bupropion and its major metabolites in a dose dependent manner by approximately 20% to
576
80%. This effect is thought to be due to the induction of bupropion metabolism. Patients
577
receiving ritonavir may need increased doses of bupropion, but the maximum recommended
578
dose of bupropion should not be exceeded (see CLINICAL PHARMACOLOGY: Metabolism).
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
579
While not systematically studied, certain drugs may induce the metabolism of bupropion (e.g.,
580
carbamazepine, phenobarbital, phenytoin).
581
Multiple oral doses of bupropion had no statistically significant effects on the single dose
582
pharmacokinetics of lamotrigine in 12 healthy volunteers.
583
Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in
584
humans. In one study, following chronic administration of bupropion, 100 mg 3 times daily to 8
585
healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism.
586
Nevertheless, there may be the potential for clinically important alterations of blood levels of
587
coadministered drugs.
588
Drugs Metabolized by Cytochrome P450IID6 (CYP2D6): Many drugs, including most
589
antidepressants (SSRIs, many tricyclics), beta-blockers, antiarrhythmics, and antipsychotics are
590
metabolized by the CYP2D6 isoenzyme. Although bupropion is not metabolized by this
591
isoenzyme, bupropion and hydroxybupropion are inhibitors of the CYP2D6 isoenzyme in vitro.
592
In a study of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of the
593
CYP2D6 isoenzyme, daily doses of bupropion given as 150 mg twice daily followed by a single
594
dose of 50 mg desipramine increased the Cmax, AUC, and t1/2 of desipramine by an average of
595
approximately 2-, 5- and 2-fold, respectively. The effect was present for at least 7 days after the
596
last dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6
597
has not been formally studied.
598
Therefore, coadministration of bupropion with drugs that are metabolized by CYP2D6
599
isoenzyme including certain antidepressants (e.g., nortriptyline, imipramine, desipramine,
600
paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine),
601
beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide),
602
should be approached with caution and should be initiated at the lower end of the dose range of
603
the concomitant medication. If bupropion is added to the treatment regimen of a patient already
604
receiving a drug metabolized by CYP2D6, the need to decrease the dose of the original
605
medication should be considered, particularly for those concomitant medications with a narrow
606
therapeutic index.
607
Although citalopram is not primarily metabolized by CYP2D6, in one study bupropion
608
increased the Cmax and AUC of citalopram by 30% and 40%, respectively. Citalopram did not
609
affect the pharmacokinetics of bupropion and its 3 metabolites.
610
MAO Inhibitors: Studies in animals demonstrate that the acute toxicity of bupropion is
611
enhanced by the MAO inhibitor phenelzine (see CONTRAINDICATIONS).
612
Levodopa and Amantadine: Limited clinical data suggest a higher incidence of adverse
613
experiences in patients receiving bupropion concurrently with either levodopa or amantadine.
614
Administration of WELLBUTRIN to patients receiving either levodopa or amantadine
615
concurrently should be undertaken with caution, using small initial doses and small gradual dose
616
increases.
617
Drugs that Lower Seizure Threshold: Concurrent administration of WELLBUTRIN and
618
agents (e.g., antipsychotics, other antidepressants, theophylline, systemic steroids, etc.) that
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
619
lower seizure threshold should be undertaken only with extreme caution (see WARNINGS).
620
Low initial dosing and small gradual dose increases should be employed.
621
Nicotine Transdermal System: (see PRECAUTIONS: Cardiovascular Effects).
622
Alcohol: In postmarketing experience, there have been rare reports of adverse
623
neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol
624
during treatment with WELLBUTRIN. The consumption of alcohol during treatment with
625
WELLBUTRIN should be minimized or avoided (also see CONTRAINDICATIONS).
626
Carcinogenesis, Mutagenesis, Impairment of Fertility: Lifetime carcinogenicity studies
627
were performed in rats and mice at doses up to 300 and 150 mg/kg/day, respectively. In the rat
628
study there was an increase in nodular proliferative lesions of the liver at doses of 100 to
629
300 mg/kg/day; lower doses were not tested. The question of whether or not such lesions may be
630
precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen
631
in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in
632
either study.
633
Bupropion produced a borderline positive response (2 to 3 times control mutation rate) in
634
some strains in the Ames bacterial mutagenicity test, and a high oral dose (300 mg/kg, but not
635
100 or 200 mg/kg) produced a low incidence of chromosomal aberrations in rats. The relevance
636
of these results in estimating the risk of human exposure to therapeutic doses is unknown.
637
A fertility study was performed in rats; no evidence of impairment of fertility was
638
encountered at oral doses up to 300 mg/kg/day.
639
Pregnancy: Teratogenic Effects: Pregnancy Category C. In studies conducted in rats and
640
rabbits, bupropion was administered orally at doses up to 450 and 150 mg/kg/day, respectively
641
(approximately 11 and 7 times the MRHD, respectively, on a mg/m2 basis), during the period of
642
organogenesis. No clear evidence of teratogenic activity was found in either species; however, in
643
rabbits, slightly increased incidences of fetal malformations and skeletal variations were
644
observed at the lowest dose tested (25 mg/kg/day, approximately equal to the MRHD on a mg/m2
645
basis) and greater. Decreased fetal weights were seen at 50 mg/kg and greater.
646
When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately
647
7 times the MRHD on a mg/m2 basis) prior to mating and throughout pregnancy and lactation,
648
there were no apparent adverse effects on offspring development.
649
One study has been conducted in pregnant women. This retrospective, managed-care database
650
study assessed the risk of congenital malformations overall and cardiovascular malformations
651
specifically, following exposure to bupropion in the first trimester compared to the risk of these
652
malformations following exposure to other antidepressants in the first trimester and bupropion
653
outside of the first trimester. This study included 7,005 infants with antidepressant exposure
654
during pregnancy, 1,213 of whom were exposed to bupropion in the first trimester. The study
655
showed no greater risk for congenital malformations overall or cardiovascular malformations
656
specifically, following first trimester bupropion exposure compared to exposure to all other
657
antidepressants in the first trimester, or bupropion outside of the first trimester. The results of
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
658
this study have not been corroborated. WELLBUTRIN should be used during pregnancy only if
659
the potential benefit justifies the potential risk to the fetus.
660
Labor and Delivery: The effect of WELLBUTRIN on labor and delivery in humans is
661
unknown.
662
Nursing Mothers: Like many other drugs, bupropion and its metabolites are secreted in human
663
milk. Because of the potential for serious adverse reactions in nursing infants from
664
WELLBUTRIN, a decision should be made whether to discontinue nursing or to discontinue the
665
drug, taking into account the importance of the drug to the mother.
666
Pediatric Use: Safety and effectiveness in the pediatric population have not been established
667
(see BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk in Treating
668
Psychiatric Disorders). Anyone considering the use of WELLBUTRIN in a child or adolescent
669
must balance the potential risks with the clinical need.
670
Geriatric Use: Of the approximately 6,000 patients who participated in clinical trials with
671
bupropion sustained-release tablets (depression and smoking cessation studies), 275 were 65 and
672
over and 47 were 75 and over. In addition, several hundred patients 65 and over participated in
673
clinical trials using the immediate-release formulation of bupropion (depression studies). No
674
overall differences in safety or effectiveness were observed between these subjects and younger
675
subjects, and other reported clinical experience has not identified differences in responses
676
between the elderly and younger patients, but greater sensitivity of some older individuals cannot
677
be ruled out.
678
A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its
679
metabolites in elderly subjects was similar to that of younger subjects; however, another
680
pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased
681
risk for accumulation of bupropion and its metabolites (see CLINICAL PHARMACOLOGY).
682
Bupropion is extensively metabolized in the liver to active metabolites, which are further
683
metabolized and excreted by the kidneys. The risk of toxic reaction to this drug may be greater in
684
patients with impaired renal function. Because elderly patients are more likely to have decreased
685
renal function, care should be taken in dose selection, and it may be useful to monitor renal
686
function (see PRECAUTIONS: Renal Impairment and DOSAGE AND ADMINISTRATION).
687
688
ADVERSE REACTIONS
689
(See also WARNINGS and PRECAUTIONS.)
690
Adverse events commonly encountered in patients treated with WELLBUTRIN are agitation,
691
dry mouth, insomnia, headache/migraine, nausea/vomiting, constipation, and tremor.
692
Adverse events were sufficiently troublesome to cause discontinuation of treatment with
693
WELLBUTRIN in approximately 10% of the 2,400 patients and volunteers who participated in
694
clinical trials during the product’s initial development. The more common events causing
695
discontinuation include neuropsychiatric disturbances (3.0%), primarily agitation and
696
abnormalities in mental status; gastrointestinal disturbances (2.1%), primarily nausea and
697
vomiting; neurological disturbances (1.7%), primarily seizures, headaches, and sleep
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
698
disturbances; and dermatologic problems (1.4%), primarily rashes. It is important to note,
699
however, that many of these events occurred at doses that exceed the recommended daily dose.
700
Accurate estimates of the incidence of adverse events associated with the use of any drug are
701
difficult to obtain. Estimates are influenced by drug dose, detection technique, setting, physician
702
judgments, etc. Consequently, Table 2 is presented solely to indicate the relative frequency of
703
adverse events reported in representative controlled clinical studies conducted to evaluate the
704
safety and efficacy of WELLBUTRIN under relatively similar conditions of daily dosage (300 to
705
600 mg), setting, and duration (3 to 4 weeks). The figures cited cannot be used to predict
706
precisely the incidence of untoward events in the course of usual medical practice where patient
707
characteristics and other factors must differ from those which prevailed in the clinical trials.
708
These incidence figures also cannot be compared with those obtained from other clinical studies
709
involving related drug products as each group of drug trials is conducted under a different set of
710
conditions.
711
Finally, it is important to emphasize that the tabulation does not reflect the relative severity
712
and/or clinical importance of the events. A better perspective on the serious adverse events
713
associated with the use of WELLBUTRIN is provided in WARNINGS and PRECAUTIONS.
714
715
Table 2. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled
716
Clinical Trialsa (Percent of Patients Reporting)
Adverse Experience
WELLBUTRIN Patients
(n = 323)
Placebo Patients
(n = 185)
Cardiovascular
Cardiac arrhythmias
5.3
4.3
Dizziness
22.3
16.2
Hypertension
4.3
1.6
Hypotension
2.5
2.2
Palpitations
3.7
2.2
Syncope
1.2
0.5
Tachycardia
10.8
8.6
Dermatologic
Pruritus
Rash
2.2
8.0
0.0
6.5
Gastrointestinal
Anorexia
18.3
18.4
Appetite increase
3.7
2.2
Constipation
26.0
17.3
Diarrhea
6.8
8.6
Dyspepsia
3.1
2.2
Nausea/vomiting
22.9
18.9
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Weight gain
Weight loss
13.6
23.2
22.7
23.2
Genitourinary
Impotence
3.4
3.1
Menstrual complaints
4.7
1.1
Urinary frequency
2.5
2.2
Urinary retention
1.9
2.2
Musculoskeletal
Arthritis
3.1
2.7
Neurological
Akathisia
1.5
1.1
Akinesia/bradykinesia
8.0
8.6
Cutaneous temperature
1.9
1.6
disturbance
Dry mouth
27.6
18.4
Excessive sweating
22.3
14.6
Headache/migraine
25.7
22.2
Impaired sleep quality
4.0
1.6
Increased salivary flow
3.4
3.8
Insomnia
18.6
15.7
Muscle spasms
1.9
3.2
Pseudoparkinsonism
1.5
1.6
Sedation
19.8
19.5
Sensory disturbance
4.0
3.2
Tremor
21.1
7.6
Neuropsychiatric
Agitation
31.9
22.2
Anxiety
3.1
1.1
Confusion
8.4
4.9
Decreased libido
3.1
1.6
Delusions
1.2
1.1
Disturbed concentration
3.1
3.8
Euphoria
1.2
0.5
Hostility
5.6
3.8
Nonspecific
Fatigue
Fever/chills
5.0
1.2
8.6
0.5
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Respiratory
Upper respiratory complaints
5.0
11.4
Special Senses
Auditory disturbance
Blurred vision
Gustatory disturbance
5.3
14.6
3.1
3.2
10.3
1.1
717
a Events reported by at least 1% of patients receiving WELLBUTRIN are included.
718
719
Other Events Observed During the Development of WELLBUTRIN: The conditions
720
and duration of exposure to WELLBUTRIN varied greatly, and a substantial proportion of the
721
experience was gained in open and uncontrolled clinical settings. During this experience,
722
numerous adverse events were reported; however, without appropriate controls, it is impossible
723
to determine with certainty which events were or were not caused by WELLBUTRIN. The
724
following enumeration is organized by organ system and describes events in terms of their
725
relative frequency of reporting in the data base. Events of major clinical importance are also
726
described in WARNINGS and PRECAUTIONS.
727
The following definitions of frequency are used: Frequent adverse events are defined as those
728
occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to
729
1/1,000 patients, while rare events are those occurring in less than 1/1,000 patients.
730
Cardiovascular: Frequent was edema; infrequent were chest pain, electrocardiogram (ECG)
731
abnormalities (premature beats and nonspecific ST-T changes), and shortness of breath/dyspnea;
732
rare were flushing, pallor, phlebitis, and myocardial infarction.
733
Dermatologic: Frequent were nonspecific rashes; infrequent were alopecia and dry skin;
734
rare were change in hair color, hirsutism, and acne.
735
Endocrine: Infrequent was gynecomastia; rare were glycosuria and hormone level change.
736
Gastrointestinal: Infrequent were dysphagia, thirst disturbance, and liver damage/jaundice;
737
rare were rectal complaints, colitis, gastrointestinal bleeding, intestinal perforation, and stomach
738
ulcer.
739
Genitourinary: Frequent was nocturia; infrequent were vaginal irritation, testicular swelling,
740
urinary tract infection, painful erection, and retarded ejaculation; rare were dysuria, enuresis,
741
urinary incontinence, menopause, ovarian disorder, pelvic infection, cystitis, dyspareunia, and
742
painful ejaculation.
743
Hematologic/Oncologic: Rare were lymphadenopathy, anemia, and pancytopenia.
744
Musculoskeletal: Rare was musculoskeletal chest pain.
745
Neurological: (see WARNINGS) Frequent were ataxia/incoordination, seizure, myoclonus,
746
dyskinesia, and dystonia; infrequent were mydriasis, vertigo, and dysarthria; rare were
747
electroencephalogram (EEG) abnormality, abnormal neurological exam, impaired attention,
748
sciatica, and aphasia.
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
749
Neuropsychiatric: (see PRECAUTIONS) Frequent were mania/hypomania, increased
750
libido, hallucinations, decrease in sexual function, and depression; infrequent were memory
751
impairment, depersonalization, psychosis, dysphoria, mood instability, paranoia, formal thought
752
disorder, and frigidity; rare was suicidal ideation.
753
Oral Complaints: Frequent was stomatitis; infrequent were toothache, bruxism, gum
754
irritation, and oral edema; rare was glossitis.
755
Respiratory: Infrequent were bronchitis and shortness of breath/dyspnea; rare were
756
epistaxis, rate or rhythm disorder, pneumonia, and pulmonary embolism.
757
Special Senses: Infrequent was visual disturbance; rare was diplopia.
758
Nonspecific: Frequent were flu-like symptoms; infrequent was nonspecific pain; rare were
759
body odor, surgically related pain, infection, medication reaction, and overdose.
760
Postintroduction Reports: Voluntary reports of adverse events temporally associated with
761
bupropion that have been received since market introduction and which may have no causal
762
relationship with the drug include the following:
763
Body (General): arthralgia, myalgia, and fever with rash and other symptoms suggestive of
764
delayed hypersensitivity. These symptoms may resemble serum sickness (see PRECAUTIONS).
765
Cardiovascular: hypertension (in some cases severe, see PRECAUTIONS), orthostatic
766
hypotension, third degree heart block
767
Endocrine: syndrome of inappropriate antidiuretic hormone secretion, hyperglycemia,
768
hypoglycemia
769
Gastrointestinal: esophagitis, hepatitis, liver damage
770
Hemic and Lymphatic: ecchymosis, leukocytosis, leukopenia, thrombocytopenia. Altered
771
PT and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were
772
observed when bupropion was coadministered with warfarin.
773
Musculoskeletal: arthralgia, myalgia, muscle rigidity/fever/rhabdomyolysis, muscle
774
weakness
775
Nervous: aggression, coma, completed suicide, delirium, dream abnormalities, paranoid
776
ideation, paresthesia, restlessness, suicide attempt, unmasking of tardive dyskinesia
777
Skin and Appendages: Stevens-Johnson syndrome, angioedema, exfoliative dermatitis,
778
urticaria
779
Special Senses: tinnitus, increased intraocular pressure
780
DRUG ABUSE AND DEPENDENCE
781
Humans: Controlled clinical studies conducted in normal volunteers, in subjects with a history
782
of multiple drug abuse, and in depressed patients showed some increase in motor activity and
783
agitation/excitement.
784
In a population of individuals experienced with drugs of abuse, a single dose of 400 mg of
785
WELLBUTRIN produced mild amphetamine-like activity as compared to placebo on the
786
Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI) and a
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
787
score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These
788
scales measure general feelings of euphoria and drug desirability.
789
Findings in clinical trials, however, are not known to predict the abuse potential of drugs
790
reliably. Nonetheless, evidence from single-dose studies does suggest that the recommended
791
daily dosage of bupropion when administered in divided doses is not likely to be especially
792
reinforcing to amphetamine or stimulant abusers. However, higher doses that could not be tested
793
because of the risk of seizure might be modestly attractive to those who abuse stimulant drugs.
794
Animals: Studies in rodents have shown that bupropion exhibits some pharmacologic actions
795
common to psychostimulants including increases in locomotor activity and the production of a
796
mild stereotyped behavior and increases in rates of responding in several schedule-controlled
797
behavior paradigms. Drug discrimination studies in rats showed stimulus generalization between
798
bupropion and amphetamine and other psychostimulants. Rhesus monkeys have been shown to
799
self-administer bupropion intravenously.
800
OVERDOSAGE
801
Human Overdose Experience: Overdoses of up to 30 g or more of bupropion have been
802
reported. Seizure was reported in approximately one-third of all cases. Other serious reactions
803
reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus
804
tachycardia, and ECG changes such as conduction disturbances (including QRS prolongation) or
805
arrhythmias. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory
806
failure have been reported mainly when bupropion was part of multiple drug overdoses.
807
Although most patients recovered without sequelae, deaths associated with overdoses of
808
bupropion alone have been reported in patients ingesting large doses of the drug. Multiple
809
uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported
810
in these patients.
811
Overdosage Management: Ensure an adequate airway, oxygenation, and ventilation.
812
Monitor cardiac rhythm and vital signs. EEG monitoring is also recommended for the first
813
48 hours post-ingestion. General supportive and symptomatic measures are also recommended.
814
Induction of emesis is not recommended.
815
Activated charcoal should be administered. There is no experience with the use of forced
816
diuresis, dialysis, hemoperfusion, or exchange transfusion in the management of bupropion
817
overdoses. No specific antidotes for bupropion are known.
818
Due to the dose-related risk of seizures with WELLBUTRIN, hospitalization following
819
suspected overdose should be considered. Based on studies in animals, it is recommended that
820
seizures be treated with intravenous benzodiazepine administration and other supportive
821
measures, as appropriate.
822
In managing overdosage, consider the possibility of multiple drug involvement. The physician
823
should consider contacting a poison control center for additional information on the treatment of
824
any overdose. Telephone numbers for certified poison control centers are listed in the
825
Physicians’ Desk Reference (PDR).
23
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
826
DOSAGE AND ADMINISTRATION
827
General Dosing Considerations: It is particularly important to administer WELLBUTRIN
828
in a manner most likely to minimize the risk of seizure (see WARNINGS). Increases in dose
829
should not exceed 100 mg/day in a 3-day period. Gradual escalation in dosage is also important
830
if agitation, motor restlessness, and insomnia, often seen during the initial days of treatment, are
831
to be minimized. If necessary, these effects may be managed by temporary reduction of dose or
832
the short-term administration of an intermediate to long-acting sedative hypnotic. A sedative
833
hypnotic usually is not required beyond the first week of treatment. Insomnia may also be
834
minimized by avoiding bedtime doses. If distressing, untoward effects supervene, dose escalation
835
should be stopped.
836
No single dose of WELLBUTRIN should exceed 150 mg. WELLBUTRIN should be
837
administered 3 times daily, preferably with at least 6 hours between successive doses.
838
Usual Dosage for Adults: The usual adult dose is 300 mg/day, given 3 times daily. Dosing
839
should begin at 200 mg/day, given as 100 mg twice daily. Based on clinical response, this dose
840
may be increased to 300 mg/day, given as 100 mg 3 times daily, no sooner than 3 days after
841
beginning therapy (see Table 3).
842
843
Table 3. Dosing Regimen
Treatment Day
Total Daily Dose
Tablet Strength
Number of Tablets
Morning Midday
Evening
1
4
200 mg
300 mg
100 mg
100 mg
1
1
0
1
1
1
844
845
Increasing the Dosage Above 300 mg/Day: As with other antidepressants, the full
846
antidepressant effect of WELLBUTRIN may not be evident until 4 weeks of treatment or longer.
847
An increase in dosage, up to a maximum of 450 mg/day, given in divided doses of not more than
848
150 mg each, may be considered for patients in whom no clinical improvement is noted after
849
several weeks of treatment at 300 mg/day. Dosing above 300 mg/day may be accomplished
850
using the 75- or 100-mg tablets. The 100-mg tablet must be administered 4 times daily with at
851
least 4 hours between successive doses, in order not to exceed the limit of 150 mg in a single
852
dose. WELLBUTRIN should be discontinued in patients who do not demonstrate an adequate
853
response after an appropriate period of treatment at 450 mg/day.
854
Maintenance Treatment: The lowest dose that maintains remission is recommended.
855
Although it is not known how long the patient should remain on WELLBUTRIN, it is generally
856
recognized that acute episodes of depression require several months or longer of antidepressant
857
drug treatment.
858
Dosage Adjustment for Patients with Impaired Hepatic Function: WELLBUTRIN
859
should be used with extreme caution in patients with severe hepatic cirrhosis. The dose should
860
not exceed 75 mg once a day in these patients. WELLBUTRIN should be used with caution in
861
patients with hepatic impairment (including mild-to-moderate hepatic cirrhosis) and a reduced
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
862
frequency and/or dose should be considered in patients with mild-to-moderate hepatic cirrhosis
863
(see CLINICAL PHARMACOLOGY, WARNINGS, and PRECAUTIONS).
864
Dosage Adjustment for Patients with Impaired Renal Function: WELLBUTRIN
865
should be used with caution in patients with renal impairment and a reduced frequency and/or
866
dose should be considered (see CLINICAL PHARMACOLOGY and PRECAUTIONS).
867
HOW SUPPLIED
868
WELLBUTRIN Tablets, 75 mg of bupropion hydrochloride, are yellow-gold, round, biconvex
869
tablets printed with “WELLBUTRIN 75” in bottles of 100 (NDC 0173-0177-55).
870
WELLBUTRIN Tablets, 100 mg of bupropion hydrochloride, are red, round, biconvex tablets
871
printed with “WELLBUTRIN 100” in bottles of 100 (NDC 0173-0178-55).
872
Store at 15° to 25°C (59° to 77°F). Protect from light and moisture.
873
874
MEDICATION GUIDE
875
WELLBUTRIN® (WELL byu-trin)
876
(bupropion hydrochloride) Tablets
877
878
Read this Medication Guide carefully before you start using WELLBUTRIN and each time you
879
get a refill. There may be new information. This information does not take the place of talking
880
with your doctor about your medical condition or your treatment. If you have any questions
881
about WELLBUTRIN, ask your doctor or pharmacist.
882
883
IMPORTANT: Be sure to read the three sections of this Medication Guide. The first
884
section is about the risk of suicidal thoughts and actions with antidepressant medicines; the
885
second section is about the risk of changes in thinking and behavior, depression and
886
suicidal thoughts or actions with medicines used to quit smoking; and the third section is
887
entitled “What Other Important Information Should I Know About WELLBUTRIN?”
888
889
Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and
890
Suicidal Thoughts or Actions
891
892
This section of the Medication Guide is only about the risk of suicidal thoughts and actions
893
with antidepressant medicines. Talk to your, or your family member’s, healthcare provider
894
about:
895
• all risks and benefits of treatment with antidepressant medicines
896
• all treatment choices for depression or other serious mental illness
897
898
What is the most important information I should know about antidepressant medicines,
899
depression and other serious mental illnesses, and suicidal thoughts or actions?
25
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
900
1. Antidepressant medicines may increase suicidal thoughts or actions in some children,
901
teenagers, and young adults within the first few months of treatment.
902
2. Depression and other serious mental illnesses are the most important causes of suicidal
903
thoughts and actions. Some people may have a particularly high risk of having suicidal
904
thoughts or actions. These include people who have (or have a family history of) bipolar
905
illness (also called manic-depressive illness) or suicidal thoughts or actions.
906
3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a
907
family member?
908
• Pay close attention to any changes, especially sudden changes, in mood, behaviors,
909
thoughts, or feelings. This is very important when an antidepressant medicine is started or
910
when the dose is changed.
911
• Call the healthcare provider right away to report new or sudden changes in mood,
912
behavior, thoughts, or feelings.
913
• Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare
914
provider between visits as needed, especially if you have concerns about symptoms.
915
916
Call a healthcare provider right away if you or your family member has any of the
917
following symptoms, especially if they are new, worse, or worry you:
918
• thoughts about suicide or dying
• trouble sleeping (insomnia)
• attempts to commit suicide
• new or worse irritability
• new or worse depression
• acting aggressive, being angry, or violent
• new or worse anxiety
• acting on dangerous impulses
• feeling very agitated or restless
• an extreme increase in activity and talking (mania)
• panic attacks
• other unusual changes in behavior or mood
919
920
What else do I need to know about antidepressant medicines?
921
• Never stop an antidepressant medicine without first talking to a healthcare provider.
922
Stopping an antidepressant medicine suddenly can cause other symptoms.
923
• Antidepressants are medicines used to treat depression and other illnesses. It is
924
important to discuss all the risks of treating depression and also the risks of not treating it.
925
Patients and their families or other caregivers should discuss all treatment choices with the
926
healthcare provider, not just the use of antidepressants.
927
• Antidepressant medicines have other side effects. Talk to the healthcare provider about the
928
side effects of the medicine prescribed for you or your family member.
929
• Antidepressant medicines can interact with other medicines. Know all of the medicines
930
that you or your family member takes. Keep a list of all medicines to show the healthcare
931
provider. Do not start new medicines without first checking with your healthcare provider.
26
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
955
932
• Not all antidepressant medicines prescribed for children are FDA approved for use in
933
children. Talk to your child’s healthcare provider for more information.
934
935
WELLBUTRIN has not been studied in children under the age of 18 and is not approved for use
936
in children and teenagers.
937
938
Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior,
939
Depression, and Suicidal Thoughts or Actions
940
941
This section of the Medication Guide is only about the risk of changes in thinking and behavior,
942
depression and suicidal thoughts or actions with drugs used to quit smoking.
943
944
Although WELLBUTRIN is not a treatment for quitting smoking, it contains the same active
945
ingredient (bupropion hydrochloride) as ZYBAN® which is used to help patients quit smoking.
946
947
Some people have had changes in behavior, hostility, agitation, depression, suicidal thoughts or
948
actions while taking bupropion to help them quit smoking. These symptoms can develop during
949
treatment with bupropion or after stopping treatment with bupropion.
950
951
If you, your family member, or your caregiver notice agitation, hostility, depression, or changes
952
in thinking or behavior that are not typical for you, or you have any of the following symptoms,
953
stop taking bupropion and call your healthcare provider right away:
954
• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• panic attacks
• feeling very agitated or restless
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• abnormal thoughts or sensations
• seeing or hearing things that are not there
(hallucinations)
• feeling people are against you (paranoia)
• feeling confused
• other unusual changes in behavior or mood
956
When you try to quit smoking, with or without bupropion, you may have symptoms that may be
957
due to nicotine withdrawal, including urge to smoke, depressed mood, trouble sleeping,
958
irritability, frustration, anger, feeling anxious, difficulty concentrating, restlessness, decreased
959
heart rate, and increased appetite or weight gain. Some people have even experienced suicidal
960
thoughts when trying to quit smoking without medication. Sometimes quitting smoking can lead
961
to worsening of mental health problems that you already have, such as depression.
962
27
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
963
Before taking bupropion, tell your healthcare provider if you have ever had depression or other
964
mental illnesses. You should also tell your doctor about any symptoms you had during other
965
times you tried to quit smoking, with or without bupropion.
966
967
What Other Important Information Should I Know About WELLBUTRIN?
968
969
• Seizures: There is a chance of having a seizure (convulsion, fit) with WELLBUTRIN,
970
especially in people:
971
• with certain medical problems.
972
• who take certain medicines.
973
974
The chance of having seizures increases with higher doses of WELLBUTRIN. For more
975
information, see the sections “Who should not take WELLBUTRIN?” and “What should I
976
tell my doctor before using WELLBUTRIN?” Tell your doctor about all of your medical
977
conditions and all the medicines you take. Do not take any other medicines while you are
978
using WELLBUTRIN unless your doctor has said it is okay to take them.
979
980
If you have a seizure while taking WELLBUTRIN, stop taking the tablets and call your
981
doctor right away. Do not take WELLBUTRIN again if you have a seizure.
982
983
• High blood pressure (hypertension). Some people get high blood pressure, that can be
984
severe, while taking WELLBUTRIN. The chance of high blood pressure may be higher if
985
you also use nicotine replacement therapy (such as a nicotine patch) to help you stop
986
smoking.
987
• Severe allergic reactions. Some people have severe allergic reaction to WELLBUTRIN.
988
Stop taking WELLBUTRIN and call your doctor right away if you get a rash, itching,
989
hives, fever, swollen lymph glands, painful sores in the mouth or around the eyes, swelling of
990
the lips or tongue, chest pain, or have trouble breathing. These could be signs of a serious
991
allergic reaction.
992
• Unusual thoughts or behaviors. Some patients have unusual thoughts or behaviors while
993
taking WELLBUTRIN, including delusions (believe you are someone else), hallucinations
994
(seeing or hearing things that are not there), paranoia (feeling that people are against you), or
995
feeling confused. If this happens to you, call your doctor.
996
997
What is WELLBUTRIN?
998
WELLBUTRIN is a prescription medicine used to treat adults with a certain type of depression
999
called major depressive disorder.
1000
1001
Who should not take WELLBUTRIN?
1002
Do not take WELLBUTRIN if you
28
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1003
• have or had a seizure disorder or epilepsy.
1004
• are taking ZYBAN (used to help people stop smoking) or any other medicines that
1005
contain bupropion hydrochloride, such as WELLBUTRIN SR Sustained-Release
1006
Tablets or WELLBUTRIN XL Extended-Release Tablets. Bupropion is the same active
1007
ingredient that is in WELLBUTRIN.
1008
• drink a lot of alcohol and abruptly stop drinking, or use medicines called sedatives (these
1009
make you sleepy) or benzodiazepines and you stop using them all of a sudden.
1010
• have taken within the last 14 days medicine for depression called a monoamine oxidase
1011
inhibitor (MAOI), such as NARDIL®* (phenelzine sulfate), PARNATE® (tranylcypromine
1012
sulfate), or MARPLAN®* (isocarboxazid).
1013
• have or had an eating disorder such as anorexia nervosa or bulimia.
1014
• are allergic to the active ingredient in WELLBUTRIN, bupropion, or to any of the inactive
1015
ingredients. See the end of this leaflet for a complete list of ingredients in WELLBUTRIN.
1016
1017
What should I tell my doctor before using WELLBUTRIN?
1018
Tell your doctor if you have ever had depression, suicidal thoughts or actions, or other mental
1019
health problems. See “Antidepressant Medicines, Depression and Other Serious Mental Illnesses,
1020
and Suicidal Thoughts or Actions.”
1021
1022
• Tell your doctor about your other medical conditions including if you:
1023
• are pregnant or plan to become pregnant. It is not known if WELLBUTRIN can harm
1024
your unborn baby.
1025
• are breastfeeding. WELLBUTRIN passes through your milk. It is not known if
1026
WELLBUTRIN can harm your baby.
1027
• have liver problems, especially cirrhosis of the liver.
1028
• have kidney problems.
1029
• have an eating disorder, such as anorexia nervosa or bulimia.
1030
• have had a head injury.
1031
• have had a seizure (convulsion, fit).
1032
• have a tumor in your nervous system (brain or spine).
1033
•
have had a heart attack, heart problems, or high blood pressure.
1034
• are a diabetic taking insulin or other medicines to control your blood sugar.
1035
• drink a lot of alcohol.
1036
• abuse prescription medicines or street drugs.
1037
• Tell your doctor about all the medicines you take, including prescription and non
1038
prescription medicines, vitamins, and herbal supplements. Many medicines increase your
1039
chances of having seizures or other serious side effects if you take them while you are using
1040
WELLBUTRIN.
1041
1042
How should I take WELLBUTRIN?
29
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1043
• Take WELLBUTRIN exactly as prescribed by your doctor.
1044
• Take WELLBUTRIN at the same time each day.
1045
• Take your doses of WELLBUTRIN at least 6 hours apart.
1046
• You may take WELLBUTRIN with or without food.
1047
• If you miss a dose, do not take an extra tablet to make up for the dose you forgot. Wait and
1048
take your next tablet at the regular time. This is very important. Too much WELLBUTRIN
1049
can increase your chance of having a seizure.
1050
• If you take too much WELLBUTRIN, or overdose, call your local emergency room or poison
1051
control center right away.
1052
• Do not take any other medicines while using WELLBUTRIN unless your doctor has
1053
told you it is okay.
1054
• It may take several weeks for you to feel that WELLBUTRIN is working. Once you feel
1055
better, it is important to keep taking WELLBUTRIN exactly as directed by your doctor. Call
1056
your doctor if you do not feel WELLBUTRIN is working for you.
1057
• Do not change your dose or stop taking WELLBUTRIN without talking with your doctor
1058
first.
1059
1060
What should I avoid while taking WELLBUTRIN?
1061
• Do not drink a lot of alcohol while taking WELLBUTRIN. If you usually drink a lot of
1062
alcohol, talk with your doctor before suddenly stopping. If you suddenly stop drinking
1063
alcohol, you may increase your risk of having seizures.
1064
• Do not drive a car or use heavy machinery until you know how WELLBUTRIN affects you.
1065
WELLBUTRIN can impair your ability to perform these tasks.
1066
1067
What are possible side effects of WELLBUTRIN?
1068
WELLBUTRIN can cause serious side effects. Read this entire Medication Guide for more
1069
information about these serious side effects.
1070
1071
The most common side effects of WELLBUTRIN are nervousness, constipation, trouble
1072
sleeping, dry mouth, headache, nausea, vomiting, and shakiness (tremor).
1073
1074
If you have nausea, take your medicine with food. If you have trouble sleeping, do not take your
1075
medicine too close to bedtime.
1076
1077
These are not all the side effects of WELLBUTRIN. For a complete list, ask your doctor or
1078
pharmacist.
1079
1080
Call your doctor for medical advice about side effects. You may report side effects to FDA at
1081
1-800-FDA-1088.
1082
30
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1083
How should I store WELLBUTRIN?
1084
• Store WELLBUTRIN at room temperature. Store out of direct sunlight. Keep
1085
WELLBUTRIN in its tightly closed bottle.
1086
1087
General Information about WELLBUTRIN.
1088
• Medicines are sometimes prescribed for purposes other than those listed in a Medication
1089
Guide. Do not use WELLBUTRIN for a condition for which it was not prescribed. Do not
1090
give WELLBUTRIN to other people, even if they have the same symptoms you have. It may
1091
harm them. Keep WELLBUTRIN out of the reach of children.
1092
1093
This Medication Guide summarizes important information about WELLBUTRIN. For more
1094
information, talk to your doctor. You can ask your doctor or pharmacist for information about
1095
WELLBUTRIN that is written for health professionals.
1096
1097
What are the ingredients in WELLBUTRIN?
1098
Active ingredient: bupropion hydrochloride.
1099
1100
Inactive ingredients: 75-mg tablet – D&C Yellow No. 10 Lake, FD&C Yellow No. 6 Lake,
1101
hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and
1102
titanium dioxide; 100-mg tablet – FD&C Red No. 40 Lake, FD&C Yellow No. 6 Lake,
1103
hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and
1104
titanium dioxide.
1105
1106
WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and PARNATE are registered
1107
trademarks of GlaxoSmithKline.
1108
*The following are registered trademarks of their respective manufacturers: NARDIL®/Warner
1109
Lambert Company; MARPLAN®/Oxford Pharmaceutical Services, Inc; KALETRA®/Abbott
1110
Laboratories.
1111
1112
1113
1114
This Medication Guide has been approved by the U.S. Food and Drug Administration.
1115
1116
(Date of Issue)
1117
WLT: 6MG
1118
1119 rx only
company logo
1121
Distributed by:
31
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1122
GlaxoSmithKline
1123
Research Triangle Park, NC 27709
1124
1125
Manufactured by:
1126
DSM Pharmaceuticals, Inc.
1127
Greenville, NC 27834 for
1128
GlaxoSmithKline
1129
Research Triangle Park, NC 27709
1130
1131
©2009, GlaxoSmithKline. All rights reserved.
1132
1133
(Date of Issue)
1134
WLT: 5PI
32
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
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23
24
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26
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28
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30
31
32
33
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35
36
37
38
39
40
PRESCRIBING INFORMATION
WELLBUTRIN SR®
(bupropion hydrochloride)
Sustained-Release Tablets
WARNING
Suicidality and Antidepressant Drugs
Use in Treating Psychiatric Disorders: Antidepressants increased the risk compared to
placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults
in short-term studies of major depressive disorder (MDD) and other psychiatric disorders.
Anyone considering the use of WELLBUTRIN SR or any other antidepressant in a child,
adolescent, or young adult must balance this risk with the clinical need. Short-term studies did
not show an increase in the risk of suicidality with antidepressants compared to placebo in adults
beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults
aged 65 and older. Depression and certain other psychiatric disorders are themselves associated
with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy
should be monitored appropriately and observed closely for clinical worsening, suicidality, or
unusual changes in behavior. Families and caregivers should be advised of the need for close
observation and communication with the prescriber. WELLBUTRIN SR is not approved for use
in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk in Treating
Psychiatric Disorders, PRECAUTIONS: Information for Patients, and PRECAUTIONS:
Pediatric Use.)
Use in Smoking Cessation Treatment: WELLBUTRIN®, WELLBUTRIN SR®, and
WELLBUTRIN XL® are not approved for smoking cessation treatment, but bupropion under the
name ZYBAN® is approved for this use. Serious neuropsychiatric events, including but not
limited to depression, suicidal ideation, suicide attempt, and completed suicide have been
reported in patients taking bupropion for smoking cessation. Some cases may have been
complicated by the symptoms of nicotine withdrawal in patients who stopped smoking.
Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including
suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without
medication. However, some of these symptoms have occurred in patients taking bupropion who
continued to smoke.
All patients being treated with bupropion for smoking cessation treatment should be observed
for neuropsychiatric symptoms including changes in behavior, hostility, agitation, depressed
mood, and suicide-related events, including ideation, behavior, and attempted suicide. These
symptoms, as well as worsening of pre-existing psychiatric illness and completed suicide have
been reported in some patients attempting to quit smoking while taking ZYBAN in the
postmarketing experience. When symptoms were reported, most were during treatment with
ZYBAN, but some were following discontinuation of treatment with ZYBAN. These events have
occurred in patients with and without pre-existing psychiatric disease; some have experienced
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
41
worsening of their psychiatric illnesses. Patients with serious psychiatric illness such as
42
schizophrenia, bipolar disorder, and major depressive disorder did not participate in the
43
premarketing studies of ZYBAN.
44
Advise patients and caregivers that the patient using bupropion for smoking cessation
45
should stop taking bupropion and contact a healthcare provider immediately if agitation,
46
hostility, depressed mood, or changes in thinking or behavior that are not typical for the
47
patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In
48
many postmarketing cases, resolution of symptoms after discontinuation of ZYBAN was
49
reported, although in some cases the symptoms persisted; therefore, ongoing monitoring and
50
supportive care should be provided until symptoms resolve.
51
The risks of using bupropion for smoking cessation should be weighed against the benefits of
52
its use. ZYBAN has been demonstrated to increase the likelihood of abstinence from smoking
53
for as long as 6 months compared to treatment with placebo. The health benefits of quitting
54
smoking are immediate and substantial. (See WARNINGS: Neuropsychiatric Symptoms and
55
Suicide Risk in Smoking Cessation Treatment and PRECAUTIONS: Information for Patients.)
56
DESCRIPTION
57
WELLBUTRIN SR (bupropion hydrochloride), an antidepressant of the aminoketone class, is
58
chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other
59
known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related
60
to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1
61
propanone hydrochloride. The molecular weight is 276.2. The molecular formula is
62
C13H18ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in
63
water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The
64
structural formula is: structural formula
65
66
67
WELLBUTRIN SR is supplied for oral administration as 100-mg (blue), 150-mg (purple),
68
and 200-mg (light pink), film-coated, sustained-release tablets. Each tablet contains the labeled
69
amount of bupropion hydrochloride and the inactive ingredients: carnauba wax, cysteine
70
hydrochloride, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene
71
glycol, polysorbate 80, and titanium dioxide and is printed with edible black ink. In addition, the
72
100-mg tablet contains FD&C Blue No. 1 Lake, the 150-mg tablet contains FD&C Blue No. 2
73
Lake and FD&C Red No. 40 Lake, and the 200-mg tablet contains FD&C Red No. 40 Lake.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
74
CLINICAL PHARMACOLOGY
75
Pharmacodynamics: Bupropion is a relatively weak inhibitor of the neuronal uptake of
76
norepinephrine and dopamine, and does not inhibit monoamine oxidase or the re-uptake of
77
serotonin. While the mechanism of action of bupropion, as with other antidepressants, is
78
unknown, it is presumed that this action is mediated by noradrenergic and/or dopaminergic
79
mechanisms.
80
Pharmacokinetics: Bupropion is a racemic mixture. The pharmacologic activity and
81
pharmacokinetics of the individual enantiomers have not been studied. The mean elimination
82
half-life (±SD) of bupropion after chronic dosing is 21 (±9) hours, and steady-state plasma
83
concentrations of bupropion are reached within 8 days. In a study comparing chronic dosing with
84
WELLBUTRIN SR 150 mg twice daily to the immediate-release formulation of bupropion at
85
100 mg 3 times daily, peak plasma concentrations of bupropion at steady state for
86
WELLBUTRIN SR were approximately 85% of those achieved with the immediate-release
87
formulation. There was equivalence for bupropion AUCs, as well as equivalence for both peak
88
plasma concentration and AUCs for all 3 of the detectable bupropion metabolites. Thus, at steady
89
state, WELLBUTRIN SR, given twice daily, and the immediate-release formulation of
90
bupropion, given 3 times daily, are essentially bioequivalent for both bupropion and the 3
91
quantitatively important metabolites.
92
Absorption: Following oral administration of WELLBUTRIN SR to healthy volunteers,
93
peak plasma concentrations of bupropion are achieved within 3 hours. Food increased Cmax and
94
AUC of bupropion by 11% and 17%, respectively, indicating that there is no clinically
95
significant food effect.
96
Distribution: In vitro tests show that bupropion is 84% bound to human plasma proteins at
97
concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion
98
metabolite is similar to that for bupropion, whereas the extent of protein binding of the
99
threohydrobupropion metabolite is about half that seen with bupropion.
100
Metabolism: Bupropion is extensively metabolized in humans. Three metabolites have been
101
shown to be active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group
102
of bupropion, and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion,
103
which are formed via reduction of the carbonyl group. In vitro findings suggest that cytochrome
104
P450IIB6 (CYP2B6) is the principal isoenzyme involved in the formation of hydroxybupropion,
105
while cytochrome P450 isoenzymes are not involved in the formation of threohydrobupropion.
106
Oxidation of the bupropion side chain results in the formation of a glycine conjugate of
107
meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency
108
and toxicity of the metabolites relative to bupropion have not been fully characterized. However,
109
it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is
110
one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5
111
fold less potent than bupropion. This may be of clinical importance because the plasma
112
concentrations of the metabolites are as high or higher than those of bupropion.
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
113
Because bupropion is extensively metabolized, there is the potential for drug-drug
114
interactions, particularly with those agents that are metabolized by or which inhibit/induce the
115
cytochrome P450IIB6 (CYP2B6) isoenzyme, such as ritonavir. In a healthy volunteer study,
116
ritonavir at a dose of 100 mg twice daily reduced the AUC and Cmax of bupropion by 22% and
117
21%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 23%, the
118
threohydrobupropion decreased by 38%, and the erythrohydrobupropion decreased by 48%.
119
In a second healthy volunteer study, ritonavir at a dose of 600 mg twice daily decreased the
120
AUC and the Cmax of bupropion by 66% and 62%, respectively. The exposure of the
121
hydroxybupropion metabolite was decreased by 78%, the threohydrobupropion decreased by
122
50%, and the erythrohydrobupropion decreased by 68%.
123
In another healthy volunteer study, KALETRA®* (lopinavir 400 mg/ritonavir 100 mg twice
124
daily) decreased bupropion AUC and Cmax by 57%. The AUC and Cmax of hydroxybupropion
125
were decreased by 50% and 31%, respectively (see PRECAUTIONS: Drug Interactions).
126
Although bupropion is not metabolized by cytochrome P450IID6 (CYP2D6), there is the
127
potential for drug-drug interactions when bupropion is coadministered with drugs metabolized
128
by this isoenzyme (see PRECAUTIONS: Drug Interactions).
129
Following a single dose in humans, peak plasma concentrations of hydroxybupropion occur
130
approximately 6 hours after administration of WELLBUTRIN SR. Peak plasma concentrations
131
of hydroxybupropion are approximately 10 times the peak level of the parent drug at steady state.
132
The elimination half-life of hydroxybupropion is approximately 20 (±5) hours, and its AUC at
133
steady state is about 17 times that of bupropion. The times to peak concentrations for the
134
erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the
135
hydroxybupropion metabolite. However, their elimination half-lives are longer, 33 (±10) and 37
136
(±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion,
137
respectively.
138
Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300
139
to 450 mg/day.
140
Elimination: Following oral administration of 200 mg of 14C-bupropion in humans, 87% and
141
10% of the radioactive dose were recovered in the urine and feces, respectively. However, the
142
fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent
143
with the extensive metabolism of bupropion.
144
Population Subgroups: Factors or conditions altering metabolic capacity (e.g., liver disease,
145
congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may be
146
expected to influence the degree and extent of accumulation of the active metabolites of
147
bupropion. The elimination of the major metabolites of bupropion may be affected by reduced
148
renal or hepatic function because they are moderately polar compounds and are likely to undergo
149
further metabolism or conjugation in the liver prior to urinary excretion.
150
Hepatic: The effect of hepatic impairment on the pharmacokinetics of bupropion was
151
characterized in 2 single-dose studies, one in patients with alcoholic liver disease and one in
152
patients with mild-to-severe cirrhosis. The first study showed that the half-life of
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
153
hydroxybupropion was significantly longer in 8 patients with alcoholic liver disease than in
154
8 healthy volunteers (32 ± 14 hours versus 21 ± 5 hours, respectively). Although not statistically
155
significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be
156
greater (by 53% to 57%) in patients with alcoholic liver disease. The differences in half-life for
157
bupropion and the other metabolites in the 2 patient groups were minimal.
158
The second study showed no statistically significant differences in the pharmacokinetics of
159
bupropion and its active metabolites in 9 patients with mild-to-moderate hepatic cirrhosis
160
compared to 8 healthy volunteers. However, more variability was observed in some of the
161
pharmacokinetic parameters for bupropion (AUC, Cmax, and Tmax) and its active metabolites (t½)
162
in patients with mild-to-moderate hepatic cirrhosis. In addition, in patients with severe hepatic
163
cirrhosis, the bupropion Cmax and AUC were substantially increased (mean difference: by
164
approximately 70% and 3-fold, respectively) and more variable when compared to values in
165
healthy volunteers; the mean bupropion half-life was also longer (29 hours in patients with
166
severe hepatic cirrhosis vs. 19 hours in healthy subjects). For the metabolite hydroxybupropion,
167
the mean Cmax was approximately 69% lower. For the combined amino-alcohol isomers
168
threohydrobupropion and erythrohydrobupropion, the mean Cmax was approximately 31% lower.
169
The mean AUC increased by about 1½-fold for hydroxybupropion and about 2½-fold for
170
threo/erythrohydrobupropion. The median Tmax was observed 19 hours later for
171
hydroxybupropion and 31 hours later for threo/erythrohydrobupropion. The mean half-lives for
172
hydroxybupropion and threo/erythrohydrobupropion were increased 5- and 2-fold, respectively,
173
in patients with severe hepatic cirrhosis compared to healthy volunteers (see WARNINGS,
174
PRECAUTIONS, and DOSAGE AND ADMINISTRATION).
175
Renal: There is limited information on the pharmacokinetics of bupropion in patients with
176
renal impairment. An inter-study comparison between normal subjects and patients with end
177
stage renal failure demonstrated that the parent drug Cmax and AUC values were comparable in
178
the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3-
179
and 2.8-fold increase, respectively, in AUC for patients with end-stage renal failure. A second
180
study, comparing normal subjects and patients with moderate-to-severe renal impairment (GFR
181
30.9 ± 10.8 mL/min) showed that exposure to a single 150-mg dose of sustained-release
182
bupropion was approximately 2-fold higher in patients with impaired renal function while levels
183
of the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar
184
in the 2 groups. The elimination of bupropion and/or the major metabolites of bupropion may be
185
reduced by impaired renal function (see PRECAUTIONS: Renal Impairment).
186
Left Ventricular Dysfunction: During a chronic dosing study with bupropion in
187
14 depressed patients with left ventricular dysfunction (history of CHF or an enlarged heart on
188
x-ray), no apparent effect on the pharmacokinetics of bupropion or its metabolites was revealed,
189
compared to healthy volunteers.
190
Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have not
191
been fully characterized, but an exploration of steady-state bupropion concentrations from
192
several depression efficacy studies involving patients dosed in a range of 300 to 750 mg/day, on
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193
a 3 times daily schedule, revealed no relationship between age (18 to 83 years) and plasma
194
concentration of bupropion. A single-dose pharmacokinetic study demonstrated that the
195
disposition of bupropion and its metabolites in elderly subjects was similar to that of younger
196
subjects. These data suggest there is no prominent effect of age on bupropion concentration;
197
however, another pharmacokinetic study, single and multiple dose, has suggested that the elderly
198
are at increased risk for accumulation of bupropion and its metabolites (see PRECAUTIONS:
199
Geriatric Use).
200
Gender: A single-dose study involving 12 healthy male and 12 healthy female volunteers
201
revealed no sex-related differences in the pharmacokinetic parameters of bupropion.
202
Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion were
203
studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17
204
were nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there
205
was no statistically significant difference in Cmax, half-life, Tmax, AUC, or clearance of bupropion
206
or its active metabolites between smokers and nonsmokers.
207
CLINICAL TRIALS
208
The efficacy of the immediate-release formulation of bupropion as a treatment for depression
209
was established in two 4-week, placebo-controlled trials in adult inpatients with depression and
210
in one 6-week, placebo-controlled trial in adult outpatients with depression. In the first study,
211
patients were titrated in a bupropion dose range of 300 to 600 mg/day on a 3 times daily
212
schedule; 78% of patients received maximum doses of 450 mg/day or less. This trial
213
demonstrated the effectiveness of the immediate-release formulation of bupropion on the
214
Hamilton Depression Rating Scale (HDRS) total score, the depressed mood item (item 1) from
215
that scale, and the Clinical Global Impressions (CGI) severity score. A second study included
216
2 fixed doses of the immediate-release formulation of bupropion (300 and 450 mg/day) and
217
placebo. This trial demonstrated the effectiveness of the immediate-release formulation of
218
bupropion, but only at the 450-mg/day dose; the results were positive for the HDRS total score
219
and the CGI severity score, but not for HDRS item 1. In the third study, outpatients received
220
300 mg/day of the immediate-release formulation of bupropion. This study demonstrated the
221
effectiveness of the immediate-release formulation of bupropion on the HDRS total score, HDRS
222
item 1, the Montgomery-Asberg Depression Rating Scale, the CGI severity score, and the CGI
223
improvement score.
224
Although there are not as yet independent trials demonstrating the antidepressant effectiveness
225
of the sustained-release formulation of bupropion, studies have demonstrated the bioequivalence
226
of the immediate-release and sustained-release forms of bupropion under steady-state conditions,
227
i.e., bupropion sustained-release 150 mg twice daily was shown to be bioequivalent to 100 mg
228
3 times daily of the immediate-release formulation of bupropion, with regard to both rate and
229
extent of absorption, for parent drug and metabolites.
230
In a longer-term study, outpatients meeting DSM-IV criteria for major depressive disorder,
231
recurrent type, who had responded during an 8-week open trial on WELLBUTRIN SR (150 mg
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232
twice daily) were randomized to continuation of their same dose of WELLBUTRIN SR or
233
placebo, for up to 44 weeks of observation for relapse. Response during the open phase was
234
defined as CGI Improvement score of 1 (very much improved) or 2 (much improved) for each of
235
the final 3 weeks. Relapse during the double-blind phase was defined as the investigator’s
236
judgment that drug treatment was needed for worsening depressive symptoms. Patients receiving
237
continued treatment with WELLBUTRIN SR experienced significantly lower relapse rates over
238
the subsequent 44 weeks compared to those receiving placebo.
239
INDICATIONS AND USAGE
240
WELLBUTRIN SR is indicated for the treatment of major depressive disorder.
241
The efficacy of bupropion in the treatment of a major depressive episode was established in
242
two 4-week controlled trials of depressed inpatients and in one 6-week controlled trial of
243
depressed outpatients whose diagnoses corresponded most closely to the Major Depression
244
category of the APA Diagnostic and Statistical Manual (DSM) (see CLINICAL
245
PHARMACOLOGY).
246
A major depressive episode (DSM-IV) implies the presence of 1) depressed mood or 2) loss
247
of interest or pleasure; in addition, at least 5 of the following symptoms have been present during
248
the same 2-week period and represent a change from previous functioning: depressed mood,
249
markedly diminished interest or pleasure in usual activities, significant change in weight and/or
250
appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue,
251
feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt
252
or suicidal ideation.
253
The efficacy of WELLBUTRIN SR in maintaining an antidepressant response for up to
254
44 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial
255
(see CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use
256
WELLBUTRIN SR for extended periods should periodically reevaluate the long-term usefulness
257
of the drug for the individual patient.
258
CONTRAINDICATIONS
259
WELLBUTRIN SR is contraindicated in patients with a seizure disorder.
260
WELLBUTRIN SR is contraindicated in patients treated with ZYBAN (bupropion
261
hydrochloride) Sustained-Release Tablets; WELLBUTRIN (bupropion hydrochloride), the
262
immediate-release formulation; WELLBUTRIN XL (bupropion hydrochloride), the extended
263
release formulation; or any other medications that contain bupropion because the incidence of
264
seizure is dose dependent.
265
WELLBUTRIN SR is contraindicated in patients with a current or prior diagnosis of bulimia
266
or anorexia nervosa because of a higher incidence of seizures noted in patients treated for
267
bulimia with the immediate-release formulation of bupropion.
268
WELLBUTRIN SR is contraindicated in patients undergoing abrupt discontinuation of
269
alcohol or sedatives (including benzodiazepines).
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270
The concurrent administration of WELLBUTRIN SR and a monoamine oxidase (MAO)
271
inhibitor is contraindicated. At least 14 days should elapse between discontinuation of an MAO
272
inhibitor and initiation of treatment with WELLBUTRIN SR.
273
WELLBUTRIN SR is contraindicated in patients who have shown an allergic response to
274
bupropion or the other ingredients that make up WELLBUTRIN SR.
275
WARNINGS
276
Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders: Patients
277
with major depressive disorder (MDD), both adult and pediatric, may experience worsening of
278
their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual
279
changes in behavior, whether or not they are taking antidepressant medications, and this risk may
280
persist until significant remission occurs. Suicide is a known risk of depression and certain other
281
psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.
282
There has been a long-standing concern, however, that antidepressants may have a role in
283
inducing worsening of depression and the emergence of suicidality in certain patients during the
284
early phases of treatment. Pooled analyses of short-term placebo-controlled trials of
285
antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal
286
thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with
287
major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not
288
show an increase in the risk of suicidality with antidepressants compared to placebo in adults
289
beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65
290
and older.
291
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
292
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24
293
short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of
294
placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of
295
295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000
296
patients. There was considerable variation in risk of suicidality among drugs, but a tendency
297
toward an increase in the younger patients for almost all drugs studied. There were differences in
298
absolute risk of suicidality across the different indications, with the highest incidence in MDD.
299
The risk differences (drug vs placebo), however, were relatively stable within age strata and
300
across indications. These risk differences (drug-placebo difference in the number of cases of
301
suicidality per 1,000 patients treated) are provided in Table 1.
302
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303
Table 1
Age Range
Drug-Placebo Difference in Number of Cases
of Suicidality per 1,000 Patients Treated
Increases Compared to Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
304
305
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but
306
the number was not sufficient to reach any conclusion about drug effect on suicide.
307
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
308
months. However, there is substantial evidence from placebo-controlled maintenance trials in
309
adults with depression that the use of antidepressants can delay the recurrence of depression.
310
All patients being treated with antidepressants for any indication should be monitored
311
appropriately and observed closely for clinical worsening, suicidality, and unusual changes
312
in behavior, especially during the initial few months of a course of drug therapy, or at times
313
of dose changes, either increases or decreases.
314
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
315
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
316
been reported in adult and pediatric patients being treated with antidepressants for major
317
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
318
Although a causal link between the emergence of such symptoms and either the worsening of
319
depression and/or the emergence of suicidal impulses has not been established, there is concern
320
that such symptoms may represent precursors to emerging suicidality.
321
Consideration should be given to changing the therapeutic regimen, including possibly
322
discontinuing the medication, in patients whose depression is persistently worse, or who are
323
experiencing emergent suicidality or symptoms that might be precursors to worsening depression
324
or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
325
patient’s presenting symptoms.
326
Families and caregivers of patients being treated with antidepressants for major
327
depressive disorder or other indications, both psychiatric and nonpsychiatric, should be
328
alerted about the need to monitor patients for the emergence of agitation, irritability,
329
unusual changes in behavior, and the other symptoms described above, as well as the
330
emergence of suicidality, and to report such symptoms immediately to healthcare
331
providers. Such monitoring should include daily observation by families and caregivers.
332
Prescriptions for WELLBUTRIN SR should be written for the smallest quantity of tablets
333
consistent with good patient management, in order to reduce the risk of overdose.
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334
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment:
335
WELLBUTRIN, WELLBUTRIN SR, and WELLBUTRIN XL are not approved for smoking
336
cessation treatment, but bupropion under the name ZYBAN is approved for this use. Serious
337
neuropsychiatric symptoms have been reported in patients taking bupropion for smoking
338
cessation (see BOXED WARNING, ADVERSE REACTIONS). These have included
339
changes in mood (including depression and mania), psychosis, hallucinations, paranoia,
340
delusions, homicidal ideation, hostility, agitation, aggression, anxiety, and panic, as well as
341
suicidal ideation, suicide attempt, and completed suicide. Some reported cases may have been
342
complicated by the symptoms of nicotine withdrawal in patients who stopped smoking.
343
Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including
344
suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without
345
medication. However, some of these symptoms have occurred in patients taking bupropion who
346
continued to smoke. When symptoms were reported, most were during bupropion treatment, but
347
some were following discontinuation of bupropion therapy.
348
These events have occurred in patients with and without pre-existing psychiatric disease;
349
some have experienced worsening of their psychiatric illnesses. All patients being treated with
350
bupropion as part of smoking cessation treatment should be observed for neuropsychiatric
351
symptoms or worsening of pre-existing psychiatric illness.
352
Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major
353
depressive disorder did not participate in the pre-marketing studies of ZYBAN.
354
Advise patients and caregivers that the patient using bupropion for smoking cessation
355
should stop taking bupropion and contact a healthcare provider immediately if agitation,
356
depressed mood, or changes in behavior or thinking that are not typical for the patient are
357
observed, or if the patient develops suicidal ideation or suicidal behavior. In many
358
postmarketing cases, resolution of symptoms after discontinuation of ZYBAN was
359
reported, although in some cases the symptoms persisted, therefore, ongoing monitoring
360
and supportive care should be provided until symptoms resolve.
361
The risks of using bupropion for smoking cessation should be weighed against the benefits of
362
its use. ZYBAN has been demonstrated to increase the likelihood of abstinence from smoking
363
for as long as six months compared to treatment with placebo. The health benefits of quitting
364
smoking are immediate and substantial.
365
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
366
presentation of bipolar disorder. It is generally believed (though not established in controlled
367
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
368
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
369
symptoms described above represent such a conversion is unknown. However, prior to initiating
370
treatment with an antidepressant, patients with depressive symptoms should be adequately
371
screened to determine if they are at risk for bipolar disorder; such screening should include a
372
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
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373
depression. It should be noted that WELLBUTRIN SR is not approved for use in treating bipolar
374
depression.
375
Bupropion-Containing Products: Patients should be made aware that WELLBUTRIN SR
376
contains the same active ingredient found in ZYBAN, used as an aid to smoking cessation
377
treatment, and that WELLBUTRIN SR should not be used in combination with ZYBAN, or any
378
other medications that contain bupropion, such as WELLBUTRIN (bupropion hydrochloride),
379
the immediate-release formulation or WELLBUTRIN XL (bupropion hydrochloride), the
380
extended-release formulation.
381
382
Seizures: Bupropion is associated with a dose-related risk of seizures. The risk of seizures
383
is also related to patient factors, clinical situations, and concomitant medications, which
384
must be considered in selection of patients for therapy with WELLBUTRIN SR.
385
WELLBUTRIN SR should be discontinued and not restarted in patients who experience a
386
seizure while on treatment.
387
• Dose: At doses of WELLBUTRIN SR up to a dose of 300 mg/day, the incidence of
388
seizure is approximately 0.1% (1/1,000) and increases to approximately 0.4% (4/1,000)
389
at the maximum recommended dose of 400 mg/day.
390
Data for the immediate-release formulation of bupropion revealed a seizure incidence
391
of approximately 0.4% (i.e., 13 of 3,200 patients followed prospectively) in patients
392
treated at doses in a range of 300 to 450 mg/day. The 450-mg/day upper limit of this
393
dose range is close to the currently recommended maximum dose of 400 mg/day for
394
WELLBUTRIN SR. This seizure incidence (0.4%) may exceed that of other marketed
395
antidepressants and WELLBUTRIN SR up to 300 mg/day by as much as 4-fold. This
396
relative risk is only an approximate estimate because no direct comparative studies
397
have been conducted.
398
Additional data accumulated for the immediate-release formulation of bupropion
399
suggested that the estimated seizure incidence increases almost tenfold between 450 and
400
600 mg/day, which is twice the usual adult dose and one and one-half the maximum
401
recommended daily dose (400 mg) of WELLBUTRIN SR. This disproportionate
402
increase in seizure incidence with dose incrementation calls for caution in dosing.
403
Data for WELLBUTRIN SR revealed a seizure incidence of approximately 0.1% (i.e.,
404
3 of 3,100 patients followed prospectively) in patients treated at doses in a range of 100
405
to 300 mg/day. It is not possible to know if the lower seizure incidence observed in this
406
study involving the sustained-release formulation of bupropion resulted from the
407
different formulation or the lower dose used. However, as noted above, the
408
immediate-release and sustained-release formulations are bioequivalent with regard to
409
both rate and extent of absorption during steady state (the most pertinent condition to
410
estimating seizure incidence), since most observed seizures occur under steady-state
411
conditions.
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412
• Patient factors: Predisposing factors that may increase the risk of seizure with
413
bupropion use include history of head trauma or prior seizure, central nervous system
414
(CNS) tumor, the presence of severe hepatic cirrhosis, and concomitant medications
415
that lower seizure threshold.
416
• Clinical situations: Circumstances associated with an increased seizure risk include,
417
among others, excessive use of alcohol or sedatives (including benzodiazepines);
418
addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and
419
anorectics; and diabetes treated with oral hypoglycemics or insulin.
420
• Concomitant medications: Many medications (e.g., antipsychotics, antidepressants,
421
theophylline, systemic steroids) are known to lower seizure threshold.
422
Recommendations for Reducing the Risk of Seizure: Retrospective analysis of
423
clinical experience gained during the development of bupropion suggests that the risk of
424
seizure may be minimized if
425
• the total daily dose of WELLBUTRIN SR does not exceed 400 mg,
426
• the daily dose is administered twice daily, and
427
• the rate of incrementation of dose is gradual.
428
• No single dose should exceed 200 mg to avoid high peak concentrations of bupropion
429
and/or its metabolites.
430
WELLBUTRIN SR should be administered with extreme caution to patients with a
431
history of seizure, cranial trauma, or other predisposition(s) toward seizure, or patients
432
treated with other agents (e.g., antipsychotics, other antidepressants, theophylline, systemic
433
steroids, etc.) that lower seizure threshold.
434
Hepatic Impairment: WELLBUTRIN SR should be used with extreme caution in patients
435
with severe hepatic cirrhosis. In these patients a reduced frequency and/or dose is required,
436
as peak bupropion, as well as AUC, levels are substantially increased and accumulation is
437
likely to occur in such patients to a greater extent than usual. The dose should not exceed
438
100 mg every day or 150 mg every other day in these patients (see CLINICAL
439
PHARMACOLOGY, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).
440
Potential for Hepatotoxicity: In rats receiving large doses of bupropion chronically, there
441
was an increase in incidence of hepatic hyperplastic nodules and hepatocellular hypertrophy. In
442
dogs receiving large doses of bupropion chronically, various histologic changes were seen in the
443
liver, and laboratory tests suggesting mild hepatocellular injury were noted.
444
PRECAUTIONS
445
General: Agitation and Insomnia: Patients in placebo-controlled trials with
446
WELLBUTRIN SR experienced agitation, anxiety, and insomnia as shown in Table 2.
447
12
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448
Table 2. Incidence of Agitation, Anxiety, and Insomnia in Placebo-Controlled Trials
Adverse Event Term
WELLBUTRIN SR
300 mg/day
(n = 376)
WELLBUTRIN SR
400 mg/day
(n = 114)
Placebo
(n = 385)
Agitation
Anxiety
Insomnia
3%
5%
11%
9%
6%
16%
2%
3%
6%
449
450
In clinical studies, these symptoms were sometimes of sufficient magnitude to require
451
treatment with sedative/hypnotic drugs.
452
Symptoms were sufficiently severe to require discontinuation of treatment in 1% and 2.6% of
453
patients treated with 300 and 400 mg/day, respectively, of WELLBUTRIN SR and 0.8% of
454
patients treated with placebo.
455
Psychosis, Confusion, and Other Neuropsychiatric Phenomena: Depressed
456
patients treated with an immediate-release formulation of bupropion or with WELLBUTRIN SR
457
have been reported to show a variety of neuropsychiatric signs and symptoms, including
458
delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. In some
459
cases, these symptoms abated upon dose reduction and/or withdrawal of treatment.
460
Activation of Psychosis and/or Mania: Antidepressants can precipitate manic episodes
461
in bipolar disorder patients during the depressed phase of their illness and may activate latent
462
psychosis in other susceptible patients. WELLBUTRIN SR is expected to pose similar risks.
463
Altered Appetite and Weight: In placebo-controlled studies, patients experienced weight
464
gain or weight loss as shown in Table 3.
465
466
Table 3. Incidence of Weight Gain and Weight Loss in Placebo-Controlled Trials
Weight Change
WELLBUTRIN SR
300 mg/day
(n = 339)
WELLBUTRIN SR
400 mg/day
(n = 112)
Placebo
(n = 347)
Gained >5 lbs
Lost >5 lbs
3%
14%
2%
19%
4%
6%
467
468
In studies conducted with the immediate-release formulation of bupropion, 35% of patients
469
receiving tricyclic antidepressants gained weight, compared to 9% of patients treated with the
470
immediate-release formulation of bupropion. If weight loss is a major presenting sign of a
471
patient’s depressive illness, the anorectic and/or weight-reducing potential of
472
WELLBUTRIN SR should be considered.
473
Allergic Reactions: Anaphylactoid/anaphylactic reactions characterized by symptoms such
474
as pruritus, urticaria, angioedema, and dyspnea requiring medical treatment have been reported
475
in clinical trials with bupropion. In addition, there have been rare spontaneous postmarketing
476
reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated
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477
with bupropion. A patient should stop taking WELLBUTRIN SR and consult a doctor if
478
experiencing allergic or anaphylactoid/anaphylactic reactions (e.g., skin rash, pruritus, hives,
479
chest pain, edema, and shortness of breath) during treatment.
480
Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed
481
hypersensitivity have been reported in association with bupropion. These symptoms may
482
resemble serum sickness.
483
Cardiovascular Effects: In clinical practice, hypertension, in some cases severe, requiring
484
acute treatment, has been reported in patients receiving bupropion alone and in combination with
485
nicotine replacement therapy. These events have been observed in both patients with and without
486
evidence of preexisting hypertension.
487
Data from a comparative study of the sustained-release formulation of bupropion (ZYBAN®
488
Sustained-Release Tablets), nicotine transdermal system (NTS), the combination of sustained
489
release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher
490
incidence of treatment-emergent hypertension in patients treated with the combination of
491
sustained-release bupropion and NTS. In this study, 6.1% of patients treated with the
492
combination of sustained-release bupropion and NTS had treatment-emergent hypertension
493
compared to 2.5%, 1.6%, and 3.1% of patients treated with sustained-release bupropion, NTS,
494
and placebo, respectively. The majority of these patients had evidence of preexisting
495
hypertension. Three patients (1.2%) treated with the combination of ZYBAN and NTS and
496
1 patient (0.4%) treated with NTS had study medication discontinued due to hypertension
497
compared to none of the patients treated with ZYBAN or placebo. Monitoring of blood pressure
498
is recommended in patients who receive the combination of bupropion and nicotine replacement.
499
There is no clinical experience establishing the safety of WELLBUTRIN SR Tablets in
500
patients with a recent history of myocardial infarction or unstable heart disease. Therefore, care
501
should be exercised if it is used in these groups. Bupropion was well tolerated in depressed
502
patients who had previously developed orthostatic hypotension while receiving tricyclic
503
antidepressants, and was also generally well tolerated in a group of 36 depressed inpatients with
504
stable congestive heart failure (CHF). However, bupropion was associated with a rise in supine
505
blood pressure in the study of patients with CHF, resulting in discontinuation of treatment in
506
2 patients for exacerbation of baseline hypertension.
507
Hepatic Impairment: WELLBUTRIN SR should be used with extreme caution in patients
508
with severe hepatic cirrhosis. In these patients, a reduced frequency and/or dose is required.
509
WELLBUTRIN SR should be used with caution in patients with hepatic impairment (including
510
mild-to-moderate hepatic cirrhosis) and reduced frequency and/or dose should be considered in
511
patients with mild-to-moderate hepatic cirrhosis.
512
All patients with hepatic impairment should be closely monitored for possible adverse effects
513
that could indicate high drug and metabolite levels (see CLINICAL PHARMACOLOGY,
514
WARNINGS, and DOSAGE AND ADMINISTRATION).
515
Renal Impairment: There is limited information on the pharmacokinetics of bupropion in
516
patients with renal impairment. An inter-study comparison between normal subjects and patients
14
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517
with end-stage renal failure demonstrated that the parent drug Cmax and AUC values were
518
comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion
519
metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for patients with end-stage
520
renal failure. A second study, comparing normal subjects and patients with moderate-to-severe
521
renal impairment (GFR 30.9 ± 10.8 mL/min) showed that exposure to a single 150-mg dose of
522
sustained-release bupropion was approximately 2-fold higher in patients with impaired renal
523
function while levels of the hydroxybupropion and threo/erythrohydrobupropion (combined)
524
metabolites were similar in the 2 groups. Bupropion is extensively metabolized in the liver to
525
active metabolites, which are further metabolized and subsequently excreted by the kidneys.
526
WELLBUTRIN SR should be used with caution in patients with renal impairment and a reduced
527
frequency and/or dose should be considered as bupropion and the metabolites of bupropion may
528
accumulate in such patients to a greater extent than usual. The patient should be closely
529
monitored for possible adverse effects that could indicate high drug or metabolite levels.
530
Information for Patients: Prescribers or other health professionals should inform patients,
531
their families, and their caregivers about the benefits and risks associated with treatment with
532
WELLBUTRIN SR and should counsel them in its appropriate use. A patient Medication Guide
533
about “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal
534
Thoughts or Actions,” “Quitting Smoking, Quit-Smoking Medication, Changes in Thinking and
535
Behavior, Depression, and Suicidal Thoughts or Actions,” and “What Other Important
536
Information Should I Know About WELLBUTRIN SR?” is available for WELLBUTRIN SR.
537
The prescriber or health professional should instruct patients, their families, and their caregivers
538
to read the Medication Guide and should assist them in understanding its contents. Patients
539
should be given the opportunity to discuss the contents of the Medication Guide and to obtain
540
answers to any questions they may have. The complete text of the Medication Guide is reprinted
541
at the end of this document.
542
Patients should be advised of the following issues and asked to alert their prescriber if these
543
occur while taking WELLBUTRIN SR.
544
Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders: Patients,
545
their families, and their caregivers should be encouraged to be alert to the emergence of anxiety,
546
agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia
547
(psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of
548
depression, and suicidal ideation, especially early during antidepressant treatment and when the
549
dose is adjusted up or down. Families and caregivers of patients should be advised to look for the
550
emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such
551
symptoms should be reported to the patient’s prescriber or health professional, especially if they
552
are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms
553
such as these may be associated with an increased risk for suicidal thinking and behavior and
554
indicate a need for very close monitoring and possibly changes in the medication.
555
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation
556
Treatment: Although WELLBUTRIN SR is not indicated for smoking cessation treatment, it
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
557
contains the same active ingredient as ZYBAN which is approved for this use. Patients should be
558
informed that quitting smoking, with or without ZYBAN, may be associated with nicotine
559
withdrawal symptoms (including depression or agitation), or exacerbation of pre-existing
560
psychiatric illness. Furthermore, some patients have experienced changes in mood (including
561
depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation,
562
aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed
563
suicide when attempting to quit smoking while taking ZYBAN. If patients develop agitation,
564
hostility, depressed mood, or changes in thinking or behavior that are not typical for them, or if
565
patients develop suicidal ideation or behavior, they should be urged to report these symptoms to
566
their healthcare provider immediately.
567
Bupropion-Containing Products: Patients should be made aware that
568
WELLBUTRIN SR contains the same active ingredient found in ZYBAN, used as an aid to
569
smoking cessation treatment, and that WELLBUTRIN SR should not be used in combination
570
with ZYBAN or any other medications that contain bupropion hydrochloride (such as
571
WELLBUTRIN, the immediate-release formulation and WELLBUTRIN XL, the extended
572
release formulation).
573
As dose is increased during initial titration to doses above 150 mg/day, patients should be
574
instructed to take WELLBUTRIN SR in 2 divided doses, preferably with at least 8 hours
575
between successive doses, to minimize the risk of seizures.
576
Patients should be told that WELLBUTRIN SR should be discontinued and not restarted if
577
they experience a seizure while on treatment.
578
Patients should be told that any CNS-active drug like WELLBUTRIN SR may impair their
579
ability to perform tasks requiring judgment or motor and cognitive skills. Consequently, until
580
they are reasonably certain that WELLBUTRIN SR does not adversely affect their performance,
581
they should refrain from driving an automobile or operating complex, hazardous machinery.
582
Patients should be told that the excessive use or abrupt discontinuation of alcohol or sedatives
583
(including benzodiazepines) may alter the seizure threshold. Some patients have reported lower
584
alcohol tolerance during treatment with WELLBUTRIN SR. Patients should be advised that the
585
consumption of alcohol should be minimized or avoided.
586
Patients should be advised to inform their physicians if they are taking or plan to take any
587
prescription or over-the-counter drugs. Concern is warranted because WELLBUTRIN SR and
588
other drugs may affect each other’s metabolism.
589
Patients should be advised to notify their physicians if they become pregnant or intend to
590
become pregnant during therapy.
591
Patients should be advised to swallow WELLBUTRIN SR tablets whole so that the release
592
rate is not altered. Do not chew, divide, or crush tablets, as this may lead to an increased risk of
593
adverse effects, including seizures.
594
Laboratory Tests: There are no specific laboratory tests recommended.
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
595
Drug Interactions: Few systemic data have been collected on the metabolism of bupropion
596
following concomitant administration with other drugs or, alternatively, the effect of
597
concomitant administration of bupropion on the metabolism of other drugs.
598
Because bupropion is extensively metabolized, the coadministration of other drugs may affect
599
its clinical activity. In vitro studies indicate that bupropion is primarily metabolized to
600
hydroxybupropion by the CYP2B6 isoenzyme. Therefore, the potential exists for a drug
601
interaction between WELLBUTRIN SR and drugs that are substrates of or inhibitors/inducers of
602
the CYP2B6 isoenzyme (e.g., orphenadrine, thiotepa, cyclophosphamide, ticlopidine, and
603
clopidogrel). In addition, in vitro studies suggest that paroxetine, sertraline, norfluoxetine, and
604
fluvoxamine as well as nelfinavirand efavirenz inhibit the hydroxylation of bupropion. No
605
clinical studies have been performed to evaluate this finding. The threohydrobupropion
606
metabolite of bupropion does not appear to be produced by the cytochrome P450 isoenzymes.
607
The effects of concomitant administration of cimetidine on the pharmacokinetics of bupropion
608
and its active metabolites were studied in 24 healthy young male volunteers. Following oral
609
administration of two 150-mg WELLBUTRIN SR tablets with and without 800 mg of
610
cimetidine, the pharmacokinetics of bupropion and hydroxybupropion were unaffected.
611
However, there were 16% and 32% increases in the AUC and Cmax, respectively, of the
612
combined moieties of threohydrobupropion and erythrohydrobupropion.
613
In a series of studies in healthy volunteers, ritonavir (100 mg twice daily or 600 mg twice
614
daily) or ritonavir 100 mg plus lopinavir 400 mg (KALETRA) twice daily reduced the exposure
615
of bupropion and its major metabolites in a dose dependent manner by approximately 20% to
616
80%. This effect is thought to be due to the induction of bupropion metabolism. Patients
617
receiving ritonavir may need increased doses of bupropion, but the maximum recommended
618
dose of bupropion should not be exceeded (see CLINICAL PHARMACOLOGY: Metabolism).
619
While not systematically studied, certain drugs may induce the metabolism of bupropion (e.g.,
620
carbamazepine, phenobarbital, phenytoin).
621
Multiple oral doses of bupropion had no statistically significant effects on the single-dose
622
pharmacokinetics of lamotrigine in 12 healthy volunteers.
623
Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in
624
humans. In one study, following chronic administration of bupropion, 100 mg 3 times daily to
625
8 healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism.
626
Nevertheless, there may be the potential for clinically important alterations of blood levels of
627
coadministered drugs.
628
Drugs Metabolized By Cytochrome P450IID6 (CYP2D6): Many drugs, including most
629
antidepressants (SSRIs, many tricyclics), beta-blockers, antiarrhythmics, and antipsychotics are
630
metabolized by the CYP2D6 isoenzyme. Although bupropion is not metabolized by this
631
isoenzyme, bupropion and hydroxybupropion are inhibitors of CYP2D6 isoenzyme in vitro. In a
632
study of 15 male subjects (aged 19 to 35 years) who were extensive metabolizers of the CYP2D6
633
isoenzyme, daily doses of bupropion given as 150 mg twice daily followed by a single dose of
634
50 mg desipramine increased the Cmax, AUC, and t1/2 of desipramine by an average of
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
635
approximately 2-, 5-, and 2-fold, respectively. The effect was present for at least 7 days after the
636
last dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6
637
has not been formally studied.
638
Therefore, coadministration of bupropion with drugs that are metabolized by CYP2D6
639
isoenzyme including certain antidepressants (e.g., nortriptyline, imipramine, desipramine,
640
paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine),
641
beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide),
642
should be approached with caution and should be initiated at the lower end of the dose range of
643
the concomitant medication. If bupropion is added to the treatment regimen of a patient already
644
receiving a drug metabolized by CYP2D6, the need to decrease the dose of the original
645
medication should be considered, particularly for those concomitant medications with a narrow
646
therapeutic index.
647
Although citalopram is not primarily metabolized by CYP2D6, in one study bupropion
648
increased the Cmax and AUC of citalopram by 30% and 40%, respectively. Citalopram did not
649
affect the pharmacokinetics of bupropion and its 3 metabolites.
650
MAO Inhibitors: Studies in animals demonstrate that the acute toxicity of bupropion is
651
enhanced by the MAO inhibitor phenelzine (see CONTRAINDICATIONS).
652
Levodopa and Amantadine: Limited clinical data suggest a higher incidence of adverse
653
experiences in patients receiving bupropion concurrently with either levodopa or amantadine.
654
Administration of WELLBUTRIN SR to patients receiving either levodopa or amantadine
655
concurrently should be undertaken with caution, using small initial doses and gradual dose
656
increases.
657
Drugs That Lower Seizure Threshold: Concurrent administration of
658
WELLBUTRIN SR and agents (e.g., antipsychotics, other antidepressants, theophylline,
659
systemic steroids, etc.) that lower seizure threshold should be undertaken only with extreme
660
caution (see WARNINGS). Low initial dosing and gradual dose increases should be employed.
661
Nicotine Transdermal System: (see PRECAUTIONS: Cardiovascular Effects).
662
Alcohol: In postmarketing experience, there have been rare reports of adverse
663
neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol
664
during treatment with WELLBUTRIN SR. The consumption of alcohol during treatment with
665
WELLBUTRIN SR should be minimized or avoided (also see CONTRAINDICATIONS).
666
Carcinogenesis, Mutagenesis, Impairment of Fertility: Lifetime carcinogenicity studies
667
were performed in rats and mice at doses up to 300 and 150 mg/kg/day, respectively. These
668
doses are approximately 7 and 2 times the maximum recommended human dose (MRHD),
669
respectively, on a mg/m2 basis. In the rat study there was an increase in nodular proliferative
670
lesions of the liver at doses of 100 to 300 mg/kg/day (approximately 2 to 7 times the MRHD on a
671
mg/m2 basis); lower doses were not tested. The question of whether or not such lesions may be
672
precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen
673
in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in
674
either study.
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
675
Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of 5 strains in
676
the Ames bacterial mutagenicity test and an increase in chromosomal aberrations in 1 of 3 in
677
vivo rat bone marrow cytogenetic studies.
678
A fertility study in rats at doses up to 300 mg/kg/day revealed no evidence of impaired
679
fertility.
680
Pregnancy: Teratogenic Effects: Pregnancy Category C. In studies conducted in rats and
681
rabbits, bupropion was administered orally at doses up to 450 and 150 mg/kg/day, respectively
682
(approximately 11 and 7 times the MRHD, respectively, on a mg/m2 basis), during the period of
683
organogenesis. No clear evidence of teratogenic activity was found in either species; however, in
684
rabbits, slightly increased incidences of fetal malformations and skeletal variations were
685
observed at the lowest dose tested (25 mg/kg/day, approximately equal to the MRHD on a mg/m2
686
basis) and greater. Decreased fetal weights were seen at 50 mg/kg and greater.
687
When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately
688
7 times the MRHD on a mg/m2 basis) prior to mating and throughout pregnancy and lactation,
689
there were no apparent adverse effects on offspring development.
690
One study has been conducted in pregnant women. This retrospective, managed-care database
691
study assessed the risk of congenital malformations overall and cardiovascular malformations
692
specifically, following exposure to bupropion in the first trimester compared to the risk of these
693
malformations following exposure to other antidepressants in the first trimester and bupropion
694
outside of the first trimester. This study included 7,005 infants with antidepressant exposure
695
during pregnancy, 1,213 of whom were exposed to bupropion in the first trimester. The study
696
showed no greater risk for congenital malformations overall or cardiovascular malformations
697
specifically, following first trimester bupropion exposure compared to exposure to all other
698
antidepressants in the first trimester, or bupropion outside of the first trimester. The results of
699
this study have not been corroborated. WELLBUTRIN SR should be used during pregnancy only
700
if the potential benefit justifies the potential risk to the fetus.
701
Labor and Delivery: The effect of WELLBUTRIN SR on labor and delivery in humans is
702
unknown.
703
Nursing Mothers: Like many other drugs, bupropion and its metabolites are secreted in human
704
milk. Because of the potential for serious adverse reactions in nursing infants from
705
WELLBUTRIN SR, a decision should be made whether to discontinue nursing or to discontinue
706
the drug, taking into account the importance of the drug to the mother.
707
Pediatric Use: Safety and effectiveness in the pediatric population have not been established
708
(see BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk in Treating
709
Psychiatric Disorders).
710
Anyone considering the use of WELLBUTRIN SR in a child or adolescent must balance the
711
potential risks with the clinical need.
712
Geriatric Use: Of the approximately 6,000 patients who participated in clinical trials with
713
bupropion sustained-release tablets (depression and smoking cessation studies), 275 were 65 and
714
over and 47 were 75 and over. In addition, several hundred patients 65 and over participated in
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
715
clinical trials using the immediate-release formulation of bupropion (depression studies). No
716
overall differences in safety or effectiveness were observed between these subjects and younger
717
subjects, and other reported clinical experience has not identified differences in responses
718
between the elderly and younger patients, but greater sensitivity of some older individuals cannot
719
be ruled out.
720
A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its
721
metabolites in elderly subjects was similar to that of younger subjects; however, another
722
pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased
723
risk for accumulation of bupropion and its metabolites (see CLINICAL PHARMACOLOGY).
724
Bupropion is extensively metabolized in the liver to active metabolites, which are further
725
metabolized and excreted by the kidneys. The risk of toxic reaction to this drug may be greater in
726
patients with impaired renal function. Because elderly patients are more likely to have decreased
727
renal function, care should be taken in dose selection, and it may be useful to monitor renal
728
function (see PRECAUTIONS: Renal Impairment and DOSAGE AND ADMINISTRATION).
729
ADVERSE REACTIONS
730
(See also WARNINGS and PRECAUTIONS.)
731
The information included under the Incidence in Controlled Trials subsection of ADVERSE
732
REACTIONS is based primarily on data from controlled clinical trials with WELLBUTRIN SR.
733
Information on additional adverse events associated with the sustained-release formulation of
734
bupropion in smoking cessation trials, as well as the immediate-release formulation of
735
bupropion, is included in a separate section (see Other Events Observed During the Clinical
736
Development and Postmarketing Experience of Bupropion).
737
Incidence in Controlled Trials With WELLBUTRIN SR: Adverse Events Associated
738
With Discontinuation of Treatment Among Patients Treated With
739
WELLBUTRIN SR: In placebo-controlled clinical trials, 9% and 11% of patients treated with
740
300 and 400 mg/day, respectively, of WELLBUTRIN SR and 4% of patients treated with
741
placebo discontinued treatment due to adverse events. The specific adverse events in these trials
742
that led to discontinuation in at least 1% of patients treated with either 300 or 400 mg/day of
743
WELLBUTRIN SR and at a rate at least twice the placebo rate are listed in Table 4.
744
745
Table 4. Treatment Discontinuations Due to Adverse Events in Placebo-Controlled Trials
Adverse Event Term
WELLBUTRIN SR
300 mg/day
(n = 376)
WELLBUTRIN SR
400 mg/day
(n = 114)
Placebo
(n = 385)
Rash
Nausea
Agitation
Migraine
2.4%
0.8%
0.3%
0.0%
0.9%
1.8%
1.8%
1.8%
0.0%
0.3%
0.3%
0.3%
20
746
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
747
Adverse Events Occurring at an Incidence of 1% or More Among Patients
748
Treated With WELLBUTRIN SR: Table 5 enumerates treatment-emergent adverse events that
749
occurred among patients treated with 300 and 400 mg/day of WELLBUTRIN SR and with
750
placebo in placebo-controlled trials. Events that occurred in either the 300- or 400-mg/day group
751
at an incidence of 1% or more and were more frequent than in the placebo group are included.
752
Reported adverse events were classified using a COSTART-based Dictionary.
753
Accurate estimates of the incidence of adverse events associated with the use of any drug are
754
difficult to obtain. Estimates are influenced by drug dose, detection technique, setting, physician
755
judgments, etc. The figures cited cannot be used to predict precisely the incidence of untoward
756
events in the course of usual medical practice where patient characteristics and other factors
757
differ from those that prevailed in the clinical trials. These incidence figures also cannot be
758
compared with those obtained from other clinical studies involving related drug products as each
759
group of drug trials is conducted under a different set of conditions.
760
Finally, it is important to emphasize that the tabulation does not reflect the relative severity
761
and/or clinical importance of the events. A better perspective on the serious adverse events
762
associated with the use of WELLBUTRIN SR is provided in the WARNINGS and
763
PRECAUTIONS sections.
764
765
Table 5. Treatment-Emergent Adverse Events in Placebo-Controlled Trialsa
Body System/
Adverse Event
WELLBUTRIN SR
300 mg/day
(n = 376)
WELLBUTRIN SR
400 mg/day
(n = 114)
Placebo
(n = 385)
Body (General)
Headache
26%
25%
23%
Infection
8%
9%
6%
Abdominal pain
3%
9%
2%
Asthenia
2%
4%
2%
Chest pain
3%
4%
1%
Pain
2%
3%
2%
Fever
1%
2%
—
Cardiovascular
Palpitation
2%
6%
2%
Flushing
1%
4%
—
Migraine
1%
4%
1%
Hot flashes
1%
3%
1%
Digestive
Dry mouth
17%
24%
7%
Nausea
13%
18%
8%
Constipation
10%
5%
7%
Diarrhea
5%
7%
6%
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Anorexia
Vomiting
Dysphagia
5%
4%
0%
3%
2%
2%
2%
2%
0%
Musculoskeletal
Myalgia
2%
6%
3%
Arthralgia
1%
4%
1%
Arthritis
0%
2%
0%
Twitch
1%
2%
—
Nervous system
Insomnia
11%
16%
6%
Dizziness
7%
11%
5%
Agitation
3%
9%
2%
Anxiety
5%
6%
3%
Tremor
6%
3%
1%
Nervousness
5%
3%
3%
Somnolence
2%
3%
2%
Irritability
3%
2%
2%
Memory decreased
—
3%
1%
Paresthesia
1%
2%
1%
Central nervous system
stimulation
2%
1%
1%
Respiratory
Pharyngitis
3%
11%
2%
Sinusitis
3%
1%
2%
Increased cough
1%
2%
1%
Skin
Sweating
6%
5%
2%
Rash
5%
4%
1%
Pruritus
2%
4%
2%
Urticaria
2%
1%
0%
Special senses
Tinnitus
6%
6%
2%
Taste perversion
2%
4%
—
Blurred vision or
diplopia
3%
2%
2%
Urogenital
Urinary frequency
2%
5%
2%
Urinary urgency
—
2%
0%
Vaginal hemorrhageb
0%
2%
—
Urinary tract infection
1%
0%
—
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
766
a Adverse events that occurred in at least 1% of patients treated with either 300 or 400 mg/day
767
of WELLBUTRIN SR, but equally or more frequently in the placebo group, were: abnormal
768
dreams, accidental injury, acne, appetite increased, back pain, bronchitis, dysmenorrhea,
769
dyspepsia, flatulence, flu syndrome, hypertension, neck pain, respiratory disorder, rhinitis, and
770
tooth disorder.
771
b Incidence based on the number of female patients.
772
— Hyphen denotes adverse events occurring in greater than 0 but less than 0.5% of patients.
773
774
Incidence of Commonly Observed Adverse Events in Controlled Clinical Trials:
775
Adverse events from Table 5 occurring in at least 5% of patients treated with
776
WELLBUTRIN SR and at a rate at least twice the placebo rate are listed below for the 300- and
777
400-mg/day dose groups.
778
WELLBUTRIN SR 300 mg/day: Anorexia, dry mouth, rash, sweating, tinnitus, and
779
tremor.
780
WELLBUTRIN SR 400 mg/day: Abdominal pain, agitation, anxiety, dizziness, dry
781
mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary
782
frequency.
783
Other Events Observed During the Clinical Development and Postmarketing
784
Experience of Bupropion: In addition to the adverse events noted above, the following
785
events have been reported in clinical trials and postmarketing experience with the
786
sustained-release formulation of bupropion in depressed patients and in nondepressed smokers,
787
as well as in clinical trials and postmarketing clinical experience with the immediate-release
788
formulation of bupropion.
789
Adverse events for which frequencies are provided below occurred in clinical trials with the
790
sustained-release formulation of bupropion. The frequencies represent the proportion of patients
791
who experienced a treatment-emergent adverse event on at least one occasion in
792
placebo-controlled studies for depression (n = 987) or smoking cessation (n = 1,013), or patients
793
who experienced an adverse event requiring discontinuation of treatment in an open-label
794
surveillance study with WELLBUTRIN SR Tablets (n = 3,100). All treatment-emergent adverse
795
events are included except those listed in Tables 2 through 5, those events listed in other
796
safety-related sections, those adverse events subsumed under COSTART terms that are either
797
overly general or excessively specific so as to be uninformative, those events not reasonably
798
associated with the use of the drug, and those events that were not serious and occurred in fewer
799
than 2 patients. Events of major clinical importance are described in the WARNINGS and
800
PRECAUTIONS sections of the labeling.
801
Events are further categorized by body system and listed in order of decreasing frequency
802
according to the following definitions of frequency: Frequent adverse events are defined as those
803
occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to
804
1/1,000 patients, while rare events are those occurring in less than 1/1,000 patients.
23
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
805
Adverse events for which frequencies are not provided occurred in clinical trials or
806
postmarketing experience with bupropion. Only those adverse events not previously listed for
807
sustained-release bupropion are included. The extent to which these events may be associated
808
with WELLBUTRIN SR is unknown.
809
Body (General): Infrequent were chills, facial edema, musculoskeletal chest pain, and
810
photosensitivity. Rare was malaise. Also observed were arthralgia, myalgia, and fever with rash
811
and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble
812
serum sickness (see PRECAUTIONS).
813
Cardiovascular: Infrequent were postural hypotension, stroke, tachycardia, and
814
vasodilation. Rare was syncope. Also observed were complete atrioventricular block,
815
extrasystoles, hypotension, hypertension (in some cases severe, see PRECAUTIONS),
816
myocardial infarction, phlebitis, and pulmonary embolism.
817
Digestive: Infrequent were abnormal liver function, bruxism, gastric reflux, gingivitis,
818
glossitis, increased salivation, jaundice, mouth ulcers, stomatitis, and thirst. Rare was edema of
819
tongue. Also observed were colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage,
820
hepatitis, intestinal perforation, liver damage, pancreatitis, and stomach ulcer.
821
Endocrine: Also observed were hyperglycemia, hypoglycemia, and syndrome of
822
inappropriate antidiuretic hormone.
823
Hemic and Lymphatic: Infrequent was ecchymosis. Also observed were anemia,
824
leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered PT
825
and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were
826
observed when bupropion was coadministered with warfarin.
827
Metabolic and Nutritional: Infrequent were edema and peripheral edema. Also observed
828
was glycosuria.
829
Musculoskeletal: Infrequent were leg cramps. Also observed were muscle
830
rigidity/fever/rhabdomyolysis and muscle weakness.
831
Nervous System: Infrequent were abnormal coordination, decreased libido,
832
depersonalization, dysphoria, emotional lability, hostility, hyperkinesia, hypertonia, hypesthesia,
833
suicidal ideation, and vertigo. Rare were amnesia, ataxia, derealization, and hypomania. Also
834
observed were abnormal electroencephalogram (EEG), akinesia, aggression, aphasia, coma,
835
completed suicide, delirium, delusions, dysarthria, dyskinesia, dystonia, euphoria,
836
extrapyramidal syndrome, hallucinations, hypokinesia, increased libido, manic reaction,
837
neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, and unmasking tardive
838
dyskinesia.
839
Respiratory: Rare was bronchospasm. Also observed was pneumonia.
840
Skin: Rare was maculopapular rash. Also observed were alopecia, angioedema, exfoliative
841
dermatitis, and hirsutism.
842
Special Senses: Infrequent were accommodation abnormality and dry eye. Also observed
843
were deafness, diplopia, increased intraocular pressure, and mydriasis.
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
844
Urogenital: Infrequent were impotence, polyuria, and prostate disorder. Also observed were
845
abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection,
846
salpingitis, urinary incontinence, urinary retention, and vaginitis.
847
DRUG ABUSE AND DEPENDENCE
848
Controlled Substance Class: Bupropion is not a controlled substance.
849
Humans: Controlled clinical studies of bupropion (immediate-release formulation) conducted
850
in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed patients
851
showed some increase in motor activity and agitation/excitement.
852
In a population of individuals experienced with drugs of abuse, a single dose of 400 mg of
853
bupropion produced mild amphetamine-like activity as compared to placebo on the
854
Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI), and a
855
score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These
856
scales measure general feelings of euphoria and drug desirability.
857
Findings in clinical trials, however, are not known to reliably predict the abuse potential of
858
drugs. Nonetheless, evidence from single-dose studies does suggest that the recommended daily
859
dosage of bupropion when administered in divided doses is not likely to be especially reinforcing
860
to amphetamine or stimulant abusers. However, higher doses that could not be tested because of
861
the risk of seizure might be modestly attractive to those who abuse stimulant drugs.
862
Animals: Studies in rodents and primates have shown that bupropion exhibits some
863
pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase
864
locomotor activity, elicit a mild stereotyped behavioral response, and increase rates of
865
responding in several schedule-controlled behavior paradigms. In primate models to assess the
866
positive reinforcing effects of psychoactive drugs, bupropion was self-administered
867
intravenously. In rats, bupropion produced amphetamine-like and cocaine-like discriminative
868
stimulus effects in drug discrimination paradigms used to characterize the subjective effects of
869
psychoactive drugs.
870
OVERDOSAGE
871
Human Overdose Experience: Overdoses of up to 30 g or more of bupropion have been
872
reported. Seizure was reported in approximately one-third of all cases. Other serious reactions
873
reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus
874
tachycardia, and ECG changes such as conduction disturbances (including QRS prolongation) or
875
arrhythmias. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory
876
failure have been reported mainly when bupropion was part of multiple drug overdoses.
877
Although most patients recovered without sequelae, deaths associated with overdoses of
878
bupropion alone have been reported in patients ingesting large doses of the drug. Multiple
879
uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported
880
in these patients.
881
Overdosage Management: Ensure an adequate airway, oxygenation, and ventilation.
882
Monitor cardiac rhythm and vital signs. EEG monitoring is also recommended for the first
25
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
883
48 hours post-ingestion. General supportive and symptomatic measures are also recommended.
884
Induction of emesis is not recommended.
885
Activated charcoal should be administered. There is no experience with the use of forced
886
diuresis, dialysis, hemoperfusion, or exchange transfusion in the management of bupropion
887
overdoses. No specific antidotes for bupropion are known.
888
Due to the dose-related risk of seizures with WELLBUTRIN SR, hospitalization following
889
suspected overdose should be considered. Based on studies in animals, it is recommended that
890
seizures be treated with intravenous benzodiazepine administration and other supportive
891
measures, as appropriate.
892
In managing overdosage, consider the possibility of multiple drug involvement. The physician
893
should consider contacting a poison control center for additional information on the treatment of
894
any overdose. Telephone numbers for certified poison control centers are listed in the
895
Physicians’ Desk Reference (PDR).
896
DOSAGE AND ADMINISTRATION
897
General Dosing Considerations: It is particularly important to administer
898
WELLBUTRIN SR in a manner most likely to minimize the risk of seizure (see WARNINGS).
899
Gradual escalation in dosage is also important if agitation, motor restlessness, and insomnia,
900
often seen during the initial days of treatment, are to be minimized. If necessary, these effects
901
may be managed by temporary reduction of dose or the short-term administration of an
902
intermediate to long-acting sedative hypnotic. A sedative hypnotic usually is not required beyond
903
the first week of treatment. Insomnia may also be minimized by avoiding bedtime doses. If
904
distressing, untoward effects supervene, dose escalation should be stopped. WELLBUTRIN SR
905
should be swallowed whole and not crushed, divided, or chewed, as this may lead to an increased
906
risk of adverse effects including seizures.
907
Initial Treatment: The usual adult target dose for WELLBUTRIN SR is 300 mg/day, given as
908
150 mg twice daily. Dosing with WELLBUTRIN SR should begin at 150 mg/day given as a
909
single daily dose in the morning. If the 150-mg initial dose is adequately tolerated, an increase to
910
the 300-mg/day target dose, given as 150 mg twice daily, may be made as early as day 4 of
911
dosing. There should be an interval of at least 8 hours between successive doses.
912
Increasing the Dosage Above 300 mg/day: As with other antidepressants, the full
913
antidepressant effect of WELLBUTRIN SR may not be evident until 4 weeks of treatment or
914
longer. An increase in dosage to the maximum of 400 mg/day, given as 200 mg twice daily, may
915
be considered for patients in whom no clinical improvement is noted after several weeks of
916
treatment at 300 mg/day.
917
Maintenance Treatment: It is generally agreed that acute episodes of depression require
918
several months or longer of sustained pharmacological therapy beyond response to the acute
919
episode. In a study in which patients with major depressive disorder, recurrent type, who had
920
responded during 8 weeks of acute treatment with WELLBUTRIN SR were assigned randomly
921
to placebo or to the same dose of WELLBUTRIN SR (150 mg twice daily) during 44 weeks of
26
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
922
maintenance treatment as they had received during the acute stabilization phase, longer-term
923
efficacy was demonstrated (see CLINICAL TRIALS under CLINICAL PHARMACOLOGY).
924
Based on these limited data, it is unknown whether or not the dose of WELLBUTRIN SR needed
925
for maintenance treatment is identical to the dose needed to achieve an initial response. Patients
926
should be periodically reassessed to determine the need for maintenance treatment and the
927
appropriate dose for such treatment.
928
Dosage Adjustment for Patients with Impaired Hepatic Function: WELLBUTRIN SR
929
should be used with extreme caution in patients with severe hepatic cirrhosis. The dose should
930
not exceed 100 mg every day or 150 mg every other day in these patients. WELLBUTRIN SR
931
should be used with caution in patients with hepatic impairment (including mild-to-moderate
932
hepatic cirrhosis) and a reduced frequency and/or dose should be considered in patients with
933
mild-to-moderate hepatic cirrhosis (see CLINICAL PHARMACOLOGY, WARNINGS, and
934
PRECAUTIONS).
935
Dosage Adjustment for Patients with Impaired Renal Function: WELLBUTRIN SR
936
should be used with caution in patients with renal impairment and a reduced frequency and/or
937
dose should be considered (see CLINICAL PHARMACOLOGY and PRECAUTIONS).
938
HOW SUPPLIED
939
WELLBUTRIN SR Sustained-Release Tablets, 100 mg of bupropion hydrochloride, are blue,
940
round, biconvex, film-coated tablets printed with “WELLBUTRIN SR 100” in bottles of 60
941
(NDC 0173-0947-55) tablets.
942
WELLBUTRIN SR Sustained-Release Tablets, 150 mg of bupropion hydrochloride, are
943
purple, round, biconvex, film-coated tablets printed with "WELLBUTRIN SR 150" in bottles of
944
60 (NDC 0173-0135-55) tablets.
945
WELLBUTRIN SR Sustained-Release Tablets, 200 mg of bupropion hydrochloride, are light
946
pink, round, biconvex, film-coated tablets printed with “WELLBUTRIN SR 200” in bottles of 60
947
(NDC 0173-0722-00) tablets.
948
Store at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP]. Dispense in a
949
tight, light-resistant container as defined in the USP.
950
951
MEDICATION GUIDE
952
WELLBUTRIN SR® (WELL byu-trin)
953
(bupropion hydrochloride) Sustained-Release Tablets
954
955
Read this Medication Guide carefully before you start using WELLBUTRIN SR and each time
956
you get a refill. There may be new information. This information does not take the place of
957
talking with your doctor about your medical condition or your treatment. If you have any
958
questions about WELLBUTRIN SR, ask your doctor or pharmacist.
959
27
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
960
IMPORTANT: Be sure to read the three sections of this Medication Guide. The first
961
section is about the risk of suicidal thoughts and actions with antidepressant medicines; the
962
second section is about the risk of changes in thinking and behavior, depression and
963
suicidal thoughts or actions with medicines used to quit smoking; and the third section is
964
entitled “What Other Important Information Should I Know About WELLBUTRIN SR?”
965
966
Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and
967
Suicidal Thoughts or Actions
968
969
This section of the Medication Guide is only about the risk of suicidal thoughts and actions with
970
antidepressant medicines. Talk to your, or your family member’s, healthcare provider
971
about:
972
• all risks and benefits of treatment with antidepressant medicines
973
• all treatment choices for depression or other serious mental illness
974
975
What is the most important information I should know about antidepressant medicines,
976
depression and other serious mental illnesses, and suicidal thoughts or actions?
977
1. Antidepressant medicines may increase suicidal thoughts or actions in some children,
978
teenagers, and young adults within the first few months of treatment.
979
2. Depression and other serious mental illnesses are the most important causes of suicidal
980
thoughts and actions. Some people may have a particularly high risk of having suicidal
981
thoughts or actions. These include people who have (or have a family history of) bipolar
982
illness (also called manic-depressive illness) or suicidal thoughts or actions.
983
3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a
984
family member?
985
• Pay close attention to any changes, especially sudden changes, in mood, behaviors,
986
thoughts, or feelings. This is very important when an antidepressant medicine is started or
987
when the dose is changed.
988
• Call the healthcare provider right away to report new or sudden changes in mood,
989
behavior, thoughts, or feelings.
990
• Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare
991
provider between visits as needed, especially if you have concerns about symptoms.
992
993
Call a healthcare provider right away if you or your family member has any of the
994
following symptoms, especially if they are new, worse, or worry you:
995
28
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• thoughts about suicide or dying
• trouble sleeping (insomnia)
• attempts to commit suicide
• new or worse irritability
• new or worse depression
• acting aggressive, being angry, or violent
• new or worse anxiety
• acting on dangerous impulses
• feeling very agitated or restless
• an extreme increase in activity and talking (mania)
• panic attacks
• other unusual changes in behavior or mood
996
997
What else do I need to know about antidepressant medicines?
998
• Never stop an antidepressant medicine without first talking to a healthcare provider.
999
Stopping an antidepressant medicine suddenly can cause other symptoms.
1000
• Antidepressants are medicines used to treat depression and other illnesses. It is
1001
important to discuss all the risks of treating depression and also the risks of not treating it.
1002
Patients and their families or other caregivers should discuss all treatment choices with the
1003
healthcare provider, not just the use of antidepressants.
1004
• Antidepressant medicines have other side effects. Talk to the healthcare provider about the
1005
side effects of the medicine prescribed for you or your family member.
1006
• Antidepressant medicines can interact with other medicines. Know all of the medicines
1007
that you or your family member takes. Keep a list of all medicines to show the healthcare
1008
provider. Do not start new medicines without first checking with your healthcare provider.
1009
• Not all antidepressant medicines prescribed for children are FDA approved for use in
1010
children. Talk to your child’s healthcare provider for more information.
1011
1012
WELLBUTRIN SR has not been studied in children under the age of 18 and is not approved for
1013
use in children and teenagers.
1014
1015
Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior,
1016
Depression, and Suicidal Thoughts or Actions
1017
1018
This section of the Medication Guide is only about the risk of changes in thinking and behavior,
1019
depression and suicidal thoughts or actions with drugs used to quit smoking.
1020
1021
Although WELLBUTRIN SR is not a treatment for quitting smoking, it contains the same active
1022
ingredient (bupropion hydrochloride) as ZYBAN® which is used to help patients quit smoking.
1023
1024
Some people have had changes in behavior, hostility, agitation, depression, suicidal thoughts or
1025
actions while taking bupropion to help them quit smoking. These symptoms can develop during
1026
treatment with bupropion or after stopping treatment with bupropion.
1027
29
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1028
If you, your family member, or your caregiver notice agitation, hostility, depression, or changes
1029
in thinking or behavior that are not typical for you, or you have any of the following symptoms,
1030
stop taking bupropion and call your healthcare provider right away:
1031
• thoughts about suicide or dying
• an extreme increase in activity and talking (mania)
• attempts to commit suicide
• abnormal thoughts or sensations
• new or worse depression
• seeing or hearing things that are not there
• new or worse anxiety
(hallucinations)
• panic attacks
• feeling people are against you (paranoia)
• feeling very agitated or restless
• feeling confused
• acting aggressive, being angry, or violent
• other unusual changes in behavior or mood
• acting on dangerous impulses
1032
1033
When you try to quit smoking, with or without bupropion, you may have symptoms that may be
1034
due to nicotine withdrawal, including urge to smoke, depressed mood, trouble sleeping,
1035
irritability, frustration, anger, feeling anxious, difficulty concentrating, restlessness, decreased
1036
heart rate, and increased appetite or weight gain. Some people have even experienced suicidal
1037
thoughts when trying to quit smoking without medication. Sometimes quitting smoking can lead
1038
to worsening of mental health problems that you already have, such as depression.
1039
1040
Before taking bupropion, tell your healthcare provider if you have ever had depression or other
1041
mental illnesses. You should also tell your doctor about any symptoms you had during other
1042
times you tried to quit smoking, with or without bupropion.
1043
1044
What Other Important Information Should I Know About WELLBUTRIN SR?
1045
1046
• Seizures: There is a chance of having a seizure (convulsion, fit) with WELLBUTRIN SR,
1047
especially in people:
1048
• with certain medical problems.
1049
• who take certain medicines.
1050
1051
The chance of having seizures increases with higher doses of WELLBUTRIN SR. For more
1052
information, see the sections “Who should not take WELLBUTRIN SR?” and “What should
1053
I tell my doctor before using WELLBUTRIN SR?” Tell your doctor about all of your
1054
medical conditions and all the medicines you take. Do not take any other medicines while
1055
you are using WELLBUTRIN SR unless your doctor has said it is okay to take them.
1056
1057
If you have a seizure while taking WELLBUTRIN SR, stop taking the tablets and call
1058
your doctor right away. Do not take WELLBUTRIN SR again if you have a seizure.
1059
30
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1060
• High blood pressure (hypertension). Some people get high blood pressure, that can be
1061
severe, while taking WELLBUTRIN SR. The chance of high blood pressure may be higher
1062
if you also use nicotine replacement therapy (such as a nicotine patch) to help you stop
1063
smoking.
1064
• Severe allergic reactions. Some people have severe allergic reaction to
1065
WELLBUTRIN SR. Stop taking WELLBUTRIN SR and call your doctor right away if
1066
you get a rash, itching, hives, fever, swollen lymph glands, painful sores in the mouth or
1067
around the eyes, swelling of the lips or tongue, chest pain, or have trouble breathing. These
1068
could be signs of a serious allergic reaction.
1069
• Unusual thoughts or behaviors. Some patients have unusual thoughts or behaviors while
1070
taking WELLBUTRIN SR, including delusions (believe you are someone else),
1071
hallucinations (seeing or hearing things that are not there), paranoia (feeling that people are
1072
against you), or feeling confused. If this happens to you, call your doctor.
1073
1074
What is WELLBUTRIN SR?
1075
WELLBUTRIN SR is a prescription medicine used to treat adults with a certain type of
1076
depression called major depressive disorder.
1077
1078
Who should not take WELLBUTRIN SR?
1079
Do not take WELLBUTRIN SR if you
1080
• have or had a seizure disorder or epilepsy.
1081
• are taking ZYBAN® (used to help people stop smoking) or any other medicines that
1082
contain bupropion hydrochloride, such as WELLBUTRIN® Tablets or WELLBUTRIN
1083
XL® Extended-Release Tablets. Bupropion is the same active ingredient that is in
1084
WELLBUTRIN SR.
1085
• drink a lot of alcohol and abruptly stop drinking, or use medicines called sedatives (these
1086
make you sleepy) or benzodiazepines and you stop using them all of a sudden.
1087
• have taken within the last 14 days medicine for depression called a monoamine oxidase
1088
inhibitor (MAOI), such as NARDIL®*(phenelzine sulfate), PARNATE®(tranylcypromine
1089
sulfate), or MARPLAN®*(isocarboxazid).
1090
• have or had an eating disorder such as anorexia nervosa or bulimia.
1091
• are allergic to the active ingredient in WELLBUTRIN SR, bupropion, or to any of the
1092
inactive ingredients. See the end of this leaflet for a complete list of ingredients in
1093
WELLBUTRIN SR.
1094
1095
What should I tell my doctor before using WELLBUTRIN SR?
1096
Tell your doctor if you have ever had depression, suicidal thoughts or actions, or other mental
1097
health problems. See “Antidepressant Medicines, Depression and Other Serious Mental Illnesses,
1098
and Suicidal Thoughts or Actions.”
1099
• Tell your doctor about your other medical conditions including if you:
31
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1100
• are pregnant or plan to become pregnant. It is not known if WELLBUTRIN SR can
1101
harm your unborn baby.
1102
• are breastfeeding. WELLBUTRIN SR passes through your milk. It is not known if
1103
WELLBUTRIN SR can harm your baby.
1104
• have liver problems, especially cirrhosis of the liver.
1105
• have kidney problems.
1106
• have an eating disorder such as anorexia nervosa or bulimia.
1107
• have had a head injury.
1108
• have had a seizure (convulsion, fit).
1109
• have a tumor in your nervous system (brain or spine).
1110
• have had a heart attack, heart problems, or high blood pressure.
1111
• are a diabetic taking insulin or other medicines to control your blood sugar.
1112
• drink a lot of alcohol.
1113
• abuse prescription medicines or street drugs.
1114
• Tell your doctor about all the medicines you take, including prescription and non
1115
prescription medicines, vitamins, and herbal supplements. Many medicines increase your
1116
chances of having seizures or other serious side effects if you take them while you are using
1117
WELLBUTRIN SR.
1118
1119
How should I take WELLBUTRIN SR?
1120
• Take WELLBUTRIN SR exactly as prescribed by your doctor.
1121
• Do not chew, cut, or crush WELLBUTRIN SR tablets. If you do, the medicine will be
1122
released into your body too quickly. If this happens you may be more likely to get side
1123
effects including seizures.You must swallow the tablets whole. Tell your doctor if you
1124
cannot swallow medicine tablets.
1125
• Take WELLBUTRIN SR at the same time each day.
1126
• Take your doses of WELLBUTRIN SR at least 8 hours apart.
1127
• You may take WELLBUTRIN SR with or without food.
1128
• If you miss a dose, do not take an extra tablet to make up for the dose you forgot. Wait and
1129
take your next tablet at the regular time. This is very important. Too much
1130
WELLBUTRIN SR can increase your chance of having a seizure.
1131
• If you take too much WELLBUTRIN SR, or overdose, call your local emergency room or
1132
poison control center right away.
1133
• Do not take any other medicines while using WELLBUTRIN SR unless your doctor has
1134
told you it is okay.
1135
• It may take several weeks for you to feel that WELLBUTRIN SR is working. Once you feel
1136
better, it is important to keep taking WELLBUTRIN SR exactly as directed by your doctor.
1137
Call your doctor if you do not feel WELLBUTRIN SR is working for you.
1138
• Do not change your dose or stop taking WELLBUTRIN SR without talking with your doctor
1139
first.
32
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1140
1141
What should I avoid while taking WELLBUTRIN SR?
1142
• Do not drink a lot of alcohol while taking WELLBUTRIN SR. If you usually drink a lot of
1143
alcohol, talk with your doctor before suddenly stopping. If you suddenly stop drinking
1144
alcohol, you may increase your chance of having seizures.
1145
• Do not drive a car or use heavy machinery until you know how WELLBUTRIN SR affects
1146
you. WELLBUTRIN SR can impair your ability to perform these tasks.
1147
1148
What are possible side effects of WELLBUTRIN SR?
1149
WELLBUTRIN SR can cause serious side effects. Read this entire Medication Guide for more
1150
information about these serious side effects.
1151
1152
The most common side effects of WELLBUTRIN SR are loss of appetite, dry mouth, skin rash,
1153
sweating, ringing in the ears, shakiness, stomach pain, agitation, anxiety, dizziness, trouble
1154
sleeping, muscle pain, nausea, fast heartbeat, sore throat, and urinating more often.
1155
1156
If you have nausea, take your medicine with food. If you have trouble sleeping, do not take your
1157
medicine too close to bedtime.
1158
1159
These are not all the side effects of WELLBUTRIN SR. For a complete list, ask your doctor or
1160
pharmacist.
1161
1162
Call your doctor for medical advice about side effects. You may report side effects to FDA at
1163
1-800-FDA-1088.
1164
1165
How should I store WELLBUTRIN SR?
1166
• Store WELLBUTRIN SR at room temperature. Store out of direct sunlight. Keep
1167
WELLBUTRIN SR in its tightly closed bottle.
1168
• WELLBUTRIN SR tablets may have an odor.
1169
1170
General Information about WELLBUTRIN SR.
1171
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
1172
Do not use WELLBUTRIN SR for a condition for which it was not prescribed. Do not give
1173
WELLBUTRIN SR to other people, even if they have the same symptoms you have. It may harm
1174
them. Keep WELLBUTRIN SR out of the reach of children.
1175
1176
This Medication Guide summarizes important information about WELLBUTRIN SR. For more
1177
information, talk with your doctor. You can ask your doctor or pharmacist for information about
1178
WELLBUTRIN SR that is written for health professionals.
1179
33
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1180
What are the ingredients in WELLBUTRIN SR?
1181
Active ingredient: bupropion hydrochloride.
1182
1183
Inactive ingredients: carnauba wax, cysteine hydrochloride, hypromellose, magnesium stearate,
1184
microcrystalline cellulose, polyethylene glycol, polysorbate 80, and titanium dioxide. In
1185
addition, the 100-mg tablet contains FD&C Blue No. 1 Lake, the 150-mg tablet contains FD&C
1186
Blue No. 2 Lake and FD&C Red No. 40 Lake, and the 200-mg tablet contains FD&C Red No. 40
1187
Lake. The tablets are printed with edible black ink.
1188
1189
WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, ZYBAN, and PARNATE are
1190
registered trademarks of GlaxoSmithKline.
1191
*The following are registered trademarks of their respective manufacturers: NARDIL®/Warner
1192
Lambert Company; MARPLAN®/Oxford Pharmaceutical Services, Inc.; KALETRA®/Abbott
1193
Laboratories.
1194
1195
1196
1197
This Medication Guide has been approved by the U.S. Food and Drug Administration.
1198
1199
(Date of Issue)
1200
WLS: 6MG
1201 rx only
company logo
1203
Distributed by:
1204
GlaxoSmithKline
1205
Research Triangle Park, NC 27709
1206
1207
Manufactured by:
1208
GlaxoSmithKline
1209
Research Triangle Park, NC 27709
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or DSM Pharmaceuticals, Inc.
1211
Greenville, NC 27834
1212
1213
©2009, GlaxoSmithKline. All rights reserved.
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1215
(Date of Issue)
1216
WLS: 5PI
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018644s038,020358s045lbl.pdf', 'application_number': 18644, 'submission_type': 'SUPPL ', 'submission_number': 38}
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PRESCRIBING INFORMATION
WELLBUTRIN®
(bupropion hydrochloride)
Tablets
WARNING
Suicidality and Antidepressant Drugs
Use in Treating Psychiatric Disorders: Antidepressants increased the risk compared to
placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults
in short-term studies of major depressive disorder (MDD) and other psychiatric disorders.
Anyone considering the use of WELLBUTRIN or any other antidepressant in a child, adolescent,
or young adult must balance this risk with the clinical need. Short-term studies did not show an
increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age
24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and
older. Depression and certain other psychiatric disorders are themselves associated with
increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy
should be monitored appropriately and observed closely for clinical worsening, suicidality, or
unusual changes in behavior. Families and caregivers should be advised of the need for close
observation and communication with the prescriber. WELLBUTRIN is not approved for use in
pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk in Treating
Psychiatric Disorders, PRECAUTIONS: Information for Patients, and PRECAUTIONS:
Pediatric Use.)
Use in Smoking Cessation Treatment: WELLBUTRIN®, WELLBUTRIN SR®, and
WELLBUTRIN XL® are not approved for smoking cessation treatment, but bupropion under the
name ZYBAN® is approved for this use. Serious neuropsychiatric events, including but not
limited to depression, suicidal ideation, suicide attempt, and completed suicide have been
reported in patients taking bupropion for smoking cessation. Some cases may have been
complicated by the symptoms of nicotine withdrawal in patients who stopped smoking.
Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including
suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without
medication. However, some of these symptoms have occurred in patients taking bupropion who
continued to smoke.
All patients being treated with bupropion for smoking cessation treatment should be observed
for neuropsychiatric symptoms including changes in behavior, hostility, agitation, depressed
mood, and suicide-related events, including ideation, behavior, and attempted suicide. These
symptoms, as well as worsening of pre-existing psychiatric illness and completed suicide have
been reported in some patients attempting to quit smoking while taking ZYBAN in the
postmarketing experience. When symptoms were reported, most were during treatment with
ZYBAN, but some were following discontinuation of treatment with ZYBAN. These events have
occurred in patients with and without pre-existing psychiatric disease; some have experienced
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Reference ID: 2978172
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For current labeling information, please visit https://www.fda.gov/drugsatfda
worsening of their psychiatric illnesses. Patients with serious psychiatric illness such as
schizophrenia, bipolar disorder, and major depressive disorder did not participate in the
premarketing studies of ZYBAN.
Advise patients and caregivers that the patient using bupropion for smoking cessation
should stop taking bupropion and contact a healthcare provider immediately if agitation,
hostility, depressed mood, or changes in thinking or behavior that are not typical for the
patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In
many postmarketing cases, resolution of symptoms after discontinuation of ZYBAN was
reported, although in some cases the symptoms persisted; therefore, ongoing monitoring and
supportive care should be provided until symptoms resolve.
The risks of using bupropion for smoking cessation should be weighed against the benefits of
its use. ZYBAN has been demonstrated to increase the likelihood of abstinence from smoking
for as long as 6 months compared to treatment with placebo. The health benefits of quitting
smoking are immediate and substantial. (See WARNINGS: Neuropsychiatric Symptoms and
Suicide Risk in Smoking Cessation Treatment and PRECAUTIONS: Information for Patients.)
DESCRIPTION
WELLBUTRIN (bupropion hydrochloride), an antidepressant of the aminoketone class, is
chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other
known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related
to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1
propanone hydrochloride. The molecular weight is 276.2. The empirical formula is
C13H18ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in
water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The
structural formula is: structural formula
WELLBUTRIN is supplied for oral administration as 75-mg (yellow-gold) and 100-mg (red)
film-coated tablets. Each tablet contains the labeled amount of bupropion hydrochloride and the
inactive ingredients: 75-mg tablet – D&C Yellow No. 10 Lake, FD&C Yellow No. 6 Lake,
hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and
titanium dioxide; 100-mg tablet – FD&C Red No. 40 Lake, FD&C Yellow No. 6 Lake,
hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and
titanium dioxide.
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Reference ID: 2978172
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CLINICAL PHARMACOLOGY
Pharmacodynamics: The neurochemical mechanism of the antidepressant effect of
bupropion is not known. Bupropion is a relatively weak inhibitor of the neuronal uptake of
norepinephrine and dopamine, and does not inhibit monoamine oxidase or the re-uptake of
serotonin.
Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals,
as evidenced by increased locomotor activity, increased rates of responding in various
schedule-controlled operant behavior tasks, and, at high doses, induction of mild stereotyped
behavior.
Bupropion causes convulsions in rodents and dogs at doses approximately tenfold the dose
recommended as the human antidepressant dose.
Pharmacokinetics: Bupropion is a racemic mixture. The pharmacological activity and
pharmacokinetics of the individual enantiomers have not been studied. In humans, following oral
administration of WELLBUTRIN, peak plasma bupropion concentrations are usually achieved
within 2 hours, followed by a biphasic decline. The terminal phase has a mean half-life of
14 hours, with a range of 8 to 24 hours. The distribution phase has a mean half-life of 3 to
4 hours. The mean elimination half-life (±SD) of bupropion after chronic dosing is 21 (±9)
hours, and steady-state plasma concentrations of bupropion are reached within 8 days. Plasma
bupropion concentrations are dose-proportional following single doses of 100 to 250 mg;
however, it is not known if the proportionality between dose and plasma level is maintained in
chronic use.
Absorption: The absolute bioavailability of WELLBUTRIN in humans has not been
determined because an intravenous formulation for human use is not available. However, it
appears likely that only a small proportion of any orally administered dose reaches the systemic
circulation intact.
Distribution: In vitro tests show that bupropion is 84% bound to human plasma protein at
concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion
metabolite is similar to that for bupropion, whereas the extent of protein binding of the
threohydrobupropion metabolite is about half that seen with bupropion.
Metabolism: Bupropion is extensively metabolized in humans. Three metabolites have been
shown to be active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group
of bupropion, and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion,
which are formed via reduction of the carbonyl group. In vitro findings suggest that cytochrome
P450IIB6 (CYP2B6) is the principal isoenzyme involved in the formation of hydroxybupropion,
while cytochrome P450 isoenzymes are not involved in the formation of threohydrobupropion.
Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta
chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and
toxicity of the metabolites relative to bupropion have not been fully characterized. However, it
has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is
one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5
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Reference ID: 2978172
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For current labeling information, please visit https://www.fda.gov/drugsatfda
fold less potent than bupropion. This may be of clinical importance because their plasma
concentrations are as high or higher than those of bupropion.
Because bupropion is extensively metabolized, there is the potential for drug-drug
interactions, particularly with those agents that are metabolized by or which inhibit/induce the
cytochrome P450IIB6 (CYP2B6) isoenzyme, such as ritonavir or efavirenz. In a healthy
volunteer study, ritonavir at a dose of 100 mg twice daily reduced the AUC and Cmax of
bupropion by 22% and 21%, respectively. The exposure of the hydroxybupropion metabolite was
decreased by 23%, the threohydrobupropion decreased by 38%, and the erythrohydrobupropion
decreased by 48%.
In a second healthy volunteer study, ritonavir at a dose of 600 mg twice daily decreased the
AUC and the Cmax of bupropion by 66% and 62%, respectively. The exposure of the
hydroxybupropion metabolite was decreased by 78%, the threohydrobupropion decreased by
50%, and the erythrohydrobupropion decreased by 68%.
In another healthy volunteer study, KALETRA® (lopinavir 400 mg/ritonavir 100 mg twice
daily) decreased bupropion AUC and Cmax by 57%. The AUC and Cmax of hydroxybupropion
were decreased by 50% and 31%, respectively (see PRECAUTIONS: Drug Interactions).
In a study in healthy volunteers, efavirenz 600 mg once daily for 2 weeks reduced the AUC
and Cmax of bupropion by approximately 55% and 34%, respectively. The AUC of
hydroxybupropion was unchanged, whereas Cmax of hydroxybupropion was increased by 50%.
Although bupropion is not metabolized by cytochrome P450IID6 (CYP2D6), there is the
potential for drug-drug interactions when bupropion is coadministered with drugs metabolized
by this isoenzyme (see PRECAUTIONS: Drug Interactions).
Following a single dose in humans, peak plasma concentrations of hydroxybupropion occur
approximately 3 hours after administration of WELLBUTRIN. Peak plasma concentrations of
hydroxybupropion are approximately 10 times the peak level of the parent drug at steady state.
The elimination half-life of hydroxybupropion is approximately 20 (±5) hours, and its AUC at
steady state is about 17 times that of bupropion. The times to peak concentrations for the
erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the
hydroxybupropion metabolite. However, their elimination half-lives are longer, 33 (±10) and
37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion,
respectively.
Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300
to 450 mg/day.
Elimination: Following oral administration of 200 mg of 14C-bupropion in humans, 87% and
10% of the radioactive dose were recovered in the urine and feces, respectively. However, the
fraction of the oral dose of WELLBUTRIN excreted unchanged was only 0.5%, a finding
consistent with the extensive metabolism of bupropion.
Populations Subgroups: Factors or conditions altering metabolic capacity (e.g., liver
disease, congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may
be expected to influence the degree and extent of accumulation of the active metabolites of
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Reference ID: 2978172
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bupropion. The elimination of the major metabolites of bupropion may be affected by reduced
renal or hepatic function because they are moderately polar compounds and are likely to undergo
further metabolism or conjugation in the liver prior to urinary excretion.
Hepatic: The effect of hepatic impairment on the pharmacokinetics of bupropion was
characterized in 2 single-dose studies, one in patients with alcoholic liver disease and one in
patients with mild-to-severe cirrhosis. The first study showed that the half-life of
hydroxybupropion was significantly longer in 8 patients with alcoholic liver disease than in
8 healthy volunteers (32 ± 14 hours versus 21 ± 5 hours, respectively). Although not statistically
significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be
greater (by 53% to 57%) in volunteers with alcoholic liver disease. The differences in half-life
for bupropion and the other metabolites in the 2 patient groups were minimal.
The second study showed that there were no statistically significant differences in the
pharmacokinetics of bupropion and its active metabolites in 9 patients with mild-to-moderate
hepatic cirrhosis compared to 8 healthy volunteers. However, more variability was observed in
some of the pharmacokinetic parameters for bupropion (AUC, Cmax, and Tmax) and its active
metabolites (t½) in patients with mild-to-moderate hepatic cirrhosis. In addition, in patients with
severe hepatic cirrhosis, the bupropion Cmax and AUC were substantially increased (mean
difference: by approximately 70% and 3-fold, respectively) and more variable when compared to
values in healthy volunteers; the mean bupropion half-life was also longer (29 hours in patients
with severe hepatic cirrhosis vs. 19 hours in healthy subjects). For the metabolite
hydroxybupropion, the mean Cmax was approximately 69% lower. For the combined amino-
alcohol isomers threohydrobupropion and erythrohydrobupropion, the mean Cmax was
approximately 31% lower. The mean AUC increased by about 1½-fold for hydroxybupropion
and about 2½-fold for threo/erythrohydrobupropion. The median Tmax was observed 19 hours
later for hydroxybupropion and 31 hours later for threo/erythrohydrobupropion. The mean
half-lives for hydroxybupropion and threo/erythrohydrobupropion were increased 5- and 2-fold,
respectively, in patients with severe hepatic cirrhosis compared to healthy volunteers (see
WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).
Renal: There is limited information on the pharmacokinetics of bupropion in patients with
renal impairment. An inter-study comparison between normal subjects and patients with end-
stage renal failure demonstrated that the parent drug Cmax and AUC values were comparable in
the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3-
and 2.8-fold increase, respectively, in AUC for patients with end-stage renal failure. A second
study, comparing normal subjects and patients with moderate-to-severe renal impairment (GFR
30.9 ± 10.8 mL/min) showed that exposure to a single 150-mg dose of sustained-release
bupropion was approximately 2-fold higher in patients with impaired renal function while levels
of the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar
in the 2 groups. The elimination of bupropion and/or the major metabolites of bupropion may be
reduced by impaired renal function (see PRECAUTIONS: Renal Impairment).
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Reference ID: 2978172
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Left Ventricular Dysfunction: During a chronic dosing study in 14 depressed patients
with left ventricular dysfunction (history of CHF or an enlarged heart on x-ray), no apparent
effect on the pharmacokinetics of bupropion or its metabolites was revealed, compared to healthy
volunteers.
Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have not
been fully characterized, but an exploration of steady-state bupropion concentrations from
several depression efficacy studies involving patients dosed in a range of 300 to 750 mg/day, on
a 3 times daily schedule, revealed no relationship between age (18 to 83 years) and plasma
concentration of bupropion. A single-dose pharmacokinetic study demonstrated that the
disposition of bupropion and its metabolites in elderly subjects was similar to that of younger
subjects. These data suggest there is no prominent effect of age on bupropion concentration;
however, another pharmacokinetic study, single and multiple dose, has suggested that the elderly
are at increased risk for accumulation of bupropion and its metabolites (see PRECAUTIONS:
Geriatric Use).
Gender: A single-dose study involving 12 healthy male and 12 healthy female volunteers
revealed no sex-related differences in the pharmacokinetic parameters of bupropion.
Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion were
studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17
were nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there
were no statistically significant differences in Cmax, half-life, Tmax, AUC or clearance of
bupropion or its active metabolites between smokers and nonsmokers.
INDICATIONS AND USAGE
WELLBUTRIN is indicated for the treatment of major depressive disorder. A physician
considering WELLBUTRIN for the management of a patient’s first episode of depression should
be aware that the drug may cause generalized seizures in a dose-dependent manner with an
approximate incidence of 0.4% (4/1,000). This incidence of seizures may exceed that of other
marketed antidepressants by as much as 4-fold. This relative risk is only an approximate estimate
because no direct comparative studies have been conducted (see WARNINGS).
The efficacy of WELLBUTRIN has been established in 3 placebo-controlled trials, including
2 of approximately 3 weeks’ duration in depressed inpatients and one of approximately 6 weeks’
duration in depressed outpatients. The depressive disorder of the patients studied corresponds
most closely to the Major Depression category of the APA Diagnostic and Statistical Manual III.
Major Depression implies a prominent and relatively persistent depressed or dysphoric mood
that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should
include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor
agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased
fatigability, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and
suicidal ideation or attempts.
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Reference ID: 2978172
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Effectiveness of WELLBUTRIN in long-term use, that is, for more than 6 weeks, has not
been systematically evaluated in controlled trials. Therefore, the physician who elects to use
WELLBUTRIN for extended periods should periodically reevaluate the long-term usefulness of
the drug for the individual patient.
CONTRAINDICATIONS
WELLBUTRIN is contraindicated in patients with a seizure disorder.
WELLBUTRIN is contraindicated in patients treated with ZYBAN® (bupropion
hydrochloride) Sustained-Release Tablets; WELLBUTRIN SR® (bupropion hydrochloride), the
sustained-release formulation; WELLBUTRIN XL® (bupropion hydrochloride), the extended-
release formulation; or any other medications that contain bupropion because the incidence of
seizure is dose dependent.
WELLBUTRIN is contraindicated in patients with a current or prior diagnosis of bulimia or
anorexia nervosa because of a higher incidence of seizures noted in such patients treated with
WELLBUTRIN.
WELLBUTRIN is contraindicated in patients undergoing abrupt discontinuation of alcohol or
sedatives (including benzodiazepines).
The concurrent administration of WELLBUTRIN and a monoamine oxidase (MAO) inhibitor
is contraindicated. At least 14 days should elapse between discontinuation of an MAO inhibitor
and initiation of treatment with WELLBUTRIN.
WELLBUTRIN is contraindicated in patients who have shown an allergic response to
bupropion or the other ingredients that make up WELLBUTRIN.
WARNINGS
Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders: Patients
with major depressive disorder (MDD), both adult and pediatric, may experience worsening of
their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual
changes in behavior, whether or not they are taking antidepressant medications, and this risk may
persist until significant remission occurs. Suicide is a known risk of depression and certain other
psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.
There has been a long-standing concern, however, that antidepressants may have a role in
inducing worsening of depression and the emergence of suicidality in certain patients during the
early phases of treatment. Pooled analyses of short-term placebo-controlled trials of
antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal
thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with
major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not
show an increase in the risk of suicidality with antidepressants compared to placebo in adults
beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65
and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24
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Reference ID: 2978172
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For current labeling information, please visit https://www.fda.gov/drugsatfda
short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of
placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of
295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000
patients. There was considerable variation in risk of suicidality among drugs, but a tendency
toward an increase in the younger patients for almost all drugs studied. There were differences in
absolute risk of suicidality across the different indications, with the highest incidence in MDD.
The risk differences (drug vs placebo), however, were relatively stable within age strata and
across indications. These risk differences (drug-placebo difference in the number of cases of
suicidality per 1,000 patients treated) are provided in Table 1.
Table 1
Age Range
Drug-Placebo Difference in Number of Cases
of Suicidality per 1,000 Patients Treated
Increases Compared to Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but
the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
months. However, there is substantial evidence from placebo-controlled maintenance trials in
adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored
appropriately and observed closely for clinical worsening, suicidality, and unusual changes
in behavior, especially during the initial few months of a course of drug therapy, or at times
of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
been reported in adult and pediatric patients being treated with antidepressants for major
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of
depression and/or the emergence of suicidal impulses has not been established, there is concern
that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly
discontinuing the medication, in patients whose depression is persistently worse, or who are
experiencing emergent suicidality or symptoms that might be precursors to worsening depression
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Reference ID: 2978172
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For current labeling information, please visit https://www.fda.gov/drugsatfda
or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major
depressive disorder or other indications, both psychiatric and nonpsychiatric, should be
alerted about the need to monitor patients for the emergence of agitation, irritability,
unusual changes in behavior, and the other symptoms described above, as well as the
emergence of suicidality, and to report such symptoms immediately to healthcare
providers. Such monitoring should include daily observation by families and caregivers.
Prescriptions for WELLBUTRIN should be written for the smallest quantity of tablets consistent
with good patient management, in order to reduce the risk of overdose.
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment:
WELLBUTRIN, WELLBUTRIN SR, and WELLBUTRIN XL are not approved for smoking
cessation treatment, but bupropion under the name ZYBAN is approved for this use. Serious
neuropsychiatric symptoms have been reported in patients taking bupropion for smoking
cessation (see BOXED WARNING, ADVERSE REACTIONS). These have included
changes in mood (including depression and mania), psychosis, hallucinations, paranoia,
delusions, homicidal ideation, hostility, agitation, aggression, anxiety, and panic, as well as
suicidal ideation, suicide attempt, and completed suicide. Some reported cases may have been
complicated by the symptoms of nicotine withdrawal in patients who stopped smoking.
Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including
suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without
medication. However, some of these symptoms have occurred in patients taking bupropion who
continued to smoke. When symptoms were reported, most were during bupropion treatment, but
some were following discontinuation of bupropion therapy.
These events have occurred in patients with and without pre-existing psychiatric disease;
some have experienced worsening of their psychiatric illnesses. All patients being treated with
bupropion as part of smoking cessation treatment should be observed for neuropsychiatric
symptoms or worsening of pre-existing psychiatric illness.
Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major
depressive disorder did not participate in the pre-marketing studies of ZYBAN.
Advise patients and caregivers that the patient using bupropion for smoking cessation
should stop taking bupropion and contact a healthcare provider immediately if agitation,
depressed mood, or changes in behavior or thinking that are not typical for the patient are
observed, or if the patient develops suicidal ideation or suicidal behavior. In many
postmarketing cases, resolution of symptoms after discontinuation of ZYBAN was
reported, although in some cases the symptoms persisted, therefore, ongoing monitoring
and supportive care should be provided until symptoms resolve.
The risks of using bupropion for smoking cessation should be weighed against the benefits of
its use. ZYBAN has been demonstrated to increase the likelihood of abstinence from smoking
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For current labeling information, please visit https://www.fda.gov/drugsatfda
for as long as six months compared to treatment with placebo. The health benefits of quitting
smoking are immediate and substantial.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
presentation of bipolar disorder. It is generally believed (though not established in controlled
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
symptoms described above represent such a conversion is unknown. However, prior to initiating
treatment with an antidepressant, patients with depressive symptoms should be adequately
screened to determine if they are at risk for bipolar disorder; such screening should include a
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
depression. It should be noted that WELLBUTRIN is not approved for use in treating bipolar
depression.
Bupropion-Containing Products: Patients should be made aware that WELLBUTRIN
contains the same active ingredient found in ZYBAN, used as an aid to smoking cessation
treatment, and that WELLBUTRIN should not be used in combination with ZYBAN, or any
other medications that contain bupropion, such as WELLBUTRIN SR (bupropion
hydrochloride), the sustained-release formulation or WELLBUTRIN XL (bupropion
hydrochloride), the extended-release formulation.
Seizures: Bupropion is associated with seizures in approximately 0.4% (4/1,000) of
patients treated at doses up to 450 mg/day. This incidence of seizures may exceed that of
other marketed antidepressants by as much as 4-fold. This relative risk is only an
approximate estimate because no direct comparative studies have been conducted. The
estimated seizure incidence for WELLBUTRIN increases almost tenfold between 450 and
600 mg/day, which is twice the usually required daily dose (300 mg) and one and one-third
the maximum recommended daily dose (450 mg). Given the wide variability among
individuals and their capacity to metabolize and eliminate drugs this disproportionate
increase in seizure incidence with dose incrementation calls for caution in dosing.
During the initial development, 25 among approximately 2,400 patients treated with
WELLBUTRIN experienced seizures. At the time of seizure, 7 patients were receiving daily
doses of 450 mg or below for an incidence of 0.33% (3/1,000) within the recommended dose
range. Twelve patients experienced seizures at 600 mg/day (2.3% incidence); 6 additional
patients had seizures at daily doses between 600 and 900 mg (2.8% incidence).
A separate, prospective study was conducted to determine the incidence of seizure
during an 8-week treatment exposure in approximately 3,200 additional patients who
received daily doses of up to 450 mg. Patients were permitted to continue treatment beyond
8 weeks if clinically indicated. Eight seizures occurred during the initial 8-week treatment
period and 5 seizures were reported in patients continuing treatment beyond 8 weeks,
resulting in a total seizure incidence of 0.4%.
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Reference ID: 2978172
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The risk of seizure appears to be strongly associated with dose. Sudden and large
increments in dose may contribute to increased risk. While many seizures occurred early in
the course of treatment, some seizures did occur after several weeks at fixed dose.
WELLBUTRIN should be discontinued and not restarted in patients who experience a
seizure while on treatment.
The risk of seizure is also related to patient factors, clinical situations, and concomitant
medications, which must be considered in selection of patients for therapy with
WELLBUTRIN.
• Patient factors: Predisposing factors that may increase the risk of seizure with
bupropion use include history of head trauma or prior seizure, central nervous system
(CNS) tumor, the presence of severe hepatic cirrhosis, and concomitant medications
that lower seizure threshold.
• Clinical situations: Circumstances associated with an increased seizure risk include,
among others, excessive use of alcohol or sedatives (including benzodiazepines);
addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and
anorectics; and diabetes treated with oral hypoglycemics or insulin.
• Concomitant medications: Many medications (e.g., antipsychotics, antidepressants,
theophylline, systemic steroids) are known to lower seizure threshold.
Recommendations for Reducing the Risk of Seizure: Retrospective analysis of
clinical experience gained during the development of WELLBUTRIN suggests that the risk
of seizure may be minimized if
• the total daily dose of WELLBUTRIN does not exceed 450 mg,
• the daily dose is administered 3 times daily, with each single dose not to exceed 150 mg
to avoid high peak concentrations of bupropion and/or its metabolites, and
• the rate of incrementation of dose is very gradual.
WELLBUTRIN should be administered with extreme caution to patients with a history
of seizure, cranial trauma, or other predisposition(s) toward seizure, or patients treated
with other agents (e.g., antipsychotics, other antidepressants, theophylline, systemic
steroids, etc.) that lower seizure threshold.
Hepatic Impairment: WELLBUTRIN should be used with extreme caution in patients
with severe hepatic cirrhosis. In these patients a reduced dose and/or frequency is required,
as peak bupropion, as well as AUC, levels are substantially increased and accumulation is
likely to occur in such patients to a greater extent than usual. The dose should not exceed
75 mg once a day in these patients (see CLINICAL PHARMACOLOGY, PRECAUTIONS,
and DOSAGE AND ADMINISTRATION).
Potential for Hepatotoxicity: In rats receiving large doses of bupropion chronically, there
was an increase in incidence of hepatic hyperplastic nodules and hepatocellular hypertrophy. In
dogs receiving large doses of bupropion chronically, various histologic changes were seen in the
liver, and laboratory tests suggesting mild hepatocellular injury were noted.
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PRECAUTIONS
General: Agitation and Insomnia: A substantial proportion of patients treated with
WELLBUTRIN experience some degree of increased restlessness, agitation, anxiety, and
insomnia, especially shortly after initiation of treatment. In clinical studies, these symptoms were
sometimes of sufficient magnitude to require treatment with sedative/hypnotic drugs. In
approximately 2% of patients, symptoms were sufficiently severe to require discontinuation of
treatment with WELLBUTRIN.
Psychosis, Confusion, and Other Neuropsychiatric Phenomena: Depressed
patients treated with WELLBUTRIN have been reported to show a variety of neuropsychiatric
signs and symptoms including delusions, hallucinations, psychosis, concentration disturbance,
paranoia, and confusion. Because of the uncontrolled nature of many studies, it is impossible to
provide a precise estimate of the extent of risk imposed by treatment with WELLBUTRIN. In
several cases, neuropsychiatric phenomena abated upon dose reduction and/or withdrawal of
treatment.
Activation of Psychosis and/or Mania: Antidepressants can precipitate manic episodes
in bipolar disorder patients during the depressed phase of their illness and may activate latent
psychosis in other susceptible patients. WELLBUTRIN is expected to pose similar risks.
Altered Appetite and Weight: A weight loss of greater than 5 lbs occurred in 28% of
patients receiving WELLBUTRIN. This incidence is approximately double that seen in
comparable patients treated with tricyclics or placebo. Furthermore, while 35% of patients
receiving tricyclic antidepressants gained weight, only 9.4% of patients treated with
WELLBUTRIN did. Consequently, if weight loss is a major presenting sign of a patient’s
depressive illness, the anorectic and/or weight reducing potential of WELLBUTRIN should be
considered.
Allergic Reactions: Anaphylactoid/anaphylactic reactions characterized by symptoms such
as pruritus, urticaria, angioedema, and dyspnea requiring medical treatment have been reported
in clinical trials with bupropion. In addition, there have been rare spontaneous postmarketing
reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated
with bupropion. A patient should stop taking WELLBUTRIN and consult a doctor if
experiencing allergic or anaphylactoid/anaphylactic reactions (e.g., skin rash, pruritus, hives,
chest pain, edema, and shortness of breath) during treatment.
Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed
hypersensitivity have been reported in association with bupropion. These symptoms may
resemble serum sickness.
Cardiovascular Effects: In clinical practice, hypertension, in some cases severe, requiring
acute treatment, has been reported in patients receiving bupropion alone and in combination with
nicotine replacement therapy. These events have been observed in both patients with and without
evidence of preexisting hypertension.
Data from a comparative study of the sustained-release formulation of bupropion (ZYBAN®
Sustained-Release Tablets), nicotine transdermal system (NTS), the combination of sustained
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Reference ID: 2978172
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release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher
incidence of treatment-emergent hypertension in patients treated with the combination of
sustained-release bupropion and NTS. In this study, 6.1% of patients treated with the
combination of sustained-release bupropion and NTS had treatment-emergent hypertension
compared to 2.5%, 1.6%, and 3.1% of patients treated with sustained-release bupropion, NTS,
and placebo, respectively. The majority of these patients had evidence of preexisting
hypertension. Three patients (1.2%) treated with the combination of ZYBAN and NTS and 1
patient (0.4%) treated with NTS had study medication discontinued due to hypertension
compared to none of the patients treated with ZYBAN or placebo. Monitoring of blood pressure
is recommended in patients who receive the combination of bupropion and nicotine replacement.
There is no clinical experience establishing the safety of WELLBUTRIN in patients with a
recent history of myocardial infarction or unstable heart disease. Therefore, care should be
exercised if it is used in these groups. Bupropion was well tolerated in depressed patients who
had previously developed orthostatic hypotension while receiving tricyclic antidepressants and
was also generally well tolerated in a group of 36 depressed inpatients with stable congestive
heart failure (CHF). However, bupropion was associated with a rise in supine blood pressure in
the study of patients with CHF, resulting in discontinuation of treatment in 2 patients for
exacerbation of baseline hypertension.
Hepatic Impairment: WELLBUTRIN should be used with extreme caution in patients with
severe hepatic cirrhosis. In these patients, a reduced dose and frequency is required.
WELLBUTRIN should be used with caution in patients with hepatic impairment (including
mild-to-moderate hepatic cirrhosis) and a reduced frequency and/or dose should be considered in
patients with mild-to-moderate hepatic cirrhosis.
All patients with hepatic impairment should be closely monitored for possible adverse effects
that could indicate high drug and metabolite levels (see CLINICAL PHARMACOLOGY,
WARNINGS, and DOSAGE AND ADMINISTRATION).
Renal Impairment: There is limited information on the pharmacokinetics of bupropion in
patients with renal impairment. An inter-study comparison between normal subjects and patients
with end-stage renal failure demonstrated that the parent drug Cmax and AUC values were
comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion
metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for patients with end-stage
renal failure. A second study, comparing normal subjects and patients with moderate-to-severe
renal impairment (GFR 30.9 ± 10.8 mL/min) showed that exposure to a single 150-mg dose of
sustained-release bupropion was approximately 2-fold higher in patients with impaired renal
function while levels of the hydroxybupropion and threo/erythrohydrobupropion (combined)
metabolites were similar in the 2 groups. Bupropion is extensively metabolized in the liver to
active metabolites, which are further metabolized and subsequently excreted by the kidneys.
WELLBUTRIN should be used with caution in patients with renal impairment and a reduced
frequency and/or dose should be considered as bupropion and the metabolites of bupropion may
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accumulate in such patients to a greater extent than usual. The patient should be closely
monitored for possible adverse effects that could indicate high drug or metabolite levels.
Information for Patients: Prescribers or other health professionals should inform patients,
their families, and their caregivers about the benefits and risks associated with treatment with
WELLBUTRIN and should counsel them in its appropriate use. A patient Medication Guide
about “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal
Thoughts or Actions,” “Quitting Smoking, Quit-Smoking Medication, Changes in Thinking and
Behavior, Depression, and Suicidal Thoughts or Actions,” and “What Other Important
Information Should I Know About WELLBUTRIN ?” is available for WELLBUTRIN. The
prescriber or health professional should instruct patients, their families, and their caregivers to
read the Medication Guide and should assist them in understanding its contents. Patients should
be given the opportunity to discuss the contents of the Medication Guide and to obtain answers
to any questions they may have. The complete text of the Medication Guide is reprinted at the
end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these
occur while taking WELLBUTRIN.
Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders: Patients,
their families, and their caregivers should be encouraged to be alert to the emergence of anxiety,
agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia
(psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of
depression, and suicidal ideation, especially early during antidepressant treatment and when the
dose is adjusted up or down. Families and caregivers of patients should be advised to look for the
emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such
symptoms should be reported to the patient’s prescriber or health professional, especially if they
are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms
such as these may be associated with an increased risk for suicidal thinking and behavior and
indicate a need for very close monitoring and possibly changes in the medication.
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation
Treatment: Although WELLBUTRIN is not indicated for smoking cessation treatment, it
contains the same active ingredient as ZYBAN which is approved for this use. Patients should be
informed that quitting smoking, with or without ZYBAN, may be associated with nicotine
withdrawal symptoms (including depression or agitation), or exacerbation of pre-existing
psychiatric illness. Furthermore, some patients have experienced changes in mood (including
depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation
aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed
suicide when attempting to quit smoking while taking ZYBAN. If patients develop agitation,
hostility, depressed mood, or changes in thinking or behavior that are not typical for them, or if
patients develop suicidal ideation or behavior, they should be urged to report these symptoms to
their healthcare provider immediately.
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Bupropion-Containing Products: Patients should be made aware that WELLBUTRIN
contains the same active ingredient found in ZYBAN, used as an aid to smoking cessation, and
that WELLBUTRIN should not be used in combination with ZYBAN or any other medications
that contain bupropion hydrochloride (such as WELLBUTRIN SR, the sustained-release
formulation and WELLBUTRIN XL, the extended-release formulation).
Patients should be instructed to take WELLBUTRIN in equally divided doses 3 or 4 times a
day to minimize the risk of seizure.
Patients should be told that WELLBUTRIN should be discontinued and not restarted if they
experience a seizure while on treatment.
Patients should be told that any CNS-active drug like WELLBUTRIN may impair their ability
to perform tasks requiring judgment or motor and cognitive skills. Consequently, until they are
reasonably certain that WELLBUTRIN does not adversely affect their performance, they should
refrain from driving an automobile or operating complex, hazardous machinery.
Patients should be told that the excessive use or abrupt discontinuation of alcohol or sedatives
(including benzodiazepines) may alter the seizure threshold. Some patients have reported lower
alcohol tolerance during treatment with WELLBUTRIN. Patients should be advised that the
consumption of alcohol should be minimized or avoided.
Patients should be advised to inform their physicians if they are taking or plan to take any
prescription or over-the-counter drugs. Concern is warranted because WELLBUTRIN and other
drugs may affect each other’s metabolism.
Patients should be advised to notify their physicians if they become pregnant or intend to
become pregnant during therapy.
Laboratory Tests: There are no specific laboratory tests recommended.
Drug Interactions: Few systemic data have been collected on the metabolism of bupropion
following concomitant administration with other drugs or, alternatively, the effect of
concomitant administration of bupropion on the metabolism of other drugs.
Because bupropion is extensively metabolized, the coadministration of other drugs may affect
its clinical activity. In vitro studies indicate that bupropion is primarily metabolized to
hydroxybupropion by the CYP2B6 isoenzyme. Therefore, the potential exists for a drug
interaction between WELLBUTRIN and drugs that are substrates of or inhibitors/inducers of the
CYP2B6 isoenzyme (e.g., orphenadrine, thiotepa, cyclophosphamide, ticlopidine, and
clopidogrel). In addition, in vitro studies suggest that paroxetine, sertraline, norfluoxetine, and
fluvoxamine as well as nelfinavir and efavirenz inhibit the hydroxylation of bupropion. No
clinical studies have been performed to evaluate this finding. The threohydrobupropion
metabolite of bupropion does not appear to be produced by the cytochrome P450 isoenzymes.
The effects of concomitant administration of cimetidine on the pharmacokinetics of bupropion
and its active metabolites were studied in 24 healthy young male volunteers. Following oral
administration of two 150-mg sustained-release tablets with and without 800 mg of cimetidine,
the pharmacokinetics of bupropion and hydroxybupropion were unaffected. However, there were
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Reference ID: 2978172
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16% and 32% increases in the AUC and Cmax, respectively, of the combined moieties of
threohydrobupropion and erythrohydrobupropion.
In a series of studies in healthy volunteers, ritonavir (100 mg twice daily or 600 mg twice
daily) or ritonavir 100 mg plus lopinavir 400 mg (KALETRA) twice daily reduced the exposure
of bupropion and its major metabolites in a dose dependent manner by approximately 20% to
80%. Similarly, efavirenz 600 mg once daily for 2 weeks reduced the exposure of bupropion by
approximately 55%. This effect of ritonavir, KALETRA, and efavirenz is thought to be due to
the induction of bupropion metabolism. Patients receiving any of these drugs with bupropion
may need increased doses of bupropion, but the maximum recommended dose of bupropion
should not be exceeded (see CLINICAL PHARMACOLOGY: Metabolism).
While not systematically studied, certain drugs may induce the metabolism of bupropion (e.g.,
carbamazepine, phenobarbital, phenytoin).
Multiple oral doses of bupropion had no statistically significant effects on the single dose
pharmacokinetics of lamotrigine in 12 healthy volunteers.
Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in
humans. In one study, following chronic administration of bupropion, 100 mg 3 times daily to 8
healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism.
Nevertheless, there may be the potential for clinically important alterations of blood levels of
coadministered drugs.
Drugs Metabolized by Cytochrome P450IID6 (CYP2D6): Many drugs, including most
antidepressants (SSRIs, many tricyclics), beta-blockers, antiarrhythmics, and antipsychotics are
metabolized by the CYP2D6 isoenzyme. Although bupropion is not metabolized by this
isoenzyme, bupropion and hydroxybupropion are inhibitors of the CYP2D6 isoenzyme in vitro.
In a study of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of the
CYP2D6 isoenzyme, daily doses of bupropion given as 150 mg twice daily followed by a single
dose of 50 mg desipramine increased the Cmax, AUC, and t1/2 of desipramine by an average of
approximately 2-, 5- and 2-fold, respectively. The effect was present for at least 7 days after the
last dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6
has not been formally studied.
Therefore, coadministration of bupropion with drugs that are metabolized by CYP2D6
isoenzyme including certain antidepressants (e.g., nortriptyline, imipramine, desipramine,
paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine),
beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide),
should be approached with caution and should be initiated at the lower end of the dose range of
the concomitant medication. If bupropion is added to the treatment regimen of a patient already
receiving a drug metabolized by CYP2D6, the need to decrease the dose of the original
medication should be considered, particularly for those concomitant medications with a narrow
therapeutic index.
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Reference ID: 2978172
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Drugs which require metabolic activation by CYP2D6 in order to be effective (e.g.,
tamoxifen) theoretically could have reduced efficacy when administered concomitantly with
inhibitors of CYP2D6 such as bupropion.
Although citalopram is not primarily metabolized by CYP2D6, in one study bupropion
increased the Cmax and AUC of citalopram by 30% and 40%, respectively. Citalopram did not
affect the pharmacokinetics of bupropion and its 3 metabolites.
MAO Inhibitors: Studies in animals demonstrate that the acute toxicity of bupropion is
enhanced by the MAO inhibitor phenelzine (see CONTRAINDICATIONS).
Levodopa and Amantadine: Limited clinical data suggest a higher incidence of adverse
experiences in patients receiving bupropion concurrently with either levodopa or amantadine.
Administration of WELLBUTRIN to patients receiving either levodopa or amantadine
concurrently should be undertaken with caution, using small initial doses and small gradual dose
increases.
Drugs that Lower Seizure Threshold: Concurrent administration of WELLBUTRIN and
agents (e.g., antipsychotics, other antidepressants, theophylline, systemic steroids, etc.) that
lower seizure threshold should be undertaken only with extreme caution (see WARNINGS).
Low initial dosing and small gradual dose increases should be employed.
Nicotine Transdermal System: (see PRECAUTIONS: Cardiovascular Effects).
Alcohol: In postmarketing experience, there have been rare reports of adverse
neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol
during treatment with WELLBUTRIN. The consumption of alcohol during treatment with
WELLBUTRIN should be minimized or avoided (also see CONTRAINDICATIONS).
Drug-Laboratory Test Interactions: False-positive urine immunoassay screening tests
for amphetamines have been reported in patients taking bupropion. This is due to lack of
specificity of some screening tests. False-positive test results may result even following
discontinuation of bupropion therapy. Confirmatory tests, such as gas chromatography/mass
spectrometry, will distinguish bupropion from amphetamines.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Lifetime carcinogenicity studies
were performed in rats and mice at doses up to 300 and 150 mg/kg/day, respectively. In the rat
study there was an increase in nodular proliferative lesions of the liver at doses of 100 to
300 mg/kg/day; lower doses were not tested. The question of whether or not such lesions may be
precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen
in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in
either study.
Bupropion produced a borderline positive response (2 to 3 times control mutation rate) in
some strains in the Ames bacterial mutagenicity test, and a high oral dose (300 mg/kg, but not
100 or 200 mg/kg) produced a low incidence of chromosomal aberrations in rats. The relevance
of these results in estimating the risk of human exposure to therapeutic doses is unknown.
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Reference ID: 2978172
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A fertility study was performed in rats; no evidence of impairment of fertility was
encountered at oral doses up to 300 mg/kg/day.
Pregnancy: Teratogenic Effects: Pregnancy Category C. In studies conducted in rats and
rabbits, bupropion was administered orally at doses up to 450 and 150 mg/kg/day, respectively
(approximately 11 and 7 times the MRHD, respectively, on a mg/m2 basis), during the period of
organogenesis. No clear evidence of teratogenic activity was found in either species; however, in
rabbits, slightly increased incidences of fetal malformations and skeletal variations were
observed at the lowest dose tested (25 mg/kg/day, approximately equal to the MRHD on a mg/m2
basis) and greater. Decreased fetal weights were seen at 50 mg/kg and greater.
When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately
7 times the MRHD on a mg/m2 basis) prior to mating and throughout pregnancy and lactation,
there were no apparent adverse effects on offspring development.
One study has been conducted in pregnant women. This retrospective, managed-care database
study assessed the risk of congenital malformations overall and cardiovascular malformations
specifically, following exposure to bupropion in the first trimester compared to the risk of these
malformations following exposure to other antidepressants in the first trimester and bupropion
outside of the first trimester. This study included 7,005 infants with antidepressant exposure
during pregnancy, 1,213 of whom were exposed to bupropion in the first trimester. The study
showed no greater risk for congenital malformations overall or cardiovascular malformations
specifically, following first trimester bupropion exposure compared to exposure to all other
antidepressants in the first trimester, or bupropion outside of the first trimester. The results of
this study have not been corroborated. WELLBUTRIN should be used during pregnancy only if
the potential benefit justifies the potential risk to the fetus.
Labor and Delivery: The effect of WELLBUTRIN on labor and delivery in humans is
unknown.
Nursing Mothers: Like many other drugs, bupropion and its metabolites are secreted in human
milk. Because of the potential for serious adverse reactions in nursing infants from
WELLBUTRIN, a decision should be made whether to discontinue nursing or to discontinue the
drug, taking into account the importance of the drug to the mother.
Pediatric Use: Safety and effectiveness in the pediatric population have not been established
(see BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk in Treating
Psychiatric Disorders). Anyone considering the use of WELLBUTRIN in a child or adolescent
must balance the potential risks with the clinical need.
Geriatric Use: Of the approximately 6,000 patients who participated in clinical trials with
bupropion sustained-release tablets (depression and smoking cessation studies), 275 were 65 and
over and 47 were 75 and over. In addition, several hundred patients 65 and over participated in
clinical trials using the immediate-release formulation of bupropion (depression studies). No
overall differences in safety or effectiveness were observed between these subjects and younger
subjects, and other reported clinical experience has not identified differences in responses
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Reference ID: 2978172
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between the elderly and younger patients, but greater sensitivity of some older individuals cannot
be ruled out.
A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its
metabolites in elderly subjects was similar to that of younger subjects; however, another
pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased
risk for accumulation of bupropion and its metabolites (see CLINICAL PHARMACOLOGY).
Bupropion is extensively metabolized in the liver to active metabolites, which are further
metabolized and excreted by the kidneys. The risk of toxic reaction to this drug may be greater in
patients with impaired renal function. Because elderly patients are more likely to have decreased
renal function, care should be taken in dose selection, and it may be useful to monitor renal
function (see PRECAUTIONS: Renal Impairment and DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
(See also WARNINGS and PRECAUTIONS.)
Adverse events commonly encountered in patients treated with WELLBUTRIN are agitation,
dry mouth, insomnia, headache/migraine, nausea/vomiting, constipation, and tremor.
Adverse events were sufficiently troublesome to cause discontinuation of treatment with
WELLBUTRIN in approximately 10% of the 2,400 patients and volunteers who participated in
clinical trials during the product’s initial development. The more common events causing
discontinuation include neuropsychiatric disturbances (3.0%), primarily agitation and
abnormalities in mental status; gastrointestinal disturbances (2.1%), primarily nausea and
vomiting; neurological disturbances (1.7%), primarily seizures, headaches, and sleep
disturbances; and dermatologic problems (1.4%), primarily rashes. It is important to note,
however, that many of these events occurred at doses that exceed the recommended daily dose.
Accurate estimates of the incidence of adverse events associated with the use of any drug are
difficult to obtain. Estimates are influenced by drug dose, detection technique, setting, physician
judgments, etc. Consequently, Table 2 is presented solely to indicate the relative frequency of
adverse events reported in representative controlled clinical studies conducted to evaluate the
safety and efficacy of WELLBUTRIN under relatively similar conditions of daily dosage (300 to
600 mg), setting, and duration (3 to 4 weeks). The figures cited cannot be used to predict
precisely the incidence of untoward events in the course of usual medical practice where patient
characteristics and other factors must differ from those which prevailed in the clinical trials.
These incidence figures also cannot be compared with those obtained from other clinical studies
involving related drug products as each group of drug trials is conducted under a different set of
conditions.
Finally, it is important to emphasize that the tabulation does not reflect the relative severity
and/or clinical importance of the events. A better perspective on the serious adverse events
associated with the use of WELLBUTRIN is provided in WARNINGS and PRECAUTIONS.
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Table 2. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled
Clinical Trialsa (Percent of Patients Reporting)
Adverse Experience
WELLBUTRIN Patients
(n = 323)
Placebo Patients
(n = 185)
Cardiovascular
Cardiac arrhythmias
5.3
4.3
Dizziness
22.3
16.2
Hypertension
4.3
1.6
Hypotension
2.5
2.2
Palpitations
3.7
2.2
Syncope
1.2
0.5
Tachycardia
10.8
8.6
Dermatologic
Pruritus
Rash
2.2
8.0
0.0
6.5
Gastrointestinal
Anorexia
18.3
18.4
Appetite increase
3.7
2.2
Constipation
26.0
17.3
Diarrhea
6.8
8.6
Dyspepsia
3.1
2.2
Nausea/vomiting
22.9
18.9
Weight gain
13.6
22.7
Weight loss
23.2
23.2
Genitourinary
Impotence
3.4
3.1
Menstrual complaints
4.7
1.1
Urinary frequency
2.5
2.2
Urinary retention
1.9
2.2
Musculoskeletal
Arthritis
3.1
2.7
Neurological
Akathisia
1.5
1.1
Akinesia/bradykinesia
8.0
8.6
Cutaneous temperature
disturbance
1.9
1.6
Dry mouth
27.6
18.4
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Reference ID: 2978172
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Excessive sweating
22.3
14.6
Headache/migraine
25.7
22.2
Impaired sleep quality
4.0
1.6
Increased salivary flow
3.4
3.8
Insomnia
18.6
15.7
Muscle spasms
1.9
3.2
Pseudoparkinsonism
1.5
1.6
Sedation
19.8
19.5
Sensory disturbance
4.0
3.2
Tremor
21.1
7.6
Neuropsychiatric
Agitation
31.9
22.2
Anxiety
3.1
1.1
Confusion
8.4
4.9
Decreased libido
3.1
1.6
Delusions
1.2
1.1
Disturbed concentration
3.1
3.8
Euphoria
1.2
0.5
Hostility
5.6
3.8
Nonspecific
Fatigue
Fever/chills
5.0
1.2
8.6
0.5
Respiratory
Upper respiratory complaints
5.0
11.4
Special Senses
Auditory disturbance
5.3
3.2
Blurred vision
14.6
10.3
Gustatory disturbance
3.1
1.1
a Events reported by at least 1% of patients receiving WELLBUTRIN are included.
Other Events Observed During the Development of WELLBUTRIN: The conditions
and duration of exposure to WELLBUTRIN varied greatly, and a substantial proportion of the
experience was gained in open and uncontrolled clinical settings. During this experience,
numerous adverse events were reported; however, without appropriate controls, it is impossible
to determine with certainty which events were or were not caused by WELLBUTRIN. The
following enumeration is organized by organ system and describes events in terms of their
relative frequency of reporting in the data base. Events of major clinical importance are also
described in WARNINGS and PRECAUTIONS.
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The following definitions of frequency are used: Frequent adverse events are defined as those
occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to
1/1,000 patients, while rare events are those occurring in less than 1/1,000 patients.
Cardiovascular: Frequent was edema; infrequent were chest pain, electrocardiogram (ECG)
abnormalities (premature beats and nonspecific ST-T changes), and shortness of breath/dyspnea;
rare were flushing, pallor, phlebitis, and myocardial infarction.
Dermatologic: Frequent were nonspecific rashes; infrequent were alopecia and dry skin;
rare were change in hair color, hirsutism, and acne.
Endocrine: Infrequent was gynecomastia; rare were glycosuria and hormone level change.
Gastrointestinal: Infrequent were dysphagia, thirst disturbance, and liver damage/jaundice;
rare were rectal complaints, colitis, gastrointestinal bleeding, intestinal perforation, and stomach
ulcer.
Genitourinary: Frequent was nocturia; infrequent were vaginal irritation, testicular swelling,
urinary tract infection, painful erection, and retarded ejaculation; rare were dysuria, enuresis,
urinary incontinence, menopause, ovarian disorder, pelvic infection, cystitis, dyspareunia, and
painful ejaculation.
Hematologic/Oncologic: Rare were lymphadenopathy, anemia, and pancytopenia.
Musculoskeletal: Rare was musculoskeletal chest pain.
Neurological: (see WARNINGS) Frequent were ataxia/incoordination, seizure, myoclonus,
dyskinesia, and dystonia; infrequent were mydriasis, vertigo, and dysarthria; rare were
electroencephalogram (EEG) abnormality, abnormal neurological exam, impaired attention,
sciatica, and aphasia.
Neuropsychiatric: (see PRECAUTIONS) Frequent were mania/hypomania, increased
libido, hallucinations, decrease in sexual function, and depression; infrequent were memory
impairment, depersonalization, psychosis, dysphoria, mood instability, paranoia, formal thought
disorder, and frigidity; rare was suicidal ideation.
Oral Complaints: Frequent was stomatitis; infrequent were toothache, bruxism, gum
irritation, and oral edema; rare was glossitis.
Respiratory: Infrequent were bronchitis and shortness of breath/dyspnea; rare were
epistaxis, rate or rhythm disorder, pneumonia, and pulmonary embolism.
Special Senses: Infrequent was visual disturbance; rare was diplopia.
Nonspecific: Frequent were flu-like symptoms; infrequent was nonspecific pain; rare were
body odor, surgically related pain, infection, medication reaction, and overdose.
Postintroduction Reports: Voluntary reports of adverse events temporally associated with
bupropion that have been received since market introduction and which may have no causal
relationship with the drug include the following:
Body (General): arthralgia, myalgia, and fever with rash and other symptoms suggestive of
delayed hypersensitivity. These symptoms may resemble serum sickness (see PRECAUTIONS).
Cardiovascular: hypertension (in some cases severe, see PRECAUTIONS), orthostatic
hypotension, third degree heart block
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Reference ID: 2978172
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Endocrine: syndrome of inappropriate antidiuretic hormone secretion, hyperglycemia,
hypoglycemia
Gastrointestinal: esophagitis, hepatitis, liver damage
Hemic and Lymphatic: ecchymosis, leukocytosis, leukopenia, thrombocytopenia. Altered
PT and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were
observed when bupropion was coadministered with warfarin.
Musculoskeletal: arthralgia, myalgia, muscle rigidity/fever/rhabdomyolysis, muscle
weakness
Nervous: aggression, coma, completed suicide, delirium, dream abnormalities, paranoid
ideation, paresthesia, restlessness, suicide attempt, unmasking of tardive dyskinesia
Skin and Appendages: Stevens-Johnson syndrome, angioedema, exfoliative dermatitis,
urticaria
Special Senses: tinnitus, increased intraocular pressure
DRUG ABUSE AND DEPENDENCE
Humans: Controlled clinical studies conducted in normal volunteers, in subjects with a history
of multiple drug abuse, and in depressed patients showed some increase in motor activity and
agitation/excitement.
In a population of individuals experienced with drugs of abuse, a single dose of 400 mg of
WELLBUTRIN produced mild amphetamine-like activity as compared to placebo on the
Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI) and a
score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These
scales measure general feelings of euphoria and drug desirability.
Findings in clinical trials, however, are not known to predict the abuse potential of drugs
reliably. Nonetheless, evidence from single-dose studies does suggest that the recommended
daily dosage of bupropion when administered in divided doses is not likely to be especially
reinforcing to amphetamine or stimulant abusers. However, higher doses that could not be tested
because of the risk of seizure might be modestly attractive to those who abuse stimulant drugs.
Animals: Studies in rodents have shown that bupropion exhibits some pharmacologic actions
common to psychostimulants including increases in locomotor activity and the production of a
mild stereotyped behavior and increases in rates of responding in several schedule-controlled
behavior paradigms. Drug discrimination studies in rats showed stimulus generalization between
bupropion and amphetamine and other psychostimulants. Rhesus monkeys have been shown to
self-administer bupropion intravenously.
OVERDOSAGE
Human Overdose Experience: Overdoses of up to 30 g or more of bupropion have been
reported. Seizure was reported in approximately one-third of all cases. Other serious reactions
reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus
tachycardia, and ECG changes such as conduction disturbances (including QRS prolongation) or
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arrhythmias. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory
failure have been reported mainly when bupropion was part of multiple drug overdoses.
Although most patients recovered without sequelae, deaths associated with overdoses of
bupropion alone have been reported in patients ingesting large doses of the drug. Multiple
uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported
in these patients.
Overdosage Management: Ensure an adequate airway, oxygenation, and ventilation.
Monitor cardiac rhythm and vital signs. EEG monitoring is also recommended for the first
48 hours post-ingestion. General supportive and symptomatic measures are also recommended.
Induction of emesis is not recommended.
Activated charcoal should be administered. There is no experience with the use of forced
diuresis, dialysis, hemoperfusion, or exchange transfusion in the management of bupropion
overdoses. No specific antidotes for bupropion are known.
Due to the dose-related risk of seizures with WELLBUTRIN, hospitalization following
suspected overdose should be considered. Based on studies in animals, it is recommended that
seizures be treated with intravenous benzodiazepine administration and other supportive
measures, as appropriate.
In managing overdosage, consider the possibility of multiple drug involvement. The physician
should consider contacting a poison control center for additional information on the treatment of
any overdose. Telephone numbers for certified poison control centers are listed in the
Physicians’ Desk Reference (PDR).
DOSAGE AND ADMINISTRATION
General Dosing Considerations: It is particularly important to administer WELLBUTRIN
in a manner most likely to minimize the risk of seizure (see WARNINGS). Increases in dose
should not exceed 100 mg/day in a 3-day period. Gradual escalation in dosage is also important
if agitation, motor restlessness, and insomnia, often seen during the initial days of treatment, are
to be minimized. If necessary, these effects may be managed by temporary reduction of dose or
the short-term administration of an intermediate to long-acting sedative hypnotic. A sedative
hypnotic usually is not required beyond the first week of treatment. Insomnia may also be
minimized by avoiding bedtime doses. If distressing, untoward effects supervene, dose escalation
should be stopped.
No single dose of WELLBUTRIN should exceed 150 mg. WELLBUTRIN should be
administered 3 times daily, preferably with at least 6 hours between successive doses.
Usual Dosage for Adults: The usual adult dose is 300 mg/day, given 3 times daily. Dosing
should begin at 200 mg/day, given as 100 mg twice daily. Based on clinical response, this dose
may be increased to 300 mg/day, given as 100 mg 3 times daily, no sooner than 3 days after
beginning therapy (see Table 3).
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Table 3. Dosing Regimen
Treatment Day
Total Daily Dose
Tablet Strength
Number of Tablets
Morning Midday
Evening
1
4
200 mg
300 mg
100 mg
100 mg
1
1
0
1
1
1
Increasing the Dosage Above 300 mg/Day: As with other antidepressants, the full
antidepressant effect of WELLBUTRIN may not be evident until 4 weeks of treatment or longer.
An increase in dosage, up to a maximum of 450 mg/day, given in divided doses of not more than
150 mg each, may be considered for patients in whom no clinical improvement is noted after
several weeks of treatment at 300 mg/day. Dosing above 300 mg/day may be accomplished
using the 75- or 100-mg tablets. The 100-mg tablet must be administered 4 times daily with at
least 4 hours between successive doses, in order not to exceed the limit of 150 mg in a single
dose. WELLBUTRIN should be discontinued in patients who do not demonstrate an adequate
response after an appropriate period of treatment at 450 mg/day.
Maintenance Treatment: The lowest dose that maintains remission is recommended.
Although it is not known how long the patient should remain on WELLBUTRIN, it is generally
recognized that acute episodes of depression require several months or longer of antidepressant
drug treatment.
Dosage Adjustment for Patients with Impaired Hepatic Function: WELLBUTRIN
should be used with extreme caution in patients with severe hepatic cirrhosis. The dose should
not exceed 75 mg once a day in these patients. WELLBUTRIN should be used with caution in
patients with hepatic impairment (including mild-to-moderate hepatic cirrhosis) and a reduced
frequency and/or dose should be considered in patients with mild-to-moderate hepatic cirrhosis
(see CLINICAL PHARMACOLOGY, WARNINGS, and PRECAUTIONS).
Dosage Adjustment for Patients with Impaired Renal Function: WELLBUTRIN
should be used with caution in patients with renal impairment and a reduced frequency and/or
dose should be considered (see CLINICAL PHARMACOLOGY and PRECAUTIONS).
HOW SUPPLIED
WELLBUTRIN Tablets, 75 mg of bupropion hydrochloride, are yellow-gold, round, biconvex
tablets printed with “WELLBUTRIN 75” in bottles of 100 (NDC 0173-0177-55).
WELLBUTRIN Tablets, 100 mg of bupropion hydrochloride, are red, round, biconvex tablets
printed with “WELLBUTRIN 100” in bottles of 100 (NDC 0173-0178-55).
Store at 15° to 25°C (59° to 77°F). Protect from light and moisture.
WELLBUTRIN, WELLBUTRIN SR, and WELLBUTRIN XL are registered trademarks of
GlaxoSmithKline.
KALETRA is a registered trademark of Abbott Laboratories.
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Reference ID: 2978172
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GlaxoSmithKline
Distributed by:
GlaxoSmithKline
Research Triangle Park, NC 27709
Manufactured by:
DSM Pharmaceuticals, Inc.
Greenville, NC 27834 for
GlaxoSmithKline
Research Triangle Park, NC 27709
©YEAR, GlaxoSmithKline. All rights reserved.
Month Year
WLT:XPI
Reference ID: 2978172
26
This label may not be the latest approved by FDA.
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MEDICATION GUIDE
WELLBUTRIN® (WELL byu-trin)
(bupropion hydrochloride) Tablets
Read this Medication Guide carefully before you start using WELLBUTRIN and each time you
get a refill. There may be new information. This information does not take the place of talking
with your doctor about your medical condition or your treatment. If you have any questions
about WELLBUTRIN, ask your doctor or pharmacist.
IMPORTANT: Be sure to read the three sections of this Medication Guide. The first
section is about the risk of suicidal thoughts and actions with antidepressant medicines; the
second section is about the risk of changes in thinking and behavior, depression and
suicidal thoughts or actions with medicines used to quit smoking; and the third section is
entitled “What Other Important Information Should I Know About WELLBUTRIN?”
Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and
Suicidal Thoughts or Actions
This section of the Medication Guide is only about the risk of suicidal thoughts and actions
with antidepressant medicines. Talk to your, or your family member’s, healthcare provider
about:
• all risks and benefits of treatment with antidepressant medicines
• all treatment choices for depression or other serious mental illness
What is the most important information I should know about antidepressant medicines,
depression and other serious mental illnesses, and suicidal thoughts or actions?
1. Antidepressant medicines may increase suicidal thoughts or actions in some children,
teenagers, and young adults within the first few months of treatment.
2. Depression and other serious mental illnesses are the most important causes of suicidal
thoughts and actions. Some people may have a particularly high risk of having suicidal
thoughts or actions. These include people who have (or have a family history of) bipolar
illness (also called manic-depressive illness) or suicidal thoughts or actions.
3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a
family member?
• Pay close attention to any changes, especially sudden changes, in mood, behaviors,
thoughts, or feelings. This is very important when an antidepressant medicine is started or
when the dose is changed.
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• Call the healthcare provider right away to report new or sudden changes in mood,
behavior, thoughts, or feelings.
• Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare
provider between visits as needed, especially if you have concerns about symptoms.
Call a healthcare provider right away if you or your family member has any of the
following symptoms, especially if they are new, worse, or worry you:
• thoughts about suicide or dying
• trouble sleeping (insomnia)
• attempts to commit suicide
• new or worse irritability
• new or worse depression
• acting aggressive, being angry, or violent
• new or worse anxiety
• acting on dangerous impulses
• feeling very agitated or restless
• an extreme increase in activity and talking (mania)
• panic attacks
• other unusual changes in behavior or mood
What else do I need to know about antidepressant medicines?
• Never stop an antidepressant medicine without first talking to a healthcare provider.
Stopping an antidepressant medicine suddenly can cause other symptoms.
• Antidepressants are medicines used to treat depression and other illnesses. It is
important to discuss all the risks of treating depression and also the risks of not treating it.
Patients and their families or other caregivers should discuss all treatment choices with the
healthcare provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects. Talk to the healthcare provider about the
side effects of the medicine prescribed for you or your family member.
• Antidepressant medicines can interact with other medicines. Know all of the medicines
that you or your family member takes. Keep a list of all medicines to show the healthcare
provider. Do not start new medicines without first checking with your healthcare provider.
• Not all antidepressant medicines prescribed for children are FDA approved for use in
children. Talk to your child’s healthcare provider for more information.
WELLBUTRIN has not been studied in children under the age of 18 and is not approved for use
in children and teenagers.
Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior,
Depression, and Suicidal Thoughts or Actions
This section of the Medication Guide is only about the risk of changes in thinking and behavior,
depression and suicidal thoughts or actions with drugs used to quit smoking.
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Although WELLBUTRIN is not a treatment for quitting smoking, it contains the same active
ingredient (bupropion hydrochloride) as ZYBAN® which is used to help patients quit smoking.
Some people have had changes in behavior, hostility, agitation, depression, suicidal thoughts or
actions while taking bupropion to help them quit smoking. These symptoms can develop during
treatment with bupropion or after stopping treatment with bupropion.
If you, your family member, or your caregiver notice agitation, hostility, depression, or changes
in thinking or behavior that are not typical for you, or you have any of the following symptoms,
stop taking bupropion and call your healthcare provider right away:
• thoughts about suicide or dying
• an extreme increase in activity and talking (mania)
• attempts to commit suicide
• abnormal thoughts or sensations
• new or worse depression
• seeing or hearing things that are not there
• new or worse anxiety
(hallucinations)
• panic attacks
• feeling people are against you (paranoia)
• feeling very agitated or restless
• feeling confused
• acting aggressive, being angry, or violent
• other unusual changes in behavior or mood
• acting on dangerous impulses
When you try to quit smoking, with or without bupropion, you may have symptoms that may be
due to nicotine withdrawal, including urge to smoke, depressed mood, trouble sleeping,
irritability, frustration, anger, feeling anxious, difficulty concentrating, restlessness, decreased
heart rate, and increased appetite or weight gain. Some people have even experienced suicidal
thoughts when trying to quit smoking without medication. Sometimes quitting smoking can lead
to worsening of mental health problems that you already have, such as depression.
Before taking bupropion, tell your healthcare provider if you have ever had depression or other
mental illnesses. You should also tell your doctor about any symptoms you had during other
times you tried to quit smoking, with or without bupropion.
What Other Important Information Should I Know About WELLBUTRIN?
• Seizures: There is a chance of having a seizure (convulsion, fit) with WELLBUTRIN,
especially in people:
• with certain medical problems.
• who take certain medicines.
The chance of having seizures increases with higher doses of WELLBUTRIN. For more
information, see the sections “Who should not take WELLBUTRIN?” and “What should I
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tell my doctor before using WELLBUTRIN?” Tell your doctor about all of your medical
conditions and all the medicines you take. Do not take any other medicines while you are
using WELLBUTRIN unless your doctor has said it is okay to take them.
If you have a seizure while taking WELLBUTRIN, stop taking the tablets and call your
doctor right away. Do not take WELLBUTRIN again if you have a seizure.
• High blood pressure (hypertension). Some people get high blood pressure, that can be
severe, while taking WELLBUTRIN. The chance of high blood pressure may be higher if
you also use nicotine replacement therapy (such as a nicotine patch) to help you stop
smoking.
• Severe allergic reactions. Some people have severe allergic reaction to WELLBUTRIN.
Stop taking WELLBUTRIN and call your doctor right away if you get a rash, itching,
hives, fever, swollen lymph glands, painful sores in the mouth or around the eyes, swelling of
the lips or tongue, chest pain, or have trouble breathing. These could be signs of a serious
allergic reaction.
• Unusual thoughts or behaviors. Some patients have unusual thoughts or behaviors while
taking WELLBUTRIN, including delusions (believe you are someone else), hallucinations
(seeing or hearing things that are not there), paranoia (feeling that people are against you), or
feeling confused. If this happens to you, call your doctor.
What is WELLBUTRIN?
WELLBUTRIN is a prescription medicine used to treat adults with a certain type of depression
called major depressive disorder.
Who should not take WELLBUTRIN?
Do not take WELLBUTRIN if you
• have or had a seizure disorder or epilepsy.
• are taking ZYBAN (used to help people stop smoking) or any other medicines that
contain bupropion hydrochloride, such as WELLBUTRIN SR Sustained-Release
Tablets or WELLBUTRIN XL Extended-Release Tablets. Bupropion is the same active
ingredient that is in WELLBUTRIN.
• drink a lot of alcohol and abruptly stop drinking, or use medicines called sedatives (these
make you sleepy) or benzodiazepines and you stop using them all of a sudden.
• have taken within the last 14 days medicine for depression called a monoamine oxidase
inhibitor (MAOI), such as NARDIL® (phenelzine sulfate), PARNATE® (tranylcypromine
sulfate), or MARPLAN® (isocarboxazid).
• have or had an eating disorder such as anorexia nervosa or bulimia.
• are allergic to the active ingredient in WELLBUTRIN, bupropion, or to any of the inactive
ingredients. See the end of this leaflet for a complete list of ingredients in WELLBUTRIN.
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What should I tell my doctor before using WELLBUTRIN?
Tell your doctor if you have ever had depression, suicidal thoughts or actions, or other mental
health problems. See “Antidepressant Medicines, Depression and Other Serious Mental Illnesses,
and Suicidal Thoughts or Actions.”
• Tell your doctor about your other medical conditions including if you:
• are pregnant or plan to become pregnant. It is not known if WELLBUTRIN can harm
your unborn baby.
• are breastfeeding. WELLBUTRIN passes through your milk. It is not known if
WELLBUTRIN can harm your baby.
• have liver problems, especially cirrhosis of the liver.
• have kidney problems.
• have an eating disorder, such as anorexia nervosa or bulimia.
• have had a head injury.
• have had a seizure (convulsion, fit).
• have a tumor in your nervous system (brain or spine).
• have had a heart attack, heart problems, or high blood pressure.
• are a diabetic taking insulin or other medicines to control your blood sugar.
• drink a lot of alcohol.
• abuse prescription medicines or street drugs.
• Tell your doctor about all the medicines you take, including prescription and non
prescription medicines, vitamins, and herbal supplements. Many medicines increase your
chances of having seizures or other serious side effects if you take them while you are using
WELLBUTRIN.
How should I take WELLBUTRIN?
• Take WELLBUTRIN exactly as prescribed by your doctor.
• Take WELLBUTRIN at the same time each day.
• Take your doses of WELLBUTRIN at least 6 hours apart.
• You may take WELLBUTRIN with or without food.
• If you miss a dose, do not take an extra tablet to make up for the dose you forgot. Wait and
take your next tablet at the regular time. This is very important. Too much WELLBUTRIN
can increase your chance of having a seizure.
• If you take too much WELLBUTRIN, or overdose, call your local emergency room or poison
control center right away.
• Do not take any other medicines while using WELLBUTRIN unless your doctor has
told you it is okay.
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• It may take several weeks for you to feel that WELLBUTRIN is working. Once you feel
better, it is important to keep taking WELLBUTRIN exactly as directed by your doctor. Call
your doctor if you do not feel WELLBUTRIN is working for you.
• Do not change your dose or stop taking WELLBUTRIN without talking with your doctor
first.
What should I avoid while taking WELLBUTRIN?
• Do not drink a lot of alcohol while taking WELLBUTRIN. If you usually drink a lot of
alcohol, talk with your doctor before suddenly stopping. If you suddenly stop drinking
alcohol, you may increase your risk of having seizures.
• Do not drive a car or use heavy machinery until you know how WELLBUTRIN affects you.
WELLBUTRIN can impair your ability to perform these tasks.
What are possible side effects of WELLBUTRIN?
WELLBUTRIN can cause serious side effects. Read this entire Medication Guide for more
information about these serious side effects.
The most common side effects of WELLBUTRIN are nervousness, constipation, trouble
sleeping, dry mouth, headache, nausea, vomiting, and shakiness (tremor).
If you have nausea, take your medicine with food. If you have trouble sleeping, do not take your
medicine too close to bedtime.
These are not all the side effects of WELLBUTRIN. For a complete list, ask your doctor or
pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at
1-800-FDA-1088.
How should I store WELLBUTRIN?
• Store WELLBUTRIN at room temperature. Store out of direct sunlight. Keep
WELLBUTRIN in its tightly closed bottle.
General Information about WELLBUTRIN.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use WELLBUTRIN for a condition for which it was not prescribed. Do not give
WELLBUTRIN to other people, even if they have the same symptoms you have. It may harm
them. Keep WELLBUTRIN out of the reach of children.
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If you take a urine drug screening test, WELLBUTRIN may make the test result positive for
amphetamines. If you tell the person giving you the drug screening test that you are taking
WELLBUTRIN, they can do a more specific drug screening test that should not have this
problem.
This Medication Guide summarizes important information about WELLBUTRIN. For more
information, talk to your doctor. You can ask your doctor or pharmacist for information about
WELLBUTRIN that is written for health professionals.
What are the ingredients in WELLBUTRIN?
Active ingredient: bupropion hydrochloride.
Inactive ingredients: 75-mg tablet – D&C Yellow No. 10 Lake, FD&C Yellow No. 6 Lake,
hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and
titanium dioxide; 100-mg tablet – FD&C Red No. 40 Lake, FD&C Yellow No. 6 Lake,
hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and
titanium dioxide.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and PARNATE are registered
trademarks of GlaxoSmithKline.
The following are registered trademarks of their respective manufacturers: NARDIL®/Warner
Lambert Company; MARPLAN®/Oxford Pharmaceutical Services, Inc. GlaxoSmithKline
Distributed by:
GlaxoSmithKline
Research Triangle Park, NC 27709
Manufactured by:
DSM Pharmaceuticals, Inc.
Greenville, NC 27834 for
GlaxoSmithKline
Research Triangle Park, NC 27709
©YEAR, GlaxoSmithKline. All rights reserved.
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Reference ID: 2978172
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Month Year
WLT:XMG
Reference ID: 2978172
34
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For current labeling information, please visit https://www.fda.gov/drugsatfda
PRESCRIBING INFORMATION
WELLBUTRIN SR®
(bupropion hydrochloride)
Sustained-Release Tablets
WARNING
Suicidality and Antidepressant Drugs
Use in Treating Psychiatric Disorders: Antidepressants increased the risk compared to
placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults
in short-term studies of major depressive disorder (MDD) and other psychiatric disorders.
Anyone considering the use of WELLBUTRIN SR or any other antidepressant in a child,
adolescent, or young adult must balance this risk with the clinical need. Short-term studies did
not show an increase in the risk of suicidality with antidepressants compared to placebo in adults
beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults
aged 65 and older. Depression and certain other psychiatric disorders are themselves associated
with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy
should be monitored appropriately and observed closely for clinical worsening, suicidality, or
unusual changes in behavior. Families and caregivers should be advised of the need for close
observation and communication with the prescriber. WELLBUTRIN SR is not approved for use
in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk in Treating
Psychiatric Disorders, PRECAUTIONS: Information for Patients, and PRECAUTIONS:
Pediatric Use.)
Use in Smoking Cessation Treatment: WELLBUTRIN®, WELLBUTRIN SR®, and
WELLBUTRIN XL® are not approved for smoking cessation treatment, but bupropion under the
name ZYBAN® is approved for this use. Serious neuropsychiatric events, including but not
limited to depression, suicidal ideation, suicide attempt, and completed suicide have been
reported in patients taking bupropion for smoking cessation. Some cases may have been
complicated by the symptoms of nicotine withdrawal in patients who stopped smoking.
Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including
suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without
medication. However, some of these symptoms have occurred in patients taking bupropion who
continued to smoke.
All patients being treated with bupropion for smoking cessation treatment should be observed
for neuropsychiatric symptoms including changes in behavior, hostility, agitation, depressed
mood, and suicide-related events, including ideation, behavior, and attempted suicide. These
symptoms, as well as worsening of pre-existing psychiatric illness and completed suicide have
been reported in some patients attempting to quit smoking while taking ZYBAN in the
postmarketing experience. When symptoms were reported, most were during treatment with
ZYBAN, but some were following discontinuation of treatment with ZYBAN. These events have
occurred in patients with and without pre-existing psychiatric disease; some have experienced
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worsening of their psychiatric illnesses. Patients with serious psychiatric illness such as
schizophrenia, bipolar disorder, and major depressive disorder did not participate in the
premarketing studies of ZYBAN.
Advise patients and caregivers that the patient using bupropion for smoking cessation
should stop taking bupropion and contact a healthcare provider immediately if agitation,
hostility, depressed mood, or changes in thinking or behavior that are not typical for the
patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In
many postmarketing cases, resolution of symptoms after discontinuation of ZYBAN was
reported, although in some cases the symptoms persisted; therefore, ongoing monitoring
and supportive care should be provided until symptoms resolve.
The risks of using bupropion for smoking cessation should be weighed against the benefits of
its use. ZYBAN has been demonstrated to increase the likelihood of abstinence from smoking
for as long as 6 months compared to treatment with placebo. The health benefits of quitting
smoking are immediate and substantial. (See WARNINGS: Neuropsychiatric Symptoms and
Suicide Risk in Smoking Cessation Treatment and PRECAUTIONS: Information for Patients.)
DESCRIPTION
WELLBUTRIN SR (bupropion hydrochloride), an antidepressant of the aminoketone class, is
chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other
known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related
to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1
propanone hydrochloride. The molecular weight is 276.2. The molecular formula is
C13H18ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in
water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The
structural formula is: structural formula
WELLBUTRIN SR is supplied for oral administration as 100-mg (blue), 150-mg (purple),
and 200-mg (light pink), film-coated, sustained-release tablets. Each tablet contains the labeled
amount of bupropion hydrochloride and the inactive ingredients: carnauba wax, cysteine
hydrochloride, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene
glycol, polysorbate 80, and titanium dioxide and is printed with edible black ink. In addition, the
100-mg tablet contains FD&C Blue No. 1 Lake, the 150-mg tablet contains FD&C Blue No. 2
Lake and FD&C Red No. 40 Lake, and the 200-mg tablet contains FD&C Red No. 40 Lake.
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CLINICAL PHARMACOLOGY
Pharmacodynamics: Bupropion is a relatively weak inhibitor of the neuronal uptake of
norepinephrine and dopamine, and does not inhibit monoamine oxidase or the re-uptake of
serotonin. While the mechanism of action of bupropion, as with other antidepressants, is
unknown, it is presumed that this action is mediated by noradrenergic and/or dopaminergic
mechanisms.
Pharmacokinetics: Bupropion is a racemic mixture. The pharmacologic activity and
pharmacokinetics of the individual enantiomers have not been studied. The mean elimination
half-life (±SD) of bupropion after chronic dosing is 21 (±9) hours, and steady-state plasma
concentrations of bupropion are reached within 8 days. In a study comparing chronic dosing with
WELLBUTRIN SR 150 mg twice daily to the immediate-release formulation of bupropion at
100 mg 3 times daily, peak plasma concentrations of bupropion at steady state for
WELLBUTRIN SR were approximately 85% of those achieved with the immediate-release
formulation. There was equivalence for bupropion AUCs, as well as equivalence for both peak
plasma concentration and AUCs for all 3 of the detectable bupropion metabolites. Thus, at steady
state, WELLBUTRIN SR, given twice daily, and the immediate-release formulation of
bupropion, given 3 times daily, are essentially bioequivalent for both bupropion and the 3
quantitatively important metabolites.
Absorption: Exposure Following oral administration of WELLBUTRIN SR to bupropion
may be increased when WELLBUTRIN SR tablets are taken with food. Three studies in healthy
volunteers demonstrated, peak plasma concentrations (of bupropion are achieved within 3 hours.
Food increased Cmax) and AUC of bupropion increased by 11% to 35% when administered with
food, while overall exposure (AUC) to bupropion increased by 16% to 19%. The food effectand
17%, respectively, indicating that there is not considered clinically significant and
WELLBUTRIN SR can be taken with or without food effect.
Distribution: In vitro tests show that bupropion is 84% bound to human plasma proteins at
concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion
metabolite is similar to that for bupropion, whereas the extent of protein binding of the
threohydrobupropion metabolite is about half that seen with bupropion.
Metabolism: Bupropion is extensively metabolized in humans. Three metabolites have been
shown to be active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group
of bupropion, and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion,
which are formed via reduction of the carbonyl group. In vitro findings suggest that cytochrome
P450IIB6 (CYP2B6) is the principal isoenzyme involved in the formation of hydroxybupropion,
while cytochrome P450 isoenzymes are not involved in the formation of threohydrobupropion.
Oxidation of the bupropion side chain results in the formation of a glycine conjugate of
meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency
and toxicity of the metabolites relative to bupropion have not been fully characterized. However,
it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is
one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5
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fold less potent than bupropion. This may be of clinical importance because the plasma
concentrations of the metabolites are as high or higher than those of bupropion.
Because bupropion is extensively metabolized, there is the potential for drug-drug
interactions, particularly with those agents that are metabolized by or which inhibit/induce the
cytochrome P450IIB6 (CYP2B6) isoenzyme, such as ritonavir or efavirenz. In a healthy
volunteer study, ritonavir at a dose of 100 mg twice daily reduced the AUC and Cmax of
bupropion by 22% and 21%, respectively. The exposure of the hydroxybupropion metabolite was
decreased by 23%, the threohydrobupropion decreased by 38%, and the erythrohydrobupropion
decreased by 48%.
In a second healthy volunteer study, ritonavir at a dose of 600 mg twice daily decreased the
AUC and the Cmax of bupropion by 66% and 62%, respectively. The exposure of the
hydroxybupropion metabolite was decreased by 78%, the threohydrobupropion decreased by
50%, and the erythrohydrobupropion decreased by 68%.
In another healthy volunteer study, KALETRA® (lopinavir 400 mg/ritonavir 100 mg twice
daily) decreased bupropion AUC and Cmax by 57%. The AUC and Cmax of hydroxybupropion
were decreased by 50% and 31%, respectively (see PRECAUTIONS: Drug Interactions).
In a study in healthy volunteers, efavirenz 600 mg once daily for 2 weeks reduced the AUC
and Cmax of bupropion by approximately 55% and 34%, respectively. The AUC of
hydroxybupropion was unchanged, whereas Cmax of hydroxybupropion was increased by 50%.
Although bupropion is not metabolized by cytochrome P450IID6 (CYP2D6), there is the
potential for drug-drug interactions when bupropion is coadministered with drugs metabolized
by this isoenzyme (see PRECAUTIONS: Drug Interactions).
Following a single dose in humans, peak plasma concentrations of hydroxybupropion occur
approximately 6 hours after administration of WELLBUTRIN SR. Peak plasma concentrations
of hydroxybupropion are approximately 10 times the peak level of the parent drug at steady state.
The elimination half-life of hydroxybupropion is approximately 20 (±5) hours, and its AUC at
steady state is about 17 times that of bupropion. The times to peak concentrations for the
erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the
hydroxybupropion metabolite. However, their elimination half-lives are longer, 33 (±10) and 37
(±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion,
respectively.
Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300
to 450 mg/day.
Elimination: Following oral administration of 200 mg of 14C-bupropion in humans, 87% and
10% of the radioactive dose were recovered in the urine and feces, respectively. However, the
fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent
with the extensive metabolism of bupropion.
Population Subgroups: Factors or conditions altering metabolic capacity (e.g., liver disease,
congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may be
expected to influence the degree and extent of accumulation of the active metabolites of
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bupropion. The elimination of the major metabolites of bupropion may be affected by reduced
renal or hepatic function because they are moderately polar compounds and are likely to undergo
further metabolism or conjugation in the liver prior to urinary excretion.
Hepatic: The effect of hepatic impairment on the pharmacokinetics of bupropion was
characterized in 2 single-dose studies, one in patients with alcoholic liver disease and one in
patients with mild-to-severe cirrhosis. The first study showed that the half-life of
hydroxybupropion was significantly longer in 8 patients with alcoholic liver disease than in
8 healthy volunteers (32 ± 14 hours versus 21 ± 5 hours, respectively). Although not statistically
significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be
greater (by 53% to 57%) in patients with alcoholic liver disease. The differences in half-life for
bupropion and the other metabolites in the 2 patient groups were minimal.
The second study showed no statistically significant differences in the pharmacokinetics of
bupropion and its active metabolites in 9 patients with mild-to-moderate hepatic cirrhosis
compared to 8 healthy volunteers. However, more variability was observed in some of the
pharmacokinetic parameters for bupropion (AUC, Cmax, and Tmax) and its active metabolites (t½)
in patients with mild-to-moderate hepatic cirrhosis. In addition, in patients with severe hepatic
cirrhosis, the bupropion Cmax and AUC were substantially increased (mean difference: by
approximately 70% and 3-fold, respectively) and more variable when compared to values in
healthy volunteers; the mean bupropion half-life was also longer (29 hours in patients with
severe hepatic cirrhosis vs. 19 hours in healthy subjects). For the metabolite hydroxybupropion,
the mean Cmax was approximately 69% lower. For the combined amino-alcohol isomers
threohydrobupropion and erythrohydrobupropion, the mean Cmax was approximately 31% lower.
The mean AUC increased by about 1½-fold for hydroxybupropion and about 2½-fold for
threo/erythrohydrobupropion. The median Tmax was observed 19 hours later for
hydroxybupropion and 31 hours later for threo/erythrohydrobupropion. The mean half-lives for
hydroxybupropion and threo/erythrohydrobupropion were increased 5- and 2-fold, respectively,
in patients with severe hepatic cirrhosis compared to healthy volunteers (see WARNINGS,
PRECAUTIONS, and DOSAGE AND ADMINISTRATION).
Renal: There is limited information on the pharmacokinetics of bupropion in patients with
renal impairment. An inter-study comparison between normal subjects and patients with end-
stage renal failure demonstrated that the parent drug Cmax and AUC values were comparable in
the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3-
and 2.8-fold increase, respectively, in AUC for patients with end-stage renal failure. A second
study, comparing normal subjects and patients with moderate-to-severe renal impairment (GFR
30.9 ± 10.8 mL/min) showed that exposure to a single 150-mg dose of sustained-release
bupropion was approximately 2-fold higher in patients with impaired renal function while levels
of the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar
in the 2 groups. The elimination of bupropion and/or the major metabolites of bupropion may be
reduced by impaired renal function (see PRECAUTIONS: Renal Impairment).
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Left Ventricular Dysfunction: During a chronic dosing study with bupropion in
14 depressed patients with left ventricular dysfunction (history of CHF or an enlarged heart on
x-ray), no apparent effect on the pharmacokinetics of bupropion or its metabolites was revealed,
compared to healthy volunteers.
Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have not
been fully characterized, but an exploration of steady-state bupropion concentrations from
several depression efficacy studies involving patients dosed in a range of 300 to 750 mg/day, on
a 3 times daily schedule, revealed no relationship between age (18 to 83 years) and plasma
concentration of bupropion. A single-dose pharmacokinetic study demonstrated that the
disposition of bupropion and its metabolites in elderly subjects was similar to that of younger
subjects. These data suggest there is no prominent effect of age on bupropion concentration;
however, another pharmacokinetic study, single and multiple dose, has suggested that the elderly
are at increased risk for accumulation of bupropion and its metabolites (see PRECAUTIONS:
Geriatric Use).
Gender: A single-dose study involving 12 healthy male and 12 healthy female volunteers
revealed no sex-related differences in the pharmacokinetic parameters of bupropion.
Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion were
studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17
were nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there
was no statistically significant difference in Cmax, half-life, Tmax, AUC, or clearance of bupropion
or its active metabolites between smokers and nonsmokers.
CLINICAL TRIALS
The efficacy of the immediate-release formulation of bupropion as a treatment for depression
was established in two 4-week, placebo-controlled trials in adult inpatients with depression and
in one 6-week, placebo-controlled trial in adult outpatients with depression. In the first study,
patients were titrated in a bupropion dose range of 300 to 600 mg/day on a 3 times daily
schedule; 78% of patients received maximum doses of 450 mg/day or less. This trial
demonstrated the effectiveness of the immediate-release formulation of bupropion on the
Hamilton Depression Rating Scale (HDRS) total score, the depressed mood item (item 1) from
that scale, and the Clinical Global Impressions (CGI) severity score. A second study included
2 fixed doses of the immediate-release formulation of bupropion (300 and 450 mg/day) and
placebo. This trial demonstrated the effectiveness of the immediate-release formulation of
bupropion, but only at the 450-mg/day dose; the results were positive for the HDRS total score
and the CGI severity score, but not for HDRS item 1. In the third study, outpatients received
300 mg/day of the immediate-release formulation of bupropion. This study demonstrated the
effectiveness of the immediate-release formulation of bupropion on the HDRS total score, HDRS
item 1, the Montgomery-Asberg Depression Rating Scale, the CGI severity score, and the CGI
improvement score.
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Although there are not as yet independent trials demonstrating the antidepressant effectiveness
of the sustained-release formulation of bupropion, studies have demonstrated the bioequivalence
of the immediate-release and sustained-release forms of bupropion under steady-state conditions,
i.e., bupropion sustained-release 150 mg twice daily was shown to be bioequivalent to 100 mg
3 times daily of the immediate-release formulation of bupropion, with regard to both rate and
extent of absorption, for parent drug and metabolites.
In a longer-term study, outpatients meeting DSM-IV criteria for major depressive disorder,
recurrent type, who had responded during an 8-week open trial on WELLBUTRIN SR (150 mg
twice daily) were randomized to continuation of their same dose of WELLBUTRIN SR or
placebo, for up to 44 weeks of observation for relapse. Response during the open phase was
defined as CGI Improvement score of 1 (very much improved) or 2 (much improved) for each of
the final 3 weeks. Relapse during the double-blind phase was defined as the investigator’s
judgment that drug treatment was needed for worsening depressive symptoms. Patients receiving
continued treatment with WELLBUTRIN SR experienced significantly lower relapse rates over
the subsequent 44 weeks compared to those receiving placebo.
INDICATIONS AND USAGE
WELLBUTRIN SR is indicated for the treatment of major depressive disorder.
The efficacy of bupropion in the treatment of a major depressive episode was established in
two 4-week controlled trials of depressed inpatients and in one 6-week controlled trial of
depressed outpatients whose diagnoses corresponded most closely to the Major Depression
category of the APA Diagnostic and Statistical Manual (DSM) (see CLINICAL
PHARMACOLOGY).
A major depressive episode (DSM-IV) implies the presence of 1) depressed mood or 2) loss
of interest or pleasure; in addition, at least 5 of the following symptoms have been present during
the same 2-week period and represent a change from previous functioning: depressed mood,
markedly diminished interest or pleasure in usual activities, significant change in weight and/or
appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue,
feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt
or suicidal ideation.
The efficacy of WELLBUTRIN SR in maintaining an antidepressant response for up to
44 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial
(see CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use
WELLBUTRIN SR for extended periods should periodically reevaluate the long-term usefulness
of the drug for the individual patient.
CONTRAINDICATIONS
WELLBUTRIN SR is contraindicated in patients with a seizure disorder.
WELLBUTRIN SR is contraindicated in patients treated with ZYBAN (bupropion
hydrochloride) Sustained-Release Tablets; WELLBUTRIN (bupropion hydrochloride), the
immediate-release formulation; WELLBUTRIN XL (bupropion hydrochloride), the extended
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release formulation; or any other medications that contain bupropion because the incidence of
seizure is dose dependent.
WELLBUTRIN SR is contraindicated in patients with a current or prior diagnosis of bulimia
or anorexia nervosa because of a higher incidence of seizures noted in patients treated for
bulimia with the immediate-release formulation of bupropion.
WELLBUTRIN SR is contraindicated in patients undergoing abrupt discontinuation of
alcohol or sedatives (including benzodiazepines).
The concurrent administration of WELLBUTRIN SR and a monoamine oxidase (MAO)
inhibitor is contraindicated. At least 14 days should elapse between discontinuation of an MAO
inhibitor and initiation of treatment with WELLBUTRIN SR.
WELLBUTRIN SR is contraindicated in patients who have shown an allergic response to
bupropion or the other ingredients that make up WELLBUTRIN SR.
WARNINGS
Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders: Patients
with major depressive disorder (MDD), both adult and pediatric, may experience worsening of
their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual
changes in behavior, whether or not they are taking antidepressant medications, and this risk may
persist until significant remission occurs. Suicide is a known risk of depression and certain other
psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.
There has been a long-standing concern, however, that antidepressants may have a role in
inducing worsening of depression and the emergence of suicidality in certain patients during the
early phases of treatment. Pooled analyses of short-term placebo-controlled trials of
antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal
thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with
major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not
show an increase in the risk of suicidality with antidepressants compared to placebo in adults
beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65
and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24
short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of
placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of
295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000
patients. There was considerable variation in risk of suicidality among drugs, but a tendency
toward an increase in the younger patients for almost all drugs studied. There were differences in
absolute risk of suicidality across the different indications, with the highest incidence in MDD.
The risk differences (drug vs placebo), however, were relatively stable within age strata and
across indications. These risk differences (drug-placebo difference in the number of cases of
suicidality per 1,000 patients treated) are provided in Table 1.
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Table 1
Age Range
Drug-Placebo Difference in Number of Cases
of Suicidality per 1,000 Patients Treated
Increases Compared to Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
≥65
6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but
the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
months. However, there is substantial evidence from placebo-controlled maintenance trials in
adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored
appropriately and observed closely for clinical worsening, suicidality, and unusual changes
in behavior, especially during the initial few months of a course of drug therapy, or at times
of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
been reported in adult and pediatric patients being treated with antidepressants for major
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of
depression and/or the emergence of suicidal impulses has not been established, there is concern
that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly
discontinuing the medication, in patients whose depression is persistently worse, or who are
experiencing emergent suicidality or symptoms that might be precursors to worsening depression
or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major
depressive disorder or other indications, both psychiatric and nonpsychiatric, should be
alerted about the need to monitor patients for the emergence of agitation, irritability,
unusual changes in behavior, and the other symptoms described above, as well as the
emergence of suicidality, and to report such symptoms immediately to healthcare
providers. Such monitoring should include daily observation by families and caregivers.
Prescriptions for WELLBUTRIN SR should be written for the smallest quantity of tablets
consistent with good patient management, in order to reduce the risk of overdose.
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Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment:
WELLBUTRIN, WELLBUTRIN SR, and WELLBUTRIN XL are not approved for smoking
cessation treatment, but bupropion under the name ZYBAN is approved for this use. Serious
neuropsychiatric symptoms have been reported in patients taking bupropion for smoking
cessation (see BOXED WARNING, ADVERSE REACTIONS). These have included
changes in mood (including depression and mania), psychosis, hallucinations, paranoia,
delusions, homicidal ideation, hostility, agitation, aggression, anxiety, and panic, as well as
suicidal ideation, suicide attempt, and completed suicide. Some reported cases may have been
complicated by the symptoms of nicotine withdrawal in patients who stopped smoking.
Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including
suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without
medication. However, some of these symptoms have occurred in patients taking bupropion who
continued to smoke. When symptoms were reported, most were during bupropion treatment, but
some were following discontinuation of bupropion therapy.
These events have occurred in patients with and without pre-existing psychiatric disease;
some have experienced worsening of their psychiatric illnesses. All patients being treated with
bupropion as part of smoking cessation treatment should be observed for neuropsychiatric
symptoms or worsening of pre-existing psychiatric illness.
Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major
depressive disorder did not participate in the pre-marketing studies of ZYBAN.
Advise patients and caregivers that the patient using bupropion for smoking cessation
should stop taking bupropion and contact a healthcare provider immediately if agitation,
depressed mood, or changes in behavior or thinking that are not typical for the patient are
observed, or if the patient develops suicidal ideation or suicidal behavior. In many
postmarketing cases, resolution of symptoms after discontinuation of ZYBAN was
reported, although in some cases the symptoms persisted, therefore, ongoing monitoring
and supportive care should be provided until symptoms resolve.
The risks of using bupropion for smoking cessation should be weighed against the benefits of
its use. ZYBAN has been demonstrated to increase the likelihood of abstinence from smoking
for as long as six months compared to treatment with placebo. The health benefits of quitting
smoking are immediate and substantial.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial
presentation of bipolar disorder. It is generally believed (though not established in controlled
trials) that treating such an episode with an antidepressant alone may increase the likelihood of
precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
symptoms described above represent such a conversion is unknown. However, prior to initiating
treatment with an antidepressant, patients with depressive symptoms should be adequately
screened to determine if they are at risk for bipolar disorder; such screening should include a
detailed psychiatric history, including a family history of suicide, bipolar disorder, and
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depression. It should be noted that WELLBUTRIN SR is not approved for use in treating bipolar
depression.
Bupropion-Containing Products: Patients should be made aware that WELLBUTRIN SR
contains the same active ingredient found in ZYBAN, used as an aid to smoking cessation
treatment, and that WELLBUTRIN SR should not be used in combination with ZYBAN, or any
other medications that contain bupropion, such as WELLBUTRIN (bupropion hydrochloride),
the immediate-release formulation or WELLBUTRIN XL (bupropion hydrochloride), the
extended-release formulation.
Seizures: Bupropion is associated with a dose-related risk of seizures. The risk of seizures
is also related to patient factors, clinical situations, and concomitant medications, which
must be considered in selection of patients for therapy with WELLBUTRIN SR.
WELLBUTRIN SR should be discontinued and not restarted in patients who experience a
seizure while on treatment.
• Dose: At doses of WELLBUTRIN SR up to a dose of 300 mg/day, the incidence of
seizure is approximately 0.1% (1/1,000) and increases to approximately 0.4% (4/1,000)
at the maximum recommended dose of 400 mg/day.
Data for the immediate-release formulation of bupropion revealed a seizure incidence
of approximately 0.4% (i.e., 13 of 3,200 patients followed prospectively) in patients
treated at doses in a range of 300 to 450 mg/day. The 450-mg/day upper limit of this
dose range is close to the currently recommended maximum dose of 400 mg/day for
WELLBUTRIN SR. This seizure incidence (0.4%) may exceed that of other marketed
antidepressants and WELLBUTRIN SR up to 300 mg/day by as much as 4-fold. This
relative risk is only an approximate estimate because no direct comparative studies
have been conducted.
Additional data accumulated for the immediate-release formulation of bupropion
suggested that the estimated seizure incidence increases almost tenfold between 450 and
600 mg/day, which is twice the usual adult dose and one and one-half the maximum
recommended daily dose (400 mg) of WELLBUTRIN SR. This disproportionate
increase in seizure incidence with dose incrementation calls for caution in dosing.
Data for WELLBUTRIN SR revealed a seizure incidence of approximately 0.1% (i.e.,
3 of 3,100 patients followed prospectively) in patients treated at doses in a range of 100
to 300 mg/day. It is not possible to know if the lower seizure incidence observed in this
study involving the sustained-release formulation of bupropion resulted from the
different formulation or the lower dose used. However, as noted above, the
immediate-release and sustained-release formulations are bioequivalent with regard to
both rate and extent of absorption during steady state (the most pertinent condition to
estimating seizure incidence), since most observed seizures occur under steady-state
conditions.
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• Patient factors: Predisposing factors that may increase the risk of seizure with
bupropion use include history of head trauma or prior seizure, central nervous system
(CNS) tumor, the presence of severe hepatic cirrhosis, and concomitant medications
that lower seizure threshold.
• Clinical situations: Circumstances associated with an increased seizure risk include,
among others, excessive use of alcohol or sedatives (including benzodiazepines);
addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and
anorectics; and diabetes treated with oral hypoglycemics or insulin.
• Concomitant medications: Many medications (e.g., antipsychotics, antidepressants,
theophylline, systemic steroids) are known to lower seizure threshold.
Recommendations for Reducing the Risk of Seizure: Retrospective analysis of
clinical experience gained during the development of bupropion suggests that the risk of
seizure may be minimized if
• the total daily dose of WELLBUTRIN SR does not exceed 400 mg,
• the daily dose is administered twice daily, and
• the rate of incrementation of dose is gradual.
• No single dose should exceed 200 mg to avoid high peak concentrations of bupropion
and/or its metabolites.
WELLBUTRIN SR should be administered with extreme caution to patients with a
history of seizure, cranial trauma, or other predisposition(s) toward seizure, or patients
treated with other agents (e.g., antipsychotics, other antidepressants, theophylline, systemic
steroids, etc.) that lower seizure threshold.
Hepatic Impairment: WELLBUTRIN SR should be used with extreme caution in patients
with severe hepatic cirrhosis. In these patients a reduced frequency and/or dose is required,
as peak bupropion, as well as AUC, levels are substantially increased and accumulation is
likely to occur in such patients to a greater extent than usual. The dose should not exceed
100 mg every day or 150 mg every other day in these patients (see CLINICAL
PHARMACOLOGY, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).
Potential for Hepatotoxicity: In rats receiving large doses of bupropion chronically, there
was an increase in incidence of hepatic hyperplastic nodules and hepatocellular hypertrophy. In
dogs receiving large doses of bupropion chronically, various histologic changes were seen in the
liver, and laboratory tests suggesting mild hepatocellular injury were noted.
PRECAUTIONS
General: Agitation and Insomnia: Patients in placebo-controlled trials with
WELLBUTRIN SR experienced agitation, anxiety, and insomnia as shown in Table 2.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 2. Incidence of Agitation, Anxiety, and Insomnia in Placebo-Controlled Trials
Adverse Event Term
WELLBUTRIN SR
300 mg/day
(n = 376)
WELLBUTRIN SR
400 mg/day
(n = 114)
Placebo
(n = 385)
Agitation
Anxiety
Insomnia
3%
5%
11%
9%
6%
16%
2%
3%
6%
In clinical studies, these symptoms were sometimes of sufficient magnitude to require
treatment with sedative/hypnotic drugs.
Symptoms were sufficiently severe to require discontinuation of treatment in 1% and 2.6% of
patients treated with 300 and 400 mg/day, respectively, of WELLBUTRIN SR and 0.8% of
patients treated with placebo.
Psychosis, Confusion, and Other Neuropsychiatric Phenomena: Depressed
patients treated with an immediate-release formulation of bupropion or with WELLBUTRIN SR
have been reported to show a variety of neuropsychiatric signs and symptoms, including
delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. In some
cases, these symptoms abated upon dose reduction and/or withdrawal of treatment.
Activation of Psychosis and/or Mania: Antidepressants can precipitate manic episodes
in bipolar disorder patients during the depressed phase of their illness and may activate latent
psychosis in other susceptible patients. WELLBUTRIN SR is expected to pose similar risks.
Altered Appetite and Weight: In placebo-controlled studies, patients experienced weight
gain or weight loss as shown in Table 3.
Table 3. Incidence of Weight Gain and Weight Loss in Placebo-Controlled Trials
Weight Change
WELLBUTRIN SR
300 mg/day
(n = 339)
WELLBUTRIN SR
400 mg/day
(n = 112)
Placebo
(n = 347)
Gained >5 lbs
Lost >5 lbs
3%
14%
2%
19%
4%
6%
In studies conducted with the immediate-release formulation of bupropion, 35% of patients
receiving tricyclic antidepressants gained weight, compared to 9% of patients treated with the
immediate-release formulation of bupropion. If weight loss is a major presenting sign of a
patient’s depressive illness, the anorectic and/or weight-reducing potential of
WELLBUTRIN SR should be considered.
Allergic Reactions: Anaphylactoid/anaphylactic reactions characterized by symptoms such
as pruritus, urticaria, angioedema, and dyspnea requiring medical treatment have been reported
in clinical trials with bupropion. In addition, there have been rare spontaneous postmarketing
reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated
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with bupropion. A patient should stop taking WELLBUTRIN SR and consult a doctor if
experiencing allergic or anaphylactoid/anaphylactic reactions (e.g., skin rash, pruritus, hives,
chest pain, edema, and shortness of breath) during treatment.
Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed
hypersensitivity have been reported in association with bupropion. These symptoms may
resemble serum sickness.
Cardiovascular Effects: In clinical practice, hypertension, in some cases severe, requiring
acute treatment, has been reported in patients receiving bupropion alone and in combination with
nicotine replacement therapy. These events have been observed in both patients with and without
evidence of preexisting hypertension.
Data from a comparative study of the sustained-release formulation of bupropion (ZYBAN®
Sustained-Release Tablets), nicotine transdermal system (NTS), the combination of sustained-
release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher
incidence of treatment-emergent hypertension in patients treated with the combination of
sustained-release bupropion and NTS. In this study, 6.1% of patients treated with the
combination of sustained-release bupropion and NTS had treatment-emergent hypertension
compared to 2.5%, 1.6%, and 3.1% of patients treated with sustained-release bupropion, NTS,
and placebo, respectively. The majority of these patients had evidence of preexisting
hypertension. Three patients (1.2%) treated with the combination of ZYBAN and NTS and
1 patient (0.4%) treated with NTS had study medication discontinued due to hypertension
compared to none of the patients treated with ZYBAN or placebo. Monitoring of blood pressure
is recommended in patients who receive the combination of bupropion and nicotine replacement.
There is no clinical experience establishing the safety of WELLBUTRIN SR Tablets in
patients with a recent history of myocardial infarction or unstable heart disease. Therefore, care
should be exercised if it is used in these groups. Bupropion was well tolerated in depressed
patients who had previously developed orthostatic hypotension while receiving tricyclic
antidepressants, and was also generally well tolerated in a group of 36 depressed inpatients with
stable congestive heart failure (CHF). However, bupropion was associated with a rise in supine
blood pressure in the study of patients with CHF, resulting in discontinuation of treatment in
2 patients for exacerbation of baseline hypertension.
Hepatic Impairment: WELLBUTRIN SR should be used with extreme caution in patients
with severe hepatic cirrhosis. In these patients, a reduced frequency and/or dose is required.
WELLBUTRIN SR should be used with caution in patients with hepatic impairment (including
mild-to-moderate hepatic cirrhosis) and reduced frequency and/or dose should be considered in
patients with mild-to-moderate hepatic cirrhosis.
All patients with hepatic impairment should be closely monitored for possible adverse effects
that could indicate high drug and metabolite levels (see CLINICAL PHARMACOLOGY,
WARNINGS, and DOSAGE AND ADMINISTRATION).
Renal Impairment: There is limited information on the pharmacokinetics of bupropion in
patients with renal impairment. An inter-study comparison between normal subjects and patients
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Reference ID: 2978172
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with end-stage renal failure demonstrated that the parent drug Cmax and AUC values were
comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion
metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for patients with end-stage
renal failure. A second study, comparing normal subjects and patients with moderate-to-severe
renal impairment (GFR 30.9 ± 10.8 mL/min) showed that exposure to a single 150-mg dose of
sustained-release bupropion was approximately 2-fold higher in patients with impaired renal
function while levels of the hydroxybupropion and threo/erythrohydrobupropion (combined)
metabolites were similar in the 2 groups. Bupropion is extensively metabolized in the liver to
active metabolites, which are further metabolized and subsequently excreted by the kidneys.
WELLBUTRIN SR should be used with caution in patients with renal impairment and a reduced
frequency and/or dose should be considered as bupropion and the metabolites of bupropion may
accumulate in such patients to a greater extent than usual. The patient should be closely
monitored for possible adverse effects that could indicate high drug or metabolite levels.
Information for Patients: Prescribers or other health professionals should inform patients,
their families, and their caregivers about the benefits and risks associated with treatment with
WELLBUTRIN SR and should counsel them in its appropriate use. A patient Medication Guide
about “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal
Thoughts or Actions,” “Quitting Smoking, Quit-Smoking Medication, Changes in Thinking and
Behavior, Depression, and Suicidal Thoughts or Actions,” and “What Other Important
Information Should I Know About WELLBUTRIN SR?” is available for WELLBUTRIN SR.
The prescriber or health professional should instruct patients, their families, and their caregivers
to read the Medication Guide and should assist them in understanding its contents. Patients
should be given the opportunity to discuss the contents of the Medication Guide and to obtain
answers to any questions they may have. The complete text of the Medication Guide is reprinted
at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these
occur while taking WELLBUTRIN SR.
Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders: Patients,
their families, and their caregivers should be encouraged to be alert to the emergence of anxiety,
agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia
(psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of
depression, and suicidal ideation, especially early during antidepressant treatment and when the
dose is adjusted up or down. Families and caregivers of patients should be advised to look for the
emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such
symptoms should be reported to the patient’s prescriber or health professional, especially if they
are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms
such as these may be associated with an increased risk for suicidal thinking and behavior and
indicate a need for very close monitoring and possibly changes in the medication.
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation
Treatment: Although WELLBUTRIN SR is not indicated for smoking cessation treatment, it
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contains the same active ingredient as ZYBAN which is approved for this use. Patients should be
informed that quitting smoking, with or without ZYBAN, may be associated with nicotine
withdrawal symptoms (including depression or agitation), or exacerbation of pre-existing
psychiatric illness. Furthermore, some patients have experienced changes in mood (including
depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation,
aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed
suicide when attempting to quit smoking while taking ZYBAN. If patients develop agitation,
hostility, depressed mood, or changes in thinking or behavior that are not typical for them, or if
patients develop suicidal ideation or behavior, they should be urged to report these symptoms to
their healthcare provider immediately.
Bupropion-Containing Products: Patients should be made aware that
WELLBUTRIN SR contains the same active ingredient found in ZYBAN, used as an aid to
smoking cessation treatment, and that WELLBUTRIN SR should not be used in combination
with ZYBAN or any other medications that contain bupropion hydrochloride (such as
WELLBUTRIN, the immediate-release formulation and WELLBUTRIN XL, the extended-
release formulation).
As dose is increased during initial titration to doses above 150 mg/day, patients should be
instructed to take WELLBUTRIN SR in 2 divided doses, preferably with at least 8 hours
between successive doses, to minimize the risk of seizures.
Patients should be told that WELLBUTRIN SR should be discontinued and not restarted if
they experience a seizure while on treatment.
Patients should be told that any CNS-active drug like WELLBUTRIN SR may impair their
ability to perform tasks requiring judgment or motor and cognitive skills. Consequently, until
they are reasonably certain that WELLBUTRIN SR does not adversely affect their performance,
they should refrain from driving an automobile or operating complex, hazardous machinery.
Patients should be told that the excessive use or abrupt discontinuation of alcohol or sedatives
(including benzodiazepines) may alter the seizure threshold. Some patients have reported lower
alcohol tolerance during treatment with WELLBUTRIN SR. Patients should be advised that the
consumption of alcohol should be minimized or avoided.
Patients should be advised to inform their physicians if they are taking or plan to take any
prescription or over-the-counter drugs. Concern is warranted because WELLBUTRIN SR and
other drugs may affect each other’s metabolism.
Patients should be advised to notify their physicians if they become pregnant or intend to
become pregnant during therapy.
Patients should be advised to swallow WELLBUTRIN SR tablets whole so that the release
rate is not altered. Do not chew, divide, or crush tablets, as this may lead to an increased risk of
adverse effects, including seizures.
Laboratory Tests: There are no specific laboratory tests recommended.
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Reference ID: 2978172
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Drug Interactions: Few systemic data have been collected on the metabolism of bupropion
following concomitant administration with other drugs or, alternatively, the effect of
concomitant administration of bupropion on the metabolism of other drugs.
Because bupropion is extensively metabolized, the coadministration of other drugs may affect
its clinical activity. In vitro studies indicate that bupropion is primarily metabolized to
hydroxybupropion by the CYP2B6 isoenzyme. Therefore, the potential exists for a drug
interaction between WELLBUTRIN SR and drugs that are substrates of or inhibitors/inducers of
the CYP2B6 isoenzyme (e.g., orphenadrine, thiotepa, cyclophosphamide, ticlopidine, and
clopidogrel). In addition, in vitro studies suggest that paroxetine, sertraline, norfluoxetine, and
fluvoxamine as well as nelfinavir and efavirenz inhibit the hydroxylation of bupropion. No
clinical studies have been performed to evaluate this finding. The threohydrobupropion
metabolite of bupropion does not appear to be produced by the cytochrome P450 isoenzymes.
The effects of concomitant administration of cimetidine on the pharmacokinetics of bupropion
and its active metabolites were studied in 24 healthy young male volunteers. Following oral
administration of two 150-mg WELLBUTRIN SR tablets with and without 800 mg of
cimetidine, the pharmacokinetics of bupropion and hydroxybupropion were unaffected.
However, there were 16% and 32% increases in the AUC and Cmax, respectively, of the
combined moieties of threohydrobupropion and erythrohydrobupropion.
In a series of studies in healthy volunteers, ritonavir (100 mg twice daily or 600 mg twice
daily) or ritonavir 100 mg plus lopinavir 400 mg (KALETRA) twice daily reduced the exposure
of bupropion and its major metabolites in a dose dependent manner by approximately 20% to
80%. Similarly, efavirenz 600 mg once daily for 2 weeks reduced the exposure of bupropion by
approximately 55%. This effect of ritonavir, KALETRA, and efavirenz is thought to be due to
the induction of bupropion metabolism. Patients receiving any of these drugs with bupropion
may need increased doses of bupropion, but the maximum recommended dose of bupropion
should not be exceeded (see CLINICAL PHARMACOLOGY: Metabolism).
While not systematically studied, certain drugs may induce the metabolism of bupropion (e.g.,
carbamazepine, phenobarbital, phenytoin).
Multiple oral doses of bupropion had no statistically significant effects on the single-dose
pharmacokinetics of lamotrigine in 12 healthy volunteers.
Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in
humans. In one study, following chronic administration of bupropion, 100 mg 3 times daily to
8 healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism.
Nevertheless, there may be the potential for clinically important alterations of blood levels of
coadministered drugs.
Drugs Metabolized By Cytochrome P450IID6 (CYP2D6): Many drugs, including most
antidepressants (SSRIs, many tricyclics), beta-blockers, antiarrhythmics, and antipsychotics are
metabolized by the CYP2D6 isoenzyme. Although bupropion is not metabolized by this
isoenzyme, bupropion and hydroxybupropion are inhibitors of CYP2D6 isoenzyme in vitro. In a
study of 15 male subjects (aged 19 to 35 years) who were extensive metabolizers of the CYP2D6
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Reference ID: 2978172
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isoenzyme, daily doses of bupropion given as 150 mg twice daily followed by a single dose of
50 mg desipramine increased the Cmax, AUC, and t1/2 of desipramine by an average of
approximately 2-, 5-, and 2-fold, respectively. The effect was present for at least 7 days after the
last dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6
has not been formally studied.
Therefore, coadministration of bupropion with drugs that are metabolized by CYP2D6
isoenzyme including certain antidepressants (e.g., nortriptyline, imipramine, desipramine,
paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine),
beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide),
should be approached with caution and should be initiated at the lower end of the dose range of
the concomitant medication. If bupropion is added to the treatment regimen of a patient already
receiving a drug metabolized by CYP2D6, the need to decrease the dose of the original
medication should be considered, particularly for those concomitant medications with a narrow
therapeutic index.
Drugs which require metabolic activation by CYP2D6 in order to be effective (e.g.,
tamoxifen) theoretically could have reduced efficacy when administered concomitantly with
inhibitors of CYP2D6 such as bupropion.
Although citalopram is not primarily metabolized by CYP2D6, in one study bupropion
increased the Cmax and AUC of citalopram by 30% and 40%, respectively. Citalopram did not
affect the pharmacokinetics of bupropion and its 3 metabolites.
MAO Inhibitors: Studies in animals demonstrate that the acute toxicity of bupropion is
enhanced by the MAO inhibitor phenelzine (see CONTRAINDICATIONS).
Levodopa and Amantadine: Limited clinical data suggest a higher incidence of adverse
experiences in patients receiving bupropion concurrently with either levodopa or amantadine.
Administration of WELLBUTRIN SR to patients receiving either levodopa or amantadine
concurrently should be undertaken with caution, using small initial doses and gradual dose
increases.
Drugs That Lower Seizure Threshold: Concurrent administration of
WELLBUTRIN SR and agents (e.g., antipsychotics, other antidepressants, theophylline,
systemic steroids, etc.) that lower seizure threshold should be undertaken only with extreme
caution (see WARNINGS). Low initial dosing and gradual dose increases should be employed.
Nicotine Transdermal System: (see PRECAUTIONS: Cardiovascular Effects).
Alcohol: In postmarketing experience, there have been rare reports of adverse
neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol
during treatment with WELLBUTRIN SR. The consumption of alcohol during treatment with
WELLBUTRIN SR should be minimized or avoided (also see CONTRAINDICATIONS).
Drug-Laboratory Test Interactions: False-positive urine immunoassay screening tests
for amphetamines have been reported in patients taking bupropion. This is due to lack of
specificity of some screening tests. False-positive test results may result even following
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Reference ID: 2978172
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For current labeling information, please visit https://www.fda.gov/drugsatfda
discontinuation of bupropion therapy. Confirmatory tests, such as gas chromatography/mass
spectrometry, will distinguish bupropion from amphetamines.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Lifetime carcinogenicity studies
were performed in rats and mice at doses up to 300 and 150 mg/kg/day, respectively. These
doses are approximately 7 and 2 times the maximum recommended human dose (MRHD),
respectively, on a mg/m2 basis. In the rat study there was an increase in nodular proliferative
lesions of the liver at doses of 100 to 300 mg/kg/day (approximately 2 to 7 times the MRHD on a
mg/m2 basis); lower doses were not tested. The question of whether or not such lesions may be
precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen
in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in
either study.
Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of 5 strains in
the Ames bacterial mutagenicity test and an increase in chromosomal aberrations in 1 of 3 in
vivo rat bone marrow cytogenetic studies.
A fertility study in rats at doses up to 300 mg/kg/day revealed no evidence of impaired
fertility.
Pregnancy: Teratogenic Effects: Pregnancy Category C. In studies conducted in rats and
rabbits, bupropion was administered orally at doses up to 450 and 150 mg/kg/day, respectively
(approximately 11 and 7 times the MRHD, respectively, on a mg/m2 basis), during the period of
organogenesis. No clear evidence of teratogenic activity was found in either species; however, in
rabbits, slightly increased incidences of fetal malformations and skeletal variations were
observed at the lowest dose tested (25 mg/kg/day, approximately equal to the MRHD on a mg/m2
basis) and greater. Decreased fetal weights were seen at 50 mg/kg and greater.
When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately
7 times the MRHD on a mg/m2 basis) prior to mating and throughout pregnancy and lactation,
there were no apparent adverse effects on offspring development.
One study has been conducted in pregnant women. This retrospective, managed-care database
study assessed the risk of congenital malformations overall and cardiovascular malformations
specifically, following exposure to bupropion in the first trimester compared to the risk of these
malformations following exposure to other antidepressants in the first trimester and bupropion
outside of the first trimester. This study included 7,005 infants with antidepressant exposure
during pregnancy, 1,213 of whom were exposed to bupropion in the first trimester. The study
showed no greater risk for congenital malformations overall or cardiovascular malformations
specifically, following first trimester bupropion exposure compared to exposure to all other
antidepressants in the first trimester, or bupropion outside of the first trimester. The results of
this study have not been corroborated. WELLBUTRIN SR should be used during pregnancy only
if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery: The effect of WELLBUTRIN SR on labor and delivery in humans is
unknown.
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Reference ID: 2978172
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Nursing Mothers: Like many other drugs, bupropion and its metabolites are secreted in human
milk. Because of the potential for serious adverse reactions in nursing infants from
WELLBUTRIN SR, a decision should be made whether to discontinue nursing or to discontinue
the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Safety and effectiveness in the pediatric population have not been established
(see BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk in Treating
Psychiatric Disorders). Anyone considering the use of WELLBUTRIN SR in a child or
adolescent must balance the potential risks with the clinical need.
Geriatric Use: Of the approximately 6,000 patients who participated in clinical trials with
bupropion sustained-release tablets (depression and smoking cessation studies), 275 were 65 and
over and 47 were 75 and over. In addition, several hundred patients 65 and over participated in
clinical trials using the immediate-release formulation of bupropion (depression studies). No
overall differences in safety or effectiveness were observed between these subjects and younger
subjects, and other reported clinical experience has not identified differences in responses
between the elderly and younger patients, but greater sensitivity of some older individuals cannot
be ruled out.
A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its
metabolites in elderly subjects was similar to that of younger subjects; however, another
pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased
risk for accumulation of bupropion and its metabolites (see CLINICAL PHARMACOLOGY).
Bupropion is extensively metabolized in the liver to active metabolites, which are further
metabolized and excreted by the kidneys. The risk of toxic reaction to this drug may be greater in
patients with impaired renal function. Because elderly patients are more likely to have decreased
renal function, care should be taken in dose selection, and it may be useful to monitor renal
function (see PRECAUTIONS: Renal Impairment and DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
(See also WARNINGS and PRECAUTIONS.)
The information included under the Incidence in Controlled Trials subsection of ADVERSE
REACTIONS is based primarily on data from controlled clinical trials with WELLBUTRIN SR.
Information on additional adverse events associated with the sustained-release formulation of
bupropion in smoking cessation trials, as well as the immediate-release formulation of
bupropion, is included in a separate section (see Other Events Observed During the Clinical
Development and Postmarketing Experience of Bupropion).
Incidence in Controlled Trials With WELLBUTRIN SR: Adverse Events Associated
With Discontinuation of Treatment Among Patients Treated With
WELLBUTRIN SR: In placebo-controlled clinical trials, 9% and 11% of patients treated with
300 and 400 mg/day, respectively, of WELLBUTRIN SR and 4% of patients treated with
placebo discontinued treatment due to adverse events. The specific adverse events in these trials
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Reference ID: 2978172
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that led to discontinuation in at least 1% of patients treated with either 300 or 400 mg/day of
WELLBUTRIN SR and at a rate at least twice the placebo rate are listed in Table 4.
Table 4. Treatment Discontinuations Due to Adverse Events in Placebo-Controlled Trials
WELLBUTRIN SR
WELLBUTRIN SR
300 mg/day
400 mg/day
Placebo
Adverse Event Term
(n = 376)
(n = 114)
(n = 385)
Rash
2.4%
0.9%
0.0%
Nausea
0.8%
1.8%
0.3%
Agitation
0.3%
1.8%
0.3%
Migraine
0.0%
1.8%
0.3%
Adverse Events Occurring at an Incidence of 1% or More Among Patients
Treated With WELLBUTRIN SR: Table 5 enumerates treatment-emergent adverse events that
occurred among patients treated with 300 and 400 mg/day of WELLBUTRIN SR and with
placebo in placebo-controlled trials. Events that occurred in either the 300- or 400-mg/day group
at an incidence of 1% or more and were more frequent than in the placebo group are included.
Reported adverse events were classified using a COSTART-based Dictionary.
Accurate estimates of the incidence of adverse events associated with the use of any drug are
difficult to obtain. Estimates are influenced by drug dose, detection technique, setting, physician
judgments, etc. The figures cited cannot be used to predict precisely the incidence of untoward
events in the course of usual medical practice where patient characteristics and other factors
differ from those that prevailed in the clinical trials. These incidence figures also cannot be
compared with those obtained from other clinical studies involving related drug products as each
group of drug trials is conducted under a different set of conditions.
Finally, it is important to emphasize that the tabulation does not reflect the relative severity
and/or clinical importance of the events. A better perspective on the serious adverse events
associated with the use of WELLBUTRIN SR is provided in the WARNINGS and
PRECAUTIONS sections.
Table 5. Treatment-Emergent Adverse Events in Placebo-Controlled Trialsa
WELLBUTRIN SR
WELLBUTRIN SR
Body System/
300 mg/day
400 mg/day
Placebo
Adverse Event
(n = 376)
(n = 114)
(n = 385)
Body (General)
Headache
26%
25%
23%
Infection
8%
9%
6%
Abdominal pain
3%
9%
2%
Asthenia
2%
4%
2%
Chest pain
3%
4%
1%
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Pain
Fever
2%
1%
3%
2%
2%
—
Cardiovascular
Palpitation
2%
6%
2%
Flushing
1%
4%
—
Migraine
1%
4%
1%
Hot flashes
1%
3%
1%
Digestive
Dry mouth
17%
24%
7%
Nausea
13%
18%
8%
Constipation
10%
5%
7%
Diarrhea
5%
7%
6%
Anorexia
5%
3%
2%
Vomiting
4%
2%
2%
Dysphagia
0%
2%
0%
Musculoskeletal
Myalgia
2%
6%
3%
Arthralgia
1%
4%
1%
Arthritis
0%
2%
0%
Twitch
1%
2%
—
Nervous system
Insomnia
11%
16%
6%
Dizziness
7%
11%
5%
Agitation
3%
9%
2%
Anxiety
5%
6%
3%
Tremor
6%
3%
1%
Nervousness
5%
3%
3%
Somnolence
2%
3%
2%
Irritability
3%
2%
2%
Memory decreased
—
3%
1%
Paresthesia
1%
2%
1%
Central nervous system
stimulation
2%
1%
1%
Respiratory
Pharyngitis
3%
11%
2%
Sinusitis
3%
1%
2%
Increased cough
1%
2%
1%
Skin
Sweating
Rash
6%
5%
5%
4%
2%
1%
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Pruritus
Urticaria
2%
2%
4%
1%
2%
0%
Special senses
Tinnitus
Taste perversion
Blurred vision or
diplopia
6%
2%
3%
6%
4%
2%
2%
—
2%
Urogenital
Urinary frequency
Urinary urgency
Vaginal hemorrhageb
Urinary tract infection
2%
—
0%
1%
5%
2%
2%
0%
2%
0%
—
—
a Adverse events that occurred in at least 1% of patients treated with either 300 or 400 mg/day
of WELLBUTRIN SR, but equally or more frequently in the placebo group, were: abnormal
dreams, accidental injury, acne, appetite increased, back pain, bronchitis, dysmenorrhea,
dyspepsia, flatulence, flu syndrome, hypertension, neck pain, respiratory disorder, rhinitis, and
tooth disorder.
b Incidence based on the number of female patients.
— Hyphen denotes adverse events occurring in greater than 0 but less than 0.5% of patients.
Incidence of Commonly Observed Adverse Events in Controlled Clinical Trials:
Adverse events from Table 5 occurring in at least 5% of patients treated with
WELLBUTRIN SR and at a rate at least twice the placebo rate are listed below for the 300- and
400-mg/day dose groups.
WELLBUTRIN SR 300 mg/day: Anorexia, dry mouth, rash, sweating, tinnitus, and
tremor.
WELLBUTRIN SR 400 mg/day: Abdominal pain, agitation, anxiety, dizziness, dry
mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary
frequency.
Other Events Observed During the Clinical Development and Postmarketing
Experience of Bupropion: In addition to the adverse events noted above, the following
events have been reported in clinical trials and postmarketing experience with the
sustained-release formulation of bupropion in depressed patients and in nondepressed smokers,
as well as in clinical trials and postmarketing clinical experience with the immediate-release
formulation of bupropion.
Adverse events for which frequencies are provided below occurred in clinical trials with the
sustained-release formulation of bupropion. The frequencies represent the proportion of patients
who experienced a treatment-emergent adverse event on at least one occasion in
placebo-controlled studies for depression (n = 987) or smoking cessation (n = 1,013), or patients
who experienced an adverse event requiring discontinuation of treatment in an open-label
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surveillance study with WELLBUTRIN SR (n = 3,100). All treatment-emergent adverse events
are included except those listed in Tables 2 through 5, those events listed in other safety-related
sections, those adverse events subsumed under COSTART terms that are either overly general or
excessively specific so as to be uninformative, those events not reasonably associated with the
use of the drug, and those events that were not serious and occurred in fewer than 2 patients.
Events of major clinical importance are described in the WARNINGS and PRECAUTIONS
sections of the labeling.
Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions of frequency: Frequent adverse events are defined as those
occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to
1/1,000 patients, while rare events are those occurring in less than 1/1,000 patients.
Adverse events for which frequencies are not provided occurred in clinical trials or
postmarketing experience with bupropion. Only those adverse events not previously listed for
sustained-release bupropion are included. The extent to which these events may be associated
with WELLBUTRIN SR is unknown.
Body (General): Infrequent were chills, facial edema, musculoskeletal chest pain, and
photosensitivity. Rare was malaise. Also observed were arthralgia, myalgia, and fever with rash
and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble
serum sickness (see PRECAUTIONS).
Cardiovascular: Infrequent were postural hypotension, stroke, tachycardia, and
vasodilation. Rare was syncope. Also observed were complete atrioventricular block,
extrasystoles, hypotension, hypertension (in some cases severe, see PRECAUTIONS),
myocardial infarction, phlebitis, and pulmonary embolism.
Digestive: Infrequent were abnormal liver function, bruxism, gastric reflux, gingivitis,
glossitis, increased salivation, jaundice, mouth ulcers, stomatitis, and thirst. Rare was edema of
tongue. Also observed were colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage,
hepatitis, intestinal perforation, liver damage, pancreatitis, and stomach ulcer.
Endocrine: Also observed were hyperglycemia, hypoglycemia, and syndrome of
inappropriate antidiuretic hormone.
Hemic and Lymphatic: Infrequent was ecchymosis. Also observed were anemia,
leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered PT
and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were
observed when bupropion was coadministered with warfarin.
Metabolic and Nutritional: Infrequent were edema and peripheral edema. Also observed
was glycosuria.
Musculoskeletal: Infrequent were leg cramps. Also observed were muscle
rigidity/fever/rhabdomyolysis and muscle weakness.
Nervous System: Infrequent were abnormal coordination, decreased libido,
depersonalization, dysphoria, emotional lability, hostility, hyperkinesia, hypertonia, hypesthesia,
suicidal ideation, and vertigo. Rare were amnesia, ataxia, derealization, and hypomania. Also
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observed were abnormal electroencephalogram (EEG), akinesia, aggression, aphasia, coma,
completed suicide, delirium, delusions, dysarthria, dyskinesia, dystonia, euphoria,
extrapyramidal syndrome, hallucinations, hypokinesia, increased libido, manic reaction,
neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, and unmasking tardive
dyskinesia.
Respiratory: Rare was bronchospasm. Also observed was pneumonia.
Skin: Rare was maculopapular rash. Also observed were alopecia, angioedema, exfoliative
dermatitis, and hirsutism.
Special Senses: Infrequent were accommodation abnormality and dry eye. Also observed
were deafness, diplopia, increased intraocular pressure, and mydriasis.
Urogenital: Infrequent were impotence, polyuria, and prostate disorder. Also observed were
abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection,
salpingitis, urinary incontinence, urinary retention, and vaginitis.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class: Bupropion is not a controlled substance.
Humans: Controlled clinical studies of bupropion (immediate-release formulation) conducted
in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed patients
showed some increase in motor activity and agitation/excitement.
In a population of individuals experienced with drugs of abuse, a single dose of 400 mg of
bupropion produced mild amphetamine-like activity as compared to placebo on the
Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI), and a
score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These
scales measure general feelings of euphoria and drug desirability.
Findings in clinical trials, however, are not known to reliably predict the abuse potential of
drugs. Nonetheless, evidence from single-dose studies does suggest that the recommended daily
dosage of bupropion when administered in divided doses is not likely to be especially reinforcing
to amphetamine or stimulant abusers. However, higher doses that could not be tested because of
the risk of seizure might be modestly attractive to those who abuse stimulant drugs.
Animals: Studies in rodents and primates have shown that bupropion exhibits some
pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase
locomotor activity, elicit a mild stereotyped behavioral response, and increase rates of
responding in several schedule-controlled behavior paradigms. In primate models to assess the
positive reinforcing effects of psychoactive drugs, bupropion was self-administered
intravenously. In rats, bupropion produced amphetamine-like and cocaine-like discriminative
stimulus effects in drug discrimination paradigms used to characterize the subjective effects of
psychoactive drugs.
OVERDOSAGE
Human Overdose Experience: Overdoses of up to 30 g or more of bupropion have been
reported. Seizure was reported in approximately one-third of all cases. Other serious reactions
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reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus
tachycardia, and ECG changes such as conduction disturbances (including QRS prolongation) or
arrhythmias. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory
failure have been reported mainly when bupropion was part of multiple drug overdoses.
Although most patients recovered without sequelae, deaths associated with overdoses of
bupropion alone have been reported in patients ingesting large doses of the drug. Multiple
uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported
in these patients.
Overdosage Management: Ensure an adequate airway, oxygenation, and ventilation.
Monitor cardiac rhythm and vital signs. EEG monitoring is also recommended for the first
48 hours post-ingestion. General supportive and symptomatic measures are also recommended.
Induction of emesis is not recommended.
Activated charcoal should be administered. There is no experience with the use of forced
diuresis, dialysis, hemoperfusion, or exchange transfusion in the management of bupropion
overdoses. No specific antidotes for bupropion are known.
Due to the dose-related risk of seizures with WELLBUTRIN SR, hospitalization following
suspected overdose should be considered. Based on studies in animals, it is recommended that
seizures be treated with intravenous benzodiazepine administration and other supportive
measures, as appropriate.
In managing overdosage, consider the possibility of multiple drug involvement. The physician
should consider contacting a poison control center for additional information on the treatment of
any overdose. Telephone numbers for certified poison control centers are listed in the
Physicians’ Desk Reference (PDR).
DOSAGE AND ADMINISTRATION
General Dosing Considerations: It is particularly important to administer
WELLBUTRIN SR in a manner most likely to minimize the risk of seizure (see WARNINGS).
Gradual escalation in dosage is also important if agitation, motor restlessness, and insomnia,
often seen during the initial days of treatment, are to be minimized. If necessary, these effects
may be managed by temporary reduction of dose or the short-term administration of an
intermediate to long-acting sedative hypnotic. A sedative hypnotic usually is not required beyond
the first week of treatment. Insomnia may also be minimized by avoiding bedtime doses. If
distressing, untoward effects supervene, dose escalation should be stopped. WELLBUTRIN SR
should be swallowed whole and not crushed, divided, or chewed, as this may lead to an increased
risk of adverse effects including seizures.
Initial Treatment: The usual adult target dose for WELLBUTRIN SR is 300 mg/day, given as
150 mg twice daily. Dosing with WELLBUTRIN SR should begin at 150 mg/day given as a
single daily dose in the morning. If the 150-mg initial dose is adequately tolerated, an increase to
the 300-mg/day target dose, given as 150 mg twice daily, may be made as early as day 4 of
dosing. There should be an interval of at least 8 hours between successive doses.
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Increasing the Dosage Above 300 mg/day: As with other antidepressants, the full
antidepressant effect of WELLBUTRIN SR may not be evident until 4 weeks of treatment or
longer. An increase in dosage to the maximum of 400 mg/day, given as 200 mg twice daily, may
be considered for patients in whom no clinical improvement is noted after several weeks of
treatment at 300 mg/day.
Maintenance Treatment: It is generally agreed that acute episodes of depression require
several months or longer of sustained pharmacological therapy beyond response to the acute
episode. In a study in which patients with major depressive disorder, recurrent type, who had
responded during 8 weeks of acute treatment with WELLBUTRIN SR were assigned randomly
to placebo or to the same dose of WELLBUTRIN SR (150 mg twice daily) during 44 weeks of
maintenance treatment as they had received during the acute stabilization phase, longer-term
efficacy was demonstrated (see CLINICAL TRIALS under CLINICAL PHARMACOLOGY).
Based on these limited data, it is unknown whether or not the dose of WELLBUTRIN SR needed
for maintenance treatment is identical to the dose needed to achieve an initial response. Patients
should be periodically reassessed to determine the need for maintenance treatment and the
appropriate dose for such treatment.
Dosage Adjustment for Patients with Impaired Hepatic Function: WELLBUTRIN SR
should be used with extreme caution in patients with severe hepatic cirrhosis. The dose should
not exceed 100 mg every day or 150 mg every other day in these patients. WELLBUTRIN SR
should be used with caution in patients with hepatic impairment (including mild-to-moderate
hepatic cirrhosis) and a reduced frequency and/or dose should be considered in patients with
mild-to-moderate hepatic cirrhosis (see CLINICAL PHARMACOLOGY, WARNINGS, and
PRECAUTIONS).
Dosage Adjustment for Patients with Impaired Renal Function: WELLBUTRIN SR
should be used with caution in patients with renal impairment and a reduced frequency and/or
dose should be considered (see CLINICAL PHARMACOLOGY and PRECAUTIONS).
HOW SUPPLIED
WELLBUTRIN SR Sustained-Release Tablets, 100 mg of bupropion hydrochloride, are blue,
round, biconvex, film-coated tablets printed with “WELLBUTRIN SR 100” in bottles of 60
(NDC 0173-0947-55) tablets.
WELLBUTRIN SR Sustained-Release Tablets, 150 mg of bupropion hydrochloride, are
purple, round, biconvex, film-coated tablets printed with "WELLBUTRIN SR 150" in bottles of
60 (NDC 0173-0135-55) tablets.
WELLBUTRIN SR Sustained-Release Tablets, 200 mg of bupropion hydrochloride, are light
pink, round, biconvex, film-coated tablets printed with “WELLBUTRIN SR 200” in bottles of 60
(NDC 0173-0722-00) tablets.
Store at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP]. Dispense in a
tight, light-resistant container as defined in the USP.
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WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and ZYBAN are registered
trademarks of GlaxoSmithKline.
KALETRA is a registered trademark of Abbott Laboratories. GlaxoSmithKline
Distributed by:
GlaxoSmithKline
Research Triangle Park, NC 27709
Manufactured by:
GlaxoSmithKline
Research Triangle Park, NC 27709
or DSM Pharmaceuticals, Inc.
Greenville, NC 27834
©YEAR, GlaxoSmithKline. All rights reserved
Month Year
WLS:XPI
MEDICATION GUIDE
WELLBUTRIN SR® (WELL byu-trin)
(bupropion hydrochloride) Sustained-Release Tablets
Read this Medication Guide carefully before you start using WELLBUTRIN SR and each time
you get a refill. There may be new information. This information does not take the place of
talking with your doctor about your medical condition or your treatment. If you have any
questions about WELLBUTRIN SR, ask your doctor or pharmacist.
IMPORTANT: Be sure to read the three sections of this Medication Guide. The first
section is about the risk of suicidal thoughts and actions with antidepressant medicines; the
second section is about the risk of changes in thinking and behavior, depression and
suicidal thoughts or actions with medicines used to quit smoking; and the third section is
entitled “What Other Important Information Should I Know About WELLBUTRIN SR?”
Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and
Suicidal Thoughts or Actions
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This section of the Medication Guide is only about the risk of suicidal thoughts and actions with
antidepressant medicines. Talk to your, or your family member’s, healthcare provider
about:
• all risks and benefits of treatment with antidepressant medicines
• all treatment choices for depression or other serious mental illness
What is the most important information I should know about antidepressant medicines,
depression and other serious mental illnesses, and suicidal thoughts or actions?
1. Antidepressant medicines may increase suicidal thoughts or actions in some children,
teenagers, and young adults within the first few months of treatment.
2. Depression and other serious mental illnesses are the most important causes of suicidal
thoughts and actions. Some people may have a particularly high risk of having suicidal
thoughts or actions. These include people who have (or have a family history of) bipolar
illness (also called manic-depressive illness) or suicidal thoughts or actions.
3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a
family member?
• Pay close attention to any changes, especially sudden changes, in mood, behaviors,
thoughts, or feelings. This is very important when an antidepressant medicine is started or
when the dose is changed.
• Call the healthcare provider right away to report new or sudden changes in mood,
behavior, thoughts, or feelings.
• Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare
provider between visits as needed, especially if you have concerns about symptoms.
Call a healthcare provider right away if you or your family member has any of the
following symptoms, especially if they are new, worse, or worry you:
• thoughts about suicide or dying
• trouble sleeping (insomnia)
• attempts to commit suicide
• new or worse irritability
• new or worse depression
• acting aggressive, being angry, or violent
• new or worse anxiety
• acting on dangerous impulses
• feeling very agitated or restless
• an extreme increase in activity and talking (mania)
• panic attacks
• other unusual changes in behavior or mood
What else do I need to know about antidepressant medicines?
• Never stop an antidepressant medicine without first talking to a healthcare provider.
Stopping an antidepressant medicine suddenly can cause other symptoms.
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• Antidepressants are medicines used to treat depression and other illnesses. It is
important to discuss all the risks of treating depression and also the risks of not treating it.
Patients and their families or other caregivers should discuss all treatment choices with the
healthcare provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects. Talk to the healthcare provider about the
side effects of the medicine prescribed for you or your family member.
• Antidepressant medicines can interact with other medicines. Know all of the medicines
that you or your family member takes. Keep a list of all medicines to show the healthcare
provider. Do not start new medicines without first checking with your healthcare provider.
• Not all antidepressant medicines prescribed for children are FDA approved for use in
children. Talk to your child’s healthcare provider for more information.
WELLBUTRIN SR has not been studied in children under the age of 18 and is not approved for
use in children and teenagers.
Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior,
Depression, and Suicidal Thoughts or Actions
This section of the Medication Guide is only about the risk of changes in thinking and behavior,
depression and suicidal thoughts or actions with drugs used to quit smoking.
Although WELLBUTRIN SR is not a treatment for quitting smoking, it contains the same active
ingredient (bupropion hydrochloride) as ZYBAN® which is used to help patients quit smoking.
Some people have had changes in behavior, hostility, agitation, depression, suicidal thoughts or
actions while taking bupropion to help them quit smoking. These symptoms can develop during
treatment with bupropion or after stopping treatment with bupropion.
If you, your family member, or your caregiver notice agitation, hostility, depression, or changes
in thinking or behavior that are not typical for you, or you have any of the following symptoms,
stop taking bupropion and call your healthcare provider right away:
• thoughts about suicide or dying
• an extreme increase in activity and talking (mania)
• attempts to commit suicide
• abnormal thoughts or sensations
• new or worse depression
• seeing or hearing things that are not there
• new or worse anxiety
(hallucinations)
• panic attacks
• feeling people are against you (paranoia)
• feeling very agitated or restless
• feeling confused
• acting aggressive, being angry, or violent
• other unusual changes in behavior or mood
• acting on dangerous impulses
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When you try to quit smoking, with or without bupropion, you may have symptoms that may be
due to nicotine withdrawal, including urge to smoke, depressed mood, trouble sleeping,
irritability, frustration, anger, feeling anxious, difficulty concentrating, restlessness, decreased
heart rate, and increased appetite or weight gain. Some people have even experienced suicidal
thoughts when trying to quit smoking without medication. Sometimes quitting smoking can lead
to worsening of mental health problems that you already have, such as depression.
Before taking bupropion, tell your healthcare provider if you have ever had depression or other
mental illnesses. You should also tell your doctor about any symptoms you had during other
times you tried to quit smoking, with or without bupropion.
What Other Important Information Should I Know About WELLBUTRIN SR?
• Seizures: There is a chance of having a seizure (convulsion, fit) with WELLBUTRIN SR,
especially in people:
• with certain medical problems.
• who take certain medicines.
The chance of having seizures increases with higher doses of WELLBUTRIN SR. For more
information, see the sections “Who should not take WELLBUTRIN SR?” and “What should
I tell my doctor before using WELLBUTRIN SR?” Tell your doctor about all of your
medical conditions and all the medicines you take. Do not take any other medicines while
you are using WELLBUTRIN SR unless your doctor has said it is okay to take them.
If you have a seizure while taking WELLBUTRIN SR, stop taking the tablets and call
your doctor right away. Do not take WELLBUTRIN SR again if you have a seizure.
• High blood pressure (hypertension). Some people get high blood pressure, that can be
severe, while taking WELLBUTRIN SR. The chance of high blood pressure may be higher
if you also use nicotine replacement therapy (such as a nicotine patch) to help you stop
smoking.
• Severe allergic reactions. Some people have severe allergic reaction to
WELLBUTRIN SR. Stop taking WELLBUTRIN SR and call your doctor right away if
you get a rash, itching, hives, fever, swollen lymph glands, painful sores in the mouth or
around the eyes, swelling of the lips or tongue, chest pain, or have trouble breathing. These
could be signs of a serious allergic reaction.
• Unusual thoughts or behaviors. Some patients have unusual thoughts or behaviors while
taking WELLBUTRIN SR, including delusions (believe you are someone else),
hallucinations (seeing or hearing things that are not there), paranoia (feeling that people are
against you), or feeling confused. If this happens to you, call your doctor.
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What is WELLBUTRIN SR?
WELLBUTRIN SR is a prescription medicine used to treat adults with a certain type of
depression called major depressive disorder.
Who should not take WELLBUTRIN SR?
Do not take WELLBUTRIN SR if you
• have or had a seizure disorder or epilepsy.
• are taking ZYBAN® (used to help people stop smoking) or any other medicines that
contain bupropion hydrochloride, such as WELLBUTRIN® Tablets or WELLBUTRIN
XL® Extended-Release Tablets. Bupropion is the same active ingredient that is in
WELLBUTRIN SR.
• drink a lot of alcohol and abruptly stop drinking, or use medicines called sedatives (these
make you sleepy) or benzodiazepines and you stop using them all of a sudden.
• have taken within the last 14 days medicine for depression called a monoamine oxidase
inhibitor (MAOI), such as NARDIL® (phenelzine sulfate), PARNATE® (tranylcypromine
sulfate), or MARPLAN® (isocarboxazid).
• have or had an eating disorder such as anorexia nervosa or bulimia.
• are allergic to the active ingredient in WELLBUTRIN SR, bupropion, or to any of the
inactive ingredients. See the end of this leaflet for a complete list of ingredients in
WELLBUTRIN SR.
What should I tell my doctor before using WELLBUTRIN SR?
Tell your doctor if you have ever had depression, suicidal thoughts or actions, or other mental
health problems. See “Antidepressant Medicines, Depression and Other Serious Mental Illnesses,
and Suicidal Thoughts or Actions.”
• Tell your doctor about your other medical conditions including if you:
• are pregnant or plan to become pregnant. It is not known if WELLBUTRIN SR can
harm your unborn baby.
• are breastfeeding. WELLBUTRIN SR passes through your milk. It is not known if
WELLBUTRIN SR can harm your baby.
• have liver problems, especially cirrhosis of the liver.
• have kidney problems.
• have an eating disorder such as anorexia nervosa or bulimia.
• have had a head injury.
• have had a seizure (convulsion, fit).
• have a tumor in your nervous system (brain or spine).
• have had a heart attack, heart problems, or high blood pressure.
• are a diabetic taking insulin or other medicines to control your blood sugar.
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• drink a lot of alcohol.
• abuse prescription medicines or street drugs.
• Tell your doctor about all the medicines you take, including prescription and non
prescription medicines, vitamins, and herbal supplements. Many medicines increase your
chances of having seizures or other serious side effects if you take them while you are using
WELLBUTRIN SR.
How should I take WELLBUTRIN SR?
• Take WELLBUTRIN SR exactly as prescribed by your doctor.
• Do not chew, cut, or crush WELLBUTRIN SR tablets. If you do, the medicine will be
released into your body too quickly. If this happens you may be more likely to get side
effects including seizures. You must swallow the tablets whole. Tell your doctor if you
cannot swallow medicine tablets.
• Take WELLBUTRIN SR at the same time each day.
• Take your doses of WELLBUTRIN SR at least 8 hours apart.
• You may take WELLBUTRIN SR with or without food.
• If you miss a dose, do not take an extra tablet to make up for the dose you forgot. Wait and
take your next tablet at the regular time. This is very important. Too much
WELLBUTRIN SR can increase your chance of having a seizure.
• If you take too much WELLBUTRIN SR, or overdose, call your local emergency room or
poison control center right away.
• Do not take any other medicines while using WELLBUTRIN SR unless your doctor has
told you it is okay.
• It may take several weeks for you to feel that WELLBUTRIN SR is working. Once you feel
better, it is important to keep taking WELLBUTRIN SR exactly as directed by your doctor.
Call your doctor if you do not feel WELLBUTRIN SR is working for you.
• Do not change your dose or stop taking WELLBUTRIN SR without talking with your doctor
first.
What should I avoid while taking WELLBUTRIN SR?
• Do not drink a lot of alcohol while taking WELLBUTRIN SR. If you usually drink a lot of
alcohol, talk with your doctor before suddenly stopping. If you suddenly stop drinking
alcohol, you may increase your chance of having seizures.
• Do not drive a car or use heavy machinery until you know how WELLBUTRIN SR affects
you. WELLBUTRIN SR can impair your ability to perform these tasks.
What are possible side effects of WELLBUTRIN SR?
WELLBUTRIN SR can cause serious side effects. Read this entire Medication Guide for more
information about these serious side effects.
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The most common side effects of WELLBUTRIN SR are loss of appetite, dry mouth, skin rash,
sweating, ringing in the ears, shakiness, stomach pain, agitation, anxiety, dizziness, trouble
sleeping, muscle pain, nausea, fast heartbeat, sore throat, and urinating more often.
If you have nausea, take your medicine with food. If you have trouble sleeping, do not take your
medicine too close to bedtime.
These are not all the side effects of WELLBUTRIN SR. For a complete list, ask your doctor or
pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at
1-800-FDA-1088.
How should I store WELLBUTRIN SR?
• Store WELLBUTRIN SR at room temperature. Store out of direct sunlight. Keep
WELLBUTRIN SR in its tightly closed bottle.
• WELLBUTRIN SR tablets may have an odor.
General Information about WELLBUTRIN SR.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
Do not use WELLBUTRIN SR for a condition for which it was not prescribed. Do not give
WELLBUTRIN SR to other people, even if they have the same symptoms you have. It may harm
them. Keep WELLBUTRIN SR out of the reach of children.
If you take a urine drug screening test, WELLBUTRIN SR may make the test result positive for
amphetamines. If you tell the person giving you the drug screening test that you are taking
WELLBUTRIN SR, they can do a more specific drug screening test that should not have this
problem.
This Medication Guide summarizes important information about WELLBUTRIN SR. For more
information, talk with your doctor. You can ask your doctor or pharmacist for information about
WELLBUTRIN SR that is written for health professionals.
What are the ingredients in WELLBUTRIN SR?
Active ingredient: bupropion hydrochloride.
Inactive ingredients: carnauba wax, cysteine hydrochloride, hypromellose, magnesium stearate,
microcrystalline cellulose, polyethylene glycol, polysorbate 80, and titanium dioxide. In
addition, the 100-mg tablet contains FD&C Blue No. 1 Lake, the 150-mg tablet contains FD&C
34
Reference ID: 2978172
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Blue No. 2 Lake and FD&C Red No. 40 Lake, and the 200-mg tablet contains FD&C Red No. 40
Lake. The tablets are printed with edible black ink.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, ZYBAN, and PARNATE are
registered trademarks of GlaxoSmithKline.
The following are registered trademarks of their respective manufacturers: NARDIL®/Warner
Lambert Company; MARPLAN®/Oxford Pharmaceutical Services, Inc. GlaxoSmithKline
Distributed by:
GlaxoSmithKline
Research Triangle Park, NC 27709
Manufactured by:
GlaxoSmithKline
Research Triangle Park, NC 27709
or DSM Pharmaceuticals, Inc.
Greenville, NC 27834
©YEAR, GlaxoSmithKline. All rights reserved.
Month Year
WLS:XMG
35
Reference ID: 2978172
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:48.759435
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018644s043lbl.pdf', 'application_number': 18644, 'submission_type': 'SUPPL ', 'submission_number': 43}
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NDA 18-651/S-018
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500012 3E Rev 10/2002
MARINOL®
(Dronabinol)
Capsules
DESCRIPTION
Dronabinol is a cannabinoid designated chemically as (6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-
6H-dibenzo[b,d]pyran-1-ol. Dronabinol has the following empirical and structural formulas:
Dronabinol, the active ingredient in MARINOL® Capsules, is synthetic delta-9-tetrahydrocannabinol (delta-9-
THC). Delta-9-tetrahydrocannabinol is also a naturally occurring component of Cannabis sativa L. (Marijuana).
Dronabinol is a light yellow resinous oil that is sticky at room temperature and hardens upon refrigeration.
Dronabinol is insoluble in water and is formulated in sesame oil. It has a pKa of 10.6 and an octanol-water partition
coefficient: 6,000:1 at pH 7.
Capsules for oral administration: MARINOL® Capsules is supplied as round, soft gelatin capsules containing
either 2.5 mg, 5 mg, or 10 mg dronabinol. Each MARINOL® Capsule is formulated with the following inactive
ingredients: FD&C Blue No. 1 (5 mg), FD&C Red No. 40 (5 mg), FD&C Yellow No. 6 (5 mg and 10 mg), gelatin,
glycerin, methylparaben, propylparaben, sesame oil, and titanium dioxide.
CLINICAL PHARMACOLOGY
Dronabinol is an orally active cannabinoid which, like other cannabinoids, has complex effects on the central
nervous system (CNS), including central sympathomimetic activity. Cannabinoid receptors have been discovered in
neural tissues. These receptors may play a role in mediating the effects of dronabinol and other cannabinoids.
Pharmacodynamics
Dronabinol-induced sympathomimetic activity may result in tachycardia and/or conjunctival injection. Its effects on
blood pressure are inconsistent, but occasional subjects have experienced orthostatic hypotension and/or syncope
upon abrupt standing.
Dronabinol also demonstrates reversible effects on appetite, mood, cognition, memory, and perception. These
phenomena appear to be dose-related, increasing in frequency with higher dosages, and subject to great interpatient
variability.
After oral administration, dronabinol has an onset of action of approximately 0.5 to 1 hours and peak effect at 2
to 4 hours. Duration of action for psychoactive effects is 4 to 6 hours, but the appetite stimulant effect of dronabinol
may continue for 24 hours or longer after administration.
Tachyphylaxis and tolerance develop to some of the pharmacologic effects of dronabinol and other
cannabinoids with chronic use, suggesting an indirect effect on sympathetic neurons. In a study of the
pharmacodynamics of chronic dronabinol exposure, healthy male volunteers (N = 12) received 210 mg/day
dronabinol, administered orally in divided doses, for 16 days. An initial tachycardia induced by dronabinol was
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-651/S-018
Page 4
replaced successively by normal sinus rhythm and then bradycardia. A decrease in supine blood pressure, made
worse by standing, was also observed initially. These volunteers developed tolerance to the cardiovascular and
subjective adverse CNS effects of dronabinol within 12 days of treatment initiation.
Tachyphylaxis and tolerance do not, however, appear to develop to the appetite stimulant effect of MARINOL®
Capsules. In studies involving patients with Acquired Immune Deficiency Syndrome (AIDS), the appetite stimulant
effect of MARINOL® Capsules has been sustained for up to five months in clinical trials, at dosages ranging from
2.5 mg/day to 20 mg/day.
Pharmacokinetics
Absorption and Distribution: MARINOL® (Dronabinol) Capsules is almost completely absorbed (90 to 95%) after
single oral doses. Due to the combined effects of first pass hepatic metabolism and high lipid solubility, only 10 to
20% of the administered dose reaches the systemic circulation. Dronabinol has a large apparent volume of
distribution, approximately 10 L/kg, because of its lipid solubility. The plasma protein binding of dronabinol and its
metabolites is approximately 97%.
The elimination phase of dronabinol can be described using a two compartment model with an initial (alpha)
half-life of about 4 hours and a terminal (beta) half-life of 25 to 36 hours. Because of its large volume of
distribution, dronabinol and its metabolites may be excreted at low levels for prolonged periods of time.
Metabolism: Dronabinol undergoes extensive first-pass hepatic metabolism, primarily by microsomal
hydroxylation, yielding both active and inactive metabolites. Dronabinol and its principal active metabolite, 11-OH-
delta-9-THC, are present in approximately equal concentrations in plasma. Concentrations of both parent drug and
metabolite peak at approximately 2 to 4 hours after oral dosing and decline over several days. Values for clearance
average about 0.2 L/kg-hr, but are highly variable due to the complexity of cannabinoid distribution.
Elimination: Dronabinol and its biotransformation products are excreted in both feces and urine. Biliary excretion
is the major route of elimination with about half of a radio-labeled oral dose being recovered from the feces within
72 hours as contrasted with 10 to 15% recovered from urine. Less than 5% of an oral dose is recovered unchanged
in the feces.
Following single dose administration, low levels of dronabinol metabolites have been detected for more than 5
weeks in the urine and feces.
In a study of MARINOL® Capsules involving AIDS patients, urinary cannabinoid/creatinine concentration
ratios were studied bi-weekly over a six week period. The urinary cannabinoid/creatinine ratio was closely
correlated with dose. No increase in the cannabinoid/creatinine ratio was observed after the first two weeks of
treatment, indicating that steady-state cannabinoid levels had been reached. This conclusion is consistent with
predictions based on the observed terminal half-life of dronabinol.
Special Populations: The pharmacokinetic profile of MARINOL® Capsules has not been investigated in either
pediatric or geriatric patients.
CLINICAL TRIALS
Appetite Stimulation: The appetite stimulant effect of MARINOL® (Dronabinol) Capsules in the treatment of
AIDS-related anorexia associated with weight loss was studied in a randomized, double-blind, placebo-controlled
study involving 139 patients. The initial dosage of MARINOL® Capsules in all patients was 5 mg/day,
administered in doses of 2.5 mg one hour before lunch and one hour before supper. In pilot studies, early morning
administration of MARINOL® Capsules appeared to have been associated with an increased frequency of adverse
experiences, as compared to dosing later in the day. The effect of MARINOL® Capsules on appetite, weight, mood,
and nausea was measured at scheduled intervals during the six-week treatment period. Side effects (feeling high,
dizziness, confusion, somnolence) occurred in 13 of 72 patients (18%) at this dosage level and the dosage was
reduced to 2.5 mg/day, administered as a single dose at supper or bedtime.
As compared to placebo, MARINOL® Capsules treatment resulted in a statistically significant improvement in
appetite as measured by visual analog scale (see figure). Trends toward improved body weight and mood, and
decreases in nausea were also seen.
After completing the 6-week study, patients were allowed to continue treatment with MARINOL® Capsules in
an open-label study, in which there was a sustained improvement in appetite.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-651/S-018
Page 5
Antiemetic: MARINOL® (Dronabinol) Capsules treatment of chemotherapy-induced emesis was evaluated in 454
patients with cancer, who received a total of 750 courses of treatment of various malignancies. The antiemetic
efficacy of MARINOL® Capsules was greatest in patients receiving cytotoxic therapy with MOPP for Hodgkin’s
and non-Hodgkin’s lymphomas. MARINOL® Capsules dosages ranged from 2.5 mg/day to 40 mg/day,
administered in equally divided doses every four to six hours (four times daily). As indicated in the following table,
escalating the MARINOL® Capsules dose above 7 mg/m2 increased the frequency of adverse experiences, with no
additional antiemetic benefit.
MARINOL® Capsules Dose: Response Frequency and Adverse Experiences*
(N = 750 treatment courses)
Response Frequency (%)
Adverse Events Frequency (%)
MARINOL®
Capsules Dose
Complete
Partial
Poor
None
Nondysphoric
Dysphoric
<7 mg/m2
36
32
32
23
65
12
>7 mg/m2
33
31
36
13
58
28
*Nondysphoric events consisted of drowsiness, tachycardia, etc.
Combination antiemetic therapy with MARINOL® Capsules and a phenothiazine (prochlorperazine) may result
in synergistic or additive antiemetic effects and attenuate the toxicities associated with each of the agents.
INDIVIDUALIZATION OF DOSAGES
The pharmacologic effects of MARINOL® (Dronabinol) Capsules are dose-related and subject to considerable
interpatient variability. Therefore, dosage individualization is critical in achieving the maximum benefit of
MARINOL® Capsules treatment.
Appetite Stimulation: In the clinical trials, the majority of patients were treated with 5 mg/day MARINOL®
Capsules, although the dosages ranged from 2.5 to 20 mg/day. For an adult:
1. Begin with 2.5 mg before lunch and 2.5 mg before supper. If CNS symptoms (feeling high, dizziness,
confusion, somnolence) do occur, they usually resolve in 1 to 3 days with continued dosage.
2. If CNS symptoms are severe or persistent, reduce the dose to 2.5 mg before supper. If symptoms continue to be
a problem, taking the single dose in the evening or at bedtime may reduce their severity.
3. When adverse effects are absent or minimal and further therapeutic effect is desired, increase the dose to 2.5 mg
before lunch and 5 mg before supper or 5 and 5 mg. Although most patients respond to 2.5 mg twice daily, 10
mg twice daily has been tolerated in about half of the patients in appetite stimulation studies.
The pharmacologic effects of MARINOL® Capsules are reversible upon treatment cessation.
Antiemetic: Most patients respond to 5 mg three or four times daily. Dosage may be escalated during a
chemotherapy cycle or at subsequent cycles, based upon initial results. Therapy should be initiated at the lowest
recommended dosage and titrated to clinical response. Administration of MARINOL® Capsules with
This label may not be the latest approved by FDA.
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NDA 18-651/S-018
Page 6
phenothiazines, such as prochlorperazine, has resulted in improved efficacy as compared to either drug alone,
without additional toxicity.
Pediatrics: MARINOL® Capsules is not recommended for AIDS-related anorexia in pediatric patients because it
has not been studied in this population. The pediatric dosage for the treatment of chemotherapy-induced emesis is
the same as in adults. Caution is recommended in prescribing MARINOL® Capsules for children because of the
psychoactive effects.
Geriatrics: Caution is advised in prescribing MARINOL® Capsules in elderly patients because they are generally
more sensitive to the psychoactive effects of drugs. In antiemetic studies, no difference in tolerance or efficacy was
apparent in patients >55 years old.
INDICATIONS AND USAGE
MARINOL® (Dronabinol) Capsules is indicated for the treatment of:
1. anorexia associated with weight loss in patients with AIDS; and
2. nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to
conventional antiemetic treatments.
CONTRAINDICATIONS
MARINOL® (Dronabinol) Capsules is contraindicated in any patient who has a history of hypersensitivity to any
cannabinoid or sesame oil.
WARNINGS
Patients receiving treatment with MARINOL® Capsules should be specifically warned not to drive, operate
machinery, or engage in any hazardous activity until it is established that they are able to tolerate the drug and to
perform such tasks safely.
PRECAUTIONS
General: The risk/benefit ratio of MARINOL® (Dronabinol) Capsules use should be carefully evaluated in patients
with the following medical conditions because of individual variation in response and tolerance to the effects of
MARINOL® Capsules.
MARINOL® Capsules should be used with caution in patients with cardiac disorders because of occasional
hypotension, possible hypertension, syncope, or tachycardia (see CLINICAL PHARMACOLOGY).
MARINOL® Capsules should be used with caution in patients with a history of substance abuse, including
alcohol abuse or dependence, because they may be more prone to abuse MARINOL® Capsules as well. Multiple
substance abuse is common and marijuana, which contains the same active compound, is a frequently abused
substance.
MARINOL® Capsules should be used with caution and careful psychiatric monitoring in patients with mania,
depression, or schizophrenia because MARINOL® Capsules may exacerbate these illnesses.
MARINOL® Capsules should be used with caution in patients receiving concomitant therapy with sedatives,
hypnotics or other psychoactive drugs because of the potential for additive or synergistic CNS effects.
MARINOL® Capsules should be used with caution in pregnant patients, nursing mothers, or pediatric patients
because it has not been studied in these patient populations.
Information for Patients: Patients receiving treatment with MARINOL® (Dronabinol) Capsules should be alerted
to the potential for additive central nervous system depression if MARINOL® Capsules is used concomitantly with
alcohol or other CNS depressants such as benzodiazepines and barbiturates.
Patients receiving treatment with MARINOL® Capsules should be specifically warned not to drive, operate
machinery, or engage in any hazardous activity until it is established that they are able to tolerate the drug and to
perform such tasks safely.
Patients using MARINOL® Capsules should be advised of possible changes in mood and other adverse
behavioral effects of the drug so as to avoid panic in the event of such manifestations. Patients should remain under
the supervision of a responsible adult during initial use of MARINOL® Capsules and following dosage adjustments.
Drug Interactions: In studies involving patients with AIDS and/or cancer, MARINOL® (Dronabinol) Capsules
has been co-administered with a variety of medications (e.g., cytotoxic agents, anti-infective agents, sedatives, or
opioid analgesics) without resulting in any clinically significant drug/drug interactions. Although no drug/drug
interactions were discovered during the clinical trials of MARINOL® Capsules, cannabinoids may interact with
other medications through both metabolic and pharmacodynamic mechanisms. Dronabinol is highly protein bound
to plasma proteins, and therefore, might displace other protein-bound drugs. Although this displacement has not
been confirmed in vivo, practitioners should monitor patients for a change in dosage requirements when
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-651/S-018
Page 7
administering dronabinol to patients receiving other highly protein-bound drugs. Published reports of drug/drug
interactions involving cannabinoids are summarized in the following table.
CONCOMITANT DRUG
CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic
agents
Additive hypertension, tachycardia, possibly
cardiotoxicity
Atropine, scopolamine, antihistamines, other
anticholinergic agents
Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other
tricyclic antidepressants
Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium,
opioids, buspirone, antihistamines, muscle
relaxants, other CNS depressants
Additive drowsiness and CNS depression
Disulfiram
A reversible hypomanic reaction was reported in a
28 y/o man who smoked marijuana; confirmed by
dechallenge and rechallenge
Fluoxetine
A 21 y/o female with depression and bulimia
receiving 20 mg/day fluoxetine X 4 wks became
hypomanic after smoking marijuana; symptoms
resolved after 4 days
Antipyrine, barbiturates
Decreased clearance of these agents, presumably via
competitive inhibition of metabolism
Theophylline
Increased theophylline metabolism reported with
smoking of marijuana; effect similar to that
following smoking tobacco
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies in mice and rats have been
conducted under the US National Toxicology Program (NTP). In the 2-year carcinogenicity study in rats, there was
no evidence of carcinogenicity at doses up to 50 mg/kg/day, about 20 times the maximum recommended human
dose on a body surface area basis. In the 2-year carcinogenicity study in mice, treatment with dronabinol at 125
mg/kg/day, about 25 times the maximum recommended human dose on a body surface area basis, produced thyroid
follicular cell adenoma in both male and female mice but not at 250 or 500 mg/kg/day.
Dronabinol was not genotoxic in the Ames tests, the in vitro chromosomal aberration test in Chinese hamster ovary
cells, and the in vivo mouse micronucleus test. It, however, produced a weak positive response in a sister chromatid
exchange test in Chinese hamster ovary cells.
In a long-term study (77 days) in rats, oral administration of dronabinol at doses of 30 to 150 mg/m2, equivalent to
0.3 to 1.5 times maximum recommended human dose (MRHD) of 90 mg/m2/day in cancer patients or 2 to 10 times
MRHD of 15 mg/m2/day in AIDS patients, reduced ventral prostate, seminal vesicle and epididymal weights and
caused a decrease in seminal fluid volume. Decreases in spermatogenesis, number of developing germ cells, and
number of Leydig cells in the testis were also observed. However, sperm count, mating success and testosterone
levels were not affected. The significance of these animal findings in humans is not known.
Pregnancy: Pregnancy Category C. Reproduction studies with dronabinol have been performed in mice at 15 to
450 mg/m2, equivalent to 0.2 to 5 times maximum recommended human dose (MRHD) of 90 mg/m2/day in cancer
patients or 1 to 30 times MRHD of 15 mg/m2/day in AIDS patients, and in rats at 74 to 295 mg/m2 (equivalent to 0.8
to 3 times MRHD of 90 mg/m2 in cancer patients or 5 to 20 times MRHD of 15 mg/m2/day in AIDS patients).
These studies have revealed no evidence of teratogenicity due to dronabinol. At these dosages in mice and rats,
dronabinol decreased maternal weight gain and number of viable pups and increased fetal mortality and early
resorptions. Such effects were dose dependent and less apparent at lower doses which produced less maternal
toxicity. There are no adequate and well-controlled studies in pregnant women. Dronabinol should be used only if
the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: Use of MARINOL® Capsules is not recommended in nursing mothers since, in addition to the
secretion of HIV virus in breast milk, dronabinol is concentrated in and secreted in human breast milk and is
absorbed by the nursing baby.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-651/S-018
Page 8
Geriatric Use: Clinical studies of MARINOL® (Dronabinol) Capsules in AIDS and cancer patients did not include
the sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience has not identified differences in responses between the elderly and
younger patients. In general, dose selection for an elderly patient should be cautious usually starting at the low end
of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, increased
sensitivity to psychoactive effects and of concomitant disease or other drug therapy.
ADVERSE REACTIONS
Adverse experiences information summarized in the tables below was derived from well-controlled clinical trials
conducted in the US and US territories involving 474 patients exposed to MARINOL® (Dronabinol) Capsules.
Studies of AIDS-related weight loss included 157 patients receiving dronabinol at a dose of 2.5 mg twice daily and
67 receiving placebo. Studies of different durations were combined by considering the first occurrence of events
during the first 28 days. Studies of nausea and vomiting related to cancer chemotherapy included 317 patients
receiving dronabinol and 68 receiving placebo.
A cannabinoid dose-related “high” (easy laughing, elation and heightened awareness) has been reported by
patients receiving MARINOL® Capsules in both the antiemetic (24%) and the lower dose appetite stimulant clinical
trials (8%) (see CLINICAL TRIALS).
The most frequently reported adverse experiences in patients with AIDS during placebo-controlled clinical
trials involved the CNS and were reported by 33% of patients receiving MARINOL® Capsules. About 25% of
patients reported a minor CNS adverse event during the first 2 weeks and about 4% reported such an event each
week for the next 6 weeks thereafter.
PROBABLY CAUSALLY RELATED: Incidence greater than 1%.
Rates derived from clinical trials in AIDS-related anorexia (N=157) and chemotherapy-related nausea (N=317).
Rates were generally higher in the anti-emetic use (given in parentheses).
Body as a whole: Asthenia.
Cardiovascular: Palpitations, tachycardia, vasodilation/facial flush.
Digestive: Abdominal pain*, nausea*, vomiting*.
Nervous system: (Amnesia), anxiety/nervousness, (ataxia), confusion, depersonalization, dizziness*, euphoria*,
(hallucination), paranoid reaction*, somnolence*, thinking abnormal*.
*Incidence of events 3% to 10%
PROBABLY CAUSALLY RELATED: Incidence less than 1%.
Event rates derived from clinical trials in AIDS-related anorexia (N=157) and chemotherapy-related nausea
(N=317).
Cardiovascular: Conjunctivitis*, hypotension*.
Digestive: Diarrhea*, fecal incontinence.
Musculoskeletal: Myalgias.
Nervous system: Depression, nightmares, speech difficulties, tinnitus.
Skin and Appendages: Flushing*.
Special senses: Vision difficulties.
*Incidence of events 0.3% to 1%
CAUSAL RELATIONSHIP UNKNOWN: Incidence less than 1%.
The clinical significance of the association of these events with MARINOL® Capsules treatment is unknown, but
they are reported as alerting information for the clinician.
Body as a whole: Chills, headache, malaise.
Digestive: Anorexia, hepatic enzyme elevation.
Respiratory: Cough, rhinitis, sinusitis.
Skin and Appendages: Sweating.
DRUG ABUSE AND DEPENDENCE
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-651/S-018
Page 9
MARINOL® (Dronabinol) Capsules is one of the psychoactive compounds present in cannabis, and is abusable and
controlled [Schedule III (CIII)] under the Controlled Substances Act. Both psychological and physiological
dependence have been noted in healthy individuals receiving dronabinol, but addiction is uncommon and has only
been seen after prolonged high dose administration.
Chronic abuse of cannabis has been associated with decrements in motivation, cognition, judgement, and
perception. The etiology of these impairments is unknown, but may be associated with the complex process of
addiction rather than an isolated effect of the drug. No such decrements in psychological, social or neurological
status have been associated with the administration of MARINOL® Capsules for therapeutic purposes.
In an open-label study in patients with AIDS who received MARINOL® Capsules for up to five months, no
abuse, diversion or systematic change in personality or social functioning were observed despite the inclusion of a
substantial number of patients with a past history of drug abuse.
An abstinence syndrome has been reported after the abrupt discontinuation of dronabinol in volunteers
receiving dosages of 210 mg/day for 12 to 16 consecutive days. Within 12 hours after discontinuation, these
volunteers manifested symptoms such as irritability, insomnia, and restlessness. By approximately 24 hours post-
dronabinol discontinuation, withdrawal symptoms intensified to include “hot flashes”, sweating, rhinorrhea, loose
stools, hiccoughs and anorexia.
These withdrawal symptoms gradually dissipated over the next 48 hours. Electroencephalographic changes
consistent with the effects of drug withdrawal (hyperexcitation) were recorded in patients after abrupt dechallenge.
Patients also complained of disturbed sleep for several weeks after discontinuing therapy with high dosages of
dronabinol.
OVERDOSAGE
Signs and symptoms following MILD MARINOL® (Dronabinol) Capsules intoxication include drowsiness,
euphoria, heightened sensory awareness, altered time perception, reddened conjunctiva, dry mouth and tachycardia;
following MODERATE intoxication include memory impairment, depersonalization, mood alteration, urinary
retention, and reduced bowel motility; and following SEVERE intoxication include decreased motor coordination,
lethargy, slurred speech, and postural hypotension. Apprehensive patients may experience panic reactions and
seizures may occur in patients with existing seizure disorders.
The estimated lethal human dose of intravenous dronabinol is 30 mg/kg (2100 mg/ 70 kg). Significant CNS
symptoms in antiemetic studies followed oral doses of 0.4 mg/kg (28 mg/70 kg) of MARINOL® Capsules.
Management: A potentially serious oral ingestion, if recent, should be managed with gut decontamination. In
unconscious patients with a secure airway, instill activated charcoal (30 to 100 g in adults, 1 to 2 g/kg in infants) via
a nasogastric tube. A saline cathartic or sorbitol may be added to the first dose of activated charcoal. Patients
experiencing depressive, hallucinatory or psychotic reactions should be placed in a quiet area and offered
reassurance. Benzodiazepines (5 to 10 mg diazepam po) may be used for treatment of extreme agitation.
Hypotension usually responds to Trendelenburg position and IV fluids. Pressors are rarely required.
DOSAGE AND ADMINISTRATION
Appetite Stimulation: Initially, 2.5 mg MARINOL® (Dronabinol) Capsules should be administered orally twice
daily (b.i.d.), before lunch and supper. For patients unable to tolerate this 5 mg/day dosage of MARINOL®
Capsules, the dosage can be reduced to 2.5 mg/day, administered as a single dose in the evening or at bedtime. If
clinically indicated and in the absence of significant adverse effects, the dosage may be gradually increased to a
maximum of 20 mg/day MARINOL® Capsules, administered in divided oral doses. Caution should be exercised in
escalating the dosage of MARINOL® Capsules because of the increased frequency of dose-related adverse
experiences at higher dosages (see PRECAUTIONS).
Antiemetic: MARINOL® Capsules is best administered at an initial dose of 5 mg/m2, given 1 to 3 hours prior to
the administration of chemotherapy, then every 2 to 4 hours after chemotherapy is given, for a total of 4 to 6
doses/day. Should the 5 mg/m2 dose prove to be ineffective, and in the absence of significant side effects, the dose
may be escalated by 2.5 mg/m2 increments to a maximum of 15 mg/m2 per dose. Caution should be exercised in
dose escalation, however, as the incidence of disturbing psychiatric symptoms increases significantly at maximum
dose (see PRECAUTIONS).
STORAGE CONDITIONS
MARINOL® (Dronabinol) Capsules should be packaged in a well-closed container and stored in a cool
environment between 8° and 15°C (46° and 59°F) and alternatively could be stored in a refrigerator. Protect
from freezing.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-651/S-018
Page 10
HOW SUPPLIED
MARINOL® Capsules (dronabinol solution in sesame oil in soft gelatin capsules)
2.5 mg white capsules (Identified UM or RL).
NDC 0051-0021-21 (Bottle of 60 capsules).
5 mg dark brown capsules (Identified UM or RL).
NDC 0051-0022-11 (Bottle of 25 capsules).
10 mg orange capsules (Identified UM or RL).
NDC 0051-0023-21 (Bottle of 60 capsules).
MARINOL® is a registered trademark of Unimed Pharmaceuticals, Inc. and is
Manufactured by Banner Pharmacaps, Inc.
High Point, NC 27265
500012 3E Rev 10/2002
UPI, 2002
A Solvay Pharmaceuticals, Inc. Company
Marietta, GA 30062
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/018651s018lbl.pdf', 'application_number': 18651, 'submission_type': 'SUPPL ', 'submission_number': 18}
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NDA 18-651/S-021
Page 3
500012 Rev Sep 2004
MARINOL®
(Dronabinol)
Capsules
DESCRIPTION
Dronabinol is a cannabinoid designated chemically as (6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-
trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol. Dronabinol has the following empirical and structural
formulas:
Dronabinol, the active ingredient in MARINOL® Capsules, is synthetic delta-9-
tetrahydrocannabinol (delta-9-THC). Delta-9-tetrahydrocannabinol is also a naturally occurring
component of Cannabis sativa L. (Marijuana).
Dronabinol is a light yellow resinous oil that is sticky at room temperature and hardens upon
refrigeration. Dronabinol is insoluble in water and is formulated in sesame oil. It has a pKa of 10.6
and an octanol-water partition coefficient: 6,000:1 at pH 7.
Capsules for oral administration: MARINOL® Capsules is supplied as round, soft gelatin capsules
containing either 2.5 mg, 5 mg, or 10 mg dronabinol. Each MARINOL® Capsule is formulated with
the following inactive ingredients: FD&C Blue No. 1 (5 mg), FD&C Red No. 40 (5 mg), FD&C
Yellow No. 6 (5 mg and 10 mg), gelatin, glycerin, methylparaben, propylparaben, sesame oil, and
titanium dioxide.
CLINICAL PHARMACOLOGY
Dronabinol is an orally active cannabinoid which, like other cannabinoids, has complex effects on the
central nervous system (CNS), including central sympathomimetic activity. Cannabinoid receptors
have been discovered in neural tissues. These receptors may play a role in mediating the effects of
dronabinol and other cannabinoids.
Pharmacodynamics
Dronabinol-induced sympathomimetic activity may result in tachycardia and/or conjunctival injection.
Its effects on blood pressure are inconsistent, but occasional subjects have experienced orthostatic
hypotension and/or syncope upon abrupt standing.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-651/S-021
Page 4
Dronabinol also demonstrates reversible effects on appetite, mood, cognition, memory, and
perception. These phenomena appear to be dose-related, increasing in frequency with higher dosages,
and subject to great interpatient variability.
After oral administration, dronabinol has an onset of action of approximately 0.5 to 1 hours and
peak effect at 2 to 4 hours. Duration of action for psychoactive effects is 4 to 6 hours, but the appetite
stimulant effect of dronabinol may continue for 24 hours or longer after administration.
Tachyphylaxis and tolerance develop to some of the pharmacologic effects of dronabinol and other
cannabinoids with chronic use, suggesting an indirect effect on sympathetic neurons. In a study of the
pharmacodynamics of chronic dronabinol exposure, healthy male volunteers (N = 12) received 210
mg/day dronabinol, administered orally in divided doses, for 16 days. An initial tachycardia induced
by dronabinol was replaced successively by normal sinus rhythm and then bradycardia. A decrease in
supine blood pressure, made worse by standing, was also observed initially. These volunteers
developed tolerance to the cardiovascular and subjective adverse CNS effects of dronabinol within 12
days of treatment initiation.
Tachyphylaxis and tolerance do not, however, appear to develop to the appetite stimulant effect of
MARINOL® Capsules. In studies involving patients with Acquired Immune Deficiency Syndrome
(AIDS), the appetite stimulant effect of MARINOL® Capsules has been sustained for up to five
months in clinical trials, at dosages ranging from 2.5 mg/day to 20 mg/day.
Pharmacokinetics
Absorption and Distribution: MARINOL® (Dronabinol) Capsules is almost completely absorbed (90
to 95%) after single oral doses. Due to the combined effects of first pass hepatic metabolism and high
lipid solubility, only 10 to 20% of the administered dose reaches the systemic circulation. Dronabinol
has a large apparent volume of distribution, approximately 10 L/kg, because of its lipid solubility. The
plasma protein binding of dronabinol and its metabolites is approximately 97%.
The elimination phase of dronabinol can be described using a two compartment model with an
initial (alpha) half-life of about 4 hours and a terminal (beta) half-life of 25 to 36 hours. Because of its
large volume of distribution, dronabinol and its metabolites may be excreted at low levels for
prolonged periods of time.
The pharmacokinetics of dronabinol after single doses (2.5, 5, and 10 mg) and multiple doses
(2.5, 5, and 10 mg given twice a day; BID) have been studied in healthy women and men.
Summary of Multiple-Dose Pharmacokinetic Parameters of Dronabinol
in Healthy Volunteers (n=34; 20-45 years) under Fasted Conditions
Mean (SD) PK Parameter Values
BID
Dose
Cmax
ng/mL
Median Tmax
(range), hr
AUC(0-12)
ng•hr/mL
2.5 mg
1.32 (0.62)
1.00 (0.50-4.00)
2.88 (1.57)
5 mg
2.96 (1.81)
2.50 (0.50-4.00)
6.16 (1.85)
10 mg
7.88 (4.54)
1.50 (0.50-3.50)
15.2 (5.52)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-651/S-021
Page 5
A slight increase in dose proportionality on mean Cmax and AUC (0-12) of dronabinol was
observed with increasing dose over the dose range studied.
Metabolism: Dronabinol undergoes extensive first-pass hepatic metabolism, primarily by microsomal
hydroxylation, yielding both active and inactive metabolites. Dronabinol and its principal active
metabolite, 11-OH-delta-9-THC, are present in approximately equal concentrations in plasma.
Concentrations of both parent drug and metabolite peak at approximately 0.5 to 4 hours after oral
dosing and decline over several days. Values for clearance average about 0.2 L/kg-hr, but are highly
variable due to the complexity of cannabinoid distribution.
Elimination: Dronabinol and its biotransformation products are excreted in both feces and urine.
Biliary excretion is the major route of elimination with about half of a radio-labeled oral dose being
recovered from the feces within 72 hours as contrasted with 10 to 15% recovered from urine. Less
than 5% of an oral dose is recovered unchanged in the feces.
Following single dose administration, low levels of dronabinol metabolites have been detected for
more than 5 weeks in the urine and feces.
In a study of MARINOL® Capsules involving AIDS patients, urinary cannabinoid/creatinine
concentration ratios were studied bi-weekly over a six week period. The urinary
cannabinoid/creatinine ratio was closely correlated with dose. No increase in the
cannabinoid/creatinine ratio was observed after the first two weeks of treatment, indicating that steady-
state cannabinoid levels had been reached. This conclusion is consistent with predictions based on the
observed terminal half-life of dronabinol.
Special Populations: The pharmacokinetic profile of MARINOL® Capsules has not been investigated
in either pediatric or geriatric patients.
Clinical Trials
Appetite Stimulation: The appetite stimulant effect of MARINOL® (Dronabinol) Capsules in the
treatment of AIDS-related anorexia associated with weight loss was studied in a randomized, double-
blind, placebo-controlled study involving 139 patients. The initial dosage of MARINOL® Capsules in
all patients was 5 mg/day, administered in doses of 2.5 mg one hour before lunch and one hour before
supper. In pilot studies, early morning administration of MARINOL® Capsules appeared to have been
associated with an increased frequency of adverse experiences, as compared to dosing later in the day.
The effect of MARINOL® Capsules on appetite, weight, mood, and nausea was measured at scheduled
intervals during the six-week treatment period. Side effects (feeling high, dizziness, confusion,
somnolence) occurred in 13 of 72 patients (18%) at this dosage level and the dosage was reduced to
2.5 mg/day, administered as a single dose at supper or bedtime.
As compared to placebo, MARINOL® Capsules treatment resulted in a statistically significant
improvement in appetite as measured by visual analog scale (see figure). Trends toward improved
body weight and mood, and decreases in nausea were also seen.
After completing the 6-week study, patients were allowed to continue treatment with MARINOL®
Capsules in an open-label study, in which there was a sustained improvement in appetite.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-651/S-021
Page 6
Antiemetic: MARINOL® (Dronabinol) Capsules treatment of chemotherapy-induced emesis was
evaluated in 454 patients with cancer, who received a total of 750 courses of treatment of various
malignancies. The antiemetic efficacy of MARINOL® Capsules was greatest in patients receiving
cytotoxic therapy with MOPP for Hodgkin’s and non-Hodgkin’s lymphomas. MARINOL® Capsules
dosages ranged from 2.5 mg/day to 40 mg/day, administered in equally divided doses every four to six
hours (four times daily). As indicated in the following table, escalating the MARINOL® Capsules
dose above 7 mg/m2 increased the frequency of adverse experiences, with no additional antiemetic
benefit.
MARINOL® Capsules Dose: Response Frequency and Adverse Experiences*
(N = 750 treatment courses)
Response Frequency (%)
Adverse Events Frequency (%)
MARINOL® Capsules
Dose
Complete
Partial
Poor
None
Nondysphoric
Dysphoric
<7 mg/m2
36
32
32
23
65
12
>7 mg/m2
33
31
36
13
58
28
*Nondysphoric events consisted of drowsiness, tachycardia, etc.
Combination antiemetic therapy with MARINOL® Capsules and a phenothiazine
(prochlorperazine) may result in synergistic or additive antiemetic effects and attenuate the toxicities
associated with each of the agents.
INDIVIDUALIZATION OF DOSAGES
The pharmacologic effects of MARINOL® (Dronabinol) Capsules are dose-related and subject to
considerable interpatient variability. Therefore, dosage individualization is critical in achieving the
maximum benefit of MARINOL® Capsules treatment.
Appetite Stimulation: In the clinical trials, the majority of patients were treated with 5 mg/day
MARINOL® Capsules, although the dosages ranged from 2.5 to 20 mg/day. For an adult:
1. Begin with 2.5 mg before lunch and 2.5 mg before supper. If CNS symptoms (feeling high,
dizziness, confusion, somnolence) do occur, they usually resolve in 1 to 3 days with continued
dosage.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-651/S-021
Page 7
2. If CNS symptoms are severe or persistent, reduce the dose to 2.5 mg before supper. If symptoms
continue to be a problem, taking the single dose in the evening or at bedtime may reduce their
severity.
3. When adverse effects are absent or minimal and further therapeutic effect is desired, increase the
dose to 2.5 mg before lunch and 5 mg before supper or 5 and 5 mg. Although most patients
respond to 2.5 mg twice daily, 10 mg twice daily has been tolerated in about half of the patients in
appetite stimulation studies.
The pharmacologic effects of MARINOL® Capsules are reversible upon treatment cessation.
Antiemetic: Most patients respond to 5 mg three or four times daily. Dosage may be escalated during
a chemotherapy cycle or at subsequent cycles, based upon initial results. Therapy should be initiated at
the lowest recommended dosage and titrated to clinical response. Administration of MARINOL®
Capsules with phenothiazines, such as prochlorperazine, has resulted in improved efficacy as
compared to either drug alone, without additional toxicity.
Pediatrics: MARINOL® Capsules is not recommended for AIDS-related anorexia in pediatric
patients because it has not been studied in this population. The pediatric dosage for the treatment of
chemotherapy-induced emesis is the same as in adults. Caution is recommended in prescribing
MARINOL® Capsules for children because of the psychoactive effects.
Geriatrics: Caution is advised in prescribing MARINOL® Capsules in elderly patients because they
are generally more sensitive to the psychoactive effects of drugs. In antiemetic studies, no difference
in tolerance or efficacy was apparent in patients >55 years old.
INDICATIONS AND USAGE
MARINOL® (Dronabinol) Capsules is indicated for the treatment of:
1. anorexia associated with weight loss in patients with AIDS; and
2. nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond
adequately to conventional antiemetic treatments.
CONTRAINDICATIONS
MARINOL® (Dronabinol) Capsules is contraindicated in any patient who has a history of
hypersensitivity to any cannabinoid or sesame oil.
WARNINGS
Patients receiving treatment with MARINOL® Capsules should be specifically warned not to drive,
operate machinery, or engage in any hazardous activity until it is established that they are able to
tolerate the drug and to perform such tasks safely.
PRECAUTIONS
General: The risk/benefit ratio of MARINOL® (Dronabinol) Capsules use should be carefully
evaluated in patients with the following medical conditions because of individual variation in response
and tolerance to the effects of MARINOL® Capsules.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-651/S-021
Page 8
MARINOL® Capsules should be used with caution in patients with cardiac disorders because of
occasional hypotension, possible hypertension, syncope, or tachycardia (see CLINICAL
PHARMACOLOGY).
MARINOL® Capsules should be used with caution in patients with a history of substance abuse,
including alcohol abuse or dependence, because they may be more prone to abuse MARINOL®
Capsules as well. Multiple substance abuse is common and marijuana, which contains the same active
compound, is a frequently abused substance.
MARINOL® Capsules should be used with caution and careful psychiatric monitoring in patients
with mania, depression, or schizophrenia because MARINOL® Capsules may exacerbate these
illnesses.
MARINOL® Capsules should be used with caution in patients receiving concomitant therapy with
sedatives, hypnotics or other psychoactive drugs because of the potential for additive or synergistic
CNS effects.
MARINOL® Capsules should be used with caution in pregnant patients, nursing mothers, or
pediatric patients because it has not been studied in these patient populations.
Information for Patients: Patients receiving treatment with MARINOL® (Dronabinol) Capsules
should be alerted to the potential for additive central nervous system depression if MARINOL®
Capsules is used concomitantly with alcohol or other CNS depressants such as benzodiazepines and
barbiturates.
Patients receiving treatment with MARINOL® Capsules should be specifically warned not to
drive, operate machinery, or engage in any hazardous activity until it is established that they are able to
tolerate the drug and to perform such tasks safely.
Patients using MARINOL® Capsules should be advised of possible changes in mood and other
adverse behavioral effects of the drug so as to avoid panic in the event of such manifestations. Patients
should remain under the supervision of a responsible adult during initial use of MARINOL® Capsules
and following dosage adjustments.
Drug Interactions: In studies involving patients with AIDS and/or cancer, MARINOL®
(Dronabinol) Capsules has been co-administered with a variety of medications (e.g., cytotoxic agents,
anti-infective agents, sedatives, or opioid analgesics) without resulting in any clinically significant
drug/drug interactions. Although no drug/drug interactions were discovered during the clinical trials of
MARINOL® Capsules, cannabinoids may interact with other medications through both metabolic and
pharmacodynamic mechanisms. Dronabinol is highly protein bound to plasma proteins, and therefore,
might displace other protein-bound drugs. Although this displacement has not been confirmed in vivo,
practitioners should monitor patients for a change in dosage requirements when administering
dronabinol to patients receiving other highly protein-bound drugs. Published reports of drug/drug
interactions involving cannabinoids are summarized in the following table.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-651/S-021
Page 9
CONCOMITANT DRUG
CLINICAL EFFECT(S)
Amphetamines, cocaine, other
sympathomimetic agents
Additive hypertension, tachycardia,
possibly cardiotoxicity
Atropine, scopolamine, antihistamines,
other anticholinergic agents
Additive or super-additive tachycardia,
drowsiness
Amitriptyline, amoxapine, desipramine,
other tricyclic antidepressants
Additive tachycardia, hypertension,
drowsiness
Barbiturates, benzodiazepines, ethanol,
lithium, opioids, buspirone, antihistamines,
muscle relaxants, other CNS depressants
Additive drowsiness and CNS depression
Disulfiram
A reversible hypomanic reaction was
reported in a 28 y/o man who smoked
marijuana; confirmed by dechallenge and
rechallenge
Fluoxetine
A 21 y/o female with depression and
bulimia receiving 20 mg/day fluoxetine X
4 wks became hypomanic after smoking
marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates
Decreased clearance of these agents,
presumably via competitive inhibition of
metabolism
Theophylline
Increased theophylline metabolism
reported with smoking of marijuana; effect
similar to that following smoking tobacco
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies in mice and rats
have been conducted under the US National Toxicology Program (NTP). In the 2-year carcinogenicity
study in rats, there was no evidence of carcinogenicity at doses up to 50 mg/kg/day, about 20 times the
maximum recommended human dose on a body surface area basis. In the 2-year carcinogenicity study
in mice, treatment with dronabinol at 125 mg/kg/day, about 25 times the maximum recommended
human dose on a body surface area basis, produced thyroid follicular cell adenoma in both male and
female mice but not at 250 or 500 mg/kg/day.
Dronabinol was not genotoxic in the Ames tests, the in vitro chromosomal aberration test in
Chinese hamster ovary cells, and the in vivo mouse micronucleus test. It, however, produced a weak
positive response in a sister chromatid exchange test in Chinese hamster ovary cells.
In a long-term study (77 days) in rats, oral administration of dronabinol at doses of 30 to 150
mg/m2, equivalent to 0.3 to 1.5 times maximum recommended human dose (MRHD) of 90 mg/m2/day
in cancer patients or 2 to 10 times MRHD of 15 mg/m2/day in AIDS patients, reduced ventral prostate,
seminal vesicle and epididymal weights and caused a decrease in seminal fluid volume. Decreases in
spermatogenesis, number of developing germ cells, and number of Leydig cells in the testis were also
observed. However, sperm count, mating success and testosterone levels were not affected. The
significance of these animal findings in humans is not known.
Pregnancy: Pregnancy Category C. Reproduction studies with dronabinol have been performed in
mice at 15 to 450 mg/m2, equivalent to 0.2 to 5 times maximum recommended human dose (MRHD)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-651/S-021
Page 10
of 90 mg/m2/day in cancer patients or 1 to 30 times MRHD of 15 mg/m2/day in AIDS patients, and in
rats at 74 to 295 mg/m2 (equivalent to 0.8 to 3 times MRHD of 90 mg/m2 in cancer patients or 5 to 20
times MRHD of 15 mg/m2/day in AIDS patients). These studies have revealed no evidence of
teratogenicity due to dronabinol. At these dosages in mice and rats, dronabinol decreased maternal
weight gain and number of viable pups and increased fetal mortality and early resorptions. Such
effects were dose dependent and less apparent at lower doses which produced less maternal toxicity.
There are no adequate and well-controlled studies in pregnant women. Dronabinol should be used
only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: Use of MARINOL® Capsules is not recommended in nursing mothers since, in
addition to the secretion of HIV virus in breast milk, dronabinol is concentrated in and secreted in
human breast milk and is absorbed by the nursing baby.
Geriatric Use: Clinical studies of MARINOL® (Dronabinol) Capsules in AIDS and cancer patients
did not include the sufficient numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. Other reported clinical experience has not identified differences in
responses between the elderly and younger patients. In general, dose selection for an elderly patient
should be cautious usually starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function, increased sensitivity to psychoactive effects and of
concomitant disease or other drug therapy.
ADVERSE REACTIONS
Adverse experiences information summarized in the tables below was derived from well-controlled
clinical trials conducted in the US and US territories involving 474 patients exposed to MARINOL®
(Dronabinol) Capsules. Studies of AIDS-related weight loss included 157 patients receiving
dronabinol at a dose of 2.5 mg twice daily and 67 receiving placebo. Studies of different durations
were combined by considering the first occurrence of events during the first 28 days. Studies of
nausea and vomiting related to cancer chemotherapy included 317 patients receiving dronabinol and 68
receiving placebo.
A cannabinoid dose-related “high” (easy laughing, elation and heightened awareness) has been
reported by patients receiving MARINOL® Capsules in both the antiemetic (24%) and the lower dose
appetite stimulant clinical trials (8%) (see Clinical Trials).
The most frequently reported adverse experiences in patients with AIDS during placebo-controlled
clinical trials involved the CNS and were reported by 33% of patients receiving MARINOL®
Capsules. About 25% of patients reported a minor CNS adverse event during the first 2 weeks and
about 4% reported such an event each week for the next 6 weeks thereafter.
PROBABLY CAUSALLY RELATED: Incidence greater than 1%.
Rates derived from clinical trials in AIDS-related anorexia (N=157) and chemotherapy-related nausea
(N=317). Rates were generally higher in the anti-emetic use (given in parentheses).
Body as a whole: Asthenia.
Cardiovascular: Palpitations, tachycardia, vasodilation/facial flush.
Digestive: Abdominal pain*, nausea*, vomiting*.
Nervous system: (Amnesia), anxiety/nervousness, (ataxia), confusion, depersonalization, dizziness*,
euphoria*, (hallucination), paranoid reaction*, somnolence*, thinking abnormal*.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-651/S-021
Page 11
*Incidence of events 3% to 10%
PROBABLY CAUSALLY RELATED: Incidence less than 1%.
Event rates derived from clinical trials in AIDS-related anorexia (N=157) and chemotherapy-related
nausea (N=317).
Cardiovascular: Conjunctivitis*, hypotension*.
Digestive: Diarrhea*, fecal incontinence.
Musculoskeletal: Myalgias.
Nervous system: Depression, nightmares, speech difficulties, tinnitus.
Skin and Appendages: Flushing*.
Special senses: Vision difficulties.
*Incidence of events 0.3% to 1%
CAUSAL RELATIONSHIP UNKNOWN: Incidence less than 1%.
The clinical significance of the association of these events with MARINOL® Capsules treatment is
unknown, but they are reported as alerting information for the clinician.
Body as a whole: Chills, headache, malaise.
Digestive: Anorexia, hepatic enzyme elevation.
Respiratory: Cough, rhinitis, sinusitis.
Skin and Appendages: Sweating.
DRUG ABUSE AND DEPENDENCE
MARINOL® (Dronabinol) Capsules is one of the psychoactive compounds present in cannabis, and is
abusable and controlled [Schedule III (CIII)] under the Controlled Substances Act. Both psychological
and physiological dependence have been noted in healthy individuals receiving dronabinol, but
addiction is uncommon and has only been seen after prolonged high dose administration.
Chronic abuse of cannabis has been associated with decrements in motivation, cognition,
judgement, and perception. The etiology of these impairments is unknown, but may be associated with
the complex process of addiction rather than an isolated effect of the drug. No such decrements in
psychological, social or neurological status have been associated with the administration of
MARINOL® Capsules for therapeutic purposes.
In an open-label study in patients with AIDS who received MARINOL® Capsules for up to five
months, no abuse, diversion or systematic change in personality or social functioning were observed
despite the inclusion of a substantial number of patients with a past history of drug abuse.
An abstinence syndrome has been reported after the abrupt discontinuation of dronabinol in
volunteers receiving dosages of 210 mg/day for 12 to 16 consecutive days. Within 12 hours after
discontinuation, these volunteers manifested symptoms such as irritability, insomnia, and restlessness.
By approximately 24 hours post-dronabinol discontinuation, withdrawal symptoms intensified to
include “hot flashes”, sweating, rhinorrhea, loose stools, hiccoughs and anorexia.
These withdrawal symptoms gradually dissipated over the next 48 hours. Electroencephalographic
changes consistent with the effects of drug withdrawal (hyperexcitation) were recorded in patients after
abrupt dechallenge. Patients also complained of disturbed sleep for several weeks after discontinuing
therapy with high dosages of dronabinol.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-651/S-021
Page 12
OVERDOSAGE
Signs and symptoms following MILD MARINOL® (Dronabinol) Capsules intoxication include
drowsiness, euphoria, heightened sensory awareness, altered time perception, reddened conjunctiva,
dry mouth and tachycardia; following MODERATE intoxication include memory impairment,
depersonalization, mood alteration, urinary retention, and reduced bowel motility; and following
SEVERE intoxication include decreased motor coordination, lethargy, slurred speech, and postural
hypotension. Apprehensive patients may experience panic reactions and seizures may occur in patients
with existing seizure disorders.
The estimated lethal human dose of intravenous dronabinol is 30 mg/kg (2100 mg/ 70 kg).
Significant CNS symptoms in antiemetic studies followed oral doses of 0.4 mg/kg (28 mg/70 kg) of
MARINOL® Capsules.
Management: A potentially serious oral ingestion, if recent, should be managed with gut
decontamination. In unconscious patients with a secure airway, instill activated charcoal (30 to 100 g
in adults, 1 to 2 g/kg in infants) via a nasogastric tube. A saline cathartic or sorbitol may be added to
the first dose of activated charcoal. Patients experiencing depressive, hallucinatory or psychotic
reactions should be placed in a quiet area and offered reassurance. Benzodiazepines (5 to 10 mg
diazepam po) may be used for treatment of extreme agitation. Hypotension usually responds to
Trendelenburg position and IV fluids. Pressors are rarely required.
DOSAGE AND ADMINISTRATION
Appetite Stimulation: Initially, 2.5 mg MARINOL® (Dronabinol) Capsules should be administered
orally twice daily (b.i.d.), before lunch and supper. For patients unable to tolerate this 5 mg/day
dosage of MARINOL® Capsules, the dosage can be reduced to 2.5 mg/day, administered as a single
dose in the evening or at bedtime. If clinically indicated and in the absence of significant adverse
effects, the dosage may be gradually increased to a maximum of 20 mg/day MARINOL® Capsules,
administered in divided oral doses. Caution should be exercised in escalating the dosage of
MARINOL® Capsules because of the increased frequency of dose-related adverse experiences at
higher dosages (see PRECAUTIONS).
Antiemetic: MARINOL® Capsules is best administered at an initial dose of 5 mg/m2, given 1 to 3
hours prior to the administration of chemotherapy, then every 2 to 4 hours after chemotherapy is given,
for a total of 4 to 6 doses/day. Should the 5 mg/m2 dose prove to be ineffective, and in the absence of
significant side effects, the dose may be escalated by 2.5 mg/m2 increments to a maximum of 15
mg/m2 per dose. Caution should be exercised in dose escalation, however, as the incidence of
disturbing psychiatric symptoms increases significantly at maximum dose (see PRECAUTIONS).
STORAGE CONDITIONS
MARINOL® (Dronabinol) Capsules should be packaged in a well-closed container and stored in
a cool environment between 8° and 15°C (46° and 59°F) and alternatively could be stored in a
refrigerator. Protect from freezing.
HOW SUPPLIED
MARINOL® Capsules (dronabinol solution in sesame oil in soft gelatin capsules)
2.5 mg white capsules (Identified UM or RL).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-651/S-021
Page 13
NDC 0051-0021-21 (Bottle of 60 capsules).
5 mg dark brown capsules (Identified UM or RL).
NDC 0051-0022-11 (Bottle of 25 capsules).
10 mg orange capsules (Identified UM or RL).
NDC 0051-0023-21 (Bottle of 60 capsules).
MARINOL® is a registered trademark of Unimed Pharmaceuticals, Inc. and is
Manufactured by Banner Pharmacaps, Inc.
High Point, NC 27265
500012 Rev Sep 2004
© 2004 Solvay Pharmaceuticals, Inc.
A Solvay Pharmaceuticals, Inc. Company
Marietta, GA 30062
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-651/S-021
Page 14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/018651s021lbl.pdf', 'application_number': 18651, 'submission_type': 'SUPPL ', 'submission_number': 21}
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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
WELLBUTRIN safely and effectively. See full prescribing information
for WELLBUTRIN.
WELLBUTRIN (bupropion hydrochloride) Tablets, for oral use
Initial U.S. Approval: 1985
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS; AND
NEUROPSYCHIATRIC REACTIONS
See full prescribing information for complete boxed warning.
• Increased risk of suicidal thinking and behavior in children,
adolescents, and young adults taking antidepressants. (5.1)
• Monitor for worsening and emergence of suicidal thoughts and
behaviors. (5.1)
• Serious neuropsychiatric events have been reported in patients
taking bupropion for smoking cessation. (5.2)
---------------------------RECENT MAJOR CHANGES --------------------------
Dosage and Administration (2.4, 2.5)
03/2013
Contraindications (4)
03/2013
----------------------------INDICATIONS AND USAGE ---------------------------
WELLBUTRIN is an aminoketone antidepressant, indicated for the
treatment of major depressive disorder (MDD). (1)
----------------------- DOSAGE AND ADMINISTRATION ----------------------
•
Starting Dose: 200 mg per day given as 100 mg twice daily (2.1)
•
General: Increase dose gradually to reduce seizure risk. (2.1, 5.3)
• After 3 days, may increase the dose to 300 mg per day, given as 100 mg
3 times daily at an interval of at least 6 hours between doses. (2.1)
• Usual target dose: 300 mg per day as 100 mg 3 times daily. (2.1)
• Maximum dose: 450 mg per day given as 150 mg 3 times daily. (2.1)
• Periodically reassess the dose and need for maintenance treatment. (2.1)
• Moderate to severe hepatic impairment: 75 mg once daily. (2.2, 8.7)
• Mild hepatic impairment: Consider reducing the dose and/or frequency of
dosing. (2.2, 8.7)
•
Renal Impairment: Consider reducing the dose and/or frequency. (2.3,
8.6)
--------------------- DOSAGE FORMS AND STRENGTHS --------------------
Tablets: 75 mg and 100 mg. (3)
-------------------------------CONTRAINDICATIONS ------------------------------
• Seizure disorder. (4, 5.3)
• Current or prior diagnosis of bulimia or anorexia nervosa. (4, 5.3)
• Abrupt discontinuation of alcohol, benzodiazepines, barbiturates,
antiepileptic drugs. (4, 5.3)
• Monoamine Oxidase Inhibitors (MAOIs): Do not use MAOIs intended to
treat psychiatric disorders with WELLBUTRIN or within 14 days of
stopping treatment with WELLBUTRIN. Do not use WELLBUTRIN
within 14 days of stopping an MAOI intended to treat psychiatric
disorders. In addition, do not start WELLBUTRIN in a patient who is
being treated with linezolid or intravenous methylene blue. (4, 7.6)
•
Known hypersensitivity to bupropion or other ingredients of
WELLBUTRIN. (4, 5.7)
----------------------- WARNINGS AND PRECAUTIONS ----------------------
• Seizure risk: The risk is dose-related. Can minimize risk by gradually
increasing the dose and limiting daily dose to 450 mg. Discontinue if
seizure occurs. (4, 5.3, 7.3)
•
Hypertension: WELLBUTRIN can increase blood pressure. Monitor
blood pressure before initiating treatment and periodically during
treatment. (5.4)
•
Activation of mania/hypomania: Screen patients for bipolar disorder and
monitor for these symptoms. (5.5)
•
Psychosis and other neuropsychiatric reactions: Instruct patients to
contact a healthcare professional if such reactions occur. (5.6)
------------------------------ ADVERSE REACTIONS -----------------------------
Most common adverse reactions (incidence ≥5% and ≥1% more than placebo
rate) are: agitation, dry mouth, constipation, headache/migraine,
nausea/vomiting, dizziness, excessive sweating, tremor, insomnia, blurred
vision, tachycardia, confusion, rash, hostility, cardiac arrhythmias, and
auditory disturbance. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact
GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------------------DRUG INTERACTIONS ------------------------------
• CYP2B6 inducers: Dose increase may be necessary if coadministered
with CYP2B6 inducers (e.g., ritonavir, lopinavir, efavirenz,
carbamazepine, phenobarbital, and phenytoin) based on clinical response,
but should not exceed the maximum recommended dose. (7.1)
• Drugs metabolized by CYP2D6: Bupropion inhibits CYP2D6 and can
increase concentrations of: antidepressants (e.g., venlafaxine,
nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline),
antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers
(e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone,
flecainide). Consider dose reduction when using with bupropion. (7.2)
• Drugs that lower seizure threshold: Dose WELLBUTRIN with caution.
(5.3, 7.3)
• Dopaminergic drugs (levodopa and amantadine): CNS toxicity can occur
when used concomitantly with WELLBUTRIN. (7.4)
•
MAOIs: Increased risk of hypertensive reactions can occur when used
concomitantly with WELLBUTRIN. (7.6)
•
Drug-laboratory test interactions: WELLBUTRIN can cause false-
positive urine test results for amphetamines. (7.7)
----------------------- USE IN SPECIFIC POPULATIONS ----------------------
•
Pregnancy: Use only if benefit outweighs potential risk to the fetus. (8.1)
See 17 for PATIENT COUNSELING INFORMATION and Medication
Guide.
Revised: Month Year
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS; AND
NEUROPSYCHIATRIC REACTIONS
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1
General Instructions for Use
2.2
Dose Adjustment in Patients With Hepatic Impairment
2.3
Dose Adjustment in Patients With Renal Impairment
2.4
Switching a Patient To or From a Monoamine Oxidase
Inhibitor (MAOI) Antidepressant
2.5
Use of WELLBUTRIN With Reversible MAOIs Such as
Linezolid or Methylene Blue
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Suicidal Thoughts and Behaviors in Children,
Adolescents, and Young Adults
5.2
Neuropsychiatric Symptoms and Suicide Risk in
Smoking Cessation Treatment
5.3
Seizure
5.4
Hypertension
5.5
Activation of Mania/Hypomania
5.6
Psychosis and Other Neuropsychiatric Reactions
5.7
Hypersensitivity Reactions
6 ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7 DRUG INTERACTIONS
7.1
Potential for Other Drugs to Affect WELLBUTRIN
7.2
Potential for WELLBUTRIN to Affect Other Drugs
7.3
Drugs That Lower Seizure Threshold
7.4
Dopaminergic Drugs (Levodopa and Amantadine)
7.5
Use With Alcohol
7.6
MAO Inhibitors
7.7
Drug-Laboratory Test Interactions
8 USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
1
Reference ID: 3426387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8.7
Hepatic Impairment
9
DRUG ABUSE AND DEPENDENCE
9.1
Controlled Substance
9.2
Abuse
10 OVERDOSAGE
10.1 Human Overdose Experience
10.2 Overdosage Management
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
FULL PRESCRIBING INFORMATION
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS; AND NEUROPSYCHIATRIC
REACTIONS
SUICIDALITY AND ANTIDEPRESSANT DRUGS
Antidepressants increased the risk of suicidal thoughts and behavior in children,
adolescents, and young adults in short-term trials. These trials did not show an increase in
the risk of suicidal thoughts and behavior with antidepressant use in subjects over age 24;
there was a reduction in risk with antidepressant use in subjects aged 65 and older [see
Warnings and Precautions (5.1)].
In patients of all ages who are started on antidepressant therapy, monitor closely for
worsening, and for emergence of suicidal thoughts and behaviors. Advise families and
caregivers of the need for close observation and communication with the prescriber [see
Warnings and Precautions (5.1)].
NEUROPSYCHIATRIC REACTIONS IN PATIENTS TAKING BUPROPION FOR
SMOKING CESSATION
Serious neuropsychiatric reactions have occurred in patients taking bupropion for
smoking cessation [see Warnings and Precautions (5.2)]. The majority of these reactions
occurred during bupropion treatment, but some occurred in the context of discontinuing
treatment. In many cases, a causal relationship to bupropion treatment is not certain,
because depressed mood may be a symptom of nicotine withdrawal. However, some of the
cases occurred in patients taking bupropion who continued to smoke. Although
WELLBUTRIN® is not approved for smoking cessation, observe all patients for
neuropsychiatric reactions. Instruct the patient to contact a healthcare provider if such
reactions occur [see Warnings and Precautions (5.2)].
1
INDICATIONS AND USAGE
WELLBUTRIN (bupropion hydrochloride) is indicated for the treatment of major
depressive disorder (MDD), as defined by the Diagnostic and Statistical Manual (DSM).
The efficacy of WELLBUTRIN in the treatment of a major depressive episode was
established in two 4-week controlled inpatient trials and one 6-week controlled outpatient trial of
adult subjects with MDD [see Clinical Studies (14)].
2
Reference ID: 3426387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
DOSAGE AND ADMINISTRATION
2.1
General Instructions for Use
To minimize the risk of seizure, increase the dose gradually [see Warnings and
Precautions (5.3)]. Increases in dose should not exceed 100 mg per day in a 3-day period.
WELLBUTRIN Tablets should be swallowed whole and not crushed, divided, or chewed.
WELLBUTRIN may be taken with or without food.
The recommended starting dose is 200 mg per day, given as 100 mg twice daily. After 3
days of dosing, the dose may be increased to 300 mg per day, given as 100 mg 3 times daily,
with at least 6 hours between successive doses. Dosing above 300 mg per day may be
accomplished using the 75- or 100-mg tablets.
A maximum of 450 mg per day, given in divided doses of not more than 150 mg each,
may be considered for patients who show no clinical improvement after several weeks of
treatment at 300 mg per day. Administer the 100-mg tablet 4 times daily to not exceed the limit
of 150 mg in a single dose.
It is generally agreed that acute episodes of depression require several months or longer
of antidepressant drug treatment beyond the response in the acute episode. It is unknown whether
the dose of WELLBUTRIN needed for maintenance treatment is identical to the dose that
provided an initial response. Periodically reassess the need for maintenance treatment and the
appropriate dose for such treatment.
2.2
Dose Adjustment in Patients With Hepatic Impairment
In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to15), the maximum
dose of WELLBUTRIN is 75 mg per day. In patients with mild hepatic impairment (Child-Pugh
score: 5 to 6), consider reducing the dose and/or frequency of dosing [see Use in Specific
Populations (8.7) and Clinical Pharmacology (12.3)].
2.3
Dose Adjustment in Patients With Renal Impairment
Consider reducing the dose and/or frequency of WELLBUTRIN in patients with renal
impairment (Glomerular Filtration Rate <90 mL/min) [see Use in Specific Populations (8.6) and
Clinical Pharmacology (12.3)].
2.4
Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI)
Antidepressant
At least 14 days should elapse between discontinuation of an MAOI intended to treat
depression and initiation of therapy with WELLBUTRIN. Conversely, at least 14 days should be
allowed after stopping WELLBUTRIN before starting an MAOI antidepressant [see
Contraindications (4) and Drug Interactions (7.6)].
2.5
Use of WELLBUTRIN With Reversible MAOIs Such as Linezolid or
Methylene Blue
Do not start WELLBUTRIN in a patient who is being treated with a reversible MAOI
such as linezolid or intravenous methylene blue. Drug interactions can increase the risk of
hypertensive reactions. In a patient who requires more urgent treatment of a psychiatric
3
Reference ID: 3426387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
condition, non-pharmacological interventions, including hospitalization, should be considered
[see Contraindications (4) and Drug Interactions (7.6)].
In some cases, a patient already receiving therapy with WELLBUTRIN may require
urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to
linezolid or intravenous methylene blue treatment are not available and the potential benefits of
linezolid or intravenous methylene blue treatment are judged to outweigh the risks of
hypertensive reactions in a particular patient, WELLBUTRIN should be stopped promptly, and
linezolid or intravenous methylene blue can be administered. The patient should be monitored
for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue,
whichever comes first. Therapy with WELLBUTRIN may be resumed 24 hours after the last
dose of linezolid or intravenous methylene blue.
The risk of administering methylene blue by non-intravenous routes (such as oral tablets
or by local injection) or in intravenous doses much lower than 1 mg/kg with WELLBUTRIN is
unclear. The clinician should, nevertheless, be aware of the possibility of a drug interaction with
such use [see Contraindications (4) and Drug Interactions (7.6)].
3
DOSAGE FORMS AND STRENGTHS
• 75 mg – yellow-gold, round, biconvex tablets printed with “WELLBUTRIN 75”.
• 100 mg – red, round, biconvex tablets printed with “WELLBUTRIN 100”.
4
CONTRAINDICATIONS
• WELLBUTRIN is contraindicated in patients with a seizure disorder.
• WELLBUTRIN is contraindicated in patients with a current or prior diagnosis of bulimia or
anorexia nervosa as a higher incidence of seizures was observed in such patients treated with
WELLBUTRIN [see Warnings and Precautions (5.3)].
• WELLBUTRIN is contraindicated in patients undergoing abrupt discontinuation of alcohol,
benzodiazepines, barbiturates, and antiepileptic drugs [see Warnings and Precautions (5.3)
and Drug Interactions (7.3)].
• The use of MAOIs (intended to treat psychiatric disorders) concomitantly with
WELLBUTRIN or within 14 days of discontinuing treatment with WELLBUTRIN is
contraindicated. There is an increased risk of hypertensive reactions when WELLBUTRIN is
used concomitantly with MAOIs. The use of WELLBUTRIN within 14 days of
discontinuing treatment with an MAOI is also contraindicated. Starting WELLBUTRIN in a
patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is
contraindicated [see Dosage and Administration (2.4, 2.5), Warnings and Precautions (5.4),
and Drug Interactions (7.6)].
• WELLBUTRIN is contraindicated in patients with known hypersensitivity to bupropion or
other ingredients of WELLBUTRIN. Anaphylactoid/anaphylactic reactions and Stevens-
Johnson syndrome have been reported [see Warnings and Precautions (5.7)].
4
Reference ID: 3426387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
WARNINGS AND PRECAUTIONS
5.1
Suicidal Thoughts and Behaviors in Children, Adolescents, and Young
Adults
Patients with MDD, both adult and pediatric, may experience worsening of their
depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual
changes in behavior, whether or not they are taking antidepressant medications, and this risk may
persist until significant remission occurs. Suicide is a known risk of depression and certain other
psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.
There has been a long-standing concern that antidepressants may have a role in inducing
worsening of depression and the emergence of suicidality in certain patients during the early
phases of treatment.
Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (selective
serotonin reuptake inhibitors [SSRIs] and others) show that these drugs increase the risk of
suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to
24) with MDD and other psychiatric disorders. Short-term clinical trials did not show an increase
in the risk of suicidality with antidepressants compared with placebo in adults beyond age 24;
there was a reduction with antidepressants compared with placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24
short-term trials of 9 antidepressant drugs in over 4,400 subjects. The pooled analyses of
placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of
295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000
subjects. There was considerable variation in risk of suicidality among drugs, but a tendency
toward an increase in the younger subjects for almost all drugs studied. There were differences in
absolute risk of suicidality across the different indications, with the highest incidence in MDD.
The risk differences (drug vs. placebo), however, were relatively stable within age strata and
across indications. These risk differences (drug-placebo difference in the number of cases of
suicidality per 1,000 subjects treated) are provided in Table 1.
Table 1. Risk Differences in the Number of Suicidality Cases by Age Group in the Pooled
Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Subjects
Age Range
Drug-Placebo Difference in Number of Cases of
Suicidality per 1,000 Subjects Treated
Increases Compared With Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared With Placebo
25-64
1 fewer case
≥65
6 fewer cases
5
Reference ID: 3426387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials,
but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
months. However, there is substantial evidence from placebo-controlled maintenance trials in
adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be
monitored appropriately and observed closely for clinical worsening, suicidality, and
unusual changes in behavior, especially during the initial few months of a course of drug
therapy, or at times of dose changes, either increases or decreases [see Boxed Warning].
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have
been reported in adult and pediatric patients being treated with antidepressants for major
depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of
depression and/or the emergence of suicidal impulses has not been established, there is concern
that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly
discontinuing the medication, in patients whose depression is persistently worse, or who are
experiencing emergent suicidality or symptoms that might be precursors to worsening depression
or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the
patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for MDD or
other indications, both psychiatric and nonpsychiatric, should be alerted about the need to
monitor patients for the emergence of agitation, irritability, unusual changes in behavior,
and the other symptoms described above, as well as the emergence of suicidality, and to
report such symptoms immediately to healthcare providers. Such monitoring should
include daily observation by families and caregivers. Prescriptions for WELLBUTRIN
should be written for the smallest quantity of tablets consistent with good patient
management, in order to reduce the risk of overdose.
5.2
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation
Treatment
WELLBUTRIN is not approved for smoking cessation treatment; however, bupropion
HCl sustained-release is approved for this use. Serious neuropsychiatric symptoms have been
reported in patients taking bupropion for smoking cessation. These have included changes in
mood (including depression and mania), psychosis, hallucinations, paranoia, delusions,
homicidal ideation, hostility, agitation, aggression, anxiety, and panic, as well as suicidal
ideation, suicide attempt, and completed suicide [see Boxed Warning and Adverse Reactions
(6.2)]. Observe patients for the occurrence of neuropsychiatric reactions. Instruct patients to
contact a healthcare professional if such reactions occur.
6
Reference ID: 3426387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In many of these cases, a causal relationship to bupropion treatment is not certain,
because depressed mood can be a symptom of nicotine withdrawal. However, some of the cases
occurred in patients taking bupropion who continued to smoke.
5.3
Seizure
WELLBUTRIN can cause seizure. The risk of seizure is dose-related. The dose should
not exceed 450 mg per day. Increase the dose gradually. Discontinue WELLBUTRIN and do not
restart treatment if the patient experiences a seizure.
The risk of seizures is also related to patient factors, clinical situations, and concomitant
medications that lower the seizure threshold. Consider these risks before initiating treatment with
WELLBUTRIN. WELLBUTRIN is contraindicated in patients with a seizure disorder, current or
prior diagnosis of anorexia nervosa or bulimia, or undergoing abrupt discontinuation of alcohol,
benzodiazepines, barbiturates, and antiepileptic drugs [see Contraindications (4) and Drug
Interactions (7.3)]. The following conditions can also increase the risk of seizure: severe head
injury; arteriovenous malformation; CNS tumor or CNS infection; severe stroke; concomitant
use of other medications that lower the seizure threshold (e.g., other bupropion products,
antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids); metabolic
disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia); use of
illicit drugs (e.g., cocaine); or abuse or misuse of prescription drugs such as CNS stimulants.
Additional predisposing conditions include diabetes mellitus treated with oral hypoglycemic
drugs or insulin; use of anorectic drugs; and excessive use of alcohol, benzodiazepines,
sedative/hypnotics, or opiates.
Incidence of Seizure With Bupropion Use: Bupropion is associated with seizures in
approximately 0.4% (4/1,000) of patients treated at doses up to 450 mg per day. The estimated
seizure incidence for WELLBUTRIN increases almost 10-fold between 450 and 600 mg per day.
The risk of seizure can be reduced if the dose of WELLBUTRIN does not exceed 450 mg
per day, given as 150 mg 3 times daily, and the titration rate is gradual.
5.4
Hypertension
Treatment with WELLBUTRIN can result in elevated blood pressure and hypertension.
Assess blood pressure before initiating treatment with WELLBUTRIN, and monitor periodically
during treatment. The risk of hypertension is increased if WELLBUTRIN is used concomitantly
with MAOIs or other drugs that increase dopaminergic or noradrenergic activity [see
Contraindications (4)].
Data from a comparative trial of the sustained-release formulation of bupropion HCl,
nicotine transdermal system (NTS), the combination of sustained-release bupropion plus NTS,
and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent
hypertension in patients treated with the combination of sustained-release bupropion and NTS. In
this trial, 6.1% of subjects treated with the combination of sustained-release bupropion and NTS
had treatment-emergent hypertension compared to 2.5%, 1.6%, and 3.1% of subjects treated with
sustained-release bupropion, NTS, and placebo, respectively. The majority of these subjects had
evidence of pre-existing hypertension. Three subjects (1.2%) treated with the combination of
7
Reference ID: 3426387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
sustained-release bupropion and NTS and 1 subject (0.4%) treated with NTS had study
medication discontinued due to hypertension compared with none of the subjects treated with
sustained-release bupropion or placebo. Monitoring of blood pressure is recommended in
patients who receive the combination of bupropion and nicotine replacement.
In a clinical trial of bupropion immediate-release in MDD subjects with stable congestive
heart failure (N = 36), bupropion was associated with an exacerbation of pre-existing
hypertension in 2 subjects, leading to discontinuation of bupropion treatment. There are no
controlled trials assessing the safety of bupropion in patients with a recent history of myocardial
infarction or unstable cardiac disease.
5.5
Activation of Mania/Hypomania
Antidepressant treatment can precipitate a manic, mixed, or hypomanic manic episode.
The risk appears to be increased in patients with bipolar disorder or who have risk factors for
bipolar disorder. Prior to initiating WELLBUTRIN, screen patients for a history of bipolar
disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar
disorder, suicide, or depression). WELLBUTRIN is not approved for use in treating bipolar
depression.
5.6
Psychosis and Other Neuropsychiatric Reactions
Depressed patients treated with WELLBUTRIN have had a variety of neuropsychiatric
signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbance,
paranoia, and confusion. Some of these patients had a diagnosis of bipolar disorder. In some
cases, these symptoms abated upon dose reduction and/or withdrawal of treatment. Instruct
patients to contact a healthcare professional if such reactions occur.
5.7
Hypersensitivity Reactions
Anaphylactoid/anaphylactic reactions have occurred during clinical trials with bupropion.
Reactions have been characterized by pruritus, urticaria, angioedema, and dyspnea requiring
medical treatment. In addition, there have been rare, spontaneous postmarketing reports of
erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with
bupropion. Instruct patients to discontinue WELLBUTRIN and consult a healthcare provider if
they develop an allergic or anaphylactoid/anaphylactic reaction (e.g., skin rash, pruritus, hives,
chest pain, edema, and shortness of breath) during treatment.
There are reports of arthralgia, myalgia, fever with rash and other serum sickness-like
symptoms suggestive of delayed hypersensitivity.
6
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the
labeling:
• Suicidal thoughts and behaviors in adolescents and young adults [see Boxed Warning and
Warnings and Precautions (5.1)]
• Neuropsychiatric symptoms and suicide risk in smoking cessation treatment [see Boxed
Warning and Warnings and Precautions (5.2)]
8
Reference ID: 3426387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Seizure [see Warnings and Precautions (5.3)]
• Hypertension [see Warnings and Precautions (5.4)]
• Activation of mania or hypomania [see Warnings and Precautions (5.5)]
• Psychosis and other neuropsychiatric reactions [see Warnings and Precautions (5.6)]
• Hypersensitivity reactions [see Warnings and Precautions (5.7)]
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared with rates in the
clinical trials of another drug and may not reflect the rates observed in clinical practice.
Adverse Reactions Leading to Discontinuation of Treatment: Adverse reactions
were sufficiently troublesome to cause discontinuation of treatment with WELLBUTRIN in
approximately 10% of the 2,400 subjects and healthy volunteers who participated in clinical
trials during the product’s initial development. The more common events causing discontinuation
include neuropsychiatric disturbances (3.0%), primarily agitation and abnormalities in mental
status; gastrointestinal disturbances (2.1%), primarily nausea and vomiting; neurological
disturbances (1.7%), primarily seizures, headaches, and sleep disturbances; and dermatologic
problems (1.4%), primarily rashes. It is important to note, however, that many of these events
occurred at doses that exceed the recommended daily dose.
Commonly Observed Adverse Reactions: Adverse reactions commonly encountered
in subjects treated with WELLBUTRIN are agitation, dry mouth, insomnia, headache/migraine,
nausea/vomiting, constipation, tremor, dizziness, excessive sweating, blurred vision, tachycardia,
confusion, rash, hostility, cardiac arrhythmia, and auditory disturbance.
Table 2 summarizes the adverse reactions that occurred in placebo-controlled trials at an
incidence of at least 1% of subjects receiving WELLBUTRIN and more frequently in these
subjects than in the placebo group.
Table 2. Adverse Reactions Reported by at Least 1% of Subjects and at a Greater
Frequency Than Placebo in Controlled Clinical Trials
Adverse Reaction
WELLBUTRIN
(n = 323)
%
Placebo
(n = 185)
%
Cardiovascular
Cardiac arrhythmias
Dizziness
Hypertension
Hypotension
Palpitations
Syncope
Tachycardia
5.3
22.3
4.3
2.5
3.7
1.2
10.8
4.3
16.2
1.6
2.2
2.2
0.5
8.6
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Dermatologic
Pruritus
Rash
2.2
8.0
0.0
6.5
Gastrointestinal
Appetite increase
3.7
2.2
Constipation
26.0
17.3
Dyspepsia
3.1
2.2
Nausea/vomiting
22.9
18.9
Genitourinary
Impotence
3.4
3.1
Menstrual complaints
4.7
1.1
Urinary frequency
2.5
2.2
Musculoskeletal
Arthritis
3.1
2.7
Neurological
Akathisia
1.5
1.1
Cutaneous temperature
1.9
1.6
disturbance
Dry mouth
27.6
18.4
Excessive sweating
22.3
14.6
Headache/migraine
25.7
22.2
Impaired sleep quality
4.0
1.6
Insomnia
18.6
15.7
Sedation
19.8
19.5
Sensory disturbance
4.0
3.2
Tremor
21.1
7.6
Neuropsychiatric
Agitation
31.9
22.2
Anxiety
3.1
1.1
Confusion
8.4
4.9
Decreased libido
3.1
1.6
Delusions
1.2
1.1
Euphoria
1.2
0.5
Hostility
5.6
3.8
Nonspecific
Fever/chills
1.2
0.5
Special Senses
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Auditory disturbance
5.3
3.2
Blurred vision
14.6
10.3
Gustatory disturbance
3.1
1.1
Other Adverse Reactions Observed During the Clinical Development of
WELLBUTRIN: The conditions and duration of exposure to WELLBUTRIN varied greatly, and
a substantial proportion of the experience was gained in open and uncontrolled clinical settings.
During this experience, numerous adverse events were reported; however, without appropriate
controls, it is impossible to determine with certainty which events were or were not caused by
WELLBUTRIN. The following enumeration is organized by organ system and describes events
in terms of their relative frequency of reporting in the database.
The following definitions of frequency are used: Frequent adverse reactions are defined
as those occurring in at least 1/100 subjects. Infrequent adverse reactions are those occurring in
1/100 to 1/1,000 subjects, while rare events are those occurring in less than 1/1,000 subjects.
Cardiovascular: Frequent was edema; infrequent were chest pain, electrocardiogram
(ECG) abnormalities (premature beats and nonspecific ST-T changes), and shortness of
breath/dyspnea; rare were flushing, and myocardial infarction.
Dermatologic: Infrequent was alopecia.
Endocrine: Infrequent was gynecomastia; rare was glycosuria.
Gastrointestinal: Infrequent were dysphagia, thirst disturbance, and liver
damage/jaundice; rare was intestinal perforation.
Genitourinary: Frequent was nocturia; infrequent were vaginal irritation, testicular
swelling, urinary tract infection, painful erection, and retarded ejaculation; rare were enuresis,
and urinary incontinence.
Neurological: Frequent were ataxia/incoordination, seizure, myoclonus, dyskinesia,
and dystonia; infrequent were mydriasis, vertigo, and dysarthria; rare were electroencephalogram
(EEG) abnormality, and impaired attention.
Neuropsychiatric: Frequent were mania/hypomania, increased libido, hallucinations,
decrease in sexual function, and depression; infrequent were memory impairment,
depersonalization, psychosis, dysphoria, mood instability, paranoia, formal thought disorder, and
frigidity; rare was suicidal ideation.
Oral Complaints: Frequent was stomatitis; infrequent were toothache, bruxism, gum
irritation, and oral edema.
Respiratory: Infrequent were bronchitis and shortness of breath/dyspnea; rare was
pulmonary embolism.
Special Senses: Infrequent was visual disturbance; rare was diplopia.
Nonspecific: Frequent were flu-like symptoms; infrequent was nonspecific pain; rare
was overdose.
Altered Appetite and Weight: A weight loss of greater than 5 lbs occurred in 28% of
subjects receiving WELLBUTRIN. This incidence is approximately double that seen in
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comparable subjects treated with tricyclics or placebo. Furthermore, while 35% of subjects
receiving tricyclic antidepressants gained weight, only 9.4% of subjects treated with
WELLBUTRIN did. Consequently, if weight loss is a major presenting sign of a patient’s
depressive illness, the anorectic and/or weight reducing potential of WELLBUTRIN should be
considered.
6.2
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of
WELLBUTRIN and are not described elsewhere in the label. Because these reactions are
reported voluntarily from a population of uncertain size, it is not always possible to reliably
estimate their frequency or establish a causal relationship to drug exposure.
Body (General): Arthralgia, myalgia, and fever with rash and other symptoms
suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness.
Cardiovascular: Hypertension (in some cases severe), orthostatic hypotension, third
degree heart block.
Endocrine: Syndrome of inappropriate antidiuretic hormone secretion, hyperglycemia,
hypoglycemia.
Gastrointestinal: Esophagitis, hepatitis.
Hemic and Lymphatic: Ecchymosis, leukocytosis, leukopenia, thrombocytopenia.
Altered PT and/or INR, infrequently associated with hemorrhagic or thrombotic complications,
were observed when bupropion was coadministered with warfarin.
Musculoskeletal: Muscle rigidity/fever/rhabdomyolysis, muscle weakness.
Nervous System: Aggression, coma, completed suicide, delirium, dream abnormalities,
paranoid ideation, paresthesia, restlessness, suicide attempt, unmasking of tardive dyskinesia.
Skin and Appendages: Stevens-Johnson syndrome, angioedema, exfoliative dermatitis,
urticaria.
Special Senses: Tinnitus, increased intraocular pressure.
7
DRUG INTERACTIONS
7.1
Potential for Other Drugs to Affect WELLBUTRIN
Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the
potential exists for drug interactions between WELLBUTRIN and drugs that are inhibitors or
inducers of CYP2B6.
Inhibitors of CYP2B6: Ticlopidine and Clopidogrel: Concomitant treatment with these
drugs can increase bupropion exposure but decrease hydroxybupropion exposure. Based on
clinical response, dosage adjustment of WELLBUTRIN may be necessary when coadministered
with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel) [see Clinical Pharmacology (12.3)].
Inducers of CYP2B6: Ritonavir, Lopinavir, and Efavirenz: Concomitant treatment
with these drugs can decrease bupropion and hydroxybupropion exposure. Dosage increase of
WELLBUTRIN may be necessary when coadministered with ritonavir, lopinavir, or efavirenz
[see Clinical Pharmacology (12.3)] but should not exceed the maximum recommended dose.
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Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied,
these drugs may induce the metabolism of bupropion and may decrease bupropion exposure [see
Clinical Pharmacology (12.3)]. If bupropion is used concomitantly with a CYP inducer, it may
be necessary to increase the dose of bupropion, but the maximum recommended dose should not
be exceeded.
7.2
Potential for WELLBUTRIN to Affect Other Drugs
Drugs Metabolized by CYP2D6: Bupropion and its metabolites
(erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors.
Therefore, coadministration of WELLBUTRIN with drugs that are metabolized by CYP2D6 can
increase the exposures of drugs that are substrates of CYP2D6. Such drugs include certain
antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine,
and sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g.,
metoprolol), and Type 1C antiarrhythmics (e.g., propafenone and flecainide). When used
concomitantly with WELLBUTRIN, it may be necessary to decrease the dose of these CYP2D6
substrates, particularly for drugs with a narrow therapeutic index.
Drugs that require metabolic activation by CYP2D6 to be effective (e.g., tamoxifen)
theoretically could have reduced efficacy when administered concomitantly with inhibitors of
CYP2D6 such as bupropion. Patients treated concomitantly with WELLBUTRIN and such drugs
may require increased doses of the drug [see Clinical Pharmacology (12.3)].
7.3
Drugs That Lower Seizure Threshold
Use extreme caution when coadministering WELLBUTRIN with other drugs that lower
seizure threshold (e.g., other bupropion products, antipsychotics, antidepressants, theophylline,
or systemic corticosteroids). Use low initial doses and increase the dose gradually [see
Contraindications (4) and Warnings and Precautions (5.3)].
7.4
Dopaminergic Drugs (Levodopa and Amantadine)
Bupropion, levodopa, and amantadine have dopamine agonist effects. CNS toxicity has
been reported when bupropion was coadministered with levodopa or amantadine. Adverse
reactions have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and
dizziness. It is presumed that the toxicity results from cumulative dopamine agonist effects. Use
caution when administering WELLBUTRIN concomitantly with these drugs.
7.5
Use With Alcohol
In postmarketing experience, there have been rare reports of adverse neuropsychiatric
events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with
WELLBUTRIN. The consumption of alcohol during treatment with WELLBUTRIN should be
minimized or avoided.
7.6
MAO Inhibitors
Bupropion inhibits the reuptake of dopamine and norepinephrine. Concomitant use of
MAOIs and bupropion is contraindicated because there is an increased risk of hypertensive
reactions if bupropion is used concomitantly with MAOIs. Studies in animals demonstrate that
the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine. At least 14 days
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should elapse between discontinuation of an MAOI intended to treat depression and initiation of
treatment with WELLBUTRIN. Conversely, at least 14 days should be allowed after stopping
WELLBUTRIN before starting an MAOI antidepressant [see Dosage and Administration (2.4,
2.5) and Contraindications (4)].
7.7
Drug-Laboratory Test Interactions
False-positive urine immunoassay screening tests for amphetamines have been reported
in patients taking bupropion. This is due to lack of specificity of some screening tests. False-
positive test results may result even following discontinuation of bupropion therapy.
Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish bupropion
from amphetamines.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category C
Risk Summary: Data from epidemiological studies of pregnant women exposed to
bupropion in the first trimester indicate no increased risk of congenital malformations overall.
All pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major
malformations, and 15% to 20% for pregnancy loss. No clear evidence of teratogenic activity
was found in reproductive developmental studies conducted in rats and rabbits; however, in
rabbits, slightly increased incidences of fetal malformations and skeletal variations were
observed at doses approximately equal to the maximum recommended human dose (MRHD) and
greater and decreased fetal weights were seen at doses twice the MRHD and greater.
WELLBUTRIN should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
Clinical Considerations: Consider the risks of untreated depression when discontinuing
or changing treatment with antidepressant medications during pregnancy and postpartum.
Human Data: Data from the international bupropion Pregnancy Registry (675 first-
trimester exposures) and a retrospective cohort study using the United Healthcare database
(1,213 first trimester exposures) did not show an increased risk for malformations overall.
No increased risk for cardiovascular malformations overall has been observed after
bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular
malformations in pregnancies with exposure to bupropion in the first trimester from the
international Pregnancy Registry was 1.3% (9 cardiovascular malformations/675 first-trimester
maternal bupropion exposures), which is similar to the background rate of cardiovascular
malformations (approximately 1%). Data from the United Healthcare database and a case-control
study (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular
malformations) from the National Birth Defects Prevention Study (NBDPS) did not show an
increased risk for cardiovascular malformations overall after bupropion exposure during the first
trimester.
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Study findings on bupropion exposure during the first trimester and risk for left
ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions
regarding a possible association. The United Healthcare database lacked sufficient power to
evaluate this association; the NBDPS found increased risk for LVOTO (n = 10; adjusted OR =
2.6; 95% CI: 1.2, 5.7), and the Slone Epidemiology case control study did not find increased risk
for LVOTO.
Study findings on bupropion exposure during the first trimester and risk for ventricular
septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible
association. The Slone Epidemiology Study found an increased risk for VSD following first
trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not
find increased risk for any other cardiovascular malformations studied (including LVOTO as
above). The NBDPS and United Healthcare database study did not find an association between
first trimester maternal bupropion exposure and VSD.
For the findings of LVOTO and VSD, the studies were limited by the small number of
exposed cases, inconsistent findings among studies, and the potential for chance findings from
multiple comparisons in case control studies.
Animal Data: In studies conducted in rats and rabbits, bupropion was administered
orally during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively
(approximately 11 and 7 times the MRHD, respectively, on a mg/m2 basis). No clear evidence of
teratogenic activity was found in either species; however, in rabbits, slightly increased incidences
of fetal malformations and skeletal variations were observed at the lowest dose tested (25
mg/kg/day, approximately equal to the MRHD on a mg/m2 basis) and greater. Decreased fetal
weights were observed at 50 mg/kg and greater.
When rats were administered bupropion at oral doses of up to 300 mg/kg/day
(approximately 7 times the MRHD on a mg/m2 basis) prior to mating and throughout pregnancy
and lactation, there were no apparent adverse effects on offspring development.
8.3
Nursing Mothers
Bupropion and its metabolites are present in human milk. In a lactation study of 10
women, levels of orally dosed bupropion and its active metabolites were measured in expressed
milk. The average daily infant exposure (assuming 150 mL/kg daily consumption) to bupropion
and its active metabolites was 2% of the maternal weight-adjusted dose. Exercise caution when
WELLBUTRIN is administered to a nursing woman.
8.4
Pediatric Use
Safety and effectiveness in the pediatric population have not been established [see Boxed
Warning and Warnings and Precautions (5.1)].
8.5
Geriatric Use
Of the approximately 6,000 subjects who participated in clinical trials with bupropion
sustained-release tablets (depression and smoking cessation trials), 275 were aged ≥65 years and
47 were aged ≥75 years. In addition, several hundred subjects aged ≥65 years participated in
clinical trials using the immediate-release formulation of bupropion (depression trials). No
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overall differences in safety or effectiveness were observed between these subjects and younger
subjects. Reported clinical experience has not identified differences in responses between the
elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled
out.
Bupropion is extensively metabolized in the liver to active metabolites, which are further
metabolized and excreted by the kidneys. The risk of adverse reactions may be greater in patients
with impaired renal function. Because elderly patients are more likely to have decreased renal
function, it may be necessary to consider this factor in dose selection; it may be useful to monitor
renal function [see Dosage and Administration (2.3), Use in Specific Populations (8.6), and
Clinical Pharmacology (12.3)].
8.6
Renal Impairment
Consider a reduced dose and/or dosing frequency of WELLBUTRIN in patients with
renal impairment (Glomerular Filtration Rate: <90 mL/min). Bupropion and its metabolites are
cleared renally and may accumulate in such patients to a greater extent than usual. Monitor
closely for adverse reactions that could indicate high bupropion or metabolite exposures [see
Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
8.7
Hepatic Impairment
In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the
maximum dose of WELLBUTRIN is 75 mg daily. In patients with mild hepatic impairment
(Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing [see Dosage
and Administration (2.2) and Clinical Pharmacology (12.3)].
9
DRUG ABUSE AND DEPENDENCE
9.1
Controlled Substance
Bupropion is not a controlled substance.
9.2
Abuse
Humans: Controlled clinical trials conducted in normal volunteers, in subjects with a
history of multiple drug abuse, and in depressed subjects showed some increase in motor activity
and agitation/excitement.
In a population of individuals experienced with drugs of abuse, a single dose of 400 mg
of bupropion produced mild amphetamine-like activity as compared with placebo on the
Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI) and a
score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These
scales measure general feelings of euphoria and drug desirability.
Findings in clinical trials, however, are not known to reliably predict the abuse potential
of drugs. Nonetheless, evidence from single-dose trials does suggest that the recommended daily
dosage of bupropion when administered in divided doses is not likely to be significantly
reinforcing to amphetamine or CNS stimulant abusers. However, higher doses (that could not be
tested because of the risk of seizure) might be modestly attractive to those who abuse CNS
stimulant drugs.
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Reference ID: 3426387
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Animals: Studies in rodents and primates demonstrated that bupropion exhibits some
pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase
locomotor activity, elicit a mild stereotyped behavior response, and increase rates of responding
in several schedule-controlled behavior paradigms. In primate models assessing the positive
reinforcing effects of psychoactive drugs, bupropion was self-administered intravenously. In rats,
bupropion produced amphetamine-like and cocaine-like discriminative stimulus effects in drug
discrimination paradigms used to characterize the subjective effects of psychoactive drugs.
10
OVERDOSAGE
10.1 Human Overdose Experience
Overdoses of up to 30 grams or more of bupropion have been reported. Seizure was
reported in approximately one-third of all cases. Other serious reactions reported with overdoses
of bupropion alone included hallucinations, loss of consciousness, sinus tachycardia, and ECG
changes such as conduction disturbances (including QRS prolongation) or arrhythmias. Fever,
muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been
reported mainly when bupropion was part of multiple drug overdoses.
Although most patients recovered without sequelae, deaths associated with overdoses of
bupropion alone have been reported in patients ingesting large doses of the drug. Multiple
uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported
in these patients.
10.2 Overdosage Management
Consult a Certified Poison Control Center for up-to-date guidance and advice. Telephone
numbers for certified poison control centers are listed in the Physician’s Desk Reference (PDR).
Call 1-800-222-1222 or refer to www.poison.org.
There are no known antidotes for bupropion. In case of an overdose, provide supportive
care, including close medical supervision and monitoring. Consider the possibility of multiple
drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm
and vital signs. Induction of emesis is not recommended.
11
DESCRIPTION
WELLBUTRIN (bupropion hydrochloride), an antidepressant of the aminoketone class,
is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other
known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related
to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1
propanone hydrochloride. The molecular weight is 276.2. The molecular formula is
C13 H18 ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in
water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The
structural formula is:
17
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structural formula
WELLBUTRIN is supplied for oral administration as 75-mg (yellow-gold) and 100-mg
(red) film-coated tablets. Each tablet contains the labeled amount of bupropion hydrochloride
and the inactive ingredients: 75-mg tablet – D&C Yellow No. 10 Lake, FD&C Yellow No. 6
Lake, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol,
talc, and titanium dioxide; 100-mg tablet – FD&C Red No. 40 Lake, FD&C Yellow No. 6 Lake,
hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and
titanium dioxide.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The exact mechanism of the antidepressant action of bupropion is not known, but is
presumed to be related to noradrenergic and/or dopaminergic mechanisms. Bupropion is a
relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine, and does not
inhibit the reuptake of serotonin. Bupropion does not inhibit monoamine oxidase.
12.3 Pharmacokinetics
Bupropion is a racemic mixture. The pharmacological activity and pharmacokinetics of
the individual enantiomers have not been studied. The mean elimination half-life (±SD) of
bupropion after chronic dosing is 21 (±9) hours, and steady-state plasma concentrations of
bupropion are reached within 8 days.
Absorption: The absolute bioavailability of WELLBUTRIN in humans has not been
determined because an intravenous formulation for human use is not available. However, it
appears likely that only a small proportion of any orally administered dose reaches the systemic
circulation intact. In rat and dog studies, the bioavailability of bupropion ranged from 5% to
20%.
In humans, following oral administration of WELLBUTRIN, peak plasma bupropion
concentrations are usually achieved within 2 hours. Plasma bupropion concentrations are
dose-proportional following single doses of 100 to 250 mg; however, it is not known if the
proportionality between dose and plasma level is maintained in chronic use.
Distribution: In vitro tests show that bupropion is 84% bound to human plasma proteins
at concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion
metabolite is similar to that for bupropion, whereas the extent of protein binding of the
threohydrobupropion metabolite is about half that seen with bupropion.
Metabolism: Bupropion is extensively metabolized in humans. Three metabolites are
active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of
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Reference ID: 3426387
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bupropion, and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion,
which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is
the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450
enzymes are not involved in the formation of threohydrobupropion. Oxidation of the bupropion
side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is
then excreted as the major urinary metabolite. The potency and toxicity of the metabolites
relative to bupropion have not been fully characterized. However, it has been demonstrated in an
antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion,
while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion.
This may be of clinical importance because the plasma concentrations of the metabolites are as
high as or higher than those of bupropion.
Following a single dose in humans, peak plasma concentrations of hydroxybupropion
occur approximately 3 hours after administration of WELLBUTRIN and are approximately
10 times the peak level of the parent drug at steady state. The elimination half-life of
hydroxybupropion is approximately 20 (±5) hours, and its AUC at steady state is about 17 times
that of bupropion. The times to peak concentrations for the erythrohydrobupropion and
threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite.
However, their elimination half-lives are longer, 33 (±10) and 37 (±13) hours, respectively, and
steady-state AUCs are 1.5 and 7 times that of bupropion, respectively.
Bupropion and its metabolites exhibit linear kinetics following chronic administration of
300 to 450 mg per day.
Elimination: Following oral administration of 200 mg of 14C-bupropion in humans, 87%
and 10% of the radioactive dose were recovered in the urine and feces, respectively. Only 0.5%
of the oral dose was excreted as unchanged bupropion.
Population Subgroups: Factors or conditions altering metabolic capacity (e.g., liver
disease, congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may
be expected to influence the degree and extent of accumulation of the active metabolites of
bupropion. The elimination of the major metabolites of bupropion may be affected by reduced
renal or hepatic function because they are moderately polar compounds and are likely to undergo
further metabolism or conjugation in the liver prior to urinary excretion.
Renal Impairment: There is limited information on the pharmacokinetics of
bupropion in patients with renal impairment. An inter-trial comparison between normal subjects
and subjects with end-stage renal failure demonstrated that the parent drug C max and AUC values
were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion
metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for subjects with end-stage
renal failure. A second trial, comparing normal subjects and subjects with moderate-to-severe
renal impairment (GFR 30.9 ± 10.8 mL/min) showed that after a single 150-mg dose of
sustained-release bupropion, exposure to bupropion was approximately 2-fold higher in subjects
with impaired renal function, while levels of the hydroxybupropion and
threo/erythrohydrobupropion (combined) metabolites were similar in the 2 groups. Bupropion is
19
Reference ID: 3426387
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extensively metabolized in the liver to active metabolites, which are further metabolized and
subsequently excreted by the kidneys. The elimination of the major metabolites of bupropion
may be reduced by impaired renal function. WELLBUTRIN should be used with caution in
patients with renal impairment and a reduced frequency and/or dose should be considered [see
Use in Specific Populations (8.6)].
Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of
bupropion was characterized in 2 single-dose trials, one in subjects with alcoholic liver disease
and one in subjects with mild-to-severe cirrhosis. The first trial demonstrated that the half-life of
hydroxybupropion was significantly longer in 8 subjects with alcoholic liver disease than in
8 healthy volunteers (32 ± 14 hours versus 21 ± 5 hours, respectively). Although not statistically
significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be
greater (by 53% to 57%) in volunteers with alcoholic liver disease. The differences in half-life
for bupropion and the other metabolites in the 2 groups were minimal.
The second trial demonstrated no statistically significant differences in the
pharmacokinetics of bupropion and its active metabolites in 9 subjects with mild-to-moderate
hepatic cirrhosis compared with 8 healthy volunteers. However, more variability was observed in
some of the pharmacokinetic parameters for bupropion (AUC, Cmax , and Tmax ) and its active
metabolites (t½) in subjects with mild-to-moderate hepatic cirrhosis. In subjects with severe
hepatic cirrhosis, significant alterations in the pharmacokinetics of bupropion and its metabolites
were seen (Table 3).
Table 3. Pharmacokinetics of Bupropion and Metabolites in Patients With Severe Hepatic
Cirrhosis: Ratio Relative to Healthy Matched Controls
Cmax
AUC
t½
Tmax
a
Bupropion
1.69
3.12
1.43
0.5 h
Hydroxybupropion
0.31
1.28
3.88
19 h
Threo/erythrohydrobupropion
amino alcohol
0.69
2.48
1.96
20 h
a = Difference.
Left Ventricular Dysfunction: During a chronic dosing trial with bupropion in 14
depressed subjects with left ventricular dysfunction (history of CHF or an enlarged heart on x-
ray), there was no apparent effect on the pharmacokinetics of bupropion or its metabolites,
compared with healthy volunteers.
Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have
not been fully characterized, but an exploration of steady-state bupropion concentrations from
several depression efficacy trials involving subjects dosed in a range of 300 to 750 mg per day,
on a 3 times daily schedule, revealed no relationship between age (18 to 83 years) and plasma
concentration of bupropion. A single-dose pharmacokinetic trial demonstrated that the
disposition of bupropion and its metabolites in elderly subjects was similar to that of younger
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subjects. These data suggest there is no prominent effect of age on bupropion concentration;
however, another single- and multiple-dose pharmacokinetics trial suggested that the elderly are
at increased risk for accumulation of bupropion and its metabolites [see Use in Specific
Populations (8.5)].
Gender: Pooled analysis of bupropion pharmacokinetic data from 90 healthy male
and 90 healthy female volunteers revealed no sex-related differences in the peak plasma
concentrations of bupropion. The mean systemic exposure (AUC) was approximately 13%
higher in male volunteers compared with female volunteers. The clinical significance of this
finding is unknown.
Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion
were studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and
17 were nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there
were no statistically significant differences in Cmax , half-life, Tmax , AUC, or clearance of
bupropion or its active metabolites between smokers and nonsmokers.
Drug Interactions: Potential for Other Drugs to Affect WELLBUTRIN: In vitro
studies indicate that bupropion is primarily metabolized to hydroxybupropion by CYP2B6.
Therefore, the potential exists for drug interactions between WELLBUTRIN and drugs that are
inhibitors or inducers of CYP2B6. In addition, in vitro studies suggest that paroxetine, sertraline,
norfluoxetine, fluvoxamine, and nelfinavir inhibit the hydroxylation of bupropion.
Inhibitors of CYP2B6: Ticlopidine, Clopidogrel: In a trial in healthy male
volunteers, clopidogrel 75 mg once daily or ticlopidine 250 mg twice daily increased exposures
(Cmax and AUC) of bupropion by 40% and 60% for clopidogrel, and by 38% and 85% for
ticlopidine, respectively. The exposures (C max and AUC) of hydroxybupropion were decreased
50% and 52%, respectively, by clopidogrel, and 78% and 84%, respectively, by ticlopidine. This
effect is thought to be due to the inhibition of the CYP2B6-catalyzed bupropion hydroxylation.
Prasugrel: Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects,
prasugrel increased bupropion Cmax and AUC values by 14% and 18%, respectively, and
decreased C max and AUC values of hydroxybupropion, an active metabolite of bupropion, by
32% and 24%, respectively.
Cimetidine: The threohydrobupropion metabolite of bupropion does not appear
to be produced by cytochrome P450 enzymes. The effects of concomitant administration of
cimetidine on the pharmacokinetics of bupropion and its active metabolites were studied in 24
healthy young male volunteers. Following oral administration of bupropion 300 mg with and
without cimetidine 800 mg, the pharmacokinetics of bupropion and hydroxybupropion were
unaffected. However, there were 16% and 32% increases in the AUC and Cmax , respectively of
the combined moieties of threohydrobupropion and erythrohydrobupropion.
Citalopram: Citalopram did not affect the pharmacokinetics of bupropion and its
three metabolites.
Inducers of CYP2B6: Ritonavir and Lopinavir: In a healthy volunteer trial,
ritonavir 100 mg twice daily reduced the AUC and C max of bupropion by 22% and 21%,
21
Reference ID: 3426387
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For current labeling information, please visit https://www.fda.gov/drugsatfda
respectively. The exposure of the hydroxybupropion metabolite was decreased by 23%, the
threohydrobupropion decreased by 38%, and the erythrohydrobupropion decreased by 48%.
In a second healthy volunteer trial, ritonavir 600 mg twice daily decreased the AUC and
the C max of bupropion by 66% and 62%, respectively. The exposure of the hydroxybupropion
metabolite was decreased by 78%, the threohydrobupropion decreased by 50%, and the
erythrohydrobupropion decreased by 68%.
In another healthy volunteer trial, lopinavir 400 mg/ritonavir 100 mg twice daily
decreased bupropion AUC and Cmax by 57%. The AUC and Cmax of hydroxybupropion were
decreased by 50% and 31%, respectively.
Efavirenz: In a trial in healthy volunteers, efavirenz 600 mg once daily for
2 weeks reduced the AUC and C max of bupropion by approximately 55% and 34%, respectively.
The AUC of hydroxybupropion was unchanged, whereas C max of hydroxybupropion was
increased by 50%.
Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied,
these drugs may induce the metabolism of bupropion.
Potential for WELLBUTRIN to Affect Other Drugs: Animal data indicated that
bupropion may be an inducer of drug-metabolizing enzymes in humans. In one trial, following
chronic administration of bupropion 100 mg three times daily to 8 healthy male volunteers for 14
days, there was no evidence of induction of its own metabolism. Nevertheless, there may be
potential for clinically important alterations of blood levels of co-administered drugs.
Drugs Metabolized by CYP2D6: In vitro, bupropion and its metabolites
(erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. In a
clinical trial of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of
CYP2D6, bupropion 300 mg per day followed by a single dose of 50 mg desipramine increased
the C max , AUC, and t1/2 of desipramine by an average of approximately 2-, 5-, and 2-fold,
respectively. The effect was present for at least 7 days after the last dose of bupropion.
Concomitant use of bupropion with other drugs metabolized by CYP2D6 has not been formally
studied.
Citalopram: Although citalopram is not primarily metabolized by CYP2D6, in
one trial bupropion increased the Cmax and AUC of citalopram by 30% and 40%, respectively.
Lamotrigine: Multiple oral doses of bupropion had no statistically significant
effects on the single-dose pharmacokinetics of lamotrigine in 12 healthy volunteers.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Lifetime carcinogenicity studies were performed in rats and mice at bupropion doses up
to 300 and 150 mg/kg/day, respectively. These doses are approximately 7 and 2 times the
MRHD, respectively, on a mg/m2 basis. In the rat study there was an increase in nodular
proliferative lesions of the liver at doses of 100 to 300 mg/kg/day (approximately 2 to 7 times the
MRHD on a mg/m2 basis); lower doses were not tested. The question of whether or not such
22
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For current labeling information, please visit https://www.fda.gov/drugsatfda
lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions
were not seen in the mouse study, and no increase in malignant tumors of the liver and other
organs was seen in either study.
Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of 5
strains in the Ames bacterial mutagenicity assay. Bupropion produced an increase in
chromosomal aberrations in 1 of 3 in vivo rat bone marrow cytogenetic studies.
A fertility study in rats at doses up to 300 mg/kg/day revealed no evidence of impaired
fertility.
14
CLINICAL STUDIES
The efficacy of WELLBUTRIN in the treatment of major depressive disorder was
established in two 4-week, placebo-controlled trials in adult inpatients with MDD (Trials 1 and 2
in Table 4) and in one 6-week, placebo-controlled trial in adult outpatients with MDD (Trial 3 in
Table 4). In the first trial, the dose range of WELLBUTRIN was 300 mg to 600 mg per day
administered in 3 divided doses; 78% of subjects were treated with doses of 300 mg to 450 mg
per day. The trial demonstrated the efficacy of WELLBUTRIN as measured by the Hamilton
Depression Rating Scale (HDRS) total score, the HDRS depressed mood item (item 1), and the
Clinical Global Impressions-severity score (CGI-S). The second trial included 2 doses of
WELLBUTRIN (300 and 450 mg per day) and placebo. This trial demonstrated the effectiveness
of WELLBUTRIN for only the 450-mg-per-day dose. The efficacy results were statistically
significant for the HDRS total score and the CGI-S score, but not for HDRS item 1. In the third
trial, outpatients were treated with 300 mg per day of WELLBUTRIN. This trial demonstrated
the efficacy of WELLBUTRIN as measured by the HDRS total score, the HDRS item 1, the
Montgomery-Asberg Depression Rating Scale (MADRS), the CGI-S score, and the CGI-
Improvement Scale (CGI-I) score. Effectiveness of WELLBUTRIN in long-term use, that is, for
more than 6 weeks, has not been systematically evaluated in controlled trials.
Table 4. Efficacy of WELLBUTRIN for the Treatment of Major Depressive Disorder
Trial
Number
Treatment Group
Primary Efficacy Measure: HDRS
Mean Baseline
Score (SD)
LS Mean Score at
Endpoint Visit
(SE)
Placebo
substracted
Differencea (95%
CI)
Trial 1
WELLBUTRIN
300-600 mg/dayb
(n = 48)
28.5 (5.1)
14.9 (1.3)
-4.7 (-8.8, -0.6)
Placebo (n = 27)
29.3 (7.0)
19.6 (1.6)
-
Mean Baseline
Score (SD)
LS Mean Change
from Baseline (SE)
Placebo-subtracted
Differencea (95%
CI)
23
Reference ID: 3426387
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Trial 2
WELLBUTRIN
300 mg/day
(n = 36)
32.4 (5.9)
-15.5 (1.7)
-4.1
WELLBUTRIN
450 mg/dayb
(n = 34)
34.8 (4.6)
-17.4 (1.7)
-5.9 (-10.5, -1.4)
Placebo (n=39)
32.9 (5.4)
-11.5 (1.6)
-
Trial 3
WELLBUTRIN
300 mg/dayb
(n = 110)
26.5 (4.3)
-12.0 (NA)
-3.9 (-5.7, -1.0)
Placebo (n = 106)
27.0 (3.5)
-8.7 (NA)
-
n: sample size; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI:
unadjusted confidence interval included for doses that were demonstrated to be effective; NA:
not available.
a Difference (drug minus placebo) in least-squares estimates with respect to the primary
efficacy parameter. For Trial 1, it refers to the mean score at the endpoint visit; for Trials 2
and 3, it refers to the mean change from baseline to the endpoint visit.
b Doses that are demonstrated to be statistically significantly superior to placebo.
16
HOW SUPPLIED/STORAGE AND HANDLING
WELLBUTRIN Tablets, 75 mg of bupropion hydrochloride, are yellow-gold, round,
biconvex tablets printed with “WELLBUTRIN 75” in bottles of 100 (NDC 0173-0177-55).
WELLBUTRIN Tablets, 100 mg of bupropion hydrochloride, are red, round, biconvex
tablets printed with “WELLBUTRIN 100” in bottles of 100 (NDC 0173-0178-55).
Store at room temperature, 20° to 25°C (68° to 77°F); excursions permitted between
15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature]. Protect from light
and moisture.
17
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients, their families, and their caregivers about the benefits and risks associated
with treatment with WELLBUTRIN and counsel them in its appropriate use.
A patient Medication Guide about “Antidepressant Medicines, Depression and Other
Serious Mental Illnesses, and Suicidal Thoughts or Actions,” “Quitting Smoking, Quit-Smoking
Medications, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or
Actions,” and “What Other Important Information Should I Know About WELLBUTRIN?” is
available for WELLBUTRIN. Instruct patients, their families, and their caregivers to read the
Medication Guide and assist them in understanding its contents. Patients should be given the
opportunity to discuss the contents of the Medication Guide and to obtain answers to any
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questions they may have. The complete text of the Medication Guide is reprinted at the end of
this document.
Advise patients regarding the following issues and to alert their prescriber if these occur
while taking WELLBUTRIN.
Suicidal Thoughts and Behaviors: Instruct patients, their families, and/or their
caregivers to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability,
hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania,
other unusual changes in behavior, worsening of depression, and suicidal ideation, especially
early during antidepressant treatment and when the dose is adjusted up or down. Advise families
and caregivers of patients to observe for the emergence of such symptoms on a day-to-day basis,
since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or
healthcare professional, especially if they are severe, abrupt in onset, or were not part of the
patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk
for suicidal thinking and behavior and indicate a need for very close monitoring and possibly
changes in the medication.
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment:
Although WELLBUTRIN is not indicated for smoking cessation treatment, it contains the same
active ingredient as ZYBAN® which is approved for this use. Advise patients, families and
caregivers that quitting smoking, with or without ZYBAN, may trigger nicotine withdrawal
symptoms (e.g., including depression or agitation), or worsen pre-existing psychiatric illness.
Some patients have experienced changes in mood (including depression and mania), psychosis,
hallucinations, paranoia, delusions, homicidal ideation, aggression, anxiety, and panic, as well as
suicidal ideation, suicide attempt, and completed suicide when attempting to quit smoking while
taking ZYBAN. If patients develop agitation, hostility, depressed mood, or changes in thinking
or behavior that are not typical for them, or if patients develop suicidal ideation or behavior, they
should be urged to report these symptoms to their healthcare provider immediately.
Severe Allergic Reactions: Educate patients on the symptoms of hypersensitivity and
to discontinue WELLBUTRIN if they have a severe allergic reaction.
Seizure: Instruct patients to discontinue and not restart WELLBUTRIN if they
experience a seizure while on treatment. Advise patients that the excessive use or abrupt
discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can
increase the risk of seizure. Advise patients to minimize or avoid use of alcohol.
Bupropion-Containing Products: Educate patients that WELLBUTRIN contains the
same active ingredient (bupropion hydrochloride) found in ZYBAN, which is used as an aid to
smoking cessation treatment, and that WELLBUTRIN should not be used in combination with
ZYBAN or any other medications that contain bupropion (such as WELLBUTRIN SR®, the
sustained-release formulation and WELLBUTRIN XL® or FORFIVO XL™, the extended-
release formulations, and APLENZIN®, the extended-release formulation of bupropion
hydrobromide). In addition, there are a number of generic bupropion HCl products for the
immediate-, sustained-, and extended-release formulations.
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Potential for Cognitive and Motor Impairment: Advise patients that any CNS-active
drug like WELLBUTRIN may impair their ability to perform tasks requiring judgment or motor
and cognitive skills. Advise patients that until they are reasonably certain that WELLBUTRIN
does not adversely affect their performance, they should refrain from driving an automobile or
operating complex, hazardous machinery. WELLBUTRIN may lead to decreased alcohol
tolerance.
Concomitant Medications: Counsel patients to notify their healthcare provider if they
are taking or plan to take any prescription or over-the-counter drugs because WELLBUTRIN
and other drugs may affect each others’ metabolisms.
Pregnancy: Advise patients to notify their healthcare provider if they become pregnant
or intend to become pregnant during therapy.
Precautions for Nursing Mothers: Advise patients that WELLBUTRIN is present in
human milk in small amounts.
Storage Information: Instruct patients to store WELLBUTRIN at room temperature,
between 59°F and 86°F (15°C to 30°C) and keep the tablets dry and out of the light.
Administration Information: Instruct patients to take WELLBUTRIN in equally divided
doses 3 or 4 times a day, with doses separated by least 6 hours to minimize the risk of seizure.
Instruct patients if they miss a dose, not to take an extra tablet to make up for the missed dose
and to take the next tablet at the regular time because of the dose-related risk of seizure. Instruct
patients that WELLBUTRIN Tablets should be swallowed whole and not crushed, divided, or
chewed. WELLBUTRIN can be taken with or without food.
WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and ZYBAN are registered
trademarks of the GlaxoSmithKline group of companies. The other brands listed are trademarks
of their respective owners and are not trademarks of the GlaxoSmithKline group of companies.
The makers of these brands are not affiliated with and do not endorse the GlaxoSmithKline
group of companies or its products.
Manufactured for:
company logo
Research Triangle Park, NC 27709
©2013, GlaxoSmithKline group of companies. All rights reserved.
WLT:XPI
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MEDICATION GUIDE
WELLBUTRIN® (WELL byu-trin)
(bupropion hydrochloride) Tablets
Read this Medication Guide carefully before you start taking WELLBUTRIN and each
time you get a refill. There may be new information. This information does not take
the place of talking with your healthcare provider about your medical condition or
your treatment. If you have any questions about WELLBUTRIN, ask your
healthcare provider or pharmacist.
IMPORTANT: Be sure to read the three sections of this Medication Guide.
The first section is about the risk of suicidal thoughts and actions with
antidepressant medicines; the second section is about the risk of changes
in thinking and behavior, depression and suicidal thoughts or actions with
medicines used to quit smoking; and the third section is entitled “What
Other Important Information Should I Know About WELLBUTRIN?”
Antidepressant Medicines, Depression and Other Serious Mental Illnesses,
and Suicidal Thoughts or Actions
This section of the Medication Guide is only about the risk of suicidal
thoughts and actions with antidepressant medicines. Talk to your healthcare
provider or your family member’s healthcare provider about:
• all risks and benefits of treatment with antidepressant medicines
• all treatment choices for depression or other serious mental illness
What is the most important information I should know about
antidepressant medicines, depression and other serious mental illnesses,
and suicidal thoughts or actions?
1. Antidepressant medicines may increase suicidal thoughts or actions in
some children, teenagers, or young adults within the first few months of
treatment.
2. Depression or other serious mental illnesses are the most important
causes of suicidal thoughts and actions. Some people may have a
particularly high risk of having suicidal thoughts or actions. These include
people who have (or have a family history of) bipolar illness (also called manic-
depressive illness) or suicidal thoughts or actions.
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Reference ID: 3426387
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For current labeling information, please visit https://www.fda.gov/drugsatfda
3. How can I watch for and try to prevent suicidal thoughts and actions in
myself or a family member?
• Pay close attention to any changes, especially sudden changes, in mood,
behaviors, thoughts, or feelings. This is very important when an antidepressant
medicine is started or when the dose is changed.
• Call your healthcare provider right away to report new or sudden changes in
mood, behavior, thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled. Call the
healthcare provider between visits as needed, especially if you have concerns
about symptoms.
Call your healthcare provider right away if you or your family member has
any of the following symptoms, especially if they are new, worse, or worry
you:
• thoughts about suicide or
dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling very agitated or
restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or
violent
• acting on dangerous impulses
• an extreme increase in activity and
talking (mania)
• other unusual changes in behavior
or mood
What else do I need to know about antidepressant medicines?
• Never stop an antidepressant medicine without first talking to a
healthcare provider. Stopping an antidepressant medicine suddenly can cause
other symptoms.
• Antidepressants are medicines used to treat depression and other
illnesses. It is important to discuss all the risks of treating depression and also
the risks of not treating it. Patients and their families or other caregivers should
discuss all treatment choices with the healthcare provider, not just the use of
antidepressants.
• Antidepressant medicines have other side effects. Talk to the healthcare
provider about the side effects of the medicine prescribed for you or your family
member.
• Antidepressant medicines can interact with other medicines. Know all of
the medicines that you or your family member takes. Keep a list of all medicines
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to show the healthcare provider. Do not start new medicines without first
checking with your healthcare provider.
It is not known if WELLBUTRIN is safe and effective in children under the age of
18.
Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and
Behavior, Depression, and Suicidal Thoughts or Actions
This section of the Medication Guide is only about the risk of changes in thinking
and behavior, depression and suicidal thoughts or actions with drugs used to quit
smoking.
Although WELLBUTRIN is not a treatment for quitting smoking, it contains the
same active ingredient (bupropion hydrochloride) as ZYBAN® which is used to help
patients quit smoking.
Some people have had changes in behavior, hostility, agitation, depression,
suicidal thoughts or actions while taking bupropion to help them quit smoking.
These symptoms can develop during treatment with bupropion or after stopping
treatment with bupropion.
If you, your family member, or your caregiver notice agitation, hostility,
depression, or changes in thinking or behavior that are not typical for you, or you
have any of the following symptoms, stop taking bupropion and call your
healthcare provider right away:
• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• panic attacks
• feeling very agitated or restless
• acting aggressive, being angry, or
violent
• acting on dangerous impulses
• an extreme increase in activity and
talking (mania)
• abnormal thoughts or sensations
• seeing or hearing things that are
not there (hallucinations)
• feeling people are against you
(paranoia)
• feeling confused
• other unusual changes in behavior
or mood
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When you try to quit smoking, with or without bupropion, you may have symptoms
that may be due to nicotine withdrawal, including urge to smoke, depressed mood,
trouble sleeping, irritability, frustration, anger, feeling anxious, difficulty
concentrating, restlessness, decreased heart rate, and increased appetite or weight
gain. Some people have even experienced suicidal thoughts when trying to quit
smoking without medication. Sometimes quitting smoking can lead to worsening of
mental health problems that you already have, such as depression.
Before taking bupropion, tell your healthcare provider if you have ever had
depression or other mental illnesses. You should also tell your healthcare provider
about any symptoms you had during other times you tried to quit smoking, with or
without bupropion.
What Other Important Information Should I Know About WELLBUTRIN?
• Seizures: There is a chance of having a seizure (convulsion, fit) with
WELLBUTRIN, especially in people:
o with certain medical problems.
o who take certain medicines.
The chance of having seizures increases with higher doses of WELLBUTRIN. For
more information, see the sections “Who should not take WELLBUTRIN?” and
“What should I tell my healthcare provider before taking WELLBUTRIN?” Tell your
healthcare provider about all of your medical conditions and all the medicines you
take. Do not take any other medicines while you are taking WELLBUTRIN
unless your healthcare provider has said it is okay to take them.
If you have a seizure while taking WELLBUTRIN, stop taking the tablets
and call your healthcare provider right away. Do not take WELLBUTRIN again
if you have a seizure.
• High blood pressure (hypertension). Some people get high blood
pressure that can be severe, while taking WELLBUTRIN. The chance of
high blood pressure may be higher if you also use nicotine replacement therapy
(such as a nicotine patch) to help you stop smoking.
• Manic episodes. Some people may have periods of mania while taking
WELLBUTRIN, including:
o
Greatly increased energy
o
Severe trouble sleeping
o
Racing thoughts
o
Reckless behavior
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o
Unusually grand ideas
o
Excessive happiness or irritability
o
Talking more or faster than usual
If you have any of the above symptoms of mania, call your healthcare provider.
• Unusual thoughts or behaviors. Some patients have unusual thoughts or
behaviors while taking WELLBUTRIN, including delusions (believe you are
someone else), hallucinations (seeing or hearing things that are not there),
paranoia (feeling that people are against you), or feeling confused. If this
happens to you, call your healthcare provider.
• Severe allergic reactions. Some people can have severe allergic
reactions to WELLBUTRIN. Stop taking WELLBUTRIN and call your
healthcare provider right away if you get a rash, itching, hives, fever,
swollen lymph glands, painful sores in the mouth or around the eyes, swelling of
the lips or tongue, chest pain, or have trouble breathing. These could be signs of
a serious allergic reaction.
What is WELLBUTRIN?
WELLBUTRIN is a prescription medicine used to treat adults with a certain type of
depression called major depressive disorder.
Who should not take WELLBUTRIN?
Do not take WELLBUTRIN if you
• have or had a seizure disorder or epilepsy.
• have or had an eating disorder such as anorexia nervosa or bulimia.
• are taking any other medicines that contain bupropion, including ZYBAN
(used to help people stop smoking) APLENZIN®, FORFIVO XL™ ,
WELLBUTRIN SR®, or WELLBUTRIN XL®. Bupropion is the same active
ingredient that is in WELLBUTRIN.
• drink a lot of alcohol and abruptly stop drinking, or use medicines called
sedatives (these make you sleepy), benzodiazepines, or anti-seizure medicines,
and you stop using them all of a sudden.
• take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or
pharmacist if you are not sure if you take an MAOI, including the antibiotic
linezolid.
•
do not take an MAOI within 2 weeks of stopping WELLBUTRIN unless directed
to do so by your healthcare provider.
•
do not start WELLBUTRIN if you stopped taking an MAOI in the last 2 weeks
unless directed to do so by your healthcare provider.
31
Reference ID: 3426387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• are allergic to the active ingredient in WELLBUTRIN, bupropion, or to any of the
inactive ingredients. See the end of this Medication Guide for a complete list of
ingredients in WELLBUTRIN.
What should I tell my healthcare provider before taking WELLBUTRIN?
Tell your healthcare provider if you have ever had depression, suicidal thoughts or
actions, or other mental health problems. See “Antidepressant Medicines,
Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions.”
Tell your healthcare provider about your other medical conditions including
if you:
• have liver problems, especially cirrhosis of the liver.
• have kidney problems.
• have, or have had, an eating disorder, such as anorexia nervosa or bulimia.
• have had a head injury.
• have had a seizure (convulsion, fit).
• have a tumor in your nervous system (brain or spine).
• have had a heart attack, heart problems, or high blood pressure.
• are a diabetic taking insulin or other medicines to control your blood sugar.
• drink alcohol.
• abuse prescription medicines or street drugs.
• are pregnant or plan to become pregnant.
• are breastfeeding. WELLBUTRIN passes into your milk in small amounts.
Tell your healthcare provider about all the medicines you take, including
prescription, over-the-counter medicines, vitamins, and herbal supplements. Many
medicines increase your chances of having seizures or other serious side effects if
you take them while you are taking WELLBUTRIN.
How should I take WELLBUTRIN?
• Take WELLBUTRIN exactly as prescribed by your healthcare provider.
• Take WELLBUTRIN at the same time each day.
• Take your doses of WELLBUTRIN at least 6 hours apart.
• Do not chew, cut, or crush WELLBUTRIN tablets.
• You may take WELLBUTRIN with or without food.
• If you miss a dose, do not take an extra dose to make up for the dose you
missed. Wait and take your next dose at the regular time. This is very
important. Too much WELLBUTRIN can increase your chance of having a
seizure.
32
Reference ID: 3426387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• If you take too much WELLBUTRIN, or overdose, call your local emergency room
or poison control center right away.
• Do not take any other medicines while taking WELLBUTRIN unless your
healthcare provider has told you it is okay.
• If you are taking WELLBUTRIN for the treatment of major depressive disorder, it
may take several weeks for you to feel that WELLBUTRIN is working. Once you
feel better, it is important to keep taking WELLBUTRIN exactly as directed by
your healthcare provider. Call your healthcare provider if you do not feel
WELLBUTRIN is working for you.
• Do not change your dose or stop taking WELLBUTRIN without talking with your
healthcare provider first.
What should I avoid while taking WELLBUTRIN?
• Limit or avoid using alcohol during treatment with WELLBUTRIN. If you usually
drink a lot of alcohol, talk with your healthcare provider before suddenly
stopping. If you suddenly stop drinking alcohol, you may increase your risk of
having seizures.
• Do not drive a car or use heavy machinery until you know how WELLBUTRIN
affects you. WELLBUTRIN can affect your ability to do these things safely.
What are possible side effects of WELLBUTRIN?
See “What Other Important Information Should I Know About
WELLBUTRIN?”
WELLBUTRIN can cause serious side effects.
The most common side effects of WELLBUTRIN include:
• Nervousness
• Dry mouth
• Constipation
• Headache
• Nausea or vomiting
• Dizziness
• Heavy sweating
• Shakiness (tremor)
• Trouble sleeping
• Blurred vision
• Fast heartbeat
If you have nausea, take your medicine with food. If you have trouble sleeping, do
not take your medicine too close to bedtime.
Tell your healthcare provider right away about any side effects that bother you.
33
Reference ID: 3426387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
These are not all the possible side effects of WELLBUTRIN. For more information,
ask your healthcare provider or pharmacist.
Call your healthcare provider for medical advice about side effects. You may report
side effects to FDA at 1-800-FDA-1088.
You may also report side effects to GlaxoSmithKline at 1-888-825-5249.
How should I store WELLBUTRIN?
• Store WELLBUTRIN at room temperature between 59°F and 86°F (15°C to
30°C).
• Keep WELLBUTRIN Tablets dry and out of the light.
Keep WELLBUTRIN and all medicines out of the reach of children.
General Information about WELLBUTRIN.
Medicines are sometimes prescribed for purposes other than those listed in a
Medication Guide. Do not use WELLBUTRIN for a condition for which it was not
prescribed. Do not give WELLBUTRIN to other people, even if they have the same
symptoms you have. It may harm them.
If you take a urine drug screening test, WELLBUTRIN may make the test result
positive for amphetamines. If you tell the person giving you the drug screening
test that you are taking WELLBUTRIN, they can do a more specific drug screening
test that should not have this problem.
This Medication Guide summarizes important information about WELLBUTRIN. If
you would like more information, talk with your healthcare provider. You can ask
your healthcare provider or pharmacist for information about WELLBUTRIN that is
written for healthcare professionals.
For more information about WELLBUTRIN, go to www.wellbutrin.com or call 1-888
825-5249.
What are the ingredients in WELLBUTRIN?
Active ingredient: bupropion hydrochloride.
Inactive ingredients: 75-mg tablet – D&C Yellow No. 10 Lake, FD&C Yellow No. 6
Lake, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose,
polyethylene glycol, talc, and titanium dioxide; 100-mg tablet – FD&C Red No. 40
34
Reference ID: 3426387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lake, FD&C Yellow No. 6 Lake, hydroxypropyl cellulose, hypromellose,
microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide.
This Medication Guide has been approved by the U.S. Food and Drug
Administration.
WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and ZYBAN are registered
trademarks of the GlaxoSmithKline group of companies. The other brands listed
are trademarks of their respective owners and are not trademarks of the
GlaxoSmithKline group of companies. The makers of these brands are not affiliated
with and do not endorse the GlaxoSmithKline group of companies or its products.
company logo
GlaxoSmithKline
Research Triangle Park, NC 27709
©2013, GlaxoSmithKline group of companies. All rights reserved.
Month year
WLT: MG
35
Reference ID: 3426387
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018644s046s047lbl.pdf', 'application_number': 18644, 'submission_type': 'SUPPL ', 'submission_number': 46}
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Locoid®
(hydrocortisone butyrate) Ointment, 0.1%
For topical use
DESCRIPTION
Locoid® (hydrocortisone butyrate) Ointment, 0.1% contains the topical corticosteroid, hydrocortisone
butyrate, a non-fluorinated hydrocortisone ester. It has the chemical name: 11β,17,21-Trihydroxypregn-4
ene-3,20-dione 17-butyrate; the molecular formula: C25H36O6; the molecular weight: 432.54; and the CAS
registry number: 13609-67-1.
Its structural formula is: structural formula
Each gram of Locoid® Ointment contains 1 mg of hydrocortisone butyrate in a base consisting of mineral
oil and polyethylene.
CLINICAL PHARMACOLOGY
Topical corticosteroids share anti-inflammatory, anti-pruritic and vasoconstrictive actions. The mechanism
of anti-inflammatory activity of the topical corticosteroids is unclear. Various laboratory methods,
including vasoconstrictor assays, are used to compare and predict potencies and/or clinical efficacies of the
topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between
vasoconstrictor potency and therapeutic efficacy in man.
Pharmacokinetics
The extent of percutaneous absorption of topical corticosteroids is determined by many factors including
the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings.
Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease
processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the
percutaneous absorption of topical corticosteroids.
Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways
similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in
varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the
kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile.
INDICATIONS AND USAGE
Locoid® (hydrocortisone butyrate) Ointment, 0.1% is indicated for the relief of the inflammatory and
pruritic manifestations of corticosteroid-responsive dermatoses.
CONTRAINDICATIONS
None.
Reference ID: 3650033
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRECAUTIONS
General
Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal
(HPA) axis suppression, manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria in some
patients. Conditions which augment systemic absorption include the application of the more potent
corticosteroids, use over large surface areas, prolonged use, and the addition of occlusive dressings.
Therefore, patients receiving a large dose of a potent topical corticosteroid applied to a large surface area or
under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression by
using ACTH stimulation tests.
If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency
of application, or to substitute a less potent corticosteroid.
Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug.
Infrequently, signs and symptoms of corticosteroid withdrawal may occur, requiring supplemental systemic
corticosteroids.
Children may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible
to systemic toxicity. (See PRECAUTIONS – Pediatric Use.)
If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted.
In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent
should be instituted. If a favorable response does not occur promptly, the corticosteroid should be
discontinued until the infection has been adequately controlled.
Information for Patients
Patients using topical corticosteroids should receive the following information and instructions:
1. This medication is to be used as directed by the physician. It is for external use only. Avoid contact with
the eyes.
2. Patients should be advised not to use this medication for any disorder other than that for which it was
prescribed.
3. The treated skin area should not be bandaged or otherwise covered or wrapped as to be occlusive unless
directed by the physician.
4. Patients should report any signs of local adverse reactions especially under occlusive dressing.
5. Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants on a child
being treated in the diaper area, as these garments may constitute occlusive dressings.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Note: The animal multiples of human exposure calculations in this label were based on body surface
area comparisons for an adult (i.e., mg/m2/day dose comparisons) assuming 100% human percutaneous
absorption of a maximum topical human dose (MTHD) for hydrocortisone butyrate ointment (25 g).
In a 2-year dermal rat carcinogenicity study with Locoid® Lotion, hydrocortisone butyrate was administered
to Sprague-Dawley rats at topical doses of 0.05, 0.15, and 0.3 mg/kg/day in males and 0.1, 0.25, and 0.5
mg/kg/day in females (0.1% lotion). No drug-related tumors were noted in this study up to the highest doses
evaluated in this study of 0.3 mg/kg/day in males (0.1X MTHD) and 0.5 mg/kg/day in females (0.2X
MTHD).
Hydrocortisone butyrate revealed no evidence of mutagenic or clastogenic potential based on the results of
two in vitro genotoxicity tests (Ames test and L5178Y/TK+/- mouse lymphoma assay) and one in vivo
genotoxicity test (mouse micronucleus assay).
No evidence of impairment of fertility or effect on mating performance was observed in a fertility and
general reproductive performance study conducted in male and female rats at subcutaneous doses up to and
including 1.8 mg/kg/day (0.7X MTHD). Mild effects on maternal animals, such as reduced food
consumption and a subsequent reduction in body weight gain, were seen at doses ≥0.6 mg/kg/day (0.2X
MTHD).
Reference ID: 3650033
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pregnancy Category C
Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively
low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal
application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on
teratogenic effects from topically applied corticosteroids. Therefore, topical corticosteroids should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Drugs of this class should not be used extensively on pregnant patients, in large amounts, or for prolonged
periods of time.
Systemic embryofetal development studies were conducted in rats and rabbits. Subcutaneous doses of 0.6,
1.8 and 5.4 mg/kg/day hydrocortisone butyrate were administered to pregnant female rats during gestation
days 6 – 17. In the presence of maternal toxicity, fetal effects noted at 5.4 mg/kg/day (2X MTHD) included
an increased incidence of ossification variations and unossified sternebra. No treatment-related effects on
embryofetal toxicity or teratogenicity were noted at doses of 5.4 and 1.8 mg/kg/day, respectively (2X MTHD
and 0.7X MTHD, respectively).
Subcutaneous doses of 0.1, 0.2 and 0.3 mg/kg/day hydrocortisone butyrate were administered to pregnant
female rabbits during gestation days 7 – 20. An increased incidence of abortion was noted at 0.3 mg/kg/day
(0.2X MTHD). In the absence of maternal toxicity, a dose-dependent decrease in fetal body weight was
noted at doses ≥0.1 mg/kg/day (0.1X MTHD). Additional indicators of embryofetal toxicity (reduction in
litter size, decreased number of viable fetuses, increased post-implantation loss) were noted at doses
≥0.2 mg/kg/day (0.2X MTHD). Additional fetal effects noted in this study included delayed ossification
noted at doses ≥0.1 mg/kg/day and an increased incidence of fetal malformations (primarily skeletal
malformations) noted at doses ≥0.2 mg/kg/day. A dose at which no treatment-related effects on embryofetal
toxicity or teratogenicity were observed was not established in this study.
Additional systemic embryofetal development studies were conducted in rats and mice. Subcutaneous doses
of 0.1 and 9 mg/kg/day hydrocortisone butyrate were administered to pregnant female rats during gestation
days 9 – 15. In the presence of maternal toxicity, an increase in fetal deaths and fetal resorptions and an
increase in the number of ossifications in caudal vertebrae were noted at a dose of 9 mg/kg/day (3X MTHD).
No treatment-related effects on embryofetal toxicity or teratogenicity were noted at 0.1 mg/kg/day (0.1X
MTHD).
Subcutaneous doses of 0.2 and 1 mg/kg/day hydrocortisone butyrate were administered to pregnant female
mice during gestation days 7 – 13. In the absence of maternal toxicity, an increased number of cervical ribs
and one fetus with clubbed legs were noted at a dose of 1 mg/kg/day (0.2X MTHD). No treatment-related
effects on embryofetal toxicity or teratogenicity were noted at doses of 1 and 0.2 mg/kg/day, respectively
(0.2X MTHD and 0.1X MTHD, respectively).
Topical embryofetal development studies were conducted in rats and rabbits with a hydrocortisone butyrate
ointment formulation. Topical doses of 1% and 10% hydrocortisone butyrate ointment were administered to
pregnant female rats during gestation days 6 – 15 or pregnant female rabbits during gestation days 6 – 18. A
dose-dependent increase in fetal resorptions was noted in rabbits (0.2 – 2X MTHD) and fetal resorptions
were noted in rats at the 10% hydrocortisone butyrate ointment dose (80X MTHD).
No treatment-related effects on embryofetal toxicity were noted at the 1% hydrocortisone butyrate ointment
dose in rats (8X MTHD). A dose at which no treatment-related effects on embryofetal toxicity were
observed in rabbits after topical administration of hydrocortisone butyrate ointment was not established in
this study.
No treatment-related effects on teratogenicity were noted at a dose of 10% hydrocortisone butyrate ointment
in rats or rabbits (80X MTHD and 2X MTHD, respectively).
A peri- and post-natal development study was conducted in rats. Subcutaneous doses of 0.6, 1.8 and
5.4 mg/kg/day hydrocortisone butyrate were administered to pregnant female rats from gestation day
6 – lactation day 20. In the presence of maternal toxicity, a dose-dependent decrease in fetal weight was
noted at doses ≥1.8 mg/kg/day (0.7X MTHD). No treatment-related effects on fetal toxicity were noted at
0.6 mg/kg/day (0.2X MTHD). A delay in sexual maturation was noted at 5.4 mg/kg/day (2X MTHD).
No treatment-related effects on sexual maturation were noted at 1.8 mg/kg/day. No treatment-related effects
on behavioral development or subsequent reproductive performance were noted at 5.4 mg/kg/day.
Reference ID: 3650033
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Nursing Mothers
It is not known whether topical administration of corticosteroids could result in sufficient systemic
absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids are
secreted into breast milk, in quantities not likely to have a deleterious effect on the infant. Nevertheless,
caution should be exercised when topical corticosteroids are administered to a nursing woman.
Pediatric Use
Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced HPA axis
suppression and Cushing’s syndrome than mature patients because of a larger skin surface area to body
weight ratio.
Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing’s syndrome, linear growth retardation,
delayed weight gain, and intracranial hypertension have been reported in children receiving topical
corticosteroids.
Manifestations of adrenal suppression in children include low plasma cortisol levels and absence of
response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles,
headaches, and bilateral papilledema.
Administration of topical corticosteroids to children should be limited to the least amount compatible with
an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and
development of children.
ADVERSE REACTIONS
The following local adverse reactions are reported infrequently with topical corticosteroids but may occur
more frequently with the use of occlusive dressings. These reactions are listed in an approximate
decreasing order of occurrence: burning, itching, irritation, dryness, folliculitis, hypertrichosis, acneiform
eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, maceration of the skin,
secondary infection, skin atrophy, striae, and miliaria.
DOSAGE AND ADMINISTRATION
Locoid® (hydrocortisone butyrate) Ointment, 0.1% should be applied to the affected area as a thin film two or three
times daily depending on the severity of the condition. Occlusive dressings may be used for the management of
psoriasis or recalcitrant conditions.
If an infection develops, the use of occlusive dressings should be discontinued and appropriate antimicrobial therapy
instituted.
HOW SUPPLIED
Locoid® (hydrocortisone butyrate) Ointment, 0.1% is supplied in tubes containing:
15 g
(NDC 16781-389-15)
45 g
(NDC 16781-389-45)
STORAGE
Store at controlled temperature between 2° to 30°C (36° to 86°F).
Rx only
Reference ID: 3650033
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Manufactured for:
Valeant Pharmaceuticals North America LLC
Bridgewater, NJ 08807 USA
By:Ferndale Laboratories, Inc.
Ferndale, MI 48220
Locoid is a registered trademark of Astellas Pharma Europe B.V. under license.
©Valeant Pharmaceuticals International.
9421700
Revised: 10/2014
Reference ID: 3650033
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018652s010lbl.pdf', 'application_number': 18652, 'submission_type': 'SUPPL ', 'submission_number': 10}
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Metronidazole Injection, USP RTU®
in Plastic Container
VIAFLEX Plus Container
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Metronidazole Injection, USP RTU and other
antibacterial drugs, Metronidazole Injection, USP RTU should be used only to treat or prevent infections that are proven or strongly
suspected to be caused by bacteria.
Description
Metronidazole Injection, USP RTU, is a parenteral dosage form of the synthetic antibacterial agent 1-(ß-hydroxyethyl)-2-methyl-5-
nitroimidazole.
[CHEMICAL SYMBOL GOES HERE]
Metronidazole, USP
Metronidazole Injection, USP RTU, in 100 mL VIAFLEX Plus single dose plastic container, is a sterile, nonpyrogenic, iso-osmotic, buffered
solution of 500 mg Metronidazole, USP, 790 mg Sodium Chloride, USP, 47.6 mg Dibasic Sodium Phosphate Dried, USP and 22.9 mg Citric
Acid Anhydrous, USP. Metronidazole Injection, USP RTU has an osmolarity of 310 mOsmol/L (calc) and a pH of 5.5 (4.5 to 7.0). Each
container contains 14 mEq of sodium.
The plastic container is fabricated from a specially formulated polyvinyl chloride plastic. Water can permeate from inside the container into
the overwrap in amounts insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of
its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million.
However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as
by tissue culture toxicity studies.
Clinical Pharmacology
Metronidazole is a synthetic antibacterial compound. Disposition of metronidazole in the body is similar for both oral and intravenous
dosage forms, with an average elimination half-life in healthy humans of eight hours.
The major route of elimination of metronidazole and its metabolites is via the urine (60-80% of the dose), with fecal excretion accounting for
6-15% of the dose. The metabolites that appear in the urine result primarily from side-chain oxidation [1-(ß-hydroxyethyl)-2-hydroxymethyl-
5-nitroimidazole and 2-methyl-5-nitroimidazole-1-yl-acetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for
approximately 20% of the total. Renal clearance of metronidazole is approximately 10 mL/min/1.73 m
2.
Metronidazole is the major component appearing in the plasma, with lesser quantities of the 2-hydroxymethyl metabolite also being
present. Less than 20% of the circulating metronidazole is bound to plasma proteins. Both the parent compound and the metabolite
possess in vitro bactericidal activity against most strains of anaerobic bacteria.
Metronidazole appears in cerebrospinal fluid, saliva and breast milk in concentrations similar to those found in plasma. Bactericidal
concentrations of metronidazole have also been detected in pus from hepatic abscesses.
Plasma concentrations of metronidazole are proportional to the administered dose. An eight-hour intravenous infusion of 100-4,000 mg of
metronidazole in normal subjects showed a linear relationship between dose and peak plasma concentration.
In patients treated with intravenous metronidazole, using a dosage regimen of 15 mg/kg loading dose followed six hours later by 7.5 mg/kg
every six hours, peak steady-state plasma concentrations of metronidazole averaged 25 mcg/mL with trough (minimum) concentrations
averaging 18 mcg/mL.
Decreased renal function does not alter the single-dose pharmacokinetics of metronidazole. However, plasma clearance of metronidazole
is decreased in patients with decreased liver function.
In one study newborn infants appeared to demonstrate diminished capacity to eliminate metronidazole. The elimination half-life, measured
during the first three days of life, was inversely related to gestational age. In infants whose gestational ages were between 28 and 40
weeks, the corresponding elimination half-lives ranged from 109 to 22.5 hours.
Microbiology: Metronidazole is active in vitro against most obligate anaerobes, but does not appear to possess any clinically relevant
activity against facultative anaerobes or obligate aerobes. Against susceptible organisms, metronidazole is generally bactericidal at
Warning
Metronidazole has been shown to be carcinogenic in mice and rats (see Precautions). Its
use, therefore, should be reserved for the conditions described in the Indications and
Usage section below.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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concentrations equal to or slightly higher than the minimal inhibitory concentrations. Metronidazole has been shown to have in vitro and
clinical activity against the following organisms:
Anaerobic gram-negative bacilli, including:
Bacteroides species, including the Bacteroides fragilis group (B. fragilis, B. distasonis, B. ovatus,
B. thetaiotaomicron, B. vulgatus)
Fusobacterium species
Anaerobic gram-positive bacilli, including:
Clostridium species and susceptible strains of Eubacterium
Anaerobic gram-positive cocci, including:
Peptococcus species
Peptostreptococcus species
Susceptibility Tests: Bacteriologic studies should be performed to determine the causative organisms and their susceptibility to
metronidazole; however, the rapid, routine susceptibility testing of individual isolates of anaerobic bacteria is not always practical, and
therapy may be started while awaiting these results.
Quantitative methods give the most accurate estimates of susceptibility to antibacterial drugs. A standardized agar dilution method and a
broth microdilution method are recommended
1.
Control strains are recommended for standardized susceptibility testing. Each time the test is performed, one or more of the following
strains should be included: Eubacterium lentum ATCC 43055, Bacteroides fragilis ATCC 25285, and Bacteroides thetaiotaomicron ATCC
29741. The mode metronidazole MICs for those three strains are reported to be 0.125,0.25, and 0.5 mcg/mL, respectively.
A clinical laboratory test is considered under acceptable control if the results of the control strains are within one doubling dilution of the
mode MICs reported for metronidazole.
A bacterial isolate may be considered susceptible if the MIC value for metronidazole is not more than 16 mcg/mL. An organism is
considered resistant if the MIC is greater than 16 mcg/mL. A report of "resistant" from the laboratory indicates that the infecting organism is
not likely to respond to therapy.
Indications and Usage
Treatment of Anaerobic Infections
Metronidazole Injection, USP RTU is indicated in the treatment of serious infections caused by susceptible anaerobic bacteria. Indicated
surgical procedures should be performed in conjunction with Metronidazole Injection, USP RTU® therapy. In a mixed aerobic and anaerobic
infection, antibiotics appropriate for the treatment of the aerobic infection should be used in addition to Metronidazole Injection, USP RTU.
Metronidazole Injection, USP RTU is effective in Bacteroides fragilis infections resistant to clindamycin, chloramphenicol and penicillin.
Intra-Abdominal Infections, including peritonitis, intra-abdominal abscess and liver abscess, caused by Bacteroides species including the
B. fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus), Clostridium species, Eubacterium species,
Peptococcus species and Peptostreptococcus species.
Skin and Skin Structure Infections caused by Bacteroides species including the B. fragilis group, Clostridium species, Peptococcus
species, Peptostreptococcus species and Fusobacterium species.
Gynecologic Infections, including endometritis, endomyometritis, tubo-ovarian abscess and postsurgical vaginal cuff infection, caused by
Bacteroides species including the B. fragilis group, Clostridium species, Peptostreptococcus species and Fusobacterium species.
Bacterial Septicemia caused by Bacteroides species including the B. fragilis group and Clostridium species.
Bone and Joint Infections, as adjunctive therapy, caused by Bacteroides species including the B. fragilis group.
Central Nervous System (CNS) Infections, including meningitis and brain abscess, caused by Bacteroides species including the B.
fragilis group.
Lower Respiratory Tract Infections, including pneumonia, empyema and lung abscess, caused by Bacteroides species including the B.
fragilis group.
Endocarditis caused by Bacteroides species including the B. fragilis group.
Prophylaxis
The prophylactic administration of Metronidazole Injection, USP RTU preoperatively, intraoperatively and postoperatively may reduce the
incidence of postoperative infection in patients undergoing elective colorectal surgery which is classified as contaminated or potentially
contaminated.
Prophylactic use of Metronidazole Injection, USP RTU should be discontinued within 12 hours after surgery. If there are signs of infection,
specimens for cultures should be obtained for the identification of the causative organism(s) so that appropriate therapy may be given (see
Dosage and Administration).
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Metronidazole Injection, USP RTU and other
antibacterial drugs, Metronidazole Injection, USP RTU should be used only to treat or prevent infections that are proven or strongly
suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in
selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to
the empiric selection of therapy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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Contraindications
Metronidazole Injection, USP RTU is contraindicated in patients with a prior history of hypersensitivity to metronidazole or other
nitroimidazole derivatives.
Warnings
Convulsive Seizures and Peripheral Neuropathy
Convulsive seizures and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity, have been
reported in patients treated with metronidazole. The appearance of abnormal neurologic signs demands the prompt evaluation of the
benefit/risk ratio of the continuation of therapy.
Precautions
General
Patients with severe hepatic disease metabolize metronidazole slowly, with resultant accumulation of metronidazole and its metabolites in
the plasma. Accordingly, for such patients, doses below those usually recommended should be administered cautiously.
Administration of solutions containing sodium ions may result in sodium retention. Care should be taken when administering Metronidazole
Injection, USP RTU to patients receiving corticosteroids or to patients predisposed to edema.
Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with Metronidazole Injection, USP
RTU and requires treatment with a candicidal agent.
Prescribing Metronidazole Injection, USP RTU in the absence of a proven or strongly suspected bacterial infection or a prophylactic
indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Laboratory Tests
Metronidazole is a nitroimidazole, and should be used with care in patients with evidence of or history of blood dyscrasia. A mild leukopenia
has been observed during its administration; however, no persistent hemotologic abnormalities attributable to metronidazole have been
observed in clinical studies. Total and differential leukocyte counts are recommended before and after therapy.
Drug Interactions
Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a
prolongation of prothrombin time. This possible drug interaction should be considered when Metronidazole Injection, USP RTU is
prescribed for patients on this type of anticoagulant therapy.
The simultaneous administration of drugs that induce microsomal liver enzyme activity, such as phenytoin or phenobarbital, may accelerate
the elimination of metronidazole, resulting in reduced plasma levels; impaired clearance of phenytoin has also been reported.
The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may prolong the half-life and
decrease plasma clearance of metronidazole.
Alcoholic beverages should not be consumed during metronidazole therapy because abdominal cramps, nausea, vomiting, headaches and
flushing may occur.
Psychotic reactions have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. Metronidazole
should not be given to patients who have taken disulfiram within the last two weeks.
Drug/Laboratory Test Interactions
Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST,
SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides and hexokinase glucose. Values of zero may
be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of
nicotine adenine dinucleotide (NAD+ ⇄ NADH). Interference is due to the similarity in absorbance peaks of NADH (340nm) and
metronidazole (322nm) at pH 7.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Tumorigenicity in Rodents - Metronidazole has shown evidence of carcinogenic activity in studies involving chronic, oral administration in
mice and rats, but similar studies in the hamster gave negative results. Also, metronidazole has shown mutagenic activity in a number of in
vitro assay systems, but studies in mammals (in vivo) failed to demonstrate a potential for genetic damage.
Pregnancy: Teratogenic Effects
Pregnancy Category B. Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. Reproduction studies have been
performed in rats at doses up to five times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to
metronidazole. Metronidazole administered intraperitoneally to pregnant mice at approximately the human dose caused fetotoxicity;
administered orally to pregnant mice, no fetotoxicity was observed. There are, however, no adequate and well-controlled studies in
pregnant women. Because animal reproduction studies are not always predictive of human response, and because metronidazole is a
carcinogen in rodents, these drugs should be used during pregnancy only if clearly needed.
Nursing Mothers
Because of the potential for tumorigenicity shown for metronidazole in mouse and rat studies, a decision should be made whether to
discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Metronidazole is secreted in
breast milk in concentrations similar to those found in plasma.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Information for Patients
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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Patients should be counseled that antibacterial drugs including Metronidazole Injection, USP RTU should only be used to treat bacterial
infections. They do not treat viral infections (e.g., the common cold). When Metronidazole Injection, USP RTU is prescribed to treat a
bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be
taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate
treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Metronidazole Injection, USP
RTU or other antibacterial drugs in the future.
Adverse Reactions
Two serious adverse reactions reported in patients treated with intravenous metronidazole have been convulsive seizures and peripheral
neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity. Since persistent peripheral neuropathy has been
reported in some patients receiving prolonged oral administration of metronidazole, patients should be observed carefully if neurologic
symptoms occur and a prompt evaluation made of the benefit/risk ratio of the continuation of therapy.
The following reactions have also been reported during treatment with Metronidazole Injection, USP RTU.
Gastrointestinal: Nausea, vomiting, abdominal discomfort, diarrhea and an unpleasant metallic taste.
Hematopoietic: Reversible neutropenia (leukopenia).
Dermatologic: Erythematous rash and pruritus.
Central Nervous System: Headache, dizziness, syncope, ataxia and confusion.
Local Reactions: Thrombophlebitis after intravenous infusion. This reaction can be minimized or avoided by avoiding prolonged use of
indwelling intravenous catheters.
Other: Fever. Instances of a darkened urine have also been reported, and this manifestation has been the subject of a special investigation.
Although the pigment which is probably responsible for this phenomenon has not been positively identified, it is almost certainly a
metabolite of metronidazole and seems to have no clinical significance.
The following adverse reactions have been reported during treatment with oral metronidazole:
Gastrointestinal: Nausea, sometimes accompanied by headache, anorexia and occasionally vomiting; diarrhea, epigastric distress,
abdominal cramping and constipation.
Mouth: A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis and stomatitis have occurred; these may be associated
with a sudden overgrowth of Candida which may occur during effective therapy.
Hematopoietic: Reversible neutropenia (leukopenia); rarely, reversible thrombocytopenia.
Cardiovascular: Flattening of the T-wave may be seen in electrocardiographic tracings.
Central Nervous System: Convulsive seizures, peripheral neuropathy, dizziness, vertigo, incoordination, ataxia, confusion, irritability,
depression, weakness and insomnia.
Hypersensitivity: Urticaria, erythematous rash, flushing, nasal congestion, dryness of the mouth (or vagina or vulva) and fever.
Renal: Dysuria, cystitis, polyuria, incontinence, a sense of pelvic pressure and darkened urine.
Other: Proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis and fleeting joint pains sometimes resembling
“serum sickness.” If patients receiving metronidazole drink alcoholic beverages, they may experience abdominal distress, nausea, vomiting,
flushing or headache. A modification of the taste of alcoholic beverages has also been reported. Rare cases of pancreatitis, which abated
on withdrawal of the drug, have been reported.
Crohn's disease patients are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers. There have been
some reports in the medical literature of breast and colon cancer in Crohn's disease patients who have been treated with metronidazole at
high doses for extended periods of time. A cause and effect relationship has not been established. Crohn's disease is not an approved
indication for Metronidazole Injection, USP RTU.
Overdosage
Use of dosages of intravenous metronidazole higher than those recommended has been reported. These include the use of 27 mg/kg three
times a day for 20 days, and the use of 75 mg/kg as a single loading dose followed by 7.5 mg/kg maintenance doses. No adverse reactions
were reported in either of the two cases.
Single oral dose of metronidazole, up to 15 g, have been reported in suicide attempts and accidental overdoses. Symptoms reported
included nausea, vomiting and ataxia.
Oral metronidazole has been studied as a radiation sensitizer in the treatment of malignant tumors. Neurotoxic effects, including seizures
and peripheral neuropathy, have been reported after 5 to 7 days of doses of 6 to 10.4 g every other day.
Treatment: There is no specific antidote for overdose; therefore, management of the patient should consist of symptomatic and supportive
therapy.
Dosage and Administration
In elderly patients the pharmacokinetics of metronidazole may be altered and therefore monitoring of serum levels may be necessary to
adjust the metronidazole dosage accordingly.
Treatment of Anaerobic Infections
The recommended dosage schedule for adults is:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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Loading Dose
15 mg/kg infused over one hour (approximately 1 g for a 70-kg adult).
Maintenance Dose
7.5 mg/kg infused over one hour every six hours (approximately 500 mg for a
70-kg adult). The first maintenance dose should be instituted six hours
following the initiation of the loading dose.
Parenteral therapy may be changed to oral metronidazole when conditions warrant, based upon the severity of the disease and the
response of the patient to Metronidazole Injection, USP RTU treatment. The usual adult oral dosage is 7.5 mg/kg every six hours.
A maximum of 4 g should not be exceeded during a 24-hour period.
Patients with severe hepatic disease metabolize metronidazole slowly, with resultant accumulation of metronidazole and its metabolites in
the plasma. Accordingly, for such patients, doses below those usually recommended should be administered cautiously. Close monitoring
of plasma metronidazole levels
2
and toxicity is recommended.
In patients receiving Metronidazole Injection, USP RTU in whom gastric secretions are continuously removed by nasogastric aspiration,
sufficient metronidazole may be removed in the aspirate to cause a reduction in serum levels.
The dose of Metronidazole Injection, USP RTU should not be specifically reduced in anuric patients since accumulated metabolites may
be rapidly removed by dialysis.
The usual duration of therapy is 7 to 10 days; however, infections of the bone and joint, lower respiratory tract and endocardium may
require longer treatment.
Prophylaxis
For surgical prophylactic use, to prevent postoperative infection in contaminated or potentially contaminated colorectal surgery, the
recommended dosage schedule for adults is:
a. 15 mg/kg infused over 30 to 60 minutes and completed approximately one hour before surgery;
followed by
b. 7.5 mg/kg infused over 30 to 60 minutes at 6 and 12 hours after the initial dose.
It is important that (1) administration of the initial preoperative dose be completed approximately one hour before surgery so that adequate
drug levels are present in the serum and tissues at the time of initial incision, and (2) Metronidazole Injection, USP RTU be administered, if
necessary, at 6-hour intervals to maintain effective drug levels. Prophylactic use of Metronidazole Injection, USP RTU should be limited to
the day of surgery only, following the above guidelines.
Caution: Metronidazole Injection, USP RTU is to be administered by slow intravenous drip infusion only, either as a continuous
or intermittent infusion. Additives should not be introduced into Metronidazole Injection, USP RTU. If used with a primary
intravenous fluid system, the primary solution should be discontinued during metronidazole infusion. DO NOT USE EQUIPMENT
CONTAINING ALUMINUM (e.g., NEEDLES, CANNULAE) THAT WOULD COME IN CONTACT WITH THE DRUG SOLUTION.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and
container permit.
How Supplied
Metronidazole Injection, USP RTU is supplied in 100 mL single dose plastic containers, each containing an iso-osmotic, buffered solution
of 500 mg metronidazole as follows:
2B3421 NDC 0338-1055-48 500 mg/100 mL
Store at controlled room temperature, 59° to 86°F (15° to 30°C) and protect from light during storage. Do not remove unit from overwrap
until ready for use. The overwrap is a moisture barrier. The inner bag maintains the sterility of the product. After removing overwrap, check
for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
Directions for Use of VIAFLEX Plus Plastic Container
Metronidazole Injection, USP RTU is a ready-to-use iso-osmotic solution. No dilution or buffering is required. Do not refrigerate. Each
container of Metronidazole Injection, USP RTU contains 14 mEq of sodium.
Warning: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from
the primary container before administration of the fluid from the secondary container is completed.
To open
Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the
sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually.
Check for leaks. Do not add supplementary medication.
Preparation for Administration
1. Suspend container from eyelet support.
2. Remove plastic protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
References
1.
M11-A5-Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; approved Standard-Fifth Edition, National Committee
for Clinical Laboratory Standards; and Sutter, et al.: Collaborative Evaluation of a Proposed Reference Dilution Method of
Susceptibility Testing of Anaerobic Bacteria, Antimicrob. Agents Chemother. 16:495-502 (Oct.) 1979; and Tally, et al.: In Vitro Activity
of Thienamycin, Antimicrob. Agents Chemother. 14:436-438 (Sept.) 1978.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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Page 6 of 6
2.
Ralph, E.D. and Kirby, W.M.M.: Bioassay of Metronidazole with Either Anaerobic and Aerobic Incubation, J. Infect. Dis. 132:587-591
(Nov.) 1975; or Gulaid, et al.: Determination of Metronidazole and its Major Metabolites in Biological Fluids by High Pressure Liquid
Chromatography. BR.J.Clin. Pharmacol. 6:430-432, 1978.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*BAR CODE POSITION ONLY
71938189
©Copyright 1990, 1993, Baxter Healthcare Corporation.
All rights reserved.
BAXTER and VIAFLEX are trademarks of Baxter International Inc.
Metronidazole Injection, USP RTU is manufactured under sublicense from SCS Pharmaceuticals, Chicago, IL 60680
by Baxter Healthcare Corporation, Deerfield, IL 60015
07-19-38-189
Rev. June, 2003
*BAR CODE POSITION ONLY
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:49.164398
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/18657slr026,027_metronidazole_lbl.pdf', 'application_number': 18657, 'submission_type': 'SUPPL ', 'submission_number': 27}
|
11,260
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NDA 18-651/S-025 and S-026
Page 3
MARINOL®
(dronabinol)
Capsules
DESCRIPTION
Dronabinol is a cannabinoid designated chemically as (6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-
trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol. Dronabinol has the following empirical and structural
formulas:
Dronabinol, the active ingredient in MARINOL® (dronabinol) Capsules, is synthetic delta-9-
tetrahydrocannabinol (delta-9-THC). Delta-9-tetrahydrocannabinol is also a naturally occurring
component of Cannabis sativa L. (Marijuana).
Dronabinol is a light yellow resinous oil that is sticky at room temperature and hardens upon
refrigeration. Dronabinol is insoluble in water and is formulated in sesame oil. It has a pKa of 10.6 and
an octanol-water partition coefficient: 6,000:1 at pH 7.
Capsules for oral administration: MARINOL Capsules is supplied as round, soft gelatin capsules
containing either 2.5 mg, 5 mg, or 10 mg dronabinol. Each MARINOL Capsule strength is formulated
with the following inactive ingredients: 2.5 mg capsule contains gelatin, glycerin, sesame oil, and
titanium dioxide; 5 mg capsule contains iron oxide red and iron oxide black, gelatin, glycerin, sesame
oil, and titanium dioxide; 10 mg capsule contains iron oxide red and iron oxide yellow, gelatin,
glycerin, sesame oil, and titanium dioxide.
CLINICAL PHARMACOLOGY
Dronabinol is an orally active cannabinoid which, like other cannabinoids, has complex effects on the
central nervous system (CNS), including central sympathomimetic activity. Cannabinoid receptors
have been discovered in neural tissues. These receptors may play a role in mediating the effects of
dronabinol and other cannabinoids.
Pharmacodynamics
Dronabinol-induced sympathomimetic activity may result in tachycardia and/or conjunctival injection.
Its effects on blood pressure are inconsistent, but occasional subjects have experienced orthostatic
hypotension and/or syncope upon abrupt standing.
NDA 18-651/S-025 and S-026
Page 4
Dronabinol also demonstrates reversible effects on appetite, mood, cognition, memory, and
perception. These phenomena appear to be dose-related, increasing in frequency with higher dosages,
and subject to great interpatient variability.
After oral administration, dronabinol has an onset of action of approximately 0.5 to 1 hours and
peak effect at 2 to 4 hours. Duration of action for psychoactive effects is 4 to 6 hours, but the appetite
stimulant effect of dronabinol may continue for 24 hours or longer after administration.
Tachyphylaxis and tolerance develop to some of the pharmacologic effects of dronabinol and other
cannabinoids with chronic use, suggesting an indirect effect on sympathetic neurons. In a study of the
pharmacodynamics of chronic dronabinol exposure, healthy male volunteers (N = 12) received 210
mg/day dronabinol, administered orally in divided doses, for 16 days. An initial tachycardia induced
by dronabinol was replaced successively by normal sinus rhythm and then bradycardia. A decrease in
supine blood pressure, made worse by standing, was also observed initially. These volunteers
developed tolerance to the cardiovascular and subjective adverse CNS effects of dronabinol within 12
days of treatment initiation.
Tachyphylaxis and tolerance do not, however, appear to develop to the appetite stimulant effect of
MARINOL Capsules. In studies involving patients with Acquired Immune Deficiency Syndrome
(AIDS), the appetite stimulant effect of MARINOL Capsules has been sustained for up to five months
in clinical trials, at dosages ranging from 2.5 mg/day to 20 mg/day.
Pharmacokinetics
Absorption and Distribution: MARINOL Capsules is almost completely absorbed (90 to 95%)
after single oral doses. Due to the combined effects of first pass hepatic metabolism and high lipid
solubility, only 10 to 20% of the administered dose reaches the systemic circulation. Dronabinol has a
large apparent volume of distribution, approximately 10 L/kg, because of its lipid solubility. The
plasma protein binding of dronabinol and its metabolites is approximately 97%.
The elimination phase of dronabinol can be described using a two compartment model with an
initial (alpha) half-life of about 4 hours and a terminal (beta) half-life of 25 to 36 hours. Because of its
large volume of distribution, dronabinol and its metabolites may be excreted at low levels for
prolonged periods of time.
The pharmacokinetics of dronabinol after single doses (2.5, 5, and 10 mg) and multiple doses (2.5,
5, and 10 mg given twice a day; BID) have been studied in healthy women and men.
Summary of Multiple-Dose Pharmacokinetic Parameters of Dronabinol
in Healthy Volunteers (n=34; 20-45 years) under Fasted Conditions
Mean (SD) PK Parameter Values
BID
Dose
Cmax
ng/mL
Median Tmax
(range), hr
AUC(0-12)
ng•hr/mL
2.5 mg
1.32 (0.62)
1.00 (0.50-4.00)
2.88 (1.57)
5 mg
2.96 (1.81)
2.50 (0.50-4.00)
6.16 (1.85)
10 mg
7.88 (4.54)
1.50 (0.50-3.50)
15.2 (5.52)
A slight increase in dose proportionality on mean Cmax and AUC(0-12) of dronabinol was
observed with increasing dose over the dose range studied.
NDA 18-651/S-025 and S-026
Page 5
Metabolism: Dronabinol undergoes extensive first-pass hepatic metabolism, primarily by
microsomal hydroxylation, yielding both active and inactive metabolites. Dronabinol and its principal
active metabolite, 11-OH-delta-9-THC, are present in approximately equal concentrations in plasma.
Concentrations of both parent drug and metabolite peak at approximately 0.5 to 4 hours after oral
dosing and decline over several days. Values for clearance average about 0.2 L/kg-hr, but are highly
variable due to the complexity of cannabinoid distribution.
Elimination: Dronabinol and its biotransformation products are excreted in both feces and urine.
Biliary excretion is the major route of elimination with about half of a radio-labeled oral dose being
recovered from the feces within 72 hours as contrasted with 10 to 15% recovered from urine. Less than
5% of an oral dose is recovered unchanged in the feces.
Following single dose administration, low levels of dronabinol metabolites have been detected for
more than 5 weeks in the urine and feces.
In a study of MARINOL Capsules involving AIDS patients, urinary cannabinoid/creatinine
concentration ratios were studied bi-weekly over a six week period. The urinary cannabinoid/creatinine
ratio was closely correlated with dose. No increase in the cannabinoid/creatinine ratio was observed
after the first two weeks of treatment, indicating that steady-state cannabinoid levels had been reached.
This conclusion is consistent with predictions based on the observed terminal half-life of dronabinol.
Special Populations: The pharmacokinetic profile of MARINOL Capsules has not been
investigated in either pediatric or geriatric patients.
Clinical Trials
Appetite Stimulation: The appetite stimulant effect of MARINOL Capsules in the treatment of
AIDS-related anorexia associated with weight loss was studied in a randomized, double-blind,
placebo-controlled study involving 139 patients. The initial dosage of MARINOL Capsules in all
patients was 5 mg/day, administered in doses of 2.5 mg one hour before lunch and one hour before
supper. In pilot studies, early morning administration of MARINOL Capsules appeared to have been
associated with an increased frequency of adverse experiences, as compared to dosing later in the day.
The effect of MARINOL Capsules on appetite, weight, mood, and nausea was measured at scheduled
intervals during the six-week treatment period. Side effects (feeling high, dizziness, confusion,
somnolence) occurred in 13 of 72 patients (18%) at this dosage level and the dosage was reduced to
2.5 mg/day, administered as a single dose at supper or bedtime.
Of the 112 patients that completed at least 2 visits in the randomized, double-blind, placebo-
controlled study, 99 patients had appetite data at 4-weeks (50 received MARINOL and 49 received
placebo) and 91 patients had appetite data at 6-weeks (46 received MARINOL and 45 received
placebo). A statistically significant difference between MARINOL Capsules and placebo was seen in
appetite as measured by the visual analog scale at weeks 4 and 6 (see figure). Trends toward improved
body weight and mood, and decreases in nausea were also seen.
After completing the 6-week study, patients were allowed to continue treatment with MARINOL
Capsules in an open-label study, in which there was a sustained improvement in appetite.
NDA 18-651/S-025 and S-026
Page 6
Antiemetic: MARINOL Capsules treatment of chemotherapy-induced emesis was evaluated in 454
patients with cancer, who received a total of 750 courses of treatment of various malignancies. The
antiemetic efficacy of MARINOL Capsules was greatest in patients receiving cytotoxic therapy with
MOPP for Hodgkin’s and non-Hodgkin’s lymphomas. MARINOL Capsules dosages ranged from 2.5
mg/day to 40 mg/day, administered in equally divided doses every four to six hours (four times daily).
As indicated in the following table, escalating the MARINOL Capsules dose above 7 mg/m2 increased
the frequency of adverse experiences, with no additional antiemetic benefit.
MARINOL Capsules Dose: Response Frequency and Adverse Experiences*
(N = 750 treatment courses)
Response Frequency (%)
Adverse Events Frequency (%)
MARINOL Capsules
Dose
Complete
Partial
Poor
None
Nondysphoric
Dysphoric
<7 mg/m2
36
32
32
23
65
12
>7 mg/m2
33
31
36
13
58
28
*Nondysphoric events consisted of drowsiness, tachycardia, etc.
Combination antiemetic therapy with MARINOL Capsules and a phenothiazine (prochlorperazine)
may result in synergistic or additive antiemetic effects and attenuate the toxicities associated with each
of the agents.
INDIVIDUALIZATION OF DOSAGES
The pharmacologic effects of MARINOL Capsules are dose-related and subject to considerable
interpatient variability. Therefore, dosage individualization is critical in achieving the maximum
benefit of MARINOL Capsules treatment.
Appetite Stimulation: In the clinical trials, the majority of patients were treated with 5 mg/day
MARINOL Capsules, although the dosages ranged from 2.5 to 20 mg/day. For an adult:
NDA 18-651/S-025 and S-026
Page 7
1. Begin with 2.5 mg before lunch and 2.5 mg before supper. If CNS symptoms (feeling high,
dizziness, confusion, somnolence) do occur, they usually resolve in 1 to 3 days with continued
dosage.
2. If CNS symptoms are severe or persistent, reduce the dose to 2.5 mg before supper. If symptoms
continue to be a problem, taking the single dose in the evening or at bedtime may reduce their
severity.
3. When adverse effects are absent or minimal and further therapeutic effect is desired, increase the
dose to 2.5 mg before lunch and 5 mg before supper or 5 and 5 mg. Although most patients
respond to 2.5 mg twice daily, 10 mg twice daily has been tolerated in about half of the patients in
appetite stimulation studies.
The pharmacologic effects of MARINOL Capsules are reversible upon treatment cessation.
Antiemetic: Most patients respond to 5 mg three or four times daily. Dosage may be escalated
during a chemotherapy cycle or at subsequent cycles, based upon initial results. Therapy should be
initiated at the lowest recommended dosage and titrated to clinical response. Administration of
MARINOL Capsules with phenothiazines, such as prochlorperazine, has resulted in improved efficacy
as compared to either drug alone, without additional toxicity.
Pediatrics: MARINOL Capsules is not recommended for AIDS-related anorexia in pediatric patients
because it has not been studied in this population. The pediatric dosage for the treatment of
chemotherapy-induced emesis is the same as in adults. Caution is recommended in prescribing
MARINOL Capsules for children because of the psychoactive effects.
Geriatrics: Caution is advised in prescribing MARINOL Capsules in elderly patients because they
may be more sensitive to the neurological, psychoactive and postural hypotensive effects of the drug.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of
the dosing range (See PRECAUTIONS.)
MARINOL Capsules should be used with caution when administered to elderly patients with dementia,
who are at increased risk for falls as a result of their underlying disease state which may be
exacerbated by the central nervous system effects of somnolence and dizziness associated with
MARINOL Capsules. These patients should be monitored closely and placed on fall precautions prior
to initiating MARINOL therapy. In antiemetic studies, no difference in efficacy was apparent in
patients >55 years old.
INDICATIONS AND USAGE
MARINOL Capsules is indicated for the treatment of:
1. anorexia associated with weight loss in patients with AIDS; and
2. nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond
adequately to conventional antiemetic treatments.
CONTRAINDICATIONS
MARINOL Capsules is contraindicated in any patient who has a known sensitivity to MARINOL
Capsules or any of its ingredients. It contains cannabinoid and sesame oil and should never be used by
patients allergic to these substances.
NDA 18-651/S-025 and S-026
Page 8
WARNINGS
Patients receiving treatment with MARINOL Capsules should be specifically warned not to drive,
operate machinery, or engage in any hazardous activity until it is established that they are able to
tolerate the drug and to perform such tasks safely.
PRECAUTIONS
General: The risk/benefit ratio of MARINOL Capsules use should be carefully evaluated in patients
with the following medical conditions because of individual variation in response and tolerance to the
effects of MARINOL Capsules.
Seizure and seizure-like activity have been reported in patients receiving MARINOL Capsules
during marketed use of the drug and in clinical trials. (See ADVERSE REACTIONS and
OVERDOSAGE.) MARINOL Capsules should be used with caution in patients with a history of
seizure disorder because MARINOL Capsules may lower the seizure threshold. A causal relationship
between MARINOL Capsules and these events has not been established. MARINOL Capsules should
be discontinued immediately in patients who develop seizures and medical attention should be sought
immediately.
MARINOL Capsules should be used with caution in patients with cardiac disorders because of
occasional hypotension, possible hypertension, syncope, or tachycardia. (See CLINICAL
PHARMACOLOGY.)
MARINOL Capsules should be used with caution in patients with a history of substance abuse,
including alcohol abuse or dependence, because they may be more prone to abuse MARINOL
Capsules as well. Multiple substance abuse is common and marijuana, which contains the same active
compound, is a frequently abused substance.
MARINOL Capsules should be used with caution and careful psychiatric monitoring in patients
with mania, depression, or schizophrenia because MARINOL Capsules may exacerbate these illnesses.
MARINOL Capsules should be used with caution in patients receiving concomitant therapy with
sedatives, hypnotics or other psychoactive drugs because of the potential for additive or synergistic
CNS effects.
MARINOL Capsules should be used with caution in elderly patients because they may be more
sensitive to the neurological, psychoactive, and postural hypotensive effects of the drug.(See
INDIVIDUALIZATION OF DOSAGES.)
MARINOL Capsules should be used with caution in pregnant patients, nursing mothers, or
pediatric patients because it has not been studied in these patient populations.
Information for Patients: Patients receiving treatment with MARINOL Capsules should be alerted
to the potential for additive central nervous system depression if MARINOL Capsules is used
concomitantly with alcohol or other CNS depressants such as benzodiazepines and barbiturates.
Patients receiving treatment with MARINOL Capsules should be specifically warned not to drive,
operate machinery, or engage in any hazardous activity until it is established that they are able to
tolerate the drug and to perform such tasks safely.
NDA 18-651/S-025 and S-026
Page 9
Patients using MARINOL Capsules should be advised of possible changes in mood and other
adverse behavioral effects of the drug so as to avoid panic in the event of such manifestations. Patients
should remain under the supervision of a responsible adult during initial use of MARINOL Capsules
and following dosage adjustments.
Drug Interactions: In studies involving patients with AIDS and/or cancer, MARINOL Capsules has
been co-administered with a variety of medications (e.g., cytotoxic agents, anti-infective agents,
sedatives, or opioid analgesics) without resulting in any clinically significant drug/drug interactions.
Although no drug/drug interactions were discovered during the clinical trials of MARINOL Capsules,
cannabinoids may interact with other medications through both metabolic and pharmacodynamic
mechanisms. Dronabinol is highly protein bound to plasma proteins, and therefore, might displace
other protein-bound drugs. Although this displacement has not been confirmed in vivo, practitioners
should monitor patients for a change in dosage requirements when administering dronabinol to patients
receiving other highly protein-bound drugs. Published reports of drug/drug interactions involving
cannabinoids are summarized in the following table.
CONCOMITANT DRUG
CLINICAL EFFECT(S)
Amphetamines, cocaine, other
sympathomimetic agents
Additive hypertension, tachycardia,
possibly cardiotoxicity
Atropine, scopolamine, antihistamines,
other anticholinergic agents
Additive or super-additive tachycardia,
drowsiness
Amitriptyline, amoxapine, desipramine,
other tricyclic antidepressants
Additive tachycardia, hypertension,
drowsiness
Barbiturates, benzodiazepines, ethanol,
lithium, opioids, buspirone, antihistamines,
muscle relaxants, other CNS depressants
Additive drowsiness and CNS depression
Disulfiram
A reversible hypomanic reaction was
reported in a 28 y/o man who smoked
marijuana; confirmed by dechallenge and
rechallenge
Fluoxetine
A 21 y/o female with depression and
bulimia receiving 20 mg/day fluoxetine X
4 wks became hypomanic after smoking
marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates
Decreased clearance of these agents,
presumably via competitive inhibition of
metabolism
Theophylline
Increased theophylline metabolism
reported with smoking of marijuana; effect
similar to that following smoking tobacco
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies in mice and
rats have been conducted under the US National Toxicology Program (NTP). In the 2-year
carcinogenicity study in rats, there was no evidence of carcinogenicity at doses up to 50 mg/kg/day,
about 20 times the maximum recommended human dose on a body surface area basis. In the 2-year
carcinogenicity study in mice, treatment with dronabinol at 125 mg/kg/day, about 25 times the
NDA 18-651/S-025 and S-026
Page 10
maximum recommended human dose on a body surface area basis, produced thyroid follicular cell
adenoma in both male and female mice but not at 250 or 500 mg/kg/day.
Dronabinol was not genotoxic in the Ames tests, the in vitro chromosomal aberration test in
Chinese hamster ovary cells, and the in vivo mouse micronucleus test. It, however, produced a weak
positive response in a sister chromatid exchange test in Chinese hamster ovary cells.
In a long-term study (77 days) in rats, oral administration of dronabinol at doses of 30 to 150
mg/m2, equivalent to 0.3 to 1.5 times maximum recommended human dose (MRHD) of 90 mg/m2/day
in cancer patients or 2 to 10 times MRHD of 15 mg/m2/day in AIDS patients, reduced ventral prostate,
seminal vesicle and epididymal weights and caused a decrease in seminal fluid volume. Decreases in
spermatogenesis, number of developing germ cells, and number of Leydig cells in the testis were also
observed. However, sperm count, mating success and testosterone levels were not affected. The
significance of these animal findings in humans is not known.
Pregnancy: Pregnancy Category C. Reproduction studies with dronabinol have been performed in
mice at 15 to 450 mg/m2, equivalent to 0.2 to 5 times maximum recommended human dose (MRHD)
of 90 mg/m2/day in cancer patients or 1 to 30 times MRHD of 15 mg/m2/day in AIDS patients, and in
rats at 74 to 295 mg/m2 (equivalent to 0.8 to 3 times MRHD of 90 mg/m2 in cancer patients or 5 to 20
times MRHD of 15 mg/m2/day in AIDS patients). These studies have revealed no evidence of
teratogenicity due to dronabinol. At these dosages in mice and rats, dronabinol decreased maternal
weight gain and number of viable pups and increased fetal mortality and early resorptions. Such effects
were dose dependent and less apparent at lower doses which produced less maternal toxicity. There are
no adequate and well-controlled studies in pregnant women. Dronabinol should be used only if the
potential benefit justifies the potential risk to the fetus.
Nursing Mothers: Use of MARINOL Capsules is not recommended in nursing mothers since, in
addition to the secretion of HIV virus in breast milk, dronabinol is concentrated in and secreted in
human breast milk and is absorbed by the nursing baby.
Geriatric Use: Clinical studies of MARINOL Capsules in AIDS and cancer patients did not include
the sufficient numbers of subjects aged 65 and over to determine whether they respond differently
from younger subjects. Other reported clinical experience has not identified differences in responses
between the elderly and younger patients. In general, dose selection for an elderly patient should be
cautious usually starting at the low end of the dosing range, reflecting the greater frequency of falls,
decreased hepatic, renal, or cardiac function, increased sensitivity to psychoactive effects and of
concomitant disease or other drug therapy.
ADVERSE REACTIONS
Adverse experiences information summarized in the tables below was derived from well-controlled
clinical trials conducted in the US and US territories involving 474 patients exposed to MARINOL
Capsules. Studies of AIDS-related weight loss included 157 patients receiving dronabinol at a dose of
2.5 mg twice daily and 67 receiving placebo. Studies of different durations were combined by
considering the first occurrence of events during the first 28 days. Studies of nausea and vomiting
related to cancer chemotherapy included 317 patients receiving dronabinol and 68 receiving placebo.
A cannabinoid dose-related “high” (easy laughing, elation and heightened awareness) has been
reported by patients receiving MARINOL Capsules in both the antiemetic (24%) and the lower dose
appetite stimulant clinical trials (8%). (See Clinical Trials.)
NDA 18-651/S-025 and S-026
Page 11
The most frequently reported adverse experiences in patients with AIDS during placebo-controlled
clinical trials involved the CNS and were reported by 33% of patients receiving MARINOL Capsules.
About 25% of patients reported a minor CNS adverse event during the first 2 weeks and about 4%
reported such an event each week for the next 6 weeks thereafter.
PROBABLY CAUSALLY RELATED: Incidence greater than 1%.
Rates derived from clinical trials in AIDS-related anorexia (N=157) and chemotherapy-related nausea
(N=317). Rates were generally higher in the anti-emetic use (given in parentheses).
Body as a whole: Asthenia.
Cardiovascular: Palpitations, tachycardia, vasodilation/facial flush.
Digestive: Abdominal pain*, nausea*, vomiting*.
Nervous system: (Amnesia), anxiety/nervousness, (ataxia), confusion, depersonalization, dizziness*,
euphoria*, (hallucination), paranoid reaction*, somnolence*, thinking abnormal*.
*Incidence of events 3% to 10%
PROBABLY CAUSALLY RELATED: Incidence less than 1%.
Event rates derived from clinical trials in AIDS-related anorexia (N=157) and chemotherapy-related
nausea (N=317).
Cardiovascular: Conjunctivitis*, hypotension*.
Digestive: Diarrhea*, fecal incontinence.
Musculoskeletal: Myalgias.
Nervous system: Depression, nightmares, speech difficulties, tinnitus.
Skin and Appendages: Flushing*.
Special senses: Vision difficulties.
*Incidence of events 0.3% to 1%
CAUSAL RELATIONSHIP UNKNOWN: Incidence less than 1%.
The clinical significance of the association of these events with MARINOL Capsules treatment is
unknown, but they are reported as alerting information for the clinician.
Body as a whole: Chills, headache, malaise.
Digestive: Anorexia, hepatic enzyme elevation.
Respiratory: Cough, rhinitis, sinusitis.
Skin and Appendages: Sweating.
Postmarketing Experience
Seizure and seizure-like activity have been reported in patients receiving MARINOL Capsules during
marketed use of the drug and in clinical trials. (See PRECAUTIONS and OVERDOSAGE.) Reports
of fatigue have also been received. A causal relationship between MARINOL Capsules and these
events has not been established.
DRUG ABUSE AND DEPENDENCE
MARINOL Capsules is one of the psychoactive compounds present in cannabis, and is abusable and
controlled [Schedule III (CIII)] under the Controlled Substances Act. Both psychological and
physiological dependence have been noted in healthy individuals receiving dronabinol, but addiction is
uncommon and has only been seen after prolonged high dose administration.
NDA 18-651/S-025 and S-026
Page 12
Chronic abuse of cannabis has been associated with decrements in motivation, cognition,
judgement, and perception. The etiology of these impairments is unknown, but may be associated with
the complex process of addiction rather than an isolated effect of the drug. No such decrements in
psychological, social or neurological status have been associated with the administration of
MARINOL Capsules for therapeutic purposes.
In an open-label study in patients with AIDS who received MARINOL Capsules for up to five
months, no abuse, diversion or systematic change in personality or social functioning were observed
despite the inclusion of a substantial number of patients with a past history of drug abuse.
An abstinence syndrome has been reported after the abrupt discontinuation of dronabinol in
volunteers receiving dosages of 210 mg/day for 12 to 16 consecutive days. Within 12 hours after
discontinuation, these volunteers manifested symptoms such as irritability, insomnia, and restlessness.
By approximately 24 hours post-dronabinol discontinuation, withdrawal symptoms intensified to
include “hot flashes”, sweating, rhinorrhea, loose stools, hiccoughs and anorexia.
These withdrawal symptoms gradually dissipated over the next 48 hours. Electroencephalographic
changes consistent with the effects of drug withdrawal (hyperexcitation) were recorded in patients after
abrupt dechallenge. Patients also complained of disturbed sleep for several weeks after discontinuing
therapy with high dosages of dronabinol.
OVERDOSAGE
Signs and symptoms following MILD MARINOL Capsules intoxication include drowsiness, euphoria,
heightened sensory awareness, altered time perception, reddened conjunctiva, dry mouth and
tachycardia; following MODERATE intoxication include memory impairment, depersonalization,
mood alteration, urinary retention, and reduced bowel motility; and following SEVERE intoxication
include decreased motor coordination, lethargy, slurred speech, and postural hypotension.
Apprehensive patients may experience panic reactions and seizures may occur in patients with existing
seizure disorders.
The estimated lethal human dose of intravenous dronabinol is 30 mg/kg (2100 mg/ 70 kg).
Significant CNS symptoms in antiemetic studies followed oral doses of 0.4 mg/kg (28 mg/70 kg) of
MARINOL Capsules.
Management: A potentially serious oral ingestion, if recent, should be managed with gut
decontamination. In unconscious patients with a secure airway, instill activated charcoal (30 to 100 g
in adults, 1 to 2 g/kg in infants) via a nasogastric tube. A saline cathartic or sorbitol may be added to
the first dose of activated charcoal. Patients experiencing depressive, hallucinatory or psychotic
reactions should be placed in a quiet area and offered reassurance. Benzodiazepines (5 to 10 mg
diazepam po) may be used for treatment of extreme agitation. Hypotension usually responds to
Trendelenburg position and IV fluids. Pressors are rarely required.
DOSAGE AND ADMINISTRATION
Appetite Stimulation: Initially, 2.5 mg MARINOL Capsules should be administered orally twice
daily (b.i.d.), before lunch and supper. For patients unable to tolerate this 5 mg/day dosage of
MARINOL Capsules, the dosage can be reduced to 2.5 mg/day, administered as a single dose in the
evening or at bedtime. If clinically indicated and in the absence of significant adverse effects, the
dosage may be gradually increased to a maximum of 20 mg/day MARINOL Capsules, administered in
NDA 18-651/S-025 and S-026
Page 13
divided oral doses. Caution should be exercised in escalating the dosage of MARINOL Capsules
because of the increased frequency of dose-related adverse experiences at higher dosages. (See
PRECAUTIONS.)
Antiemetic: MARINOL Capsules is best administered at an initial dose of 5 mg/m2, given 1 to 3
hours prior to the administration of chemotherapy, then every 2 to 4 hours after chemotherapy is given,
for a total of 4 to 6 doses/day. Should the 5 mg/m2 dose prove to be ineffective, and in the absence of
significant side effects, the dose may be escalated by 2.5 mg/m2 increments to a maximum of 15
mg/m2 per dose. Caution should be exercised in dose escalation, however, as the incidence of
disturbing psychiatric symptoms increases significantly at maximum dose. (See PRECAUTIONS.)
Storage Conditions
MARINOL Capsules should be packaged in a well-closed container and stored in a cool
environment between 8° and 15°C (46° and 59°F) and alternatively could be stored in a
refrigerator. Protect from freezing.
HOW SUPPLIED
MARINOL Capsules (dronabinol solution in sesame oil in soft gelatin capsules)
2.5 mg white capsules (Identified UM).
NDC 0051-0021-21 (Bottle of 60 capsules).
5 mg dark brown capsules (Identified UM).
NDC 0051-0022-21 (Bottle of 60 capsules).
10 mg orange capsules (Identified UM).
NDC 0051-0023-21 (Bottle of 60 capsules).
MARINOL is a registered trademark of Unimed Pharmaceuticals, Inc. and is
Manufactured by Banner Pharmacaps, Inc.
High Point, NC 27265
For:
Unimed Pharmaceuticals, Inc.
A Solvay Pharmaceuticals, Inc. Company
Marietta, GA 30062-2224, USA
500012 Rev Jul 2006
© 2006 Solvay Pharmaceuticals, Inc.
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/018651s025s026lbl.pdf', 'application_number': 18651, 'submission_type': 'SUPPL ', 'submission_number': 26}
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NDA 18-657/S-029
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*BAR CODE LOCATION ONLY
071959414
Baxter
Metronidazole Injection, USP RTU®
in Plastic Container
VIAFLEX Plus Container
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Metronidazole
Injection, USP RTU® and other antibacterial drugs, Metronidazole Injection, USP RTU® should be
used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.
Warning
Metronidazole has been shown to be carcinogenic in mice and rats (see Precautions). Its
use, therefore, should be reserved for the conditions described in the Indications and
Usage section below.
DESCRIPTION
Metronidazole Injection, USP RTU®, is a parenteral dosage form of the synthetic antibacterial agent 1
(ß-hydroxyethyl)-2-methyl-5-nitroimidazole. Structural formula of Metronidazole
Metronidazole Injection, USP RTU®, in 100 mL VIAFLEX Plus single dose plastic container, is a
sterile, nonpyrogenic, iso-osmotic, buffered solution of 500 mg Metronidazole, USP, 790 mg Sodium
Chloride, USP, 47.6 mg Dibasic Sodium Phosphate Dried, USP and 22.9 mg Citric Acid Anhydrous,
USP. Metronidazole Injection, USP RTU® has an osmolarity of 310 mOsmol/L (calc) and a pH of 5.5
(4.5 to 7.0). Each container contains 14 mEq of sodium.
The plastic container is fabricated from a specially formulated polyvinyl chloride plastic. Water can
permeate from inside the container into the overwrap in amounts insufficient to affect the solution
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-657/S-029
Page 6
significantly. Solutions in contact with the plastic container can leach out certain of its chemical
components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP),
up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals
according to USP biological tests for plastic containers as well as by tissue culture toxicity studies.
CLINICAL PHARMACOLOGY
Metronidazole is a synthetic antibacterial compound. Disposition of metronidazole in the body is
similar for both oral and intravenous dosage forms, with an average elimination half-life in healthy
humans of eight hours.
The major route of elimination of metronidazole and its metabolites is via the urine (60-80% of the
dose), with fecal excretion accounting for 6-15% of the dose. The metabolites that appear in the urine
result primarily from side-chain oxidation [1-(ß-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and
2-methyl-5-nitroimidazole-1-yl-acetic acid] and glucuronide conjugation, with unchanged
metronidazole accounting for approximately 20% of the total. Renal clearance of metronidazole is
approximately 10 mL/min/1.73 m2.
Metronidazole is the major component appearing in the plasma, with lesser quantities of the 2
hydroxymethyl metabolite also being present. Less than 20% of the circulating metronidazole is bound
to plasma proteins. Both the parent compound and the metabolite possess in vitro bactericidal activity
against most strains of anaerobic bacteria.
Metronidazole appears in cerebrospinal fluid, saliva and breast milk in concentrations similar to those
found in plasma. Bactericidal concentrations of metronidazole have also been detected in pus from
hepatic abscesses.
Plasma concentrations of metronidazole are proportional to the administered dose. An eight-hour
intravenous infusion of 100-4,000 mg of metronidazole in normal subjects showed a linear relationship
between dose and peak plasma concentration.
In patients treated with intravenous metronidazole, using a dosage regimen of 15 mg/kg loading dose
followed six hours later by 7.5 mg/kg every six hours, peak steady-state plasma concentrations of
metronidazole averaged 25 mcg/mL with trough (minimum) concentrations averaging 18 mcg/mL.
Decreased renal function does not alter the single-dose pharmacokinetics of metronidazole. However,
plasma clearance of metronidazole is decreased in patients with decreased liver function.
In one study newborn infants appeared to demonstrate diminished capacity to eliminate metronidazole.
The elimination half-life, measured during the first three days of life, was inversely related to
gestational age. In infants whose gestational ages were between 28 and 40 weeks, the corresponding
elimination half-lives ranged from 109 to 22.5 hours.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-657/S-029
Page 7
Microbiology:
Metronidazole is active in vitro against most obligate anaerobes, but does not appear to possess any
clinically relevant activity against facultative anaerobes or obligate aerobes. Against susceptible
organisms, metronidazole is generally bactericidal at concentrations equal to or slightly higher than the
minimal inhibitory concentrations. Metronidazole has been shown to have in vitro and clinical activity
against the following organisms:
Anaerobic gram-negative bacilli, including:
Bacteroides species, including the Bacteroides fragilis group (B. fragilis,
B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus)
Fusobacterium species
Anaerobic gram-positive bacilli, including:
Clostridium species and susceptible strains of Eubacterium
Anaerobic gram-positive cocci, including:
Peptococcus species
Peptostreptococcus species
Susceptibility Tests:
Bacteriologic studies should be performed to determine the causative organisms and their susceptibility
to metronidazole; however, the rapid, routine susceptibility testing of individual isolates of anaerobic
bacteria is not always practical, and therapy may be started while awaiting these results.
Quantitative methods give the most accurate estimates of susceptibility to antibacterial drugs. A
standardized agar dilution method and a broth microdilution method are recommended1.
Control strains are recommended for standardized susceptibility testing. Each time the test is
performed, one or more of the following strains should be included: Eubacterium lentum ATCC 43055,
Bacteroides fragilis ATCC 25285, and Bacteroides thetaiotaomicron ATCC 29741. The mode
metronidazole MICs for those three strains are reported to be 0.125, 0.25, and 0.5 mcg/mL,
respectively.
A clinical laboratory test is considered under acceptable control if the results of the control strains are
within one doubling dilution of the mode MICs reported for metronidazole.
A bacterial isolate may be considered susceptible if the MIC value for metronidazole is not more than
16 mcg/mL. An organism is considered resistant if the MIC is greater than 16 mcg/mL. A report of
"resistant" from the laboratory indicates that the infecting organism is not likely to respond to therapy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-657/S-029
Page 8
INDICATIONS AND USAGE
Treatment of Anaerobic Infections
Metronidazole Injection, USP RTU® is indicated in the treatment of serious infections caused by
susceptible anaerobic bacteria. Indicated surgical procedures should be performed in conjunction with
Metronidazole Injection, USP RTU® therapy. In a mixed aerobic and anaerobic infection, antibiotics
appropriate for the treatment of the aerobic infection should be used in addition to Metronidazole
Injection, USP RTU®.
Metronidazole Injection, USP RTU® is effective in Bacteroides fragilis infections resistant to
clindamycin, chloramphenicol and penicillin.
Intra-Abdominal Infections, including peritonitis, intra-abdominal abscess and liver abscess, caused
by Bacteroides species including the B. fragilis group (B. fragilis, B. distasonis, B. ovatus, B.
thetaiotaomicron, B. vulgatus), Clostridium species, Eubacterium species, Peptococcus species and
Peptostreptococcus species.
Skin and Skin Structure Infections caused by Bacteroides species including the B. fragilis group,
Clostridium species, Peptococcus species, Peptostreptococcus species and Fusobacterium species.
Gynecologic Infections, including endometritis, endomyometritis, tubo-ovarian abscess and
postsurgical vaginal cuff infection, caused by Bacteroides species including the B. fragilis group,
Clostridium species, Peptostreptococcus species and Fusobacterium species.
Bacterial Septicemia caused by Bacteroides species including the B. fragilis group and Clostridium
species.
Bone and Joint Infections, as adjunctive therapy, caused by Bacteroides species including the B.
fragilis group.
Central Nervous System (CNS) Infections, including meningitis and brain abscess, caused by
Bacteroides species including the B. fragilis group.
Lower Respiratory Tract Infections, including pneumonia, empyema and lung abscess, caused by
Bacteroides species including the B. fragilis group.
Endocarditis caused by Bacteroides species including the B. fragilis group.
Prophylaxis
The prophylactic administration of Metronidazole Injection, USP RTU® preoperatively,
intraoperatively and postoperatively may reduce the incidence of postoperative infection in patients
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-657/S-029
Page 9
undergoing elective colorectal surgery which is classified as contaminated or potentially contaminated.
Prophylactic use of Metronidazole Injection, USP RTU® should be discontinued within 12 hours after
surgery. If there are signs of infection, specimens for cultures should be obtained for the identification
of the causative organism(s) so that appropriate therapy may be given (see Dosage and
Administration).
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Metronidazole
Injection, USP RTU® and other antibacterial drugs, Metronidazole Injection, USP RTU® should be
used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible
bacteria. When culture and susceptibility information are available, they should be considered in
selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and
susceptibility patterns may contribute to the empiric selection of therapy.
CONTRAINDICATIONS
Metronidazole Injection, USP RTU® is contraindicated in patients with a prior history of
hypersensitivity to metronidazole or other nitroimidazole derivatives.
WARNINGS
Central And Peripheral Nervous System Effects
Encephalopathy and peripheral neuropathy: Cases of encephalopathy and peripheral neuropathy
(including optic neuropathy) have been reported with metronidazole.
Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia,
dizziness, and dysarthria. CNS lesions seen on MRI have been described in reports of encephalopathy.
CNS symptoms are generally reversible within days to weeks upon discontinuation of metronidazole.
CNS lesions seen on MRI have also been described as reversible.
Peripheral neuropathy, mainly of sensory type has been reported and is characterized by numbness or
paresthesia of an extremity.
Convulsive seizures have been reported in patients treated with metronidazole.
Aseptic meningitis: Cases of aseptic meningitis have been reported with metronidazole. Symptoms
can occur within hours of dose administration and generally resolve after metronidazole therapy is
discontinued.
The appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of the
benefit/risk ratio of the continuation of therapy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-657/S-029
Page 10
PRECAUTIONS
General
Patients with severe hepatic disease metabolize metronidazole slowly, with resultant accumulation of
metronidazole and its metabolites in the plasma. Accordingly, for such patients, doses below those
usually recommended should be administered cautiously.
Administration of solutions containing sodium ions may result in sodium retention. Care should be
taken when administering Metronidazole Injection, USP RTU® to patients receiving corticosteroids or
to patients predisposed to edema.
Known or previously unrecognized candidiasis may present more prominent symptoms during therapy
with Metronidazole Injection, USP RTU® and requires treatment with a candicidal agent.
Prescribing Metronidazole Injection, USP RTU® in the absence of a proven or strongly suspected
bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases
the risk of the development of drug-resistant bacteria.
Laboratory Tests
Metronidazole is a nitroimidazole, and should be used with care in patients with evidence of or history
of blood dyscrasia. A mild leukopenia has been observed during its administration; however, no
persistent hematologic abnormalities attributable to metronidazole have been observed in clinical
studies. Total and differential leukocyte counts are recommended before and after therapy.
Drug Interactions
Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral
coumarin anticoagulants, resulting in a prolongation of prothrombin time. This possible drug interaction
should be considered when Metronidazole Injection, USP RTU® is prescribed for patients on this type
of anticoagulant therapy.
The simultaneous administration of drugs that induce microsomal liver enzyme activity, such as
phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced
plasma levels; impaired clearance of phenytoin has also been reported.
The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as
cimetidine, may prolong the half-life and decrease plasma clearance of metronidazole.
Alcoholic beverages should not be consumed during metronidazole therapy because abdominal cramps,
nausea, vomiting, headaches and flushing may occur.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-657/S-029
Page 11
Psychotic reactions have been reported in alcoholic patients who are using metronidazole and
disulfiram concurrently. Metronidazole should not be given to patients who have taken disulfiram
within the last two weeks.
Drug/Laboratory Test Interactions
Metronidazole may interfere with certain types of determinations of serum chemistry values, such as
aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate
dehydrogenase (LDH), triglycerides and hexokinase glucose. Values of zero may be observed. All of
the assays in which interference has been reported involve enzymatic coupling of the assay to
oxidation-reduction of nicotine adenine dinucleotide (NAD
+ ⇌NADH). Interference is due to the
similarity in absorbance peaks of NADH (340nm) and metronidazole (322nm) at pH 7.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Tumorigenicity in Rodents - Metronidazole has shown evidence of carcinogenic activity in studies
involving chronic, oral administration in mice and rats, but similar studies in the hamster gave negative
results. Also, metronidazole has shown mutagenic activity in a number of in vitro assay systems, but
studies in mammals (in vivo) failed to demonstrate a potential for genetic damage.
Pregnancy
Teratogenic Effects
Pregnancy Category B
Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. Reproduction studies
have been performed in rats at doses up to five times the human dose and have revealed no evidence of
impaired fertility or harm to the fetus due to metronidazole. Metronidazole administered
intraperitoneally to pregnant mice at approximately the human dose caused fetotoxicity; administered
orally to pregnant mice, no fetotoxicity was observed. There are, however, no adequate and well-
controlled studies in pregnant women. Because animal reproduction studies are not always predictive of
human response, and because metronidazole is a carcinogen in rodents, these drugs should be used
during pregnancy only if clearly needed.
Nursing Mothers
Because of the potential for tumorigenicity shown for metronidazole in mouse and rat studies, a
decision should be made whether to discontinue nursing or to discontinue the drug, taking into account
the importance of the drug to the mother. Metronidazole is secreted in breast milk in concentrations
similar to those found in plasma.
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Page 12
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Information for Patients
Patients should be counseled that antibacterial drugs including Metronidazole Injection, USP RTU®
should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common
cold). When Metronidazole Injection, USP RTU® is prescribed to treat a bacterial infection, patients
should be told that although it is common to feel better early in the course of therapy, the medication
should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1)
decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will
develop resistance and will not be treatable by Metronidazole Injection, USP RTU® or other
antibacterial drugs in the future.
ADVERSE REACTIONS
The most serious adverse reactions reported in patients treated with metronidazole injection have been
convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter
characterized mainly by numbness or paresthesia of an extremity. Since persistent peripheral
neuropathy has been reported in some patients receiving prolonged oral administration of
metronidazole, patients should be observed carefully if neurologic symptoms occur and a prompt
evaluation made of the benefit/risk ratio of the continuation of therapy.
The following reactions have also been reported during treatment with Metronidazole Injection, USP
RTU®.
Gastrointestinal: Nausea, vomiting, abdominal discomfort, diarrhea and an unpleasant metallic taste.
Hematopoietic: Reversible neutropenia (leukopenia).
Dermatologic: Erythematous rash and pruritus.
Central Nervous System: Encephalopathy, aseptic meningitis, optic neuropathy, headache, dizziness,
syncope, ataxia, confusion and dysarthria.
Hypersensitivity: Urticaria, erythematous rash, Stevens-Johnson Syndrome, flushing, nasal congestion,
dryness of the mouth (or vagina or vulva) and fever.
Local Reactions: Thrombophlebitis after intravenous infusion. This reaction can be minimized or
avoided by avoiding prolonged use of indwelling intravenous catheters.
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NDA 18-657/S-029
Page 13
Other: Fever. Instances of a darkened urine have also been reported, and this manifestation has been the
subject of a special investigation. Although the pigment which is probably responsible for this
phenomenon has not been positively identified, it is almost certainly a metabolite of metronidazole and
seems to have no clinical significance.
The following adverse reactions have been reported during treatment with oral metronidazole:
Gastrointestinal: Nausea, sometimes accompanied by headache, anorexia and occasionally vomiting;
diarrhea, epigastric distress, abdominal cramping and constipation.
Mouth: A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis and stomatitis have
occurred; these may be associated with a sudden overgrowth of Candida which may occur during
effective therapy.
Hematopoietic: Reversible neutropenia (leukopenia); rarely, reversible thrombocytopenia.
Cardiovascular: Flattening of the T-wave may be seen in electrocardiographic tracings.
Central Nervous System: Encephalopathy, aseptic meningitis, convulsive seizures, optic neuropathy,
peripheral neuropathy, dizziness, vertigo, incoordination, ataxia, confusion, dysarthria, irritability,
depression, weakness and insomnia.
Hypersensitivity: Urticaria, erythematous rash, Stevens-Johnson Syndrome, flushing, nasal congestion,
dryness of the mouth (or vagina or vulva) and fever.
Renal: Dysuria, cystitis, polyuria, incontinence, a sense of pelvic pressure and darkened urine.
Other: Proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis and fleeting
joint pains sometimes resembling “serum sickness.” If patients receiving metronidazole drink alcoholic
beverages, they may experience abdominal distress, nausea, vomiting, flushing or headache. A
modification of the taste of alcoholic beverages has also been reported. Rare cases of pancreatitis,
which abated on withdrawal of the drug, have been reported.
Crohn's disease patients are known to have an increased incidence of gastrointestinal and certain
extraintestinal cancers. There have been some reports in the medical literature of breast and colon
cancer in Crohn's disease patients who have been treated with metronidazole at high doses for extended
periods of time. A cause and effect relationship has not been established. Crohn's disease is not an
approved indication for Metronidazole Injection, USP RTU®.
OVERDOSAGE
Use of dosages of intravenous metronidazole higher than those recommended has been reported. These
include the use of 27 mg/kg three times a day for 20 days, and the use of 75 mg/kg as a single loading
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NDA 18-657/S-029
Page 14
dose followed by 7.5 mg/kg maintenance doses. No adverse reactions were reported in either of the two
cases.
Single oral dose of metronidazole, up to 15 g, have been reported in suicide attempts and accidental
overdoses. Symptoms reported included nausea, vomiting and ataxia.
Oral metronidazole has been studied as a radiation sensitizer in the treatment of malignant tumors.
Neurotoxic effects, including seizures and peripheral neuropathy, have been reported after 5 to 7 days
of doses of 6 to 10.4 g every other day.
Treatment: There is no specific antidote for overdose; therefore, management of the patient should
consist of symptomatic and supportive therapy.
DOSAGE AND ADMINISTRATION
In elderly patients the pharmacokinetics of metronidazole may be altered and therefore monitoring of
serum levels may be necessary to adjust the metronidazole dosage accordingly.
Treatment of Anaerobic Infections
The recommended dosage schedule for adults is:
Loading Dose
15 mg/kg infused over one hour (approximately 1 g for a 70-kg adult).
Maintenance Dose
7.5 mg/kg infused over one hour every six hours (approximately 500 mg for a
70-kg adult). The first maintenance dose should be instituted six hours
following the initiation of the loading dose.
Parenteral therapy may be changed to oral metronidazole when conditions warrant, based upon the
severity of the disease and the response of the patient to Metronidazole Injection, USP RTU® treatment.
The usual adult oral dosage is 7.5 mg/kg every six hours.
A maximum of 4 g should not be exceeded during a 24-hour period.
Patients with severe hepatic disease metabolize metronidazole slowly, with resultant accumulation of
metronidazole and its metabolites in the plasma. Accordingly, for such patients, doses below those
usually recommended should be administered cautiously. Close monitoring of plasma metronidazole
levels2 and toxicity is recommended.
In patients receiving Metronidazole Injection, USP RTU® in whom gastric secretions are continuously
removed by nasogastric aspiration, sufficient metronidazole may be removed in the aspirate to cause a
reduction in serum levels.
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Page 15
The dose of Metronidazole Injection, USP RTU® should not be specifically reduced in anuric patients
since accumulated metabolites may be rapidly removed by dialysis.
The usual duration of therapy is 7 to 10 days; however, infections of the bone and joint, lower
respiratory tract and endocardium may require longer treatment.
Prophylaxis
For surgical prophylactic use, to prevent postoperative infection in contaminated or potentially
contaminated colorectal surgery, the recommended dosage schedule for adults is:
a. 15 mg/kg infused over 30 to 60 minutes and completed approximately one hour before surgery;
followed by
b. 7.5 mg/kg infused over 30 to 60 minutes at 6 and 12 hours after the initial dose.
It is important that (1) administration of the initial preoperative dose be completed approximately one
hour before surgery so that adequate drug levels are present in the serum and tissues at the time of
initial incision, and (2) Metronidazole Injection, USP RTU® be administered, if necessary, at 6-hour
intervals to maintain effective drug levels. Prophylactic use of Metronidazole Injection, USP RTU®
should be limited to the day of surgery only, following the above guidelines.
Caution: Metronidazole Injection, USP RTU® is to be administered by slow intravenous drip
infusion only, either as a continuous or intermittent infusion. Additives should not be introduced
into Metronidazole Injection, USP RTU®. If used with a primary intravenous fluid system, the
primary solution should be discontinued during metronidazole infusion. DO NOT USE
EQUIPMENT CONTAINING ALUMINUM (e.g., NEEDLES, CANNULAE) THAT WOULD
COME IN CONTACT WITH THE DRUG SOLUTION.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration, whenever solution and container permit.
HOW SUPPLIED
Metronidazole Injection, USP RTU® is supplied in 100 mL single dose plastic containers, each
containing an iso-osmotic, buffered solution of 500 mg metronidazole as follows:
2B3421
NDC 0338-1055-48
500 mg/100 mL
Store at controlled room temperature, 59° to 86°F (15° to 30°C) and protect from light during storage.
Do not remove unit from overwrap until ready for use. The overwrap is a moisture barrier. The inner
bag maintains the sterility of the product. After removing overwrap, check for minute leaks by
squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
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Page 16
DIRECTIONS FOR USE OF VIAFLEX PLUS PLASTIC CONTAINER
Metronidazole Injection, USP RTU® is a ready-to-use iso-osmotic solution. No dilution or buffering is
required. Do not refrigerate. Each container of Metronidazole Injection, USP RTU® contains 14 mEq
of sodium.
Warning: Do not use plastic containers in series connections. Such use could result in air embolism
due to residual air being drawn from the primary container before administration of the fluid from the
secondary container is completed.
To open
Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to
moisture absorption during the sterilization process may be observed. This is normal and does not affect
the solution quality or safety. The opacity will diminish gradually. Check for leaks. Do not add
supplementary medication.
Preparation for Administration
1. Suspend container from eyelet support.
2. Remove plastic protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
REFERENCES
1.
M11-A5-Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; approved
Standard-Fifth Edition, National Committee for Clinical Laboratory Standards; and Sutter, et al.:
Collaborative Evaluation of a Proposed Reference Dilution Method of Susceptibility Testing of
Anaerobic Bacteria, Antimicrob. Agents Chemother. 16:495-502 (Oct.) 1979; and Tally, et al.: In
Vitro Activity of Thienamycin, Antimicrob. Agents Chemother. 14:436-438 (Sept.) 1978.
2.
Ralph, E.D. and Kirby, W.M.M.: Bioassay of Metronidazole with Either Anaerobic and Aerobic
Incubation, J. Infect. Dis. 132:587-591 (Nov.) 1975; or Gulaid, et al.: Determination of
Metronidazole and its Major Metabolites in Biological Fluids by High Pressure Liquid
Chromatography. BR.J.Clin. Pharmacol. 6:430-432, 1978.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
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NDA 18-657/S-029
Page 17
*BAR CODE POSITION ONLY
071959414
©Copyright 1990, 1993, Baxter Healthcare Corporation.
All rights reserved.
BAXTER and VIAFLEX are trademarks of Baxter International Inc.
Metronidazole Injection, USP RTU® is manufactured under sublicense from SCS
Pharmaceuticals, Chicago, IL 60680
by Baxter Healthcare Corporation, Deerfield, IL 60015
07-19-59-414
Rev. June, 2009
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For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:49.461719
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018657s029lbl.pdf', 'application_number': 18657, 'submission_type': 'SUPPL ', 'submission_number': 29}
|
11,265
|
Metronidazole Injection, USP
in Plastic Container
VIAFLEX Plus Container
To reduce the development of drug-resistant bacteria and maintain the effectiveness of
Metronidazole Injection, USP and other antibacterial drugs, Metronidazole Injection,
USP should be used only to treat or prevent infections that are proven or strongly
suspected to be caused by bacteria.
WARNING
Metronidazole has been shown to be carcinogenic in mice and rats (see
PRECAUTIONS). Unnecessary use of the drug should be avoided. Its use should be
reserved for the conditions described in the INDICATIONS AND USAGE section
below.
DESCRIPTION
Metronidazole Injection, USP, is a parenteral formulation of the synthetic nitroimidazole
antibacterial agent 2-methyl-5-nitro-1H-imidazole-1-ethanol. structural formula
Metronidazole Injection, USP, in 100 mL VIAFLEX Plus single dose plastic container, is
a sterile, nonpyrogenic, iso-osmotic, buffered solution of 500 mg Metronidazole, USP,
790 mg Sodium Chloride, USP, 47.6 mg Dibasic Sodium Phosphate Dried, USP and 22.9
mg Citric Acid Anhydrous, USP. Metronidazole Injection, USP has an osmolarity of 310
mOsmol/L (calc) and a pH of 5.5 (4.5 to 7.0). Each container contains 14 mEq of sodium.
The plastic container is fabricated from a specially formulated polyvinyl chloride plastic.
Water can permeate from inside the container into the overwrap in amounts insufficient
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to affect the solution significantly. Solutions in contact with the plastic container can
leach out certain of its chemical components in very small amounts within the expiration
period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the
safety of the plastic has been confirmed in tests in animals according to USP biological
tests for plastic containers as well as by tissue culture toxicity studies.
CLINICAL PHARMACOLOGY
In patients treated with intravenous metronidazole, using a dosage regimen of 15 mg/kg
loading dose followed 6 hours later by 7.5 mg/kg every 6 hours, the average peak steady-
state plasma concentrations (Cmax) and trough concentrations (Cmin) were 25 mcg/mL and
18 mcg/mL, respectively. Plasma concentrations of metronidazole are proportional to the
administered dose. An eight-hour intravenous infusion of 100 mg to 4,000 mg of
metronidazole in normal subjects showed a linear relationship between dose and peak
plasma concentration. The average elimination half-life of metronidazole in healthy
subjects is eight hours.
Distribution
Metronidazole is the major component appearing in the plasma, with lesser quantities of
metabolites also being present. Less than 20% of the circulating metronidazole is bound
to plasma proteins. Metronidazole appears in cerebrospinal fluid, saliva and breast milk
in concentrations similar to those found in plasma. Bactericidal concentrations of
metronidazole have also been detected in pus from hepatic abscesses.
Following a single intravenous dose of metronidazole 500 mg, 4 healthy subjects who
underwent gastrointestinal endoscopy had peak gastric juice metronidazole
concentrations of 5 to 6 mcg/mL at one hour post-dose. In patients receiving intravenous
metronidazole in whom gastric secretions are continuously removed by nasogastric
aspiration, sufficient metronidazole may be removed in the aspirate to cause a reduction
in serum levels.
Metabolism
The metabolites of metronidazole result primarily from side-chain oxidation [1-(ß
hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-yl
acetic acid] and glucuronide conjugation. Both the parent compound and the hydroxyl
metabolite possess in vitro antimicrobial activity.
Excretion
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The major route of elimination of metronidazole and its metabolites is via the urine (60
80% of the dose), with approximately 20% of the amount excreted appearing as
unchanged metronidazole. Renal clearance of metronidazole is approximately
10 mL/min/1.73 m2. Fecal excretion accounts for 6-15% of the dose.
Renal Impairment
Decreased renal function does not alter the single-dose pharmacokinetics of
metronidazole.
Subjects with end-stage renal disease (ESRD; CLCR= 8.1±9.1 mL/min) and who received
a single intravenous infusion of metronidazole 500 mg had no significant change in
metronidazole pharmacokinetics but had 2-fold higher Cmax of hydroxy-metronidazole
and 5-fold higher Cmax of metronidazole acetate, compared to healthy subjects with
normal renal function (CLCR= 126 ± 16 mL/min). Thus, on account of the potential
accumulation of metronidazole metabolites in ESRD patients, monitoring for
metronidazole associated adverse events is recommended (see PRECAUTIONS).
Effect of Dialysis
Following a single intravenous infusion or oral dose of metronidazole 500 mg, the
clearance of metronidazole was investigated in ESRD subjects undergoing hemodialysis
or continuous ambulatory peritoneal dialysis (CAPD). A hemodialysis session lasting for
4 to 8 hours removed 40% to 65% of the administered metronidazole dose, depending on
the type of the dialyzer membrane used and the duration of the dialysis session. If the
administration of metronidazole cannot be separated from the dialysis session,
supplementation of metronidazole dose following hemodialysis should be considered (see
DOSAGE AND ADMINISTRATION). A peritoneal dialysis session lasting for 7.5
hours removed approximately 10% of the administered metronidazole dose. No
adjustment in metronidazole dose is needed in ESRD patients undergoing CAPD.
Hepatic Impairment
Following a single intravenous infusion of 500 mg metronidazole, the mean AUC24 of
metronidazole was higher by 114% in patients with severe (Child-Pugh C) hepatic
impairment, and by 54% and 53% in patients with a mild (Child-Pugh A) and moderate
(Child-Pugh B) hepatic impairment, respectively, compared to healthy control subjects.
There were no significant changes in the AUC24 of hydroxy-metronidazole in these
hepatically impaired patients. A reduction in metronidazole dosage by 50% is
recommended in patients with severe (Child-Pugh C) hepatic impairment (see DOSAGE
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AND ADMINISTRATION). No dosage adjustment is needed for patients with mild to
moderate hepatic impairment. Patients with mild to moderate hepatic impairment should
be monitored for metronidazole associated adverse events (see PRECAUTIONS and
DOSAGE AND ADMINISTRATION).
Geriatric Patients
Following a single 500 mg oral or IV dose of metronidazole, subjects >70 years old with
no apparent renal or hepatic dysfunction had a 40% to 80% higher mean AUC of
hydroxy-metronidazole (active metabolite), with no apparent increase in the mean AUC
of metronidazole (parent compound), compared to young healthy controls < 40 years old.
In geriatric patients, monitoring for metronidazole associated adverse events is
recommended (see PRECAUTIONS).
Pediatric Patients
In one study newborn infants appeared to demonstrate diminished capacity to eliminate
metronidazole. The elimination half-life, measured during the first three days of life, was
inversely related to gestational age. In infants whose gestational ages were between 28
and 40 weeks, the corresponding elimination half-lives ranged from 109 to 22.5 hours.
Microbiology
Mechanism of Action
Metronidazole exerts antibacterial effects in an anaerobic environment by the following
possible mechanism: Once metronidazole enters the organism, the drug is reduced by
intra-cellular electron transport proteins. Because of this alteration to the metronidazole
molecule, a concentration gradient is created and maintained which promotes the drug’s
intracellular transport. Presumably, free radicals are formed which, in turn, react with
cellular components resulting in death of bacteria.
Metronidazole is active against most obligate anaerobes, but does not possess any
clinically relevant activity against facultative anaerobes or obligate aerobes.
Activity In Vitro and In Vivo
Metronidazole has been shown to be active against most isolates of the following bacteria
both in vitro and in clinical infections as described in the INDICATIONS AND USAGE
section.
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Gram-positive anaerobes
Clostridium species
Eubacterium species
Peptococcus species
Peptostreptococcus species
Gram-negative anaerobes
Bacteroides fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron,
B. vulgatus)
Fusobacterium species
The following in vitro data are available, but their clinical significance is unknown.
Metronidazole exhibits in vitro minimal inhibitory concentrations (MIC’s) of 8 mcg/mL
or less against most (≥ 90%) isolates of the following bacteria; however, the safety and
effectiveness of metronidazole in treating clinical infections due to these bacteria have
not been established in adequate and well-controlled clinical trials.
Gram-negative anaerobes
Bacteroides fragilis group (B. caccae, B. uniformis)
Prevotella species (P. bivia, P. buccae, P. disiens)
Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide results of in vitro
susceptibility test results for antimicrobial drug products used in resident hospitals to the
physician as periodic reports that describe the susceptibility profile of nosocomial or
community-acquired pathogens. These reports should aid the physician in selecting an
antibacterial drug product for treatment.
Anaerobic Techniques
Quantitative methods are used to determine antimicrobial inhibitory concentrations
(MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial
compounds. For anaerobic bacteria, the susceptibility to metronidazole can be determined
by the reference broth and/or agar method. 1,2
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The MIC values should be interpreted according to the criteria provided in the following
table.
Susceptibility Test Interpretive Criteria for Metronidazole*†
MIC (mcg/mL)
Interpretation
≤ 8
Susceptible (S)
16
Intermediate (I)
≥ 32
Resistant (R)
* Agar dilution method is recommended for all anaerobes.
† Broth microdilution method is only recommended for testing Bacteroides fragilis group; for this group
the MIC values for agar or broth microdilution are considered equivalent.
A report of “Susceptible” indicates that the antimicrobial is likely to inhibit growth of the
pathogen if the antimicrobial compound reaches the concentrations at the infection site
necessary to inhibit growth of the pathogen. A report of “Intermediate” indicates that the
result should be considered equivocal, and, if the microorganism is not fully susceptible
to alternative, clinically feasible drugs, the test should be repeated. This category implies
possible clinical applicability in body sites where the drug is physiologically concentrated
or in situations where a high dosage of the drug product can be used. This category also
provides a buffer zone that prevents small uncontrolled technical factors from causing
major discrepancies in interpretation. A report of “Resistant” indicates that the
antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial
compound reaches the concentrations usually achievable at the infection site; other
therapy should be selected.
Quality Control
Standardized susceptibility test procedures require the use of laboratory controls to
monitor and ensure the accuracy and precision of supplies and reagents used in the assay,
and the techniques of the individuals performing the test.1,2 Standard metronidazole
powder should provide a value within the MIC ranges noted in the following table:
Acceptable Quality Control Ranges for Metronidazole
Minimum Inhibitory
QC Strain
concentration (mcg/mL)
Agar
Broth
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Bacteroides fragilis ATCC 25285
0.25-1.0
0.25-2.0
Bacteroides thetaiotaomicron ATCC 29741
0.5-2.0
0.5-4.0
INDICATIONS AND USAGE
Treatment of Anaerobic Bacterial Infections
Metronidazole Injection, USP is indicated in the treatment of serious infections caused by
susceptible anaerobic bacteria. Indicated surgical procedures should be performed in
conjunction with Metronidazole Injection, USP therapy. In a mixed aerobic and
anaerobic infection, antibiotics appropriate for the treatment of the aerobic infection
should be used in addition to Metronidazole Injection, USP.
Metronidazole Injection, USP is effective in Bacteroides fragilis infections resistant to
clindamycin, chloramphenicol and penicillin.
Intra-Abdominal Infections, including peritonitis, intra-abdominal abscess and liver
abscess, caused by Bacteroides species including the B. fragilis group (B. fragilis, B.
distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus), Clostridium species,
Eubacterium species, Peptococcus species and Peptostreptococcus species.
Skin and Skin Structure Infections caused by Bacteroides species including the B.
fragilis group, Clostridium species, Peptococcus species, Peptostreptococcus species and
Fusobacterium species.
Gynecologic Infections, including endometritis, endomyometritis, tubo-ovarian abscess
and postsurgical vaginal cuff infection, caused by Bacteroides species including the B.
fragilis group, Clostridium species, Peptococcus species, Peptostreptococcus species and
Fusobacterium species.
Bacterial Septicemia caused by Bacteroides species including the B. fragilis group and
Clostridium species.
Bone and Joint Infections, as adjunctive therapy, caused by Bacteroides species
including the B. fragilis group.
Central Nervous System (CNS) Infections, including meningitis and brain abscess,
caused by Bacteroides species including the B. fragilis group.
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Lower Respiratory Tract Infections, including pneumonia, empyema and lung abscess,
caused by Bacteroides species including the B. fragilis group.
Endocarditis caused by Bacteroides species including the B. fragilis group.
Prophylaxis
The prophylactic administration of Metronidazole Injection, USP preoperatively,
intraoperatively and postoperatively may reduce the incidence of postoperative infection
in patients undergoing elective colorectal surgery which is classified as contaminated or
potentially contaminated. Prophylactic use of Metronidazole Injection, USP should be
discontinued within 12 hours after surgery. If there are signs of infection, specimens for
cultures should be obtained for the identification of the causative organism(s) so that
appropriate therapy may be given (see DOSAGE AND ADMINISTRATION).
To reduce the development of drug-resistant bacteria and maintain the effectiveness of
Metronidazole Injection, USP and other antibacterial drugs, Metronidazole Injection,
USP should be used only to treat or prevent infections that are proven or strongly
suspected to be caused by susceptible bacteria. When culture and susceptibility
information are available, they should be considered in selecting or modifying
antibacterial therapy. In the absence of such data, local epidemiology and susceptibility
patterns may contribute to the empiric selection of therapy.
CONTRAINDICATIONS
Hypersensitivity
Metronidazole Injection, USP is contraindicated in patients with a prior history of
hypersensitivity to metronidazole or other nitroimidazole derivatives.
Psychotic Reaction with Disulfiram
Use of oral metronidazole is associated with psychotic reactions in alcoholic patients who
were using disulfiram concurrently. Do not administer metronidazole to patients who
have taken disulfiram within the last two weeks (see PRECAUTIONS-Drug
Interactions).
Interaction with Alcohol
Use of oral metronidazole is associated with a disulfiram-like reaction to alcohol,
including abdominal cramps, nausea, vomiting, headaches, and flushing. Discontinue
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consumption of alcohol or products containing propylene glycol during and for at least
three days after therapy with metronidazole (see PRECAUTIONS-Drug Interactions).
WARNINGS
Central and Peripheral Nervous System Effects
Encephalopathy and peripheral neuropathy: Cases of encephalopathy and peripheral
neuropathy (including optic neuropathy) have been reported with metronidazole.
Encephalopathy has been reported in association with cerebellar toxicity characterized by
ataxia, dizziness, and dysarthria. CNS lesions seen on MRI have been described in
reports of encephalopathy. CNS symptoms are generally reversible within days to weeks
upon discontinuation of metronidazole. CNS lesions seen on MRI have also been
described as reversible.
Peripheral neuropathy, mainly of sensory type has been reported and is characterized by
numbness or paresthesia of an extremity.
Convulsive seizures have been reported in patients treated with metronidazole.
Aseptic meningitis: Cases of aseptic meningitis have been reported with metronidazole.
Symptoms can occur within hours of dose administration and generally resolve after
metronidazole therapy is discontinued.
The appearance of abnormal neurologic signs and symptoms demands the prompt
evaluation of the benefit/risk ratio of the continuation of therapy (see ADVERSE
REACTIONS).
PRECAUTIONS
General
Hepatic Impairment
Patients with hepatic impairment metabolize metronidazole slowly, with resultant
accumulation of metronidazole in the plasma. For patients with severe hepatic
impairment (Child-Pugh C), a reduced dose of METRONIDAZOLE INJECTION, USP is
recommended. For patients with mild to moderate hepatic impairment, no dosage
adjustment is needed but these patients should be monitored for metronidazole associated
adverse events (see CLINICAL PHARMACOLOGY and DOSAGE AND
ADMINISTRATION).
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Renal Impairment
Patients with end-stage renal disease may excrete metronidazole and metabolites slowly
in the urine, resulting in significant accumulation of metronidazole metabolites.
Monitoring for metronidazole associated adverse events is recommended (see
CLINICAL PHARMACOLOGY).
Fungal Superinfections
Known or previously unrecognized candidiasis may present more prominent symptoms
during therapy with Metronidazole Injection, USP and requires treatment with a
candicidal agent.
Use in Patients with Blood Dyscrasias
Metronidazole is a nitroimidazole, and should be used with care in patients with evidence
of or history of blood dyscrasia. A mild leukopenia has been observed during its
administration; however, no persistent hematologic abnormalities attributable to
metronidazole have been observed in clinical studies.
Monitoring for Leukopenia
Total and differential leukocyte counts are recommended before, during, and after
prolonged or repeated courses of metronidazole therapy.
Sodium Retention
Administration of solutions containing sodium ions may result in sodium retention. Care
should be taken when administering Metronidazole Injection, USP to patients receiving
corticosteroids or to patients predisposed to edema.
Drug-Resistant Bacteria
Prescribing Metronidazole Injection, USP in the absence of a proven or strongly
suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to
the patient and increases the risk of the development of drug-resistant bacteria.
Information for Patients
Interaction with Alcohol
Discontinue consumption of alcoholic beverages or products containing propylene glycol
while taking Metronidazole Injection, USP and for at least three days afterward because
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abdominal cramps, nausea, vomiting, headaches, and flushing may occur (see
CONTRAINDICATIONS, PRECAUTIONS-Drug Interactions).
Treatment of Bacterial Infections
Patients should be counseled that antibacterial drugs including Metronidazole Injection,
USP should only be used to treat bacterial infections. They do not treat viral infections
(e.g., the common cold). When Metronidazole Injection, USP is prescribed to treat a
bacterial infection, patients should be told that although it is common to feel better early
in the course of therapy, the medication should be taken exactly as directed. Skipping
doses or not completing the full course of therapy may (1) decrease the effectiveness of
the immediate treatment and (2) increase the likelihood that bacteria will develop
resistance and will not be treatable by Metronidazole Injection, USP or other antibacterial
drugs in the future.
Drug Interactions
Disulfiram
Psychotic reactions have been reported in alcoholic patients who are using metronidazole
and disulfiram concurrently. Metronidazole should not be given to patients who have
taken disulfiram within the last two weeks (see CONTRAINDICATIONS).
Alcoholic Beverages
Abdominal cramps, nausea, vomiting, headaches and flushing may occur if alcoholic
beverages or products containing propylene glycol are consumed during or following
metronidazole therapy (see CONTRAINDICATIONS).
Warfarin and other Oral Anticoagulants
Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and
other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time.
When Metronidazole Injection, USP is prescribed for patients on this type of
anticoagulant therapy, prothrombin time and INR should be carefully monitored.
Lithium
In patients stabilized on relatively high doses of lithium, short-term metronidazole
therapy has been associated with elevation of serum lithium and, in a few cases, signs of
lithium toxicity. Serum lithium and serum creatinine levels should be obtained several
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days after beginning metronidazole to detect any increase that may precede clinical
symptoms of lithium intoxication.
Busulfan
Metronidazole has been reported to increase plasma concentrations of busulfan, which
can result in an increased risk for serious busulfan toxicity. Metronidazole should not be
administered concomitantly with busulfan unless the benefit outweighs the risk. If no
therapeutic alternatives to metronidazole are available, and concomitant administration
with busulfan is medically needed, frequent monitoring of busulfan plasma concentration
should be performed and the busulfan dose should be adjusted accordingly.
Drugs that Inhibit CYP450 Enzymes
The simultaneous administration of drugs that decrease microsomal liver enzyme
activity, such as cimetidine, may prolong the half-life and decrease plasma clearance of
metronidazole.
Drugs that Induce CYP450 Enzymes
The simultaneous administration of drugs that induce microsomal liver enzyme activity,
such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole,
resulting in reduced plasma levels; impaired clearance of phenytoin has also been
reported.
Drug/Laboratory Test Interactions
Metronidazole may interfere with certain types of determinations of serum chemistry
values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase
(ALT, SGPT), lactate dehydrogenase (LDH), triglycerides and glucose hexokinase.
Values of zero may be observed. All of the assays in which interference has been
reported involve enzymatic coupling of the assay to oxidation-reduction of nicotine
adenine dinucleotide (NAD
+ ⇌NADH). Interference is due to the similarity in absorbance
peaks of NADH (340nm) and metronidazole (322nm) at pH 7.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Tumors affecting the liver, lung, mammary and lymphatic tissues have been detected in
several studies of metronidazole in rats and mice, but not hamsters.
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Pulmonary tumors have been observed in all six reported studies in the mouse, including
one study in which the animals were dosed on an intermittent schedule (administration
during every fourth week only). Malignant tumors were increased in male mice treated at
approximately 1500 mg/m2 (similar to the maximum recommended daily dose, based on
body surface area comparisons). Malignant lymphomas and pulmonary neoplasms were
also increased with lifetime feeding of the drug to mice. Mammary and hepatic tumors
were increased among female rats administered oral metronidazole compared to
concurrent controls. Two lifetime tumorigenicity studies in hamsters have been
performed and reported to be negative.
Metronidazole has shown mutagenic activity in in vitro assay systems including the
Ames test. Studies in mammals in vivo have failed to demonstrate a potential for genetic
damage.
Metronidazole failed to produce any adverse effects on fertility or testicular function in
male rats at doses up to 400 mg/kg/day (approximately 2 times the maximum
recommended daily dose based on body surface area comparison) for 28 days. However,
rats treated at the same dose for 6 weeks, or longer were infertile and showed severe
degeneration of the seminiferous epithelium in the testes as well as marked decreases in
testicular spermatid counts and epididymal sperm counts. Fertility was restored in most
rats after an eight week, drug-free recovery period.
Fertility studies have been performed in male mice at doses up to six times the maximum
recommended human dose based on mg/m2 and have revealed no evidence of impaired
fertility. However, metronidazole was associated with reversible adverse effects on the
male reproductive system (significantly decreased testes and epididymides weight,
decreased sperm viability, and increased the incidence of abnormal sperm).
Pregnancy
Teratogenic Effects
Pregnancy Category B
There are no adequate and well-controlled studies of Metronidazole Injection, USP in
pregnant women. There are published data from case-control studies, cohort studies, and
2 meta-analyses that include more than 5000 pregnant women who used metronidazole
during pregnancy. Many studies included first trimester exposures. One study showed an
increased risk of cleft lip, with or without cleft palate, in infants exposed to
metronidazole in utero; however, these findings were not confirmed. In addition, more
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than ten randomized, placebo-controlled clinical trials enrolled more than 5000 pregnant
women to assess the use of antibiotic treatment (including metronidazole) for bacterial
vaginosis on the incidence of preterm delivery. Most studies did not show an increased
risk for congenital anomalies or other adverse fetal outcomes following metronidazole
exposure during pregnancy. Three studies conducted to assess the risk of infant cancer
following metronidazole exposure during pregnancy did not show an increased risk;
however, the ability of these studies to detect such a signal was limited.
Metronidazole crosses the placental barrier and its effects on the human fetal
organogenesis are not known. Reproduction studies have been performed in rats, rabbits
and mice at doses similar to the maximum recommended daily dose based on body
surface area comparisons. There was no evidence of harm to the fetus due to
metronidazole.
Nursing Mothers
Metronidazole is present in human milk at concentrations similar to maternal serum
levels, and infant serum levels can be close to or comparable to infant therapeutic levels.
Because of the potential for tumorigenicity shown for metronidazole in mouse and rat
studies, a decision should be made whether to discontinue nursing or to discontinue the
drug, taking into account the importance of the drug to the mother. Alternatively, a
nursing mother may choose to pump and discard human milk for the duration of
metronidazole therapy, and for 24 hours after therapy ends and feed her infant stored
human milk or formula.
Geriatric Use
In geriatric patients, monitoring for metronidazole associated adverse events is
recommended (see CLINICAL PHARMACOLOGY, PRECAUTIONS). Decreased
liver function in geriatric patients can result in increased concentrations of metronidazole
that may necessitate adjustment of metronidazole dosage (see DOSAGE AND
ADMINISTRATION).
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
ADVERSE REACTIONS
The following reactions have been reported during treatment with metronidazole.
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Central Nervous System
The most serious adverse reactions reported in patients treated with metronidazole have
been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral
neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity.
Since persistent peripheral neuropathy has been reported in some patients receiving
prolonged administration of metronidazole, patients should be specifically warned about
these reactions and should be told to stop the drug and report immediately to their
physicians if any neurologic symptoms occur. In addition, patients have reported
headache, syncope, dizziness, vertigo, incoordination, ataxia, confusion, dysarthria,
irritability, depression, weakness, and insomnia (see WARNINGS).
The following reactions have also been reported during treatment with metronidazole.
Gastrointestinal
The most common adverse reactions reported have been referable to the gastrointestinal
tract, particularly nausea, sometimes accompanied by headache, anorexia and
occasionally vomiting, diarrhea; epigastric distress; abdominal cramping; and
constipation.
Mouth
A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis and stomatitis
have occurred; these may be associated with a sudden overgrowth of Candida which may
occur during effective therapy.
Dermatologic
Erythematous rash and pruritus.
Hematopoietic
Reversible neutropenia (leukopenia); rarely, reversible thrombocytopenia.
Local Reactions
Thrombophlebitis after intravenous infusion. This reaction can be minimized or avoided
by avoiding prolonged use of indwelling intravenous catheters.
Cardiovascular
Flattening of the T-wave may be seen in electrocardiographic tracings.
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Hypersensitivity
Urticaria, erythematous rash, Stevens-Johnson syndrome, toxic epidermal necrolysis,
flushing, nasal congestion, dryness of the mouth (or vagina or vulva) and fever.
Renal
Dysuria, cystitis, polyuria, incontinence, and a sense of pelvic pressure. Instances of
darkened urine have been reported by approximately one patient in 100,000. Although
the pigment which is probably responsible for this phenomenon has not been positively
identified, it is almost certainly a metabolite of metronidazole and seems to have no
clinical significance.
Other
Proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis and
fleeting joint pains sometimes resembling “serum sickness”. Rare cases of pancreatitis,
which abated on withdrawal of the drug, have been reported.
Patients with Crohn's disease are known to have an increased incidence of
gastrointestinal and certain extraintestinal cancers. There have been some reports in the
medical literature of breast and colon cancer in Crohn's disease patients who have been
treated with metronidazole at high doses for extended periods of time. A cause and effect
relationship has not been established. Crohn's disease is not an approved indication for
Metronidazole Injection, USP.
OVERDOSAGE
Use of dosages of intravenous metronidazole higher than those recommended has been
reported. These include the use of 27 mg/kg three times a day for 20 days, and the use of
75 mg/kg as a single loading dose followed by 7.5 mg/kg maintenance doses. No adverse
reactions were reported in either of the two cases.
Single oral dose of metronidazole, up to 15 g, have been reported in suicide attempts and
accidental overdoses. Symptoms reported included nausea, vomiting and ataxia.
Oral metronidazole has been studied as a radiation sensitizer in the treatment of
malignant tumors. Neurotoxic effects, including seizures and peripheral neuropathy, have
been reported after 5 to 7 days of doses of 6 to 10.4 g every other day.
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Treatment of Overdosage
There is no specific antidote for metronidazole overdose; therefore, management of the
patient should consist of symptomatic and supportive therapy.
DOSAGE AND ADMINISTRATION
Treatment of Anaerobic Bacterial Infections
The recommended dosage schedule for adults is:
Loading Dose
15 mg/kg infused over one hour (approximately 1 g for a 70-kg adult).
Maintenance Dose
7.5 mg/kg infused over one hour every six hours (approximately 500 mg for a
70-kg adult). The first maintenance dose should be instituted six hours
following the initiation of the loading dose.
Parenteral therapy may be changed to oral metronidazole when conditions warrant, based
upon the severity of the disease and the response of the patient to Metronidazole
Injection, USP treatment. The usual adult oral dosage is 7.5 mg/kg every six hours
(approximately 500 mg for a 7-kg adult).
A maximum of 4 g should not be exceeded during a 24-hour period.
The usual duration of therapy is 7 to 10 days; however, infections of the bone and joint,
lower respiratory tract and endocardium may require longer treatment.
Dosage Adjustments
Patients with Severe Hepatic Impairment
For patients with severe hepatic impairment (Child-Pugh C), the metronidazole dose
should be reduced by 50% (see CLINICAL PHARMACOLOGY and
PRECAUTIONS).
Patients Undergoing Hemodialysis
Hemodialysis removes significant amounts of metronidazole and its metabolites from
systemic circulation. The clearance of metronidazole will depend on the type of dialysis
membrane used, the duration of the dialysis session, and other factors. If the
administration of metronidazole cannot be separated from a hemodialysis session,
supplementation of metronidazole dosage following a hemodialysis session should be
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considered, depending on the patient’s clinical situation (see CLINICAL
PHARMACOLOGY).
Prophylaxis
For surgical prophylactic use, to prevent postoperative infection in contaminated or
potentially contaminated colorectal surgery, the recommended dosage schedule for adults
is:
a. 15 mg/kg infused over 30 to 60 minutes and completed approximately one hour
before surgery; followed by
b. 7.5 mg/kg infused over 30 to 60 minutes at 6 and 12 hours after the initial dose.
It is important that (1) administration of the initial preoperative dose be completed
approximately one hour before surgery so that adequate drug levels are present in the
serum and tissues at the time of initial incision, and (2) Metronidazole Injection, USP be
administered, if necessary, at 6-hour intervals to maintain effective drug levels.
Prophylactic use of Metronidazole Injection, USP should be limited to the day of surgery
only, following the above guidelines.
Caution: Metronidazole Injection, USP is to be administered by slow intravenous
drip infusion only, either as a continuous or intermittent infusion. Additives should
not be introduced into Metronidazole Injection, USP. If used with a primary
intravenous fluid system, the primary solution should be discontinued during
metronidazole infusion. DO NOT USE EQUIPMENT CONTAINING ALUMINUM
(e.g., NEEDLES, CANNULAE) THAT WOULD COME IN CONTACT WITH
THE DRUG SOLUTION.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
HOW SUPPLIED
Metronidazole Injection, USP is supplied in 100 mL single dose plastic containers, each
containing an iso-osmotic, buffered solution of 500 mg metronidazole as follows:
2B3421
NDC 0338-1055-48
500 mg/100 mL
Store at controlled room temperature (77°F or 25°C) and protect from light during
storage. Do not remove unit from overwrap until ready for use. The overwrap is a
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moisture barrier. The inner bag maintains the sterility of the product. After removing
overwrap, check for minute leaks by squeezing inner bag firmly. If leaks are found,
discard solution as sterility may be impaired.
DIRECTIONS FOR USE OF VIAFLEX PLUS PLASTIC CONTAINER
Metronidazole Injection, USP is a ready-to-use iso-osmotic solution. No dilution or
buffering is required. Do not refrigerate. Each container of Metronidazole Injection,
USP contains 14 mEq of sodium.
Warning: Do not use plastic containers in series connections. Such use could result in air
embolism due to residual air being drawn from the primary container before
administration of the fluid from the secondary container is completed.
To open
Tear overwrap down side at slit and remove solution container. Some opacity of the
plastic due to moisture absorption during the sterilization process may be observed. This
is normal and does not affect the solution quality or safety. The opacity will diminish
gradually. Check for leaks. Do not add supplementary medication.
Preparation for Administration
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
REFERENCES
1.
Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial
Susceptibility Testing of Anaerobic Bacteria; Approved Standard—Eighth Edition.
CLSI Document M11-A8, CLSI, 950 West Valley Road, Suite 2500, Wayne,
Pennsylvania 19087-1898 USA, 2012.
2.
Clinical and Laboratory Standards Institute (CLSI). Performance Standards for
Antimicrobial Susceptibility Testing; Twenty-third Informational Supplement, CLSI
Document M100-S23, CLSI, 950 West Valley Road, Suite 2500, Wayne,
Pennsylvania 19087-1898, USA, 2013.
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Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
Baxter and Viaflex are registered trademarks of Baxter International Inc.
ATCC is a registered trademark of the American Type Culture Collection
F7-19-67-812
Rev. Sept 2013
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|
custom-source
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2025-02-12T13:44:49.591930
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018657s032lbl.pdf', 'application_number': 18657, 'submission_type': 'SUPPL ', 'submission_number': 32}
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Page 3
Metronidazole Injection, USP RTU
in Plastic Container
VIAFLEX Plus Container
To reduce the development of drug-resistant bacteria and maintain the effectiveness of
Metronidazole Injection, USP RTU and other antibacterial drugs, Metronidazole Injection, USP
RTU should be used only to treat or prevent infections that are proven or strongly suspected to
be caused by bacteria.
Warning
Metronidazole has been shown to be carcinogenic in mice and rats (see Precautions). Its
use, therefore, should be reserved for the conditions described in the Indications and
Usage section below.
DESCRIPTION
Metronidazole Injection, USP RTU, is a parenteral dosage form of the synthetic antibacterial
agent 1-(ß-hydroxyethyl)-2-methyl-5-nitroimidazole. structural formula
Metronidazole Injection, USP RTU, in 100 mL VIAFLEX Plus single dose plastic container, is a
sterile, nonpyrogenic, iso-osmotic, buffered solution of 500 mg Metronidazole, USP, 790 mg
Sodium Chloride, USP, 47.6 mg Dibasic Sodium Phosphate Dried, USP and 22.9 mg Citric Acid
Anhydrous, USP. Metronidazole Injection, USP RTU has an osmolarity of 310 mOsmol/L (calc)
and a pH of 5.5 (4.5 to 7.0). Each container contains 14 mEq of sodium.
The plastic container is fabricated from a specially formulated polyvinyl chloride plastic. Water
can permeate from inside the container into the overwrap in amounts insufficient to affect the
solution significantly. Solutions in contact with the plastic container can leach out certain of its
chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl
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NDA 018657/S-31
Page 4
phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been
confirmed in tests in animals according to USP biological tests for plastic containers as well as
by tissue culture toxicity studies.
CLINICAL PHARMACOLOGY
Metronidazole is a synthetic antibacterial compound. Disposition of metronidazole in the body is
similar for both oral and intravenous dosage forms, with an average elimination half-life in
healthy humans of eight hours.
The major route of elimination of metronidazole and its metabolites is via the urine (60-80% of
the dose), with fecal excretion accounting for 6-15% of the dose. The metabolites that appear in
the urine result primarily from side-chain oxidation [1-(ß-hydroxyethyl)-2-hydroxymethyl-5
nitroimidazole and 2-methyl-5-nitroimidazole-1-yl-acetic acid] and glucuronide conjugation,
with unchanged metronidazole accounting for approximately 20% of the total. Renal clearance
of metronidazole is approximately 10 mL/min/1.73 m2.
Metronidazole is the major component appearing in the plasma, with lesser quantities of the 2
hydroxymethyl metabolite also being present. Less than 20% of the circulating metronidazole is
bound to plasma proteins. Both the parent compound and the metabolite possess in vitro
bactericidal activity against most strains of anaerobic bacteria.
Metronidazole appears in cerebrospinal fluid, saliva and breast milk in concentrations similar to
those found in plasma. Bactericidal concentrations of metronidazole have also been detected in
pus from hepatic abscesses.
Plasma concentrations of metronidazole are proportional to the administered dose. An eight-hour
intravenous infusion of 100-4,000 mg of metronidazole in normal subjects showed a linear
relationship between dose and peak plasma concentration.
In patients treated with intravenous metronidazole, using a dosage regimen of 15 mg/kg loading
dose followed six hours later by 7.5 mg/kg every six hours, peak steady-state plasma
concentrations of metronidazole averaged 25 mcg/mL with trough (minimum) concentrations
averaging 18 mcg/mL.
Decreased renal function does not alter the single-dose pharmacokinetics of metronidazole.
However, plasma clearance of metronidazole is decreased in patients with decreased liver
function.
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In one study newborn infants appeared to demonstrate diminished capacity to eliminate
metronidazole. The elimination half-life, measured during the first three days of life, was
inversely related to gestational age. In infants whose gestational ages were between 28 and 40
weeks, the corresponding elimination half-lives ranged from 109 to 22.5 hours.
Microbiology:
Metronidazole is active in vitro against most obligate anaerobes, but does not appear to possess
any clinically relevant activity against facultative anaerobes or obligate aerobes. Against
susceptible organisms, metronidazole is generally bactericidal at concentrations equal to or
slightly higher than the minimal inhibitory concentrations. Metronidazole has been shown to
have in vitro and clinical activity against the following organisms:
Anaerobic gram-negative bacilli, including:
Bacteroides species, including the Bacteroides fragilis group (B. fragilis,
B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus)
Fusobacterium species
Anaerobic gram-positive bacilli, including:
Clostridium species and susceptible strains of Eubacterium
Anaerobic gram-positive cocci, including:
Peptococcus species
Peptostreptococcus species
Many nonspore-forming, gram-positive anaerobic rods are resistant to metronidazole1
Susceptibility Tests:
Bacteriologic studies should be performed to determine the causative organisms and their
susceptibility to metronidazole; however, the rapid, routine susceptibility testing of individual
isolates of anaerobic bacteria is not always practical, and therapy may be started while awaiting
these results.
Quantitative methods give the most accurate estimates of susceptibility to antibacterial drugs. A
standardized agar dilution method and a broth microdilution method are recommended1.
Interpretive criteria for determining the susceptibility of an organism to metronidazole are:
Dilution a
MIC (mcg/mL)
Interpretation
≤ 8
(S) Susceptible
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16
(I) Intermediate
≥ 32
(R) Resistant
a.
MIC values for agar or broth microdilution are considered equivalent.
A bacterial isolate may be considered susceptible if the MIC value for metronidazole is not more
than 8 mcg/mL. An organism with a metronidazole MIC of 16 mcg/mL is considered
intermediate in susceptibility. An organism is considered resistant if the MIC is greater than 16
mcg/mL. The intermediate range was established because of the difficulty in reading endpoints
and the clustering of MICs at or near breakpoint concentrations. Where data are available, the
interpretive guidelines are based on pharmacokinetic data, population distributions of MICs, and
studies of clinical efficacy. To achieve the best possible levels of a drug in abscesses and/or
poorly perfused tissues, which are encountered commonly in these infections, maximum
approved dosages of antimicrobial agents are recommended for therapy of anaerobic infections.
When maximum dosages are used along with appropriate ancillary therapy, it is believed that
organisms with susceptible endpoints are generally amenable to therapy, and those with
intermediate endpoints may respond, but patient response should be carefully monitored.
Ancillary therapy, such as drainage procedures and debridement, are of great importance for the
proper management of anaerobic infections. A report of "resistant" from the laboratory indicates
that the infecting organism is not likely to respond to therapy. Routine testing of metronidazole
for management of C difficile-associated diarrhea is not recommended because correlation with
clinical failures has not been established.1
Control strains are recommended for standardized susceptibility testing. Each time the test is
performed, one or more control strains should be included. A clinical laboratory test is
considered under acceptable control if the results of the control strains are within the MIC ranges
reported below.2
For reference agar dilution testing, metronidazole MIC ranges associated with control strains are:
Control Strain
ATCC® numbera
MIC range (mcg/mL)
Bacteroides fragilis
25285
0.25 - 1
Bacteroides thetaiotaomicron
2974
0.5 - 2
Clostridium difficile
700057
0.125 – 0.5
a.
ATTC is a registered trademark of the American Type Culture Collection
For broth microdilution testing, metronidazole MIC ranges associated with control strains are:
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Control Strain
ATCC® numbera
MIC range (mcg/mL)
Bacteroides fragilis
25285
0.25 - 2
Bacteroides thetaiotaomicron
2974
0.5 - 4
Eubacterium lentum
43055
0.125 – 0.5
a.
ATTC is a registered trademark of the American Type Culture Collection
INDICATIONS AND USAGE
Treatment of Anaerobic Infections
Metronidazole Injection, USP RTU is indicated in the treatment of serious infections caused by
susceptible anaerobic bacteria. Indicated surgical procedures should be performed in conjunction
with Metronidazole Injection, USP RTU therapy. In a mixed aerobic and anaerobic infection,
antibiotics appropriate for the treatment of the aerobic infection should be used in addition to
Metronidazole Injection, USP RTU.
Metronidazole Injection, USP RTU is effective in Bacteroides fragilis infections resistant to
clindamycin, chloramphenicol and penicillin.
Intra-Abdominal Infections, including peritonitis, intra-abdominal abscess and liver abscess,
caused by Bacteroides species including the B. fragilis group (B. fragilis, B. distasonis, B.
ovatus, B. thetaiotaomicron, B. vulgatus), Clostridium species, Eubacterium species,
Peptococcus species and Peptostreptococcus species.
Skin and Skin Structure Infections caused by Bacteroides species including the B. fragilis
group, Clostridium species, Peptococcus species, Peptostreptococcus species and Fusobacterium
species.
Gynecologic Infections, including endometritis, endomyometritis, tubo-ovarian abscess and
postsurgical vaginal cuff infection, caused by Bacteroides species including the B. fragilis group,
Clostridium species, Peptostreptococcus species and Fusobacterium species.
Bacterial Septicemia caused by Bacteroides species including the B. fragilis group and
Clostridium species.
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Bone and Joint Infections, as adjunctive therapy, caused by Bacteroides species including the
B. fragilis group.
Central Nervous System (CNS) Infections, including meningitis and brain abscess, caused by
Bacteroides species including the B. fragilis group.
Lower Respiratory Tract Infections, including pneumonia, empyema and lung abscess, caused
by Bacteroides species including the B. fragilis group.
Endocarditis caused by Bacteroides species including the B. fragilis group.
Prophylaxis
The prophylactic administration of Metronidazole Injection, USP RTU preoperatively,
intraoperatively and postoperatively may reduce the incidence of postoperative infection in
patients undergoing elective colorectal surgery which is classified as contaminated or potentially
contaminated. Prophylactic use of Metronidazole Injection, USP RTU should be discontinued
within 12 hours after surgery. If there are signs of infection, specimens for cultures should be
obtained for the identification of the causative organism(s) so that appropriate therapy may be
given (see Dosage and Administration).
To reduce the development of drug-resistant bacteria and maintain the effectiveness of
Metronidazole Injection, USP RTU and other antibacterial drugs, Metronidazole Injection, USP
RTU should be used only to treat or prevent infections that are proven or strongly suspected to
be caused by susceptible bacteria. When culture and susceptibility information are available, they
should be considered in selecting or modifying antibacterial therapy. In the absence of such data,
local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
CONTRAINDICATIONS
Metronidazole Injection, USP RTU is contraindicated in patients with a prior history of
hypersensitivity to metronidazole or other nitroimidazole derivatives.
WARNINGS
Central And Peripheral Nervous System Effects
Encephalopathy and peripheral neuropathy: Cases of encephalopathy and peripheral neuropathy
(including optic neuropathy) have been reported with metronidazole.
Reference ID: 2984567
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018657/S-31
Page 9
Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia,
dizziness, and dysarthria. CNS lesions seen on MRI have been described in reports of
encephalopathy. CNS symptoms are generally reversible within days to weeks upon
discontinuation of metronidazole. CNS lesions seen on MRI have also been described as
reversible.
Peripheral neuropathy, mainly of sensory type has been reported and is characterized by
numbness or paresthesia of an extremity.
Convulsive seizures have been reported in patients treated with metronidazole.
Aseptic meningitis: Cases of aseptic meningitis have been reported with metronidazole.
Symptoms can occur within hours of dose administration and generally resolve after
metronidazole therapy is discontinued.
The appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of
the benefit/risk ratio of the continuation of therapy.
PRECAUTIONS
General
Patients with severe hepatic disease metabolize metronidazole slowly, with resultant
accumulation of metronidazole and its metabolites in the plasma. Accordingly, for such patients,
doses below those usually recommended should be administered cautiously.
Administration of solutions containing sodium ions may result in sodium retention. Care should
be taken when administering Metronidazole Injection, USP RTU to patients receiving
corticosteroids or to patients predisposed to edema.
Known or previously unrecognized candidiasis may present more prominent symptoms during
therapy with Metronidazole Injection, USP RTU and requires treatment with a candicidal agent.
Prescribing Metronidazole Injection, USP RTU in the absence of a proven or strongly suspected
bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and
increases the risk of the development of drug-resistant bacteria.
Reference ID: 2984567
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018657/S-31
Page 10
Laboratory Tests
Metronidazole is a nitroimidazole, and should be used with care in patients with evidence of or
history of blood dyscrasia. A mild leukopenia has been observed during its administration;
however, no persistent hematologic abnormalities attributable to metronidazole have been
observed in clinical studies. Total and differential leukocyte counts are recommended before and
after therapy.
Drug Interactions
Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral
coumarin anticoagulants, resulting in a prolongation of prothrombin time. This possible drug
interaction should be considered when Metronidazole Injection, USP RTU is prescribed for
patients on this type of anticoagulant therapy.
The simultaneous administration of drugs that induce microsomal liver enzyme activity, such as
phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in
reduced plasma levels; impaired clearance of phenytoin has also been reported.
The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such
as cimetidine, may prolong the half-life and decrease plasma clearance of metronidazole.
Alcoholic beverages should not be consumed during metronidazole therapy because abdominal
cramps, nausea, vomiting, headaches and flushing may occur.
Psychotic reactions have been reported in alcoholic patients who are using metronidazole and
disulfiram concurrently. Metronidazole should not be given to patients who have taken
disulfiram within the last two weeks.
Drug/Laboratory Test Interactions
Metronidazole may interfere with certain types of determinations of serum chemistry values,
such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT),
lactate dehydrogenase (LDH), triglycerides and hexokinase glucose. Values of zero may be
observed. All of the assays in which interference has been reported involve enzymatic coupling
of the assay to oxidation-reduction of nicotine adenine dinucleotide (NAD
+ ⇌NADH).
Interference is due to the similarity in absorbance peaks of NADH (340nm) and metronidazole
(322nm) at pH 7.
Reference ID: 2984567
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018657/S-31
Page 11
Carcinogenesis, Mutagenesis, Impairment of Fertility
Tumorigenicity in Rodents - Metronidazole has shown evidence of carcinogenic activity in
studies involving chronic, oral administration in mice and rats, but similar studies in the hamster
gave negative results. Also, metronidazole has shown mutagenic activity in a number of in vitro
assay systems, but studies in mammals (in vivo) failed to demonstrate a potential for genetic
damage.
Pregnancy
Teratogenic Effects
Pregnancy Category B
Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. Reproduction
studies have been performed in rats at doses up to five times the human dose and have revealed
no evidence of impaired fertility or harm to the fetus due to metronidazole. Metronidazole
administered intraperitoneally to pregnant mice at approximately the human dose caused
fetotoxicity; administered orally to pregnant mice, no fetotoxicity was observed. There are,
however, no adequate and well-controlled studies in pregnant women. Because animal
reproduction studies are not always predictive of human response, and because metronidazole is
a carcinogen in rodents, these drugs should be used during pregnancy only if clearly needed.
Nursing Mothers
Because of the potential for tumorigenicity shown for metronidazole in mouse and rat studies, a
decision should be made whether to discontinue nursing or to discontinue the drug, taking into
account the importance of the drug to the mother. Metronidazole is secreted in breast milk in
concentrations similar to those found in plasma.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Information for Patients
Patients should be counseled that antibacterial drugs including Metronidazole Injection, USP
RTU should only be used to treat bacterial infections. They do not treat viral infections (e.g., the
common cold). When Metronidazole Injection, USP RTU is prescribed to treat a bacterial
Reference ID: 2984567
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018657/S-31
Page 12
infection, patients should be told that although it is common to feel better early in the course of
therapy, the medication should be taken exactly as directed. Skipping doses or not completing
the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2)
increase the likelihood that bacteria will develop resistance and will not be treatable by
Metronidazole Injection, USP RTU or other antibacterial drugs in the future.
ADVERSE REACTIONS
The most serious adverse reactions reported in patients treated with metronidazole injection have
been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy,
the latter characterized mainly by numbness or paresthesia of an extremity. Since persistent
peripheral neuropathy has been reported in some patients receiving prolonged oral administration
of metronidazole, patients should be observed carefully if neurologic symptoms occur and a
prompt evaluation made of the benefit/risk ratio of the continuation of therapy.
The following reactions have also been reported during treatment with Metronidazole Injection,
USP RTU.
Gastrointestinal: Nausea, vomiting, abdominal discomfort, diarrhea and an unpleasant metallic
taste.
Hematopoietic: Reversible neutropenia (leukopenia).
Dermatologic: Erythematous rash and pruritus.
Central Nervous System: Encephalopathy, aseptic meningitis, optic neuropathy, headache,
dizziness, syncope, ataxia, confusion and dysarthria.
Hypersensitivity: Urticaria, erythematous rash, Stevens-Johnson Syndrome, flushing, nasal
congestion, dryness of the mouth (or vagina or vulva) and fever.
Local Reactions: Thrombophlebitis after intravenous infusion. This reaction can be minimized or
avoided by avoiding prolonged use of indwelling intravenous catheters.
Other: Fever. Instances of a darkened urine have also been reported, and this manifestation has
been the subject of a special investigation. Although the pigment which is probably responsible
for this phenomenon has not been positively identified, it is almost certainly a metabolite of
metronidazole and seems to have no clinical significance.
The following adverse reactions have been reported during treatment with oral metronidazole:
Reference ID: 2984567
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018657/S-31
Page 13
Gastrointestinal: Nausea, sometimes accompanied by headache, anorexia and occasionally
vomiting; diarrhea, epigastric distress, abdominal cramping and constipation.
Mouth: A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis and stomatitis
have occurred; these may be associated with a sudden overgrowth of Candida which may occur
during effective therapy.
Hematopoietic: Reversible neutropenia (leukopenia); rarely, reversible thrombocytopenia.
Cardiovascular: Flattening of the T-wave may be seen in electrocardiographic tracings.
Central Nervous System: Encephalopathy, aseptic meningitis, convulsive seizures, optic
neuropathy, peripheral neuropathy, dizziness, vertigo, incoordination, ataxia, confusion,
dysarthria, irritability, depression, weakness and insomnia.
Hypersensitivity: Urticaria, erythematous rash, Stevens-Johnson Syndrome, flushing, nasal
congestion, dryness of the mouth (or vagina or vulva) and fever.
Renal: Dysuria, cystitis, polyuria, incontinence, a sense of pelvic pressure and darkened urine.
Other: Proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis and
fleeting joint pains sometimes resembling “serum sickness.” If patients receiving metronidazole
drink alcoholic beverages, they may experience abdominal distress, nausea, vomiting, flushing or
headache. A modification of the taste of alcoholic beverages has also been reported. Rare cases
of pancreatitis, which abated on withdrawal of the drug, have been reported.
Crohn's disease patients are known to have an increased incidence of gastrointestinal and certain
extraintestinal cancers. There have been some reports in the medical literature of breast and
colon cancer in Crohn's disease patients who have been treated with metronidazole at high doses
for extended periods of time. A cause and effect relationship has not been established. Crohn's
disease is not an approved indication for Metronidazole Injection, USP RTU.
OVERDOSAGE
Use of dosages of intravenous metronidazole higher than those recommended has been reported.
These include the use of 27 mg/kg three times a day for 20 days, and the use of 75 mg/kg as a
single loading dose followed by 7.5 mg/kg maintenance doses. No adverse reactions were
reported in either of the two cases.
Single oral dose of metronidazole, up to 15 g, have been reported in suicide attempts and
accidental overdoses. Symptoms reported included nausea, vomiting and ataxia.
Reference ID: 2984567
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018657/S-31
Page 14
Oral metronidazole has been studied as a radiation sensitizer in the treatment of malignant
tumors. Neurotoxic effects, including seizures and peripheral neuropathy, have been reported
after 5 to 7 days of doses of 6 to 10.4 g every other day.
Treatment: There is no specific antidote for overdose; therefore, management of the patient
should consist of symptomatic and supportive therapy.
DOSAGE AND ADMINISTRATION
In elderly patients the pharmacokinetics of metronidazole may be altered and therefore
monitoring of serum levels may be necessary to adjust the metronidazole dosage accordingly.
Treatment of Anaerobic Infections
The recommended dosage schedule for adults is:
Loading Dose
15 mg/kg infused over one hour (approximately 1 g for a 70-kg adult).
Maintenance Dose
7.5 mg/kg infused over one hour every six hours (approximately 500 mg for a
70-kg adult). The first maintenance dose should be instituted six hours
following the initiation of the loading dose.
Parenteral therapy may be changed to oral metronidazole when conditions warrant, based upon
the severity of the disease and the response of the patient to Metronidazole Injection, USP RTU
treatment. The usual adult oral dosage is 7.5 mg/kg every six hours.
A maximum of 4 g should not be exceeded during a 24-hour period.
Patients with severe hepatic disease metabolize metronidazole slowly, with resultant
accumulation of metronidazole and its metabolites in the plasma. Accordingly, for such patients,
doses below those usually recommended should be administered cautiously. Close monitoring of
plasma metronidazole levels3 and toxicity is recommended.
In patients receiving Metronidazole Injection, USP RTU in whom gastric secretions are
continuously removed by nasogastric aspiration, sufficient metronidazole may be removed in the
aspirate to cause a reduction in serum levels.
The dose of Metronidazole Injection, USP RTU should not be specifically reduced in anuric
patients since accumulated metabolites may be rapidly removed by dialysis.
Reference ID: 2984567
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018657/S-31
Page 15
The usual duration of therapy is 7 to 10 days; however, infections of the bone and joint, lower
respiratory tract and endocardium may require longer treatment.
Prophylaxis
For surgical prophylactic use, to prevent postoperative infection in contaminated or potentially
contaminated colorectal surgery, the recommended dosage schedule for adults is:
a. 15 mg/kg infused over 30 to 60 minutes and completed approximately one hour before
surgery; followed by
b. 7.5 mg/kg infused over 30 to 60 minutes at 6 and 12 hours after the initial dose.
It is important that (1) administration of the initial preoperative dose be completed approximately
one hour before surgery so that adequate drug levels are present in the serum and tissues at the
time of initial incision, and (2) Metronidazole Injection, USP RTU be administered, if necessary,
at 6-hour intervals to maintain effective drug levels. Prophylactic use of Metronidazole Injection,
USP RTU should be limited to the day of surgery only, following the above guidelines.
Caution: Metronidazole Injection, USP RTU is to be administered by slow intravenous
drip infusion only, either as a continuous or intermittent infusion. Additives should not be
introduced into Metronidazole Injection, USP RTU. If used with a primary intravenous
fluid system, the primary solution should be discontinued during metronidazole infusion.
DO NOT USE EQUIPMENT CONTAINING ALUMINUM (e.g., NEEDLES,
CANNULAE) THAT WOULD COME IN CONTACT WITH THE DRUG SOLUTION.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit.
HOW SUPPLIED
Metronidazole Injection, USP RTU is supplied in 100 mL single dose plastic containers, each
containing an iso-osmotic, buffered solution of 500 mg metronidazole as follows:
2B3421
NDC 0338-1055-48
500 mg/100 mL
Store at controlled room temperature, 59° to 86°F (15° to 30°C) and protect from light during
storage. Do not remove unit from overwrap until ready for use. The overwrap is a moisture
barrier. The inner bag maintains the sterility of the product. After removing overwrap, check for
Reference ID: 2984567
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018657/S-31
Page 16
minute leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may
be impaired.
DIRECTIONS FOR USE OF VIAFLEX PLUS PLASTIC CONTAINER
Metronidazole Injection, USP RTU is a ready-to-use iso-osmotic solution. No dilution or
buffering is required. Do not refrigerate. Each container of Metronidazole Injection, USP RTU
contains 14 mEq of sodium.
Warning: Do not use plastic containers in series connections. Such use could result in air
embolism due to residual air being drawn from the primary container before administration of
the fluid from the secondary container is completed.
To open
Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due
to moisture absorption during the sterilization process may be observed. This is normal and does
not affect the solution quality or safety. The opacity will diminish gradually. Check for leaks. Do
not add supplementary medication.
Preparation for Administration
1. Suspend container from eyelet support.
2. Remove protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
REFERENCES
1.
Clinical and Laboratory Standards Institute. Methods for Antimicrobial Susceptibility
Testing of Anaerobic Bacteria; Approved Standard—Seventh Edition. CLSI document
M11-A7. Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400,
Wayne, Pennsylvania 19087-1898 USA, 2007.
2.
Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial
Susceptibility Testing of Anaerobic Bacteria; Informational Supplement. CLSI document
M11-S1 Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400,
Wayne, Pennsylvania 19087-1898 USA, 2009
Reference ID: 2984567
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 018657/S-31
Page 17
3.
Ralph, E.D. and Kirby, W.M.M.: Bioassay of Metronidazole with Either Anaerobic and
Aerobic Incubation, J. Infect. Dis. 132:587-591 (Nov.) 1975; or Gulaid, et al.:
Determination of Metronidazole and its Major Metabolites in Biological Fluids by High
Pressure Liquid Chromatography. BR.J.Clin. Pharmacol. 6:430-432, 1978.
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Printed in USA
*BAR CODE POSITION ONLY
07-19-xx-xxxx
©Copyright 1990, 1993, Baxter Healthcare Corporation.
All rights reserved.
Baxter and Viaflex are registered trademarks of Baxter International Inc. ATTC is a registered
trademark of the American Type Culture Collection
Metronidazole Injection, USP RTU is manufactured under sublicense from SCS
Pharmaceuticals, Chicago, IL 60680
by Baxter Healthcare Corporation, Deerfield, IL 60015
07-19-66-437
Rev. April, 2011
Reference ID: 2984567
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:49.837945
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018657s031lbl.pdf', 'application_number': 18657, 'submission_type': 'SUPPL ', 'submission_number': 31}
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C I A 7 0 2 3 0 K
Dextromethorphan Polistirex
Extended-Release Suspension (Cough Suppressant)
Contains
No Fever
Reducer
or Pain
Reliever
148 mL (5 fl oz)
Alcohol-free
Flavored Liquid
Flavored Liquid
FRONT LABEL
2 1/4"
2 7/8"
8137787
022014
NDC 63824-177-65
PT# C I A 60331
Reference ID: 3610277
(b) (4)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
C I A 70236M
PT# C I A 60333
8137779
Distributed by: Reckitt Benckiser, Parsippany, NJ 07054-0224 ©2014 RB 022114
Drug Facts
Active ingredient (in each 5 mL)
Purpose
Dextromethorphan polistirex equivalent to
30 mg dextromethorphan hydrobromide...................Cough suppressant
Uses temporarily relieves
I cough due to minor throat and bronchial irritation as may occur with
the common cold or inhaled irritants
I the impulse to cough to help you get to sleep
Warnings
Do not use if you are now taking a prescription monoamine oxidase
inhibitor (MAOI) (certain drugs for depression, psychiatric or emotional
conditions, or Parkinson’s disease), or for 2 weeks after stopping the
MAOI drug. If you do not know if your prescription drug contains an
MAOI, ask a doctor or pharmacist before taking this product.
Ask a doctor before use if you have
I chronic cough that lasts as occurs with smoking, asthma or emphysema
I cough that occurs with too much phlegm (mucus)
Stop use and ask a doctor if cough lasts more than 7 days, cough comes
back, or occurs with fever, rash or headache that lasts. These could be
signs of a serious condition.
If pregnant or breast-feeding, ask a health professional before use.
Keep out of reach of children. In case of overdose, get medical help or
contact a Poison Control Center right away.
Directions I shake bottle well before use
I measure only with dosing cup provided
I do not use dosing cup with other products
I dose as follows or as directed by a doctor
I mL = milliliter
adults and children
10 mL every 12 hours,
12 years of age and over
not to exceed 20 mL in 24 hours
children 6 to under
5 mL every 12 hours,
12 years of age
not to exceed 10 mL in 24 hours
children 4 to under
2.5 mL every 12 hours,
6 years of age
not to exceed 5 mL in 24 hours
children under 4 years of age
do not use
Other information I each 5 mL contains: sodium 7 mg
I store at 20-25°C (68-77°F) I dosing cup provided
Inactive ingredients citric acid, edetate disodium, ethylcellulose,
FD&C Yellow No. 6, flavor, high fructose corn syrup, methylparaben,
partially hydrogenated vegetable oil (soybean, cottonseed), polyethylene
glycol 3350, polysorbate 80, propylene glycol, propylparaben, purified
water, sucrose, tragacanth, xanthan gum
Questions? 1-888-963-3382
You may also report side effects to this phone number.
Also Available
In Grape Flavor
Please visit
our web site:
www.delsym.com
TAMPER EVIDENT: Do not use if the
neckband printed with is broken or missing.
See back panel for full dosing directions.
SHAKE WELL BEFORE USE.
Measure only with dosing cup provided.
Do not use dosing cup with other products.
mL = milliliter
10 mL
EVERY 12 HOURS
12 years
to adult
6 to
under 12
4 to
under 6
5 mL
EVERY 12 HOURS
2.5 mL
EVERY 12 HOURS
Under 4
Do not use
DELSYM® DOSING
Age (yr)
Dose
12 Hour Cough Relief
12 Hour Cough Relief
12 Hour
Cough Relief
Contains
No Fever Reducer
or Pain Reliever
Dosing Cup Included
Lot No.:
Exp. Date:
Dextromethorphan Polistirex
Extended-Release Suspension (Cough Suppressant)
Dextromethorphan Polistirex
Extended-Release Suspension (Cough Suppressant)
Flavored Liquid
Flavored Liquid
Alcohol-free
ay
ay
Ch
e
Dextromethorphan Polistirex
Extended-Release Suspension (Cough Suppressant)
Flavored Liquid
Flavored Liquid
NDC 63824-177-65
148 mL (5 fl oz)
3-63824-27665-6
(UPC @ 100% truncated)
Code 128
70236M
5 11/16"
1 11/16"
2 3/4"
Reference ID: 3610277
(b) (4)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Dextromethorphan Polistirex
Extended-Release Suspension (Cough Suppressant)
Alcohol-free
Flavored Liquid
Flavored Liquid
C I A 7 1 9 7 7 G
Contains
No Fever
Reducer
or Pain
Reliever
148 mL (5 fl oz)
Day or
FRONT LABEL
2 1/4"
2 7/8"
NDC 63824-173-65
PT# C I A 60331
8137790
022114
Reference ID: 3610277
(b) (4)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
C I A 71978J
PT# C I A 60333
8137782
Distributed by: Reckitt Benckiser, Parsippany, NJ 07054-0224 ©2014 RB 022014
Drug Facts
Active ingredient (in each 5 mL)
Purpose
Dextromethorphan polistirex equivalent to
30 mg dextromethorphan hydrobromide...................Cough suppressant
Uses temporarily relieves
I cough due to minor throat and bronchial irritation as may occur with
the common cold or inhaled irritants
I the impulse to cough to help you get to sleep
Warnings
Do not use if you are now taking a prescription monoamine oxidase
inhibitor (MAOI) (certain drugs for depression, psychiatric or emotional
conditions, or Parkinson’s disease), or for 2 weeks after stopping the
MAOI drug. If you do not know if your prescription drug contains an
MAOI, ask a doctor or pharmacist before taking this product.
Ask a doctor before use if you have
I chronic cough that lasts as occurs with smoking, asthma or emphysema
I cough that occurs with too much phlegm (mucus)
Stop use and ask a doctor if cough lasts more than 7 days, cough comes
back, or occurs with fever, rash or headache that lasts. These could be
signs of a serious condition.
If pregnant or breast-feeding, ask a health professional before use.
Keep out of reach of children. In case of overdose, get medical help or
contact a Poison Control Center right away.
Directions I shake bottle well before use
I measure only with dosing cup provided
I do not use dosing cup with other products
I dose as follows or as directed by a doctor
I mL = milliliter
adults and children
10 mL every 12 hours,
12 years of age and over
not to exceed 20 mL in 24 hours
children 6 to under
5 mL every 12 hours,
12 years of age
not to exceed 10 mL in 24 hours
children 4 to under
2.5 mL every 12 hours,
6 years of age
not to exceed 5 mL in 24 hours
children under 4 years of age
do not use
Other information I each 5 mL contains: sodium 7 mg
I store at 20-25°C (68-77°F) I dosing cup provided
Inactive ingredients citric acid anhydrous, D&C Red #33, edetate
disodium, ethylcellulose, FD&C Blue #1, flavor, high fructose corn syrup,
methylparaben, partially hydrogenated vegetable oil (soybean, cottonseed),
polyethylene glycol 3350, polysorbate 80, propylene glycol, propylparaben,
purified water, sucrose, tragacanth, xanthan gum
Questions? 1-888-963-3382
You may also report side effects to this phone number.
Please visit
our web site:
www.delsym.com
TAMPER EVIDENT: Do not use if the
neckband printed with is broken or missing.
Contains
No Fever Reducer
or Pain Reliever
Lot No.:
Exp. Date:
12 Hour
Cough Relief
Flavored Liquid
Flavored Liquid
See back panel for full dosing directions.
SHAKE WELL BEFORE USE.
Measure only with dosing cup provided.
Do not use dosing cup with other products.
mL = milliliter
10 mL
EVERY 12 HOURS
12 years
to adult
6 to
under 12
4 to
under 6
5 mL
EVERY 12 HOURS
2.5 mL
EVERY 12 HOURS
Under 4
Do not use
DELSYM® DOSING
Age (yr)
Dose
12 Hour Cough Relief
Dosing Cup Included
Dextromethorphan Polistirex
Extended-Release Suspension (Cough Suppressant)
12 Hour Cough Relief
Dextromethorphan Polistirex
Extended-Release Suspension (Cough Suppressant)
Also Available
In Orange Flavor
148 mL (5 fl oz)
Alcohol-free
a
t
a
t
Ch
e
Dextromethorphan Polistirex
Extended-Release Suspension (Cough Suppressant)
NDC 63824-173-65
Flavored Liquid
Flavored Liquid
UPC area is 1/16”
below score and is
1-7/32”w x 11/16”h
3-63824-27265-8
(UPC @ 100% truncated)
Code 128
71978J
5 11/16"
1 11/16"
2 3/4"
Reference ID: 3610277
(b) (4)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:50.006907
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018658Orig1s030lbl_replacement.pdf', 'application_number': 18658, 'submission_type': 'SUPPL ', 'submission_number': 30}
|
11,267
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ACCUTANE®
(isotretinoin)
CAPSULES
CAUSES BIRTH DEFECTS
AVOID PREGNANCY
CONTRAINDICATIONS AND WARNINGS: Accutane must not be used by females who are pregnant.
Although not every fetus exposed to Accutane has resulted in a deformed child, there is an extremely high
risk that a deformed infant can result if pregnancy occurs while taking Accutane in any amount even for
short periods of time. Potentially any fetus exposed during pregnancy can be affected. Presently, there are no
accurate means of determining, after Accutane exposure, which fetus has been affected and which fetus has
not been affected.
Major human fetal abnormalities related to Accutane administration in females have been documented.
There is an increased risk of spontaneous abortion. In addition, premature births have been reported.
Documented external abnormalities include: skull abnormality; ear abnormalities (including anotia,
micropinna, small or absent external auditory canals); eye abnormalities (including microphthalmia), facial
dysmorphia; cleft palate. Documented internal abnormalities include: CNS abnormalities (including cerebral
abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular
abnormalities; thymus gland abnormality; parathyroid hormone deficiency. In some cases death has
occurred with certain of the abnormalities previously noted.
Cases of IQ scores less than 85 with or without obvious CNS abnormalities have also been reported.
Accutane is contraindicated in females of childbearing potential unless the patient meets all of the following
conditions:
•
must NOT be pregnant or breast feeding.
•
must be capable of complying with the mandatory contraceptive measures required for Accutane therapy
and understand behaviors associated with an increased risk of pregnancy.
•
must be reliable in understanding and carrying out instructions.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Accutane must be prescribed under the System to Manage Accutane Related Teratogenicity
(S.M.A.R.T.
).
To prescribe Accutane, the prescriber must obtain a supply of yellow self-adhesive Accutane Qualification
Stickers. To obtain these stickers:
1) Read the booklet entitled System to Manage Accutane Related Teratogenicity
(S.M.A.R.T.
) Guide to
Best Practices.
2) Sign and return the completed S.M.A.R.T. Letter of Understanding containing the following Prescriber
Checklist:
•
I know the risk and severity of fetal injury/birth defects from Accutane
•
I know how to diagnose and treat the various presentations of acne
•
I know the risk factors for unplanned pregnancy and the effective measures for avoidance of unplanned
pregnancy
•
It is the informed patient’s responsibility to avoid pregnancy during Accutane therapy and for a month
after stopping Accutane. To help patients have the knowledge and tools to do so: before beginning
treatment of female patients with Accutane I will refer for expert, detailed pregnancy prevention
counseling and prescribing, reimbursed by the manufacturer, OR I have the expertise to perform this
function and elect to do so
•
I understand, and will properly use throughout the Accutane treatment course, the S.M.A.R.T.
procedures for Accutane, including monthly pregnancy avoidance counseling, pregnancy testing and use
of Accutane Qualification Stickers
3) To use the yellow self-adhesive Accutane Qualification Sticker: Accutane should not be prescribed or
dispensed to any patient (male or female) without a yellow self-adhesive Accutane Qualification Sticker.
For female patients, the yellow self-adhesive Accutane Qualification Sticker signifies that she:
•
Must have had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL
before receiving the initial Accutane prescription. The first test (a screening test) is obtained by the
prescriber when the decision is made to pursue qualification of the patient for Accutane. The second
pregnancy test (a confirmation test) should be done during the first five days of the menstrual period
immediately preceding the beginning of Accutane therapy. For patients with amenorrhea, the second test
should be done at least 11 days after the last act of unprotected sexual intercourse (without using two
effective forms of contraception). Each month of therapy, the patient must have a negative result from a
urine or serum pregnancy test. A pregnancy test must be repeated every month prior to the female
patient receiving each prescription. The manufacturer will make available urine pregnancy test kits for
female Accutane patients for the initial, second and monthly testing during therapy.
•
Must have selected and have committed to use two forms of effective contraception simultaneously, at
least one of which must be a primary form, unless absolute abstinence is the chosen method, or the
patient has undergone a hysterectomy. Patients must use two forms of effective contraception for at least
one month prior to initiation of Accutane therapy, during Accutane therapy, and for one month after
discontinuing Accutane therapy. Counseling about contraception and behaviors associated with an
increased risk of pregnancy must be repeated on a monthly basis.
Effective forms of contraception include both primary and secondary forms of contraception. Primary
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
forms of contraception include: tubal ligation, partner’s vasectomy, intrauterine devices, birth control
pills, and injectable/implantable/insertable hormonal birth control products. Secondary forms of
contraception include diaphragms, latex condoms, and cervical caps; each must be used with a
spermicide.
Any birth control method can fail. Therefore, it is critically important that women of childbearing
potential use two effective forms of contraception simultaneously. A drug interaction that decreases
effectiveness of hormonal contraceptives has not been entirely ruled out for Accutane. Although
hormonal contraceptives are highly effective, there have been reports of pregnancy from women who
have used oral contraceptives, as well as injectable/implantable contraceptive products. These reports
occurred while these patients were taking Accutane. These reports are more frequent for women who use
only a single method of contraception. Patients must receive written warnings about the rates of possible
contraception failure (included in patient education kits).
Prescribers are advised to consult the package insert of any medication administered concomitantly with
hormonal contraceptives, since some medications may decrease the effectiveness of these birth control
products. Patients should be prospectively cautioned not to self-medicate with the herbal supplement St.
John’s Wort because a possible interaction has been suggested with hormonal contraceptives based on
reports of breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort.
Pregnancies have been reported by users of combined hormonal contraceptives who also used some form
of St. John's Wort (see PRECAUTIONS).
•
Must have signed a Patient Information/Consent form that contains warnings about the risk of potential
birth defects if the fetus is exposed to isotretinoin.
•
Must have been informed of the purpose and importance of participating in the Accutane Survey and has
been given the opportunity to enroll (see PRECAUTIONS).
The yellow self-adhesive Accutane Qualification Sticker documents that the female patient is qualified, and
includes the date of qualification, patient gender, cut-off date for filling the prescription, and up to a 30-day
supply limit with no refills.
These yellow self-adhesive Accutane Qualification Stickers should also be used for male patients: check off
the “male” gender box without checking the qualification statement.
If a pregnancy does occur during treatment of a woman with Accutane, the prescriber and patient should
discuss the desirability of continuing the pregnancy. Prescribers are strongly encouraged to report all cases of
pregnancy to Roche @ 1-800-526-6367 where a Roche Pregnancy Prevention Program Specialist will be
available to discuss Roche pregnancy information, or prescribers may contact the Food and Drug
Administration MedWatch Program @ 1-800-FDA-1088.
Accutane should be prescribed only by prescribers who have demonstrated special competence in the
diagnosis and treatment of severe recalcitrant nodular acne, are experienced in the use of systemic retinoids,
have read the S.M.A.R.T.
Guide to Best Practices, signed and returned the completed S.M.A.R.T. Letter of
Understanding, and obtained self-adhesive Accutane Qualification Stickers. Accutane should not be
prescribed or dispensed without a yellow self-adhesive Accutane Qualification Sticker.
INFORMATION FOR PHARMACISTS:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ACCUTANE MUST ONLY BE DISPENSED:
• IN NO MORE THAN A 1-MONTH SUPPLY
• ONLY ON PRESENTATION OF AN ACCUTANE PRESCRIPTION WITH A
YELLOW SELF-ADHESIVE ACCUTANE QUALIFICATION STICKER WRITTEN
• WITHIN THE PREVIOUS 7 DAYS
• REFILLS REQUIRE A NEW PRESCRIPTION WITH A YELLOW SELF-
ADHESIVE ACCUTANE QUALIFICATION STICKER
• NO TELEPHONE OR COMPUTERIZED PRESCRIPTIONS ARE PERMITTED.
AN ACCUTANE MEDICATION GUIDE MUST BE GIVEN TO THE PATIENT EACH TIME
ACCUTANE IS DISPENSED, AS REQUIRED BY LAW. THIS ACCUTANE MEDICATION GUIDE IS
AN IMPORTANT PART OF THE RISK MANAGEMENT PROGRAM FOR THE PATIENT.
DESCRIPTION: Isotretinoin, a retinoid, is available as Accutane in 10-mg, 20-mg and 40-mg soft gelatin capsules
for oral administration. Each capsule contains beeswax, butylated hydroxyanisole, edetate disodium, hydrogenated
soybean oil flakes, hydrogenated vegetable oil, and soybean oil. Gelatin capsules contain glycerin and parabens
(methyl and propyl), with the following dye systems: 10 mg — iron oxide (red) and titanium dioxide; 20 mg —
FD&C Red No. 3, FD&C Blue No. 1, and titanium dioxide; 40 mg — FD&C Yellow No. 6, D&C Yellow No. 10,
and titanium dioxide.
Chemically, isotretinoin is 13-cis-retinoic acid and is related to both retinoic acid and retinol (vitamin A). It is a
yellow-orange to orange crystalline powder with a molecular weight of 300.44. The structural formula is:
CLINICAL PHARMACOLOGY: Isotretinoin is a retinoid, which when administered in pharmacologic dosages
of 0.5 to 1.0 mg/kg/day (see DOSAGE AND ADMINISTRATION), inhibits sebaceous gland function and
keratinization. The exact mechanism of action of isotretinoin is unknown.
Nodular Acne: Clinical improvement in patients with nodular acne occurs in association with a reduction in sebum
secretion. The decrease in sebum secretion is temporary and is related to the dose and duration of treatment with
Accutane, and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.1
Pharmacokinetics: Absorption:. Due to its high lipophilicity, oral absorption of isotretinoin is enhanced when
given with a high-fat meal . In a crossover study, 74 healthy adult subjects received a single 80 mg oral dose (2 x 40
mg capsules) of Accutane under fasted and fed conditions. Both peak plasma concentration (Cmax) and the total
exposure (AUC) of isotretinoin were more than doubled following a standardized high fat meal when compared with
Accutane given under fasted conditions (see Table 1 below). The observed elimination half-life was unchanged.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This lack of change in half-life suggests that food increases the bioavailability of isotretinoin without altering its
disposition. The time to peak concentration (Tmax) was also increased with food and may be related to a longer
absorption phase. Therefore, Accutane capsules should always be taken with food (see DOSAGE AND
ADMINISTRATION). Clinical studies have shown that there is no difference in the pharmacokinetics of
isotretinoin between patients with nodular acne and healthy subjects with normal skin.
Table 1. Pharmacokinetic Parameters of Isotretinoin
Mean (%CV), N=74
Accutane
2 x 40 mg
Capsules
AUC0-∞∞∞∞
(ng⋅⋅⋅⋅hr/mL)
Cmax
(ng/mL)
Tmax
(hr)
t1/2
(hr)
Fed
10,004 (22%)
862 (22%)
5.3 (77%)
21 (39%)
Fasted
3,703 (46%)
301 (63%)
3.2 (56%)
21 (30%)
Distribution: Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.
Metabolism: Following oral administration of isotretinoin at least three metabolites have been identified in human
plasma: 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). Retinoic acid and 13-
cis-retinoic acid are geometric isomers and show reversible interconversion. The administration of one isomer will
give rise to the other. Isotretinoin is also irreversibly oxidized to 4-oxo-isotretinoin, which forms its geometric
isomer 4-oxo-tretinoin.
After a single 80 mg oral dose of Accutane to 74 healthy adult subjects, concurrent administration of food increased
the extent of formation of all metabolites in plasma when compared to the extent of formation under fasted
conditions.
All of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent
isotretinoin. After multiple oral dose administration of isotretinoin to adult cystic acne patients (≥18 years), the
exposure of patients to 4-oxo-isotretinoin at steady state under fasted and fed conditions was approximately 3.4
times higher than that of isotretinoin. Given its abundance and degree of retinoid activity, it is most likely that 4-
oxo-isotretinoin is a significant contributor to the activity of Accutane.
In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4, and
2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and
feces.
Elimination: Following oral administration of an 80 mg dose of 14C-isotretinoin as a liquid suspension, 14C-activity
in blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are ultimately
excreted in the feces and urine in relatively equal amounts (total of 65% to 83%). After a single 80 mg oral dose of
Accutane to 74 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (t1/2) of isotretinoin
and 4-oxo-isotretinoin were 21.0 ± 8.2 hours and 24.0 ± 5.3 hours, respectively. After both single and multiple
doses, the observed accumulation ratios of isotretinoin ranged from 0.90 to 5.43 in patients with cystic acne.
INDICATIONS AND USAGE: Severe Recalcitrant Nodular Acne: Accutane is indicated for the treatment of
severe recalcitrant nodular acne. Nodules are inflammatory lesions with a diameter of 5 mm or greater. The nodules
may become suppurative or hemorrhagic. “Severe,” by definition,2 means “many” as opposed to “few or several”
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
nodules. Because of significant adverse effects associated with its use, Accutane should be reserved for patients with
severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition,
Accutane is indicated only for those females who are not pregnant, because Accutane can cause severe birth defects
(see boxed CONTRAINDICATIONS AND WARNINGS).
A single course of therapy for 15 to 20 weeks has been shown to result in complete and prolonged remission of
disease in many patients.1,3,4 If a second course of therapy is needed, it should not be initiated until at least 8 weeks
after completion of the first course, because experience has shown that patients may continue to improve while off
Accutane. The optimal interval before retreatment has not been defined for patients who have not completed skeletal
growth (see WARNINGS: Skeletal: Hyperostosis and Premature Epiphyseal Closure).
CONTRAINDICATIONS: Pregnancy: Category X. See boxed CONTRAINDICATIONS AND WARNINGS.
Allergic Reactions: Accutane is contraindicated in patients who are hypersensitive to this medication or to any of its
components. Accutane should not be given to patients who are sensitive to parabens, which are used as preservatives
in the gelatin capsule (see PRECAUTIONS: Hypersensitivity).
WARNINGS: Psychiatric Disorders: Accutane may cause depression, psychosis and, rarely, suicidal ideation,
suicide attempts and suicide. Discontinuation of Accutane therapy may be insufficient; further evaluation
may be necessary. No mechanism of action has been established for these events (see ADVERSE
REACTIONS: Psychiatric).
Pseudotumor Cerebri: Accutane use has been associated with a number of cases of pseudotumor cerebri
(benign intracranial hypertension), some of which involved concomitant use of tetracyclines. Concomitant
treatment with tetracyclines should therefore be avoided. Early signs and symptoms of pseudotumor cerebri
include papilledema, headache, nausea and vomiting, and visual disturbances. Patients with these symptoms
should be screened for papilledema and, if present, they should be told to discontinue Accutane immediately
and be referred to a neurologist for further diagnosis and care (see ADVERSE REACTIONS: Neurological).
Pancreatitis: Acute pancreatitis has been reported in patients with either elevated or normal serum triglyceride
levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. Accutane should be stopped if
hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur.
Lipids: Elevations of serum triglycerides have been reported in patients treated with Accutane. Marked elevations of
serum triglycerides in excess of 800 mg/dL were reported in approximately 25% of patients receiving Accutane in
clinical trials. In addition, approximately 15% developed a decrease in high-density lipoproteins and about 7%
showed an increase in cholesterol levels. In clinical trials, the effects on triglycerides, HDL, and cholesterol were
reversible upon cessation of Accutane therapy. Some patients have been able to reverse triglyceride elevation by
reduction in weight, restriction of dietary fat and alcohol, and reduction in dose while continuing Accutane.5
Blood lipid determinations should be performed before Accutane is given and then at intervals until the lipid
response to Accutane is established, which usually occurs within 4 weeks. Especially careful consideration must be
given to risk/benefit for patients who may be at high risk during Accutane therapy (patients with diabetes, obesity,
increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If Accutane
therapy is instituted, more frequent checks of serum values for lipids and/or blood sugar are recommended (see
PRECAUTIONS: Laboratory Tests).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The cardiovascular consequences of hypertriglyceridemia associated with Accutane are unknown. Animal Studies:
In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 to 5.3 times the recommended clinical dose of 1.0 mg/kg/day
after normalization for total body surface area) for 18 months or longer, the incidences of focal calcification, fibrosis
and inflammation of the myocardium, calcification of coronary, pulmonary and mesenteric arteries, and metastatic
calcification of the gastric mucosa were greater than in control rats of similar age. Focal endocardial and myocardial
calcifications associated with calcification of the coronary arteries were observed in two dogs after approximately 6
to 7 months of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day (30 to 60 times the recommended
clinical dose of 1.0 mg/kg/day, respectively, after normalization for total body surface area).
Hearing Impairment: Impaired hearing has been reported in patients taking Accutane; in some cases, the hearing
impairment has been reported to persist after therapy has been discontinued. Mechanism(s) and causality for this
event have not been established. Patients who experience tinnitus or hearing impairment should discontinue
Accutane treatment and be referred for specialized care for further evaluation (see ADVERSE REACTIONS:
Special Senses).
Hepatotoxicity: Clinical hepatitis considered to be possibly or probably related to Accutane therapy has been
reported. Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15% of
individuals treated during clinical trials, some of which normalized with dosage reduction or continued
administration of the drug. If normalization does not readily occur or if hepatitis is suspected during treatment with
Accutane, the drug should be discontinued and the etiology further investigated.
Inflammatory Bowel Disease: Accutane has been associated with inflammatory bowel disease (including regional
ileitis) in patients without a prior history of intestinal disorders. In some instances, symptoms have been reported to
persist after Accutane treatment has been stopped. Patients experiencing abdominal pain, rectal bleeding or severe
diarrhea should discontinue Accutane immediately (see ADVERSE REACTIONS: Gastrointestinal).
Skeletal: Hyperostosis: A high prevalence of skeletal hyperostosis was noted in clinical trials for disorders of
keratinization with a mean dose of 2.24 mg/kg/day. Additionally, skeletal hyperostosis was noted in 6 of 8 patients
in a prospective study of disorders of keratinization.6 Minimal skeletal hyperostosis and calcification of ligaments
and tendons have also been observed by x-ray in prospective studies of nodular acne patients treated with a single
course of therapy at recommended doses. The skeletal effects of multiple Accutane treatment courses for acne are
unknown.
Premature Epiphyseal Closure: There are spontaneous reports of premature epiphyseal closure in acne patients
receiving recommended doses, but it is not known if there is a causal relationship with Accutane. In clinical trials
for disorders of keratinization with a mean dose of 2.24 mg/kg/day, two children showed x-ray findings suggestive
of premature epiphyseal closure. The skeletal effects of multiple Accutane treatment courses for acne are unknown.
Vision Impairment: Visual problems should be carefully monitored. All Accutane patients experiencing visual
difficulties should discontinue Accutane treatment and have an ophthalmological examination (see ADVERSE
REACTIONS: Special Senses).
Corneal Opacities: Corneal opacities have occurred in patients receiving Accutane for acne and more frequently
when higher drug dosages were used in patients with disorders of keratinization. The corneal opacities that have
been observed in clinical trial patients treated with Accutane have either completely resolved or were resolving at
follow-up 6 to 7 weeks after discontinuation of the drug (see ADVERSE REACTIONS: Special Senses).
Decreased Night Vision: Decreased night vision has been reported during Accutane therapy and in some instances
the event has persisted after therapy was discontinued. Because the onset in some patients was sudden, patients
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For current labeling information, please visit https://www.fda.gov/drugsatfda
should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at
night.
PRECAUTIONS: The Accutane pregnancy prevention risk management program consists of the System to Manage
Accutane Related Teratogenicity (S.M.A.R.T.) and the Accutane Pregnancy Prevention Program® (PPP).
S.M.A.R.T. should be followed for prescribing Accutane with the goal of preventing fetal exposure to isotretinoin. It
consists of: 1) reading the booklet entitled System to Manage Accutane Related Teratogenicity (S.M.A.R.T.) Guide to
Best Practices, 2) signing and returning the completed S.M.A.R.T. Letter of Understanding containing the Prescriber
Checklist, 3) a yellow self-adhesive Accutane Qualification Sticker to be affixed to the prescription page. In
addition, the patient educational material, Be Smart, Be Safe, Be Sure, in the Accutane Pregnancy Prevention
Program® (PPP) should be used with each patient.
The following further describes each component:
1) The S.M.A.R.T. Guide to Best Practices includes: Accutane teratogenic potential, information on pregnancy
testing, specific information about effective contraception, the limitations of contraceptive methods and
behaviors associated with an increased risk of contraceptive failure and pregnancy, the methods to evaluate
pregnancy risk, and the method to complete a qualified Accutane prescription.
2) The S.M.A.R.T. Letter of Understanding attests that Accutane prescribers understand that Accutane is a
teratogen, have read the S.M.A.R.T. Guide to Best Practices, understand their responsibilities in preventing
exposure of pregnant females to Accutane and the procedures for qualifying female patients as defined in the
boxed CONTRAINDICATIONS AND WARNINGS.
The Prescriber Checklist attests that Accutane prescribers know the risk and severity of injury/birth defects
from Accutane; know how to diagnose and treat the various presentations of acne; know the risk factors for
unplanned pregnancy and the effective measures for avoidance; will refer the patient for, or provide, detailed
pregnancy prevention counseling to help the patient have knowledge and tools needed to fulfill their ultimate
responsibility to avoid becoming pregnant; understand and properly use throughout the Accutane treatment
course, the revised risk management procedures, including monthly pregnancy avoidance counseling,
pregnancy testing, and use of qualified prescriptions with the yellow self-adhesive Accutane Qualification
Sticker.
3) The yellow self-adhesive Accutane Qualification Sticker is used as documentation that the prescriber has
qualified the female patient according to the qualification criteria (see boxed CONTRAINDICATIONS AND
WARNINGS).
4) Accutane Pregnancy Prevention Program (PPP) is a systematic approach to comprehensive patient education
about their responsibilities and includes education for contraception compliance and reinforcement of
educational messages. The PPP includes information on the risks and benefits of Accutane which is linked to
the Accutane Medication Guide dispensed by pharmacists with each prescription.
Male and female patients are provided with separate booklets. Each booklet contains information on Accutane
therapy, including precautions and warnings, an Informed Consent/Patient Agreement form, and a toll-free line
which provides Accutane information in 13 languages.
The booklet for male patients also includes information about male reproduction, a warning not to share
Accutane with others or to donate blood during Accutane therapy and for 1 month following discontinuation of
Accutane.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The booklet for female patients also includes a referral program that offers females free contraception
counseling, reimbursed by the manufacturer, by a reproductive specialist; a second Patient Information/Consent
form concerning birth defects, obtaining her consent to be treated within this agreement; an enrollment form for
the Accutane Survey; and a qualification checklist affirming the conditions under which female patients may
receive Accutane. In addition, there is information on the types of contraceptive methods, the selection and use
of appropriate, effective contraception, and the rates of possible contraceptive failure; a toll-free contraception
counseling line; and a video about the most common reasons for unplanned pregnancies.
Information for Patients and Prescribers:
•
Patients should be instructed to read the Medication Guide supplied as required by law when Accutane is
dispensed. The complete text of the Medication Guide is reprinted at the end of this document. For additional
information, patients should also read the Patient Information Brochure, “Important Information Concerning
Your Treatment with Accutane (isotretinoin)”. All patients should sign the Informed Consent/Patient
Agreement.
•
Females of childbearing potential should be instructed that they must not be pregnant when Accutane therapy is
initiated, and that they should use two forms of effective contraception 1 month before starting Accutane, while
taking Accutane, and for 1 month after Accutane has been stopped. They should also sign a consent form prior
to beginning Accutane therapy. They should be given an opportunity to enroll in the Accutane Survey and to
review the patient videotape provided by the manufacturer to the prescriber. It includes information about
contraception, the most common reasons that contraception fails, and the importance of using two forms of
effective contraception when taking teratogenic drugs. Female patients should be seen by their prescribers
monthly and have a urine or serum pregnancy test performed each month during treatment to confirm negative
pregnancy status before another Accutane prescription is written (see boxed CONTRAINDICATIONS AND
WARNINGS).
•
Accutane is found in the semen of male patients taking Accutane, but the amount delivered to a female partner
would be about 1 million times lower than an oral dose of 40 mg. While the no-effect limit for isotretinoin-
induced embryopathy is unknown, 20 years of postmarketing reports include 4 with isolated defects compatible
with features of retinoid exposed fetuses. None of these cases had the combination of malformations
characteristic of retinoid exposure, and all had other possible explanations for the defects observed.
•
Patients may report mental health problems or family history of psychiatric disorders. These reports should be
discussed with the patient and/or the patient’s family. A referral to a mental health professional may be
necessary. The physician should consider whether or not Accutane therapy is appropriate in this setting (see
WARNINGS: Psychiatric).
•
Patients should be informed that they must not share Accutane with anyone else because of the risk of birth
defects and other serious adverse events.
•
Patients should not donate blood during therapy and for 1 month following discontinuance of the drug because
the blood might be given to a pregnant woman whose fetus must not be exposed to Accutane.
•
Patients should be reminded to take Accutane with a meal (see Dosage and Administration). To decrease the
risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid.
•
Patients should be informed that transient exacerbation (flare) of acne has been seen, generally during the initial
period of therapy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Wax epilation and skin resurfacing procedures (such as dermabrasion, laser) should be avoided during Accutane
therapy and for at least 6 months thereafter due to the possibility of scarring (see ADVERSE REACTIONS:
Skin and Appendages).
•
Patients should be advised to avoid prolonged exposure to UV rays or sunlight.
•
Patients should be informed that they may experience decreased tolerance to contact lenses during and after
therapy.
•
Patients should be informed that approximately 16% of patients treated with Accutane in a clinical trial
developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these symptoms were
mild to moderate, but occasionally required discontinuation of the drug. Transient pain in the chest has been
reported less frequently. In the clinical trial, these symptoms generally cleared rapidly after discontinuation of
Accutane, but in some cases persisted (see ADVERSE REACTIONS: Musculoskeletal). There have been rare
post-marketing reports of rhabdomyolysis, some associated with strenuous physical activity (see Laboratory
Tests: CPK).
•
Neutropenia and rare cases of agranulocytosis have been reported. Accutane should be discontinued if
clinically significant decreases in white cell counts occur.
Hypersensitivity: Anaphylactic reactions and other allergic reactions have been reported. Cutaneous allergic
reactions and serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and
extracutaneous involvement (including renal) have been reported. Severe allergic reaction necessitates
discontinuation of therapy and appropriate medical management.
Drug Interactions:
•
Vitamin A: Because of the relationship of Accutane to vitamin A, patients should be advised against taking
vitamin supplements containing vitamin A to avoid additive toxic effects.
•
Tetracyclines: Concomitant treatment with Accutane and tetracyclines should be avoided because Accutane use
has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of
which involved concomitant use of tetracyclines.
•
Micro-dosed Progesterone Preparations: Micro-dosed progesterone preparations (“minipills” that do not
contain an estrogen) may be an inadequate method of contraception during Accutane therapy. Although other
hormonal contraceptives are highly effective, there have been reports of pregnancy from women who have used
combined oral contraceptives, as well as injectable/implantable contraceptive products. These reports are more
frequent for women who use only a single method of contraception. It is not known if hormonal contraceptives
differ in their effectiveness when used with Accutane. Therefore, it is critically important for women of
childbearing potential to select and commit to use two forms of effective contraception simultaneously, at least
one of which must be a primary form, unless absolute abstinence is the chosen method, or the patient has
undergone a hysterectomy (see boxed CONTRAINDICATIONS AND WARNINGS).
•
Phenytoin: Accutane has not been shown to alter the pharmacokinetics of phenytoin in a study in seven healthy
volunteers. These results are consistent with the in vitro finding that neither isotretinoin nor its metabolites
induce or inhibit the activity of the CYP 2C9 human hepatic P450 enzyme.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Prescribers are advised to consult the package insert of medication administered concomitantly with hormonal
contraceptives, since some medications may decrease the effectiveness of these birth control products. Accutane use
is associated with depression in some patients (see WARNINGS: Psychiatric and ADVERSE REACTIONS:
Psychiatric). Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John’s
Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of
breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies have been reported
by users of combined hormonal contraceptives who also used some form of St. John's Wort.
Laboratory Tests:
Pregnancy Test: Female patients of childbearing potential must have negative results from two urine or serum
pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial Accutane prescription. The first
test is obtained by the prescriber when the decision is made to pursue qualification of the patient for Accutane (a
screening test). The second pregnancy test (a confirmation test) should be done during the first five days of the
menstrual period immediately preceding the beginning of Accutane therapy. For patients with amenorrhea, the
second test should be done at least 11 days after the last act of unprotected sexual intercourse (without using two
effective forms of contraception).
Each month of therapy, the patient must have a negative result from a urine or serum pregnancy test. A
pregnancy test must be repeated each month prior to the female patient receiving each prescription.
•
Lipids: Pretreatment and follow-up blood lipids should be obtained under fasting conditions. After consumption
of alcohol, at least 36 hours should elapse before these determinations are made. It is recommended that these
tests be performed at weekly or biweekly intervals until the lipid response to Accutane is established. The
incidence of hypertriglyceridemia is 1 patient in 4 on Accutane therapy (see WARNINGS: Lipids).
•
Liver Function Tests: Since elevations of liver enzymes have been observed during clinical trials, and hepatitis
has been reported, pretreatment and follow-up liver function tests should be performed at weekly or biweekly
intervals until the response to Accutane has been established (see WARNINGS: Hepatotoxicity).
•
Glucose: Some patients receiving Accutane have experienced problems in the control of their blood sugar. In
addition, new cases of diabetes have been diagnosed during Accutane therapy, although no causal relationship
has been established.
•
CPK: Some patients undergoing vigorous physical activity while on Accutane therapy have experienced
elevated CPK levels; however, the clinical significance is unknown. There have been rare post-marketing
reports of rhabdomyolysis, some associated with strenuous physical activity.
Carcinogenesis, Mutagenesis and Impairment of Fertility: In male and female Fischer 344 rats given oral
isotretinoin at dosages of 8 or 32 mg/kg/day (1.3 to 5.3 times the recommended clinical dose of 1.0 mg/kg/day,
respectively, after normalization for total body surface area) for greater than 18 months, there was a dose-related
increased incidence of pheochromocytoma relative to controls. The incidence of adrenal medullary hyperplasia was
also increased at the higher dosage in both sexes. The relatively high level of spontaneous pheochromocytomas
occurring in the male Fischer 344 rat makes it an equivocal model for study of this tumor; therefore, the relevance of
this tumor to the human population is uncertain.
The Ames test was conducted with isotretinoin in two laboratories. The results of the tests in one laboratory were
negative while in the second laboratory a weakly positive response (less than 1.6 x background) was noted in S.
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typhimurium TA100 when the assay was conducted with metabolic activation. No dose-response effect was seen and
all other strains were negative. Additionally, other tests designed to assess genotoxicity (Chinese hamster cell assay,
mouse micronucleus test, S. cerevisiae D7 assay, in vitro clastogenesis assay with human-derived lymphocytes, and
unscheduled DNA synthesis assay) were all negative.
In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were observed at
oral dosages of isotretinoin of 2, 8, or 32 mg/kg/day (0.3, 1.3, or 5.3 times the recommended clinical dose of 1.0
mg/kg/day, respectively, after normalization for total body surface area).
In dogs, testicular atrophy was noted after treatment with oral isotretinoin for approximately 30 weeks at dosages of
20 or 60 mg/kg/day (10 or 30 times the recommended clinical dose of 1.0 mg/kg/day, respectively, after
normalization for total body surface area). In general, there was microscopic evidence for appreciable depression of
spermatogenesis but some sperm were observed in all testes examined and in no instance were completely atrophic
tubules seen. In studies of 66 men, 30 of whom were patients with nodular acne under treatment with oral
isotretinoin, no significant changes were noted in the count or motility of spermatozoa in the ejaculate. In a study of
50 men (ages 17 to 32 years) receiving Accutane (isotretinoin) therapy for nodular acne, no significant effects were
seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose.
Pregnancy: Category X. See boxed CONTRAINDICATIONS AND WARNINGS.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because of the potential for adverse
effects, nursing mothers should not receive Accutane.
Geriatric Use: Clinical studies of isotretinoin did not include sufficient numbers of subjects aged 65 years and over
to determine whether they respond differently from younger subjects. Although reported clinical experience has not
identified differences in responses between the elderly and younger patients, effects of aging might be expected to
increase some risks associated with isotretinoin therapy (see Warnings and Precautions)
ADVERSE REACTIONS: Clinical Trials and Postmarketing Surveillance: The adverse reactions listed below
reflect the experience from investigational studies of Accutane, and the postmarketing experience. The relationship
of some of these events to Accutane therapy is unknown. Many of the side effects and adverse reactions seen in
patients receiving Accutane are similar to those described in patients taking very high doses of vitamin A (dryness
of the skin and mucous membranes, eg, of the lips, nasal passage, and eyes).
Dose Relationship: Cheilitis and hypertriglyceridemia are usually dose related. Most adverse reactions reported in
clinical trials were reversible when therapy was discontinued; however, some persisted after cessation of therapy
(see WARNINGS and ADVERSE REACTIONS).
Body as a Whole: allergic reactions, including vasculitis, systemic hypersensitivity (see PRECAUTIONS:
Hypersensitivity), edema, fatigue, lymphadenopathy, weight loss
Cardiovascular: palpitation, tachycardia, vascular thrombotic disease, stroke
Endocrine/Metabolic: hypertriglyceridemia (see WARNINGS: Lipids), alterations in blood sugar levels (see
PRECAUTIONS: Laboratory Tests)
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Gastrointestinal: inflammatory bowel disease (see WARNINGS: Inflammatory Bowel Disease), hepatitis (see
WARNINGS: Hepatotoxicity), pancreatitis (see WARNINGS: Lipids), bleeding and inflammation of the gums,
colitis, esophagitis/esophageal ulceration, ileitis, nausea, other nonspecific gastrointestinal symptoms
Hematologic: allergic reactions (see PRECAUTIONS: Hypersensitivity), anemia, thrombocytopenia, neutropenia,
rare reports of agranulocytosis (see PRECAUTIONS: Information for Patients and Prescribers). See
PRECAUTIONS: Laboratory Tests for other hematological parameters.
Musculoskeletal: skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure (see
WARNINGS: Skeletal), mild to moderate musculoskeletal symptoms including arthralgia (see PRECAUTIONS:
Information for Patients and Prescribers), transient pain in the chest (see PRECAUTIONS: Information for Patients
and Prescribers),), arthritis, tendonitis, other types of bone abnormalities, elevations of CPK/rare reports of
rhabdomyolysis (see PRECAUTIONS: Laboratory Tests).
Neurological: pseudotumor cerebri (see WARNINGS: Pseudotumor Cerebri), dizziness, drowsiness, headache,
insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness
Psychiatric: suicidal ideation, suicide attempts, suicide, depression, psychosis (see WARNINGS: Psychiatric
Disorders), emotional instability
Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and
recurred with reinstitution of therapy.
Reproductive System: abnormal menses
Respiratory: bronchospasms (with or without a history of asthma), respiratory infection, voice alteration
Skin and Appendages: acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry
mouth, dry nose, dry skin, epistaxis, eruptive xanthomas,7 flushing, fragility of skin, hair abnormalities, hirsutism,
hyperpigmentation and hypopigmentation, infections (including disseminated herpes simplex), nail dystrophy,
paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash
(including facial erythema, seborrhea, and eczema), sunburn susceptibility increased, sweating, urticaria, vasculitis
(including Wegener’s granulomastosis; see PRECAUTIONS: Hypersensitivity), abnormal wound healing (delayed
healing or exuberant granulation tissue with crusting; see PRECAUTIONS: Information for Patients and
Prescribers)
Special Senses: Hearing: hearing impairment (see WARNINGS: Hearing Impairment), tinnitus. Vision: corneal
opacities (see WARNINGS: Corneal Opacities), decreased night vision which may persist (see WARNINGS:
Decreased Night Vision), cataracts, color vision disorder, conjunctivitis, dry eyes, eyelid inflammation, keratitis,
optic neuritis, photophobia, visual disturbances
Urinary System: glomerulonephritis (see PRECAUTIONS: Hypersensitivity), nonspecific urogenital findings (see
PRECAUTIONS: Laboratory Tests for other urological parameters)
Laboratory: Elevation of plasma triglycerides (see WARNINGS: Lipids), decrease in serum high-density
lipoprotein (HDL) levels, elevations of serum cholesterol during treatment
Increased alkaline phosphatase, SGOT (AST), SGPT (ALT), GGTP or LDH (see WARNINGS: Hepatotoxicity)
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Elevation of fasting blood sugar, elevations of CPK (see PRECAUTIONS: Laboratory Tests), hyperuricemia
Decreases in red blood cell parameters, decreases in white blood cell counts (including severe neutropenia and rare
reports of agranulocytosis; see PRECAUTIONS: Information for Patients and Prescribers), elevated sedimentation
rates, elevated platelet counts, thrombocytopenia
White cells in the urine, proteinuria, microscopic or gross hematuria
OVERDOSAGE: The oral LD50 of isotretinoin is greater than 4000 mg/kg in rats and mice ((>600 times the
recommended clinical dose of 1.0 mg/kg/day after normalization of the rat dose for total body surface area and >300
times the recommended clinical dose of 1.0 mg/kg/day after normalization of the mouse dose for total body surface
area) and is approximately 1960 mg/kg in rabbits (653 times the recommended clinical dose of 1.0 mg/kg/day after
normalization for total body surface area). In humans, overdosage has been associated with vomiting, facial
flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. All symptoms quickly resolved without
apparent residual effects.
Accutane causes serious birth defects at any dosage (see Boxed Contraindications and Warnings). Females with
childbearing potential who present with isotretinoin overdose must be evaluated for pregnancy. Patients who are
pregnant should receive counseling about the risks to the fetus, as described in the Boxed Warning. Non-pregnant
patients must be warned to avoid pregnancy for at least one month and receive contraceptive counseling as described
in the Boxed Warning. Educational materials for such patients can be obtained by calling the manufacturer. Because
an overdose would be expected to result in higher levels of isotretinoin in semen than found during a normal
treatment course, male patients should use a condom, or avoid reproductive sexual activity with a female who is or
might become pregnant, for 30 days after the overdose. All patients with isotretinoin overdose should not donate
blood for at least 30 days.
DOSAGE AND ADMINISTRATION: Accutane should be administered with a meal (see Precautions).
The recommended dosage range for Accutane is 0.5 to 1.0 mg/kg/day given in two divided doses for 15 to 20 weeks.
In studies comparing 0.1, 0.5, and 1.0 mg/kg/day,8 it was found that all dosages provided initial clearing of disease,
but there was a greater need for retreatment with the lower dosages. During treatment, the dose may be adjusted
according to response of the disease and/or the appearance of clinical side effects — some of which may be dose
related. Patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dose
adjustments up to 2.0 mg/kg/day [13-15], as tolerated. Failure to take Accutane with food will significantly decrease
absorption. Before upward dose adjustments are made, the patient should be questioned about their compliance with
food instructions.
The safety of once daily dosing with Accutane has not been established. Once daily dosing is not recommended.
If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, the
drug may be discontinued. After a period of 2 months or more off therapy, and if warranted by persistent or
recurring severe nodular acne, a second course of therapy may be initiated. The optimal interval before retreatment
has not been defined for patients who have not completed skeletal growth (see WARNINGS: Skeletal: Hyperostosis
and Premature Epiphyseal Closure).
Contraceptive measures must be followed for any subsequent course of therapy (see boxed
CONTRAINDICATIONS AND WARNINGS).
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3. Accutane Dosing by Body Weight (Based on Administration With Food)
Body Weight
Total mg/day
kilograms
Pounds
0.5 mg/kg
1 mg/kg
2 mg/kg*
40
88
20
40
80
50
110
25
50
100
60
132
30
60
120
70
154
35
70
140
80
176
40
80
160
90
198
45
90
180
100
220
50
100
200
* See Dosage and Administration: the recommended dosage range is 0.5 to 1.0 mg/kg/day
Information for Pharmacists: Accutane must only be dispensed in no more than a 1-month
supply and only on presentation of an Accutane prescription with a yellow self-adhesive
Accutane Qualification Sticker written within the previous 7 days. REFILLS REQUIRE A
NEW WRITTEN PRESCRIPTION WITH AN ACCUTANE QUALIFICATION
STICKER WITHIN THE PREVIOUS 7 DAYS. No telephone or computerized prescriptions
are permitted.
An Accutane Medication Guide must be given to the patient each time Accutane is dispensed, as
required by law. This Accutane Medication Guide is an important part of the risk management
program for the patient.
HOW SUPPLIED: Soft gelatin capsules, 10 mg (light pink), imprinted ACCUTANE 10 ROCHE. Boxes of 100
containing 10 Prescription Paks of 10 capsules (NDC 0004-0155-49).
Soft gelatin capsules, 20 mg (maroon), imprinted ACCUTANE 20 ROCHE. Boxes of 100 containing 10
Prescription Paks of 10 capsules (NDC 0004-0169-49).
Soft gelatin capsules, 40 mg (yellow), imprinted ACCUTANE 40 ROCHE. Boxes of 100 containing 10 Prescription
Paks of 10 capsules (NDC 0004-0156-49).
Store at controlled room temperature (59° to 86°F, 15° to 30°C). Protect from light.
REFERENCES:
1. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic
acid. N Engl J Med 300:329-333, 1979. 2. Pochi PE, Shalita AR, Strauss JS, Webster SB. Report of the consensus
conference on acne classification. J Am Acad Dermatol 24:495-500, 1991. 3. Farrell LN, Strauss JS, Stranieri AM.
The treatment of severe cystic acne with 13-cis-retinoic acid: evaluation of sebum production and the clinical
response in a multiple-dose trial. J Am Acad Dermatol 3:602-611, 1980. 4. Jones H, Blanc D, Cunliffe WJ. 13-cis-
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
retinoic acid and acne. Lancet 2:1048-1049, 1980. 5. Katz RA, Jorgensen H, Nigra TP. Elevation of serum
triglyceride levels from oral isotretinoin in disorders of keratinization. Arch Dermatol 116:1369-1372, 1980. 6. Ellis
CN, Madison KC, Pennes DR, Martel W, Voorhees JJ. Isotretinoin therapy is associated with early skeletal
radiographic changes. J Am Acad Dermatol 10:1024-1029, 1984. 7. Dicken CH, Connolly SM. Eruptive xanthomas
associated with isotretinoin (13-cis-retinoic acid). Arch Dermatol 116:951-952, 1980. 8. Strauss JS, Rapini RP,
Shalita AR, et al. Isotretinoin therapy for acne: results of a multicenter dose-response study. J Am Acad Dermatol
10:490-496, 1984.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PATIENT INFORMATION/CONSENT (for female patients concerning birth defects)
To be completed by the patient, her parent/guardian*
and signed by her prescriber.
Read each item below and initial in the space provided to show that you understand each item and agree to follow
your prescriber's instructions. Do not sign this consent and do not take Accutane if there is anything that you
do not understand.
*A parent or guardian of a minor patient (under age 18) must also read and initial each item before signing the
consent.
____________________________________________________________
(Patient’s Name)
1. I understand that there is a very high risk that my unborn baby could have severe birth defects if I am pregnant
or become pregnant while taking Accutane in any amount even for short periods of time. This is why I must not
be pregnant while taking Accutane.
Initial: ______
2. I understand that I must not take Accutane (isotretinoin) if I am pregnant.
Initial: ______
3. I understand that I must not get pregnant during the entire time of my treatment and for 1 month after the end of
my treatment with Accutane.
Initial: ________
4. I understand that I must avoid sexual intercourse completely, or I must use 2 separate, effective forms of birth
control (contraception) at the same time. The only exception is if I have had surgery to remove the womb (a
hysterectomy).
Initial: ________
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5. I understand that birth control pills and injectable/implantable/insertable hormonal birth control products are
among the most effective forms of birth control. However, any single form of birth control can fail. Therefore,
I must use 2 different methods at the same time, every time I have sexual intercourse, even if 1 of the methods I
choose is birth control pills or injections.
Initial: ______
6. I will talk with my prescriber about any drugs or herbal products I plan to take during my Accutane treatment
because hormonal birth control methods (for example, birth control pills) may not work if I am taking certain
drugs or herbal products (for example, St. John’s Wort).
Initial: ______
7. I understand that the following are considered effective forms of birth control:
Primary:
Tubal ligation (tying my tubes), partner’s vasectomy, birth control pills,
injectable/implantable/insertable hormonal birth control products, and an IUD (intrauterine
device).
Secondary:
Diaphragms, latex condoms, and cervical caps. Each must be used with a spermicide, which is a
special cream or jelly that kills sperm.
I understand that at least one of my two methods of birth control must be a primary method.
Initial: ________
8. I understand that I may receive a free contraceptive (birth control) counseling session and pregnancy testing
from a doctor or other family planning expert. My Accutane prescriber can give me an Accutane Patient
Referral Form for this free consultation.
Initial: ______
9. I understand that I must begin using the birth control methods I have chosen as described above at least one
month before I start taking Accutane.
Initial: ______
10. I understand that I cannot get a prescription for Accutane unless I have 2 negative pregnancy test results. The
first pregnancy test should be done when my prescriber decides to prescribe Accutane. The second pregnancy
test should be done during the first five days of my menstrual period right before starting Accutane therapy, or
as instructed by my prescriber. I will then have one pregnancy test every month during my Accutane therapy.
Initial: ______
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11. I understand that I should not start taking Accutane until I am sure that I am not pregnant and have negative
results from 2 pregnancy tests.
Initial: ______
12. I have read and understand the materials my prescriber has given to me, including the brochure Important
Information Concerning Your Treatment with Accutane® (isotretinoin). My prescriber gave me and asked me to
watch the video about contraception. I was told about a confidential counseling line that I may call for more
information about birth control. I have received information on emergency contraception (birth control).
Initial: ______
13. I understand that I must stop taking Accutane right away and inform my prescriber if I get pregnant, miss my
menstrual period, stop using birth control, or have sexual intercourse without using my two birth control
methods at any time.
Initial: ______
14. My prescriber gave me information about the confidential Accutane Survey and explained to me how important
it is to take part in the Accutane Survey.
Initial: ______
15. I understand that the yellow self-adhesive Accutane Qualification Sticker on my prescription for Accutane
means that I am qualified to receive an Accutane prescription, because I:
•
have had two negative urine or serum pregnancy tests before receiving the initial Accutane prescription. I must
have a negative result from a urine or serum pregnancy test repeated each month prior to my receiving each
subsequent prescription.
•
have selected and committed to use two forms of effective contraception simultaneously, at least one of which
must be a primary form, unless absolute abstinence is the chosen method, or I have undergone a hysterectomy. I
must use two forms of contraception for at least 1 month prior to initiation of Accutane therapy, during therapy,
and for 1 month after discontinuing therapy. I must receive counseling, repeated on a monthly basis, about
contraception and behaviors associated with an increased risk of pregnancy.
•
have signed a Patient Information/Consent form that contains warnings about the risk of potential birth defects
if I am pregnant or become pregnant and my unborn baby is exposed to isotretinoin.
•
have been informed of the purpose and importance of participating in the Accutane Survey and given the
opportunity to enroll.
Initial: ______
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My prescriber has answered all my questions about Accutane and I understand that it is my responsibility not to
get pregnant during Accutane treatment or for a month after I stop taking Accutane.
Initial: ______
I now authorize my prescriber ________________ to begin my treatment with Accutane.
Patient signature:________________________________ Date:____________________
Parent/guardian signature (if under age 18):____________________ Date:___________
Please print: Patient name and address________________________________________
______________________________________ Telephone (area code)______________
I have fully explained to the patient, __________________, the nature and purpose of the treatment described above
and the risks to females of childbearing potential. I have asked the patient if she has any questions regarding her
treatment with Accutane and have answered those questions to the best of my ability.
Prescriber signature: ______________________________ Date:__________________
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INFORMED CONSENT/PATIENT AGREEMENT (for all patients):
To be completed by patient (parent or guardian if patient is under age 18) and signed by the prescriber.
Read each item below and initial in the space provided if you understand each item and agree to follow your
prescriber’s instructions. A parent or guardian of a patient under age 18 must also read and understand each
item before signing the agreement.
Do not sign this agreement and do not take Accutane if there is anything that you do not understand about all
the information you have received about using Accutane.
1. I, ____________________________________________________________,
(Patient’s Name)
understand that Accutane is a medicine used to treat severe nodular acne that cannot be cleared up by any other
acne treatments, including antibiotics. In severe nodular acne, many red, swollen, tender lumps form in the skin.
If untreated, severe nodular acne can lead to permanent scars.
Initials: ______
2. My prescriber has told me about my choices for treating my acne.
Initials: ______
3. I understand that there are serious side effects that may happen while I am taking Accutane. These have been
explained to me. These side effects include serious birth defects in babies of pregnant females. (Note: There is a
second Informed Consent form for female patients concerning birth defects.)
Initials: ______
4. I understand that some patients, while taking Accutane or soon after stopping Accutane,
have become depressed or developed other serious mental problems. Symptoms of these
problems include sad, “anxious” or empty mood, irritability, anger, loss of pleasure or
interest in social or sports activities, sleeping too much or too little, changes in weight or
appetite, school or work performance going down, or trouble concentrating. Some
patients taking Accutane have had thoughts about hurting themselves or putting an end to
their own lives (suicidal thoughts). Some people tried to end their own lives. And some
people have ended their own lives. There were reports that some of these people did not
appear depressed. No one knows if Accutane caused these behaviors or if they would have
happened even if the person did not take Accutane. Some people have had other signs of
depression while taking Accutane (see #7 below).
Initials: ______
5. Before I start taking Accutane, I agree to tell my prescriber if, to the best of my
knowledge, I have ever had symptoms of depression (see #7 below), been psychotic,
attempted suicide, had any other mental problems, or take medicine for any of these
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problems. Being psychotic means having a loss of contact with reality, such as hearing
voices or seeing things that are not there.
Initials: ______
6. Before I start taking Accutane, I agree to tell my prescriber if, to the best of my
knowledge, anyone in my family has ever had symptoms of depression, been psychotic,
attempted suicide, or had any other serious mental problems.
Initials: ______
7. Once I start taking Accutane, I agree to stop using Accutane and tell my prescriber right away if any of the
following happen. I:
•
Start to feel sad or have crying spells
•
Lose interest in activities I once enjoyed
•
Sleep too much or have trouble sleeping
•
Become more irritable than usual
•
Have a change in my appetite or body weight
•
Have trouble concentrating
•
Withdraw from my friends or family
•
Feel like I have no energy
•
Have feelings of worthlessness or inappropriate guilt
•
Start having thoughts about hurting myself or taking my own life (suicidal thoughts)
Initials: ______
8. I agree to return to see my prescriber every month I take Accutane to get a new prescription for
Accutane, to check my progress, and to check for signs of side effects.
Initials: ______
9. Accutane will be prescribed just for me—I will not share Accutane with other people because it may
cause serious side effects, including birth defects.
Initials: ______
10. I will not give blood while taking Accutane or for 1 month after I stop taking Accutane. I understand that
if someone who is pregnant gets my donated blood, her baby may be exposed to Accutane and may be
born with serious birth defects.
Initials: ______
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11. I have read the brochure Important Information Concerning Your Treatment with Accutane and other
materials my provider gave me containing important safety information about Accutane. I understand all
the information I received.
Initials: ______
12. My prescriber and I have decided I should take Accutane. I understand that each of my Accutane
prescriptions must have a yellow self-adhesive Accutane Qualification Sticker on it. I understand that I
can stop taking Accutane at any time. I agree to tell my prescriber if I stop taking Accutane.
Initials: ______
I now authorize my prescriber ___________________________ to begin my treatment with Accutane.
Patient Signature: _________________________________________ Date: __________
Parent/Guardian Signature (if under age 18): _____________________ Date: _________
Patient Name (print) ___________________________________
Patient Address ________________________________ Telephone (___.___.___)
________________________________
I have:
•
fully explained to the patient, __________________, the nature and purpose of Accutane treatment, including
its benefits and risks
•
given the patient the appropriate educational materials, Be Smart, Be Safe, Be Sure, for Accutane and asked the
patient if he/she has any questions regarding his/her treatment with Accutane
•
answered those questions to the best of my ability
•
placed the yellow self-adhesive Accutane Qualification Sticker on the prescription.
Prescriber Signature: ______________________________________ Date: _________
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For current labeling information, please visit https://www.fda.gov/drugsatfda
MEDICATION GUIDE:
Read this Medication Guide every time you get a prescription or a refill for Accutane (ACK-u-tane). There
may be new information. This information does not take the place of talking with your prescriber (doctor or
other health care provider).
What is the most important information I should know about Accutane?
Accutane is used to treat a type of severe acne (nodular acne) that has not been helped by other treatments, including
antibiotics. However, Accutane can cause serious side effects. Before starting Accutane, discuss with your
prescriber how bad your acne is, the possible benefits of Accutane, and its possible side effects, to decide if
Accutane is right for you. Your prescriber will ask you to read and sign a form or forms indicating you understand
some of the serious risks of Accutane.
Possible serious side effects of taking Accutane include birth defects and mental disorders.
1. Birth defects. Accutane can cause birth defects (deformed babies) if taken by a pregnant woman.
It can also cause miscarriage (losing the baby before birth), premature (early) birth, or death of the
baby. Do not take Accutane if you are pregnant or plan to become pregnant while you are taking
Accutane. Do not get pregnant for 1 month after you stop taking Accutane. Also, if you get pregnant
while taking Accutane, stop taking it right away and call your prescriber.
All females should read the section in this Medication Guide "What are the important warnings for
females taking Accutane?"
2. Mental problems and suicide. Some patients, while taking Accutane or soon after stopping Accutane,
have become depressed or developed other serious mental problems. Symptoms of these problems
include sad, “anxious” or empty mood, irritability, anger, loss of pleasure or interest in social or sports
activities, sleeping too much or too little, changes in weight or appetite, school or work performance
going down, or trouble concentrating. Some patients taking Accutane have had thoughts about hurting
themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own
lives. And some people have ended their own lives. There were reports that some of these people did
not appear depressed. No one knows if Accutane caused these behaviors or if they would have
happened even if the person did not take Accutane.
All patients should read the section in this Medication Guide "What are the signs of mental
problems?"
For other possible serious side effects of Accutane, see "What are the possible side effects of
Accutane?" in this Medication Guide.
What are the important warnings for females taking Accutane?
You must not become pregnant while taking Accutane, or for 1 month after you stop taking Accutane. Accutane can
cause severe birth defects in babies of women who take it while they are pregnant, even if they take Accutane for
only a short time. There is an extremely high risk that your baby will be deformed or will die if you are
pregnant while taking Accutane. Taking Accutane also increases the chance of miscarriage and premature births.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Female patients will not get their first prescription for Accutane unless there is proof they have had 2 negative
pregnancy tests. The first test must be done when your prescriber decides to prescribe Accutane. The second
pregnancy test must be done during the first five days of the menstrual period right before starting Accutane therapy,
or as instructed by your prescriber. Each month of treatment, you must have a negative result from a urine or serum
pregnancy test. Female patients cannot get another prescription for Accutane unless there is proof that they have had
a negative pregnancy test.
A yellow self-adhesive Accutane Qualification Sticker on your prescription indicates to the pharmacist that you are
qualified by your prescriber to get Accutane.
While you are taking Accutane, you must use effective birth control. You must use 2 separate effective forms of
birth control at the same time for at least 1 month before starting Accutane, while you take it, and for 1 month
after you stop taking it. You can either discuss effective birth control methods with your prescriber or go for a free
visit to discuss birth control with another physician or family planning expert. Your prescriber can arrange this free
visit, which will be paid for by the manufacturer.
You must use 2 separate forms of effective birth control because any method, including birth control pills and
sterilization, can fail. There are only 2 reasons you would not need to use 2 separate methods of effective birth
control:
1. You have had your womb removed by surgery (a hysterectomy).
2. You are absolutely certain you will not have genital-to-genital sexual contact with a male before, during, and
for 1 month after Accutane treatment.
If you have sex at any time without using 2 forms of effective birth control, get pregnant, or miss your period,
stop using Accutane and call your prescriber right away.
All patients should read the rest of this Medication Guide.
What are the signs of mental problems?
Tell your prescriber if, to the best of your knowledge, you or someone in your family has ever had any mental
illness, including depression, suicidal behavior, or psychosis. Psychosis means a loss of contact with reality, such as
hearing voices or seeing things that are not there. Also, tell your prescriber if you take medicines for any of these
problems.
Stop using Accutane and tell your provider right away if you:
• Start to feel sad or have crying spells
• Lose interest in activities you once enjoyed
• Sleep too much or have trouble sleeping
• Become more irritable than usual
• Have a change in your appetite or body weight
• Have trouble concentrating
• Withdraw from your friends or family
• Feel like you have no energy
• Have feelings of worthlessness or inappropriate guilt
• Start having thoughts about hurting yourself or taking your own life (suicidal thoughts)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
What is Accutane?
Accutane is used to treat the most severe form of acne (nodular acne) that cannot be cleared up by any other acne
treatments, including antibiotics. In severe nodular acne, many red, swollen, tender lumps form in the skin. These
can be the size of pencil erasers or larger. If untreated, nodular acne can lead to permanent scars. However, because
Accutane can have serious side effects, you should talk with your prescriber about all of the possible treatments for
your acne, and whether Accutane’s possible benefits outweigh its possible risks.
Who should not take Accutane?
•
Do not take Accutane if you are pregnant, plan to become pregnant, or become pregnant during
Accutane treatment. Accutane causes severe birth defects. All females should read the section “What are the
important warnings for females taking Accutane?” for more information and warnings about Accutane and
pregnancy.
•
Do not take Accutane unless you completely understand its possible risks and are willing to follow all of the
instructions in this Medication Guide.
Tell your prescriber if you or someone in your family has had any kind of mental problems, asthma, liver disease,
diabetes, heart disease, or any other important health problems. Tell your prescriber about any food or drug allergies
you have had in the past. These problems do not necessarily mean you cannot take Accutane, but your prescriber
needs this information to discuss if Accutane is right for you.
How should I take Accutane?
•
You will get no more than a 1 month supply of Accutane at a time, to be sure you check in with your prescriber
each month to discuss side effects.
•
Your prescription should have a special yellow self-adhesive sticker attached to it. The sticker is YELLOW. If
your prescription does not have this yellow self-adhesive sticker, call your prescriber. The pharmacy should not
fill your prescription unless it has the yellow self-adhesive sticker.
•
The amount of Accutane you take has been specially chosen for you and may change during treatment.
•
You will take Accutane 2 times a day with a meal, unless your prescriber tells you otherwise. Swallow your
Accutane capsules with a full glass of liquid. This will help prevent the medication inside the capsule from
irritating the lining of your esophagus (connection between mouth and stomach). For the same reason, do not
chew or suck on the capsule.
•
If you miss a dose, just skip that dose. Do not take 2 doses the next time.
•
You should return to your prescriber as directed to make sure you don’t have signs of serious side effects.
Because some of Accutane’s serious side effects show up in blood tests, some of these visits may involve blood
tests (monthly visits for female patients should always include a urine or serum pregnancy test).
What should I avoid while taking Accutane?
•
Do not get pregnant while taking Accutane. See “What is the most important information I should know about
Accutane?” and “What are the important warnings for females taking Accutane?”
•
Do not breast feed while taking Accutane and for 1 month after stopping Accutane. We do not know if
Accutane can pass through your milk and harm the baby.
•
Do not give blood while you take Accutane and for 1 month after stopping Accutane. If someone who is
pregnant gets your donated blood, her baby may be exposed to Accutane and may be born with birth defects.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Do not take vitamin A supplements. Vitamin A in high doses has many of the same side effects as Accutane.
Taking both together may increase your chance of getting side effects.
•
Do not have cosmetic procedures to smooth your skin, including waxing, dermabrasion, or laser
procedures, while you are using Accutane and for at least 6 months after you stop. Accutane can increase
your chance of scarring from these procedures. Check with your prescriber for advice about when you can have
cosmetic procedures.
•
Avoid sunlight and ultraviolet lights as much as possible. Tanning machines use ultraviolet lights. Accutane
may make your skin more sensitive to light.
•
Do not use birth control pills that do not contain estrogen (“minipills”). They may not work while you take
Accutane. Ask your prescriber or pharmacist if you are not sure what type you are using.
•
Talk with your doctor if you plan to take other drugs or herbal products. This is especially important for
patients using birth control pills and other hormonal types of birth control because the birth control may not
work as effectively if you are taking certain drugs or herbal products. You should not take the herbal
supplement St. John’s Wort because this herbal supplement may make birth control pills not work as
effectively.
•
Do not share Accutane with other people. It can cause birth defects and other serious health problems.
•
Do not take Accutane with antibiotics unless you talk to your prescriber. For some antibiotics, you may
have to stop taking Accutane until the antibiotic treatment is finished. Use of both drugs together can increase
the chances of getting increased pressure in the brain.
What are the possible side effects of Accutane?
Accutane has possible serious side effects
•
Accutane can cause birth defects, premature births, and death in babies whose mothers took Accutane
while they were pregnant. See “What is the most important information I should know about Accutane?” and
“What are the important warnings for females taking Accutane?”
•
Serious mental health problems. See “What is the most important information I should know about
Accutane?”
•
Serious brain problems. Accutane can increase the pressure in your brain. This can lead to permanent loss of
sight, or in rare cases, death. Stop taking Accutane and call your prescriber right away if you get any of these
signs of increased brain pressure: bad headache, blurred vision, dizziness, nausea, or vomiting. Also, some
patients taking Accutane have had seizures (convulsions) or stroke.
•
Abdomen (stomach area) problems. Certain symptoms may mean that your internal organs are being
damaged. These organs include the liver, pancreas, bowel (intestines), and esophagus (connection between
mouth and stomach). If your organs are damaged, they may not get better even after you stop taking Accutane.
Stop taking Accutane and call your prescriber if you get severe stomach, chest or bowel pain, trouble
swallowing or painful swallowing, new or worsening heartburn, diarrhea, rectal bleeding, yellowing of your
skin or eyes, or dark urine.
•
Bone and muscle problems. Accutane may affect bones, muscles, and ligaments and cause pain in your joints
or muscles. Tell your prescriber if you plan vigorous physical activity during treatment with Accutane. Tell
your prescriber if you develop pain. Muscle weakness with or without pain can be a sign of serious muscle
damage. If this happens, stop taking Accutane and call your prescriber right away. If a bone breaks, tell your
prescriber you take Accutane. No one knows if taking Accutane for acne will reduce bone healing or stunt
growth.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
•
Hearing problems. Some people taking Accutane have developed hearing problems. It is possible that hearing
loss can be permanent. Stop using Accutane and call your prescriber if your hearing gets worse or if you have
ringing in your ears.
•
Vision problems. While taking Accutane you may develop a sudden inability to see in the dark, so driving at
night can be dangerous. This condition usually clears up after you stop taking Accutane, but it may be
permanent. Other serious eye effects can occur. Stop taking Accutane and call your prescriber right away if you
have any problems with your vision or dryness of the eyes that is painful or constant.
•
Lipid (fats and cholesterol in blood) problems. Many people taking Accutane develop high levels of
cholesterol and other fats in their blood. This can be a serious problem. Return to your prescriber for blood tests
to check your lipids and to get any needed treatment. These problems generally go away when Accutane
treatment is finished.
•
Allergic reactions. In some people, Accutane can cause serious allergic reactions. Stop taking Accutane and get
emergency care right away if you develop hives, a swollen face or mouth, or have trouble breathing. Stop taking
Accutane and call your prescriber if you develop a fever, rash, or red patches or bruises on your legs.
•
Signs of other possibly serious problems. Accutane may cause other problems. Tell your prescriber if you
have trouble breathing (shortness of breath), are fainting, are very thirsty or urinate a lot, feel weak, have leg
swelling, convulsions, slurred speech, problems moving, or any other serious or unusual problems. Frequent
urination and thirst can be signs of blood sugar problems.
Serious permanent problems do not happen often. However, because the symptoms listed above may be signs of
serious problems, if you get these symptoms, stop taking Accutane and call your prescriber. If not treated, they
could lead to serious health problems. Even if these problems are treated, they may not clear up after you stop taking
Accutane.
Accutane has less serious possible side effects
The common less serious side effects of Accutane are dry skin, chapped lips, dry eyes, and dry nose that may lead to
nosebleeds. People who wear contact lenses may have trouble wearing them while taking Accutane and after
therapy. Sometimes, people’s acne may get worse for a while. They should continue taking Accutane unless told to
stop by their prescriber.
These are not all of Accutane’s possible side effects. Your prescriber or pharmacist can give you more detailed
information that is written for health care professionals.
This Medication Guide is only a summary of some important information about Accutane. Medicines are sometimes
prescribed for purposes other than those listed in a Medication Guide. If you have any concerns or questions about
Accutane, ask your prescriber. Do not use Accutane for a condition for which it was not prescribed.
Active Ingredient: Isotretinoin.
Inactive Ingredients: beeswax, butylated hydroxyanisole, edetate disodium, hydrogenated soybean oil flakes,
hydrogenated vegetable oil, and soybean oil. Gelatin capsules contain glycerin and parabens (methyl and propyl),
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
with the following dye systems: 10 mg — iron oxide (red) and titanium dioxide; 20 mg — FD&C Red No. 3, FD&C
Blue No. 1, and titanium dioxide; 40 mg — FD&C Yellow No. 6, D&C Yellow No. 10, and titanium dioxide.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Rx only
xxxxxxxx-xxxx
Revised: December, 2001
Printed in USA
Copyright © 2000-2001 by Roche Laboratories Inc. All rights reserved.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
Hon-Sum Ko
12/31/01 01:00:14 PM
for Jonathan K. Wilkin, M.D.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:50.150190
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/18662s41s45lbl.pdf', 'application_number': 18662, 'submission_type': 'SUPPL ', 'submission_number': 41}
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ACCUTANE
(isotretinoin)
CAPSULES
CAUSES BIRTH DEFECTS
DO NOT GET PREGNANT
CONTRAINDICATIONS AND WARNINGS: Accutane must not be used by
females who are pregnant. Although not every fetus exposed to Accutane has
resulted in a deformed child, there is an extremely high risk that a deformed infant
can result if pregnancy occurs while taking Accutane in any amount even for short
periods of time. Potentially any fetus exposed during pregnancy can be affected.
Presently, there are no accurate means of determining, after Accutane exposure,
which fetus has been affected and which fetus has not been affected.
Major human fetal abnormalities related to Accutane administration in females
have been documented. There is an increased risk of spontaneous abortion. In
addition, premature births have been reported.
Documented external abnormalities include: skull abnormality; ear abnormalities
(including anotia, micropinna, small or absent external auditory canals); eye
abnormalities (including microphthalmia); facial dysmorphia; cleft palate.
Documented internal abnormalities include: CNS abnormalities (including cerebral
abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial nerve
deficit); cardiovascular abnormalities; thymus gland abnormality; parathyroid
hormone deficiency. In some cases death has occurred with certain of the
abnormalities previously noted.
Cases of IQ scores less than 85 with or without obvious CNS abnormalities have also
been reported.
Accutane is contraindicated in females of childbearing potential unless the patient
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
meets all of the following conditions:
• Must NOT be pregnant or breast feeding.
• Must be capable of complying with the mandatory contraceptive measures
required for Accutane therapy and understand behaviors associated with an
increased risk of pregnancy.
• Must be reliable in understanding and carrying out instructions.
Accutane must be prescribed under the System to Manage Accutane Related
Teratogenicity
(S.M.A.R.T.
).
To prescribe Accutane, the prescriber must obtain a supply of yellow self-adhesive
Accutane Qualification Stickers. To obtain these stickers:
1) Read the booklet entitled System to Manage Accutane Related Teratogenicity
(S.M.A.R.T.) Guide to Best Practices.
2) Sign and return the completed S.M.A.R.T. Letter of Understanding containing the
following Prescriber Checklist:
• I know the risk and severity of fetal injury/birth defects from Accutane
• I know how to diagnose and treat the various presentations of acne
• I know the risk factors for unplanned pregnancy and the effective measures for
avoidance of unplanned pregnancy
• It is the informed patient’s responsibility to avoid pregnancy during Accutane
therapy and for 1 month after stopping Accutane. To help patients have the
knowledge and tools to do so: Before beginning treatment of female patients with
Accutane I will refer for expert, detailed pregnancy prevention counseling and
prescribing, reimbursed by the manufacturer, OR I have the expertise to perform
this function and elect to do so
• I understand, and will properly use throughout the Accutane treatment course,
the S.M.A.R.T. procedures for Accutane, including monthly pregnancy avoidance
counseling, pregnancy testing and use of the yellow self-adhesive Accutane
Qualification Stickers
3) To use the yellow self-adhesive Accutane Qualification Sticker: Accutane should
not be prescribed or dispensed to any patient (male or female) without a yellow
self-adhesive Accutane Qualification Sticker.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
For female patients, the yellow self-adhesive Accutane Qualification Sticker signifies
that she:
• Must have had 2 negative urine or serum pregnancy tests with a sensitivity of at
least 25 mIU/mL before receiving the initial Accutane prescription. The first test
(a screening test) is obtained by the prescriber when the decision is made to
pursue qualification of the patient for Accutane. The second pregnancy test (a
confirmation test) should be done during the first 5 days of the menstrual period
immediately preceding the beginning of Accutane therapy. For patients with
amenorrhea, the second test should be done at least 11 days after the last act of
unprotected sexual intercourse (without using 2 effective forms of contraception).
Each month of therapy, the patient must have a negative result from a urine or
serum pregnancy test. A pregnancy test must be repeated every month prior to
the female patient receiving each prescription. The manufacturer will make
available urine pregnancy test kits for female Accutane patients for the initial,
second and monthly testing during therapy.
• Must have selected and have committed to use 2 forms of effective contraception
simultaneously, at least 1 of which must be a primary form, unless absolute
abstinence is the chosen method, or the patient has undergone a hysterectomy.
Patients must use 2 forms of effective contraception for at least 1 month prior to
initiation of Accutane therapy, during Accutane therapy, and for 1 month after
discontinuing Accutane therapy. Counseling about contraception and behaviors
associated with an increased risk of pregnancy must be repeated on a monthly
basis.
Effective forms of contraception include both primary and secondary forms of
contraception. Primary forms of contraception include: tubal ligation, partner’s
vasectomy, intrauterine devices, birth control pills, and
injectable/implantable/insertable hormonal birth control products. Secondary
forms of contraception include diaphragms, latex condoms, and cervical caps; each
must be used with a spermicide.
Any birth control method can fail. Therefore, it is critically important that women
of childbearing potential use 2 effective forms of contraception simultaneously. A
drug interaction that decreases effectiveness of hormonal contraceptives has not
been entirely ruled out for Accutane. Although hormonal contraceptives are
highly effective, there have been reports of pregnancy from women who have used
oral contraceptives, as well as injectable/implantable contraceptive products.
These reports occurred while these patients were taking Accutane. These reports
are more frequent for women who use only a single method of contraception.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients must receive written warnings about the rates of possible contraception
failure (included in patient education kits).
Prescribers are advised to consult the package insert of any medication
administered concomitantly with hormonal contraceptives, since some medications
may decrease the effectiveness of these birth control products. Patients should be
prospectively cautioned not to self-medicate with the herbal supplement St. John’s
Wort because a possible interaction has been suggested with hormonal
contraceptives based on reports of breakthrough bleeding on oral contraceptives
shortly after starting St. John's Wort. Pregnancies have been reported by users of
combined hormonal contraceptives who also used some form of St. John's Wort
(see PRECAUTIONS).
• Must have signed a Patient Information/Consent form that contains warnings
about the risk of potential birth defects if the fetus is exposed to isotretinoin.
• Must have been informed of the purpose and importance of participating in the
Accutane Survey and have been given the opportunity to enroll (see
PRECAUTIONS).
The yellow self-adhesive Accutane Qualification Sticker documents that the female
patient is qualified, and includes the date of qualification, patient gender, cut-off
date for filling the prescription, and up to a 30-day supply limit with no refills.
These yellow self-adhesive Accutane Qualification Stickers should also be used for
male patients.
Table 1. Use of Pregnancy Tests and Accutane Qualification Stickers for Patients
Patient Type
Pregnancy
Test
Required
Qualification Date
Accutane
Qualification
Sticker Necessary
Dispense Within
7 Days of
Qualification Date
All Males
No
Date Prescription
Written
Yes
Yes
Females of
Childbearing
Potential
Yes
Date of
Confirmatory
Negative Pregnancy
Test
Yes
Yes
Females* Not of
Childbearing
Potential
No
Date Prescription
Written
Yes
Yes
*Females who have had a hysterectomy or who are postmenopausal are not considered to be of
childbearing potential.
If a pregnancy does occur during treatment of a woman with Accutane, the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
prescriber and patient should discuss the desirability of continuing the pregnancy.
Prescribers are strongly encouraged to report all cases of pregnancy to Roche
@ 1-800-526-6367 where a Roche Pregnancy Prevention Program Specialist will be
available to discuss Roche pregnancy information, or prescribers may contact the
Food and Drug Administration MedWatch Program @ 1-800-FDA-1088.
Accutane should be prescribed only by prescribers who have demonstrated special
competence in the diagnosis and treatment of severe recalcitrant nodular acne, are
experienced in the use of systemic retinoids, have read the S.M.A.R.T. Guide to Best
Practices, signed and returned the completed S.M.A.R.T. Letter of Understanding,
and obtained yellow self-adhesive Accutane Qualification Stickers. Accutane should
not be prescribed or dispensed without a yellow self-adhesive Accutane
Qualification Sticker.
INFORMATION FOR PHARMACISTS:
ACCUTANE MUST ONLY BE DISPENSED:
• IN NO MORE THAN A 30-DAY SUPPLY
• ONLY ON PRESENTATION OF AN ACCUTANE PRESCRIPTION WITH A
YELLOW SELF-ADHESIVE ACCUTANE QUALIFICATION STICKER
• WRITTEN WITHIN THE PREVIOUS 7 DAYS
• REFILLS REQUIRE A NEW PRESCRIPTION WITH A YELLOW SELF-
ADHESIVE ACCUTANE QUALIFICATION STICKER
• NO TELEPHONE OR COMPUTERIZED PRESCRIPTIONS ARE
PERMITTED.
AN ACCUTANE MEDICATION GUIDE MUST BE GIVEN TO THE PATIENT
EACH TIME ACCUTANE IS DISPENSED, AS REQUIRED BY LAW. THIS
ACCUTANE MEDICATION GUIDE IS AN IMPORTANT PART OF THE RISK
MANAGEMENT PROGRAM FOR THE PATIENT.
DESCRIPTION: Isotretinoin, a retinoid, is available as Accutane in 10-mg, 20-mg and 40-mg
soft gelatin capsules for oral administration. Each capsule contains beeswax, butylated
hydroxyanisole, edetate disodium, hydrogenated soybean oil flakes, hydrogenated vegetable oil,
and soybean oil. Gelatin capsules contain glycerin and parabens (methyl and propyl), with the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
following dye systems: 10 mg — iron oxide (red) and titanium dioxide; 20 mg — FD&C Red
No. 3, FD&C Blue No. 1, and titanium dioxide; 40 mg — FD&C Yellow No. 6, D&C Yellow
No. 10, and titanium dioxide.
Chemically, isotretinoin is 13-cis-retinoic acid and is related to both retinoic acid and retinol
(vitamin A). It is a yellow to orange crystalline powder with a molecular weight of 300.44. The
structural formula is:
CLINICAL PHARMACOLOGY: Isotretinoin is a retinoid, which when administered in
pharmacologic dosages of 0.5 to 1.0 mg/kg/day (see DOSAGE AND ADMINISTRATION),
inhibits sebaceous gland function and keratinization. The exact mechanism of action of
isotretinoin is unknown.
Nodular Acne: Clinical improvement in nodular acne patients occurs in association with a
reduction in sebum secretion. The decrease in sebum secretion is temporary and is related to the
dose and duration of treatment with Accutane, and reflects a reduction in sebaceous gland size
and an inhibition of sebaceous gland differentiation.1
Pharmacokinetics: Absorption: Due to its high lipophilicity, oral absorption of isotretinoin is
enhanced when given with a high-fat meal. In a crossover study, 74 healthy adult subjects
received a single 80 mg oral dose (2 x 40 mg capsules) of Accutane under fasted and fed
conditions. Both peak plasma concentration (Cmax) and the total exposure (AUC) of isotretinoin
were more than doubled following a standardized high-fat meal when compared with Accutane
given under fasted conditions (see Table 2 below). The observed elimination half-life was
unchanged. This lack of change in half-life suggests that food increases the bioavailability of
isotretinoin without altering its disposition. The time to peak concentration (Tmax) was also
increased with food and may be related to a longer absorption phase. Therefore, Accutane
capsules should always be taken with food (see DOSAGE AND ADMINISTRATION). Clinical
studies have shown that there is no difference in the pharmacokinetics of isotretinoin between
patients with nodular acne and healthy subjects with normal skin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 2. Pharmacokinetic Parameters of Isotretinoin
Mean (%CV), N=74
Accutane
2 x 40 mg
Capsules
AUC0-∞∞∞∞
(ng⋅⋅⋅⋅hr/mL)
Cmax
(ng/mL)
Tmax
(hr)
t1/2
(hr)
Fed*
10,004 (22%)
862 (22%)
5.3 (77%)
21 (39%)
Fasted
3,703 (46%)
301 (63%)
3.2 (56%)
21 (30%)
*Eating a standardized high-fat meal
Distribution: Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.
Metabolism: Following oral administration of isotretinoin, at least three metabolites have been
identified in human plasma: 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid
(4-oxo-tretinoin). Retinoic acid and 13-cis-retinoic acid are geometric isomers and show
reversible interconversion. The administration of one isomer will give rise to the other.
Isotretinoin is also irreversibly oxidized to 4-oxo-isotretinoin, which forms its geometric isomer
4-oxo-tretinoin.
After a single 80 mg oral dose of Accutane to 74 healthy adult subjects, concurrent
administration of food increased the extent of formation of all metabolites in plasma when
compared to the extent of formation under fasted conditions.
All of these metabolites possess retinoid activity that is in some in vitro models more than that of
the parent isotretinoin. However, the clinical significance of these models is unknown. After
multiple oral dose administration of isotretinoin to adult cystic acne patients (≥18 years), the
exposure of patients to 4-oxo-isotretinoin at steady-state under fasted and fed conditions was
approximately 3.4 times higher than that of isotretinoin.
In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are
2C8, 2C9, 3A4, and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates,
which are then excreted in urine and feces.
Elimination: Following oral administration of an 80 mg dose of 14C-isotretinoin as a liquid
suspension, 14C-activity in blood declined with a half-life of 90 hours. The metabolites of
isotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively equal
amounts (total of 65% to 83%). After a single 80 mg oral dose of Accutane to 74 healthy adult
subjects under fed conditions, the mean ± SD elimination half-lives (t1/2) of isotretinoin and 4-
oxo-isotretinoin were 21.0 ± 8.2 hours and 24.0 ± 5.3 hours, respectively. After both single and
multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.90 to 5.43 in
patients with cystic acne.
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Special Patient Populations: Pediatric Patients: The pharmacokinetics of isotretinoin were
evaluated after single and multiple doses in 38 pediatric patients (12 to 15 years) and 19 adult
patients (≥18 years) who received Accutane for the treatment of severe recalcitrant nodular acne.
In both age groups, 4-oxo-isotretinoin was the major metabolite; tretinoin and 4-oxo-tretinoin
were also observed. The dose-normalized pharmacokinetic parameters for isotretinoin following
single and multiple doses are summarized in Table 3 for pediatric patients. There were no
statistically significant differences in the pharmacokinetics of isotretinoin between pediatric and
adult patients.
Table 3. Pharmacokinetic Parameters of Isotretinoin Following Single and Multiple Dose
Administration in Pediatric Patients, 12 to 15 Years of Age
Mean (±±±± SD), N=38*
Parameter
Isotretinoin
(Single Dose)
Isotretinoin
(Steady-State)
Cmax (ng/mL)
573.25 (278.79)
731.98 (361.86)
AUC(0-12) (ng⋅hr/mL)
3033.37 (1394.17)
5082.00 (2184.23)
AUC(0-24) (ng⋅hr/mL)
6003.81 (2885.67)
–
Tmax (hr)†
6.00 (1.00-24.60)
4.00 (0-12.00)
Cssmin (ng/mL)
–
352.32 (184.44)
T1/2 (hr)
–
15.69 (5.12)
CL/F (L/hr)
–
17.96 (6.27)
*The single and multiple dose data in this table were obtained following a non-standardized meal
that is not comparable to the high-fat meal that was used in the study in Table 2.
†Median (range)
In pediatric patients (12 to 15 years), the mean ± SD elimination half-lives (t1/2) of isotretinoin
and 4-oxo-isotretinoin were 15.7 ± 5.1 hours and 23.1 ± 5.7 hours, respectively. The
accumulation ratios of isotretinoin ranged from 0.46 to 3.65 for pediatric patients.
INDICATIONS AND USAGE: Severe Recalcitrant Nodular Acne: Accutane is indicated for
the treatment of severe recalcitrant nodular acne. Nodules are inflammatory lesions with a
diameter of 5 mm or greater. The nodules may become suppurative or hemorrhagic. “Severe,” by
definition,2 means “many” as opposed to “few or several” nodules. Because of significant
adverse effects associated with its use, Accutane should be reserved for patients with severe
nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In
addition, Accutane is indicated only for those females who are not pregnant, because Accutane
can cause severe birth defects (see boxed CONTRAINDICATIONS AND WARNINGS).
A single course of therapy for 15 to 20 weeks has been shown to result in complete and
prolonged remission of disease in many patients.1,3,4 If a second course of therapy is needed, it
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should not be initiated until at least 8 weeks after completion of the first course, because
experience has shown that patients may continue to improve while off Accutane. The optimal
interval before retreatment has not been defined for patients who have not completed skeletal
growth (see WARNINGS: Skeletal: Bone Mineral Density, Hyperostosis, and Premature
Epiphyseal Closure).
CONTRAINDICATIONS: Pregnancy: Category X. See boxed CONTRAINDICATIONS
AND WARNINGS.
Allergic Reactions: Accutane is contraindicated in patients who are hypersensitive to this
medication or to any of its components. Accutane should not be given to patients who are
sensitive to parabens, which are used as preservatives in the gelatin capsule (see
PRECAUTIONS: Hypersensitivity).
WARNINGS: Psychiatric Disorders: Accutane may cause depression, psychosis and, rarely,
suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors.
Discontinuation of Accutane therapy may be insufficient; further evaluation may be
necessary. No mechanism of action has been established for these events (see ADVERSE
REACTIONS: Psychiatric). Prescribers should read the brochure, Recognizing Psychiatric
Disorders in Adolescents and Young Adults: A Guide for Prescribers of Accutane
(isotretinoin).
Pseudotumor Cerebri: Accutane use has been associated with a number of cases of
pseudotumor cerebri (benign intracranial hypertension), some of which involved
concomitant use of tetracyclines. Concomitant treatment with tetracyclines should
therefore be avoided. Early signs and symptoms of pseudotumor cerebri include
papilledema, headache, nausea and vomiting, and visual disturbances. Patients with these
symptoms should be screened for papilledema and, if present, they should be told to
discontinue Accutane immediately and be referred to a neurologist for further diagnosis
and care (see ADVERSE REACTIONS: Neurological).
Pancreatitis: Acute pancreatitis has been reported in patients with either elevated or normal
serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been
reported. Accutane should be stopped if hypertriglyceridemia cannot be controlled at an
acceptable level or if symptoms of pancreatitis occur.
Lipids: Elevations of serum triglycerides have been reported in patients treated with Accutane.
Marked elevations of serum triglycerides in excess of 800 mg/dL were reported in approximately
25% of patients receiving Accutane in clinical trials. In addition, approximately 15% developed
a decrease in high-density lipoproteins and about 7% showed an increase in cholesterol levels.
In clinical trials, the effects on triglycerides, HDL, and cholesterol were reversible upon
cessation of Accutane therapy. Some patients have been able to reverse triglyceride elevation by
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reduction in weight, restriction of dietary fat and alcohol, and reduction in dose while continuing
Accutane.5
Blood lipid determinations should be performed before Accutane is given and then at intervals
until the lipid response to Accutane is established, which usually occurs within 4 weeks.
Especially careful consideration must be given to risk/benefit for patients who may be at high
risk during Accutane therapy (patients with diabetes, obesity, increased alcohol intake, lipid
metabolism disorder or familial history of lipid metabolism disorder). If Accutane therapy is
instituted, more frequent checks of serum values for lipids and/or blood sugar are recommended
(see PRECAUTIONS: Laboratory Tests).
The cardiovascular consequences of hypertriglyceridemia associated with Accutane are
unknown. Animal Studies: In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 to 5.3 times the
recommended clinical dose of 1.0 mg/kg/day after normalization for total body surface area) for
18 months or longer, the incidences of focal calcification, fibrosis and inflammation of the
myocardium, calcification of coronary, pulmonary and mesenteric arteries, and metastatic
calcification of the gastric mucosa were greater than in control rats of similar age. Focal
endocardial and myocardial calcifications associated with calcification of the coronary arteries
were observed in two dogs after approximately 6 to 7 months of treatment with isotretinoin at a
dosage of 60 to 120 mg/kg/day (30 to 60 times the recommended clinical dose of 1.0 mg/kg/day,
respectively, after normalization for total body surface area).
Hearing Impairment: Impaired hearing has been reported in patients taking Accutane; in some
cases, the hearing impairment has been reported to persist after therapy has been discontinued.
Mechanism(s) and causality for this event have not been established. Patients who experience
tinnitus or hearing impairment should discontinue Accutane treatment and be referred for
specialized care for further evaluation (see ADVERSE REACTIONS: Special Senses).
Hepatotoxicity: Clinical hepatitis considered to be possibly or probably related to Accutane
therapy has been reported. Additionally, mild to moderate elevations of liver enzymes have been
observed in approximately 15% of individuals treated during clinical trials, some of which
normalized with dosage reduction or continued administration of the drug. If normalization does
not readily occur or if hepatitis is suspected during treatment with Accutane, the drug should be
discontinued and the etiology further investigated.
Inflammatory Bowel Disease: Accutane has been associated with inflammatory bowel disease
(including regional ileitis) in patients without a prior history of intestinal disorders. In some
instances, symptoms have been reported to persist after Accutane treatment has been stopped.
Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue
Accutane immediately (see ADVERSE REACTIONS: Gastrointestinal).
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Skeletal: Bone Mineral Density: Effects of multiple courses of Accutane on the developing
musculoskeletal system are unknown. There is some evidence that long-term, high-dose, or
multiple courses of therapy with isotretinoin have more of an effect than a single course of
therapy on the musculoskeletal system. In an open-label clinical trial (N=217) of a single course
of therapy with Accutane for severe recalcitrant nodular acne, bone density measurements at
several skeletal sites were not significantly decreased (lumbar spine change >-4% and total hip
change >-5%) or were increased in the majority of patients. One patient had a decrease in
lumbar spine bone mineral density >4% based on unadjusted data. Sixteen (7.9%) patients had
decreases in lumbar spine bone mineral density >4%, and all the other patients (92%) did not
have significant decreases or had increases (adjusted for body mass index). Nine patients (4.5%)
had a decrease in total hip bone mineral density >5% based on unadjusted data. Twenty-one
(10.6%) patients had decreases in total hip bone mineral density >5%, and all the other patients
(89%) did not have significant decreases or had increases (adjusted for body mass index).
Follow-up studies performed in 8 of the patients with decreased bone mineral density for up to
11 months thereafter demonstrated increasing bone density in 5 patients at the lumbar spine,
while the other 3 patients had lumbar spine bone density measurements below baseline values.
Total hip bone mineral densities remained below baseline (range –1.6% to -7.6%) in 5 of 8
patients (62.5%).
In a separate open-label extension study of 10 patients, ages 13-18 years, who started a second
course of Accutane 4 months after the first course, two patients showed a decrease in mean
lumbar spine bone mineral density up to 3.25% (adjusted for body mass index).
Spontaneous reports of osteoporosis, osteopenia, bone fractures, and delayed healing of bone
fractures have been seen in the Accutane population. While causality to Accutane has not been
established, an effect cannot be ruled out. Longer term effects have not been studied. It is
important that Accutane be given at the recommended doses for no longer than the recommended
duration.
Hyperostosis: A high prevalence of skeletal hyperostosis was noted in clinical trials for disorders
of keratinization with a mean dose of 2.24 mg/kg/day. Additionally, skeletal hyperostosis was
noted in 6 of 8 patients in a prospective study of disorders of keratinization.6 Minimal skeletal
hyperostosis and calcification of ligaments and tendons have also been observed by x-ray in
prospective studies of nodular acne patients treated with a single course of therapy at
recommended doses. The skeletal effects of multiple Accutane treatment courses for acne are
unknown.
In a clinical study of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne,
hyperostosis was not observed after 16 to 20 weeks of treatment with approximately 1 mg/kg/day
of Accutane given in two divided doses. Hyperostosis may require a longer time frame to
appear. The clinical course and significance remain unknown.
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Premature Epiphyseal Closure: There are spontaneous reports of premature epiphyseal closure
in acne patients receiving recommended doses of Accutane. The effect of multiple courses of
Accutane on epiphyseal closure is unknown.
Vision Impairment: Visual problems should be carefully monitored. All Accutane patients
experiencing visual difficulties should discontinue Accutane treatment and have an
ophthalmological examination (see ADVERSE REACTIONS: Special Senses).
Corneal Opacities: Corneal opacities have occurred in patients receiving Accutane for acne and
more frequently when higher drug dosages were used in patients with disorders of keratinization.
The corneal opacities that have been observed in clinical trial patients treated with Accutane
have either completely resolved or were resolving at follow-up 6 to 7 weeks after discontinuation
of the drug (see ADVERSE REACTIONS: Special Senses).
Decreased Night Vision: Decreased night vision has been reported during Accutane therapy and
in some instances the event has persisted after therapy was discontinued. Because the onset in
some patients was sudden, patients should be advised of this potential problem and warned to be
cautious when driving or operating any vehicle at night.
PRECAUTIONS: The Accutane Pregnancy Prevention and Risk Management Programs consist
of the System to Manage Accutane Related Teratogenicity (S.M.A.R.T.) and the Accutane
Pregnancy Prevention Program (PPP). S.M.A.R.T. should be followed for prescribing Accutane
with the goal of preventing fetal exposure to isotretinoin. It consists of: 1) reading the booklet
entitled System to Manage Accutane Related Teratogenicity (S.M.A.R.T.) Guide to Best
Practices, 2) signing and returning the completed S.M.A.R.T. Letter of Understanding
containing the Prescriber Checklist, 3) a yellow self-adhesive Accutane Qualification Sticker to
be affixed to the prescription page. In addition, the patient educational material, Be Smart, Be
Safe, Be Sure, should be used with each patient.
The following further describes each component:
1) The S.M.A.R.T. Guide to Best Practices includes: Accutane teratogenic potential,
information on pregnancy testing, specific information about effective contraception, the
limitations of contraceptive methods and behaviors associated with an increased risk of
contraceptive failure and pregnancy, the methods to evaluate pregnancy risk, and the method
to complete a qualified Accutane prescription.
2) The S.M.A.R.T. Letter of Understanding attests that Accutane prescribers understand that
Accutane is a teratogen, have read the S.M.A.R.T. Guide to Best Practices, understand their
responsibilities in preventing exposure of pregnant females to Accutane and the procedures
for qualifying female patients as defined in the boxed CONTRAINDICATIONS AND
WARNINGS.
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The Prescriber Checklist attests that Accutane prescribers know the risk and severity of
injury/birth defects from Accutane; know how to diagnose and treat the various presentations
of acne; know the risk factors for unplanned pregnancy and the effective measures for
avoidance; will refer the patient for, or provide, detailed pregnancy prevention counseling to
help the patient have knowledge and tools needed to fulfill their ultimate responsibility to
avoid becoming pregnant; understand and properly use throughout the Accutane treatment
course, the revised risk management procedures, including monthly pregnancy avoidance
counseling, pregnancy testing, and use of qualified prescriptions with the yellow self-
adhesive Accutane Qualification Sticker.
3) The yellow self-adhesive Accutane Qualification Sticker is used as documentation that the
prescriber has qualified the female patient according to the qualification criteria (see boxed
CONTRAINDICATIONS AND WARNINGS).
4) Accutane Pregnancy Prevention Program (PPP) is a systematic approach to comprehensive
patient education about their responsibilities and includes education for contraception
compliance and reinforcement of educational messages. The PPP includes information on the
risks and benefits of Accutane which is linked to the Accutane Medication Guide dispensed
by pharmacists with each prescription.
Male and female patients are provided with separate booklets. Each booklet contains
information on Accutane therapy, including precautions and warnings, an Informed
Consent/Patient Agreement form, and a toll-free line which provides Accutane information in
13 languages.
The booklet for male patients, Be Smart, Be Safe, Be Sure, Accutane Risk Management
Program for Men, also includes information about male reproduction, a warning not to share
Accutane with others or to donate blood during Accutane therapy and for 1 month following
discontinuation of Accutane.
The booklet for female patients, Be Smart, Be Safe, Be Sure, Accutane Pregnancy Prevention
and Risk Management Program for Women, also includes a referral program that offers
females free contraception counseling, reimbursed by the manufacturer, by a reproductive
specialist; a second Patient Information/Consent form concerning birth defects, obtaining her
consent to be treated within this agreement; an enrollment form for the Accutane Survey; and
a qualification checklist affirming the conditions under which female patients may receive
Accutane. In addition, there is information on the types of contraceptive methods, the
selection and use of appropriate, effective contraception, and the rates of possible
contraceptive failure; a toll-free contraception counseling line; and a video about the most
common reasons for unplanned pregnancies.
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General: Although an effect of Accutane on bone loss is not established, physicians should use
caution when prescribing Accutane to patients with a genetic predisposition for age-related
osteoporosis, a history of childhood osteoporosis conditions, osteomalacia, or other disorders of
bone metabolism. This would include patients diagnosed with anorexia nervosa and those who
are on chronic drug therapy that causes drug-induced osteoporosis/osteomalacia and/or affects
vitamin D metabolism, such as systemic corticosteroids and any anticonvulsant.
Patients may be at increased risk when participating in sports with repetitive impact where the
risks of spondylolisthesis with and without pars fractures and hip growth plate injuries in early
and late adolescence are known. There are spontaneous reports of fractures and/or delayed
healing in patients while on treatment with Accutane or following cessation of treatment with
Accutane while involved in these activities. While causality to Accutane has not been
established, an effect cannot be ruled out.
Information for Patients and Prescribers:
• Patients should be instructed to read the Medication Guide supplied as required by law when
Accutane is dispensed. The complete text of the Medication Guide is reprinted at the end of
this document. For additional information, patients should also read the Patient Product
Information, Important Information Concerning Your Treatment with Accutane
(isotretinoin). All patients should sign the Informed Consent/Patient Agreement.
• Females of childbearing potential should be instructed that they must not be pregnant when
Accutane therapy is initiated, and that they should use 2 forms of effective contraception 1
month before starting Accutane, while taking Accutane, and for 1 month after Accutane has
been stopped. They should also sign a consent form prior to beginning Accutane therapy.
They should be given an opportunity to enroll in the Accutane Survey and to review the
patient videotape provided by the manufacturer to the prescriber. It includes information
about contraception, the most common reasons that contraception fails, and the importance of
using 2 forms of effective contraception when taking teratogenic drugs. Female patients
should be seen by their prescribers monthly and have a urine or serum pregnancy test
performed each month during treatment to confirm negative pregnancy status before another
Accutane prescription is written (see boxed CONTRAINDICATIONS AND WARNINGS).
• Accutane is found in the semen of male patients taking Accutane, but the amount delivered to
a female partner would be about 1 million times lower than an oral dose of 40 mg. While the
no-effect limit for isotretinoin-induced embryopathy is unknown, 20 years of postmarketing
reports include 4 with isolated defects compatible with features of retinoid exposed fetuses.
None of these cases had the combination of malformations characteristic of retinoid
exposure, and all had other possible explanations for the defects observed.
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•
Patients may report mental health problems or family history of psychiatric disorders. These reports should be
discussed with the patient and/or the patient’s family. A referral to a mental health professional may be
necessary. The physician should consider whether or not Accutane therapy is appropriate in this setting (see
WARNINGS: Psychiatric).
•
Patients should be informed that they must not share Accutane with anyone else because of the risk of birth
defects and other serious adverse events.
• Patients should not donate blood during therapy and for 1 month following discontinuance of
the drug because the blood might be given to a pregnant woman whose fetus must not be
exposed to Accutane.
• Patients should be reminded to take Accutane with a meal (see DOSAGE AND
ADMINISTRATION). To decrease the risk of esophageal irritation, patients should swallow
the capsules with a full glass of liquid.
• Patients should be informed that transient exacerbation (flare) of acne has been seen,
generally during the initial period of therapy.
• Wax epilation and skin resurfacing procedures (such as dermabrasion, laser) should be
avoided during Accutane therapy and for at least 6 months thereafter due to the possibility of
scarring (see ADVERSE REACTIONS: Skin and Appendages).
• Patients should be advised to avoid prolonged exposure to UV rays or sunlight.
• Patients should be informed that they may experience decreased tolerance to contact lenses
during and after therapy.
• Patients should be informed that approximately 16% of patients treated with Accutane in a
clinical trial developed musculoskeletal symptoms (including arthralgia) during treatment. In
general, these symptoms were mild to moderate, but occasionally required discontinuation of
the drug. Transient pain in the chest has been reported less frequently. In the clinical trial,
these symptoms generally cleared rapidly after discontinuation of Accutane, but in some
cases persisted (see ADVERSE REACTIONS: Musculoskeletal). There have been rare
postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity
(see Laboratory Tests: CPK).
• Pediatric patients and their caregivers should be informed that approximately 29% (104/358)
of pediatric patients treated with Accutane developed back pain. Back pain was severe in
13.5% (14/104) of the cases and occurred at a higher frequency in female than male patients.
Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe
in 7.6% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be
done in patients who present with these symptoms during or after a course of Accutane.
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Consideration should be given to discontinuation of Accutane if any significant abnormality
is found.
• Neutropenia and rare cases of agranulocytosis have been reported. Accutane should be
discontinued if clinically significant decreases in white cell counts occur.
Hypersensitivity: Anaphylactic reactions and other allergic reactions have been reported.
Cutaneous allergic reactions and serious cases of allergic vasculitis, often with purpura (bruises
and red patches) of the extremities and extracutaneous involvement (including renal) have been
reported. Severe allergic reaction necessitates discontinuation of therapy and appropriate medical
management.
Drug Interactions:
• Vitamin A: Because of the relationship of Accutane to vitamin A, patients should be advised
against taking vitamin supplements containing vitamin A to avoid additive toxic effects.
• Tetracyclines: Concomitant treatment with Accutane and tetracyclines should be avoided
because Accutane use has been associated with a number of cases of pseudotumor cerebri
(benign intracranial hypertension), some of which involved concomitant use of tetracyclines.
• Micro-dosed Progesterone Preparations: Micro-dosed progesterone preparations
(“minipills” that do not contain an estrogen) may be an inadequate method of contraception
during Accutane therapy. Although other hormonal contraceptives are highly effective, there
have been reports of pregnancy from women who have used combined oral contraceptives, as
well as injectable/implantable contraceptive products. These reports are more frequent for
women who use only a single method of contraception. It is not known if hormonal
contraceptives differ in their effectiveness when used with Accutane. Therefore, it is
critically important for women of childbearing potential to select and commit to use 2 forms
of effective contraception simultaneously, at least 1 of which must be a primary form, unless
absolute abstinence is the chosen method, or the patient has undergone a hysterectomy (see
boxed CONTRAINDICATIONS AND WARNINGS).
• Phenytoin: Accutane has not been shown to alter the pharmacokinetics of phenytoin in a
study in seven healthy volunteers. These results are consistent with the in vitro finding that
neither isotretinoin nor its metabolites induce or inhibit the activity of the CYP 2C9 human
hepatic P450 enzyme. Phenytoin is known to cause osteomalacia. No formal clinical studies
have been conducted to assess if there is an interactive effect on bone loss between phenytoin
and Accutane. Therefore, caution should be exercised when using these drugs together.
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• Systemic Corticosteroids: Systemic corticosteroids are known to cause osteoporosis. No
formal clinical studies have been conducted to assess if there is an interactive effect on bone
loss between systemic corticosteroids and Accutane. Therefore, caution should be exercised
when using these drugs together.
Prescribers are advised to consult the package insert of medication administered concomitantly
with hormonal contraceptives, since some medications may decrease the effectiveness of these
birth control products. Accutane use is associated with depression in some patients (see
WARNINGS: Psychiatric and ADVERSE REACTIONS: Psychiatric). Patients should be
prospectively cautioned not to self-medicate with the herbal supplement St. John’s Wort because
a possible interaction has been suggested with hormonal contraceptives based on reports of
breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies
have been reported by users of combined hormonal contraceptives who also used some form of
St. John's Wort.
Laboratory Tests:
Pregnancy Test: Female patients of childbearing potential must have negative results from 2
urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the
initial Accutane prescription. The first test is obtained by the prescriber when the decision is
made to pursue qualification of the patient for Accutane (a screening test). The second
pregnancy test (a confirmation test) should be done during the first 5 days of the menstrual
period immediately preceding the beginning of Accutane therapy. For patients with amenorrhea,
the second test should be done at least 11 days after the last act of unprotected sexual intercourse
(without using 2 effective forms of contraception).
Each month of therapy, the patient must have a negative result from a urine or serum pregnancy test. A pregnancy
test must be repeated each month prior to the female patient receiving each prescription.
• Lipids: Pretreatment and follow-up blood lipids should be obtained under fasting conditions.
After consumption of alcohol, at least 36 hours should elapse before these determinations are
made. It is recommended that these tests be performed at weekly or biweekly intervals until
the lipid response to Accutane is established. The incidence of hypertriglyceridemia is 1
patient in 4 on Accutane therapy (see WARNINGS: Lipids).
• Liver Function Tests: Since elevations of liver enzymes have been observed during clinical
trials, and hepatitis has been reported, pretreatment and follow-up liver function tests should
be performed at weekly or biweekly intervals until the response to Accutane has been
established (see WARNINGS: Hepatotoxicity).
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• Glucose: Some patients receiving Accutane have experienced problems in the control of their
blood sugar. In addition, new cases of diabetes have been diagnosed during Accutane
therapy, although no causal relationship has been established.
• CPK: Some patients undergoing vigorous physical activity while on Accutane therapy have
experienced elevated CPK levels; however, the clinical significance is unknown. There have
been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical
activity. In a clinical trial of 217 pediatric patients (12 to 17 years) with severe recalcitrant
nodular acne, transient elevations in CPK were observed in 12% of patients, including those
undergoing strenuous physical activity in association with reported musculoskeletal adverse
events such as back pain, arthralgia, limb injury, or muscle sprain. In these patients,
approximately half of the CPK elevations returned to normal within 2 weeks and half
returned to normal within 4 weeks. No cases of rhabdomyolysis were reported in this trial.
Carcinogenesis, Mutagenesis and Impairment of Fertility: In male and female Fischer 344 rats
given oral isotretinoin at dosages of 8 or 32 mg/kg/day (1.3 to 5.3 times the recommended
clinical dose of 1.0 mg/kg/day, respectively, after normalization for total body surface area) for
greater than 18 months, there was a dose-related increased incidence of pheochromocytoma
relative to controls. The incidence of adrenal medullary hyperplasia was also increased at the
higher dosage in both sexes. The relatively high level of spontaneous pheochromocytomas
occurring in the male Fischer 344 rat makes it an equivocal model for study of this tumor;
therefore, the relevance of this tumor to the human population is uncertain.
The Ames test was conducted with isotretinoin in two laboratories. The results of the tests in one
laboratory were negative while in the second laboratory a weakly positive response (less than 1.6
x background) was noted in S. typhimurium TA100 when the assay was conducted with
metabolic activation. No dose-response effect was seen and all other strains were negative.
Additionally, other tests designed to assess genotoxicity (Chinese hamster cell assay, mouse
micronucleus test, S. cerevisiae D7 assay, in vitro clastogenesis assay with human-derived
lymphocytes, and unscheduled DNA synthesis assay) were all negative.
In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition
were observed at oral dosages of isotretinoin of 2, 8, or 32 mg/kg/day (0.3, 1.3, or 5.3 times the
recommended clinical dose of 1.0 mg/kg/day, respectively, after normalization for total body
surface area).
In dogs, testicular atrophy was noted after treatment with oral isotretinoin for approximately 30 weeks at dosages of
20 or 60 mg/kg/day (10 or 30 times the recommended clinical dose of 1.0 mg/kg/day, respectively, after
normalization for total body surface area). In general, there was microscopic evidence for appreciable depression of
spermatogenesis but some sperm were observed in all testes examined and in no instance were completely atrophic
tubules seen. In studies of 66 men, 30 of whom were patients with nodular acne under treatment with oral
isotretinoin, no significant changes were noted in the count or motility of spermatozoa in the ejaculate. In a study of
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50 men (ages 17 to 32 years) receiving Accutane (isotretinoin) therapy for nodular acne, no significant effects were
seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose.
Pregnancy: Category X. See boxed CONTRAINDICATIONS AND WARNINGS.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because of the
potential for adverse effects, nursing mothers should not receive Accutane.
Pediatric Use: The use of Accutane in pediatric patients less than 12 years of age has not been
studied. The use of Accutane for the treatment of severe recalcitrant nodular acne in pediatric
patients ages 12 to 17 years should be given careful consideration, especially for those patients
where a known metabolic or structural bone disease exists (see PRECAUTIONS: General). Use
of Accutane in this age group for severe recalcitrant nodular acne is supported by evidence from
a clinical study comparing 103 pediatric patients (13 to 17 years) to 197 adult patients (≥18
years). Results from this study demonstrated that Accutane, at a dose of 1 mg/kg/day given in
two divided doses, was equally effective in treating severe recalcitrant nodular acne in both
pediatric and adult patients.
In studies with Accutane, adverse reactions reported in pediatric patients were similar to those
described in adults except for the increased incidence of back pain and arthralgia (both of which
were sometimes severe) and myalgia in pediatric patients (see ADVERSE REACTIONS).
In an open-label clinical trial (N=217) of a single course of therapy with Accutane for severe
recalcitrant nodular acne, bone density measurements at several skeletal sites were not
significantly decreased (lumbar spine change >-4% and total hip change >-5%) or were increased
in the majority of patients. One patient had a decrease in lumbar spine bone mineral density
>4% based on unadjusted data. Sixteen (7.9%) patients had decreases in lumbar spine bone
mineral density >4%, and all the other patients (92%) did not have significant decreases or had
increases (adjusted for body mass index). Nine patients (4.5%) had a decrease in total hip bone
mineral density >5% based on unadjusted data. Twenty-one (10.6%) patients had decreases in
total hip bone mineral density >5%, and all the other patients (89%) did not have significant
decreases or had increases (adjusted for body mass index). Follow-up studies performed in 8 of
the patients with decreased bone mineral density for up to 11 months thereafter demonstrated
increasing bone density in 5 patients at the lumbar spine, while the other 3 patients had lumbar
spine bone density measurements below baseline values. Total hip bone mineral densities
remained below baseline (range –1.6% to -7.6%) in 5 of 8 patients (62.5%).
Geriatric Use: Clinical studies of isotretinoin did not include sufficient numbers of subjects aged
65 years and over to determine whether they respond differently from younger subjects.
Although reported clinical experience has not identified differences in responses between elderly
and younger patients, effects of aging might be expected to increase some risks associated with
isotretinoin therapy (see WARNINGS and PRECAUTIONS).
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ADVERSE REACTIONS: Clinical Trials and Postmarketing Surveillance: The adverse
reactions listed below reflect the experience from investigational studies of Accutane, and the
postmarketing experience. The relationship of some of these events to Accutane therapy is
unknown. Many of the side effects and adverse reactions seen in patients receiving Accutane are
similar to those described in patients taking very high doses of vitamin A (dryness of the skin
and mucous membranes, eg, of the lips, nasal passage, and eyes).
Dose Relationship: Cheilitis and hypertriglyceridemia are usually dose related. Most adverse
reactions reported in clinical trials were reversible when therapy was discontinued; however,
some persisted after cessation of therapy (see WARNINGS and ADVERSE REACTIONS).
Body as a Whole: allergic reactions, including vasculitis, systemic hypersensitivity (see
PRECAUTIONS: Hypersensitivity), edema, fatigue, lymphadenopathy, weight loss
Cardiovascular: palpitation, tachycardia, vascular thrombotic disease, stroke
Endocrine/Metabolic: hypertriglyceridemia (see WARNINGS: Lipids), alterations in blood sugar
levels (see PRECAUTIONS: Laboratory Tests)
Gastrointestinal: inflammatory bowel disease (see WARNINGS: Inflammatory Bowel Disease),
hepatitis (see WARNINGS: Hepatotoxicity), pancreatitis (see WARNINGS: Lipids), bleeding
and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea, other
nonspecific gastrointestinal symptoms
Hematologic: allergic reactions (see PRECAUTIONS: Hypersensitivity), anemia,
thrombocytopenia, neutropenia, rare reports of agranulocytosis (see PRECAUTIONS:
Information for Patients and Prescribers). See PRECAUTIONS: Laboratory Tests for other
hematological parameters.
Musculoskeletal: skeletal hyperostosis, calcification of tendons and ligaments, premature
epiphyseal closure, decreases in bone mineral density (see WARNINGS: Skeletal),
musculoskeletal symptoms (sometimes severe) including back pain and arthralgia (see
PRECAUTIONS: Information for Patients and Prescribers), transient pain in the chest (see
PRECAUTIONS: Information for Patients and Prescribers), arthritis, tendonitis, other types of
bone abnormalities, elevations of CPK/rare reports of rhabdomyolysis (see PRECAUTIONS:
Laboratory Tests)
Neurological: pseudotumor cerebri (see WARNINGS: Pseudotumor Cerebri), dizziness,
drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke,
syncope, weakness
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Psychiatric: suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression,
violent behaviors (see WARNINGS: Psychiatric Disorders), emotional instability
Of the patients reporting depression, some reported that the depression subsided with
discontinuation of therapy and recurred with reinstitution of therapy.
Reproductive System: abnormal menses
Respiratory: bronchospasms (with or without a history of asthma), respiratory infection, voice
alteration
Skin and Appendages: acne fulminans, alopecia (which in some cases persists), bruising, cheilitis
(dry lips), dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas,7 flushing, fragility of
skin, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, infections
(including disseminated herpes simplex), nail dystrophy, paronychia, peeling of palms and soles,
photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial
erythema, seborrhea, and eczema), sunburn susceptibility increased, sweating, urticaria,
vasculitis (including Wegener’s granulomatosis; see PRECAUTIONS: Hypersensitivity),
abnormal wound healing (delayed healing or exuberant granulation tissue with crusting; see
PRECAUTIONS: Information for Patients and Prescribers)
Special Senses: Hearing: hearing impairment (see WARNINGS: Hearing Impairment), tinnitus.
Vision: corneal opacities (see WARNINGS: Corneal Opacities), decreased night vision which
may persist (see WARNINGS: Decreased Night Vision), cataracts, color vision disorder,
conjunctivitis, dry eyes, eyelid inflammation, keratitis, optic neuritis, photophobia, visual
disturbances
Urinary System: glomerulonephritis (see PRECAUTIONS: Hypersensitivity), nonspecific
urogenital findings (see PRECAUTIONS: Laboratory Tests for other urological parameters)
Laboratory: Elevation of plasma triglycerides (see WARNINGS: Lipids), decrease in serum
high-density lipoprotein (HDL) levels, elevations of serum cholesterol during treatment
Increased alkaline phosphatase, SGOT (AST), SGPT (ALT), GGTP or LDH (see WARNINGS:
Hepatotoxicity)
Elevation of fasting blood sugar, elevations of CPK (see PRECAUTIONS: Laboratory Tests),
hyperuricemia
Decreases in red blood cell parameters, decreases in white blood cell counts (including severe
neutropenia and rare reports of agranulocytosis; see PRECAUTIONS: Information for Patients
and Prescribers), elevated sedimentation rates, elevated platelet counts, thrombocytopenia
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White cells in the urine, proteinuria, microscopic or gross hematuria
OVERDOSAGE: The oral LD50 of isotretinoin is greater than 4000 mg/kg in rats and mice
(>600 times the recommended clinical dose of 1.0 mg/kg/day after normalization of the rat dose
for total body surface area and >300 times the recommended clinical dose of 1.0 mg/kg/day after
normalization of the mouse dose for total body surface area) and is approximately 1960 mg/kg in
rabbits (653 times the recommended clinical dose of 1.0 mg/kg/day after normalization for total
body surface area). In humans, overdosage has been associated with vomiting, facial flushing,
cheilosis, abdominal pain, headache, dizziness, and ataxia. All symptoms quickly resolved
without apparent residual effects.
Accutane causes serious birth defects at any dosage (see boxed CONTRAINDICATIONS AND
WARNINGS). Females of childbearing potential who present with isotretinoin overdose must be
evaluated for pregnancy. Patients who are pregnant should receive counseling about the risks to
the fetus, as described in the boxed CONTRAINDICATIONS AND WARNINGS. Non-pregnant
patients must be warned to avoid pregnancy for at least one month and receive contraceptive
counseling as described in the boxed CONTRAINDICATIONS AND WARNINGS. Educational
materials for such patients can be obtained by calling the manufacturer. Because an overdose
would be expected to result in higher levels of isotretinoin in semen than found during a normal
treatment course, male patients should use a condom, or avoid reproductive sexual activity with a
female who is or might become pregnant, for 30 days after the overdose. All patients with
isotretinoin overdose should not donate blood for at least 30 days.
DOSAGE AND ADMINISTRATION: Accutane should be administered with a meal (see
PRECAUTIONS: Information for Patients and Prescribers).
The recommended dosage range for Accutane is 0.5 to 1.0 mg/kg/day given in two divided doses
with food for 15 to 20 weeks. In studies comparing 0.1, 0.5, and 1.0 mg/kg/day,8 it was found
that all dosages provided initial clearing of disease, but there was a greater need for retreatment
with the lower dosages. During treatment, the dose may be adjusted according to response of the
disease and/or the appearance of clinical side effects — some of which may be dose related.
Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk
may require dose adjustments up to 2.0 mg/kg/day, as tolerated. Failure to take Accutane with
food will significantly decrease absorption. Before upward dose adjustments are made, the
patients should be questioned about their compliance with food instructions.
The safety of once daily dosing with Accutane has not been established. Once daily dosing is not
recommended.
If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks
of treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and
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if warranted by persistent or recurring severe nodular acne, a second course of therapy may be
initiated. The optimal interval before retreatment has not been defined for patients who have not
completed skeletal growth. Long-term use of Accutane, even in low doses, has not been studied,
and is not recommended. It is important that Accutane be given at the recommended doses for
no longer than the recommended duration. The effect of long-term use of Accutane on bone loss
is unknown (see WARNINGS: Skeletal: Bone Mineral Density, Hyperostosis, and Premature
Epiphyseal Closure).
Contraceptive measures must be followed for any subsequent course of therapy (see boxed
CONTRAINDICATIONS AND WARNINGS).
Table 4. Accutane Dosing by Body Weight (Based on Administration With Food)
Body Weight
Total mg/day
kilograms
pounds
0.5 mg/kg
1 mg/kg
2 mg/kg*
40
88
20
40
80
50
110
25
50
100
60
132
30
60
120
70
154
35
70
140
80
176
40
80
160
90
198
45
90
180
100
220
50
100
200
*See DOSAGE AND ADMINISTRATION: the recommended dosage range is 0.5 to
1.0 mg/kg/day.
Information for Pharmacists: Accutane must only be dispensed in no more than a 30-day
supply and only on presentation of an Accutane prescription with a yellow self-adhesive
Accutane Qualification Sticker written within the previous 7 days. REFILLS REQUIRE A
NEW WRITTEN PRESCRIPTION WITH A YELLOW SELF-ADHESIVE ACCUTANE
QUALIFICATION STICKER WITHIN THE PREVIOUS 7 DAYS. No telephone or
computerized prescriptions are permitted.
An Accutane Medication Guide must be given to the patient each time Accutane is dispensed, as
required by law. This Accutane Medication Guide is an important part of the risk management
program for the patient.
HOW SUPPLIED: Soft gelatin capsules, 10 mg (light pink), imprinted ACCUTANE 10
ROCHE. Boxes of 100 containing 10 Prescription Paks of 10 capsules (NDC 0004-0155-49).
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Soft gelatin capsules, 20 mg (maroon), imprinted ACCUTANE 20 ROCHE. Boxes of 100
containing 10 Prescription Paks of 10 capsules (NDC 0004-0169-49).
Soft gelatin capsules, 40 mg (yellow), imprinted ACCUTANE 40 ROCHE. Boxes of 100
containing 10 Prescription Paks of 10 capsules (NDC 0004-0156-49).
Store at controlled room temperature (59° to 86°F, 15° to 30°C). Protect from light.
REFERENCES:
1. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and conglobate acne
with 13-cis-retinoic acid. N Engl J Med 300:329-333, 1979. 2. Pochi PE, Shalita AR, Strauss JS,
Webster SB. Report of the consensus conference on acne classification. J Am Acad Dermatol
24:495-500, 1991. 3. Farrell LN, Strauss JS, Stranieri AM. The treatment of severe cystic acne
with 13-cis-retinoic acid: evaluation of sebum production and the clinical response in a multiple-
dose trial. J Am Acad Dermatol 3:602-611, 1980. 4. Jones H, Blanc D, Cunliffe WJ. 13-cis-
retinoic acid and acne. Lancet 2:1048-1049, 1980. 5. Katz RA, Jorgensen H, Nigra TP.
Elevation of serum triglyceride levels from oral isotretinoin in disorders of keratinization. Arch
Dermatol 116:1369-1372, 1980. 6. Ellis CN, Madison KC, Pennes DR, Martel W, Voorhees JJ.
Isotretinoin therapy is associated with early skeletal radiographic changes. J Am Acad Dermatol
10:1024-1029, 1984. 7. Dicken CH, Connolly SM. Eruptive xanthomas associated with
isotretinoin (13-cis-retinoic acid). Arch Dermatol 116:951-952, 1980. 8. Strauss JS, Rapini RP,
Shalita AR, et al. Isotretinoin therapy for acne: results of a multicenter dose-response study. J
Am Acad Dermatol 10:490-496, 1984.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
PATIENT INFORMATION/CONSENT (for female patients concerning birth defects):
To be completed by the patient, her parent/guardian*
and signed by her prescriber.
Read each item below and initial in the space provided to show that you understand each item
and agree to follow your prescriber's instructions. Do not sign this consent and do not take
Accutane if there is anything that you do not understand.
*A parent or guardian of a minor patient (under age 18) must also read and initial each item
before signing the consent.
____________________________________________________________
(Patient’s Name)
1. I understand that there is a very high risk that my unborn baby could have severe birth
defects if I am pregnant or become pregnant while taking Accutane in any amount even for
short periods of time. This is why I must not be pregnant while taking Accutane.
Initial: ______
2. I understand that I must not take Accutane (isotretinoin) if I am pregnant.
Initial: ______
3. I understand that I must not get pregnant during the entire time of my treatment and for 1
month after the end of my treatment with Accutane.
Initial: ________
4. I understand that I must avoid sexual intercourse completely, or I must use 2 separate,
effective forms of birth control (contraception) at the same time. The only exception is if I
have had surgery to remove the womb (a hysterectomy).
Initial: ________
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5. I understand that birth control pills and injectable/implantable/insertable hormonal birth
control products are among the most effective forms of birth control. However, any single
form of birth control can fail. Therefore, I must use 2 different methods at the same time,
every time I have sexual intercourse, even if 1 of the methods I choose is birth control pills or
injections.
Initial: ______
6. I will talk with my prescriber about any drugs or herbal products I plan to take during my
Accutane treatment because hormonal birth control methods (for example, birth control pills)
may not work if I am taking certain drugs or herbal products (for example, St. John’s Wort).
Initial: ______
7. I understand that the following are considered effective forms of birth control:
Primary:
Tubal ligation (tying my tubes), partner’s vasectomy, birth control pills,
injectable/implantable/insertable hormonal birth control products, and an IUD
(intrauterine device).
Secondary: Diaphragms, latex condoms, and cervical caps. Each must be used with a
spermicide, which is a special cream or jelly that kills sperm.
I understand that at least 1 of my 2 methods of birth control must be a primary method.
Initial: ________
8. I understand that I may receive a free contraceptive (birth control) counseling session and
pregnancy testing from a doctor or other family planning expert. My Accutane prescriber can
give me an Accutane Patient Referral Form for this free consultation.
Initial: ______
9. I understand that I must begin using the birth control methods I have chosen as described
above at least 1 month before I start taking Accutane.
Initial: ______
10. I understand that I cannot get a prescription for Accutane unless I have 2 negative pregnancy
test results. The first pregnancy test should be done when my prescriber decides to prescribe
Accutane. The second pregnancy test should be done during the first 5 days of my menstrual
period right before starting Accutane therapy, or as instructed by my prescriber. I will then
have 1 pregnancy test every month during my Accutane therapy.
Initial: ______
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11. I understand that I should not start taking Accutane until I am sure that I am not pregnant and
have negative results from 2 pregnancy tests.
Initial: ______
12. I have read and understand the materials my prescriber has given to me, including the Patient
Product Information, Important Information Concerning Your Treatment with Accutane
(isotretinoin). My prescriber gave me and asked me to watch the video about contraception. I
was told about a confidential counseling line that I may call for more information about birth
control. I have received information on emergency contraception (birth control).
Initial: ______
13. I understand that I must stop taking Accutane right away and inform my prescriber if I get
pregnant, miss my menstrual period, stop using birth control, or have sexual intercourse
without using my 2 birth control methods at any time.
Initial: ______
14. My prescriber gave me information about the confidential Accutane Survey and explained to
me how important it is to take part in the Accutane Survey.
Initial: ______
15. I understand that the yellow self-adhesive Accutane Qualification Sticker on my prescription
for Accutane means that I am qualified to receive an Accutane prescription, because I:
• have had 2 negative urine or serum pregnancy tests before receiving the initial Accutane
prescription. I must have a negative result from a urine or serum pregnancy test repeated each
month prior to my receiving each subsequent prescription.
• have selected and committed to use 2 forms of effective contraception simultaneously, at
least 1 of which must be a primary form, unless absolute abstinence is the chosen method, or
I have undergone a hysterectomy. I must use 2 forms of contraception for at least 1 month
prior to initiation of Accutane therapy, during therapy, and for 1 month after discontinuing
therapy. I must receive counseling, repeated on a monthly basis, about contraception and
behaviors associated with an increased risk of pregnancy.
• have signed a Patient Information/Consent form that contains warnings about the risk of
potential birth defects if I am pregnant or become pregnant and my unborn baby is exposed
to isotretinoin.
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• have been informed of the purpose and importance of participating in the Accutane Survey
and given the opportunity to enroll.
Initial: ______
My prescriber has answered all my questions about Accutane and I understand that it is my
responsibility not to get pregnant during Accutane treatment or for 1 month after I stop taking
Accutane.
Initial: ______
I now authorize my prescriber ________________ to begin my treatment with Accutane.
Patient signature:________________________________ Date:____________________
Parent/guardian signature (if under age 18):____________________ Date:___________
Please print: Patient name and address________________________________________
______________________________________ Telephone _______________________
I have fully explained to the patient, __________________, the nature and purpose of the
treatment described above and the risks to females of childbearing potential. I have asked the
patient if she has any questions regarding her treatment with Accutane and have answered those
questions to the best of my ability.
Prescriber signature: ______________________________ Date:__________________
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INFORMED CONSENT/PATIENT AGREEMENT (for all patients):
To be completed by patient (parent or guardian if patient is under age 18) and signed by the prescriber.
Read each item below and initial in the space provided if you understand each item and
agree to follow your prescriber’s instructions. A parent or guardian of a patient under age
18 must also read and understand each item before signing the agreement.
Do not sign this agreement and do not take Accutane if there is anything that you do not
understand about all the information you have received about using Accutane.
1. I, ____________________________________________________________,
(Patient’s Name)
understand that Accutane is a medicine used to treat severe nodular acne that cannot be
cleared up by any other acne treatments, including antibiotics. In severe nodular acne, many
red, swollen, tender lumps form in the skin. If untreated, severe nodular acne can lead to
permanent scars.
Initials: ______
2. My prescriber has told me about my choices for treating my acne.
Initials: ______
3. I understand that there are serious side effects that may happen while I am taking Accutane.
These have been explained to me. These side effects include serious birth defects in babies of
pregnant females. (Note: There is a second Informed Consent form for female patients
concerning birth defects.)
Initials: ______
4. I understand that some patients, while taking Accutane or soon
after stopping Accutane, have become depressed or developed
other serious mental problems. Symptoms of these problems
include sad, “anxious” or empty mood, irritability, anger, loss of
pleasure or interest in social or sports activities, sleeping too
much or too little, changes in weight or appetite, school or work
performance going down, or trouble concentrating. Some
patients taking Accutane have had thoughts about hurting
themselves or putting an end to their own lives (suicidal
thoughts). Some people tried to end their own lives. And some
people have ended their own lives. There were reports that some
of these people did not appear depressed. There have been
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reports of patients on Accutane becoming aggressive or violent.
No one knows if Accutane caused these behaviors or if they
would have happened even if the person did not take Accutane.
Some people have had other signs of depression while taking
Accutane (see #7 below).
Initials: ______
5. Before I start taking Accutane, I agree to tell my prescriber if,
to the best of my knowledge, I have ever had symptoms of
depression (see #7 below), been psychotic, attempted suicide,
had any other mental problems, or take medicine for any of
these problems. Being psychotic means having a loss of contact
with reality, such as hearing voices or seeing things that are not
there.
Initials: ______
6. Before I start taking Accutane, I agree to tell my prescriber if,
to the best of my knowledge, anyone in my family has ever had
symptoms of depression, been psychotic, attempted suicide, or
had any other serious mental problems.
Initials: ______
7. Once I start taking Accutane, I agree to stop using Accutane and tell my prescriber right
away if any of the following happen. I:
• Start to feel sad or have crying spells
• Lose interest in activities I once enjoyed
• Sleep too much or have trouble sleeping
• Become more irritable, angry, or aggressive than usual (for example, temper outbursts,
thoughts of violence)
• Have a change in my appetite or body weight
• Have trouble concentrating
• Withdraw from my friends or family
• Feel like I have no energy
• Have feelings of worthlessness or inappropriate guilt
• Start having thoughts about hurting myself or taking my own life (suicidal thoughts)
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Initials: ______
8. I agree to return to see my prescriber every month I take Accutane to get a new
prescription for Accutane, to check my progress, and to check for signs of side effects.
Initials: ______
9. Accutane will be prescribed just for me—I will not share Accutane with other people
because it may cause serious side effects, including birth defects.
Initials: ______
10. I will not give blood while taking Accutane or for 1 month after I stop taking Accutane.
I understand that if someone who is pregnant gets my donated blood, her baby may be
exposed to Accutane and may be born with serious birth defects.
Initials: ______
11. I have read the Patient Product Information, Important Information Concerning Your
Treatment with Accutane
(isotretinoin), and other materials my provider gave me
containing important safety information about Accutane. I understand all the
information I received.
Initials: ______
12. My prescriber and I have decided I should take Accutane. I understand that each of my
Accutane prescriptions must have a yellow self-adhesive Accutane Qualification Sticker
on it. I understand that I can stop taking Accutane at any time. I agree to tell my
prescriber if I stop taking Accutane.
Initials: ______
I now authorize my prescriber ___________________________ to begin my treatment with
Accutane.
Patient Signature: __________________________________________ Date: _________
Parent/Guardian Signature (if under age 18): _____________________ Date: _________
Patient Name (print) ___________________________________
Patient address ____________________________________ Telephone (___.___.___)
______________________________________
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I have:
• fully explained to the patient, __________________, the nature and purpose of Accutane
treatment, including its benefits and risks
• given the patient the appropriate educational materials, Be Smart, Be Safe, Be Sure, for
Accutane and asked the patient if he/she has any questions regarding his/her treatment with
Accutane
• answered those questions to the best of my ability
• placed the yellow self-adhesive Accutane Qualification Sticker on the prescription.
Prescriber Signature: ___________________________________ Date:______________
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For current labeling information, please visit https://www.fda.gov/drugsatfda
MEDICATION GUIDE:
Read this Medication Guide every time you get a prescription or a refill for Accutane (ACK-u-tane). There may be
new information. This information does not take the place of talking with your prescriber (doctor or other health
care provider).
What is the most important information I should know about Accutane?
Accutane is used to treat a type of severe acne (nodular acne) that has not been helped by other
treatments, including antibiotics. However, Accutane can cause serious side effects. Before
starting Accutane, discuss with your prescriber how bad your acne is, the possible benefits of
Accutane, and its possible side effects, to decide if Accutane is right for you. Your prescriber
will ask you to read and sign a form or forms indicating you understand some of the serious risks
of Accutane.
Possible serious side effects of taking Accutane include birth defects and mental disorders.
1. Birth defects. Accutane can cause birth defects (deformed babies) if taken by a
pregnant woman. It can also cause miscarriage (losing the baby before birth),
premature (early) birth, or death of the baby. Do not take Accutane if you are
pregnant or plan to become pregnant while you are taking Accutane. Do not get
pregnant for 1 month after you stop taking Accutane. Also, if you get pregnant while
taking Accutane, stop taking it right away and call your prescriber.
All females should read the section in this Medication Guide "What are the
important warnings for females taking Accutane?"
2. Mental problems and suicide. Some patients, while taking Accutane or soon after
stopping Accutane, have become depressed or developed other serious mental
problems. Symptoms of these problems include sad, “anxious” or empty mood,
irritability, anger, loss of pleasure or interest in social or sports activities, sleeping too
much or too little, changes in weight or appetite, school or work performance going
down, or trouble concentrating. Some patients taking Accutane have had thoughts
about hurting themselves or putting an end to their own lives (suicidal thoughts).
Some people tried to end their own lives. And some people have ended their own
lives. There were reports that some of these people did not appear depressed. There
have been reports of patients on Accutane becoming aggressive or violent. No one
knows if Accutane caused these behaviors or if they would have happened even if the
person did not take Accutane.
All patients should read the section in this Medication Guide "What are the signs
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
of mental problems?"
For other possible serious side effects of Accutane, see "What are the possible side
effects of Accutane?" in this Medication Guide.
What are the important warnings for females taking Accutane?
You must not become pregnant while taking Accutane, or for 1 month after you stop taking
Accutane. Accutane can cause severe birth defects in babies of women who take it while they are
pregnant, even if they take Accutane for only a short time. There is an extremely high risk that
your baby will be deformed or will die if you are pregnant while taking Accutane. Taking
Accutane also increases the chance of miscarriage and premature births.
Female patients will not get their first prescription for Accutane unless there is proof they have
had 2 negative pregnancy tests. The first test must be done when your prescriber decides to
prescribe Accutane. The second pregnancy test must be done during the first 5 days of the
menstrual period right before starting Accutane therapy, or as instructed by your prescriber. Each
month of treatment, you must have a negative result from a urine or serum pregnancy test.
Female patients cannot get another prescription for Accutane unless there is proof that they have
had a negative pregnancy test.
A yellow self-adhesive Accutane Qualification Sticker on your prescription indicates to the
pharmacist that you are qualified by your prescriber to get Accutane.
While you are taking Accutane, you must use effective birth control. You must use 2 separate
effective forms of birth control at the same time for at least 1 month before starting Accutane,
while you take it, and for 1 month after you stop taking it. You can either discuss effective birth
control methods with your prescriber or go for a free visit to discuss birth control with another
physician or family planning expert. Your prescriber can arrange this free visit, which will be
paid for by the manufacturer.
You must use 2 separate forms of effective birth control because any method, including birth
control pills and sterilization, can fail. There are only 2 reasons you would not need to use 2
separate methods of effective birth control:
1. You have had your womb removed by surgery (a hysterectomy).
2. You are absolutely certain you will not have genital-to-genital sexual contact with a male
before, during, and for 1 month after Accutane treatment.
If you have sex at any time without using 2 forms of effective birth control, get pregnant, or
miss your period, stop using Accutane and call your prescriber right away.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
All patients should read the rest of this Medication Guide.
What are the signs of mental problems?
Tell your prescriber if, to the best of your knowledge, you or someone in your family has ever
had any mental illness, including depression, suicidal behavior, or psychosis. Psychosis means a
loss of contact with reality, such as hearing voices or seeing things that are not there. Also, tell
your prescriber if you take medicines for any of these problems.
Stop using Accutane and tell your provider right away if you:
• Start to feel sad or have crying spells
• Lose interest in activities you once enjoyed
• Sleep too much or have trouble sleeping
• Become more irritable, angry, or aggressive than usual (for example, temper outbursts,
thoughts of violence)
• Have a change in your appetite or body weight
• Have trouble concentrating
• Withdraw from your friends or family
• Feel like you have no energy
• Have feelings of worthlessness or inappropriate guilt
• Start having thoughts about hurting yourself or taking your own life (suicidal thoughts)
What is Accutane?
Accutane is used to treat the most severe form of acne (nodular acne) that cannot be cleared up
by any other acne treatments, including antibiotics. In severe nodular acne, many red, swollen,
tender lumps form in the skin. These can be the size of pencil erasers or larger. If untreated,
nodular acne can lead to permanent scars. However, because Accutane can have serious side
effects, you should talk with your prescriber about all of the possible treatments for your acne,
and whether Accutane’s possible benefits outweigh its possible risks.
Who should not take Accutane?
• Do not take Accutane if you are pregnant, plan to become pregnant, or become
pregnant during Accutane treatment. Accutane causes severe birth defects. All females
should read the section “What are the important warnings for females taking Accutane?” for
more information and warnings about Accutane and pregnancy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Do not take Accutane unless you completely understand its possible risks and are willing to
follow all of the instructions in this Medication Guide.
Tell your prescriber if you or someone in your family has had any kind of mental problems,
asthma, liver disease, diabetes, heart disease, osteoporosis (bone loss), weak bones, anorexia
nervosa (an eating disorder where people eat too little), or any other important health problems.
Tell your prescriber about any food or drug allergies you have had in the past. These problems
do not necessarily mean you cannot take Accutane, but your prescriber needs this information to
discuss if Accutane is right for you.
How should I take Accutane?
• You will get no more than a 30-day supply of Accutane at a time, to be sure you check in
with your prescriber each month to discuss side effects.
• Your prescription should have a special yellow self-adhesive sticker attached to it. The
sticker is YELLOW. If your prescription does not have this yellow self-adhesive sticker, call
your prescriber. The pharmacy should not fill your prescription unless it has the yellow self-
adhesive sticker.
• The amount of Accutane you take has been specially chosen for you and may change during
treatment.
• You will take Accutane 2 times a day with a meal, unless your prescriber tells you otherwise.
Swallow your Accutane capsules with a full glass of liquid. This will help prevent the
medication inside the capsule from irritating the lining of your esophagus (connection
between mouth and stomach). For the same reason, do not chew or suck on the capsule.
• If you miss a dose, just skip that dose. Do not take 2 doses the next time.
• You should return to your prescriber as directed to make sure you don’t have signs of serious
side effects. Because some of Accutane’s serious side effects show up in blood tests, some of
these visits may involve blood tests (monthly visits for female patients should always include
a urine or serum pregnancy test).
What should I avoid while taking Accutane?
• Do not get pregnant while taking Accutane. See “What is the most important information I
should know about Accutane?” and “What are the important warnings for females taking
Accutane?”
• Do not breast feed while taking Accutane and for 1 month after stopping Accutane. We do
not know if Accutane can pass through your milk and harm the baby.
• Do not give blood while you take Accutane and for 1 month after stopping Accutane. If
someone who is pregnant gets your donated blood, her baby may be exposed to Accutane and
may be born with birth defects.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Do not take vitamin A supplements. Vitamin A in high doses has many of the same side
effects as Accutane. Taking both together may increase your chance of getting side effects.
• Do not have cosmetic procedures to smooth your skin, including waxing, dermabrasion,
or laser procedures, while you are using Accutane and for at least 6 months after you
stop. Accutane can increase your chance of scarring from these procedures. Check with your
prescriber for advice about when you can have cosmetic procedures.
• Avoid sunlight and ultraviolet lights as much as possible. Tanning machines use ultraviolet
lights. Accutane may make your skin more sensitive to light.
• Do not use birth control pills that do not contain estrogen (“minipills”). They may not
work while you take Accutane. Ask your prescriber or pharmacist if you are not sure what
type you are using.
• Talk with your doctor if you plan to take other drugs or herbal products. This is
especially important for patients using birth control pills and other hormonal types of birth
control because the birth control may not work as effectively if you are taking certain drugs
or herbal products. You should not take the herbal supplement St. John’s Wort because this
herbal supplement may make birth control pills not work as effectively.
• Talk with your doctor if you are currently taking an oral or injected corticosteroid or
anticonvulsant (seizure) medication prior to using Accutane. These drugs may weaken
your bones.
• Do not share Accutane with other people. It can cause birth defects and other serious
health problems.
• Do not take Accutane with antibiotics unless you talk to your prescriber. For some
antibiotics, you may have to stop taking Accutane until the antibiotic treatment is finished.
Use of both drugs together can increase the chances of getting increased pressure in the brain.
What are the possible side effects of Accutane?
Accutane has possible serious side effects
• Accutane can cause birth defects, premature births, and death in babies whose mothers
took Accutane while they were pregnant. See “What is the most important information I
should know about Accutane?” and “What are the important warnings for females taking
Accutane?”
• Serious mental health problems. See “What is the most important information I should
know about Accutane?”
• Serious brain problems. Accutane can increase the pressure in your brain. This can lead to
permanent loss of sight, or in rare cases, death. Stop taking Accutane and call your prescriber
right away if you get any of these signs of increased brain pressure: bad headache, blurred
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
vision, dizziness, nausea, or vomiting. Also, some patients taking Accutane have had seizures
(convulsions) or stroke.
• Abdomen (stomach area) problems. Certain symptoms may mean that your internal organs
are being damaged. These organs include the liver, pancreas, bowel (intestines), and
esophagus (connection between mouth and stomach). If your organs are damaged, they may
not get better even after you stop taking Accutane. Stop taking Accutane and call your
prescriber if you get severe stomach, chest or bowel pain, trouble swallowing or painful
swallowing, new or worsening heartburn, diarrhea, rectal bleeding, yellowing of your skin or
eyes, or dark urine.
• Bone and muscle problems. Accutane may affect bones, muscles, and ligaments and cause
pain in your joints or muscles. Tell your prescriber if you plan vigorous physical activity
during treatment with Accutane. Tell your prescriber if you develop pain, particularly back
pain or joint pain. There are reports that some patients have had stunted growth after taking
Accutane for acne as directed. There are also some reports of broken bones or reduced
healing of broken bones after taking Accutane for acne as directed. No one knows if taking
Accutane for acne will affect your bones. If you have a broken bone, tell your provider that
you are taking Accutane. Muscle weakness with or without pain can be a sign of serious
muscle damage. If this happens, stop taking Accutane and call your prescriber right away.
• Hearing problems. Some people taking Accutane have developed hearing problems. It is
possible that hearing loss can be permanent. Stop using Accutane and call your prescriber if
your hearing gets worse or if you have ringing in your ears.
• Vision problems. While taking Accutane you may develop a sudden inability to see in the
dark, so driving at night can be dangerous. This condition usually clears up after you stop
taking Accutane, but it may be permanent. Other serious eye effects can occur. Stop taking
Accutane and call your prescriber right away if you have any problems with your vision or
dryness of the eyes that is painful or constant.
• Lipid (fats and cholesterol in blood) problems. Many people taking Accutane develop high
levels of cholesterol and other fats in their blood. This can be a serious problem. Return to
your prescriber for blood tests to check your lipids and to get any needed treatment. These
problems generally go away when Accutane treatment is finished.
• Allergic reactions. In some people, Accutane can cause serious allergic reactions. Stop
taking Accutane and get emergency care right away if you develop hives, a swollen face or
mouth, or have trouble breathing. Stop taking Accutane and call your prescriber if you
develop a fever, rash, or red patches or bruises on your legs.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Signs of other possibly serious problems. Accutane may cause other problems. Tell your
prescriber if you have trouble breathing (shortness of breath), are fainting, are very thirsty or
urinate a lot, feel weak, have leg swelling, convulsions, slurred speech, problems moving, or
any other serious or unusual problems. Frequent urination and thirst can be signs of blood
sugar problems.
Serious permanent problems do not happen often. However, because the symptoms listed above
may be signs of serious problems, if you get these symptoms, stop taking Accutane and call your
prescriber. If not treated, they could lead to serious health problems. Even if these problems are
treated, they may not clear up after you stop taking Accutane.
Accutane has less serious possible side effects
The common less serious side effects of Accutane are dry skin, chapped lips, dry eyes, and dry
nose that may lead to nosebleeds. People who wear contact lenses may have trouble wearing
them while taking Accutane and after therapy. Sometimes, people’s acne may get worse for a
while. They should continue taking Accutane unless told to stop by their prescriber.
These are not all of Accutane’s possible side effects. Your prescriber or pharmacist can give you
more detailed information that is written for health care professionals.
This Medication Guide is only a summary of some important information about Accutane.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
If you have any concerns or questions about Accutane, ask your prescriber. Do not use Accutane
for a condition for which it was not prescribed.
Active Ingredient: Isotretinoin.
Inactive Ingredients: beeswax, butylated hydroxyanisole, edetate disodium, hydrogenated
soybean oil flakes, hydrogenated vegetable oil, and soybean oil. Gelatin capsules contain
glycerin and parabens (methyl and propyl), with the following dye systems: 10 mg — iron oxide
(red) and titanium dioxide; 20 mg — FD&C Red No. 3, FD&C Blue No. 1, and titanium dioxide;
40 mg — FD&C Yellow No. 6, D&C Yellow No. 10, and titanium dioxide.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Rx only
27898276-0602
Revised: June 2002
Printed in USA
Copyright © 2000-2002 by Roche Laboratories Inc. All rights reserved.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
[text printed on 'prescription pak' blister cards]
ALL PATIENTS:
It is important for your health that you read all the information you received
with this prescription and from your prescriber
This package provides reminders of important safety facts about Accutane, but it does not
contain all the information you need to know. It is important for you to know how to take
Accutane correctly and what side effects to watch for.
Read all the information you get about Accutane from your prescriber and pharmacist, including
the Medication Guide provided with this package.
The prescription you got at your prescriber's office should have had a special yellow self-
adhesive sticker on it. The sticker is YELLOW. If your prescriptions for Accutane do not have
this yellow self-adhesive sticker, call your prescriber. The pharmacy should not fill prescriptions
for Accutane unless they have the yellow self-adhesive sticker.
You should read, understand and sign an Informed Consent/Patient Agreement before you take
Accutane. Contact your prescriber if you have not signed this form (male patients must sign one
form and female patients must sign two forms).
Never share Accutane because it can cause serious side effects
including severe birth defects.
Special Warning for Female Patients
CAUSES BIRTH DEFECTS
DO NOT GET PREGNANT
Accutane causes serious birth defects. Do NOT take Accutane if you are pregnant.
It is very important for you to read and understand the information about preventing
pregnancy on the back of this package, in the Medication Guide, and in the materials given
to you by your prescriber. If you do not have the Medication Guide, and a video and the Be
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Smart, Be Safe, Be Sure booklet about pregnancy prevention, don’t start taking Accutane.
Call your prescriber.
Most people have further questions after reading so much important information about
pregnancy prevention and birth defects. If there is anything you are not sure about, do not take
Accutane until your questions have been answered by your prescriber.
Important Information for All Patients
Before you start taking Accutane, tell your prescriber if you:
• Are currently taking an oral or injected corticosteroid or an anticonvulsant (seizure)
medication.
• Take part in sports where you are more likely to break a bone.
• Have anorexia nervosa (a type of eating disorder), back pain, a history of problems with
healing of bone fractures, or problems with bone metabolism.
Mental problems and suicide
Some patients have become depressed or developed other serious mental problems while they
were taking Accutane or shortly after stopping Accutane. Some patients taking Accutane have
had thoughts of ending their own lives (suicidal thoughts). Some people have tried to end their
own lives (attempted suicide) and some people have ended their own lives (committed suicide).
There have been reports of patients on Accutane becoming aggressive or violent. No one knows
if Accutane caused these problems or behaviors or if they would have happened even if the
person did not take Accutane.
Stop taking Accutane and call your prescriber right away if you:
• Start to feel sad or have crying spells.
• Lose interest in activities you once enjoyed.
• Sleep too much or have trouble sleeping.
• Become more irritable, angry, or aggressive than usual (for example, temper outbursts,
thoughts of violence)
• Have a change in your appetite or body weight.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Have trouble concentrating.
• Withdraw from your friends or family.
• Feel like you have no energy.
• Have feelings of worthlessness or inappropriate guilt.
• Start having thoughts about hurting yourself or taking your own life (suicidal thoughts).
Tell your prescriber if you or someone in your family has ever had a mental illness or if you take
any medicines for a mental illness (for example, depression).
Other serious side effects to watch for
Stop taking Accutane and call your prescriber if you develop any of the problems on this
list or any other unusual or severe problems. If not treated, they could lead to serious health
problems. Serious permanent problems do not happen often.
• Headaches, nausea, vomiting, blurred vision (increased brain pressure).
• Severe stomach pain, diarrhea, rectal bleeding, or trouble swallowing.
• Yellowing of your skin or eyes and/or dark urine.
• Changes in hearing.
• Allergic reactions (if you know you are sensitive to “parabens”, tell your prescriber because
it is a preservative in the gelatin capsule of Accutane).
• Bone or muscle pain.
• Vision changes, including trouble seeing at night (this can start suddenly, so be very careful
when driving or operating any vehicle at night).
• Persistent fever, chills, or sore throat.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Other Important Information is found in the Medication Guide and in the booklet from
your prescriber:
• Common side effects that are not serious but that you should tell your prescriber about.
• How to take Accutane.
• Things to avoid during Accutane treatment.
• Ways to get more information if you need it.
Accutane Causes Serious Birth Defects
[text appearing on main back panel outside of card]
Highlights of Warning to Female Patients. (It is important to
watch the video and read all information in the Be Smart, Be Safe, Be
Sure booklet given to you by your prescriber.)
• You MUST NOT take Accutane if you are pregnant because any amount can cause severe
birth defects, even for short periods during pregnancy.
• You MUST NOT become pregnant while taking Accutane, or for 1 month after you stop
taking Accutane.
• You will not get your first prescription for Accutane until there is proof you have had 2
negative pregnancy tests as instructed by your prescriber (a negative test means that it does
not show pregnancy).
• You cannot get monthly refills for Accutane unless there is proof that you have had a
negative pregnancy test every month during Accutane treatment.
• Even the best methods of birth control can fail. Therefore, 2 separate, effective forms of
contraception must be used at the same time for at least 1 month before beginning therapy,
during therapy, and for 1 month after Accutane therapy has stopped.
• Stop taking Accutane right away and call your prescriber immediately if you have sex
without birth control, miss your period or become pregnant while you are taking Accutane. If
you get pregnant in the month after you have stopped Accutane treatment, call your
prescriber immediately.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Very severe birth defects have occurred with Accutane use including:
• Severe Internal Defects: defects that you cannot see—involving the brain (including lower IQ
scores), heart, glands and nervous system.
• Severe External Defects: defects that you can see—such as low-set, deformed or absent ears,
wide-set eyes, depressed bridge of nose, enlarged head and small chin.
[illustration of how to remove capsules]
Figure AStore at controlled room temperature (59° to 86°F, 15° to 30°C). Protect from light.
[binder copy]
FEMALE PATIENTS:
xx MG
DO NOT GET PREGNANT
xxxxxxxx-xxxxxxxxxxxx-xxxx
xxxxxxxx-xxxx
Copyright © 2002 by Roche Laboratories Inc. All rights reserved.
Revised: June 2002
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
Jonathan Wilkin
6/20/02 03:41:51 PM
minor formatting changes needed by sponsor in consent document
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:50.256163
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/18662s051lbl.pdf', 'application_number': 18662, 'submission_type': 'SUPPL ', 'submission_number': 51}
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3
NARRATION SCRIPT Revised 2/6/03
FLK100VID
ACCUTANE PREGNANCY VIDEO
Opening Segment
“ACCUTANE® CANNOT BE TAKEN BY WOMEN WHO ARE PREGNANT, BECAUSE ACCUTANE CAN CAUSE SEVERE
BIRTH DEFECTS OR DEATH TO AN UNBORN BABY.
In this video we will see what can happen to an unborn baby if the baby’s
mother takes Accutane.
A woman must not take Accutane at any time during pregnancy.
Storyboard P2
Accutane is usually prescribed for males and females to treat the most severe
form of acne called nodular acne. This type of acne cannot be cleared up by
any other acne treatments, including antibiotic pills. Nodular acne has many red,
swollen, tender lumps that form in the skin. These lumps are the size of a pencil
eraser or larger and can result in permanent scars if not treated.
Because of serious side effects and birth defects, patients should use Accutane
only if other treatments including antibiotic pills have not worked.
Storyboard P3
“FEMALE PATIENTS MUST NOT TAKE ACCUTANE IF THEY ARE PREGNANT, PLAN TO BECOME PREGNANT OR
BECOME PREGNANT DURING THERAPY. TO AVOID PREGNANCY, WOMEN MUST USE TWO FORMS OF EFFECTIVE
CONTRACEPTION ONE MONTH BEFORE STARTING ACCUTANE, WHILE TAKING ACCUTANE, AND FOR ONE MONTH
AFTER STOPPING ACCUTANE UNLESS THEY ARE ABSOLUTELY ABSTINENT, NEVER HAVING SEX, OR HAVE HAD
THEIR UTERUS OR WOMB REMOVED”.
Storyboard P4
“ACCUTANE CAPSULES BREAK DOWN IN THE BODY AND THE MEDICINE ENTERS INTO THE BLOODSTREAM
Storyboard P5
“AND THE BLOOD IS CARRIED INTO THE PLACENTA WHERE IT REACHES THE UNBORN FETUS.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
The medicine can cause severe birth defects.”
Storyboard P6
“It is highly possible that the unborn baby may die because the baby’s mother
took Accutane.”
Storyboard P7
“If the fetus lives, as the fetus develops, several birth defects can begin to take
place.
These birth defects may be caused by taking Accutane during pregnancy”.
Storyboard P8
“One of these birth defects may be abnormal skull development”. “Use of
Accutane during pregnancy may cause an under development or over
development of the skull”.
Storyboard P9
“Development of the ears may also be affected”.“The ears may not fully develop
if Accutane is used during pregnancy. The outer ear may be deformed and the
ear canal may be very small or absent entirely causing deformity”.
Storyboard P10
“The eyes also may not develop fully”.
“The eye socket may be very small or not develop at all causing facial deformity
Storyboard P11
“As face structure begins to form”
“the fetus can have a flattening of the nose and a twisting of the mouth. These
birth defects could happen from using Accutane during pregnancy”.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Storyboard P12
“The baby may also be born with a separation of the roof of the mouth and
sometimes the lips which is known as a cleft palate”.
Storyboard P13
IN ADDITION TO THE VISIBLE DEFECTS, SEVERAL INTERNAL SERIOUS AND LIFE-THREATENING BIRTH DEFECTS
MAY DEVELOP IN THE HEART AND IN THE ENTIRE HEART AND BLOOD FLOW SYSTEM.
One of these defects can include an abnormal heart that has the arteries and
veins in the wrong position”
Storyboard P14“
The system that helps to fight infection may also be affected. One of the glands
in this system - the thymus gland may not develop and the baby then would
have trouble fighting infections.” “In addition, another gland -the parathyroid
gland may not develop. The parathyroid gland helps the baby to form bones by
controlling the amount of calcium in the body.
Storyboard P15
Brain and nervous system defects including an abnormal brain may occur…” OR
AN UNDERDEVELOPMENT OF THE BRAIN. IT HAS ALSO BEEN REPORTED THAT SOME CHILDREN HAVE LOW IQ
SCORES”.
Storyboard P17In summary, taking Accutane during pregnancy can result in
any or all of these birth defects:
The skull may over- or under- develop.
FACIAL DYSMORPHIA CAN OCCUR, CAUSING A FLATTENING OF THE NOSE AND DISTORTION OF FACIAL
STRUCTURE.
Enlargement of the brain may occur.
Eye sockets may be very small or not develop at all.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
The brain can also under-develop.
Ears may not fully develop.
The thymus gland may not develop, affecting an infant’s ability to fight off
disease.
Abnormalities in the heart and entire cardiac system can be life threatening.
A cleft palate may form.
Storyboard P18
UNLIKE THE BIRTH DEFECTS THAT ARE SEEN IN THE BABIES WHEN MOTHERS TAKE ACCUTANE, THERE IS NO
PATTERN OF BIRTH DEFECTS WHEN FATHERS TAKE ACCUTANE.
But men who take Accutane should be careful in other ways.” Men might not
realize that they should not donate blood during, and for a period of one month
following, the end of their Accutane treatment”.
Storyboard P 19
“As discussed earlier, Accutane is carried through the bloodstream and a
pregnant woman could, unknowingly accept a blood transfusion from a man or a
women who took Accutane. The blood and medicine could then pass into the
placenta possibly harming an unborn baby”.
Therefore, it is extremely important that both men and women taking Accutane
do not donate blood during treatment and for a period of at least one month
following the end of their Accutane treatment
Storyboard P 20
“Neither men nor women should ever share their Accutane with another
woman...”
Storyboard P 21
“...BECAUSE OF THE RISK THAT SHE MAY BE PREGNANT.”
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
“No one should ever share any medicine with anyone else, because the
medicine may harm the other person.”
Black Box
YOU MUST NOT BECOME PREGNANT WHILE TAKING ACCUTANE, OR FOR ONE MONTH AFTER YOU STOP TAKING
ACCUTANE.
Accutane can cause severe birth defects in babies of women who take it while
they are pregnant, even if they take Accutane for only a short time.
There is an extremely high risk that your baby will be deformed or will die
if you are pregnant while taking Accutane. Taking Accutane also increases the
chance of miscarriage and premature births
Female patients will not get their first prescription for Accutane unless there is
proof they have had two negative pregnancy tests. The first test must be done
when your prescriber decides to prescribe Accutane. The second pregnancy
test must be done during the first five days of the menstrual period right before
starting Accutane therapy, or as instructed by your prescriber. Each month of
treatment, you must have a negative result from a urine or serum pregnancy
test. Female patients cannot get another prescription for Accutane unless there
is proof that they have had a negative pregnancy test.
A yellow self-adhesive Accutane Qualification Sticker on your prescription
indicates to the pharmacist that you are qualified by your prescriber to get
Accutane.
WHILE YOU ARE TAKING ACCUTANE, YOU MUST USE EFFECTIVE BIRTH
CONTROL. YOU MUST USE 2 SEPARATE, EFFECTIVE FORMS OF BIRTH
CONTROL AT THE SAME TIME FOR AT LEAST ONE MONTH BEFORE
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8
STARTING ACCUTANE, WHILE YOU TAKE IT, AND FOR ONE MONTH AFTER
YOU STOP TAKING IT. YOU CAN EITHER DISCUSS EFFECTIVE BIRTH
CONTROL METHODS WITH YOUR PRESCRIBER OR GO FOR A FREE VISIT
TO DISCUSS BIRTH CONTROL WITH ANOTHER PHYSICIAN OR FAMILY
PLANNING EXPERT. YOUR PRESCRIBER CAN ARRANGE THIS FREE VISIT,
WHICH WILL BE PAID FOR BY THE MANUFACTURER.
You must use two separate forms of effective birth control because any method,
including birth control pills and sterilization, can fail. There are only 2 reasons
that you would not need to use 2 separate methods of effective birth control:
• 1. You have had your womb removed by surgery – a hysterectomy or
• 2. You are absolutely certain you will not have genital-to-genital sexual
contact with a male before, during and for one month after Accutane
treatment.
IF YOU HAVE SEX AT ANY TIME WITHOUT USING TWO FORMS OF
EFFECTIVE BIRTH CONTROL, GET PREGNANT, OR MISS YOUR PERIOD,
STOP USING ACCUTANE AND CALL YOUR PRESCRIBER RIGHT AWAY.
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9
ACCUTANE
(isotretinoin)
CAPSULES
CAUSES BIRTH
DEFECTS
DO NOT GET
PREGNANT
CONTRAINDICATIONS AND WARNINGS
Accutane must not be used by females who are pregnant. Although not every fetus exposed to
Accutane has resulted in a deformed child, there is an extremely high risk that a deformed infant
can result if pregnancy occurs while taking Accutane in any amount even for short periods of
time. Potentially any fetus exposed during pregnancy can be affected. Presently, there are no
accurate means of determining, after Accutane exposure, which fetus has been affected and
which fetus has not been affected.
Major human fetal abnormalities related to Accutane administration in females have been
documented. There is an increased risk of spontaneous abortion. In addition, premature births
have been reported.
Documented external abnormalities include: skull abnormality; ear abnormalities (including
anotia, micropinna, small or absent external auditory canals); eye abnormalities (including
microphthalmia); facial dysmorphia; cleft palate. Documented internal abnormalities include:
CNS abnormalities (including cerebral abnormalities, cerebellar malformation, hydrocephalus,
microcephaly, cranial nerve deficit); cardiovascular abnormalities; thymus gland abnormality;
parathyroid hormone deficiency. In some cases death has occurred with certain of the
abnormalities previously noted.
Cases of IQ scores less than 85 with or without obvious CNS abnormalities have also been
reported.
Accutane is contraindicated in females of childbearing potential unless the patient meets all of
the following conditions:
• Must NOT be pregnant or breast feeding.
• Must be capable of complying with the mandatory contraceptive measures required for
Accutane therapy and understand behaviors associated with an increased risk of pregnancy.
• Must be reliable in understanding and carrying out instructions.
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Accutane must be prescribed under the System to Manage Accutane Related Teratogenicity
(S.M.A.R.T.).
To prescribe Accutane, the prescriber must obtain a supply of yellow self-adhesive Accutane
Qualification Stickers. To obtain these stickers:
1) Read the booklet entitled System to Manage Accutane Related Teratogenicity (S.M.A.R.T.)
Guide to Best Practices.
2) Sign and return the completed S.M.A.R.T. Letter of Understanding containing the following
Prescriber Checklist:
• I know the risk and severity of fetal injury/birth defects from Accutane
• I know how to diagnose and treat the various presentations of acne
• I know the risk factors for unplanned pregnancy and the effective measures for avoidance of
unplanned pregnancy
• It is the informed patient’s responsibility to avoid pregnancy during Accutane therapy and
for 1 month after stopping Accutane. To help patients have the knowledge and tools to do so:
Before beginning treatment of female patients with Accutane I will refer for expert, detailed
pregnancy prevention counseling and prescribing, reimbursed by the manufacturer, OR I
have the expertise to perform this function and elect to do so
• I understand, and will properly use throughout the Accutane treatment course, the
S.M.A.R.T. procedures for Accutane, including monthly pregnancy avoidance counseling,
pregnancy testing and use of the yellow self-adhesive Accutane Qualification Stickers
3) To use the yellow self-adhesive Accutane Qualification Sticker: Accutane should not be
prescribed or dispensed to any patient (male or female) without a yellow self-adhesive
Accutane Qualification Sticker.
For female patients, the yellow self-adhesive Accutane Qualification Sticker signifies that she:
• Must have had 2 negative urine or serum pregnancy tests with a sensitivity of at least 25
mIU/mL before receiving the initial Accutane prescription. The first test (a screening test) is
obtained by the prescriber when the decision is made to pursue qualification of the patient
for Accutane. The second pregnancy test (a confirmation test) should be done during the first
5 days of the menstrual period immediately preceding the beginning of Accutane therapy.
For patients with amenorrhea, the second test should be done at least 11 days after the last
act of unprotected sexual intercourse (without using 2 effective forms of contraception). Each
month of therapy, the patient must have a negative result from a urine or serum pregnancy
test. A pregnancy test must be repeated every month prior to the female patient receiving
each prescription.
• Must have selected and have committed to use 2 forms of effective contraception
simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the
chosen method, or the patient has undergone a hysterectomy. Patients must use 2 forms of
effective contraception for at least 1 month prior to initiation of Accutane therapy, during
Accutane therapy, and for 1 month after discontinuing Accutane therapy. Counseling about
contraception and behaviors associated with an increased risk of pregnancy must be repeated
on a monthly basis.
Effective forms of contraception include both primary and secondary forms of contraception.
Primary forms of contraception include: tubal ligation, partner’s vasectomy, intrauterine
devices, birth control pills, and topical/injectable/implantable/insertable hormonal birth control
products. Secondary forms of contraception include diaphragms, latex condoms, and cervical
caps; each must be used with a spermicide.
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11
Any birth control method can fail. Therefore, it is critically important that women of
childbearing potential use 2 effective forms of contraception simultaneously. A drug interaction
that decreases effectiveness of hormonal contraceptives has not been entirely ruled out for
Accutane. Although hormonal contraceptives are highly effective, there have been reports of
pregnancy
from
women
who
have
used
oral
contraceptives,
as
well
as
topical/injectable/implantable/insertable hormonal birth control products. These reports
occurred while these patients were taking Accutane. These reports are more frequent for women
who use only a single method of contraception. Patients must receive written warnings about the
rates of possible contraception failure (included in patient education kits).
Prescribers are advised to consult the package insert of any medication administered
concomitantly with hormonal contraceptives, since some medications may decrease the
effectiveness of these birth control products. Patients should be prospectively cautioned not to
self-medicate with the herbal supplement St. John’s Wort because a possible interaction has been
suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral
contraceptives shortly after starting St. John's Wort. Pregnancies have been reported by users
of combined hormonal contraceptives who also used some form of St. John's Wort (see
PRECAUTIONS).
• Must have signed a Patient Information/Consent form that contains warnings about the risk
of potential birth defects if the fetus is exposed to isotretinoin.
• Must have been informed of the purpose and importance of participating in the Accutane
Survey and have been given the opportunity to enroll (see PRECAUTIONS).
The yellow self-adhesive Accutane Qualification Sticker documents that the female patient is
qualified, and includes the date of qualification, patient gender, cut-off date for filling the
prescription, and up to a 30-day supply limit with no refills.
These yellow self-adhesive Accutane Qualification Stickers should also be used for male patients.
Table 1. Use of Pregnancy Tests and Accutane Qualification Stickers for Patients
Patient Type
Pregnancy
Test Required
Qualification Date
Accutane
Qualification Sticker
Necessary
Dispense Within
7 Days of
Qualification Date
All Males
No
Date Prescription
Written
Yes
Yes
Females of
Childbearing
Potential
Yes
Date Sample Taken for
Confirmatory Negative
Pregnancy Test
Yes
Yes
Females* Not of
Childbearing
Potential
No
Date Prescription
Written
Yes
Yes
*Females who have had a hysterectomy or who are postmenopausal are not considered to be of
childbearing potential.
If a pregnancy does occur during treatment of a woman with Accutane, the prescriber and
patient should discuss the desirability of continuing the pregnancy. Prescribers are strongly
encouraged to report all cases of pregnancy to Roche @ 1-800-526-6367 where a Roche
Pregnancy Prevention Program Specialist will be available to discuss Roche pregnancy
information, or prescribers may contact the Food and Drug Administration MedWatch Program
@ 1-800-FDA-1088.
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12
Accutane should be prescribed only by prescribers who have demonstrated special competence
in the diagnosis and treatment of severe recalcitrant nodular acne, are experienced in the use of
systemic retinoids, have read the S.M.A.R.T. Guide to Best Practices, signed and returned the
completed S.M.A.R.T. Letter of Understanding, and obtained yellow self-adhesive Accutane
Qualification Stickers. Accutane should not be prescribed or dispensed without a yellow self-
adhesive Accutane Qualification Sticker.
INFORMATION FOR PHARMACISTS:
ACCUTANE MUST ONLY BE DISPENSED:
• IN NO MORE THAN A 30-DAY SUPPLY
• ONLY ON PRESENTATION OF AN ACCUTANE PRESCRIPTION WITH A YELLOW
SELF-ADHESIVE ACCUTANE QUALIFICATION STICKER
• WITHIN 7 DAYS OF THE QUALIFICATION DATE
• REFILLS REQUIRE A NEW PRESCRIPTION WITH A YELLOW SELF-ADHESIVE
ACCUTANE QUALIFICATION STICKER
• NO TELEPHONE OR COMPUTERIZED PRESCRIPTIONS ARE PERMITTED.
AN ACCUTANE MEDICATION GUIDE MUST BE GIVEN TO THE PATIENT EACH TIME
ACCUTANE IS DISPENSED, AS REQUIRED BY LAW. THIS ACCUTANE MEDICATION
GUIDE IS AN IMPORTANT PART OF THE RISK MANAGEMENT PROGRAM FOR THE
PATIENT.
DESCRIPTION
Isotretinoin, a retinoid, is available as Accutane in 10-mg, 20-mg and 40-mg soft gelatin capsules for
oral administration. Each capsule contains beeswax, butylated hydroxyanisole, edetate disodium,
hydrogenated soybean oil flakes, hydrogenated vegetable oil, and soybean oil. Gelatin capsules contain
glycerin and parabens (methyl and propyl), with the following dye systems: 10 mg — iron oxide (red)
and titanium dioxide; 20 mg — FD&C Red No. 3, FD&C Blue No. 1, and titanium dioxide; 40 mg —
FD&C Yellow No. 6, D&C Yellow No. 10, and titanium dioxide.
Chemically, isotretinoin is 13-cis-retinoic acid and is related to both retinoic acid and retinol (vitamin
A). It is a yellow to orange crystalline powder with a molecular weight of 300.44. The structural
formula is:
CLINICAL PHARMACOLOGY
Isotretinoin is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1.0 mg/kg/day
(see DOSAGE AND ADMINISTRATION), inhibits sebaceous gland function and keratinization. The
exact mechanism of action of isotretinoin is unknown.
Nodular Acne
Clinical improvement in nodular acne patients occurs in association with a reduction in sebum
secretion. The decrease in sebum secretion is temporary and is related to the dose and duration of
treatment with Accutane, and reflects a reduction in sebaceous gland size and an inhibition of
sebaceous gland differentiation.1
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Pharmacokinetics
Absorption
Due to its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a high-fat
meal. In a crossover study, 74 healthy adult subjects received a single 80 mg oral dose (2 x 40 mg
capsules) of Accutane under fasted and fed conditions. Both peak plasma concentration (Cmax) and the
total exposure (AUC) of isotretinoin were more than doubled following a standardized high-fat meal
when compared with Accutane given under fasted conditions (see Table 2 below). The observed
elimination half-life was unchanged. This lack of change in half-life suggests that food increases the
bioavailability of isotretinoin without altering its disposition. The time to peak concentration (Tmax)
was also increased with food and may be related to a longer absorption phase. Therefore, Accutane
capsules should always be taken with food (see DOSAGE AND ADMINISTRATION). Clinical
studies have shown that there is no difference in the pharmacokinetics of isotretinoin between patients
with nodular acne and healthy subjects with normal skin.
Table 2. Pharmacokinetic Parameters of Isotretinoin Mean (%CV), N=74
Accutane
2 x 40 mg
Capsules
AUC0-∞
(ng⋅hr/mL)
Cmax
(ng/mL)
Tmax
(hr)
t1/2
(hr)
Fed*
10,004 (22%)
862 (22%)
5.3 (77%)
21 (39%)
Fasted
3,703 (46%)
301 (63%)
3.2 (56%)
21 (30%)
*Eating a standardized high-fat meal
Distribution
Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.
Metabolism
Following oral administration of isotretinoin, at least three metabolites have been identified in human
plasma: 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). Retinoic
acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion. The
administration of one isomer will give rise to the other. Isotretinoin is also irreversibly oxidized to
4-oxo-isotretinoin, which forms its geometric isomer 4-oxo-tretinoin.
After a single 80 mg oral dose of Accutane to 74 healthy adult subjects, concurrent administration of
food increased the extent of formation of all metabolites in plasma when compared to the extent of
formation under fasted conditions.
All of these metabolites possess retinoid activity that is in some in vitro models more than that of the
parent isotretinoin. However, the clinical significance of these models is unknown. After multiple oral
dose administration of isotretinoin to adult cystic acne patients (≥18 years), the exposure of patients to
4-oxo-isotretinoin at steady-state under fasted and fed conditions was approximately 3.4 times higher
than that of isotretinoin.
In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are 2C8,
2C9, 3A4, and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are
then excreted in urine and feces.
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Elimination
Following oral administration of an 80 mg dose of 14C-isotretinoin as a liquid suspension, 14C-activity
in blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are
ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%). After a
single 80 mg oral dose of Accutane to 74 healthy adult subjects under fed conditions, the mean ± SD
elimination half-lives (t1/2) of isotretinoin and 4-oxo-isotretinoin were 21.0 ± 8.2 hours and 24.0 ± 5.3
hours, respectively. After both single and multiple doses, the observed accumulation ratios of
isotretinoin ranged from 0.90 to 5.43 in patients with cystic acne.
Special Patient Populations
Pediatric Patients
The pharmacokinetics of isotretinoin were evaluated after single and multiple doses in 38 pediatric
patients (12 to 15 years) and 19 adult patients (≥18 years) who received Accutane for the treatment of
severe recalcitrant nodular acne. In both age groups, 4-oxo-isotretinoin was the major metabolite;
tretinoin and 4-oxo-tretinoin were also observed. The dose-normalized pharmacokinetic parameters for
isotretinoin following single and multiple doses are summarized in Table 3 for pediatric patients. There
were no statistically significant differences in the pharmacokinetics of isotretinoin between pediatric
and adult patients.
Table 3. Pharmacokinetic Parameters of Isotretinoin Following Single and Multiple Dose
Administration in Pediatric Patients, 12 to 15 Years of Age
Mean (± SD), N=38*
Parameter
Isotretinoin
(Single Dose)
Isotretinoin
(Steady-State)
Cmax (ng/mL)
573.25 (278.79)
731.98 (361.86)
AUC(0-12) (ng⋅hr/mL)
3033.37 (1394.17)
5082.00 (2184.23)
AUC(0-24) (ng⋅hr/mL)
6003.81 (2885.67)
–
Tmax (hr)†
6.00 (1.00-24.60)
4.00 (0-12.00)
Cssmin (ng/mL)
–
352.32 (184.44)
T1/2 (hr)
–
15.69 (5.12)
CL/F (L/hr)
–
17.96 (6.27)
*The single and multiple dose data in this table were obtained following a
non-standardized meal that is not comparable to the high-fat meal that was used in the
study in Table 2.
†Median (range)
In pediatric patients (12 to 15 years), the mean ± SD elimination half-lives (t1/2) of isotretinoin and 4-
oxo-isotretinoin were 15.7 ± 5.1 hours and 23.1 ± 5.7 hours, respectively. The accumulation ratios of
isotretinoin ranged from 0.46 to 3.65 for pediatric patients.
INDICATIONS AND USAGE
Severe Recalcitrant Nodular Acne
Accutane is indicated for the treatment of severe recalcitrant nodular acne. Nodules are inflammatory
lesions with a diameter of 5 mm or greater. The nodules may become suppurative or hemorrhagic.
“Severe,” by definition,2 means “many” as opposed to “few or several” nodules. Because of significant
adverse effects associated with its use, Accutane should be reserved for patients with severe nodular
acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition,
Accutane is indicated only for those females who are not pregnant, because Accutane can cause severe
birth defects (see boxed CONTRAINDICATIONS AND WARNINGS).
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A single course of therapy for 15 to 20 weeks has been shown to result in complete and prolonged
remission of disease in many patients.1,3,4 If a second course of therapy is needed, it should not be
initiated until at least 8 weeks after completion of the first course, because experience has shown that
patients may continue to improve while off Accutane. The optimal interval before retreatment has not
been defined for patients who have not completed skeletal growth (see WARNINGS: Skeletal: Bone
Mineral Density, Hyperostosis, and Premature Epiphyseal Closure).
CONTRAINDICATIONS
Pregnancy: Category X. See boxed CONTRAINDICATIONS AND WARNINGS.
Allergic Reactions
Accutane is contraindicated in patients who are hypersensitive to this medication or to any of its
components. Accutane should not be given to patients who are sensitive to parabens, which are used as
preservatives in the gelatin capsule (see PRECAUTIONS: Hypersensitivity).
WARNINGS
Psychiatric Disorders
Accutane may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts,
suicide, and aggressive and/or violent behaviors. Discontinuation of Accutane therapy may be
insufficient; further evaluation may be necessary. No mechanism of action has been established
for these events (see ADVERSE REACTIONS: Psychiatric). Prescribers should read the
brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for
Prescribers of Accutane (isotretinoin).
Pseudotumor Cerebri
Accutane use has been associated with a number of cases of pseudotumor cerebri (benign
intracranial hypertension), some of which involved concomitant use of tetracyclines.
Concomitant treatment with tetracyclines should therefore be avoided. Early signs and
symptoms of pseudotumor cerebri include papilledema, headache, nausea and vomiting, and
visual disturbances. Patients with these symptoms should be screened for papilledema and, if
present, they should be told to discontinue Accutane immediately and be referred to a
neurologist for further diagnosis and care (see ADVERSE REACTIONS: Neurological).
Pancreatitis
Acute pancreatitis has been reported in patients with either elevated or normal serum triglyceride
levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. Accutane should be
stopped if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of
pancreatitis occur.
Lipids
Elevations of serum triglycerides in excess of 800 mg/dL have been reported in patients treated with
Accutane. Marked elevations of serum triglycerides were reported in approximately 25% of patients
receiving Accutane in clinical trials. In addition, approximately 15% developed a decrease in high-
density lipoproteins and about 7% showed an increase in cholesterol levels. In clinical trials, the
effects on triglycerides, HDL, and cholesterol were reversible upon cessation of Accutane therapy.
Some patients have been able to reverse triglyceride elevation by reduction in weight, restriction of
dietary fat and alcohol, and reduction in dose while continuing Accutane.5
Blood lipid determinations should be performed before Accutane is given and then at intervals until the
lipid response to Accutane is established, which usually occurs within 4 weeks. Especially careful
consideration must be given to risk/benefit for patients who may be at high risk during Accutane
therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial
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16
history of lipid metabolism disorder). If Accutane therapy is instituted, more frequent checks of serum
values for lipids and/or blood sugar are recommended (see PRECAUTIONS: Laboratory Tests).
The cardiovascular consequences of hypertriglyceridemia associated with Accutane are unknown.
Animal Studies: In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 to 5.3 times the recommended
clinical dose of 1.0 mg/kg/day after normalization for total body surface area) for 18 months or longer,
the incidences of focal calcification, fibrosis and inflammation of the myocardium, calcification of
coronary, pulmonary and mesenteric arteries, and metastatic calcification of the gastric mucosa were
greater than in control rats of similar age. Focal endocardial and myocardial calcifications associated
with calcification of the coronary arteries were observed in two dogs after approximately 6 to 7 months
of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day (30 to 60 times the recommended
clinical dose of 1.0 mg/kg/day, respectively, after normalization for total body surface area).
Hearing Impairment
Impaired hearing has been reported in patients taking Accutane; in some cases, the hearing impairment
has been reported to persist after therapy has been discontinued. Mechanism(s) and causality for this
event have not been established. Patients who experience tinnitus or hearing impairment should
discontinue Accutane treatment and be referred for specialized care for further evaluation (see
ADVERSE REACTIONS: Special Senses).
Hepatotoxicity
Clinical hepatitis considered to be possibly or probably related to Accutane therapy has been reported.
Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15%
of individuals treated during clinical trials, some of which normalized with dosage reduction or
continued administration of the drug. If normalization does not readily occur or if hepatitis is suspected
during treatment with Accutane, the drug should be discontinued and the etiology further investigated.
Inflammatory Bowel Disease
Accutane has been associated with inflammatory bowel disease (including regional ileitis) in patients
without a prior history of intestinal disorders. In some instances, symptoms have been reported to
persist after Accutane treatment has been stopped. Patients experiencing abdominal pain, rectal
bleeding or severe diarrhea should discontinue Accutane immediately (see ADVERSE REACTIONS:
Gastrointestinal).
Skeletal
Bone Mineral Density
Effects of multiple courses of Accutane on the developing musculoskeletal system are unknown.
There is some evidence that long-term, high-dose, or multiple courses of therapy with isotretinoin have
more of an effect than a single course of therapy on the musculoskeletal system. In an open-label
clinical trial (N=217) of a single course of therapy with Accutane for severe recalcitrant nodular acne,
bone density measurements at several skeletal sites were not significantly decreased (lumbar spine
change >-4% and total hip change >-5%) or were increased in the majority of patients. One patient
had a decrease in lumbar spine bone mineral density >4% based on unadjusted data. Sixteen (7.9%)
patients had decreases in lumbar spine bone mineral density >4%, and all the other patients (92%) did
not have significant decreases or had increases (adjusted for body mass index). Nine patients (4.5%)
had a decrease in total hip bone mineral density >5% based on unadjusted data. Twenty-one (10.6%)
patients had decreases in total hip bone mineral density >5%, and all the other patients (89%) did not
have significant decreases or had increases (adjusted for body mass index). Follow-up studies
performed in 8 of the patients with decreased bone mineral density for up to 11 months thereafter
demonstrated increasing bone density in 5 patients at the lumbar spine, while the other 3 patients had
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17
lumbar spine bone density measurements below baseline values. Total hip bone mineral densities
remained below baseline (range –1.6% to -7.6%) in 5 of 8 patients (62.5%).
In a separate open-label extension study of 10 patients, ages 13-18 years, who started a second course
of Accutane 4 months after the first course, two patients showed a decrease in mean lumbar spine bone
mineral density up to 3.25% (see PRECAUTIONS: Pediatric Use).
Spontaneous reports of osteoporosis, osteopenia, bone fractures, and delayed healing of bone fractures
have been seen in the Accutane population. While causality to Accutane has not been established, an
effect cannot be ruled out. Longer term effects have not been studied. It is important that Accutane be
given at the recommended doses for no longer than the recommended duration.
Hyperostosis
A high prevalence of skeletal hyperostosis was noted in clinical trials for disorders of keratinization
with a mean dose of 2.24 mg/kg/day. Additionally, skeletal hyperostosis was noted in 6 of 8 patients in
a prospective study of disorders of keratinization.6 Minimal skeletal hyperostosis and calcification of
ligaments and tendons have also been observed by x-ray in prospective studies of nodular acne patients
treated with a single course of therapy at recommended doses. The skeletal effects of multiple
Accutane treatment courses for acne are unknown.
In a clinical study of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne,
hyperostosis was not observed after 16 to 20 weeks of treatment with approximately 1 mg/kg/day of
Accutane given in two divided doses. Hyperostosis may require a longer time frame to appear. The
clinical course and significance remain unknown.
Premature Epiphyseal Closure
There are spontaneous reports of premature epiphyseal closure in acne patients receiving
recommended doses of Accutane. The effect of multiple courses of Accutane on epiphyseal closure is
unknown.
Vision Impairment
Visual problems should be carefully monitored. All Accutane patients experiencing visual difficulties
should discontinue Accutane treatment and have an ophthalmological examination (see ADVERSE
REACTIONS: Special Senses).
Corneal Opacities
Corneal opacities have occurred in patients receiving Accutane for acne and more frequently when
higher drug dosages were used in patients with disorders of keratinization. The corneal opacities that
have been observed in clinical trial patients treated with Accutane have either completely resolved or
were resolving at follow-up 6 to 7 weeks after discontinuation of the drug (see ADVERSE
REACTIONS: Special Senses).
Decreased Night Vision
Decreased night vision has been reported during Accutane therapy and in some instances the event has
persisted after therapy was discontinued. Because the onset in some patients was sudden, patients
should be advised of this potential problem and warned to be cautious when driving or operating any
vehicle at night.
PRECAUTIONS
The Accutane Pregnancy Prevention and Risk Management Programs consist of the System to Manage
Accutane Related Teratogenicity (S.M.A.R.T.) and the Accutane Pregnancy Prevention Program
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(PPP). S.M.A.R.T. should be followed for prescribing Accutane with the goal of preventing fetal
exposure to isotretinoin. It consists of: 1) reading the booklet entitled System to Manage Accutane
Related Teratogenicity (S.M.A.R.T.) Guide to Best Practices, 2) signing and returning the completed
S.M.A.R.T. Letter of Understanding containing the Prescriber Checklist, 3) a yellow self-adhesive
Accutane Qualification Sticker to be affixed to the prescription page. In addition, the patient
educational material, Be Smart, Be Safe, Be Sure, should be used with each patient.
The following further describes each component:
1) The S.M.A.R.T. Guide to Best Practices includes: Accutane teratogenic potential, information on
pregnancy testing, specific information about effective contraception, the limitations of
contraceptive methods and behaviors associated with an increased risk of contraceptive failure and
pregnancy, the methods to evaluate pregnancy risk, and the method to complete a qualified
Accutane prescription.
2) The S.M.A.R.T. Letter of Understanding attests that Accutane prescribers understand that
Accutane is a teratogen, have read the S.M.A.R.T. Guide to Best Practices, understand their
responsibilities in preventing exposure of pregnant females to Accutane and the procedures for
qualifying female patients as defined in the boxed CONTRAINDICATIONS AND WARNINGS.
The Prescriber Checklist attests that Accutane prescribers know the risk and severity of injury/birth
defects from Accutane; know how to diagnose and treat the various presentations of acne; know
the risk factors for unplanned pregnancy and the effective measures for avoidance; will refer the
patient for, or provide, detailed pregnancy prevention counseling to help the patient have
knowledge and tools needed to fulfill their ultimate responsibility to avoid becoming pregnant;
understand and properly use throughout the Accutane treatment course, the revised risk
management procedures, including monthly pregnancy avoidance counseling, pregnancy testing,
and use of qualified prescriptions with the yellow self-adhesive Accutane Qualification Sticker.
3) The yellow self-adhesive Accutane Qualification Sticker is used as documentation that the
prescriber has qualified the female patient according to the qualification criteria (see boxed
CONTRAINDICATIONS AND WARNINGS).
4) Accutane Pregnancy Prevention Program (PPP) is a systematic approach to comprehensive patient
education about their responsibilities and includes education for contraception compliance and
reinforcement of educational messages. The PPP includes information on the risks and benefits of
Accutane which is linked to the Accutane Medication Guide dispensed by pharmacists with each
prescription.
Male and female patients are provided with separate booklets. Each booklet contains information
on Accutane therapy, including precautions and warnings, an Informed Consent/Patient Agreement
form, and a toll-free line which provides Accutane information in 13 languages.
The booklet for male patients, Be Smart, Be Safe, Be Sure, Accutane Risk Management Program
for Men, also includes information about male reproduction, a warning not to share Accutane with
others or to donate blood during Accutane therapy and for 1 month following discontinuation of
Accutane.
The booklet for female patients, Be Smart, Be Safe, Be Sure, Accutane Pregnancy Prevention and
Risk Management Program for Women, also includes a referral program that offers females free
contraception counseling, reimbursed by the manufacturer, by a reproductive specialist; a second
Patient Information/Consent form concerning birth defects, obtaining her consent to be treated
within this agreement; an enrollment form for the Accutane Survey; and a qualification checklist
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19
affirming the conditions under which female patients may receive Accutane. In addition, there is
information on the types of contraceptive methods, the selection and use of appropriate, effective
contraception, and the rates of possible contraceptive failure; a toll-free contraception counseling
line; and patient education videos — the video “Be Prepared, Be Protected” and the video “Be
Aware: The Risk of Pregnancy While on Accutane”.
General
Although an effect of Accutane on bone loss is not established, physicians should use caution when
prescribing Accutane to patients with a genetic predisposition for age-related osteoporosis, a history of
childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism. This would
include patients diagnosed with anorexia nervosa and those who are on chronic drug therapy that
causes drug-induced osteoporosis/osteomalacia and/or affects vitamin D metabolism, such as systemic
corticosteroids and any anticonvulsant.
Patients may be at increased risk when participating in sports with repetitive impact where the risks of
spondylolisthesis with and without pars fractures and hip growth plate injuries in early and late
adolescence are known. There are spontaneous reports of fractures and/or delayed healing in patients
while on treatment with Accutane or following cessation of treatment with Accutane while involved in
these activities. While causality to Accutane has not been established, an effect cannot be ruled out.
Information for Patients and Prescribers
• Patients should be instructed to read the Medication Guide supplied as required by law when
Accutane is dispensed. The complete text of the Medication Guide is reprinted at the end of this
document. For additional information, patients should also read the Patient Product Information,
Important Information Concerning Your Treatment with Accutane (isotretinoin). All patients
should sign the Informed Consent/Patient Agreement.
• Females of childbearing potential should be instructed that they must not be pregnant when
Accutane therapy is initiated, and that they should use 2 forms of effective contraception 1 month
before starting Accutane, while taking Accutane, and for 1 month after Accutane has been stopped.
They should also sign a consent form prior to beginning Accutane therapy. They should be given
an opportunity to enroll in the Accutane Survey and to review the patient videotapes provided by
the manufacturer to the prescriber. The videos include information about contraception, the most
common reasons that contraception fails, and the importance of using 2 forms of effective
contraception when taking teratogenic drugs and comprehensive information about types of
potential birth defects which could occur if a woman who is pregnant takes Accutane at any time
during pregnancy. Female patients should be seen by their prescribers monthly and have a urine or
serum pregnancy test performed each month during treatment to confirm negative pregnancy status
before another Accutane prescription is written (see boxed CONTRAINDICATIONS AND
WARNINGS).
• Accutane is found in the semen of male patients taking Accutane, but the amount delivered to a
female partner would be about 1 million times lower than an oral dose of 40 mg. While the no-
effect limit for isotretinoin-induced embryopathy is unknown, 20 years of postmarketing reports
include 4 with isolated defects compatible with features of retinoid exposed fetuses. None of these
cases had the combination of malformations characteristic of retinoid exposure, and all had other
possible explanations for the defects observed.
• Patients may report mental health problems or family history of psychiatric disorders. These
reports should be discussed with the patient and/or the patient’s family. A referral to a mental
health professional may be necessary. The physician should consider whether or not Accutane
therapy is appropriate in this setting (see WARNINGS: Psychiatric Disorders).
• Patients should be informed that they must not share Accutane with anyone else because of the risk
of birth defects and other serious adverse events.
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20
• Patients should not donate blood during therapy and for 1 month following discontinuance of the
drug because the blood might be given to a pregnant woman whose fetus must not be exposed to
Accutane.
• Patients should be reminded to take Accutane with a meal (see DOSAGE AND
ADMINISTRATION). To decrease the risk of esophageal irritation, patients should swallow the
capsules with a full glass of liquid.
• Patients should be informed that transient exacerbation (flare) of acne has been seen, generally
during the initial period of therapy.
• Wax epilation and skin resurfacing procedures (such as dermabrasion, laser) should be avoided
during Accutane therapy and for at least 6 months thereafter due to the possibility of scarring (see
ADVERSE REACTIONS: Skin and Appendages).
• Patients should be advised to avoid prolonged exposure to UV rays or sunlight.
• Patients should be informed that they may experience decreased tolerance to contact lenses during
and after therapy.
• Patients should be informed that approximately 16% of patients treated with Accutane in a clinical
trial developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these
symptoms were mild to moderate, but occasionally required discontinuation of the drug. Transient
pain in the chest has been reported less frequently. In the clinical trial, these symptoms generally
cleared rapidly after discontinuation of Accutane, but in some cases persisted (see ADVERSE
REACTIONS: Musculoskeletal). There have been rare postmarketing reports of rhabdomyolysis,
some associated with strenuous physical activity (see Laboratory Tests: CPK).
• Pediatric patients and their caregivers should be informed that approximately 29% (104/358) of
pediatric patients treated with Accutane developed back pain. Back pain was severe in 13.5%
(14/104) of the cases and occurred at a higher frequency in female than male patients. Arthralgias
were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in 7.6% (6/79) of
patients. Appropriate evaluation of the musculoskeletal system should be done in patients who
present with these symptoms during or after a course of Accutane. Consideration should be given
to discontinuation of Accutane if any significant abnormality is found.
• Neutropenia and rare cases of agranulocytosis have been reported. Accutane should be
discontinued if clinically significant decreases in white cell counts occur.
Hypersensitivity
Anaphylactic reactions and other allergic reactions have been reported. Cutaneous allergic reactions
and serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities
and extracutaneous involvement (including renal) have been reported. Severe allergic reaction
necessitates discontinuation of therapy and appropriate medical management.
Drug Interactions
• Vitamin A: Because of the relationship of Accutane to vitamin A, patients should be advised
against taking vitamin supplements containing vitamin A to avoid additive toxic effects.
• Tetracyclines: Concomitant treatment with Accutane and tetracyclines should be avoided because
Accutane use has been associated with a number of cases of pseudotumor cerebri (benign
intracranial hypertension), some of which involved concomitant use of tetracyclines.
• Micro-dosed Progesterone Preparations: Micro-dosed progesterone preparations (“minipills” that
do not contain an estrogen) may be an inadequate method of contraception during Accutane
therapy. Although other hormonal contraceptives are highly effective, there have been reports of
pregnancy from women who have used combined oral contraceptives, as well as
topical/injectable/implantable/insertable hormonal birth control products. These reports are more
frequent for women who use only a single method of contraception. It is not known if hormonal
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21
contraceptives differ in their effectiveness when used with Accutane. Therefore, it is critically
important for women of childbearing potential to select and commit to use 2 forms of effective
contraception simultaneously, at least 1 of which must be a primary form, unless absolute
abstinence is the chosen method, or the patient has undergone a hysterectomy (see boxed
CONTRAINDICATIONS AND WARNINGS).
• Phenytoin: Accutane has not been shown to alter the pharmacokinetics of phenytoin in a study in
seven healthy volunteers. These results are consistent with the in vitro finding that neither
isotretinoin nor its metabolites induce or inhibit the activity of the CYP 2C9 human hepatic P450
enzyme. Phenytoin is known to cause osteomalacia. No formal clinical studies have been
conducted to assess if there is an interactive effect on bone loss between phenytoin and Accutane.
Therefore, caution should be exercised when using these drugs together.
• Systemic Corticosteroids: Systemic corticosteroids are known to cause osteoporosis. No formal
clinical studies have been conducted to assess if there is an interactive effect on bone loss between
systemic corticosteroids and Accutane. Therefore, caution should be exercised when using these
drugs together.
Prescribers are advised to consult the package insert of medication administered concomitantly with
hormonal contraceptives, since some medications may decrease the effectiveness of these birth control
products. Accutane use is associated with depression in some patients (see WARNINGS:
Psychiatric Disorders and ADVERSE REACTIONS: Psychiatric). Patients should be prospectively
cautioned not to self-medicate with the herbal supplement St. John’s Wort because a possible
interaction has been suggested with hormonal contraceptives based on reports of breakthrough
bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies have been reported
by users of combined hormonal contraceptives who also used some form of St. John's Wort.
Laboratory Tests
Pregnancy Test
Female patients of childbearing potential must have negative results from 2 urine or serum pregnancy
tests with a sensitivity of at least 25 mIU/mL before receiving the initial Accutane prescription. The
first test is obtained by the prescriber when the decision is made to pursue qualification of the patient
for Accutane (a screening test). The second pregnancy test (a confirmation test) should be done during
the first 5 days of the menstrual period immediately preceding the beginning of Accutane therapy. For
patients with amenorrhea, the second test should be done at least 11 days after the last act of
unprotected sexual intercourse (without using 2 effective forms of contraception).
Each month of therapy, the patient must have a negative result from a urine or serum pregnancy test. A
pregnancy test must be repeated each month prior to the female patient receiving each prescription.
• Lipids: Pretreatment and follow-up blood lipids should be obtained under fasting conditions. After
consumption of alcohol, at least 36 hours should elapse before these determinations are made. It is
recommended that these tests be performed at weekly or biweekly intervals until the lipid response
to Accutane is established. The incidence of hypertriglyceridemia is 1 patient in 4 on Accutane
therapy (see WARNINGS: Lipids).
• Liver Function Tests: Since elevations of liver enzymes have been observed during clinical trials,
and hepatitis has been reported, pretreatment and follow-up liver function tests should be
performed at weekly or biweekly intervals until the response to Accutane has been established (see
WARNINGS: Hepatotoxicity).
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22
• Glucose: Some patients receiving Accutane have experienced problems in the control of their
blood sugar. In addition, new cases of diabetes have been diagnosed during Accutane therapy,
although no causal relationship has been established.
• CPK: Some patients undergoing vigorous physical activity while on Accutane therapy have
experienced elevated CPK levels; however, the clinical significance is unknown. There have been
rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity. In
a clinical trial of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne,
transient elevations in CPK were observed in 12% of patients, including those undergoing
strenuous physical activity in association with reported musculoskeletal adverse events such as
back pain, arthralgia, limb injury, or muscle sprain. In these patients, approximately half of the
CPK elevations returned to normal within 2 weeks and half returned to normal within 4 weeks. No
cases of rhabdomyolysis were reported in this trial.
Carcinogenesis, Mutagenesis and Impairment of Fertility
In male and female Fischer 344 rats given oral isotretinoin at dosages of 8 or 32 mg/kg/day (1.3 to 5.3
times the recommended clinical dose of 1.0 mg/kg/day, respectively, after normalization for total body
surface area) for greater than 18 months, there was a dose-related increased incidence of
pheochromocytoma relative to controls. The incidence of adrenal medullary hyperplasia was also
increased at the higher dosage in both sexes. The relatively high level of spontaneous
pheochromocytomas occurring in the male Fischer 344 rat makes it an equivocal model for study of
this tumor; therefore, the relevance of this tumor to the human population is uncertain.
The Ames test was conducted with isotretinoin in two laboratories. The results of the tests in one
laboratory were negative while in the second laboratory a weakly positive response (less than 1.6 x
background) was noted in S. typhimurium TA100 when the assay was conducted with metabolic
activation. No dose-response effect was seen and all other strains were negative. Additionally, other
tests designed to assess genotoxicity (Chinese hamster cell assay, mouse micronucleus test, S.
cerevisiae D7 assay, in vitro clastogenesis assay with human-derived lymphocytes, and unscheduled
DNA synthesis assay) were all negative.
In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were
observed at oral dosages of isotretinoin of 2, 8, or 32 mg/kg/day (0.3, 1.3, or 5.3 times the
recommended clinical dose of 1.0 mg/kg/day, respectively, after normalization for total body surface
area).
In dogs, testicular atrophy was noted after treatment with oral isotretinoin for approximately 30 weeks
at dosages of 20 or 60 mg/kg/day (10 or 30 times the recommended clinical dose of 1.0 mg/kg/day,
respectively, after normalization for total body surface area). In general, there was microscopic
evidence for appreciable depression of spermatogenesis but some sperm were observed in all testes
examined and in no instance were completely atrophic tubules seen. In studies of 66 men, 30 of whom
were patients with nodular acne under treatment with oral isotretinoin, no significant changes were
noted in the count or motility of spermatozoa in the ejaculate. In a study of 50 men (ages 17 to 32
years) receiving Accutane (isotretinoin) therapy for nodular acne, no significant effects were seen on
ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose.
Pregnancy: Category X. See boxed CONTRAINDICATIONS AND
WARNINGS.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because of the potential for adverse
effects, nursing mothers should not receive Accutane.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
Pediatric Use
The use of Accutane in pediatric patients less than 12 years of age has not been studied. The use of
Accutane for the treatment of severe recalcitrant nodular acne in pediatric patients ages 12 to 17 years
should be given careful consideration, especially for those patients where a known metabolic or
structural bone disease exists (see PRECAUTIONS: General). Use of Accutane in this age group for
severe recalcitrant nodular acne is supported by evidence from a clinical study comparing 103 pediatric
patients (13 to 17 years) to 197 adult patients (≥18 years). Results from this study demonstrated that
Accutane, at a dose of 1 mg/kg/day given in two divided doses, was equally effective in treating severe
recalcitrant nodular acne in both pediatric and adult patients.
In studies with Accutane, adverse reactions reported in pediatric patients were similar to those
described in adults except for the increased incidence of back pain and arthralgia (both of which were
sometimes severe) and myalgia in pediatric patients (see ADVERSE REACTIONS).
In an open-label clinical trial (N=217) of a single course of therapy with Accutane for severe
recalcitrant nodular acne, bone density measurements at several skeletal sites were not significantly
decreased (lumbar spine change >-4% and total hip change >-5%) or were increased in the majority of
patients. One patient had a decrease in lumbar spine bone mineral density >4% based on unadjusted
data. Sixteen (7.9%) patients had decreases in lumbar spine bone mineral density >4%, and all the
other patients (92%) did not have significant decreases or had increases (adjusted for body mass
index). Nine patients (4.5%) had a decrease in total hip bone mineral density >5% based on
unadjusted data. Twenty-one (10.6%) patients had decreases in total hip bone mineral density >5%,
and all the other patients (89%) did not have significant decreases or had increases (adjusted for body
mass index). Follow-up studies performed in 8 of the patients with decreased bone mineral density for
up to 11 months thereafter demonstrated increasing bone density in 5 patients at the lumbar spine,
while the other 3 patients had lumbar spine bone density measurements below baseline values. Total
hip bone mineral densities remained below baseline (range –1.6% to -7.6%) in 5 of 8 patients (62.5%).
In a separate open-label extension study of 10 patients, ages 13-18 years, who started a second course
of Accutane 4 months after the first course, two patients showed a decrease in mean lumbar spine bone
mineral density up to 3.25% (see WARNINGS: Skeletal: Bone Mineral Density).
Geriatric Use
Clinical studies of isotretinoin did not include sufficient numbers of subjects aged 65 years and over to
determine whether they respond differently from younger subjects. Although reported clinical
experience has not identified differences in responses between elderly and younger patients, effects of
aging might be expected to increase some risks associated with isotretinoin therapy (see WARNINGS
and PRECAUTIONS).
ADVERSE REACTIONS
Clinical Trials and Postmarketing Surveillance
The adverse reactions listed below reflect the experience from investigational studies of Accutane, and
the postmarketing experience. The relationship of some of these events to Accutane therapy is
unknown. Many of the side effects and adverse reactions seen in patients receiving Accutane are
similar to those described in patients taking very high doses of vitamin A (dryness of the skin and
mucous membranes, eg, of the lips, nasal passage, and eyes).
Dose Relationship
Cheilitis and hypertriglyceridemia are usually dose related. Most adverse reactions reported in clinical
trials were reversible when therapy was discontinued; however, some persisted after cessation of
therapy (see WARNINGS and ADVERSE REACTIONS).
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For current labeling information, please visit https://www.fda.gov/drugsatfda
24
Body as a Whole
allergic
reactions,
including
vasculitis,
systemic
hypersensitivity
(see
PRECAUTIONS:
Hypersensitivity), edema, fatigue, lymphadenopathy, weight loss
Cardiovascular
palpitation, tachycardia, vascular thrombotic disease, stroke
Endocrine/Metabolic
hypertriglyceridemia (see WARNINGS: Lipids), alterations in blood sugar levels (see
PRECAUTIONS: Laboratory Tests)
Gastrointestinal
inflammatory bowel disease (see WARNINGS: Inflammatory Bowel Disease), hepatitis (see
WARNINGS: Hepatotoxicity), pancreatitis (see WARNINGS: Lipids), bleeding and inflammation of
the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea, other nonspecific gastrointestinal
symptoms
Hematologic
allergic reactions (see PRECAUTIONS: Hypersensitivity), anemia, thrombocytopenia, neutropenia,
rare reports of agranulocytosis (see PRECAUTIONS: Information for Patients and Prescribers). See
PRECAUTIONS: Laboratory Tests for other hematological parameters.
Musculoskeletal
skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, decreases
in bone mineral density (see WARNINGS: Skeletal), musculoskeletal symptoms (sometimes severe)
including back pain and arthralgia (see PRECAUTIONS: Information for Patients and Prescribers),
transient pain in the chest (see PRECAUTIONS: Information for Patients and Prescribers), arthritis,
tendonitis, other types of bone abnormalities, elevations of CPK/rare reports of rhabdomyolysis (see
PRECAUTIONS: Laboratory Tests).
Neurological
pseudotumor cerebri (see WARNINGS: Pseudotumor Cerebri), dizziness, drowsiness, headache,
insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness
Psychiatric
suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors (see
WARNINGS: Psychiatric Disorders), emotional instability
Of the patients reporting depression, some reported that the depression subsided with discontinuation
of therapy and recurred with reinstitution of therapy.
Reproductive System
abnormal menses
Respiratory
bronchospasms (with or without a history of asthma), respiratory infection, voice alteration
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For current labeling information, please visit https://www.fda.gov/drugsatfda
25
Skin and Appendages
acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry
nose, dry skin, epistaxis, eruptive xanthomas,7 flushing, fragility of skin, hair abnormalities, hirsutism,
hyperpigmentation and hypopigmentation, infections (including disseminated herpes simplex), nail
dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus,
pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), sunburn susceptibility
increased, sweating, urticaria, vasculitis (including Wegener’s granulomatosis; see PRECAUTIONS:
Hypersensitivity), abnormal wound healing (delayed healing or exuberant granulation tissue with
crusting; see PRECAUTIONS: Information for Patients and Prescribers)
Special Senses
Hearing
hearing impairment (see WARNINGS: Hearing Impairment), tinnitus.
Vision
corneal opacities (see WARNINGS: Corneal Opacities), decreased night vision which may persist (see
WARNINGS: Decreased Night Vision), cataracts, color vision disorder, conjunctivitis, dry eyes, eyelid
inflammation, keratitis, optic neuritis, photophobia, visual disturbances
Urinary System
glomerulonephritis (see PRECAUTIONS: Hypersensitivity), nonspecific urogenital findings (see
PRECAUTIONS: Laboratory Tests for other urological parameters)
Laboratory
Elevation of plasma triglycerides (see WARNINGS: Lipids), decrease in serum high-density
lipoprotein (HDL) levels, elevations of serum cholesterol during treatment
Increased alkaline phosphatase, SGOT (AST), SGPT (ALT), GGTP or LDH (see WARNINGS:
Hepatotoxicity)
Elevation of fasting blood sugar, elevations of CPK (see PRECAUTIONS: Laboratory Tests),
hyperuricemia
Decreases in red blood cell parameters, decreases in white blood cell counts (including severe
neutropenia and rare reports of agranulocytosis; see PRECAUTIONS: Information for Patients and
Prescribers), elevated sedimentation rates, elevated platelet counts, thrombocytopenia
White cells in the urine, proteinuria, microscopic or gross hematuria
OVERDOSAGE
The oral LD50 of isotretinoin is greater than 4000 mg/kg in rats and mice (>600 times the
recommended clinical dose of 1.0 mg/kg/day after normalization of the rat dose for total body surface
area and >300 times the recommended clinical dose of 1.0 mg/kg/day after normalization of the mouse
dose for total body surface area) and is approximately 1960 mg/kg in rabbits (653 times the
recommended clinical dose of 1.0 mg/kg/day after normalization for total body surface area). In
humans, overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain,
headache, dizziness, and ataxia. All symptoms quickly resolved without apparent residual effects.
Accutane causes serious birth defects at any dosage (see boxed CONTRAINDICATIONS AND
WARNINGS). Females of childbearing potential who present with isotretinoin overdose must be
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For current labeling information, please visit https://www.fda.gov/drugsatfda
26
evaluated for pregnancy. Patients who are pregnant should receive counseling about the risks to the
fetus, as described in the boxed CONTRAINDICATIONS AND WARNINGS. Non-pregnant patients
must be warned to avoid pregnancy for at least one month and receive contraceptive counseling as
described in the boxed CONTRAINDICATIONS AND WARNINGS. Educational materials for such
patients can be obtained by calling the manufacturer. Because an overdose would be expected to result
in higher levels of isotretinoin in semen than found during a normal treatment course, male patients
should use a condom, or avoid reproductive sexual activity with a female who is or might become
pregnant, for 30 days after the overdose. All patients with isotretinoin overdose should not donate
blood for at least 30 days.
DOSAGE AND ADMINISTRATION
Accutane should be administered with a meal (see PRECAUTIONS: Information for Patients and
Prescribers).
The recommended dosage range for Accutane is 0.5 to 1.0 mg/kg/day given in two divided doses with
food for 15 to 20 weeks. In studies comparing 0.1, 0.5, and 1.0 mg/kg/day,8 it was found that all
dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower
dosages. During treatment, the dose may be adjusted according to response of the disease and/or the
appearance of clinical side effects — some of which may be dose related. Adult patients whose disease
is very severe with scarring or is primarily manifested on the trunk may require dose adjustments up to
2.0 mg/kg/day, as tolerated. Failure to take Accutane with food will significantly decrease absorption.
Before upward dose adjustments are made, the patients should be questioned about their compliance
with food instructions.
The safety of once daily dosing with Accutane has not been established. Once daily dosing is not
recommended.
If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of
treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and if
warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated.
The optimal interval before retreatment has not been defined for patients who have not completed
skeletal growth. Long-term use of Accutane, even in low doses, has not been studied, and is not
recommended. It is important that Accutane be given at the recommended doses for no longer than the
recommended duration. The effect of long-term use of Accutane on bone loss is unknown (see
WARNINGS: Skeletal: Bone Mineral Density, Hyperostosis, and Premature Epiphyseal Closure).
Contraceptive measures must be followed for any subsequent course of therapy (see boxed
CONTRAINDICATIONS AND WARNINGS).
Table 4. Accutane Dosing by Body Weight (Based on Administration With Food)
Body Weight
Total mg/day
kilograms
pounds
0.5 mg/kg
1 mg/kg
2 mg/kg*
40
88
20
40
80
50
110
25
50
100
60
132
30
60
120
70
154
35
70
140
80
176
40
80
160
90
198
45
90
180
100
220
50
100
200
*See DOSAGE AND ADMINISTRATION: the recommended dosage range is 0.5 to 1.0 mg/kg/day.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
27
Information for Pharmacists
Accutane must only be dispensed in no more than a 30-day supply and only on presentation of an
Accutane prescription with a yellow self-adhesive Accutane Qualification Sticker within 7 days of the
qualification date. REFILLS REQUIRE A NEW WRITTEN PRESCRIPTION WITH A
YELLOW SELF-ADHESIVE ACCUTANE QUALIFICATION STICKER WITHIN 7 DAYS
OF THE QUALIFICATION DATE. No telephone or computerized prescriptions are permitted.
An Accutane Medication Guide must be given to the patient each time Accutane is dispensed, as
required by law. This Accutane Medication Guide is an important part of the risk management
program for the patient.
HOW SUPPLIED
Soft gelatin capsules, 10 mg (light pink), imprinted ACCUTANE 10 ROCHE. Boxes of 100 containing
10 Prescription Paks of 10 capsules (NDC 0004-0155-49).
Soft gelatin capsules, 20 mg (maroon), imprinted ACCUTANE 20 ROCHE. Boxes of 100 containing
10 Prescription Paks of 10 capsules (NDC 0004-0169-49).
Soft gelatin capsules, 40 mg (yellow), imprinted ACCUTANE 40 ROCHE. Boxes of 100 containing
10 Prescription Paks of 10 capsules (NDC 0004-0156-49).
Storage
Store at controlled room temperature (59° to 86°F, 15° to 30°C). Protect from light.
REFERENCES
1. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and conglobate acne with 13-
cis-retinoic acid. N Engl J Med 300:329-333, 1979. 2. Pochi PE, Shalita AR, Strauss JS, Webster SB.
Report of the consensus conference on acne classification. J Am Acad Dermatol 24:495-500, 1991. 3.
Farrell LN, Strauss JS, Stranieri AM. The treatment of severe cystic acne with 13-cis-retinoic acid:
evaluation of sebum production and the clinical response in a multiple-dose trial. J Am Acad Dermatol
3:602-611, 1980. 4. Jones H, Blanc D, Cunliffe WJ. 13-cis-retinoic acid and acne. Lancet 2:1048-1049,
1980. 5. Katz RA, Jorgensen H, Nigra TP. Elevation of serum triglyceride levels from oral isotretinoin
in disorders of keratinization. Arch Dermatol 116:1369-1372, 1980. 6. Ellis CN, Madison KC, Pennes
DR, Martel W, Voorhees JJ. Isotretinoin therapy is associated with early skeletal radiographic changes.
J Am Acad Dermatol 10:1024-1029, 1984. 7. Dicken CH, Connolly SM. Eruptive xanthomas
associated with isotretinoin (13-cis-retinoic acid). Arch Dermatol 116:951-952, 1980. 8. Strauss JS,
Rapini RP, Shalita AR, et al. Isotretinoin therapy for acne: results of a multicenter dose-response
study. J Am Acad Dermatol 10:490-496, 1984.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
28
PATIENT INFORMATION/CONSENT (FOR FEMALE PATIENTS CONCERNING BIRTH DEFECTS)
To be completed by the patient, her parent/guardian*
and signed by her prescriber.
Read each item below and initial in the space provided to show that you understand each item and
agree to follow your prescriber's instructions. Do not sign this consent and do not take Accutane if
there is anything that you do not understand.
*A parent or guardian of a minor patient (under age 18) must also read and initial each item before
signing the consent.
________________________________________________________________________
(Patient’s Name)
1. I understand that there is a very high risk that my unborn baby could have severe birth defects if I
am pregnant or become pregnant while taking Accutane in any amount even for short periods of
time. This is why I must not be pregnant while taking Accutane.
Initial: ______
2. I understand that I must not take Accutane (isotretinoin) if I am pregnant.
Initial: ______
3. I understand that I must not get pregnant during the entire time of my treatment and for 1 month
after the end of my treatment with Accutane.
Initial: ______
4. I understand that I must avoid sexual intercourse completely, or I must use 2 separate, effective
forms of birth control (contraception) at the same time. The only exception is if I have had
surgery to remove the womb (a hysterectomy).
Initial: ______
5. I understand that birth control pills and topical/injectable/implantable/insertable hormonal birth
control products are among the most effective forms of birth control. However, any form of birth
control can fail. Therefore, I must use 2 different methods at the same time, every time I have
sexual intercourse, even if 1 of the methods I choose is birth control pills or
topical/injectable/implantable/insertable hormonal birth control.
Initial: ______
6. I will talk with my prescriber about any drugs or herbal products I plan to take during my Accutane
treatment because hormonal birth control methods (for example, birth control pills) may not work
if I am taking certain drugs or herbal products (for example, St. John’s Wort).
Initial: ______
7. I understand that the following are considered effective forms of birth control:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
29
Primary:
Tubal ligation (tying my tubes), partner’s vasectomy, birth control pills,
topical/injectable/implantable/insertable hormonal birth control products, and an IUD
(intrauterine device).
Secondary: Diaphragms, latex condoms, and cervical caps. Each must be used with a spermicide,
which is a special cream or jelly that kills sperm.
I understand that at least 1 of my 2 methods of birth control must be a primary method.
Initial: ______
8. I understand that I may receive a free contraceptive (birth control) counseling session from a doctor
or other family planning expert. My Accutane prescriber can give me an Accutane Patient Referral
Form for this free consultation.
Initial: ______
9. I understand that I must begin using the birth control methods I have chosen as described above at
least 1 month before I start taking Accutane.
Initial: ______
10. I understand that I cannot get a prescription for Accutane unless I have 2 negative pregnancy test
results. The first pregnancy test should be done when my prescriber decides to prescribe Accutane.
The second pregnancy test should be done during the first 5 days of my menstrual period right
before starting Accutane therapy, or as instructed by my prescriber. I will then have 1 pregnancy
test every month during my Accutane therapy.
Initial: ______
11. I understand that I should not start taking Accutane until I am sure that I am not pregnant and have
negative results from 2 pregnancy tests.
Initial: ______
12. I have read and understand the materials my prescriber has given to me, including the Patient
Product Information, Important Information Concerning Your Treatment with Accutane
(isotretinoin). My prescriber gave me and asked me to watch the videos about contraception. I was
told about a confidential counseling line that I may call for more information about birth control. I
have received information on emergency contraception (birth control).
Initial: ______
13. I understand that I must stop taking Accutane right away and inform my prescriber if I get
pregnant, miss my menstrual period, stop using birth control, or have sexual intercourse without
using my 2 birth control methods at any time.
Initial: ______
14. My prescriber gave me information about the confidential Accutane Survey and explained to me
how important it is to take part in the Accutane Survey.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
30
Initial: ______
15. I understand that the yellow self-adhesive Accutane Qualification Sticker on my prescription for
Accutane means that I am qualified to receive an Accutane prescription, because I:
• have had 2 negative urine or serum pregnancy tests before receiving the initial Accutane
prescription. I must have a negative result from a urine or serum pregnancy test repeated each
month prior to my receiving each subsequent prescription.
• have selected and committed to use 2 forms of effective contraception simultaneously, at least 1 of
which must be a primary form, unless absolute abstinence is the chosen method, or I have
undergone a hysterectomy. I must use 2 forms of contraception for at least 1 month prior to
initiation of Accutane therapy, during therapy, and for 1 month after discontinuing therapy. I must
receive counseling, repeated on a monthly basis, about contraception and behaviors associated with
an increased risk of pregnancy.
• have signed a Patient Information/Consent form that contains warnings about the risk of potential
birth defects if I am pregnant or become pregnant and my unborn baby is exposed to isotretinoin.
• have been informed of the purpose and importance of participating in the Accutane Survey and
given the opportunity to enroll.
Initial: ______
My prescriber has answered all my questions about Accutane and I understand that it is my
responsibility not to get pregnant during Accutane treatment or for 1 month after I stop taking
Accutane.
Initial: ______
I now authorize my prescriber ________________ to begin my treatment with Accutane.
Patient Signature:________________________________ Date:____________________
Parent/Guardian Signature (if under age 18):____________________ Date:___________
Please print: Patient Name and Address________________________________________
_______________________________________ Telephone _______________________
I have fully explained to the patient, __________________, the nature and purpose of the treatment
described above and the risks to females of childbearing potential. I have asked the patient if she has
any questions regarding her treatment with Accutane and have answered those questions to the best of
my ability.
Prescriber Signature: ______________________________ Date:__________________
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31
INFORMED CONSENT/PATIENT AGREEMENT (FOR ALL PATIENTS):
To be completed by patient (parent or guardian if patient is under age 18) and signed by the prescriber.
Read each item below and initial in the space provided if you understand each item and agree to follow
your prescriber’s instructions. A parent or guardian of a patient under age 18 must also read and
understand each item before signing the agreement.
Do not sign this agreement and do not take Accutane if there is anything that you do not
understand about all the information you have received about using Accutane.
1. I, ____________________________________________________________,
(Patient’s Name)
understand that Accutane is a medicine used to treat severe nodular acne that cannot be cleared up
by any other acne treatments, including antibiotics. In severe nodular acne, many red, swollen,
tender lumps form in the skin. If untreated, severe nodular acne can lead to permanent scars.
Initials: ______
2. My prescriber has told me about my choices for treating my acne.
Initials: ______
3. I understand that there are serious side effects that may happen while I am taking Accutane. These
have been explained to me. These side effects include serious birth defects in babies of pregnant
females. (Note: There is a second Informed Consent form for female patients concerning birth
defects.)
Initials: ______
4. I understand that some patients, while taking Accutane or soon after stopping Accutane, have
become depressed or developed other serious mental problems. Symptoms of these problems
include sad, “anxious” or empty mood, irritability, anger, loss of pleasure or interest in social or
sports activities, sleeping too much or too little, changes in weight or appetite, school or work
performance going down, or trouble concentrating. Some patients taking Accutane have had
thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some
people tried to end their own lives. And some people have ended their own lives. There were
reports that some of these people did not appear depressed. There have been reports of patients on
Accutane becoming aggressive or violent. No one knows if Accutane caused these behaviors or if
they would have happened even if the person did not take Accutane. Some people have had other
signs of depression while taking Accutane (see #7 below).
Initials: ______
5. Before I start taking Accutane, I agree to tell my prescriber if, to the best of my knowledge, I have
ever had symptoms of depression (see #7 below), been psychotic, attempted suicide, had any other
mental problems, or take medicine for any of these problems. Being psychotic means having a loss
of contact with reality, such as hearing voices or seeing things that are not there.
Initials: ______
This label may not be the latest approved by FDA.
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32
6. Before I start taking Accutane, I agree to tell my prescriber if, to the best of my knowledge, anyone
in my family has ever had symptoms of depression, been psychotic, attempted suicide, or had any
other serious mental problems.
Initials: ______
7. Once I start taking Accutane, I agree to stop using Accutane and tell my prescriber right away if
any of the following happen. I:
• Start to feel sad or have crying spells
• Lose interest in activities I once enjoyed
• Sleep too much or have trouble sleeping
• Become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of
violence)
• Have a change in my appetite or body weight
• Have trouble concentrating
• Withdraw from my friends or family
• Feel like I have no energy
• Have feelings of worthlessness or inappropriate guilt
• Start having thoughts about hurting myself or taking my own life (suicidal thoughts)
Initials: ______
8. I agree to return to see my prescriber every month I take Accutane to get a new prescription
for Accutane, to check my progress, and to check for signs of side effects.
Initials: ______
9. Accutane will be prescribed just for me—I will not share Accutane with other people because it
may cause serious side effects, including birth defects.
Initials: ______
10. I will not give blood while taking Accutane or for 1 month after I stop taking Accutane. I
understand that if someone who is pregnant gets my donated blood, her baby may be exposed to
Accutane and may be born with serious birth defects.
Initials: ______
11. I have read the Patient Product Information, Important Information Concerning Your Treatment
with Accutane (isotretinoin), and other materials my provider gave me containing important
safety information about Accutane. I understand all the information I received.
Initials: ______
12. My prescriber and I have decided I should take Accutane. I understand that each of my Accutane
prescriptions must have a yellow self-adhesive Accutane Qualification Sticker on it. I understand
that I can stop taking Accutane at any time. I agree to tell my prescriber if I stop taking Accutane.
Initials: ______
I now authorize my prescriber ___________________________ to begin my treatment with Accutane.
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33
Patient Signature: __________________________________________ Date: _________
Parent/Guardian Signature (if under age 18): _____________________ Date: _________
Patient Name (print) ___________________________________
Patient Address ____________________________________ Telephone (___.___.___)
____________________________________
I have:
• fully explained to the patient, __________________, the nature and purpose of Accutane
treatment, including its benefits and risks
• given the patient the appropriate educational materials, Be Smart, Be Safe, Be Sure, for Accutane
and asked the patient if he/she has any questions regarding his/her treatment with Accutane
• answered those questions to the best of my ability
• placed the yellow self-adhesive Accutane Qualification Sticker on the prescription.
Prescriber Signature: ___________________________________ Date:______________
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For current labeling information, please visit https://www.fda.gov/drugsatfda
34
MEDICATION GUIDE
Read this Medication Guide every time you get a prescription or a refill for Accutane (ACK-u-tane).
There may be new information. This information does not take the place of talking with your
prescriber (doctor or other health care provider).
What is the most important information I should know about Accutane?
Accutane is used to treat a type of severe acne (nodular acne) that has not been helped by other
treatments, including antibiotics. However, Accutane can cause serious side effects. Before starting
Accutane, discuss with your prescriber how bad your acne is, the possible benefits of Accutane, and its
possible side effects, to decide if Accutane is right for you. Your prescriber will ask you to read and
sign a form or forms indicating you understand some of the serious risks of Accutane.
Possible serious side effects of taking Accutane include birth defects and mental disorders.
1. Birth defects. Accutane can cause birth defects (deformed babies) if taken by a pregnant
woman. It can also cause miscarriage (losing the baby before birth), premature (early) birth, or
death of the baby. Do not take Accutane if you are pregnant or plan to become pregnant while you
are taking Accutane. Do not get pregnant for 1 month after you stop taking Accutane. Also, if you
get pregnant while taking Accutane, stop taking it right away and call your prescriber.
All females should read the section in this Medication Guide "What are the important warnings for
females taking Accutane?"
2. Mental problems and suicide. Some patients, while taking Accutane or soon after stopping
Accutane, have become depressed or developed other serious mental problems. Symptoms of these
problems include sad, “anxious” or empty mood, irritability, anger, loss of pleasure or interest in
social or sports activities, sleeping too much or too little, changes in weight or appetite, school or
work performance going down, or trouble concentrating. Some patients taking Accutane have had
thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some
people tried to end their own lives. And some people have ended their own lives. There were
reports that some of these people did not appear depressed. There have been reports of patients on
Accutane becoming aggressive or violent. No one knows if Accutane caused these behaviors or if
they would have happened even if the person did not take Accutane.
All patients should read the section in this Medication Guide "What are the signs of mental
problems?"
For other possible serious side effects of Accutane, see "What are the possible side effects of
Accutane?" in this Medication Guide.
What are the important warnings for females taking Accutane?
You must not become pregnant while taking Accutane, or for 1 month after you stop taking Accutane.
Accutane can cause severe birth defects in babies of women who take it while they are pregnant, even
if they take Accutane for only a short time. There is an extremely high risk that your baby will be
deformed or will die if you are pregnant while taking Accutane. Taking Accutane also increases the
chance of miscarriage and premature births.
Female patients will not get their first prescription for Accutane unless there is proof they have had 2
negative pregnancy tests. The first test must be done when your prescriber decides to prescribe
Accutane. The second pregnancy test must be done during the first 5 days of the menstrual period right
before starting Accutane therapy, or as instructed by your prescriber. Each month of treatment, you
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
35
must have a negative result from a urine or serum pregnancy test. Female patients cannot get another
prescription for Accutane unless there is proof that they have had a negative pregnancy test.
A yellow self-adhesive Accutane Qualification Sticker on your prescription indicates to the pharmacist
that you are qualified by your prescriber to get Accutane.
While you are taking Accutane, you must use effective birth control. You must use 2 separate
effective forms of birth control at the same time for at least 1 month before starting Accutane, while
you take it, and for 1 month after you stop taking it. You can either discuss effective birth control
methods with your prescriber or go for a free visit to discuss birth control with another physician or
family planning expert. Your prescriber can arrange this free visit, which will be paid for by the
manufacturer.
You must use 2 separate forms of effective birth control because any method, including birth control
pills and sterilization, can fail. There are only 2 reasons you would not need to use 2 separate methods
of effective birth control:
1. You have had your womb removed by surgery (a hysterectomy).
2. You are absolutely certain you will not have genital-to-genital sexual contact with a male before,
during, and for 1 month after Accutane treatment.
If you have sex at any time without using 2 forms of effective birth control, get pregnant, or miss
your period, stop using Accutane and call your prescriber right away.
All patients should read the rest of this Medication Guide.
What are the signs of mental problems?
Tell your prescriber if, to the best of your knowledge, you or someone in your family has ever had any
mental illness, including depression, suicidal behavior, or psychosis. Psychosis means a loss of contact
with reality, such as hearing voices or seeing things that are not there. Also, tell your prescriber if you
take medicines for any of these problems.
Stop using Accutane and tell your provider right away if you:
• Start to feel sad or have crying spells
• Lose interest in activities you once enjoyed
• Sleep too much or have trouble sleeping
• Become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of
violence)
• Have a change in your appetite or body weight
• Have trouble concentrating
• Withdraw from your friends or family
• Feel like you have no energy
• Have feelings of worthlessness or inappropriate guilt
• Start having thoughts about hurting yourself or taking your own life (suicidal thoughts)
What is Accutane?
Accutane is used to treat the most severe form of acne (nodular acne) that cannot be cleared up by any
other acne treatments, including antibiotics. In severe nodular acne, many red, swollen, tender lumps
form in the skin. These can be the size of pencil erasers or larger. If untreated, nodular acne can lead to
permanent scars. However, because Accutane can have serious side effects, you should talk with your
prescriber about all of the possible treatments for your acne, and whether Accutane’s possible benefits
outweigh its possible risks.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
36
Who should not take Accutane?
• Do not take Accutane if you are pregnant, plan to become pregnant, or become pregnant
during Accutane treatment. Accutane causes severe birth defects. All females should read the
section “What are the important warnings for females taking Accutane?” for more information and
warnings about Accutane and pregnancy.
• Do not take Accutane unless you completely understand its possible risks and are willing to follow
all of the instructions in this Medication Guide.
Tell your prescriber if you or someone in your family has had any kind of mental problems, asthma,
liver disease, diabetes, heart disease, osteoporosis (bone loss), weak bones, anorexia nervosa (an eating
disorder where people eat too little), or any other important health problems. Tell your prescriber about
any food or drug allergies you have had in the past. These problems do not necessarily mean you
cannot take Accutane, but your prescriber needs this information to discuss if Accutane is right for
you.
How should I take Accutane?
• You will get no more than a 30-day supply of Accutane at a time, to be sure you check in with your
prescriber each month to discuss side effects.
• Your prescription should have a special yellow self-adhesive sticker attached to it. The sticker is
YELLOW. If your prescription does not have this yellow self-adhesive sticker, call your prescriber.
The pharmacy should not fill your prescription unless it has the yellow self-adhesive sticker.
• The amount of Accutane you take has been specially chosen for you and may change during
treatment.
• You will take Accutane 2 times a day with a meal, unless your prescriber tells you otherwise.
Swallow your Accutane capsules with a full glass of liquid. This will help prevent the medication
inside the capsule from irritating the lining of your esophagus (connection between mouth and
stomach). For the same reason, do not chew or suck on the capsule.
• If you miss a dose, just skip that dose. Do not take 2 doses the next time.
• You should return to your prescriber as directed to make sure you don’t have signs of serious side
effects. Because some of Accutane’s serious side effects show up in blood tests, some of these
visits may involve blood tests (monthly visits for female patients should always include a urine or
serum pregnancy test).
What should I avoid while taking Accutane?
• Do not get pregnant while taking Accutane. See “What is the most important information I should
know about Accutane?” and “What are the important warnings for females taking Accutane?”
• Do not breast feed while taking Accutane and for 1 month after stopping Accutane. We do not
know if Accutane can pass through your milk and harm the baby.
• Do not give blood while you take Accutane and for 1 month after stopping Accutane. If someone
who is pregnant gets your donated blood, her baby may be exposed to Accutane and may be born
with birth defects.
• Do not take vitamin A supplements. Vitamin A in high doses has many of the same side effects as
Accutane. Taking both together may increase your chance of getting side effects.
• Do not have cosmetic procedures to smooth your skin, including waxing, dermabrasion, or
laser procedures, while you are using Accutane and for at least 6 months after you stop.
Accutane can increase your chance of scarring from these procedures. Check with your prescriber
for advice about when you can have cosmetic procedures.
• Avoid sunlight and ultraviolet lights as much as possible. Tanning machines use ultraviolet
lights. Accutane may make your skin more sensitive to light.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
37
• Do not use birth control pills that do not contain estrogen (“minipills”). They may not work
while you take Accutane. Ask your prescriber or pharmacist if you are not sure what type you are
using.
• Talk with your doctor if you plan to take other drugs or herbal products. This is especially
important for patients using birth control pills and other hormonal types of birth control because
the birth control may not work as effectively if you are taking certain drugs or herbal products. You
should not take the herbal supplement St. John’s Wort because this herbal supplement may make
birth control pills not work as effectively.
• Talk with your doctor if you are currently taking an oral or injected corticosteroid or
anticonvulsant (seizure) medication prior to using Accutane. These drugs may weaken your
bones.
• Do not share Accutane with other people. It can cause birth defects and other serious health
problems.
• Do not take Accutane with antibiotics unless you talk to your prescriber. For some antibiotics,
you may have to stop taking Accutane until the antibiotic treatment is finished. Use of both drugs
together can increase the chances of getting increased pressure in the brain.
What are the possible side effects of Accutane?
Accutane has possible serious side effects
• Accutane can cause birth defects, premature births, and death in babies whose mothers took
Accutane while they were pregnant. See “What is the most important information I should know
about Accutane?” and “What are the important warnings for females taking Accutane?”
• Serious mental health problems. See “What is the most important information I should know
about Accutane?”
• Serious brain problems. Accutane can increase the pressure in your brain. This can lead to
permanent loss of sight, or in rare cases, death. Stop taking Accutane and call your prescriber right
away if you get any of these signs of increased brain pressure: bad headache, blurred vision,
dizziness, nausea, or vomiting. Also, some patients taking Accutane have had seizures
(convulsions) or stroke.
• Abdomen (stomach area) problems. Certain symptoms may mean that your internal organs are
being damaged. These organs include the liver, pancreas, bowel (intestines), and esophagus
(connection between mouth and stomach). If your organs are damaged, they may not get better
even after you stop taking Accutane. Stop taking Accutane and call your prescriber if you get
severe stomach, chest or bowel pain, trouble swallowing or painful swallowing, new or worsening
heartburn, diarrhea, rectal bleeding, yellowing of your skin or eyes, or dark urine.
• Bone and muscle problems. Accutane may affect bones, muscles, and ligaments and cause pain in
your joints or muscles. Tell your prescriber if you plan vigorous physical activity during treatment
with Accutane. Tell your prescriber if you develop pain, particularly back pain or joint pain. There
are reports that some patients have had stunted growth after taking Accutane for acne as directed.
There are also some reports of broken bones or reduced healing of broken bones after taking
Accutane for acne as directed. No one knows if taking Accutane for acne will affect your bones. If
you have a broken bone, tell your provider that you are taking Accutane. Muscle weakness with or
without pain can be a sign of serious muscle damage. If this happens, stop taking Accutane and call
your prescriber right away.
• Hearing problems. Some people taking Accutane have developed hearing problems. It is possible
that hearing loss can be permanent. Stop using Accutane and call your prescriber if your hearing
gets worse or if you have ringing in your ears.
• Vision problems. While taking Accutane you may develop a sudden inability to see in the dark, so
driving at night can be dangerous. This condition usually clears up after you stop taking Accutane,
but it may be permanent. Other serious eye effects can occur. Stop taking Accutane and call your
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
38
prescriber right away if you have any problems with your vision or dryness of the eyes that is
painful or constant.
• Lipid (fats and cholesterol in blood) problems. Many people taking Accutane develop high
levels of cholesterol and other fats in their blood. This can be a serious problem. Return to your
prescriber for blood tests to check your lipids and to get any needed treatment. These problems
generally go away when Accutane treatment is finished.
• Allergic reactions. In some people, Accutane can cause serious allergic reactions. Stop taking
Accutane and get emergency care right away if you develop hives, a swollen face or mouth, or
have trouble breathing. Stop taking Accutane and call your prescriber if you develop a fever, rash,
or red patches or bruises on your legs.
• Signs of other possibly serious problems. Accutane may cause other problems. Tell your
prescriber if you have trouble breathing (shortness of breath), are fainting, are very thirsty or
urinate a lot, feel weak, have leg swelling, convulsions, slurred speech, problems moving, or any
other serious or unusual problems. Frequent urination and thirst can be signs of blood sugar
problems.
Serious permanent problems do not happen often. However, because the symptoms listed above may
be signs of serious problems, if you get these symptoms, stop taking Accutane and call your prescriber.
If not treated, they could lead to serious health problems. Even if these problems are treated, they may
not clear up after you stop taking Accutane.
Accutane has less serious possible side effects
The common less serious side effects of Accutane are dry skin, chapped lips, dry eyes, and dry nose
that may lead to nosebleeds. People who wear contact lenses may have trouble wearing them while
taking Accutane and after therapy. Sometimes, people’s acne may get worse for a while. They should
continue taking Accutane unless told to stop by their prescriber.
These are not all of Accutane’s possible side effects. Your prescriber or pharmacist can give you more
detailed information that is written for health care professionals.
This Medication Guide is only a summary of some important information about Accutane. Medicines
are sometimes prescribed for purposes other than those listed in a Medication Guide. If you have any
concerns or questions about Accutane, ask your prescriber. Do not use Accutane for a condition for
which it was not prescribed.
Active Ingredient: Isotretinoin.
Inactive Ingredients: beeswax, butylated hydroxyanisole, edetate disodium, hydrogenated soybean oil
flakes, hydrogenated vegetable oil, and soybean oil. Gelatin capsules contain glycerin and parabens
(methyl and propyl), with the following dye systems: 10 mg — iron oxide (red) and titanium dioxide;
20 mg — FD&C Red No. 3, FD&C Blue No. 1, and titanium dioxide; 40 mg — FD&C Yellow No. 6,
D&C Yellow No. 10, and titanium dioxide.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Rx only
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
39
xxxxxxxx-xxxx
Revised: Month Year
Copyright © 2000-xxxx by Roche Laboratories Inc. All rights reserved.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
40
((PPP logo))
((Roche Pharmaceuticals logo))
System to Manage Accutane Related Teratogenicity™
S.M.A.R.T.™ Guide
to Best Practices
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For current labeling information, please visit https://www.fda.gov/drugsatfda
41
Table of Contents
Facts About Accutane® (isotretinoin)
Guidelines for Successful Outcomes 1
The S.M.A.R.T.™ Guide to Best Practices 1
About Accutane
2
Risk Management Program
Accutane Pregnancy Prevention and Risk Management Program
3
S.M.A.R.T. Procedures
6
S.M.A.R.T. Outcomes
6
How to Use the PPP
Educating Female Patients
7
Obtaining Consent
7
Reinforcing Education
8
Female Qualification Criteria
Pregnancy Testing
9
Assessing Reproductive Health and Contraception Methods Before Prescribing
Accutane
10
Confidential Contraception Counseling Line 11
Educating Patients
11
Encouraging Patient Compliance
11
Contraception During Accutane Therapy
12
Assessing Patient Misinformation About Contraception
12
Accessing Contraception Information
12
Discussing the Role of the Sexual Partner
12
Selecting Contraception
Primary Forms of Contraception
13
Secondary Forms of Contraception 14
Emergency Contraception
15
Informed Consent
15
The Accutane Survey 16
Accutane Product Information
18
Reordering Supplies 18
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42
Accutane® (isotretinoin) is indicated for the treatment of severe recalcitrant nodular
acne. In addition, for female patients of childbearing potential, Accutane is indicated only
for those females who are not pregnant (see CONTRAINDICATIONS AND
WARNINGS).
Guidelines
for Successful Outcomes
Important Facts About Accutane
• Accutane is highly teratogenic.
• Treatment with Accutane during pregnancy is contraindicated. Female patients should
not be pregnant or become pregnant while on Accutane therapy and for 1 month
thereafter.
• Fetal exposure to isotretinoin may result in life-threatening congenital abnormalities.
The S.M.A.R.T.™ Guide to Best Practices
This guide has been developed to assist you in fulfilling
the requirements for Accutane pregnancy prevention
risk management. Please refer to the Accutane CONTRAINDICATIONS and
WARNINGS and the PRECAUTIONS of the Accutane Product Information.
The following are the CONTRAINDICATIONS and WARNINGS from the approved
labeling for Accutane:
((Boxed Copy))
CONTRAINDICATIONS AND WARNINGS: Accutane must not be used by females
who are pregnant. Although not every fetus exposed to Accutane has resulted in a
deformed child, there is an extremely high risk that a deformed infant can result if
pregnancy occurs while taking Accutane in any amount even for short periods of time.
Potentially any fetus exposed during pregnancy can be affected. Presently, there are no
accurate means of determining, after Accutane exposure, which fetus has been affected
and which fetus has not been affected.
Major human fetal abnormalities related to Accutane administration in females have been
documented. There is an increased risk of spontaneous abortion. In addition, premature
births have been reported.
Documented external abnormalities include: skull abnormality; ear abnormalities
(including anotia, micropinna, small or absent external auditory canals); eye
abnormalities (including microphthalmia), facial dysmorphia; cleft palate. Documented
internal abnormalities include: CNS abnormalities (including cerebral abnormalities,
cerebellar malformation, hydrocephalus, microcephaly, cranial nerve deficit);
cardiovascular abnormalities; thymus gland abnormality; parathyroid hormone
deficiency. In some cases death has occurred with certain of the abnormalities previously
noted.
Cases of IQ scores less than 85 with or without obvious CNS abnormalities have also
been reported.
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43
Accutane is contraindicated in females of childbearing potential unless the patient meets
all of the following conditions:
• Must NOT be pregnant or breast feeding.
• Must be capable of complying with the mandatory contraceptive measures required for
Accutane therapy and understand behaviors associated with an increased risk of
pregnancy.
• Must be reliable in understanding and carrying out instructions.
Accutane must be prescribed under the System to Manage Accutane Related
Teratogenicity™ (S.M.A.R.T.™).
To prescribe Accutane, the prescriber must obtain a supply of yellow self-adhesive
Accutane Qualification Stickers. To obtain these stickers:
1) Read the booklet entitled System to Manage Accutane Related Teratogenicity
(S.M.A.R.T.) Guide to Best Practices
2) Sign and return the completed S.M.A.R.T. Letter of Understanding containing the
following Prescriber Checklist:
• I know the risk and severity of fetal injury/birth defects from Accutane
• I know how to diagnose and treat the various presentations of acne
• I know the risk factors for unplanned pregnancy and the effective measures for
avoidance of unplanned pregnancy
• It is the informed patient’s responsibility to avoid pregnancy during Accutane therapy
and for 1 month after stopping Accutane. To help patients have the knowledge and tools
to do so: Before beginning treatment of female patients with Accutane I will refer for
expert, detailed pregnancy prevention counseling and prescribing, reimbursed by the
manufacturer, OR I have the expertise to perform this function and elect to do so
• I understand, and will properly use throughout the Accutane treatment course, the
S.M.A.R.T. procedures for Accutane, including monthly pregnancy avoidance
counseling, pregnancy testing and use of the yellow self-adhesive Accutane Qualification
Stickers
3) To use the yellow self-adhesive Accutane Qualification Sticker: Accutane should not
be prescribed or dispensed to any patient (male or female) without a yellow self-adhesive
Accutane Qualification Sticker.
For female patients, the yellow self-adhesive Accutane Qualification Sticker signifies that
she:
• Must have had 2 negative urine or serum pregnancy tests with a sensitivity of at least
25 mIU/mL before receiving the initial Accutane prescription. The first test (a screening
test) is obtained by the prescriber when the decision is made to pursue qualification of the
patient for Accutane. The second pregnancy test (a confirmation test) should be done
during the first 5 days of the menstrual period immediately preceding the beginning of
Accutane therapy. For patients with amenorrhea, the second test should be done at least
11 days after the last act of unprotected sexual intercourse (without using 2 effective
forms of contraception). Each month of therapy, the patient must have a negative result
from a urine or serum pregnancy test.
A pregnancy test must be repeated every month prior to the female patient receiving each
prescription.
• Must have selected and have committed to use 2 forms of effective contraception
simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is
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44
the chosen method, or the patient has undergone a hysterectomy. Patients must use 2
forms of effective contraception for at least 1 month prior to initiation of Accutane
therapy, during Accutane therapy, and for 1 month after discontinuing Accutane therapy.
Counseling about contraception and behaviors associated with an increased risk of
pregnancy must be repeated on a monthly basis.
Effective forms of contraception include both primary and secondary forms of
contraception. Primary forms of contraception include: tubal ligation, partner’s
vasectomy, intrauterine devices, birth control pills, and
topical/injectable/implantable/insertable hormonal birth control products. Secondary
forms of contraception include diaphragms, latex condoms, and cervical caps; each must
be used with a spermicide.
Any birth control method can fail. Therefore, it is critically important that women of
childbearing potential use 2 effective forms of contraception simultaneously. A drug
interaction that decreases effectiveness of hormonal contraceptives has not been entirely
ruled out for Accutane. Although hormonal contraceptives are highly effective, there
have been reports of pregnancy from women who have used oral contraceptives, as well
as topical/injectable/implantable/insertable hormonal birth control products. These
reports occurred while these patients were taking Accutane. These reports are more
frequent for women who use only a single method of contraception. Patients must receive
written warnings about the rates of possible contraception failure (included in patient
education kits).
Prescribers are advised to consult the package insert of any medication administered
concomitantly with hormonal contraceptives, since some medications may decrease the
effectiveness of these birth control products. Patients should be prospectively cautioned
not to self-medicate with the herbal supplement St. John’s Wort because a possible
interaction has been suggested with hormonal contraceptives based on reports of
breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort.
Pregnancies have been reported by users of combined hormonal contraceptives who also
used some form of St. John's Wort (see precautions).
• Must have signed a Patient Information/Consent form that contains warnings about the
risk of potential birth defects if the fetus is exposed to isotretinoin.
• Must have been informed of the purpose and importance of participating in the
Accutane Survey and have been given the opportunity to enroll (see PRECAUTIONS).
The yellow self-adhesive Accutane Qualification Sticker documents that the female
patient is qualified, and includes the date of qualification, patient gender, cut-off date for
filling the prescription, and up to a 30-day supply limit with no refills.
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45
These yellow self-adhesive Accutane Qualification Stickers should also be used for male
patients:
Table 1.
Use of Pregnancy Tests and Accutane Qualification Stickers for Patients
Patient Type Pregnancy
Qualification
Accutane
Dispense Within
Test Required Date
Qualification Sticker 7 Days of
Necessary
Qualification Date
All Males
No
Date
Yes
Yes
Prescription
Written
Females of
Yes
Date Sample
Yes
Yes
Childbearing
Taken for
Confirmatory
Potential
Negative
Pregnancy
Test
Females*
No
Date
Yes
Yes
Not of
Prescription
Childbearing
Written
Potential
If a pregnancy does occur during treatment of a woman with Accutane, the prescriber and
patient should discuss the desirability of continuing the pregnancy. Prescribers are
strongly encouraged to report all cases of pregnancy to Roche @ 1-800-526-6367 where
a Roche Pregnancy Prevention Program Specialist will be available to discuss Roche
pregnancy information, or prescribers may contact the Food and Drug Administration
MedWatch Program @ 1-800-FDA-1088.
Accutane should be prescribed only by prescribers who have demonstrated special
competence in the diagnosis and treatment of severe recalcitrant nodular acne, are
experienced in the use of systemic retinoids, have read the S.M.A.R.T. Guide to Best
Practices, signed and returned the completed S.M.A.R.T. Letter of Understanding, and
obtained yellow self-adhesive Accutane Qualification Stickers. Accutane should not be
prescribed or dispensed without a yellow self-adhesive Accutane Qualification Sticker.
INFORMATION FOR PHARMACISTS:
ACCUTANE MUST ONLY BE DISPENSED:
• IN NO MORE THAN A 30-day SUPPLY
• ONLY ON PRESENTATION OF AN ACCUTANE PRESCRIPTION WITH A
YELLOW SELF-ADHESIVE ACCUTANE QUALIFICATION STICKER
• WITHIN 7 DAYS OF THE QUALIFICATION DATE
• REFILLS REQUIRE A NEW PRESCRIPTION WITH A YELLOW SELF-
ADHESIVE ACCUTANE QUALIFICATION STICKER
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46
• NO TELEPHONE OR COMPUTERIZED PRESCRIPTIONS ARE PERMITTED.
AN ACCUTANE MEDICATION GUIDE MUST BE GIVEN TO THE PATIENT
EACH TIME ACCUTANE IS DISPENSED, AS REQUIRED BY LAW. THIS
ACCUTANE MEDICATION GUIDE IS AN IMPORTANT PART OF THE RISK
MANAGEMENT PROGRAM FOR THE PATIENT.
*Females who have had a hysterectomy or who are postmenopausal are not considered to
be of childbearing potential.
((End Boxed Copy))
Please see the enclosed complete product information, including
CONTRAINDICATIONS AND WARNINGS, on the inside back cover.
((Inside back cover))
To Order Supplies
After you send your S.M.A.R.T. Letter of Understanding and have received your initial
materials, you can reorder through the phone line.
Services available through the phone line
After you press 1 to select Accutane (isotretinoin), the following seven branches are
available:
1. Branch One - Prescribers
• Inquire about the S.M.A.R.T. Program and obtain Accutane Qualification Stickers
2. Branch Two - Pharmacists
• Inquire about the S.M.A.R.T. criteria for dispensing Accutane
3. Branch Three - Prescribers, office staff, pharmacists
• Order materials for the S.M.A.R.T. and Accutane Pregnancy Prevention Programs
• Inquiries about the status of past orders
4. Branch Four - Contraception counselors
• Submit reimbursement requests
• Inquiries about the status of past reimbursement requests
5. Branch Five - Prescribers
• Hear recorded information about Accutane
6. Branch Six
• Listen again to the Accutane menu options
7. Branch Seven
• Return to the main menu
To place an order by phone:
• Dial 1-800-93-ROCHE (1-800-937-6243)
• Press 1 for Accutane
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47
• Follow the on-line instructions to access Branch 3
• When you have accessed Branch 3 you will be immediately connected with a
representative who will process your order. Just give the representative your name and
address. Service representatives are available to assist you from 9 am to 7 pm (EST). At
all other times, please leave your name and telephone number. A representative will
return your call the next business day.
Please allow 2 to 3 weeks for delivery.
Please see the enclosed complete product information, including
CONTRAINDICATIONS AND WARNINGS, on the inside back cover.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
48
((Back Cover))
((PPP logo))
Where to find information.
((Table, 1st column))
Female Qualification Criteria
Must have had 2 negative urine or serum pregnancy tests with a sensitivity
of at least 25 mIU/mL before receiving the initial Accutane (isotretinoin) prescription.
The first test (a screening test) is obtained by the prescriber when the decision is made to
pursue qualification of the patient for Accutane. The second pregnancy test (a
confirmation test) should be done during the first 5 days of the menstrual period
immediately preceding the beginning of Accutane therapy. For patients with amenorrhea,
the second test should be done at least 11 days after the last act of unprotected sexual
intercourse (without using 2 effective forms of contraception). Each month of therapy,
the patient must have a negative result from a urine or serum pregnancy test. A pregnancy
test must be repeated every month prior to the female patient receiving each prescription.
Must have selected and have committed to use 2 forms of effective contraception
simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is
the chosen method, or the patient has undergone a hysterectomy. Patients must use 2
forms of effective contraception for at least 1 month prior to initiation of Accutane
therapy, during Accutane therapy, and for 1 month following discontinuation of Accutane
therapy. Counseling about contraception and behaviors associated with an increased risk
of pregnancy must be repeated on a monthly basis.
Must have signed a Patient Information/Consent form that contains
warnings about the risk of potential birth defects if the fetus is exposed
to isotretinoin.
Must have been informed of the purpose and importance of participating
in the Accutane Survey and have been given the opportunity to enroll.
((Table, 2nd column))
Find the information
S.M.A.R.T. Guide to Best Practices
Be Smart, Be Safe, Be Sure Accutane Pregnancy Prevention and Risk Management
Program for Women
S.M.A.R.T. Guide to Best Practices
Be Smart, Be Safe, Be Sure Accutane Pregnancy Prevention and Risk Management
Program for Women
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49
S.M.A.R.T. Guide to Best Practices
Be Smart, Be Safe, Be Sure Accutane Pregnancy Prevention and Risk Management
Program for Women
S.M.A.R.T. Guide to Best Practices
Be Smart, Be Safe, Be Sure Accutane Pregnancy Prevention and Risk Management
Program for Women
((Table, 3rd column))
In Section
S.M.A.R.T. Letter of Understanding, inside back cover
Patient Product Information, Section 1: Education
Contraception Counseling Referral Form, Section 1: Education
Patient Information/Consent Form, Section 2: Consent
Patient Qualification Form for Pregnancy Prevention and Contraception Compliance,
Section 2: Consent
Preventing Pregnancy — A Guide to Contraception, Section 3: Education Reinforcement
S.M.A.R.T. Letter of Understanding, inside back cover
Contraception Counseling Referral Form, Section 1: Education
Patient Product Information, Section 1: Education
Patient Information/Consent Form, Section 2: Consent
Patient Qualification Form for Pregnancy Prevention and Contraception Compliance,
Section 2: Consent
Preventing Pregnancy — A Guide to Contraception, Section 3: Education Reinforcement
S.M.A.R.T. Letter of Understanding, inside back cover
Patient Information/Consent Form, Section 2: Consent
Patient Qualification Form for Pregnancy Prevention and Contraception Compliance,
Section 2: Consent
S.M.A.R.T. Letter of Understanding, inside back cover
Accutane Survey Enrollment Form, Section 2: Consent
Patient Information/Consent Form, Section 2: Consent
Patient Qualification Form for Pregnancy Prevention and Contraception Compliance,
Section 2: Consent
Preventing Pregnancy — A Guide to Contraception, Section 3: Education Reinforcement
References: 1. Dai WS, Hsu M-A, Itri LM. Safety of pregnancy after discontinuation of
isotretinoin. Arch Dermatol. 1989;125:362-365. 2. Trussell J, Card JJ, Rowland Hogue
CJ. Adolescent sexual behavior, pregnancy, and childbearing. In: Hatcher RA, Trussell J,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
50
Steward F, et al, eds. Contraceptive Technology. 17th ed. New York, NY: Ardent Media,
Inc.; 1998:701-744. 3. Brunton SA. Physicians as patient teachers. West J Med.
1984;141:855-860. 4. Meichenbaum D, Turk DC. Facilitating Treatment Adherence.
New York, NY: Plenum Press; 1987: chap 2-5. 5. Terry K. Telling patients more will
save you time. Med Econ. July 15, 1994;40-52. 6. Lipkin M. The medical interview and
related skills. In: Branch WT Jr, ed. Office Practice of Medicine. 2nd ed. Philadelphia,
Pa: WB Saunders Co; 1987:1287-1306. 7. Planned Parenthood. Emergency
Contraception. Available at http://www.plannedparenthood.org/ec/html. Accessed
February 24, 2000.
((Accutane logo))
Please see the enclosed complete product information, including
CONTRAINDICATIONS AND WARNINGS, on the inside back cover.
((Roche logo and address))
Copyright © 2002 by Roche Laboratories Inc. All rights reserved.
PRINTED IN USA
PLANDEX 101002
18-002-101-010-1102
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51
((Inside Pages))
((Tab copy))
Facts About Accutane
((PPP logo))
About Accutane
Accutane is a powerful agent used to treat severe recalcitrant nodular acne. Accutane
belongs to a class of drugs known as retinoids, commonly understood to include all
natural and synthetic analogues of vitamin A. Therapy with Accutane should
not be undertaken before conventional treatment has been tried first, including the use of
systemic antibiotic therapy, and the patient has been fully counseled about the warnings
and precautions in the Accutane package insert.
Accutane is teratogenic and must not be used by pregnant women. Women should not
become pregnant within 1 month after discontinuing Accutane therapy. A patient who
becomes pregnant during treatment should stop taking Accutane and immediately contact
her prescriber.
Accutane use is associated with other potentially serious adverse events, as well as more
frequent, but less serious side effects. More frequent, less serious side effects include
cheilitis, dry skin, skin fragility, pruritus, epistaxis, dry nose and dry mouth, and
conjunctivitis.
Adverse Event Warnings include psychiatric disorders* (depression, psychosis and,
rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent
behaviors); pseudotumor cerebri; pancreatitis; hyperlipidemia; hearing impairment*;
hepatotoxicity; inflammatory bowel disease; skeletal changes† (bone mineral density
changes, hyperostosis, premature epiphyseal closure); visual impairment (corneal
opacities, decreased night vision).
Patients should be reminded to read the Medication Guide, distributed by the pharmacist
at the time the Accutane is dispensed.
Pregnancy After Accutane Therapy
The terminal elimination half-life of Accutane varies but is generally within 10 to 20
hours. The elimination half-life of one of the isotretinoin metabolites, 4-oxoisotretinoin,
is approximately 25 hours. Since plasma elimination is host dependent, prescribers
should warn patients not to become pregnant for 1 month posttreatment. Women who
become pregnant during this month should be counseled as to the outcome data. In 1989,
Dai et al1 reported the results of an epidemiologic study of pregnancies that occurred in
women who conceived after discontinuing Accutane. They studied women from 5 days to
more than 60 days between their last dose of isotretinoin and conception. The incidence
of birth defects in former Accutane patients was not significantly different from the rate
in the general population.
Accutane is found in the semen of male patients taking Accutane, but the amount
delivered to a female partner would be about 1 million times lower than an oral dose of
40 mg. While the no-effect limit for isotretinoin-induced embryopathy is unknown, 20
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52
years of postmarketing reports include 4 with isolated defects compatible with features of
retinoid-exposed fetuses. None of these cases had the combination of malformations
characteristic of retinoid exposure, and all had other possible explanations for the defects
observed.
Birth Defects
There is an extremely high risk that a deformed infant will result
if pregnancy occurs while female patients are taking Accutane in any amount even for
short periods of time. Potentially any fetus exposed during pregnancy can be affected.
Not every fetus exposed to Accutane has resulted in a deformed child; however, there are
no accurate means of determining which fetus has been affected and which fetus has not
been affected.
When Accutane is taken during pregnancy, it has been associated with fetal
malformations, and there is an increased risk for spontaneous abortions, and premature
birth.
The following human fetal abnormalities have been documented:
External Abnormalities
Skull abnormality; ear abnormalities (including anotia, micropinna, small or absent
external auditory canals); eye abnormalities (including microphthalmia), facial
dysmorphia; cleft palate.
Internal Abnormalities
CNS abnormalities including cerebral abnormalities, cerebellar malformation,
hydrocephalus, microcephaly, cranial nerve deficit; cardiovascular abnormalities; thymus
gland abnormalities; parathyroid hormone deficiencies.
In some cases death has occurred with certain of the abnormalities noted.
*No mechanism of action has been established for these events.
†The use of Accutane in patients age 12 to 17 should be given careful consideration,
especially when a known metabolic or structural bone disease exists.
Please see the enclosed complete product information, including
CONTRAINDICATIONS AND WARNINGS, on the inside back cover.
((Baby Defect pictures 1))
((caption))
Line drawing represents the possible abnormalities of low-set deformed or absent ears,
wide-set eyes, depressed bridge of nose, enlarged head and small chin.
((Baby Defect pictures 2))
((caption))
Line drawing represents the possible abnormalities of the brain, heart, and thymus gland
that may occur.
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53
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
54
((callouts))
ear abnormalities
parathyroid hormone
deficiency
thymus gland abnormality
cardiovascular abnormalities
Accutane Pregnancy Prevention and Risk Management Program
The Accutane Pregnancy Prevention and Risk Management Program consists of the
System to Manage Accutane Related Teratogenicity™ (S.M.A.R.T.™) and the
Accutane® Pregnancy Prevention Program (PPP).
S.M.A.R.T. should be followed for prescribing Accutane with the goal of preventing fetal
exposure to isotretinoin.
The components of S.M.A.R.T. are:
1) The booklet entitled System to Manage Accutane Related Teratogenicity (S.M.A.R.T.)
Guide to Best Practices
2) The S.M.A.R.T. Letter of Understanding containing the Prescriber Checklist
3) A yellow self-adhesive Accutane Qualification Sticker to be affixed to your
prescription form
The following further describes each component:
1) The S.M.A.R.T. Guide to Best Practices includes: Accutane (isotretinoin) teratogenic
potential, information on pregnancy testing, specific information about effective
contraception, the limitations of contraceptive methods and behaviors associated with an
increased risk of contraceptive failure and pregnancy, the methods to evaluate pregnancy
risk, and the method to complete a qualified Accutane prescription.
2) The S.M.A.R.T. Letter of Understanding attests that Accutane prescribers understand
that Accutane is a teratogen, have read the S.M.A.R.T. Guide to Best Practices and
understand their responsibilities to minimize the risk of fetal exposure
to Accutane, and understand how to qualify female patients for an Accutane prescription
(see CONTRAINDICATIONS AND WARNINGS).
The Prescriber Checklist is a self-certification by potential Accutane prescribers:
• I know the risk and severity of fetal injury/birth defects from Accutane
• I know how to diagnose and treat the various presentations of acne
• I know the risk factors for unplanned pregnancy and the effective measures for
avoidance of unplanned pregnancy
• It is the informed patient’s responsibility to avoid pregnancy during Accutane therapy
and for 1 month after stopping Accutane. To help patients have the knowledge and tools
to do so: Before beginning treatment of female patients with Accutane I will refer for
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
55
expert, detailed pregnancy prevention counseling and prescribing, reimbursed by the
manufacturer, OR I have the expertise to perform this function and elect to do so
• I understand, and will properly use throughout the Accutane treatment course, the
S.M.A.R.T. procedures for Accutane, including monthly pregnancy avoidance
counseling, pregnancy testing and use of the yellow self-adhesive Accutane Qualification
Stickers
3) The yellow self-adhesive Accutane Qualification Sticker is documentation for the
dispensing pharmacist that the prescriber has qualified the female patient according to the
qualification criteria in the CONTRAINDICATIONS AND WARNINGS of the
approved package insert.
Prescribers must obtain yellow self-adhesive Accutane Qualification Stickers designed to
adhere to the center portion of the patient’s Accutane prescription (see sticker diagram
below). The yellow self-adhesive Accutane Qualification Stickers can only be obtained
by reading the S.M.A.R.T. Guide to Best Practices and signing and returning the
completed S.M.A.R.T. Letter of Understanding. Additional Accutane Qualification
Stickers can then be obtained by calling 1-800-93-ROCHE toll-free.
Pharmacists will have the option to verify the authorization for the yellow self-adhesive
Accutane Qualification Sticker by calling 1-800-93-ROCHE, but this step is not required.
Accutane prescriptions should not be filled more than 7 days after patient qualification.
The yellow self-adhesive Accutane Qualification Sticker should also be used on
prescriptions for male patients. Thus, ALL prescriptions for Accutane should have the
yellow self-adhesive sticker.
((Qualification Sticker and Rx pad art))
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For current labeling information, please visit https://www.fda.gov/drugsatfda
56
((Tab copy))
Risk Management Program
((PPP logo))
Qualifying Female Patients
Data support that there are key issues in identifying female patients for treatment with
Accutane: 1) identify patients whose acne could be effectively managed without
Accutane and avoid prescribing it for such patients; 2) identify those who are already
pregnant when you are considering Accutane; and 3) identify those who may not be
reliable in avoiding pregnancy for the required period before, during and after therapy.
The patient should understand that ultimately, it is her responsibility to avoid exposing an
unborn baby to Accutane. The patient must understand the critical responsibility she
assumes in electing to undertake therapy with Accutane and that any method of birth
control, apart from complete abstinence, can fail.
The prescriber must verify that each individual patient receives adequate counseling
about all her pregnancy prevention options (including abstinence) and that she knows
how to select and use 2 separate, effective contraceptive methods.
The qualification criteria for female patients are:
• Must have had 2 negative urine or serum pregnancy tests with a sensitivity of at least 25
mIU/mL before receiving the initial Accutane prescription. The first test (a screening
test) is obtained by the prescriber when the decision is made to pursue qualification of the
patient for Accutane. The second pregnancy test (a confirmation test) should be done
during the first 5 days of the menstrual period immediately preceding the beginning of
Accutane therapy. For patients with amenorrhea, the second test should be done at least
11 days after the last act of unprotected sexual intercourse (without using 2 effective
forms of contraception). Each month of therapy, the patient must have a negative result
from a urine or serum pregnancy test. A pregnancy test must be repeated every month
prior to the female patient receiving each prescription.
• Must have selected and have committed to use 2 forms of effective contraception
simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is
the chosen method, or the patient has undergone a hysterectomy. Patients must use 2
forms of effective contraception for at least 1 month prior to initiation of Accutane
therapy, during Accutane therapy, and for 1 month after discontinuing Accutane therapy.
Counseling about contraception and behaviors associated with an increased risk of
pregnancy must be repeated on a monthly basis.
Effective forms of contraception include both primary and secondary forms of
contraception. Primary forms of contraception include: tubal ligation, partner’s
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57
vasectomy, intrauterine devices, birth control pills, and topical/injectable/
implantable/insertable hormonal birth control products. Secondary forms of contraception
include diaphragms, latex condoms, and cervical caps; each must be used with a
spermicide.
Any birth control method can fail. Therefore, it is critically important that women of
childbearing potential use 2 effective forms of contraception simultaneously. A drug
interaction that decreases effectiveness of hormonal contraceptives has not been entirely
ruled out for Accutane (isotretinoin). Although hormonal contraceptives are highly
effective, there have been reports of pregnancy from women who have used oral
contraceptives, as well as topical/injectable/implantable/insertable hormonal birth control
products. These reports occurred while these patients were taking Accutane. These
reports are more frequent for women who use only a single method of contraception.
Patients must receive written warnings about the rates of possible contraception failure
(included in patient education kits).
Prescribers are advised to consult the package insert of any medication administered
concomitantly with hormonal contraceptives, since some medications may decrease the
effectiveness of these birth control products. Patients should be prospectively cautioned
not to self-medicate with the herbal supplement St. John’s Wort because a possible
interaction has been suggested with hormonal contraceptives based on reports of
breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort.
Pregnancies have been reported by users of combined hormonal contraceptives who also
used some form of St. John's Wort (see precautions).
• Must have signed a Patient Information/Consent form that contains warnings about the
risk of potential birth defects if the fetus is exposed to isotretinoin.
• Must have been informed of the purpose and importance of participating in the
Accutane Survey and have been given the opportunity to enroll (see PRECAUTIONS).
Reports indicate that 14% of the women who reported being pregnant during Accutane
therapy were pregnant at the time Accutane was initially prescribed and either did not
have a pregnancy test or did not wait for the results of the pregnancy test. Be sure to
establish negative pregnancy status at the time of the screening visit and BEFORE giving
the patient a prescription for Accutane.
Reports indicate that 12% of the women who reported being pregnant during Accutane
therapy became pregnant after obtaining and beginning Accutane therapy, but before
their next menses. Be sure to confirm negative pregnancy status during the first 5 days of
the normal menses immediately preceding the start of Accutane therapy (some
contraception methods, for example hormone implants, may cause amenorrhea. In that
case, the second test should be done at least 11 days after the last act of unprotected
sexual intercourse, ie, without using 2 separate effective forms of contraception).
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58
Reports indicate that 64% of the women who reported being pregnant during therapy had
not been able to avoid behavior that created a high risk of pregnancy. Pregnancy occurred
most often when only using one form of birth control. Continued monthly counseling is
critical to maintaining negative pregnancy status. Continued negative pregnancy status
must be confirmed by monthly pregnancy testing. Hysterectomy and reliable abstinence
are the only exceptions to the use of dual contraceptive methods. However, ALL female
patients MUST undergo monthly pregnancy testing in order to receive Accutane.
In a survey conducted in women in the United States, it was reported that approximately
50% of their pregnancies were unintended. Even the most widely used contraceptive, the
combination birth control
pill, has a 5% unintended pregnancy rate during the first year of use.
Please read this Guide carefully and use the Accutane Pregnancy Prevention Program
with EVERY female patient.
Qualification criteria continued on page 5.
Please see the enclosed complete product information, including
CONTRAINDICATIONS AND WARNINGS, on the inside back cover.
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59
((PPP logo))
S.M.A.R.T. Procedures
S.M.A.R.T. is described fully within the CONTRAINDICATIONS and WARNINGS and
the Precautions sections of the Accutane package insert. The following provides the
necessary steps prescribers must take to be in compliance with the
risk management components of the Accutane package insert.
To receive the first shipment of Accutane Qualification Stickers:
1. Read the S.M.A.R.T. Guide to Best Practices (enclosed).
2. Sign and return, in the postage paid envelope provided, the completed S.M.A.R.T.
Letter of Understanding (enclosed), which states:
• I know the risk and severity of fetal injury/birth defects from Accutane
• I know how to diagnose and treat the various presentations of acne
• I know the risk factors for unplanned pregnancy and the effective measures for
avoidance of unplanned pregnancy
• It is the informed patient’s responsibility to avoid pregnancy during Accutane
therapy and for 1 month after stopping Accutane. To help patients have the knowledge
and tools to do so: Before beginning treatment of female patients with Accutane I will
refer for expert, detailed pregnancy prevention counseling and prescribing, reimbursed by
the manufacturer, OR I have the expertise to perform this function and elect to do so
• I understand, and will properly use throughout the Accutane treatment course,
the S.M.A.R.T. procedures for Accutane, including monthly pregnancy avoidance
counseling, pregnancy testing and use of the yellow self-adhesive Accutane Qualification
Stickers
Additional Stickers can then be obtained as needed by calling 1-800-93-ROCHE.
Prior to writing the Accutane prescription:
Obtain screening and confirmation pregnancy tests for ALL female patients. Ensure each
female patient is qualified according to criteria identified in the contraindications and
warnings of the package insert.
Monthly visits:
1. Obtain a monthly pregnancy test for ALL female patients. Repeat counseling about
contraception and behaviors associated with an increased risk of pregnancy and
encourage women who have not yet enrolled in the Accutane Survey to do so.
2. Affix a yellow self-adhesive Accutane Qualification Sticker on each Accutane
prescription for both male and female patients; phoned, faxed, or electronic prescriptions
are not acceptable.
3. Prescribe no more than a 30-day supply of Accutane.
Roche supports an initial referral to a contraception counselor trained to provide family
planning services for contraceptive counseling should you feel that this is necessary. A
referral form is contained within the booklet, Be Smart, Be Safe, Be Sure™ Accutane®
Pregnancy Prevention and Risk Management Program for Women.
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60
S.M.A.R.T. Outcomes
To measure the progress of S.M.A.R.T., Roche will use several outcomes approaches.
Roche will continue to track how many women join the Accutane Survey, which is
conducted by SI International. Roche has committed to increasing enrollment of female
patients to 60% from 25-40% currently. We understand that this number will
be difficult to accomplish, and we therefore ask prescribers to remind and encourage
patients to join the Accutane Survey. An application form is contained inside both the
female patient booklet, Be Smart, Be Safe, Be Sure Accutane Pregnancy Prevention and
Risk Management Program for Women and in the Accutane blister pak.
Further, an independent audit of pharmacies will be performed to assess the use of the
Accutane Qualification Stickers. As part of the validation for this component, the audit
will be both retrospective and prospective in nature. The data collected will not be
identifiable to any specific prescriber or patient.
Please see the enclosed complete product information, including
CONTRAINDICATIONS AND WARNINGS, on the inside back cover.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
61
((PPP logo))
((Tab copy))
How to Use the PPP
Be Smart, Be Safe, Be Sure
Accutane Pregnancy Prevention and Risk Management Program for Women
The Accutane Pregnancy Prevention Program is a systematic approach to comprehensive
patient education about their responsibilities and includes education for contraception
compliance and reinforcement of educational messages. The PPP consists of information
on the risks and benefits of Accutane (isotretinoin), which is linked to the Accutane
Medication Guide.
Information for male and female patients is provided in separate booklets, called Be
Smart, Be Safe, Be Sure Accutane Pregnancy Prevention and Risk Management Program
for Women and Be Smart, Be Safe, Be Sure™ Accutane® Risk Management Program
for Men. Each booklet contains information on Accutane therapy, including precautions
and warnings, an Informed Consent/Patient Agreement form, and a toll-free line that
provides Accutane information in 13 languages.
How to Use the Be Smart, Be Safe, Be Sure Accutane Pregnancy Prevention and Risk
Management Program for Women
Educating Female Patients
Patient Product Information,
Important Information Concerning Your Treatment with Accutane® (isotretinoin)
Patient education material for Accutane that provides complete pregnancy warnings to
female patients, plus information about severe recalcitrant nodular acne and what to
expect with treatment, including warnings and precautions. The patient may refer to this
information throughout therapy.
((art))
Contraception Counseling Referral Program
Your patient may benefit from FREE expert contraception counseling; Roche will
reimburse consultant specialists who provide this service. Details covering
reimbursement criteria are available on the form itself or by calling Roche.
((art))
Obtaining Consent
Accutane Survey Enrollment Form
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62
An enrollment form for the Accutane Survey, a confidential survey conducted
independently by SI International. Please encourage your female patients to enroll while
they are completing the rest of the forms. And please keep reminding them monthly until
they do.
((art))
For All Patients: Informed Consent/Patient Agreement
A form that helps to document that the patient and/or her parent/guardian* understand the
risks of treatment with Accutane, including potential adverse events. The form’s
comprehensive list of points makes it an important addition to her file.
*If patient is a minor under the age of 18.
((art))
For Female Patients: Patient Information/Consent
A form that helps document that the patient and/or her parent/guardian* understand the
teratogenic risks of treatment with Accutane, the need to avoid pregnancy, and her
responsibilities before, during and after therapy. The form’s comprehensive list of points
makes it an important addition to her file.
*If patient is a minor under the age of 18.
((art))
Patient Qualification Form for Pregnancy Prevention and Contraception Compliance
A form that confirms that a female patient has met the 4 qualification criteria as outlined
in the CONTRAINDICATIONS and WARNINGS in the Accutane package insert.
((art))
Reinforcing Education
Preventing Pregnancy—A Guide to Contraception
Information your patient needs to know about the optimal use of various contraception
methods, especially those that are considered primary and secondary methods and the
myths that influence the behavioral factors in pregnancy risk.
((art))
Confidential Contraception Counseling Line
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For current labeling information, please visit https://www.fda.gov/drugsatfda
63
The Confidential Contraception Counseling Line is a 24-hour toll-free telephone line that
provides patient information on Accutane, pregnancy, contraception and pregnancy
prevention. As always, patients are referred to their prescriber for additional information
and clarification. The Confidential Contraception Counseling Line toll-free number is 1-
800-542-6900.
((art))
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For current labeling information, please visit https://www.fda.gov/drugsatfda
64
Accutane® InfoLine
Useful for every female patient, but especially those who have difficulty reading, the
Accutane InfoLine is a toll-free telephone service that provides an audio version of the
pregnancy warnings. The Accutane InfoLine supports English, Spanish and the 11 other
most widely spoken languages—13 in all. The Accutane InfoLine toll-free number is 1-
800-950-4411.
((art))
Be Prepared, Be Protected Video/Storyboard
This nonbranded video provides no-nonsense information about contraception and the
risk of pregnancy for female patients. It is available for you to give to female patients.
((art))
Be Aware: The Risk of Pregnancy While on Accutane
This video provides comprehensive information about types of potential birth defects
which could occur if a woman who is pregnant takes Accutane at any time during
pregnancy. It is available for you to give to female patients.
((art))
Contraception Knowledge Self-Assessment
A tool that helps the prescriber assess each female patient’s level of compliance and
knowledge of contraception. This 10-question test is located at the back of Preventing
Pregnancy—A Guide to Contraception and should be completed by the patient after
reading that guide.
((art))
Additional components of the Accutane Pregnancy Prevention and Risk Management
Program for Women
Additional components of the Accutane Pregnancy Prevention and Risk Management
Program for Women have been developed to help in achieving success. To receive these
components, please request them by calling 1-800-93-ROCHE.
Please see the enclosed complete product information, including
CONTRAINDICATIONS AND WARNINGS, on the inside back cover.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
65
((PPP logo))
((Tab copy))
Female Qualification Criteria
Meeting the 4 Female Qualification Criteria
1. Female patients must have had 2 negative urine or serum pregnancy tests with a
sensitivity of at least 25 mIU/mL before receiving the initial Accutane (isotretinoin)
prescription. The first test (a screening test) is obtained by the prescriber when the
decision is made to pursue qualification of the patient for Accutane. The second
pregnancy test (a confirmation test) should be done during the first 5 days of the
menstrual period immediately preceding the beginning of Accutane therapy. For patients
with amenorrhea, the second test should be done at least 11 days after the last act of
unprotected sexual intercourse (without using 2 effective forms of contraception). Each
month of therapy, the patient must have a negative result from a urine or serum
pregnancy test. A pregnancy test must be repeated every month prior to the female
patient receiving each prescription.
Pregnancy Testing
Human chorionic gonadotropin (hCG) is a glycopeptide hormone normally produced
during pregnancy from the chorion, which is the membrane that becomes a placenta. In a
normal pregnancy, hCG can be detected in serum and urine about 7 days following
conception.
Levels of hCG double every 2 days for the first 3-4 weeks following implantation of the
embryo.
((Table copy))
Days
hCG levels (mIU/mL)
Men
0
Nonpregnant women
0
Pregnant women
7-10 days after conception
10-30
12-16 days after conception
50-250
42-112 days after conception
37,000-50,000
Peak
50,000
Remainder of the pregnancy
Decreases by
10%-30%
Postpartum women
14 days postpartum
<50
21-28 days postpartum
0
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66
Pregnancy testing can be done either by using serum or urine. Both serum and urine
testing report a level of hCG.
Urine Pregnancy Tests
Most urine pregnancy tests that can be used are a system combining monoclonal and
polyclonal antibodies, which will detect hCG with a high degree of specificity and
sensitivity. This detection is possible 10-14 days postconception.
A urine pregnancy test with a sensitivity of at least 25 mIU/mL should be utilized. Data
from clinical testing by the manufacturer indicate that when directions are followed,
barring human error, the tests are 99% accurate.
Assessing Reproductive Health and Contraception Methods Before Prescribing Accutane
2. Female patients must have selected and have committed to use 2 forms of effective
contraception simultaneously, at least 1 of which must be a primary form, unless absolute
abstinence is the chosen method, or the patient has undergone a hysterectomy. Patients
must use 2 forms of effective contraception for at least 1 month prior to initiation of
Accutane therapy, during Accutane therapy, and for 1 month after discontinuing
Accutane therapy. Counseling about contraception and behaviors associated with an
increased risk of pregnancy must be repeated on a monthly basis.
For the last 20 years, convenient once-a-day oral contraceptives have been available, and
therefore procreation decisions can be made through conscious choice; and yet every year
half of the pregnancies in the US are unintended or mistimed. Data support that 64% of
the reported pregnancies with Accutane occurred in women who became pregnant after
beginning Accutane therapy. There are many reasons why unplanned pregnancies occur.
The most common reasons for these pregnancies are:
• Inability to maintain absolute abstinence
• Use of ineffective contraceptive methods
• Inconsistent use of effective contraception
• Unexpected sexual intercourse
• Contraceptive method failure
Better education and the ability to follow instructions precisely can make a difference.
Therefore, it is especially important to be able to assess your patient’s ability to
understand her responsibilities and your instructions, and to reinforce these instructions at
every clinical visit.
It is very important to be able to make a careful assessment of a woman’s reproductive
history, contraceptive knowledge and previous use of contraception methods. This
assessment and contraceptive education should continue throughout Accutane treatment.
When trying to obtain information, it is important to be aware that the patient may
respond to questions according to what she thinks her sexual activity should be, or what
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67
she thinks you want to hear, in contrast to what the reality is for her. Because of this, the
skill of being able to assess your patient and respond with treatment and counseling
specific to her is key to the success of your communication.
• Pay particular attention to nonverbal clues that may lead you to question what was said.
• Some of the overt behaviors to look for are a change in demeanor, a change in eye
contact, looking down and uneasiness apparent in body movements.
Interviewing Patients
During the assessment phase:
• Do not allow patients to dismiss questions.
Whether or not a formal tool is used, it is vital that you are sure that the patient
understands the questions fully. Pregnancy has occurred in patients who said that they
were not sexually active, were using birth control or had an infertile partner.
• Do not assume that an adolescent is not involved in sexual activity.
The percentage of teenage girls having sexual intercourse at earlier ages is gradually
rising. About 14% of girls born in the early 1970s had had sexual intercourse by the age
of 15.2 Many females seek contraceptive care for the first time as early as mid-
adolescence. An adolescent or young adult will be reluctant to discuss her sexuality in
front of her parent. If you cannot see her alone, or obtain information from her, perhaps
some general questions about relationships and boyfriends will give you an idea of
potential risk.
REGARDLESS OF AGE, SOCIOECONOMIC STATUS, OR EDUCATION, ALL
FEMALES OF CHILDBEARING POTENTIAL MUST HAVE CONTRACEPTION
COUNSELING EITHER BY YOU, YOUR STAFF OR THROUGH USE
OF THE CONTRACEPTION COUNSELING REFERRAL PROGRAM.
Please see the enclosed complete product information, including
CONTRAINDICATIONS AND WARNINGS, on the inside back cover.
Confidential Contraception Counseling Line
For those patients who may have questions that they have not asked during the prescriber
visits, Roche has provided a Confidential Contraception Counseling Line for patients to
obtain contraception information 24 hours a day, 7 days a week. The patient can call a
toll-free number (1-800-542-6900) and obtain information on a variety of subjects.
The categories include:
1. Birth defects/teratogenicity
2. Sex and birth control
3. Methods of birth control
4. Emergency contraception
5. Pregnancy and pregnancy testing
6. The Accutane Survey
7. Repeat choices
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68
As always, patients are referred to their prescribers for additional information and
clarification.
Educating Patients
Your ability to effectively communicate necessary information to the patient plays a
significant role in the degree of compliance achieved. The results from compliance
studies consistently focus on the prescriber-patient relationship and the aspects of those
relationships that are either productive or counterproductive to patient compliance.3
You must allow sufficient time to provide adequate patient education on contraception.
Study results show:
• 50% of patients forget instructional statements immediately after an office visit4
• 35% to 92% of patients will not understand general information given to them4
• Prescribers overestimated, by a factor of 9, the amount of time they thought they spent
on patient education5
• In 65% of the cases, prescribers thought that patients wanted less information than they
actually did5
Encouraging Patient Compliance
Things to do every month of Accutane treatment:
• Repeat pregnancy testing.
Pregnancy testing should be done monthly before each prescription is written during
Accutane treatment.
• Prescribe no more than a 30-day supply of Accutane (isotretinoin) as provided in the
package information with a yellow self-adhesive Accutane Qualification Sticker.
Accutane should be prescribed on a monthly basis; no refills, telephone or computerized
prescriptions are allowed.
• Repeat contraception counseling.
Contraception counseling should be repeated on a monthly basis during Accutane
treatment so that the patient's concerns and questions are answered on an ongoing basis.
Prescriber-patient interaction that encourages the patient to talk about sensitive sexual
issues in an atmosphere that is characterized by interest and friendliness and the absence
of prescriber domination results in greater patient satisfaction.6 Practice the “four E's”:
• Engage the patient
• Empathize with the patient
• Educate the patient
• Enlist the patient in her own healthcare
Contraception During Accutane Therapy
Once you have determined that the patient will require contraception during therapy, you
must be thorough in assessing contraception history, explaining the contraception
requirements and ensuring that she is educated in contraception methods. Explain to the
patient that she must consistently use 2 separate, effective forms of contraception
simultaneously:
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69
• At least 1 month before initiation of Accutane therapy;
• Consistently during Accutane therapy; and
• For 1 month after Accutane therapy stops.
Review the Education Reinforcement Section of the patient booklet, Be Smart, Be Safe,
Be Sure, including Preventing Pregnancy––A Guide to Contraception, to help you as you
explain the contraception requirements with Accutane treatment.
Assess and address all potential compliance problems with the patient. Ask the patient to
tell you what she thinks may cause a compliance problem during her Accutane treatment.
Additionally, it is very important to discuss alcohol and/or drug use with the patient.
These substances can impair judgment, lower inhibitions and affect awareness in the
patient or her sexual partner, and can significantly impact compliance with contraceptive
measures.
Assessing Patient Misinformation About Contraception
Misinformation about contraception can exist regardless of patient age, social status,
sexual experience or education. Numerous myths exist regarding conception and how it
can be prevented. For example, some mistakenly believe that conception is impossible
the first time a person has sexual intercourse. Additionally, some think that douching or
having sexual intercourse in a certain position will prevent pregnancy. Additional myths
and facts can be found in the Preventing Pregnancy––A Guide to Contraception section
of the Education Reinforcement Section of Be Smart, Be Safe, Be Sure. However,
because it is not possible to identify all existing contraception misinformation that any
one patient may have, emphasize to the patient that only specific methods of
contraception are recommended while taking Accutane.
Remind your patient that it is imperative to always follow instructions exactly. No matter
what 2 forms of contraception she is using simultaneously, if she uses them inconsistently
or incorrectly, she can become pregnant.
Although certain times of a woman's monthly cycle are safer than others, no time exists
that is completely safe, which includes during the menses. Many individuals are unaware
that conception is possible during this time; this fact should be discussed with your
patient.
Remember, not all vaginal bleeding occurs during the hormonal menses. Bleeding can
occur off-cycle, or can be a sign of uterine or vaginal infection.
Accessing Contraception Information
Your patient may need assistance accessing affordable contraception counseling. Roche
Laboratories Inc., the manufacturer of Accutane, will reimburse a licensed contraception
counselor for contraception counseling. Forms to be used for referring your patient to a
contraception counselor are part of the individual female patient booklets. Consider
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70
establishing a relationship with a reproductive practice(s); in this way, contraception
counselors at that practice(s) will be knowledgeable about the contraceptive requirements
while taking Accutane.
Discussing the Role of the Sexual Partner
Discuss the patient's sexual partner's involvement in contraception. Encourage the patient
to discuss her Accutane treatment and the requirement for continual use of 2 separate,
effective forms of contraception simultaneously, with her sexual partner. Explain and
discuss the Preventing Pregnancy––A Guide to Contraception (Your Sexual Partner)
section of the Education Reinforcement Section of Be Smart, Be Safe, Be Sure.
Encourage her to give the patient booklet to her partner and to discuss the contents with
him. Assure the patient that you will be happy to speak with her partner and answer any
questions he may have about her Accutane treatment and the need to use 2 separate,
effective forms of contraception during the required period. An alternative to an office
visit by the partner may be a telephone call to your office, or written or e-mailed
questions. This may be a good time to tell your patient about the Confidential
Contraception Counseling Line. The toll-free number is 1-800-542-6900.
Please see the enclosed complete product information, including
CONTRAINDICATIONS AND WARNINGS, on the inside back cover.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
71
((PPP LOGO))
((Tab copy))
Selecting Contraception
Selecting Contraception2
Asking the patient about her choice of contraception takes special skill, and you may
wish to refer your female patients to a reproductive health and contraception counselor.
You may use the Roche-supported free referral in order to accomplish this goal; however,
if you wish to assess your patient’s attitudes and beliefs for yourself, you may wish to
follow the information provided here.
Patients should be asked as discreetly as possible, “Have you ever had or are you
currently having sexual intercourse, sex play or oral sex with a male partner?”
It is not unusual to have a patient indicate that she is practicing abstinence; however,
through questioning the prescriber may find out, for example, that the patient is
practicing abstinence because her sexual partner is away. Continuous abstinence is only a
description of her history—not an indication of her future. Remember that the patient's
situation may change. Abstinence means no sexual contact. A patient needs to understand
that pregnancy is possible if semen or pre-ejaculate is spilled on the vulva. The
effectiveness of abstinence cannot be determined because it exists only when it is
practiced.
Because it is not possible to measure contraceptive effectiveness directly, the prescriber
can evaluate probabilities of pregnancy during contraceptive use. These are obtained
from surveys as well as research studies.
The percentages that follow for the perfect use and typical use of a contraceptive indicate
the percentages of women experiencing an unintended pregnancy during their first year
of use. Perfect use describes the use of the method correctly and consistently with every
act of intercourse. Typical use reflects the average user, who does not always use the
method correctly and consistently, and may not use it with every act of intercourse.
Primary (Most Effective) Forms of Contraception
ORAL CONTRACEPTION
Perfect Use:
0.1%
(Rate of unintended pregnancies)
Typical Use: 5%
Combination Oral Contraceptives
(estrogen and progestin available in a variety of
formulations)7
Mechanism of Action — ovulation suppression.
Instructions for Use — take pill at same time daily — hormone pills for 3 weeks;
placebos for 1 week.
Pills containing no estrogen (progestin-only “minipills”) are not recommended during
Accutane (isotretinoin) therapy.
If the Pill is recommended for your patient as the primary method, she must also use a
secondary method at all times.
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72
IMPLANTABLE HORMONES
Perfect Use:
0.05%
(Rate of unintended pregnancies)
Typical Use: 0.05%
Norplant® (No longer available to patients after July 2002.)
progestin only — levonorgestrel implants
Mechanism of Action — suppresses ovulation in 50% of cycles, thickens cervical mucus,
and atrophies endometrium.
Instruction for Use — 6 capsules inserted by clinician subdermally in upper arm; must be
replaced every 5 years.
If Implantable Hormones are recommended for your patient as the primary method, she
must also use a secondary method at all times.
INJECTABLE HORMONES
Perfect Use:
0.2%-0.3%
(Rate of unintended pregnancies)
Typical Use: 0.2%-0.3%
Depo-Provera®
progestin-only injection
Mechanism of Action — suppresses ovulation; thickens cervical mucus; atrophies
endometrium.
Instructions — receive injection every 12 weeks
(150 mg/1 cc IM).
Lunelle™
combination hormone (estrogen and progestins) injection
Mechanism of Action — similar to that of Depo-Provera.
Instructions — receive injection every 4 weeks (28 to 33 days).
If Injectable Hormones are recommended for your patient as the primary method, she
must also use a secondary method at all times.
INTRAUTERINE DEVICE (IUD)
Perfect Use: 0.1%-1.5%
(Rate of unintended pregnancies)
Typical Use: 0.1%-2%
IUD
Description — 3 types used in the US: CuT 380A — made of polyethylene covered with
copper; Progesterone T — made of ethylene vinyl acetate copolymer containing
progesterone; LNg20 — made of polyethylene and containing levonorgestrel.
Mechanism of Action — CuT 380A — prevents fertilization by altering tubal and uterine
transport of sperm; Progesterone T and LNg20 — release progesterone, which alters
uterine and tubal motility, thickens cervical mucus, alters endometrium, and disrupts
ovulatory patterns.
Instructions for Use — patient should check for IUD strings often in the first few months
after insertion and after each period. If the patient cannot find the strings or if strings feel
shorter or longer, or if she can feel the IUD itself, or if there are any signs or symptoms
of pelvic inflammatory disease (PID) or if she misses a period, instruct the patient to call
her prescriber.
If the IUD is recommended for your patient as the primary method, she must also use a
secondary method at all times.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
73
HORMONAL VAGINAL
contraceptive ring
Perfect Use:
0.77%
(Rate of unintended pregnancies)
Typical Use: 1%-2%
NuvaRing®
estrogen (etonogestrel) and progestin (ethinyl estradiol) combination
Mechanism of Action — releases a continuous low dose of hormones per day over a 21-
day period of use.
Instructions for use — patient inserts ring in the vagina, where it should remain for 3
weeks; she then removes ring for 1 week, during which she will have her menstrual
period. A new ring is used each month for continuous contraception.
If the Hormonal Vaginal Contraceptive Ring is recommended for your patient as a
primary method, she must also use a secondary method at all times. A diaphragm cannot
be used as a secondary method as the vaginal contraceptive ring may interfere with
correct placement and position of the diaphragm.
TOPICAL HORMONAL PATCH
Birth Control Patch
Perfect Use:
1%
(Rate of unintended pregnancies)
Typical Use: Unknown
Ortho Evra®
norelgestromin/ethinyl estradiol transdermal system
Mechanism of Action — ovulation suppression, and changes in cervical mucous and the
endometrium.
Instructions for use — apply a new patch each week for 3 weeks. Every new patch should
be applied on the same day of the week. The fourth week is patch-free, during which she
will have her menstrual period. The transdermal patch has been found to be less effective
in women over 198 pounds. If the patch falls off or is partially detached for less than 24
hours, try to reapply it to the same place or replace with a new patch immediately. This
patch should be changed on the usual change day. If the patch is detached for more than 1
day, a new cycle with a new change day should be started by applying a new patch. It
will not be effective for contraception for the first week
If the Transdermal Patch is recommended for your patient as the primary method, she
must also use a secondary method at all times.
STERILIZATION
Perfect Use: 0.1%-0.5%
(Rate of unintended pregnancies)
Typical Use: 0.15%-0.5%
Female Sterilization
Mechanism of Action — prevents fertilization by mechanically blocking fallopian tubes.
Male Sterilization (Vasectomy)
Mechanism of Action — prevents sperm from entering the seminal fluid by blocking the
vasa deferentia; semen analysis advised after 20 ejaculations to be sure semen is free of
sperm.
If Sterilization is your patient’s primary method, she must also use a secondary method at
all times.
Secondary (Moderately Effective) Forms
of Contraception
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
74
Condoms, diaphragms and cervical caps are barrier methods that are considered
moderately effective when used in combination with a spermicide.
CONDOMS
Perfect Use:
3% with spermicide
(Rate of unintended
pregnancies)
Typical Use: 14% with spermicide
Male Condom (Latex)
Mechanism of Action — prevents sperm from entering vagina.
Instructions for Use — unroll condom onto erect penis before there is any contact with
female genitals; use only water-based lubricants with latex condoms.
If the Condom is one of your patient’s methods of contraception, she must also use a
primary method at all times.
DIAPHRAGM
Perfect Use:
6% with spermicide
(Rate of unintended
pregnancies)
Typical Use: 20% with spermicide
Diaphragm
Description — dome-shaped rubber cup with a flexible rim available in many sizes (50-
95 mm diameter) and different styles.
Mechanism of Action — acts as a physical barrier to prevent sperm from entering cervix
and contains spermicide to kill sperm (may help to hold spermicide against cervix).
If the Diaphragm is one of your patient’s methods of contraception, she must also use a
primary method at all times.
CERVICAL CAP
Perfect Use:
9% with spermicide
(Rate of unintended
pregnancies in
Typical Use: 20% with spermicide
nulliparous women)
Cervical Cap
Description — deep rubber cap with firm rim and a groove inside the rim that fits snugly
around the cervix.
Mechanism of Action — acts as a physical barrier to prevent sperm from entering cervix
and uses chemical action of spermicide to kill sperm.
If the Cervical Cap is one of your patient’s methods of contraception, she must also use a
primary method at all times.
WITHDRAWAL OR PERIODIC ABSTINENCE ARE NOT RECOMMENDED FOR
WOMEN TAKING ACCUTANE.
((footnote copy))
Norplant® System is a registered trademark of Wyeth Laboratories,
a Wyeth-Ayerst Company.
Depo-Provera® is a registered trademark of Pharmacia Corporation.
Lunelle™ is a trademark of Pharmacia Corporation.
NuvaRing® is a registered trademark of Organon.
Ortho Evra® is a registered trademark of Ortho-McNeil Pharmaceuticals.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
75
Please see the enclosed complete product information, including
CONTRAINDICATIONS AND WARNINGS, on the inside back cover.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
76
((PPP logo))
Emergency Contraception7
Types of Emergency Contraception
Emergency birth control is provided in one of two ways: emergency contraception pills,
or insertion of an IUD.
EMERGENCY CONTRACEPTION PILLS (ECPs)—Used within 3 days of unprotected
sexual intercourse
Emergency hormonal contraception is a sequence of high doses of certain oral
contraceptives. The first dose of the ECPs must be taken no later than 72 hours after
having unprotected sex. The sooner the ECP is taken, the more likely it is to be effective.
INSERTION OF INTRAUTERINE DEVICE (IUD)—Used within 5 days of unprotected
sexual intercourse
The second method used for emergency contraception is the insertion of an IUD.
Insertion of an IUD can be done by a healthcare professional within 5 days of
unprotected sex.
IUD insertion for emergency contraception is not recommended for women who have not
had a child, or are at risk for sexually transmitted infections. This includes:
• Women with more than 1 sex partner or whose partners have more than 1 partner
• Women with new partners
• Women who have been raped
The names and phone numbers of emergency contraception prescribers in your area can
be obtained by calling toll free:
1-888-NOT-2-LATE (1-888-668-2528).
Informed Consent
3. Female patients must have signed a Patient Information/Consent form that contains
warnings about the risk of potential birth defects if the fetus is exposed to isotretinoin.
Signing the informed consent provided in the female booklet allows an opportunity for
you to review that she has the ability to read and understand the information that you
have given her and that she understands her responsibilities to avoid pregnancy before,
during and for 1 month after Accutane (isotretinoin) therapy.
The Accutane Survey
4. Female patients must have been informed of the purpose and importance of
participating in the Accutane Survey and have been given the opportunity to enroll (see
precautions).
The Accutane Survey is conducted independently by SI International. Patients will
receive a payment for enrolling—it is important that ALL female patients who use
Accutane enroll in this survey.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
77
The Accutane Survey is a large epidemiologic study of women who have taken Accutane.
Data from this Survey are reported to the FDA and are used to assess the effectiveness of
S.M.A.R.T. Roche also uses the data to evaluate possible ways to further reduce fetal
exposure.
This confidential survey collects information from patients on their understanding of the
risks of pregnancy during Accutane therapy, and other aspects of the Accutane Pregnancy
Prevention and Risk Management Program. After enrollment in the Accutane Survey,
female patients will be requested to complete 2 or 3 brief questionnaires.
Continue to encourage female patients to enroll at every office visit until they actually do
so. Survey enrollment forms are enclosed in each Prescription Pak of Accutane and in
each individual patient booklet.
Confidentiality
Information gathered in the Accutane Survey will be used for statistical purposes only
and will be held in the strictest confidence. Only the Accutane Survey researchers at SI
International have access to personal patient information.
Payment
An initial payment of $20 will be made to every female patient who enrolls in the
Accutane Survey. An additional payment of $10 will be made after the patient completes
the final questionnaire.
Convenience
Enrollment is simple and convenient for patients. An enrollment form is enclosed in
every Prescription Pak of Accutane and in every female patient booklet.
Encouragement
Your encouragement is important to the patient. Patient feedback indicates that patients
decided not to enroll because:
• They did not receive information about the survey at their prescriber’s office
• They were concerned about their privacy
• They were concerned about the amount of time involved
However, the patients who decided to enroll did so because:
• They felt it would benefit others
• The prescriber had recommended their participation
If the patient believed that the prescriber supported the survey, they joined. Please
encourage your patients to participate. Assure them that there are only 2 or 3 short forms
to complete during the entire course of therapy, that their responses are completely
confidential, and that they will be compensated for their efforts. Explain to patients that
their participation is an important contribution to improving the program for prevention
of pregnancies among women taking Accutane.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
78
Reaching the Goal
The importance of enrolling female patients in the Accutane Survey cannot be overstated.
Please encourage all of your female Accutane patients to enroll—without exception.
Our objective is clear—the enrollment of every female patient. To reach this goal, we
need your support, and your patients need your encouragement.
Please see the enclosed complete product information, including
CONTRAINDICATIONS AND WARNINGS, on the inside back cover.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Food and Drug Administration
Rockville, MD 20857
((Letter insert copy))
System to Manage Accutane Related Teratogenicity™ (S.M.A.R.T.™)
Letter of Understanding for Prescribers
The System to Manage Accutane Related Teratogenicity (S.M.A.R.T.) allows Accutane® (isotretinoin)
prescribers to be in compliance with the approved Accutane package insert. I acknowledge that by
completing this form I demonstrate my understanding of the safe and effective use of Accutane as
described in the Checklist below, in the Accutane package insert, and in educational resources
provided with this Letter.
• I know the risk and severity of fetal injury/birth defects from Accutane
• I know how to diagnose and treat the various presentations of acne
• I know the risk factors for unplanned pregnancy and the effective measures for avoidance of
unplanned pregnancy
• It is the informed patient’s responsibility to avoid pregnancy during Accutane therapy and for 1
month after stopping Accutane. To help patients have the knowledge and tools to do so: Before
beginning treatment of female patients with Accutane I will refer for expert, detailed pregnancy
prevention counseling and prescribing, reimbursed by the manufacturer, OR I have the expertise to
perform this function and elect to do so
• I understand, and will properly use throughout the Accutane treatment course, the S.M.A.R.T.
procedures for Accutane, including monthly pregnancy avoidance counseling, pregnancy testing and
use of the yellow self-adhesive Accutane Qualification Stickers
I understand that use of the yellow self–adhesive Accutane Qualification Sticker means that a female
patient is qualified to receive an Accutane prescription, as defined in the CONTRAINDICATIONS
AND WARNINGS of the approved labeling. Specifically, she:
• Must have had 2 negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL
before receiving the initial Accutane prescription. The first test (a screening test) is obtained by the
prescriber when the decision is made to pursue qualification of the patient for Accutane. The second
pregnancy test (a confirmation test) should be done during the first 5 days of the menstrual period
immediately preceding the beginning of Accutane therapy. For patients with amenorrhea, the second
test should be done at least
11 days after the last act of unprotected sexual intercourse (without using 2 effective forms of
contraception). Each month of therapy, the patient must have a negative result from a urine or serum
pregnancy test. A pregnancy test must be repeated each month prior to the female patient receiving
each prescription.
• Must have selected and have committed to use 2 forms of effective contraception simultaneously, at
least 1 of which must be a primary form, unless absolute abstinence is the chosen method, or the
patient has undergone a hysterectomy. Patients must use 2 forms of effective contraception for at least
1 month prior to initiation of Accutane therapy, during Accutane therapy, and for 1 month after
discontinuing Accutane therapy. Counseling about contraception and behaviors associated with an
increased risk of pregnancy must be repeated on a monthly basis.
• Must have signed a Patient Information/Consent form that contains warnings about the risk of
potential birth defects if the fetus is exposed to isotretinoin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
2
• Must have been informed of the purpose and importance of participating in the Accutane Survey and
given the opportunity to enroll (see PRECAUTIONS).
See the enclosed complete product information, including CONTRAINDICATIONS AND
WARNINGS, in the attached package insert.
To participate in S.M.A.R.T. and obtain the yellow self-adhesive Accutane Qualification Stickers,
please complete the information below and return it to Roche in the preaddressed envelope provided.
Prescriber name (Last)
(First) (MI)
DEA number
Last four digits of Social Security number
Prescriber address
City
State
Zip code
Telephone
Fax
Prescriber signature
Date
Information provided above will be held by a third party associated with Roche for the sole purpose of
distributing Accutane Qualification Stickers. If you have any questions, please contact the S.M.A.R.T.
Program staff at 1-800-93-ROCHE.
((Roche Pharmaceuticals logo))
xx-xxx-xxx-xxx-xxxx
((BRM copy))
BUSINESS REPLY MAIL
FIRST-CLASS MAIL PERMIT NO. 9775 RESTON VA
POSTAGE WILL BE PAID BY ADDRESSEE
System to Manage Accutane® Related Teratogenicity
Program Coordinator
12012 Sunset Hills Rd 8th Fl
Reston VA 20190-9869
NO POSTAGE NECESSARY
IF MAILED
IN THE
UNITED STATES
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
3
((PPP Logo))
((Roche Logo))
Be Smart Be Safe Be Sure™
Accutane® Pregnancy Prevention and Risk Management Program for Women
Prevent Pregnancy
IMPORTANT: ACCUTANE CAN CAUSE BIRTH DEFECTS IF TAKEN DURING PREGNANCY.
((Boxed Copy))
If you have any questions about your therapy, please contact:
Name:______________________________________________
(to be completed by Prescriber)
Telephone: ______________________________________________
((End Boxed Copy))
Complete the three sections in this order:
Section 1
Education — Review this material before completing the consent forms
• Patient Product Information, Important information concerning
your treatment with Accutane® (isotretinoin)
• Contraception Counseling Referral form
Section 2
Consent — Complete this section with your prescriber
• Accutane Survey enrollment form
• Informed Consent/Patient Agreement form
• Patient Information/Consent form
• Patient Qualification Form for Pregnancy Prevention and Contraception Compliance
Section 3
Education Reinforcement — This additional information will reinforce
what you have already learned — complete it in the office or take it home
• Preventing Pregnancy — A Guide to Contraception
– Introduction
– My role
– Contraception Counseling Referral Program
– Preventing pregnancy
– Contraception methods
– Pregnancy and pregnancy testing
– Emergency contraception
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
4
– Your sexual partner
– The Accutane Survey
– Confidential Contraception Counseling Line
– Accutane InfoLine
– Scenes from the video
– Summary
– Contraception knowledge self-assessment
IMPORTANT INFORMATION TO READ BEFORE YOU RECEIVE YOUR ACCUTANE®
(isotretinoin) PRESCRIPTION
((TAB Copy))
section 1
EDUCATION
Tenth Edition
Month/Year
Patient Product Information
Important information concerning your treatment with
((Accutane Logo))
Read this brochure carefully before you start taking Accutane (ACK-u-tane). This brochure provides
important facts about Accutane, but it does not contain all information about this medication. When
you pick up your Accutane prescription at the pharmacy, you should receive a copy of the Accutane
Medication Guide with your Accutane. If there is anything else you want to know, or if you have any
questions, talk to your prescriber.
Things you should know about
Accutane (isotretinoin) is used to treat the most severe form of acne (nodular acne) that has not been
helped by other treatments, including antibiotics. However, Accutane can cause serious side effects.
Before you decide to take Accutane, you must discuss with your prescriber how bad your acne is, the
possible benefits of using Accutane, and its possible side effects. It is important for you to know how
to take it correctly and what to expect. Your prescriber will ask you to read and sign a form or forms to
show that you understand some of the serious risks of Accutane. Please read this brochure carefully
and ask your prescriber any questions you may have.
Possible serious side effects of Accutane include birth defects and mental disorders.
IMPORTANT INFORMATION FOR FEMALE PATIENTS:
BIRTH DEFECTS (Causes Birth Defects)
((Boxed Copy))
You MUST NOT take Accutane if you are pregnant.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
5
You MUST NOT become pregnant while taking Accutane, or for 1 month after you stop taking
Accutane.
Severe birth defects are known to occur in babies of females taking Accutane in any amount even for
short periods during pregnancy. There is an extremely high risk that your baby will be deformed or
will die if you become pregnant while taking Accutane. Potentially any exposed baby can be affected.
There is also an increased risk of losing the baby before it is born (miscarriage) or that it will be
delivered early (premature).
You will not get your first prescription for Accutane until there is proof that you have had 2 negative
pregnancy tests. The first test must be done when your prescriber decides to prescribe Accutane. The
second pregnancy test must be done during the first 5 days of your menstrual period right before
starting Accutane therapy, or as instructed by your prescriber. Only when the 2 required tests show that
you are not pregnant can you get your first prescription for a 30-day supply of Accutane. You will
have one pregnancy test every month during your Accutane therapy. Female patients cannot get
monthly refills for Accutane unless there is proof that they have had a negative pregnancy test. You
can only get a refill each month by returning to your prescriber for a repeat pregnancy test and
counseling about pregnancy prevention.
Effective contraception (birth control) should be discussed with your prescriber. Two separate,
effective forms of contraception must be used at the same time for at least 1 month before beginning
therapy and during therapy, and for 1 month after Accutane treatment has stopped. Any birth control
method can fail, including oral contraceptives (birth control pills) and topical/injectable
(shots)/implantable/insertable hormonal birth control products.
There are only 2 reasons that you would not need to use 2 separate birth control methods:
• You commit to being absolutely and consistently abstinent (no sexual intercourse). This means that
you are absolutely sure that you will not have genital-to-genital contact with a male, during and for 1
month after your Accutane treatment.
• You have had your uterus surgically removed (a hysterectomy).
Immediately stop taking Accutane if you have sex without birth control, miss your period or become
pregnant while you are taking Accutane or in the month after you have stopped treatment. Call your
prescriber immediately.
((Illustration of deformed babies))
Line drawing representing some common birth defects associated with Accutane use during
pregnancy. Some of the defects that you can see are deformed eyes, nose, ears or absent ears, enlarged
head and small chin. More severe defects than these can occur, including mental retardation. This
picture does not show all the severe internal defects that may occur, including those of the brain, heart,
glands, and nervous system.
((End Boxed Copy))
Be Aware: The Risk of Pregnancy While on Accutane
A video is available from your prescriber that contains full information about the types of potential
birth defects that could occur if a woman who is pregnant takes Accutane at any time during
pregnancy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
6
((Image of videocassette))
Important information for all patients
Mental disorders and suicide
Some patients have become depressed or developed other serious mental problems while they were
taking Accutane or shortly after stopping Accutane. It is not known if Accutane caused these problems.
Some signs of depression include sad, “anxious” or empty mood, loss of pleasure or interest in social
or sports activities, sleeping too much or too little, changes in weight or appetite, school or work
performance going down, or trouble concentrating. Some patients taking Accutane have had thoughts
of ending their own lives (suicidal thoughts). Some people have tried to end their own lives (attempted
suicide) and some people have ended their own lives (committed suicide). No one knows if Accutane
caused these behaviors.
Tell your prescriber if you or someone in your family has ever had a mental illness, including
depression, suicidal thoughts or attempts, or psychosis. Psychosis means a loss of contact with reality,
such as hearing voices or seeing things that are not there. Tell your prescriber if you take any
medicines for any of these problems.
Stop taking Accutane and call your prescriber right away if you:
• Start to feel sad or have crying spells
• Lose interest in activities you once enjoyed
• Sleep too much or have trouble sleeping
• Become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of
violence)
• Have a change in your appetite or body weight
• Have trouble concentrating
• Withdraw from your friends or family
• Feel like you have no energy
• Have feelings of worthlessness or inappropriate guilt
• Start having thoughts about hurting yourself or taking your own life (suicidal thoughts)
What is Accutane?
Accutane is used to treat the most severe form of acne (nodular acne)
that has not been helped by other treatments, including antibiotics.
((Normal anatomy artwork with Tim Peters copyright line))
Facts about nodular acne
Nodular acne is a severe skin disease that can leave permanent scars. Although acne is considered by
many to be a disease of adolescents, a person can be affected with acne into his or her 30s and 40s.
Males tend to get more severe acne than females.
Acne develops in the oil-producing structures of the skin called sebaceous glands. One or more
sebaceous glands accompany each hair follicle (see figures). These glands secrete an oily mixture
called sebum that normally passes to the skin surface. During adolescence, the sebaceous glands grow
larger and produce more sebum, especially in the face, chest and back areas. Acne occurs when the
normal route of sebum to the skin surface is blocked. In the case of nodular acne, the sebum builds up
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
7
in the gland and mixes with dead cells. This accumulation finally ruptures the follicle wall, forming an
inflamed nodule under the skin. Scarring usually results from these nodules.
Acne is not caused by a poor diet, dirt or an oily complexion. Factors that may make acne worse
include emotional stress, fatigue, cosmetics, and drugs such as iodides and bromides.
Who should not take Accutane?
Do not take Accutane if you are pregnant, plan to become pregnant, or become pregnant during
Accutane treatment. Accutane causes severe birth defects. Please carefully read “Important
Information for Female Patients: Birth Defects” on page 1.2.
General guidelines for taking your medication
Do not take Accutane (isotretinoin) unless you completely understand its possible risks and are willing
to follow all of the instructions in this brochure. When you pick up your Accutane prescription at the
pharmacy, you should receive a copy of the Accutane Medication Guide with your Accutane.
Tell your prescriber if you or anyone in your family has had any kind of mental problems, asthma,
liver disease, diabetes, heart disease, osteoporosis (bone loss), weak bones, anorexia nervosa (an eating
disorder where people eat too little), or any other important health problems. Tell your prescriber if
you have any food or drug allergies. This information is important to determine if Accutane is right for
you.
How should you take Accutane?
• You will get a 30-day supply of Accutane at a time, to be sure you check in with your prescriber each
month to discuss side effects and pregnancy prevention.
• Your prescription should have a yellow self-adhesive Accutane Qualification Sticker on it. If your
prescription does not have this sticker, call your prescriber. The pharmacy should not fill your
prescription unless it has a yellow sticker.
((Qualification Sticker art))
• The amount of Accutane you take has been specially chosen for you and may change during your
treatment; do not change the number of pills you are taking unless your prescriber tells you to do so.
• You will take Accutane 2 times a day with food, unless your prescriber tells you otherwise. Swallow
your Accutane capsules with a full glass of liquid. This will help prevent the medication inside the
capsule from irritating the lining of your esophagus (connection between mouth and stomach). For the
same reason, do not chew or suck on the capsule.
• If you miss a dose, just skip that dose. Do not take 2 doses next time.
• You should return to your prescriber as directed to make sure you don’t have signs of serious side
effects. Because some of Accutane’s serious side effects show up in blood tests, some of these visits
may involve blood tests. Monthly visits for female patients should always include a pregnancy test.
During your treatment:
what should you avoid while taking Accutane?
DO NOT GET PREGNANT (for female patients)
• Do not get pregnant while taking Accutane and for 1 month after stopping Accutane.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
8
• Do not breast feed while taking Accutane and for 1 month after stopping Accutane. We do not know
if Accutane can pass through your milk and harm the baby.
• Do not give blood while you take Accutane and for 1 month after stopping Accutane. If someone
who is pregnant gets your donated blood, her baby may be exposed to Accutane and may be born with
birth defects.
• Do not take vitamin A supplements. Taking both together may increase your chance of getting side
effects.
• Do not have cosmetic procedures to smooth your skin, including waxing, dermabrasion,
or laser procedures while you are using Accutane and for at least 6 months after you
stop. Accutane may increase your chance of scarring from these procedures. Check with your
prescriber for advice about when you can have cosmetic procedures.
• Avoid sunlight and ultraviolet lights as much as possible. Tanning machines use ultraviolet light.
Accutane may make your skin more sensitive to light.
• Do not use birth control pills that do not contain estrogen. They may not work while
you take Accutane. Ask your prescriber or pharmacist if you are not sure what type of birth control
pills you are using.
Important information for all patients
• Talk with your prescriber if you plan to take other drugs or herbal products. This is especially
important for patients using birth control pills and other hormonal types of birth control because the
birth control may not work if you are taking certain drugs or herbal products. You should not take the
herbal supplement St. John’s Wort because this herbal supplement may make birth control pills not
work as effectively.
• Talk with your prescriber if you are currently taking an oral or injected corticosteroid or
anticonvulsant (seizure) medication prior to using Accutane. These drugs may weaken your bones.
• Do not share Accutane with other people. It can cause birth defects and other serious
health problems.
• Do not take Accutane with antibiotics unless you talk to your prescriber. For some antibiotics, you
may have to stop taking Accutane until the antibiotic treatment is finished. Use of both drugs together
can increase the chances of getting increased pressure in the brain.
You should be aware that certain SERIOUS SIDE EFFECTS have been reported in patients taking
Accutane. Serious problems do not happen in most patients. If you experience any of the following
side effects or any other unusual or severe problems, stop taking Accutane right away and call your
prescriber because they may result in permanent effects.
• Accutane can cause birth defects and death in babies whose mothers took Accutane while they were
pregnant. Please read “Important Information for Female Patients: Birth Defects” on page 1.2.
• Serious mental health problems. Please see “Mental disorders and suicide” on page 1.3.
• Serious brain problems. Accutane can increase the pressure in your brain. This can lead to permanent
loss of sight, or in rare cases, death. Stop taking Accutane and call your prescriber right away if you
get any of these signs of increased brain pressure: bad headache, blurred vision, dizziness, nausea, or
vomiting. Also, some patients taking Accutane have had seizures (convulsions) or stroke.
• Abdomen (stomach area) problems. Certain symptoms may mean that your internal organs are being
damaged. These organs include the liver, pancreas, bowel (intestines), and esophagus (connection
between mouth and stomach). If your organs are damaged, they may not get better even after you stop
taking Accutane. Stop taking Accutane and
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
9
call your prescriber if you get severe stomach, chest, or bowel pain; have trouble swallowing or painful
swallowing; get new or worsening heartburn, diarrhea, rectal bleeding, yellowing of your skin or eyes,
or dark urine.
• Bone and muscle problems. Accutane may affect bones, muscles, and ligaments and cause pain in
your joints or muscles. Tell your prescriber if you plan vigorous physical activity during treatment with
Accutane. Tell your prescriber if you develop pain, particularly back pain or joint pain. There are
reports that some patients have had stunted growth after taking Accutane for acne as directed. There
are also some reports of broken bones or reduced healing of broken bones after taking Accutane for
acne as directed. No one knows if taking Accutane for acne will affect your bones. If you have a
broken bone, tell your prescriber that you are taking Accutane. Muscle weakness with or without pain
can be a sign of serious muscle damage. If this happens, stop taking Accutane, and call your prescriber
right away.
• Hearing problems. Some people taking Accutane have developed hearing problems.
It is possible that hearing loss can be permanent. Stop using Accutane and call your prescriber if your
hearing gets worse or if you have ringing in your ears.
• Vision problems. While taking Accutane you may develop a sudden inability to see in the dark, so
driving at night can be dangerous. This condition usually clears up when you stop taking Accutane, but
it may be permanent. Other serious eye effects can occur. Stop taking Accutane and call your
prescriber right away if you have any problems with your vision or dryness of the eyes that is painful
or constant.
After your treatment is completed
• Lipid (fats and cholesterol in blood) problems. Many people taking Accutane (isotretinoin) develop
high levels of cholesterol and other fats in their blood. This can be a serious problem. Return to your
prescriber for blood tests to check your lipids and to get any needed treatment. These problems
generally go away when Accutane treatment is finished.
• Allergic reactions. In some people, Accutane can cause serious allergic reactions. Stop taking
Accutane and get emergency care right away if you develop hives, a swollen face or mouth, or have
trouble breathing. Stop taking Accutane and call your prescriber if you develop a fever, rash, or red
patches or bruises on your legs.
• Signs of other possibly serious problems. Accutane may cause other problems. Tell your prescriber if
you have trouble breathing (shortness of breath), are fainting, are very thirsty or urinate a lot, feel
weak, have leg swelling, convulsions, slurred speech, problems moving, or any other serious or
unusual problems. Frequent urination and thirst can be signs of blood sugar problems.
Accutane has more common, less serious possible side effects.
The common, less serious side effects of Accutane are dry skin, chapped lips, dry eyes, and dry nose
that may lead to nosebleeds. People who wear contact lenses may have trouble wearing them while
taking Accutane and after therapy. Sometimes, people’s acne may get worse for a while. They should
continue taking Accutane unless told to stop by their prescriber.
These side effects usually do not last long and disappear when treatment is stopped, but some may
continue after stopping Accutane. If you develop any of these side effects, check with your prescriber
to determine if any change in the amount of your medication is needed. Also, ask your prescriber to
recommend a lotion or cream if drying or chapping develops.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
10
These are not all of Accutane’s possible side effects. Your prescriber or pharmacist can give you more
detailed information that is written for healthcare professionals.
Be sure to return to your prescriber as scheduled. He or she will want to check your progress with
Accutane.
Medicines are sometimes prescribed for purposes other than those listed in this brochure. Patients
should ask their prescriber about any concerns. Accutane should not be used for a condition other than
that for which it is prescribed.
After your treatment is completed
For female patients:
• You must continue using 2 separate, effective forms of contraception (birth control) for 1 month after
your treatment with Accutane has ended. This is because it takes time for all of the Accutane to leave
your bloodstream.
For all patients:
• Like most patients, you may find that your skin continues to improve even after completing a course
of treatment with Accutane. However, some patients treated with Accutane have needed a second
course of therapy for satisfactory results. If this is necessary for you, the second course of therapy may
begin 8 or more weeks after the first course.
• Do not donate blood for 1 month after your treatment with Accutane has ended. This is because it
takes time for all of the Accutane to leave your bloodstream.
• Do not give leftover Accutane to anyone. It can cause birth defects and other serious health problems.
Contraception Counseling Referral Program
Expert Advice At No Cost
((PPP Logo))
Before you can start taking Accutane, you have to be sure that you are not pregnant and that you
understand how to avoid pregnancy. That’s why Roche Laboratories Inc., the manufacturer of
Accutane, will pay for you to go to a contraception counselor. This specialist will provide you with
expert counseling about birth control (contraception).
This counseling is very important, even if you already feel you know about birth control, and even if
you are not having sex or do not plan to have sex.
6 Simple Instructions
1 Make an appointment to see a contraception counselor and give him/her the attached forms. The
counselor should call your prescriber if there are any questions about why
you are there or about how the program works.
2 Notify your prescriber after you have had contraception counseling.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
11
3 Ask the contraception counselor to mail a copy of the form to your Accutane prescriber.
You will not get your first prescription for Accutane until your prescriber has received this signed form
and you have negative results from 2 urine or serum pregnancy tests. Your first test will be obtained as
a screening test and the second test will be obtained as a confirmation test during the first 5 days of the
menstrual period just before beginning Accutane therapy or as instructed by your prescriber.
4 You must use 2 separate, effective methods of birth control, at the same time, for at least 1 month
before treatment, during treatment and for at least 1 month after treatment with Accutane.
5 You are not required to pay any charges for the counseling by the contraception counselor. The
counselor should follow the instructions on the attached forms. The fee will be paid by Roche
Laboratories Inc.
Accutane Prescriber’s Referral Form
((PPP Logo))
Complete for Patients Being Referred for Contraception Counseling.
This patient, _____________________________________, is being considered for treatment with
Accutane (isotretinoin). She has been referred to you for contraception counseling before she receives
a prescription for Accutane.
Accutane is a potent teratogen; therefore, it is essential to rule out pregnancy before her treatment
begins and for you to fully inform the patient about effective contraception. The typical course of
therapy with Accutane is 15 to 20 weeks in length. The patient must choose 2 separate, effective forms
of contraception to be used simultaneously for this period, for at least 1 month preceding and 1 month
following therapy. According to the Accutane package insert, the following are considered effective
forms of contraception:
Primary: Tubal ligation, partner’s vasectomy, intrauterine devices, birth control pills, and
topical/injectable/implantable/insertable hormonal birth control products
Secondary: Diaphragms, latex condoms, and cervical caps: each must be used with a spermicide
The patient must choose at least 1 primary form of contraception.
Please explain the patient’s options for contraception, the risk of possible contraceptive failure and the
requirements for achieving maximal effectiveness with her chosen methods. Please inform me if the
patient does not choose 2 methods of contraception. The patient should also be counseled about
emergency contraception.
Therapy cannot begin until pregnancy has been ruled out by negative results from 2 pregnancy tests.
The first test is to be done by me as a screening test, and the second test is to be done, as a
confirmation test, during the first 5 days of the menstrual period immediately preceding the beginning
of Accutane therapy or, if they have amenorrhea, it should be done at least 11 days after the patient’s
last unprotected (without using 2 forms of contraception) act of sexual intercourse.
Accutane Prescriber’s name___________________________________________
(Please affix label, or type or print clearly)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
12
Address________________________________
Telephone ________________________________
Accutane Prescriber’s signature____________________________Date_____________
Record of contraception counseling to be sent to Accutane prescriber
I have provided the following for your patient _____________________________
(Name)
[] Comprehensive contraception counseling.
[] Information about emergency contraception.
[] The patient has had a negative pregnancy test on ______________.
(Date)
The patient has chosen 2 methods of contraception.
[] Yes [] No
Primary method _____________________________
Secondary method _____________________________
Name _____________________________________
(Please affix label, or type or print clearly)
Address _____________________________
Telephone _____________________________
Contraception Counselor’s signature __________________________ Date________
Accutane Prescriber Copy
18-013A-101-008-1102
((NCR FORM [3-part/part 2] ))
Accutane Prescriber’s Referral Form
((PPP Logo))
Complete for Patients Being Referred for Contraception Counseling.
This patient, _____________________________________, is being considered for treatment with
Accutane (isotretinoin). She has been referred to you for contraception counseling before she receives
a prescription for Accutane.
Accutane is a potent teratogen; therefore, it is essential to rule out pregnancy before her treatment
begins and for you to fully inform the patient about effective contraception. The typical course of
therapy with Accutane is 15 to 20 weeks in length. The patient must choose 2 separate, effective forms
of contraception to be used simultaneously for this period, for at least 1 month preceding and 1 month
following therapy. According to the Accutane package insert, the following are considered effective
forms of contraception:
Primary: Tubal ligation, partner’s vasectomy, intrauterine devices, birth control pills, and
topical/injectable/implantable/insertable hormonal birth control products
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
13
Secondary: Diaphragms, latex condoms, and cervical caps: each must be used with a spermicide
The patient must choose at least 1 primary form of contraception.
Please explain the patient’s options for contraception, the risk of possible contraceptive failure and the
requirements for achieving maximal effectiveness with her chosen methods. Please inform me if the
patient does not choose 2 methods of contraception. The patient should also be counseled about
emergency contraception.
Therapy cannot begin until pregnancy has been ruled out by negative results from 2 pregnancy tests.
The first test is to be done by me as a screening test, and the second test is to be done, as a
confirmation test, during the first 5 days of the menstrual period immediately preceding the beginning
of Accutane therapy or, if they have amenorrhea, it should be done at least 11 days after the patient’s
last unprotected (without using 2 forms of contraception) act of sexual intercourse.
Accutane Prescriber’s name_________________________________________
(Please affix label, or type or print clearly)
Address________________________________
Telephone ________________________________
Accutane Prescriber’s signature____________________________Date_____________
Record of contraception counseling to be sent to Accutane prescriber
I have provided the following for your patient _____________________________
(Name)
[] Comprehensive contraception counseling.
[] Information about emergency contraception.
[] The patient has had a negative pregnancy test on ______________.
(Date)
The patient has chosen 2 methods of contraception.
[] Yes [] No
Primary method _____________________________
Secondary method _____________________________
Name _______________________________________
(Please affix label, or type or print clearly)
Address _____________________________
Telephone _____________________________
Contraception Counselor’s signature __________________________ Date________
Contraception Counselor Copy
18-013A-101-008-1102
((Back of NCR))
Reimbursement
NOTE: Reimbursement is offered only for contraception counseling. Other services that may be
provided during this visit are not eligible for reimbursement.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
14
The prescriber who actually prescribes Accutane (isotretinoin) is not eligible to use this reimbursement
provision.
REIMBURSEMENT INSTRUCTIONS
To receive reimbursement, you must call a toll-free number and enter the designated branch for
reimbursement. (If you are calling from a rotary phone, you will be forwarded to an operator who will
direct your call.) After you have provided all the requested information, a check will be sent to you by
first class mail.
Steps: Dial 1-800-93-ROCHE (1-800-937-6243).
• You will hear recorded instructions on how to obtain reimbursement as a contraception counselor.
• You will be asked to provide the following information:
- Your name and address
- Your office phone number
- Name of graduate school from which you graduated
- Year of graduation
- The name and address of the referring Accutane prescriber
- The patient’s name
- Whether you have provided contraception counseling and information on emergency
contraception
- Your normal and customary charge for providing these services
• You will have an opportunity to record information for up to 5 patients on one call.
• A check will then be processed and mailed to you within 10 days.
• To check on the status of a previous request, you will need only to provide your name, address and
phone number. A representative will contact you to update your request status.
NOTE TO CONSULTANTS: By participating in this program you agree to provide Roche with access
to additional information should it become necessary to confirm the appropriateness of this request for
reimbursement. Roche reserves the right to place limitations on reimbursements or deny
reimbursements in certain situations.
((NCR FORM [3-part/part 3] ))
Accutane Prescriber’s Referral Form
((PPP Logo))
Complete for Patients Being Referred for Contraception Counseling.
This patient, _____________________________________, is being considered for treatment with
Accutane (isotretinoin). She has been referred to you for contraception counseling before she receives
a prescription for Accutane.
Accutane is a potent teratogen; therefore, it is essential to rule out pregnancy before her treatment
begins and for you to fully inform the patient about effective contraception. The typical course of
therapy with Accutane is 15 to 20 weeks in length. The patient must choose 2 separate, effective forms
of contraception to be used simultaneously for this period, for at least 1 month preceding and 1 month
following therapy. According to the Accutane package insert, the following are considered effective
forms of contraception:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
15
Primary: Tubal ligation, partner’s vasectomy, intrauterine devices, birth control pills, and
topical/injectable/implantable/insertable hormonal birth control products
Secondary: Diaphragms, latex condoms, and cervical caps: each must be used with a spermicide
The patient must choose at least 1 primary form of contraception.
Please explain the patient’s options for contraception, the risk of possible contraceptive failure and the
requirements for achieving maximal effectiveness with her chosen methods. Please inform me if the
patient does not choose 2 methods of contraception. The patient should also be counseled about
emergency contraception.
Therapy cannot begin until pregnancy has been ruled out by negative results from 2 pregnancy tests.
The first test is to be done by me as a screening test, and the second test is to be done, as a
confirmation test, during the first 5 days of the menstrual period immediately preceding the beginning
of Accutane therapy or, if they have amenorrhea, it should be done at least 11 days after the patient’s
last unprotected (without using 2 forms of contraception) act of sexual intercourse.
Accutane Prescriber’s name_________________________________________
(Please affix label, or type or print clearly)
Address________________________________
Telephone ________________________________
Accutane Prescriber’s signature____________________________Date_____________
Record of contraception counseling to be sent to Accutane prescriber
I have provided the following for your patient _____________________________
(Name)
[] Comprehensive contraception counseling.
[] Information about emergency contraception.
[] The patient has had a negative pregnancy test on ______________.
(Date)
The patient has chosen 2 methods of contraception.
[] Yes [] No
Primary method _____________________________
Secondary method _____________________________
Name ______________________________________
(Please affix label, or type or print clearly)
Address _____________________________
Telephone _____________________________
Contraception Counselor’s signature __________________________ Date________
Return this copy to Accutane Prescriber
18-013A-101-008-1102
((Back of NCR))
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
16
Reimbursement
NOTE: Reimbursement is offered only for contraception counseling. Other services that may be
provided during this visit are not eligible for reimbursement.
The prescriber who actually prescribes Accutane (isotretinoin) is not eligible to use this reimbursement
provision.
REIMBURSEMENT INSTRUCTIONS
To receive reimbursement, you must call a toll-free number and enter the designated branch for
reimbursement. (If you are calling from a rotary phone, you will be forwarded to an operator who will
direct your call.) After you have provided all the requested information, a check will be sent to you by
first class mail.
Steps: Dial 1-800-93-ROCHE (1-800-937-6243).
• You will hear recorded instructions on how to obtain reimbursement as a contraception counselor.
• You will be asked to provide the following information:
- Your name and address
- Your office phone number
- Name of graduate school from which you graduated
- Year of graduation
- The name and address of the referring Accutane prescriber
- The patient’s name
- Whether you have provided contraception counseling and information on emergency
contraception
- Your normal and customary charge for providing these services
• You will have an opportunity to record information for up to 5 patients on one call.
• A check will then be processed and mailed to you within 10 days.
• To check on the status of a previous request, you will need only to provide your name, address and
phone number. A representative will contact you to update your request status.
NOTE TO CONSULTANTS: By participating in this program you agree to provide Roche with access
to additional information should it become necessary to confirm the appropriateness of this request for
reimbursement. Roche reserves the right to place limitations on reimbursements or deny
reimbursements in certain situations.
PLEASE COMPLETE THIS SECTION WITH
YOUR PRESCRIBER OR NURSE
((TAB Copy))
SECTION 2
CONSENT
((SI International Logo))
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
17
Accutane® Survey Enrollment Form – FEMALES ONLY
purpose of the Accutane survey
The Accutane Survey is designed to gather information about how women use Accutane (isotretinoin).
The Accutane Survey seeks information on a number of factors including: patient understanding of
how Accutane is to be used; previous acne therapy; patient understanding of the hazards of becoming
pregnant while taking Accutane; the methods of contraception used during therapy with Accutane; and,
if pregnancy occurs, the reason
why and the outcome. The information you provide will help in assessing the System to Manage
Accutane Related Teratogenicity™ (S.M.A.R.T.™) risk management program.
HOW THE ACCUTANE SURVEY WORKS
Your participation is voluntary, but it is important that all female patients who use Accutane enroll in
this Survey. Women are asked to complete a few brief questionnaires by mail during and after their
Accutane treatment.
CONFIDENTIALITY
SI International conducts the Survey with its clinical consultants. We will keep any information that
would identify you strictly confidential. Your confidentiality will be legally protected through a federal
Certificate of Confidentiality granted to this Survey.
PAYMENT
To compensate you for participating in the Survey, we will send $20 when you enroll and another $10
when you complete your last questionnaire.
ENROLLMENT
Please complete this form now, seal it, and mail it postage-free today (your prescriber will mail it for
you if you’d like). If you prefer to enroll by telephone, please do so by calling 1-888-860-7357.
I agree to participate in the Accutane Survey described above.
Please fold where indicated and glue shut prior to mailing.
(Please print)
Name______________________Date of birth______________________Sex_______
First Last
Month/Day/Year
Street address______________________
City______________________ State_________ Zip_________________
Telephone number_______________The best time to reach me by phone__________
Area Code
Prescriber’s name______________________
First Last
Prescriber’s city______________________Prescriber’s state______________________
Month/Day/Year
Month/Day/Year
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
18
Date Accutane treatment began______________________
Signature______________________Date_________
Please be sure that all information is complete.
18-013B-101-008-1102
((BRM Information))
((NCR FORM [2-part/part 1] ))
ACCUTANE® (isotretinoin)
Informed Consent/PATIENT AGREEMENT
(for all patients)
To be completed by patient (parent or guardian if patient is under age 18) and signed by the prescriber
Read each item below and initial in the space provided if you understand each item and agree to follow
your prescriber’s instructions. A parent or guardian of a patient under age 18 must also read and
understand each item before signing the agreement.
Do not sign this agreement and do not take Accutane if there is anything that you do not understand
about all the information you have received about using Accutane.
1. I, ___________________________________________________________,
(Patient’s Name)
understand that Accutane is a medicine used to treat severe nodular acne that cannot be cleared up by
any other acne treatments, including antibiotics. In severe nodular acne, many red, swollen, tender
lumps form in the skin. If untreated, severe nodular acne can lead to permanent scars.
Initials: ______
2. My prescriber has told me about my choices for treating my acne.
Initials: ______
3. I understand that there are serious side effects that may happen while I am taking Accutane. These
have been explained to me. These side effects include serious birth defects in babies of pregnant
females. (Note: There is a second Informed Consent form for female patients concerning birth defects.)
Initials: ______
4. I understand that some patients, while taking Accutane or soon after stopping Accutane, have
become depressed or developed other serious mental problems. Symptoms of these problems include
sad, “anxious” or empty mood, irritability, anger, loss of pleasure or interest in social or sports
activities, sleeping too much or too little, changes in weight or appetite, school or work performance
going down, or trouble concentrating. Some patients taking Accutane have had thoughts about hurting
themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own
lives. And some people have ended their own lives. There were reports that some of these people did
not appear depressed. There have been reports of patients on Accutane becoming aggressive or violent.
No one knows if Accutane caused these behaviors or if they would have happened even if the person
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
19
did not take Accutane. Some people have had other signs of depression while taking Accutane (see
#7).
Initials: ______
5. Before I start taking Accutane, I agree to tell my prescriber if, to the best of my knowledge, I have
ever had symptoms of depression (see #7), been psychotic, attempted suicide, had any other mental
problems, or take medicine for any of these problems. Being psychotic means having a loss of contact
with reality, such as hearing voices or seeing things that are not there.
Initials: ______
6. Before I start taking Accutane, I agree to tell my prescriber if, to the best of my knowledge, anyone
in my family has ever had symptoms of depression, been psychotic, attempted suicide, or had any
other serious mental problems.
Initials: ______
7. Once I start taking Accutane, I agree to stop using Accutane and tell my prescriber right away if any
of the following happen. I:
• Start to feel sad or have crying spells
• Lose interest in activities I once enjoyed
• Sleep too much or have trouble sleeping
• Become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of
violence)
• Have a change in my appetite or body weight
• Have trouble concentrating
• Withdraw from my friends or family
• Feel like I have no energy
• Have feelings of worthlessness or inappropriate guilt
• Start having thoughts about hurting myself or taking my own life (suicidal thoughts)
Initials: ______
8. I agree to return to see my prescriber every month I take Accutane to get a new prescription for
Accutane, to check my progress, and to check for signs of side effects.
Initials: ______
9. Accutane will be prescribed just for me — I will not share Accutane with other people because it
may cause serious side effects, including birth defects.
Initials: ______
10. I will not give blood while taking Accutane or for 1 month after I stop taking Accutane. I
understand that if someone who is pregnant gets my donated blood, her baby may be exposed to
Accutane and may be born with serious birth defects.
Initials: ______
11. I have read the Patient Product Information, Important Information Concerning Your Treatment
with Accutane® (isotretinoin) and other materials my prescriber gave me containing important safety
information about Accutane. I understand all the information I received.
Initials: ______
12. My prescriber and I have decided I should take Accutane. I understand that each of
my Accutane prescriptions must have a yellow self-adhesive Accutane Qualification Sticker on it. I
understand that I can stop taking Accutane at any time. I agree to tell my prescriber if I stop taking
Accutane.
Initials: ______
I now authorize my prescriber _________________________________________ to begin my
treatment with Accutane.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
20
Patient Signature____________________Date______________
Parent/Guardian Signature (if under age 18)_________________Date _______________
Patient Name (print)______________________________
Patient Address__________________________Telephone ( ____ ) ______________
_______________________________________________________________________
I have:
• fully explained to the patient,_______________, the nature and purpose of Accutane treatment,
including its benefits and risks
• given the patient the appropriate educational materials, Be Smart, Be Safe, Be Sure, for Accutane and
asked the patient if he/she has any questions regarding his/her treatment
with Accutane
• answered those questions to the best of my ability
• placed the yellow self-adhesive Accutane Qualification Sticker on the prescription.
Prescriber Signature___________________________Date__________________
Issued: November 2002
Prescriber Copy
18-013C-101-008-1102
((NCR FORM [2-part/part 2] ))
ACCUTANE® (isotretinoin)
Informed Consent/PATIENT AGREEMENT
(for all patients)
To be completed by patient (parent or guardian if patient is under age 18) and signed by the prescriber
Read each item below and initial in the space provided if you understand each item and agree to follow
your prescriber’s instructions. A parent or guardian of a patient under age 18 must also read and
understand each item before signing the agreement.
Do not sign this agreement and do not take Accutane if there is anything that you do not understand
about all the information you have received about using Accutane.
1. I, ___________________________________________________________,
(Patient’s Name)
understand that Accutane is a medicine used to treat severe nodular acne that cannot be cleared up by
any other acne treatments, including antibiotics. In severe nodular acne, many red, swollen, tender
lumps form in the skin. If untreated, severe nodular acne can lead to permanent scars.
Initials: ______
2. My prescriber has told me about my choices for treating my acne.
Initials: ______
3. I understand that there are serious side effects that may happen while I am taking Accutane. These
have been explained to me. These side effects include serious birth defects in babies of pregnant
females. (Note: There is a second Informed Consent form for female patients concerning birth defects.)
Initials: ______
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
21
4. I understand that some patients, while taking Accutane or soon after stopping Accutane, have
become depressed or developed other serious mental problems. Symptoms of these problems include
sad, “anxious” or empty mood, irritability, anger, loss of pleasure or interest in social or sports
activities, sleeping too much or too little, changes in weight or appetite, school or work performance
going down, or trouble concentrating. Some patients taking Accutane have had thoughts about hurting
themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own
lives. And some people have ended their own lives. There were reports that some of these people did
not appear depressed. There have been reports of patients on Accutane becoming aggressive or violent.
No one knows if Accutane caused these behaviors or if they would have happened even if the person
did not take Accutane. Some people have had other signs of depression while taking Accutane (see
#7).
Initials: ______
5. Before I start taking Accutane, I agree to tell my prescriber if, to the best of my knowledge, I have
ever had symptoms of depression (see #7), been psychotic, attempted suicide, had any other mental
problems, or take medicine for any of these problems. Being psychotic means having a loss of contact
with reality, such as hearing voices or seeing things that are not there.
Initials: ______
6. Before I start taking Accutane, I agree to tell my prescriber if, to the best of my knowledge, anyone
in my family has ever had symptoms of depression, been psychotic, attempted suicide, or had any
other serious mental problems.
Initials: ______
7. Once I start taking Accutane, I agree to stop using Accutane and tell my prescriber right away if any
of the following happen. I:
• Start to feel sad or have crying spells
• Lose interest in activities I once enjoyed
• Sleep too much or have trouble sleeping
• Become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of
violence)
• Have a change in my appetite or body weight
• Have trouble concentrating
• Withdraw from my friends or family
• Feel like I have no energy
• Have feelings of worthlessness or inappropriate guilt
• Start having thoughts about hurting myself or taking my own life (suicidal thoughts)
Initials: ______
8. I agree to return to see my prescriber every month I take Accutane to get a new prescription for
Accutane, to check my progress, and to check for signs of side effects.
Initials: ______
9. Accutane will be prescribed just for me — I will not share Accutane with other people because it
may cause serious side effects, including birth defects.
Initials: ______
10. I will not give blood while taking Accutane or for 1 month after I stop taking Accutane. I
understand that if someone who is pregnant gets my donated blood, her baby may be exposed to
Accutane and may be born with serious birth defects.
Initials: ______
11. I have read the Patient Product Information, Important Information Concerning Your Treatment
with Accutane® (isotretinoin) and other materials my prescriber gave me containing important safety
information about Accutane. I understand all the information I received.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
22
Initials: ______
12. My prescriber and I have decided I should take Accutane. I understand that each of
my Accutane prescriptions must have a yellow self-adhesive Accutane Qualification Sticker on it. I
understand that I can stop taking Accutane at any time. I agree to tell my prescriber if I stop taking
Accutane.
Initials: ______
I now authorize my prescriber _________________________________________ to begin my
treatment with Accutane.
Patient Signature____________________Date______________
Parent/Guardian Signature (if under age 18)_________________Date _______________
Patient Name (print)______________________________
Patient Address__________________________Telephone ( ____ ) ______________
_______________________________________________________________________
I have:
• fully explained to the patient,__________________, the nature and purpose of Accutane treatment,
including its benefits and risks
• given the patient the appropriate educational materials, Be Smart, Be Safe, Be Sure, for Accutane and
asked the patient if he/she has any questions regarding his/her treatment
with Accutane
• answered those questions to the best of my ability
• placed the yellow self-adhesive Accutane Qualification Sticker on the prescription.
Prescriber Signature___________________________Date__________________
Issued: November 2002
Patient Copy
18-013C-101-008-1102
((NCR FORM [2-part/part 1] ))
ACCUTANE® (isotretinoin)
PATIENT information/consent
(for all female patients)
To be completed by patient (parent or guardian if patient is under age 18) and signed by the prescriber
Read each item below and initial in the space provided if you understand each item and agree to follow
your prescriber’s instructions. A parent or guardian of a patient under age 18 must also read and
understand each item before signing the agreement.
Do not sign this agreement and do not take Accutane if there is anything that you do not understand
about all the information you have received about using Accutane.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
23
(Patient’s Name)
1. I understand that there is a very high risk that my unborn baby could have severe birth defects if I
am pregnant or become pregnant while taking Accutane in any amount even for short periods of time.
This is why I must not be pregnant while taking Accutane.
Initial:
2. I understand that I must not take Accutane (isotretinoin) if I am pregnant.
Initial:
3. I understand that I must not get pregnant during the entire time of my treatment and for
1 month after the end of my treatment with Accutane.
Initial:
4. I understand that I must avoid sexual intercourse completely, or I must use 2 separate, effective
forms of birth control (contraception) at the same time. The only exception is if I have had surgery to
remove the womb (a hysterectomy).
Initial:
5. I understand that birth control pills and topical/injectable/implantable/insertable hormonal birth
control products are among the most effective forms of birth control. However, any form of birth
control can fail. Therefore, I must use 2 different methods at the same time, every time I have sexual
intercourse, even if 1 of the methods I choose is birth control pills or
topical/injectable/implantable/insertable hormonal birth control.
Initial:
6. I will talk with my prescriber about any drugs or herbal products I plan to take during my Accutane
treatment because hormonal birth control methods (for example, birth control pills) may not work if I
am taking certain drugs or herbal products (for example, St. John’s Wort).
Initial:
7. I understand that the following are considered effective forms of birth control:
Primary: Tubal ligation (tying my tubes), partner’s vasectomy, birth control pills,
topical/injectable/implantable/insertable hormonal birth control products, and an IUD (intrauterine
device).
Secondary: Diaphragms, latex condoms, and cervical caps. Each must be used with a spermicide,
which is a special cream or jelly that kills sperm.
I understand that at least 1 of my 2 methods of birth control must be a primary method.
Initial:
8. I understand that I may receive a free contraceptive (birth control) counseling session from a
prescriber or other family planning expert. My Accutane prescriber can give me an Accutane Patient
Referral Form for this free consultation.
Initial:
9. I understand that I must begin using the birth control methods I have chosen as described above at
least 1 month before I start taking Accutane.
Initial:
10. I understand that I cannot get a prescription for Accutane unless I have 2 negative pregnancy test
results. The first pregnancy test should be done when my prescriber
decides to prescribe Accutane. The second pregnancy test should be done during the first 5 days of my
menstrual period right before starting Accutane therapy, or as instructed by my prescriber. I will then
have 1 pregnancy test every month during my Accutane therapy.
Initial:
11. I understand that I should not start taking Accutane until I am sure that I am not pregnant and have
negative results from 2 pregnancy tests.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
24
Initial:
12. I have read and understand the materials my prescriber has given to me, including the Patient
Product Information, Important Information Concerning Your Treatment with Accutane®
(isotretinoin). My prescriber gave me and asked me to watch the videos about contraception. I was told
about a confidential counseling line that I may call for more information about birth control. I have
received information on emergency contraception (birth control).
Initial:
13. I understand that I must stop taking Accutane right away and inform my prescriber if I get
pregnant, miss my menstrual period, stop using birth control, or have sexual intercourse without using
my 2 methods of birth control at any time.
Initial:
14. My prescriber gave me information about the confidential Accutane Survey and explained to me
how important it is to take part in the Accutane Survey.
Initial:
15. I understand that the yellow self-adhesive Accutane Qualification Sticker on my prescription for
Accutane means that I am qualified to receive an Accutane prescription, because I:
• have had 2 negative urine or serum pregnancy tests before receiving the initial Accutane prescription.
I must have a negative result from a urine or serum pregnancy test repeated each month prior to my
receiving each subsequent prescription.
• have selected and committed to use 2 forms of effective contraception simultaneously, at least 1 of
which must be a primary form, unless absolute abstinence is the chosen method, or I have undergone a
hysterectomy. I must use 2 forms of contraception for at least 1 month prior to initiation of Accutane
therapy, during therapy, and for 1 month after discontinuing therapy. I must receive counseling,
repeated on a monthly basis, about contraception and behaviors associated with an increased risk of
pregnancy.
• have signed a Patient Information/Consent form that contains warnings about the risk of potential
birth defects if I am pregnant or become pregnant and my unborn baby is exposed to isotretinoin.
• have been informed of the purpose and importance of participating in the Accutane Survey and given
the opportunity to enroll.
My prescriber has answered all my questions about Accutane and I understand that it is my
responsibility not to get pregnant during Accutane treatment or for 1 month after I stop taking
Accutane.
Initial:
I now authorize my prescriber _________________________________________ to begin my
treatment with Accutane.
Patient Signature________________________Date_____________
Parent/Guardian Signature (if under age 18) _____________________Date__________
Patient Name (print)_________________________
Patient Address_________________________Telephone ( ___ ) ______________
_______________________________________________________________________
I have:
• fully explained to the patient,____________________________ , the nature and purpose of Accutane
treatment, including its benefits and risks
• given the patient the appropriate educational materials, Be Smart, Be Safe, Be Sure, for Accutane and
asked the patient if he/she has any questions regarding his/her treatment with Accutane
• answered those questions to the best of my ability
• placed the yellow self-adhesive Accutane Qualification Sticker on the prescription.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
25
Prescriber Signature______________________Date___________
Issued: November 2002
Prescriber Copy
18-013D-101-008-1102
((NCR FORM [2-part/part 2] ))
ACCUTANE® (isotretinoin)
PATIENT information/consent
(for all female patients)
To be completed by patient (parent or guardian if patient is under age 18) and signed by the prescriber
Read each item below and initial in the space provided if you understand each item and agree to follow
your prescriber’s instructions. A parent or guardian of a patient under age 18 must also read and
understand each item before signing the agreement.
Do not sign this agreement and do not take Accutane if there is anything that you do not understand
about all the information you have received about using Accutane.
(Patient’s Name)
1. I understand that there is a very high risk that my unborn baby could have severe birth defects if I
am pregnant or become pregnant while taking Accutane in any amount even for short periods of time.
This is why I must not be pregnant while taking Accutane.
Initial:
2. I understand that I must not take Accutane (isotretinoin) if I am pregnant.
Initial:
3. I understand that I must not get pregnant during the entire time of my treatment and for
1 month after the end of my treatment with Accutane.
Initial:
4. I understand that I must avoid sexual intercourse completely, or I must use 2 separate, effective
forms of birth control (contraception) at the same time. The only exception is if I have had surgery to
remove the womb (a hysterectomy).
Initial:
5. I understand that birth control pills and topical/injectable/implantable/insertable hormonal birth
control products are among the most effective forms of birth control. However, any form of birth
control can fail. Therefore, I must use 2 different methods at the same time, every time I have sexual
intercourse, even if 1 of the methods I choose is birth control pills or
topical/injectable/implantable/insertable hormonal birth control.
Initial:
6. I will talk with my prescriber about any drugs or herbal products I plan to take during my Accutane
treatment because hormonal birth control methods (for example, birth control pills) may not work if I
am taking certain drugs or herbal products (for example, St. John’s Wort).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
26
Initial:
7. I understand that the following are considered effective forms of birth control:
Primary:
Tubal ligation (tying my tubes), partner’s vasectomy, birth control
pills, topical/injectable/implantable/insertable hormonal birth control products, and an IUD
(intrauterine device).
Secondary:
Diaphragms, latex condoms, and cervical caps. Each must be used
with a spermicide, which is a special cream or jelly that kills sperm.
I understand that at least 1 of my 2 methods of birth control must be a primary method.
Initial:
8. I understand that I may receive a free contraceptive (birth control) counseling session from a
prescriber or other family planning expert. My Accutane prescriber can give me an Accutane Patient
Referral Form for this free consultation.
Initial:
9. I understand that I must begin using the birth control methods I have chosen as described above at
least 1 month before I start taking Accutane.
Initial:
10. I understand that I cannot get a prescription for Accutane unless I have 2 negative pregnancy test
results. The first pregnancy test should be done when my prescriber decides to prescribe Accutane. The
second pregnancy test should be done during the first 5 days of my menstrual period right before
starting Accutane therapy, or as instructed by my prescriber. I will then have 1 pregnancy test every
month during my Accutane therapy.
Initial:
11. I understand that I should not start taking Accutane until I am sure that I am not pregnant and have
negative results from 2 pregnancy tests.
Initial:
12. I have read and understand the materials my prescriber has given to me, including the Patient
Product Information, Important Information Concerning Your Treatment with Accutane®
(isotretinoin). My prescriber gave me and asked me to watch the videos about contraception. I was told
about a confidential counseling line that I may call for more information about birth control. I have
received information on emergency contraception (birth control).
Initial:
13. I understand that I must stop taking Accutane right away and inform my prescriber if I get
pregnant, miss my menstrual period, stop using birth control, or have sexual intercourse without using
my 2 methods of birth control at any time.
Initial:
14. My prescriber gave me information about the confidential Accutane Survey and explained to me
how important it is to take part in the Accutane Survey.
Initial:
15. I understand that the yellow self-adhesive Accutane Qualification Sticker on my prescription for
Accutane means that I am qualified to receive an Accutane prescription, because I:
• have had 2 negative urine or serum pregnancy tests before receiving the initial Accutane prescription.
I must have a negative result from a urine or serum pregnancy test repeated each month prior to my
receiving each subsequent prescription.
• have selected and committed to use 2 forms of effective contraception simultaneously, at least 1 of
which must be a primary form, unless absolute abstinence is the chosen method, or I have undergone a
hysterectomy. I must use 2 forms of contraception for at least 1 month prior to initiation of Accutane
therapy, during therapy, and for 1 month after discontinuing therapy. I must receive counseling,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
27
repeated on a monthly basis, about contraception and behaviors associated with an increased risk of
pregnancy.
• have signed a Patient Information/Consent form that contains warnings about the risk of potential
birth defects if I am pregnant or become pregnant and my unborn baby is exposed to isotretinoin.
• have been informed of the purpose and importance of participating in the Accutane Survey and given
the opportunity to enroll.
My prescriber has answered all my questions about Accutane and I understand that it is my
responsibility not to get pregnant during Accutane treatment or for 1 month after I stop taking
Accutane.
Initial:
I now authorize my prescriber _________________________________________ to begin my
treatment with Accutane.
Patient Signature________________________Date_____________
Parent/Guardian Signature (if under age 18) _____________________Date__________
Patient Name (print)_________________________
Patient Address_________________________Telephone ( ___ ) ______________
_______________________________________________________________________
I have:
• fully explained to the patient,____________________________ , the nature and purpose of Accutane
treatment, including its benefits and risks
• given the patient the appropriate educational materials, Be Smart, Be Safe, Be Sure, for Accutane and
asked the patient if he/she has any questions regarding his/her treatment with Accutane
• answered those questions to the best of my ability
• placed the yellow self-adhesive Accutane Qualification Sticker on the prescription.
Prescriber Signature______________________Date___________
Issued: November 2002
Patient Copy
18-013D-101-008-1102
((NCR FORM [2-part/part 1] ))
Patient Qualification Form
for Pregnancy Prevention and
Contraception Compliance
((PPP Logo))
To be completed by the patient
Accutane (isotretinoin) is a very powerful medicine with the potential for serious Adverse Events. It is
used to treat severe nodular acne that did not get better with other treatments, including oral
antibiotics. Accutane can cause severe birth defects to your unborn baby if you use it while you are
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
28
pregnant. It is contraindicated in females of childbearing potential unless your prescriber can qualify
you with the following statements.
Patient qualification checklist
1. I am required to have 2 negative pregnancy tests showing that I am not pregnant before my
prescriber can prescribe Accutane. I agree to schedule regular monthly appointments throughout my
therapy for pregnancy tests and for other tests to monitor my body’s response to Accutane. It is
important to my health and well-being to keep every scheduled appointment faithfully. 1. [ ] YES [ ]
NO
2. I am aware of the effects that Accutane may have on my unborn baby if I become pregnant during
treatment and for 1 month following treatment. I have selected as my:
primary contraception method___________________________
and
secondary contraception method_________________________.
I will use both of these methods at the same time while on therapy and for 1 month afterward. 2. [ ]
YES [ ] NO
3. My prescriber has given both oral and written warnings of the hazards of taking Accutane during
pregnancy (exposing the fetus to the drug), and I have signed the Patient Information/Consent Form.
3. [ ] YES [ ] NO
4. I have been given the opportunity to participate in the Accutane Survey. 4. [ ] YES [ ] NO
______________________________________________
Patient’s Name (print)
Patient’s Signature
Date
Prescriber Copy
18-013E-101-008-1102
((NCR FORM [2-part/part 1] ))
Patient Qualification Form
for Pregnancy Prevention and
Contraception Compliance
((PPP Logo))
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
29
To be completed by the patient
Accutane (isotretinoin) is a very powerful medicine with the potential for serious Adverse Events. It is
used to treat severe nodular acne that did not get better with other treatments, including oral
antibiotics. Accutane can cause severe birth defects to your unborn baby if you use it while you are
pregnant. It is contraindicated in females of childbearing potential unless your prescriber can qualify
you with the following statements.
Patient qualification checklist
1. I am required to have 2 negative pregnancy tests showing that I am not pregnant before my
prescriber can prescribe Accutane. I agree to schedule regular monthly appointments throughout my
therapy for pregnancy tests and for other tests to monitor my body’s response to Accutane. It is
important to my health and well-being to keep every scheduled appointment faithfully. 1. [ ] YES [ ]
NO
2. I am aware of the effects that Accutane may have on my unborn baby if I become pregnant during
treatment and for 1 month following treatment. I have selected as my:
primary contraception method___________________________
and
secondary contraception method_________________________.
I will use both of these methods at the same time while on therapy and for 1 month afterward. 2. [ ]
YES [ ] NO
3. My prescriber has given both oral and written warnings of the hazards of taking Accutane during
pregnancy (exposing the fetus to the drug), and I have signed the Patient Information/Consent Form.
3. [ ] YES [ ] NO
4. I have been given the opportunity to participate in the Accutane Survey. 4. [ ] YES [ ] NO
______________________________________________
Patient’s Name (print)
Patient’s Signature
Date
Patient Copy
18-013E-101-008-1102
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
30
THIS SECTION CONTAINS MORE
INFORMATION FOR YOU
PLEASE READ THIS SECTION AND REVIEW
THESE DOCUMENTS AS OFTEN AS YOU NEED
((TAB Copy))
section 3
EDUCATION REINFORCEMENT
Preventing Pregnancy
A Guide to Contraception
Before, During and After Treatment with Accutane® (isotretinoin)
Complete the Contraception Knowledge self-assessment located in the back of this booklet
Table of contents
Introduction
Why is this information very important to me?
3.3
My role
What must I do before I can begin to take Accutane (isotretinoin)? 3.4
What must I do during my treatment with Accutane?
3.4
What must I do after I stop taking Accutane?
3.5
Why must I use 2 separate effective methods of birth control?
3.5
What kinds of birth defects occur with Accutane use?
3.5
Contraception Counseling Referral Program 3.6
Preventing pregnancy
Separating the myths from the facts 3.7
How can I be 100% certain that I will not become pregnant?
3.8
What is abstinence? 3.8
Using abstinence
3.8
Reasons women become pregnant
3.9
How can I avoid becoming pregnant?
3.9
Contraception methods
Primary (most effective) methods of birth control
3.10
Secondary (moderately effective) forms of birth control
3.13
Other contraception methods 3.15
Pregnancy and pregnancy testing
Early signs of pregnancy
3.16
Ectopic pregnancies 3.16
Emergency contraception
What is emergency contraception and how does it work?
3.18
When would you use emergency contraception?
3.18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
31
Where can you get emergency contraception?
3.18
Types of emergency contraception
3.19
Your sexual partner
How can I explain the importance of preventing pregnancy while taking Accutane?
3.20
What should I tell my sexual partner about Accutane treatment?
3.20
The Accutane Survey 3.21
Confidential Contraception Counseling Line 3.22
Accutane InfoLine
3.23
Scenes from the video 3.25
Summary
Before you take Accutane
3.26
During Accutane treatment
3.26
After stopping Accutane treatment
3.26
Contraception knowledge self-assessment
3.27
Introduction
Why is this information very important to me?
Your dermatologist may prescribe Accutane to be used in your treatment. Accutane is used to treat the
most severe form of acne (nodular acne) that has not been helped by other therapies, including
systemic antibiotics. Accutane causes severe birth defects. Accutane is indicated only for females who
are not pregnant. This booklet contains very important facts about Accutane that you must know and
understand before you can begin treatment with Accutane.
The section of this booklet called My role explains the birth control (contraception) steps you must
take before you can start taking Accutane; what you must do during Accutane treatment; and what you
must do for 1 month after you stop your Accutane treatment. The severe birth defects that are
associated with Accutane use, and the risks that those deformities will occur if Accutane is taken by a
woman during pregnancy, are discussed.
Of course, knowing these risks, you will want to avoid becoming pregnant while taking Accutane. To
help you, a special Contraception Counseling Referral Program is available from your prescriber that
will pay for you to go to another healthcare professional to receive contraception counseling. Details of
this program are given in the section called Contraception Counseling Referral Program.
Many of the ways that will and will not prevent pregnancy are discussed in the section called
Preventing pregnancy. Emergency contraception or emergency birth control is used to prevent
pregnancy following unprotected intercourse or sex. Details on emergency birth control are provided in
the section called Emergency contraception.
Also, it is extremely important that your sexual partner understand that you must use 2 separate,
effective methods of birth control for 1 month before, during and for 1 month after treatment with
Accutane. It is very important that your sexual partner understand you must not be pregnant and the
special precautions that must be taken during treatment with Accutane and for 1 month after you
completely stop taking Accutane. The section called Your sexual partner is provided to help you as
you talk to your sexual
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
32
partner about his important role in your treatment with Accutane.
Because you need to understand all the facts in this booklet, read it all the way through. Do NOT skip
any section of the booklet. After you have read through the booklet once, read it through again. As you
read through the second time, write down a list of questions for your prescriber to answer. Do not
worry if you think the question is silly or may be unimportant. You have to understand all the facts in
this booklet. Your prescriber wants you to understand everything in this booklet and everything that he
or she tells you about Accutane treatment. The facts in this booklet about Accutane and Accutane
treatment are very important to your health and well-being.
My role
What must I do before I can begin to take Accutane?
You must receive both oral and written warnings of the hazards of taking Accutane (isotretinoin)
during pregnancy and the possibility of birth defects if your unborn baby is exposed to Accutane. You
must also sign the Patient Information/Consent Form.
You must use 2 separate, effective methods of birth control at the same time for at least
1 month—BEFORE taking Accutane—even when one is a hormonal contraceptive method.
You must have negative results for 2 pregnancy tests (either blood or urine tests):
• The first test will be at the time your prescriber decides to prescribe Accutane for you
• The second pregnancy test will be done during the first 5 days of your menstrual period right before
you start taking Accutane, or as directed by your prescriber.
The test measures the amount of a pregnancy hormone you have in your urine or blood. This hormone,
called hCG, begins to increase within 48 hours after you become pregnant, but your test may not show
a positive result until 7 days later. In order to be very sure that the results are negative and that you are
not pregnant, it is important to take the second test when your prescriber tells you to.
These steps must be taken so that you and your prescriber know that you are not pregnant when you
begin taking Accutane.
What must I do during my treatment with Accutane?
1. You must return to your prescriber to obtain a new prescription each month.
2. You must be tested for pregnancy each month before you get another prescription for Accutane.
3. You must continue to use 2 separate, effective methods of birth control at the same time—at all
times during your treatment with Accutane (even when 1 is a hormonal contraceptive method).
These steps must be taken so that you and your prescriber know you are not pregnant while you are
taking Accutane.
You must have the opportunity to join the Accutane Survey. An enrollment form is contained inside
this booklet and in the Accutane blister pak. This confidential survey will collect and analyze data to
help prevent exposure of pregnant women to Accutane.
Remember: No birth control method will work if you do not use it.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
33
Remember: No birth control method will work if you do not use it correctly and consistently (all the
time).
Warning: The effects of alcohol or drugs can impair your judgment, lower your inhibitions and affect
your awareness, which can lead to incorrect use of birth control methods.
What must I do after I stop taking Accutane?
You must continue to use 2 separate, effective methods of birth control at the same time for 1 month
after stopping Accutane treatment—even when 1 is a hormonal contraceptive method—because some
of the Accutane may remain in your body for this period of time after you stop taking it.
You may be worried about risks to your health with certain birth control methods. It is not unusual for
people to have some concerns. You should discuss your concerns about your risks in using the
different birth control methods with your prescriber or contraception counselor.
Why must I use 2 separate, effective methods of birth control?
You must use 2 separate, effective methods of birth control at the same time to prevent pregnancy,
because any birth control method can fail and your baby could be born with severe birth defects if you
are taking Accutane while you are pregnant.
There is an extremely high risk that a deformed baby can result if you become pregnant while taking
Accutane in any amount, even for short periods of time. When an unborn baby is exposed to Accutane,
there is a higher risk of deformities or a miscarriage. Mothers who were taking Accutane when they
got pregnant had deformed infants. This explains the need for the precautions that must be taken
before, during and for 1 month after Accutane use. Remember, not 1 but 2 separate, effective methods
of birth control are required while you are taking Accutane.
What kinds of birth defects occur with Accutane use?
Very severe birth defects have occurred with Accutane use including:
• Severe internal defects: defects that you cannot see—involving the brain (including lower IQ scores),
heart, glands and nervous system.
• Severe external defects: defects that you can see—such as low-set, deformed or absent ears, wide-set
eyes, depressed bridge of nose, enlarged head and small chin, and small or enlarged skull.
Watch the video Be Aware: The Risk of Pregnancy While on Accutane (available from your
prescriber).
((Illustrations of deformed babies))
Line drawing representing some common birth defects associated with Accutane use during
pregnancy. Some of the defects that you can see are deformed eyes, nose, ears or absent ears, enlarged
head and small chin. More severe defects than these can occur, including mental retardation. This
picture does not show all the severe internal defects that may occur, including those of the brain, heart,
glands, and nervous system.
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Contraception Counseling Referral Program
Be sure to ask your prescriber about the Contraception
Counseling Referral Program
Before you can start taking Accutane (isotretinoin), you and your prescriber must be sure that you are
not pregnant and that you understand how to avoid becoming pregnant. Because it is so very important
that you understand how to avoid becoming pregnant while taking Accutane, a special Contraception
Counseling Referral Program has been established by the manufacturer of Accutane.
You or your prescriber can arrange for you to see a contraception counselor who specializes in the
female reproductive system. This healthcare professional will provide you with expert counseling
about birth control.
Even if you feel that you know about birth control, and even if you are not having sex or do not plan to
have sex, this counseling is very important in planning your treatment with Accutane. You will not be
required to pay for the counseling that they may do. Be sure to ask your prescriber about the
Contraception Counseling Referral Program.
Preventing pregnancy
Separating the myths from the facts
There are many myths that you may have heard or read about becoming pregnant. These are simply
NOT true. Here are some of the more common myths and the actual facts.
• MYTH (not true): I cannot become pregnant if I am having sex for the first time.
FACT: There is a possibility that you will become pregnant any time that you have sex.
• MYTH (not true): I cannot become pregnant if I have sex standing up.
FACT: There is a possibility that you will become pregnant any time that you have sex
in any position.
• MYTH (not true): I cannot become pregnant if I do not have an orgasm.
FACT: There is a possibility that you will become pregnant any time that you have sex.
• MYTH (not true): Douching will keep me from getting pregnant.
FACT: Douching does not prevent pregnancy.
• MYTH (not true): I do not have to use birth control every time I have sex.
FACT: Unless you use birth control correctly and every time you have sex, you can become pregnant.
You must always follow directions exactly for any method of birth control. If you do not understand a
direction completely or you are not absolutely sure about directions, ask your healthcare professional.
• MYTH (not true): There is a “safe time of the month” when I cannot become pregnant.
FACT: There is NO safe time. Even fertility awareness methods can fail. You can even become
pregnant if you have sex during your menstrual period.
• MYTH (not true): I cannot become pregnant if my partner withdraws his penis before he ejaculates or
“comes.”
FACT: You can become pregnant even if your male partner ejaculates outside you, away from your
vagina. Fluid that contains sperm can leak from the penis before ejaculation. You can get pregnant
even if your partner does not enter you, if fluid that contains sperm leaks into you.
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• MYTH (not true): I cannot become pregnant because I have not started menstruating (my period).
FACT: You will ovulate (release an egg) before your first menstrual cycle, so you are at risk of
becoming pregnant if you have sexual intercourse.
• MYTH (not true): I cannot become pregnant if I have sex underwater.
FACT: Water does not protect you from becoming pregnant during sexual intercourse.
• MYTH (not true): I cannot become pregnant if I have ovary or womb disease (women’s problems).
FACT: There is a possibility that you will become pregnant any time that you have sex.
• MYTH (not true): My partner is sterile because he had mumps. He has never gotten anyone else
pregnant, so he cannot get me pregnant either.
FACT: Mumps rarely causes sterility, so there is a possibility that you will become pregnant if you
have unprotected sex.
• MYTH (not true): I cannot get pregnant if I miss only one birth control pill.
FACT: Birth control pills are most effective when taken as prescribed. Their effectiveness may be
reduced if the woman misses even 1 pill.
• MYTH (not true): I cannot get pregnant using fertility awareness or natural family planning if I have
regular periods (or by having sex only during certain times of the month).
FACT: There is no “safe time” during your cycle for unprotected sex. You may become pregnant any
time that you have sex.
• MYTH (not true): Sexually active means you have to move during sex—if I do not move, I cannot
get pregnant.
FACT: You may become pregnant any time you have sex, whether you move about or lie still during
sexual intercourse.
• Other: You may have heard or read about something that is not listed here that you think might keep
you from becoming pregnant. Be sure to ask your healthcare professional about any method that you
cannot find in this book that you think, or have heard, will keep you from becoming pregnant.
How can I be 100% certain that I will not become pregnant?
Abstinence from sexual intercourse and sexual physical contact 24 hours a day, 7 days a week, is the
only way to be 100% sure you will not become pregnant.
What is abstinence?
Abstinence means that you have no physical contact of a sexual nature with a male partner. Abstinence
is not considered a method of birth control.
Using abstinence
If you are not currently having any physical contact of a sexual nature with a male partner, it is
extremely important that you ask yourself:
Will I definitely remain abstinent while I am taking Accutane (isotretinoin)?
If your answer is no, talk to your prescriber immediately.
Preventing pregnancy
Reasons women become pregnant
It is not unusual for women to become pregnant when they do not wish to be pregnant. But it is VERY
important that this does not happen to you especially while you are taking Accutane. You must be sure
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you are not pregnant before, or become pregnant while you are taking Accutane or for 1 month after.
In a survey conducted in women in the US, it was reported that approximately 50% of their
pregnancies were unintended. And the reasons are very common:
• They were not abstinent
• They chose a birth control method that was not effective
• They did not use birth control every time
• They did not use birth control correctly
• They had unexpected sexual activity
• Their birth control method failed
Be smart—Know the facts
Be safe—Select safe and effective birth control methods
Be sure—Do not leave anything to chance
How can I avoid becoming pregnant?
Any method of birth control can fail. Even if you use one of the most effective birth control methods
correctly, there is still a risk of getting pregnant.
Therefore, 2 separate, effective methods of birth control must always be used together at
the same time by female patients starting 1 month before, during and 1 month after stopping Accutane
therapy.
Contraception methods1
Primary (most effective) methods of birth control
At least 1 of the 2 separate methods of birth control must be a primary method of birth control.
((Boxed Copy))
This information does not contain all available information about contraception. As always, you should
discuss this and any other medical question with your prescriber or contraception counselor.
((End Boxed Copy))
THE PILL (oral contraception)
Two kinds of birth control pills are available and they work in different ways.
Combination pills, which contain 2 hormones, thicken vaginal mucus to keep the sperm from joining
the egg, and may prevent a fertilized egg from attaching to the womb. In addition, combination pills
prevent eggs from being released. Your healthcare professional will discuss the different types of pills
and help you decide which one is right for you.
Mini-pills, which contain only 1 type of hormone, thicken vaginal mucus to keep the sperm from
joining the egg, and may prevent a fertilized egg from attaching to the womb. Mini-pills are not
recommended for birth control during Accutane (isotretinoin) use.
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With the Pill method of birth control, 1 pill is taken once a day until the package is completed. The Pill
is usually started the first Sunday after a normal menstrual period or as instructed by your healthcare
professional. One package is completed every menstrual cycle. Not all pills provide protection from
the start; you can become pregnant during the first 4 weeks after you start taking the Pill. Pills should
be taken at the same time every day, and it may be helpful to use a calendar. Strike an “X” for the first
day of a new package of pills, and check each day thereafter.
With perfect use (correctly and consistently), about 1 woman in 1000 becomes pregnant. For typical
use (not always correctly or consistently), the rate is 5 in 100.
The Pill can have a variety of side effects; most are considered minor. Some rare, but serious, health
risks do exist, including blood clots, heart attack and stroke. Women who are older than 35 years, who
smoke or who are greatly overweight are at greater risk for these side effects, so it is important to
discuss these issues with your prescriber.
If a dose of the combination pill is missed, you can take one when you realize it and then continue
taking the others at their regular time. If you miss an entire day, it is okay to take 2 pills together if
necessary. If you miss taking your pills more than 2 days in a row, you can become pregnant. Do not
have sexual intercourse at this time. If you miss more than 2 days, you should call your healthcare
professional as soon as you realize it. You are at greatest risk for pregnancy if you start a package late
or miss taking pills during the first week of each package.
Remember: If the Pill is your primary method, you must still use a secondary method at the same time.
Contraception methods
IMPLANTABLE HORMONES
With this birth control method, your healthcare professional puts 6 small rod-shaped capsules under
the skin of your upper arm. The procedure is simple and can be done during an office visit. The
capsules release small amounts of hormone that stop eggs from being released and thicken vaginal
mucus to keep sperm from joining the egg. The capsules remain effective for a number of years, and
they can be removed by your healthcare professional at any time.
Implantable hormones are convenient, and there is no daily pill to worry about forgetting. Generally,
the side effects are similar to those that occur if you take the Pill. There is only a small chance of an
irritation at the spot where the capsules are implanted. The contraceptive effectiveness of these
hormones begins 3 days after being implanted.
With perfect use, about 5 women in 10,000 become pregnant.
For typical use, the rate is also 5 in 10,000.
Remember: If implantable hormones are your primary method, you must still use a secondary method
at the same time.
INJECTABLE HORMONES
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This method of birth control is a shot or needle injection of a hormone in your arm or buttocks, given
to you by your healthcare professional at specific intervals every 4 to 12 weeks. The hormone shot
stops eggs from being released, thickens vaginal mucus to keep the sperm from joining the egg, and
keeps a fertilized egg from attaching to the womb.
Injectable hormones are convenient, and there is no daily pill to worry about forgetting. Generally, the
side effects are similar to those that occur if you take the Pill. This form of birth control is reversible,
but it may take several months after stopping the shots before you can become pregnant.
With perfect use, about 2-3 women in 1000 become pregnant.
For typical use, the rate is also 2-3 in 1000.
Injectable hormones can take up to 1 week to be fully effective; you can become pregnant during this
week. Patients who have certain illnesses, or a family history of some illnesses, may not be suited for
this type of birth control, so it is important to discuss these issues with your healthcare professional.
Remember: If injectable hormones are your primary method, you must still use a secondary method at
the same time.
Contraception methods
THE INTRAUTERINE DEVICE (IUD)
The intrauterine device, which is called the IUD, is a plastic device that contains either copper or
hormones. Your healthcare professional puts the small plastic IUD in your womb. The copper or
hormones in the IUD keep the sperm from joining the egg and prevent a fertilized egg from attaching
to the womb.
IUDs that contain hormones can be left in place for between 1 and 5 years. The copper-containing
IUDs can be left in place for up to 10 years. Side effects of all types of IUDs may include increased
cramps and heavier and longer periods. Women with new sex partners, women with more than one
partner, or women whose partners have other partners have an increased chance of tubal infection
(which may lead to sterility).
These risks should be discussed with your healthcare professional. He or she will also explain how to
check the IUD for proper position by feeling for a “tail” or string in the vagina. If the string cannot be
felt, the IUD may have been expelled or dislodged from its proper position and a healthcare
professional should be consulted. This method is not recommended for women who have not had a
child.
With perfect use, about 1.5 women in 100 become pregnant.
For typical use, the rate is 2 in 100.
Remember: If an IUD is your primary method, you must still use a secondary method at the same time.
HORMONAL VAGINAL CONTRACEPTIVE RING
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((Illustrations of “ring” insertion))
This method of birth control is inserted by you into your vagina and contains a combination of
hormones similar to the Pill. After the ring is inserted, it releases a continuous low dose of hormones
into your body. The hormones stop the release of an egg and alter cervical mucus to keep sperm from
entering the womb. You leave it in for 3 weeks, and then you remove it for 1 week. During this time,
your menstrual period will begin. For your first cycle, the ring should be inserted between day 1 and
day 5 of your menstrual period. It may take up to 1 week to become fully effective in the first cycle.
Generally, the side effects are similar to those of the Pill. Other side effects may include vaginal
discharge or irritation. Like the Pill, the hormonal vaginal contraceptive ring may increase the risk of
blood clots, heart attack, and stroke, especially in women who smoke. It should not be used by women
with certain types of cancer or other medical conditions, so it is important to discuss these issues with
your prescriber.
With perfect use, about 7-8 women in 1000 become pregnant.
For typical use, the rate is 1-2 in 100.
Remember: If the hormonal vaginal ring is your primary method, you must still use a secondary
method at the same time. You cannot use the diaphragm as a secondary method because the vaginal
contraceptive ring may interfere with correct placement and position of a diaphragm.
TRANSDERMAL HORMONAL PATCH
This method of birth control is delivered by a patch that you wear on your body and contains a
combination of hormones similar to the Pill. After the patch is applied, its hormones are continuously
transferred through your skin into your blood stream. The hormones prevent the release of an egg, alter
vaginal mucous to keep the sperm from entering the womb, and keep a fertilized egg from attaching to
the womb.
The patch should be applied once a week on the same day each week. During week 4, do not wear a
patch. You should get your period during this week. Following week 4, repeat the same application
routine every month.
The patch can be started either during the first 24 hours of your menstrual period, or on the first
Sunday after your menstrual period begins. The patch may take up to one week to become fully
effective. The patch can be applied on your buttock, abdomen, upper body (except breasts), or on the
outside of your upper arm.
Generally, the side effects are similar to those of the Pill. The most common side effects include breast
symptoms, headache, skin irritation at the application site, nausea, upper respiratory illness, menstrual
cramps, and abdominal cramps. Like the Pill, the hormonal transdermal patch may increase the risk of
blood clots, heart attack, and stroke, especially in women who smoke. It should not be used by women
with certain types of cancer or other medical conditions, so it is important to discuss these issues with
your prescriber.
If the patch falls off or is partially detached for less than 24 hours, try to reapply it to the same place or
replace with a new patch immediately. This patch should be changed on the usual change day. If the
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
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patch is detached for more than 1 day, apply a new patch and begin a new 4-week cycle with a new
Patch Change Day. This new patch will not be effective for contraception for the first week.
With perfect use, about 1 woman in 100 become pregnant.
For typical use, the rate is unknown.
Remember: If the hormonal transdermal patch is your primary method, you must still use a secondary
method at the same time.
Contraception methods
STERILIZATION: TUBAL LIGATION AND VASECTOMY
Sterilization of either a man or woman requires an operation. A tubal tying (ligation) is intended to
permanently block a woman’s tubes where the sperm joins with the egg. A vasectomy is intended to
permanently block a man’s semen duct that carries sperm. However, it takes 15 to 20 ejaculations to
clear sperm from the man’s semen.
You may become pregnant if your male partner has not had 2 sperm counts in a row that show there
are no sperm in the semen.
There are no lasting side effects and sterilization has no effect on sexual pleasure. Mild bleeding or
infection may occur right after the procedure. Sterilization is intended to be permanent; reversing the
operation is very difficult and cannot be guaranteed.
Women or men who choose sterilization must consult with their healthcare professional before
resuming unprotected intercourse.
With perfect use, about 5 women in 1000 (using female sterilization) or 1 woman in 1000 (using male
sterilization) become pregnant. For typical use, the rates are 5 in 1000 (female) and 1.5 in 1000 (male).
Remember: If sterilization is your primary method, you must still use a secondary method at the same
time.
Secondary (moderately effective) forms of birth control
CONDOM, DIAPHRAGM OR CERVICAL CAP
Each of these is called a “barrier” method of birth control. They are used with a special gel called a
spermicide. A spermicide is a substance that kills sperm. By itself, it is NOT an adequate birth control
method for Accutane (isotretinoin) users. Spermicides come in several forms—creams, jellies, foams
and suppositories, which should be applied 10 to 30 minutes before each intercourse.
Spermicide must be applied each time you have sexual intercourse. Your contraception counselor
should explain to you exactly how to use the spermicide with the “barrier” method you choose. The
barrier method, plus the spermicide, only count as ONE of the 2 effective methods of birth control you
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NDA 18-882/S048/S052
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must choose before starting Accutane. The diaphragm or cervical cap must be left in place for 6 hours
after your last sexual act, and a woman should not douche or rinse the vagina during this time.
You should understand exactly how to and how not to use barrier methods of birth control. You need
to be aware of common mistakes in their use that may result in pregnancy. These barrier methods of
birth control are considered less reliable than the other methods discussed earlier.
Contraception methods
((Illustration of condom use))
CONDOM
The condom, also called a “rubber,” is a thin sheath that traps the sperm. Condoms are made of latex,
plastic or animal tissue. Condoms, when used properly and consistently, and with a spermicide, can be
effective in preventing pregnancy. It is also believed that latex condoms reduce the spread of some
STDs (sexually transmitted diseases), including HIV. Synthetic and natural skin condoms, or those
made from the skin of lamb’s intestines, are equally effective at preventing pregnancy. However,
natural skin condoms do not protect against STDs.
Proper use of a condom means several things. If you choose this method, it is important to have your
contraception counselor explain exactly how to follow these directions. The condom has to have been
stored in a cool, dry place and not exposed to heat or pressure. It should be rolled onto the erect penis
before any contact with the woman’s genitals. The rolled rim should always remain on the outside of
the condom. If the condom has been rolled incorrectly (backward), it should be discarded and replaced
with a new one. A 1/2 inch of empty space should be left at the tip, but no air should be trapped. Air at
the tip could cause the condom to break.
The condom should be removed immediately after intercourse to prevent spillage of semen. A condom
can be used only once. Oil-based lubricants, like petroleum jelly and baby oil, should not be used with
a condom. Water-based lubricants are safe to use and will not destroy the condom. However, since it is
necessary to use a spermicide with a condom, this can be used as a lubricant. Care should be taken to
avoid ripping, tearing or slipping off during sexual activity.
With perfect use, about 3 women in 100 become pregnant.
For typical use, the rate is 14 in 100.
Remember: Condoms should never be used alone without a primary birth control method.
DIAPHRAGM
The diaphragm is a shallow latex cup. Its purpose is to cover the cervix and prevent sperm from
passing up into the womb. Because the size around the cervix varies from woman to woman, a
diaphragm has to be custom fit by a healthcare professional. The fit needs to be checked at least once
every 2 years, if a weight gain or loss of 10 or more pounds occurs, or after pregnancy or an abortion.
((Illustrations of diaphragm use))
Contraception methods
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The diaphragm can be inserted into the vagina up to 6 hours before sexual intercourse. Spermicide
jelly or cream is placed in the diaphragm and around the rim before insertion. Fresh spermicide should
be applied with each sexual intercourse or if 6 hours have elapsed before sexual intercourse occurs.
The diaphragm should not be removed when spermicide is reapplied. The diaphragm must be left in
place for at least 6 hours after the last sexual intercourse; it should not be left in place for longer than a
total of 24 hours because of the risk of serious infection (toxic shock syndrome). Once fitted, the
diaphragm is inserted into the vagina so that the dome covers the cervix and the rim fits snugly on the
vaginal walls.
With perfect use (with spermicide), about 6 women in 100 become pregnant.
For typical use (with spermicide), the rate is 20 in 100.
Remember: A diaphragm should always be used with spermicide and only as a secondary method.
A separate primary method must always be used.
CERVICAL CAP
The cervical cap is a barrier method that must be individually fitted and prescribed by a healthcare
provider. The cervical cap is inserted by the female before each sexual intercourse and must be used in
combination with a spermicide to be considered moderately effective as a birth control method. The
cervical cap is made of latex and should never be used with an oil-based lubricant, such as petroleum
jelly, as this will destroy the cap.
The cervical cap actually fits over the cervix. The cap should be left in place for at least 6 hours after
the last sexual intercourse, but not longer than 48 hours because of the risk of toxic shock syndrome.
Spermicide is placed in the cap before insertion, but it is best to add more spermicide with each
intercourse while the cap is still in place. The cervical cap should not be removed while the spermicide
is being reapplied. Inserting and removing the cervical cap can be somewhat more difficult than
inserting and removing the diaphragm. However, with sufficient instruction and practice, insertion and
removal can usually be accomplished.
With perfect use, about 9 women in 100 become pregnant.
For typical use, the rate is 20 in 100.
Remember: A cervical cap should always be used with a spermicide and only as a secondary method.
A separate primary method must always be used.
((Illustrations of cervical cap use))
Other contraception methods
Do not use less effective methods of birth control such as birth control pills without estrogen, natural
family planning, (having sex only certain times of the month) fertility awareness, or withdrawal while
taking Accutane (isotretinoin), a medication that can cause birth defects to your unborn child. Ask your
healthcare professional about other contraception methods that you may use or have heard about.
Reference: 1. Trussell J, Card JJ, Rowland Hogue CJ. Adolescent sexual behavior, pregnancy, and
childbearing. In: Hatcher RA, Trussell J, Stewart F, et al, eds. Contraceptive Technology. 17th ed.
New York, NY: Ardent Media, Inc.; 1998:701-744.
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Pregnancy and pregnancy testing
Early signs of pregnancy
While you are taking Accutane (isotretinoin), you want to be sure that you are not pregnant or do not
become pregnant. That is the reason you are using 2 methods of safe and effective birth control. But
any birth control method can fail, so it is important to know the early signs of pregnancy. If you think
you might be pregnant, stop taking Accutane immediately and call your prescriber.
Missing your period may be your first sign that you are pregnant—and usually by that time pregnancy
can be confirmed by either a urine or blood test. However, some women do not miss their period early
in their pregnancies. This is why it is so important for you to return each month to your prescriber for a
pregnancy test before you get your prescription for more Accutane.
These other signs may, or may not, happen. Remember, if you think you might be pregnant, don’t
guess!
Stop Accutane immediately and call your prescriber.
• Morning sickness
Pregnant women may feel nauseous or queasy at any time of the day (only about 50% of women have
this feeling).
• Breast tenderness
Similar to the feeling you may experience during your monthly period, some women experience sore,
swollen and tingling breasts during early pregnancy. Usually, this tenderness goes away over time.
• Fatigue
Feeling not just sleepy but “bone weary” (as if you have run a marathon) is a strong indicator that you
are pregnant.
• Frequent urination
Rising levels of hormones can cause a feeling of congestion and pressure, which results in more trips
to the bathroom.
• Slight bleeding
About 8 days after pregnancy begins, or sometimes at the time of their expected period, some women
experience a small amount of bleeding or spotting. Do not mistake this for a regular period—this
spotting may be the result of the embryo embedding in the womb.
• Darkening of and around the nipples of the breast
This darkening is caused by an increase in hormones. Some women notice a change in the color of
their nipples.
Ectopic pregnancies
Sometimes a pregnancy begins outside of a woman’s womb; this is a very serious problem. Call your
prescriber or contraceptive counselor immediately if you are experiencing any of the following signs:
• Sudden pain or severe cramping in your lower abdomen
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• Irregular bleeding or spotting with abdominal pain when your period is late
• Fainting or dizziness lasting more than a few seconds
Testing for Pregnancy
If you have any questions about whether or not you are pregnant, please speak to your prescriber or
contraception counselor. There are many urine pregnancy tests available. Please review and follow
specific test instructions on the kit you choose to use.
Emergency contraception
What is emergency contraception and how does it work?
Emergency contraception (EC), also called emergency birth control, is commonly known as “after sex”
or “morning after” contraception. EC is used to prevent pregnancy following unprotected intercourse
or sex. EC prevents release of the egg, joining of the sperm and the egg, or implanting of the egg in the
womb. EC will not cause an abortion. EC is for use only if a woman is sure she is not already pregnant
from an earlier act of intercourse.
When would you use emergency contraception?
You would use EC:
• If you had unprotected sex
• If you forgot to take your birth control pills and had sex without using another method of birth
control
• If you are late for your contraception injection and had sex without using another method of birth
control
• If your partner’s condom broke or slipped off
• If your diaphragm or cervical cap slipped out of place or is ripped or split
Emergency contraception is meant only for emergency situations. It is not a replacement or substitute
for your usual 2 methods of birth control. EC is not to be used as birth control because it is not as
effective as regular birth control methods. EC should not be used on a regular basis as a replacement
for the other birth control methods described.
Where can you get emergency contraception?
Contact your prescriber immediately if you have had unprotected sex. You can get EC from:
• Private doctors or nurse practitioners
• Planned Parenthood
• Women’s health centers
• Hospital emergency rooms (unless they are owned by organizations that oppose
the use of birth control)
You can get the name and phone number of EC providers nearest you by calling, toll free, the
Emergency Contraception Hotline at 1-888-NOT-2-LATE, which in numbers is 1-888-668-2528.
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Emergency contraception
Types of emergency contraception
Emergency birth control is provided in 2 ways: high doses of contraception pills or insertion of an
IUD.
EMERGENCY CONTRACEPTION PILLS (ECPs)—used within 3 days
Emergency hormonal contraception is a sequence of high doses of certain oral contraceptives. Your
healthcare professional will help you choose the dose and pill that is right for you. The first dose of the
ECPs must be taken no later than 72 hours after having unprotected sex. The sooner the ECP is taken,
the more likely it is to be effective.
INSERTION OF INTRAUTERINE DEVICE (IUD)—used within 5 days
The second method used for emergency contraception is the insertion of an IUD. Insertion of an IUD
can be done by a healthcare professional within 5 days of having unprotected sex.
IUD insertion for emergency contraception is not recommended for women who have not had a child
or are at risk for sexually transmitted diseases. Such women include:
• Women with new sex partners
• Women with more than 1 partner or whose partners have other partners
• Women who have been raped
Your sexual partner
How can I explain the importance of preventing pregnancy
while taking Accutane?
• Explain that there is an extremely high risk that a deformed baby will result if you become pregnant
or are pregnant while taking Accutane (isotretinoin), in any amount, for even short periods of time
• Explain that when an unborn baby is exposed to Accutane, deformities occur in many cases
• Make sure that your partner reads about the types of birth defects as described in the My role section
so that he can understand the severity of these birth defects
What should I tell my sexual partner about Accutane treatment?
It is strongly recommended that your sexual partner read this booklet. It is very important that your
sexual partner understand all the facts about the risks of birth defects occurring in female patients who
become pregnant during Accutane therapy.
• Be very specific when you tell your sexual partner about Accutane and birth defects
• Use this booklet to help you discuss Accutane treatment
• Tell your partner how Accutane may be of benefit to you
• Explain what you and he must do to prevent pregnancy if you plan to engage in sexual activities
before you start treatment with Accutane
–Identify and use 2 separate, effective methods of birth control at the same time for 1 month before
treatment with Accutane
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
46
• Explain what you and he must do during Accutane treatment:
Continue to use 2 separate, effective methods of birth control at the same time during your treatment
with Accutane
• Explain what you and he must do for 1 month after stopping Accutane treatment: Continue to use 2
separate, effective methods of birth control at the same time for 1 month after you stop Accutane
treatment
• Have your partner watch the video Be Prepared, Be Protected with you. This reproductive health and
contraception video is available from your prescriber. Take the video home to watch
• Encourage your sexual partner to make a list of questions for your prescriber to answer.
Your sexual partner may want to come with you to speak directly with the prescriber, or he may want
to speak with your prescriber on the phone. Your prescriber wants both you and your sexual partner to
understand what must be done while you are taking Accutane. Your prescriber will gladly make
arrangements so that all of your questions may be answered and any concerns can be discussed
((Image of videocassette))
The Accutane Survey
Lots of other women who have taken Accutane have participated in the Survey. Joining the Survey is
important because it is one of the only ways we can know how women are doing with contraception
and pregnancy prevention. It is an opportunity to help women who take Accutane in the future.
Some women who did not join the Survey had decided against joining because they were worried
about privacy, thought the Survey might be too much paperwork, or were afraid that it might be like
taking a test.
Please do not worry: The Survey is absolutely confidential. Only the researchers at SI International
will know your identity, and they MUST keep it confidential. You will be asked to complete a form
about 3 times during your treatment on Accutane and once afterward. You will be paid for your time
when you join and when you finish the Survey.
You will not be asked test-like questions. In fact, the questions are the same kinds of questions that
your prescriber or nurses have already asked you. This information will help us learn more about how
women can use Accutane safely. The purpose is to find out what you remembered and what you did
with the information you were given.
Join today—you can help yourself, and you can help others.
((Image of Accutane Survey form))
Confidential Contraception Counseling Line
The Confidential Contraception Counseling Line phone number is 1-800-542-6900.
The Confidential Contraception Counseling Line is a 24-hour toll-free line available to all patients on
Accutane (isotretinoin). You can call this line as many times as you want, and at any time of day, to
receive confidential information on Accutane, birth defects, sex and birth control, contraception,
pregnancy and pregnancy prevention, emergency contraception, and the Accutane Survey. Share this
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
47
information and the phone number with members of your family and your partner. Remember, it is
completely confidential, you will never have to give your name, and you cannot be identified.
Telephone Menu: After the introduction, listen to the following menu and press the corresponding
number on your telephone keypad to learn more about:
Birth Defects/Teratogenicity — Press 1
Press 1. What does teratogenicity mean?
Press 2. How can you avoid birth defects?
Press 3. When do you have to worry about teratogenicity while using Accutane?
Press 4. How long do I have to wait after taking Accutane to become pregnant?
Press 5. What should I do if I think I may be pregnant?
Sex and Birth Control — Press 2
Press 1. What is abstinence?
Press 2. What is unprotected sex?
Press 3. Are you unsure whether or not you can get pregnant?
Press 4. Why do I need to know if I might have sex in the near future?
Press 5. Why do I need to know about the birth control I use?
Press 6. Myths about pregnancy and contraception
Contraceptive Methods/Birth Control — Press 3
Press 1. What does 2 forms of birth control mean?
Press 2. How do I use 2 in combination?
Press 3. Questions about specific methods of birth control
Press 1.
Abstinence
Press 2.
The Pill
Press 3.
Implantable hormones
Press 4.
Injectable hormones
Press 5.
Intrauterine device
Press 6.
Sterilization
Press 7.
Condom
Press 8.
Diaphragm
Press 9.
Cervical cap
Press 10. Spermicide
Press 11. Withdrawal
Press 12. Fertility awareness methods
Press 4. What if I forget my birth control or if my
birth control fails?
Information on Emergency Contraception — Press 4
Press 1. What should you do if you think you may be pregnant?
Press 2. Questions about emergency contraception
Press 3. Possible effects on the fetus/baby if you get pregnant while on Accutane
Press 4. What should you do if you think you may be pregnant?
Pregnancy and Pregnancy Testing — Press 5
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
48
Press 1. What should you do if you think you may be pregnant?
Press 2. Pregnancy tests
Press 1. When do I perform a pregnancy test?
Press 2. What is the difference between a blood and urine test?
Press 3. Where can I get a pregnancy test?
Press 4. What if I have my period? Can I take a test if I do?
Press 3. Myths about pregnancy and contraception
The Accutane Survey — Press 6
Press 1. Why should I join?
Press 2. How do I join?
Press 3. What is the benefit to me?
Press 4. Is it confidential?
This telephone line does not contain all available information about contraception. As always, you
should discuss this and any other medical questions with your prescriber or contraception counselor.
Accutane InfoLine
((PPP Logo))
ENGLISH
The Accutane InfoLine gives you information on Accutane. To call, dial toll-free 1-800-950-4411 on a
touchtone phone. When you hear the three tones, push “1” to hear the message in English. You will
hear the facts about Accutane, but you may not hear all there is to know about Accutane. Be sure to ask
your doctor for complete information. Please call…we’d like to share important facts with patients
taking Accutane.
((Also translated into Spanish, Portuguese, Italian, French, Russian, German, Polish, Vietnamese,
Korean, Japanese, and Chinese))
Scenes from the video
If you are taking Accutane, it can be harmful to your unborn baby. It’s important for you to know how
to avoid pregnancy
((PPP Logo))
Please take the time to watch the 4-minute video, Be Prepared, Be Protected
“I guess I didn’t know…now I do.”
It’s important to know what abstinence means. That means not having sex. Not once, not twice, not
ever.
“It was just one
time…this can’t be right.”
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
49
If you are having sex at any time you can’t use any excuses. It doesn’t matter if your periods are
irregular or if you think you can’t get pregnant or if you don’t have sex frequently. Once can be
enough.
“But this time,
I guess it…it didn’t work.”
Withdrawal is not reliable.
You must use effective birth control, such as the contraceptive pill, diaphragm or condom. And if you
are taking a medication that may cause birth defects to your unborn baby, you must use 2 separate,
effective methods of birth control at the same time.
“I didn’t think this would happen…”
You have to think about birth control beforehand. Don’t be caught unprepared. You may have sex, and
you might become pregnant. Don’t assume your partner will take responsibility.
“What if I get pregnant?…What am I going to do?”
Always make sure your birth control is reliable and effective. If you have any questions about it, or
about your medical treatment, ask your prescriber or nurse.
Summary
If you want to be treated with Accutane (isotretinoin), there are certain things you MUST do:
Before you take Accutane
You must use 2 separate, effective methods of birth control at the same time for 1 month—before
taking Accutane (even when 1 is a hormonal contraceptive method).
You must have negative results for 2 pregnancy tests:
• The first test will be done at the time your prescriber decides to prescribe
Accutane for you.
• The second test will be done during the first 5 days of your menstrual period right
before you start your Accutane therapy, or as directed by your prescriber.
During Accutane treatment
You must continue to use 2 separate, effective methods of birth control at the same time—at all times
during your treatment with Accutane (even when 1 is a hormonal contraceptive method).
You must return to your prescriber and have a negative pregnancy test each month before you get your
prescription.
You must have the opportunity to join the Accutane Survey. You may find the enrollment form in this
booklet or in your medication package.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
50
After stopping Accutane treatment
You must continue to use 2 separate, effective methods of birth control at the same time for 1 month
after stopping Accutane treatment (even when 1 is a hormonal contraceptive method) because some of
the Accutane may remain in your body for a short period of time after you stop taking it.
Contraception knowledge
Self-assessment
There is ONE correct answer for each question.
Circle the answer you think is correct and then check below to see if you are right! If you got any of
the answers wrong, try reading the booklet again. It is full of a lot of important information and it is
common for readers to miss answers and have more questions.
Don’t take chances: discuss all of your questions with your prescriber BEFORE taking Accutane.
1. Your prescriber tells you it is important for you to participate in a survey. Even though you are told
it is confidential, it asks for your name and address. What would you do?
a) Ask the prescriber why the information is necessary and then decide whether to participate
b) Complete the survey, but put a different name on it
c) Answer only the questions that are not personal
d) Refuse to participate in the survey
2. Your prescriber tells you that you need to have a pregnancy test before he/she can prescribe
Accutane. You would:
a) Refuse the test because you know you are not pregnant
b) Ask the prescriber to explain why you need the test
c) Go to another prescriber
d) None of the above
3. Your prescriber tells you that you must use at least 1 primary form of birth control and 1 secondary
form for 1 month before you can start Accutane. You are on the Pill, but don’t know if it is a primary
form or secondary form. What would you do?
a) Don’t worry about it now, because you are not sexually active
b) Call your friend because she is on an acne medicine
c) Ask the prescriber at the next visit
d) Review your Be Smart, Be Safe, Be Sure booklet under Section 3, Preventing Pregnancy—A Guide
to Contraception, and then speak to your prescriber
4. You are speaking to your prescriber about having your second pregnancy test so you can start
Accutane. You have been on the Pill for 1 month, and it is the second day of your period. Three days
ago, you and your partner forgot to use a condom when you had intercourse. You should:
a) Have the pregnancy test anyway because it will tell you if you are pregnant
b) Not worry because you have your period
c) Tell the prescriber you and your partner forgot to use a condom once
d) Not worry because you forgot before and never got pregnant
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
51
5. If your 2 birth control methods are the Pill and the diaphragm, and you forgot to take 2 pills in a
row, you should:
a) Not worry because you are using a diaphragm, too
b) Not have intercourse and call your prescriber because you may not be protected from becoming
pregnant
c) Take the Pill 2 at a time until you catch up
6. The reason you are being asked to use 2 separate, effective
methods of birth control at the same time while on Accutane is:
a) Accutane works better when combined with birth control
b) There is a high risk that your baby will be deformed if you become pregnant
c) There is a high risk for multiple births when on Accutane
7. Which of the following is an acceptable combination of birth control methods for someone on
Accutane?
a) Withdrawal and a condom
b) Cervical cap and a condom
c) IUD and withdrawal
d) The Pill and a diaphragm with spermicide
8. Which of the following is not one of the acceptable methods of birth control while taking Accutane?
a) Natural family planning
b) Sterilization
c) IUD
d) Cervical cap
9. An appropriate situation for using emergency contraception is:
a) As a secondary method of birth control
b) Only after a positive pregnancy test
c) If the condom slipped off or broke during sex
10. If you have questions about your contraception while you are
taking Accutane, you should:
a) Wait for your next visit and ask your prescriber
b) Call your prescriber and access the Confidential Contraception Counseling Line to get your question
answered before having sexual intercourse
c) Ask a friend or your partner
d) Stop taking your contraceptive and Accutane until your next visit
Answers: 1-a, 2-b, 3-d, 4-c, 5-b, 6-b, 7-d, 8-a, 9-c, 10-b
((Roche Logo))
Copyright © 2002-2003 by Roche Laboratories Inc. All rights reserved.
PLANDEX 101003
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
52
PRINTED IN USA
xx-xxx-xxx-xxx-xxxx
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
53
((Roche Logo))
Be Smart Be Safe Be Sure™
Accutane® (isotretinoin)
Risk Management
Program for Men
If you have any questions about your therapy, please contact:
Name:_____________________________________________
(to be completed by Prescriber)
Telephone: _____________________________________________
Complete the three sections in this order:
Section 1
Education — Review this material before completing the consent form
• Reproduction information for men
• Patient Product Information, Important information concerning
your treatment with Accutane® (isotretinoin)
Section 2
Consent — Complete this section with your prescriber
• Informed Consent/Patient Agreement form
Section 3
Education Reinforcement
• Accutane InfoLine
IMPORTANT INFORMATION TO READ
BEFORE YOU RECEIVE YOUR
ACCUTANE® (isotretinoin) PRESCRIPTION
((TAB Copy))
section 1
EDUCATION
Reproduction information for men
Booklets and packages for Accutane® (isotretinoin) include many warnings for female patients that
Accutane can cause severe birth defects if a pregnant woman takes Accutane. For this reason, male
patients who receive prescriptions for Accutane should never share their medicine with other people.
In addition to birth defects, Accutane can cause other serious side effects. Never share Accutane.
Question:
Do birth defects happen if men who are taking Accutane father a child?
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
54
Answer:
Males taking Accutane do have small amounts of the drug in the fluid that surrounds
sperm, but many years of safety reporting do not point to a pattern of birth defects caused when
Accutane is taken by the father. Potential fathers who are concerned can use a condom during the
relatively short Accutane treatment period (15-20 weeks).
Even if a person does not take Accutane, it is important to realize that about 3-5% of all newborns have
birth defects due to other known causes of birth defects.
It is also important to realize that Accutane is a chemical (isotretinoin) related to natural vitamin A and
that very small amounts of isotretinoin are formed in our bodies every day when we metabolize
vitamin A from our food. People taking Accutane have a greatly increased amount of isotretinoin
circulating in their blood. For this reason, neither males nor females should donate blood while taking
Accutane or for 1 month after stopping Accutane, as the blood levels may be high enough to cause
birth defects if the blood is given to pregnant women.
Question:
Can Accutane cause long-term damage to a male’s ability to have healthy children?
Answer:
Studies done in men taking Accutane showed no significant effects on the patients’
sperm. The tests included the amount of sperm, the activity of sperm, and the appearance of sperm.
The Patient Product Information, Important Information Concerning Your Treatment with Accutane®
(isotretinoin) following this page begins with information for women. If isotretinoin is taken during
pregnancy, the unborn babies may have terrible birth defects.
These birth defects may have been avoided if the mother had not been taking isotretinoin while she
was pregnant. Male patients should note that the Patient Product Information then contains information
very important for ALL patients.
In addition, male patients should read the Accutane Medication Guide that your pharmacy should give
to you each time you pick up an Accutane prescription.
When your prescriber gives you your Accutane prescription, it should have a yellow self-adhesive
Accutane Qualification Sticker on it. This special sticker is part of the System to Manage Accutane
Related Teratogenicity™ (S.M.A.R.T.™). The program is designed to prevent unborn babies from
being exposed to Accutane, a drug that causes severe birth defects. It is important that ALL
prescriptions have this Accutane Qualification Sticker so that the pharmacist knows patients have been
approved by their prescribers to receive
the medicine. If your prescription does not have this yellow self-adhesive sticker, please call your
prescriber and ask for a prescription with the yellow self-adhesive sticker. Your cooperation in this
effort is a very important contribution to preventing Accutane caused
birth defects.
((Qualification Sticker art))
If you have any questions about any of these issues or anything you read in the patient booklet, ask
your prescriber.
((Boxed Copy))
To summarize:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
55
• Never share Accutane with anyone else.
• Do not donate blood during your Accutane treatment or for 1 month after stopping Accutane, to give
the drug time to leave the bloodstream.
((End Boxed Copy))
For more information, please read the Patient Product Information and the Medication Guide.
Ninth Edition
November 2002
Patient Product Information
Important information concerning your treatment with
((Accutane Logo))
Read this brochure carefully before you start taking Accutane (ACK-u-tane). This brochure provides
important facts about Accutane, but it does not contain all information about this medication. When
you pick up your Accutane prescription at the pharmacy, you should receive a copy of the Accutane
Medication Guide with your Accutane. If there is anything else you want to know, or if you have any
questions, talk to your prescriber.
Things you should know about
Accutane (isotretinoin) is used to treat the most severe form of acne (nodular acne) that has not been
helped by other treatments, including antibiotics. However, Accutane can cause serious side effects.
Before you decide to take Accutane, you must discuss with your prescriber how bad your acne is, the
possible benefits of using Accutane, and its possible side effects. It is important for you to know how
to take it correctly and what to expect. Your prescriber will ask you to read and sign a form or forms to
show that you understand some of the serious risks of Accutane. Please read this brochure carefully
and ask your prescriber any questions you may have.
Possible serious side effects of Accutane include birth defects and mental disorders.
IMPORTANT INFORMATION FOR FEMALE PATIENTS:
BIRTH DEFECTS (Causes Birth Defects)
((Boxed Copy))
You MUST NOT take Accutane if you are pregnant.
You MUST NOT become pregnant while taking Accutane, or for 1 month after you stop taking
Accutane.
Severe birth defects are known to occur in babies of females taking Accutane in any amount even for
short periods during pregnancy. There is an extremely high risk that your baby will be deformed or
will die if you become pregnant while taking Accutane. Potentially any exposed baby can be affected.
There is also an increased risk of losing the baby before it is born (miscarriage) or that it will be
delivered early (premature).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
56
You will not get your first prescription for Accutane until there is proof that you have had 2 negative
pregnancy tests. The first test must be done when your prescriber decides to prescribe Accutane. The
second pregnancy test must be done during the first 5 days of your menstrual period right before
starting Accutane therapy, or as instructed by your prescriber. Only when the 2 required tests show that
you are not pregnant can you get your first prescription for a 30-day supply of Accutane. You will
have one pregnancy test every month during your Accutane therapy. Female patients cannot get
monthly refills for Accutane unless there is proof that they have had a negative pregnancy test. You
can only get a refill each month by returning to your prescriber for a repeat pregnancy test and
counseling about pregnancy prevention.
Effective contraception (birth control) should be discussed with your prescriber. Two separate,
effective forms of contraception must be used at the same time for at least 1 month before beginning
therapy and during therapy, and for 1 month after Accutane treatment has stopped. Any birth control
method can fail, including oral contraceptives (birth control pills) and topical/injectable
(shots)/implantable/insertable hormonal birth control products.
There are only 2 reasons that you would not need to use 2 separate birth control methods:
• You commit to being absolutely and consistently abstinent (no sexual intercourse). This means that
you are absolutely sure that you will not have genital-to-genital contact with a male, during and for 1
month after your Accutane treatment.
• You have had your uterus surgically removed (a hysterectomy).
Immediately stop taking Accutane if you have sex without birth control, miss your period or become
pregnant while you are taking Accutane or in the month after you have stopped treatment. Call your
prescriber immediately.
((End Boxed Copy))
((Boxed Copy))
((Image of deformed babies))
((End Boxed Copy))
Line drawing representing some common birth defects associated with Accutane use during
pregnancy. Some of the defects that you can see are deformed eyes, nose, ears or absent ears, enlarged
head and small chin. More severe defects than these can occur, including mental retardation. This
picture does not show all the severe internal defects that may occur, including those of the brain, heart,
glands, and nervous system.
Important information for all patients
Mental disorders and suicide
Some patients have become depressed or developed other serious mental problems while they were
taking Accutane or shortly after stopping Accutane. It is not known if Accutane caused these problems.
Some signs of depression include sad, “anxious” or empty mood, loss of pleasure or interest in social
or sports activities, sleeping too much or too little, changes in weight or appetite, school or work
performance going down, or trouble concentrating. Some patients taking Accutane have had thoughts
of ending their own lives (suicidal thoughts). Some people have tried to end their own lives (attempted
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
57
suicide) and some people have ended their own lives (committed suicide). No one knows if Accutane
caused these behaviors.
Tell your prescriber if you or someone in your family has ever had a mental illness, including
depression, suicidal thoughts or attempts, or psychosis. Psychosis means a loss of contact with reality,
such as hearing voices or seeing things that are not there. Tell your prescriber if you take any
medicines for any of these problems.
Stop taking Accutane and call your prescriber right away if you:
• Start to feel sad or have crying spells
• Lose interest in activities you once enjoyed
• Sleep too much or have trouble sleeping
• Become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of
violence)
• Have a change in your appetite or body weight
• Have trouble concentrating
• Withdraw from your friends or family
• Feel like you have no energy
• Have feelings of worthlessness or inappropriate guilt
• Start having thoughts about hurting yourself or taking your own life (suicidal thoughts)
What is Accutane?
Accutane is used to treat the most severe form of acne (nodular acne)
that has not been helped by other treatments, including antibiotics.
Facts about nodular acne
Nodular acne is a severe skin disease that can leave permanent scars. Although acne is considered by
many to be a disease of adolescents, a person can be affected with acne into his or her 30s and 40s.
Males tend to get more severe acne than females.
Acne develops in the oil-producing structures of the skin called sebaceous glands. One or more
sebaceous glands accompany each hair follicle (see figures). These glands secrete an oily mixture
called sebum that normally passes to the skin surface. During adolescence, the sebaceous glands grow
larger and produce more sebum, especially in the face, chest and back areas. Acne occurs when the
normal route of sebum to the skin surface is blocked. In the case of nodular acne, the sebum builds up
in the gland and mixes with dead cells. This accumulation finally ruptures the follicle wall, forming an
inflamed nodule under the skin. Scarring usually results from these nodules.
Acne is not caused by a poor diet, dirt or an oily complexion. Factors that may make acne worse
include emotional stress, fatigue, cosmetics, and drugs such as iodides and bromides.
((Images of skin cross-sections))
General guidelines for taking your medication
Who should not take Accutane?
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
58
Do not take Accutane (isotretinoin) if you are pregnant, plan to become pregnant, or become pregnant
during Accutane treatment. Accutane causes severe birth defects. Please carefully read “Important
Information for Female Patients: Birth Defects” on page 1.2.
Do not take Accutane unless you completely understand its possible risks and are willing to follow all
of the instructions in this brochure. When you pick up your Accutane prescription at the pharmacy, you
should receive a copy of the Accutane Medication Guide with your Accutane.
Tell your prescriber if you or anyone in your family has had any kind of mental problems, asthma,
liver disease, diabetes, heart disease, osteoporosis (bone loss), weak bones, anorexia nervosa (an eating
disorder where people eat too little), or any other important health problems. Tell your prescriber if
you have any food or drug allergies. This information is important to determine if Accutane is right for
you.
How should you take Accutane?
• You will get a 30-day supply of Accutane at a time, to be sure you check in with your prescriber
each month to discuss side effects and pregnancy prevention.
• Your prescription should have a yellow self-adhesive Accutane Qualification Sticker on it. If your
prescription does not have this sticker, call your prescriber. The pharmacy should not fill your
prescription unless it has a yellow sticker.
• The amount of Accutane you take has been specially chosen for you and may change during your
treatment; do not change the number of pills you are taking unless your prescriber tells you to do so.
• You will take Accutane 2 times a day with food, unless your prescriber tells you otherwise. Swallow
your Accutane capsules with a full glass of liquid. This will help prevent the medication inside the
capsule from irritating the lining of your esophagus (connection between mouth and stomach). For the
same reason, do not chew or suck on the capsule.
• If you miss a dose, just skip that dose. Do not take 2 doses next time.
• You should return to your prescriber as directed to make sure you don’t have signs of serious side
effects. Because some of Accutane’s serious side effects show up in blood tests, some of these visits
may involve blood tests. Monthly visits for female patients should always include a pregnancy test.
During your treatment:
what should you avoid while taking Accutane?
• Do not get pregnant while taking Accutane and for 1 month after stopping Accutane.
• Do not breast feed while taking Accutane and for 1 month after stopping Accutane. We do not know
if Accutane can pass through your milk and harm the baby.
• Do not give blood while you take Accutane and for 1 month after stopping Accutane. If someone
who is pregnant gets your donated blood, her baby may be exposed to Accutane and may be born with
birth defects.
• Do not take vitamin A supplements. Taking both together may increase your chance of getting side
effects.
• Do not have cosmetic procedures to smooth your skin, including waxing, dermabrasion, or laser
procedures while you are using Accutane and for at least 6 months after you stop. Accutane may
increase your chance of scarring from these procedures. Check with your prescriber for advice about
when you can have cosmetic procedures.
• Avoid sunlight and ultraviolet lights as much as possible. Tanning machines use ultraviolet light.
Accutane may make your skin more sensitive to light.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
59
Important information for all patients
• Do not use birth control pills that do not contain estrogen. They may not work while
you take Accutane. Ask your prescriber or pharmacist if you are not sure what type of birth control
pills you are using.
• Talk with your prescriber if you plan to take other drugs or herbal products. This is especially
important for patients using birth control pills and other hormonal types of birth control because the
birth control may not work if you are taking certain drugs or herbal products. You should not take the
herbal supplement St. John’s Wort because this herbal supplement may make birth control pills not
work as effectively.
• Talk with your prescriber if you are currently taking an oral or injected corticosteroid
or anticonvulsant (seizure) medication prior to using Accutane. These drugs may weaken your bones.
• Do not share Accutane with other people. It can cause birth defects and other serious
health problems.
• Do not take Accutane with antibiotics unless you talk to your prescriber. For some antibiotics, you
may have to stop taking Accutane until the antibiotic treatment is finished. Use of both drugs together
can increase the chances of getting increased pressure in the brain.
You should be aware that certain SERIOUS SIDE EFFECTS have been reported in patients taking
Accutane. Serious problems do not happen in most patients. If you experience any of the following
side effects or any other unusual or severe problems, stop taking Accutane right away and call your
prescriber because they may result in permanent effects.
• Accutane can cause birth defects and death in babies whose mothers took Accutane while they were
pregnant. Please read “Important Information for Female Patients: Birth Defects” on page 1.2.
• Serious mental health problems. Please see “Mental disorders and suicide” on page 1.3.
• Serious brain problems. Accutane can increase the pressure in your brain. This can lead to
permanent loss of sight, or in rare cases, death. Stop taking Accutane and call your prescriber right
away if you get any of these signs of increased brain pressure: bad headache, blurred vision, dizziness,
nausea, or vomiting. Also, some patients taking Accutane have had seizures (convulsions) or stroke.
• Abdomen (stomach area) problems. Certain symptoms may mean that your internal organs are being
damaged. These organs include the liver, pancreas, bowel (intestines), and esophagus (connection
between mouth and stomach). If your organs are damaged, they may not get better even after you stop
taking Accutane. Stop taking Accutane and call your prescriber if you get severe stomach, chest or
bowel pain; have trouble swallowing or painful swallowing; get new or worsening heartburn, diarrhea,
rectal bleeding, yellowing of your skin or eyes, or dark urine.
• Bone and muscle problems. Accutane may affect bones, muscles, and ligaments and cause pain in
your joints or muscles. Tell your prescriber if you plan vigorous physical activity during treatment with
Accutane. Tell your prescriber if you develop pain, particularly back pain or joint pain. There are
reports that some patients have had stunted growth after taking Accutane for acne as directed. There
are also some reports of broken bones or reduced healing of broken bones after taking Accutane for
acne as directed. No one knows if taking Accutane for acne will affect your bones. If you have a
broken bone, tell your prescriber that you are taking Accutane. Muscle weakness with or without pain
can be a sign of serious muscle damage. If this happens, stop taking Accutane, and call your prescriber
right away.
• Hearing problems. Some people taking Accutane have developed hearing problems. It is possible
that hearing loss can be permanent. Stop using Accutane and call your prescriber if your hearing gets
worse or if you have ringing in your ears.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
60
• Vision problems. While taking Accutane you may develop a sudden inability to see in the dark, so
driving at night can be dangerous. This condition usually clears up when you stop taking Accutane, but
it may be permanent. Other serious eye effects can occur. Stop taking Accutane and call your
prescriber right away if you have any problems with your vision or dryness of the eyes that is painful
or constant.
After your treatment is completed
• Lipid (fats and cholesterol in blood) problems. Many people taking Accutane (isotretinoin) develop
high levels of cholesterol and other fats in their blood. This can be a serious problem. Return to your
prescriber for blood tests to check your lipids and to get any needed treatment. These problems
generally go away when Accutane treatment is finished.
• Allergic reactions. In some people, Accutane can cause serious allergic reactions. Stop taking
Accutane and get emergency care right away if you develop hives, a swollen face or mouth, or have
trouble breathing. Stop taking Accutane and call your prescriber if you develop a fever, rash, or red
patches
or bruises on your legs.
• Signs of other possibly serious problems. Accutane may cause other problems. Tell your prescriber
if you have trouble breathing (shortness of breath), are fainting, are very thirsty or urinate a lot, feel
weak, have leg swelling, convulsions, slurred speech, problems moving, or any other serious or
unusual problems. Frequent urination and thirst can be signs of blood sugar problems.
Accutane has more common, less serious possible side effects.
The common, less serious side effects of Accutane are dry skin, chapped lips, dry eyes, and dry nose
that may lead to nosebleeds. People who wear contact lenses may have trouble wearing them while
taking Accutane and after therapy. Sometimes, people’s acne may get worse for a while. They should
continue taking Accutane unless told to stop by their prescriber.
These side effects usually do not last long and disappear when treatment is stopped, but some may
continue after stopping Accutane. If you develop any of these side effects, check with your prescriber
to determine if any change in the amount of your medication is needed. Also, ask your prescriber to
recommend a lotion or cream if drying or chapping develops.
These are not all of Accutane’s possible side effects. Your prescriber or pharmacist can give you more
detailed information that is written for health care professionals.
Be sure to return to your prescriber as scheduled. He or she will want to check your progress with
Accutane.
Medicines are sometimes prescribed for purposes other than those listed in this brochure. Patients
should ask their prescriber about any concerns. Accutane should not be used for a condition other than
that for which it is prescribed.
After your treatment is completed
For female patients:
• You must continue using 2 separate, effective forms of contraception (birth control) for 1 month
after your treatment with Accutane has ended. This is because it takes time for all of the Accutane to
leave your bloodstream.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
61
For all patients:
• Like most patients, you may find that your skin continues to improve even after completing a course
of treatment with Accutane. However, some patients treated with Accutane have needed a second
course of therapy for satisfactory results. If this is necessary for you, the second course of therapy may
begin 8 or more weeks after the first course.
• Do not donate blood for 1 month after your treatment with Accutane has ended. This is because it
takes time for all of the Accutane to leave your bloodstream.
• Do not give leftover Accutane to anyone. It can cause birth defects and other serious health
problems.
PLEASE COMPLETE THIS SECTION WITH
YOUR PRESCRIBER OR NURSE
((TAB Copy))
SECTION 2
CONSENT
((NCR FORM))
ACCUTANE® (isotretinoin)
Informed Consent/PATIENT AGREEMENT
(for all patients)
To be completed by patient (parent or guardian if patient is under age 18) and signed by the prescriber
Read each item below and initial in the space provided if you understand each item and agree to follow
your prescriber’s instructions. A parent or guardian of a patient under age 18 must also read and
understand each item before signing the agreement.
Do not sign this agreement and do not take Accutane if there is anything that you do not understand
about all the information you have received about using Accutane.
1.
I, ___________________________________________________________,
(Patient’s Name)
understand that Accutane is a medicine used to treat severe nodular acne that cannot be cleared up by
any other acne treatments, including antibiotics. In severe nodular acne, many red, swollen, tender
lumps form in the skin. If untreated, severe nodular acne can lead to permanent scars.
Initials: ______
2.
My prescriber has told me about my choices for treating my acne.
Initials: ______
3.
I understand that there are serious side effects that may happen while I am taking Accutane.
These have been explained to me. These side effects include serious birth defects in babies of pregnant
females. (Note: There is a second Informed Consent form for female patients concerning birth defects.)
Initials: ______
4.
I understand that some patients, while taking Accutane or soon after stopping Accutane, have
become depressed or developed other serious mental problems. Symptoms of these problems include
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
62
sad, “anxious” or empty mood, irritability, anger, loss of pleasure or interest in social or sports
activities, sleeping too much or too little, changes in weight or appetite, school or work performance
going down, or trouble concentrating. Some patients taking Accutane have had thoughts about hurting
themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own
lives. And some people have ended their own lives. There were reports that some of these people did
not appear depressed. There have been reports of patients on Accutane becoming aggressive or violent.
No one knows if Accutane caused these behaviors or if they would have happened even if the person
did not take Accutane. Some people have had other signs of depression while taking Accutane (see
#7).
Initials: ______
5.
Before I start taking Accutane, I agree to tell my prescriber if, to the best of my knowledge, I
have ever had symptoms of depression (see #7), been psychotic, attempted suicide, had any other
mental problems, or take medicine for any of these problems. Being psychotic means having a loss of
contact with reality, such as hearing voices or seeing things that are not there.
Initials: ______
6.
Before I start taking Accutane, I agree to tell my prescriber if, to the best of my knowledge,
anyone in my family has ever had symptoms of depression, been psychotic, attempted suicide, or had
any other serious mental problems.
Initials: ______
7.
Once I start taking Accutane, I agree to stop using Accutane and tell my prescriber right away
if any of the following happen. I:
• Start to feel sad or have crying spells
• Lose interest in activities I once enjoyed
• Sleep too much or have trouble sleeping
• Become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of
violence)
• Have a change in my appetite or body weight
• Have trouble concentrating
• Withdraw from my friends or family
• Feel like I have no energy
• Have feelings of worthlessness or inappropriate guilt
• Start having thoughts about hurting myself or taking my own life (suicidal thoughts)
Initials: ______
8.
I agree to return to see my prescriber every month I take Accutane to get a new prescription for
Accutane, to check my progress, and to check for signs of side effects.
Initials: ______
9.
Accutane will be prescribed just for me — I will not share Accutane with other people because
it may cause serious side effects, including birth defects.
Initials: ______
10.
I will not give blood while taking Accutane or for 1 month after I stop taking Accutane. I
understand that if someone who is pregnant gets my donated blood, her baby may be exposed to
Accutane and may be born with serious birth defects.
Initials: ______
11.
I have read the Patient Product Information, Important Information Concerning Your Treatment
with Accutane® (isotretinoin) and other materials my prescriber gave me containing important safety
information about Accutane. I understand all the information I received.
Initials: ______
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
63
12.
My prescriber and I have decided I should take Accutane. I understand that each of my
Accutane prescriptions must have a yellow self-adhesive Accutane Qualification Sticker on it. I
understand that I can stop taking Accutane at any time. I agree to tell my prescriber if I stop taking
Accutane.
Initials: ______
I now authorize my prescriber _________________________________________ to begin my
treatment with Accutane.
Patient Signature_____________Date___________
Parent/Guardian Signature (if under age 18)_______________Date____________
Patient Name (print)____________________
Patient Address____________________Telephone ( ______ ) __________________
____________________________________________________________________
I have:
• fully explained to the patient,________________, the nature and purpose of Accutane treatment,
including its benefits and risks
• given the patient the appropriate educational materials, Be Smart, Be Safe, Be Sure, for Accutane and
asked the patient if he/she has any questions regarding his/her treatment
with Accutane
• answered those questions to the best of my ability
• placed the yellow self-adhesive Accutane Qualification Sticker on the prescription.
Prescriber Signature______________________________Date____________
Issued: November 2002
Prescriber Copy
18-013-101-009-1102
((NCR FORM))
ACCUTANE® (isotretinoin)
Informed Consent/PATIENT AGREEMENT
(for all patients)
To be completed by patient (parent or guardian if patient is under age 18) and signed by the prescriber
Read each item below and initial in the space provided if you understand each item and agree to follow
your prescriber’s instructions. A parent or guardian of a patient under age 18 must also read and
understand each item before signing the agreement.
Do not sign this agreement and do not take Accutane if there is anything that you do not understand
about all the information you have received about using Accutane.
1.
I, ___________________________________________________________,
(Patient’s Name)
understand that Accutane is a medicine used to treat severe nodular acne that cannot be cleared up by
any other acne treatments, including antibiotics. In severe nodular acne, many red, swollen, tender
lumps form in the skin. If untreated, severe nodular acne can lead to permanent scars.
Initials: ______
2.
My prescriber has told me about my choices for treating my acne.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
64
Initials: ______
3.
I understand that there are serious side effects that may happen while I am taking Accutane.
These have been explained to me. These side effects include serious birth defects in babies of pregnant
females. (Note: There is a second Informed Consent form for female patients concerning birth defects.)
Initials: ______
4.
I understand that some patients, while taking Accutane or soon after stopping Accutane, have
become depressed or developed other serious mental problems. Symptoms of these problems include
sad, “anxious” or empty mood, irritability, anger, loss of pleasure or interest in social or sports
activities, sleeping too much or too little, changes in weight or appetite, school or work performance
going down, or trouble concentrating. Some patients taking Accutane have had thoughts about hurting
themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own
lives. And some people have ended their own lives. There were reports that some of these people did
not appear depressed. There have been reports of patients on Accutane becoming aggressive or violent.
No one knows if Accutane caused these behaviors or if they would have happened even if the person
did not take Accutane. Some people have had other signs of depression while taking Accutane (see
#7).
Initials: ______
5.
Before I start taking Accutane, I agree to tell my prescriber if, to the best of my knowledge, I
have ever had symptoms of depression (see #7), been psychotic, attempted suicide, had any other
mental problems, or take medicine for any of these problems. Being psychotic means having a loss of
contact with reality, such as hearing voices or seeing things that are not there.
Initials: ______
6.
Before I start taking Accutane, I agree to tell my prescriber if, to the best of my knowledge,
anyone in my family has ever had symptoms of depression, been psychotic, attempted suicide, or had
any other serious mental problems.
Initials: ______
7.
Once I start taking Accutane, I agree to stop using Accutane and tell my prescriber right away
if any of the following happen. I:
• Start to feel sad or have crying spells
• Lose interest in activities I once enjoyed
• Sleep too much or have trouble sleeping
• Become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of
violence)
• Have a change in my appetite or body weight
• Have trouble concentrating
• Withdraw from my friends or family
• Feel like I have no energy
• Have feelings of worthlessness or inappropriate guilt
• Start having thoughts about hurting myself or taking my own life (suicidal thoughts)
Initials: ______
8.
I agree to return to see my prescriber every month I take Accutane to get a new prescription for
Accutane, to check my progress, and to check for signs of side effects.
Initials: ______
9.
Accutane will be prescribed just for me — I will not share Accutane with other people because
it may cause serious side effects, including birth defects.
Initials: ______
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
65
10.
I will not give blood while taking Accutane or for 1 month after I stop taking Accutane. I
understand that if someone who is pregnant gets my donated blood, her baby may be exposed to
Accutane and may be born with serious birth defects.
Initials: ______
11.
I have read the Patient Product Information, Important Information Concerning Your Treatment
with Accutane® (isotretinoin) and other materials my prescriber gave me containing important safety
information about Accutane. I understand all the information I received.
Initials: ______
12.
My prescriber and I have decided I should take Accutane. I understand that each of my
Accutane prescriptions must have a yellow self-adhesive Accutane Qualification Sticker on it. I
understand that I can stop taking Accutane at any time. I agree to tell my prescriber if I stop taking
Accutane.
Initials: ______
I now authorize my prescriber _________________________________________ to begin my
treatment with Accutane.
Patient Signature_____________Date___________
Parent/Guardian Signature (if under age 18)_______________Date____________
Patient Name (print)____________________
Patient Address____________________Telephone ( ______ ) __________________
____________________________________________________________________
I have:
• fully explained to the patient,________________, the nature and purpose of Accutane treatment,
including its benefits and risks
• given the patient the appropriate educational materials, Be Smart, Be Safe, Be Sure, for Accutane and
asked the patient if he/she has any questions regarding his/her treatment
with Accutane
• answered those questions to the best of my ability
• placed the yellow self-adhesive Accutane Qualification Sticker on the prescription.
Prescriber Signature______________________________Date____________
Issued: November 2002
Patient Copy
18-013-101-009-1102
THIS SECTION CONTAINS MORE
INFORMATION FOR YOU
((TAB Copy))
section 3
EDUCATION REINFORCEMENT
Accutane InfoLine
ENGLISH
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
66
The Accutane (isotretinoin) InfoLine gives you information on Accutane. To call, dial toll-free 1-800-
950-4411 on a touchtone phone. When you hear the three tones, push “1” to hear the message in
English. You will hear the facts about Accutane, but you may not hear all there is to know about
Accutane. Be sure to ask your doctor for complete information. Please call…we’d like to share
important facts with patients taking Accutane.
((Also translated into Spanish, Portuguese, Italian, French, Russian, German, Polish, Vietnamese,
Korean, Japanese, and Chinese))
((Roche Signoff))
Copyright © 2002-2003 by Roche Laboratories Inc. All rights reserved.
PLANDEX 101004
PRINTED IN USA
xx-xxx-xxx-xxx-xxxx
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-882/S048/S052
67
ACCUTANE QUALIFICATION STICKER
_____ Female _____ Male
Pharmacist:
Female patient has been qualified as
described in CONTRAINDICATIONS
AND WARNINGS of package
insert on ______________________
Qualification date
QSXXXXXXXX
DEA # ABXXXXXXX
•
Dispense within 7 days of
qualification date
•
No more than 30-day supply ONLY
•
No refills allowed
Copyright 2003 by Roche Laboratories Inc. All rights reserved.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:50.631979
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/18662slr048,052_accutane_lbl.pdf', 'application_number': 18662, 'submission_type': 'SUPPL ', 'submission_number': 52}
|
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NDA 18-676/S-022
Page 5
Y36-002-487
PACKAGE INSERT
HepatAmine® (8% Amino Acid Injection)
Protect from light until use.
DESCRIPTION
Rx only
HepatAmine (8% Amino Acid Injection) is a sterile, nonpyrogenic, hypertonic solution
containing crystalline amino acids. A 500 mL unit provides a total of 40 g of amino acids and 6 g
of nitrogen (38 g of protein equivalent).
Each 100 mL contains:
Essential amino acids
Isoleucine USP
0.90 g
Leucine USP
1.10 g
Lysine
0.61 g
(added as lysine acetate USP
0.86 g)
Methionine USP
0.10 g
Phenylalanine USP
0.10 g
Threonine USP
0.45 g
Tryptophan USP
0.066 g
Valine USP
0.84 g
Nonessential amino acids
Alanine USP
0.77 g
Arginine USP
0.60 g
Histidine USP
0.24 g
Proline USP
0.80 g
Serine USP
0.50 g
Glycine USP
0.90 g
Cysteine
<0.014 g
(as Cysteine HCl•H2O USP
<0.020 g)
Phosphoric Acid NF
0.115 g
Sodium Bisulfite (as an antioxidant)
<0.1 g
Water for Injection USP qs
pH adjusted with Glacial Acetic Acid USP
pH: 6.5 (6.0-6.8)
Calculated Osmolarity: 785 mOsmol/liter
Concentration of Electrolytes (mEq/liter): Sodium 10; Chloride <3; Phosphate (HPO =
4) 20 (10
mmole P/liter); Acetate Approx. 62 (provided as acetic acid and Iysine acetate)
CLINICAL PHARMACOLOGY
HepatAmine provides a mixture of essential and nonessential amino acids with high
concentrations of the branched chain amino acids isoleucine, leucine, and valine, and low
concentrations of methionine and the aromatic amino acids phenylalanine and tryptophan,
relative to general purpose amino acid injections. This amino acid composition has been
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-676/S-022
Page 6
specifically formulated to provide a well tolerated nitrogen source for nutritional support and
therapy of patients with liver disease who have hepatic encephalopathy.
The precise mechanisms which produce the therapeutic effects of HepatAmine are not known.
The etiopathology of hepatic encephalopathy is also unknown and is thought to be of
multifactorial origin. The rationale for HepatAmine is based on observations of plasma amino
acid imbalances in patients with liver disease and on theories which postulate that these
abnormal patterns are causally related to the development of hepatic encephalopathy.
Clinical studies in patients with hepatic encephalopathy showed that infusion of HepatAmine
reversed the abnormal plasma amino acid pattern characterized by decreased levels of branched
chain amino acids and elevated levels of aromatic amino acids and methionine. The trend toward
normalization of these amino acids was generally associated with an improvement in mental
status and EEG patterns. This clinical response was observed in the majority of patients studied.
Nitrogen balance was significantly improved and mortality reduced in these typically protein-
intolerant patients who received substantial amounts of protein equivalent as HepatAmine.
When infused with hypertonic dextrose as a calorie source, supplemented with electrolytes,
vitamins, and minerals, HepatAmine provides total parenteral nutrition in patients with liver
disease, with the exception of essential fatty acids.
Phosphate is a major intracellular anion which participates in providing energy for metabolism of
substrates and contributes to significant metabolic and enzymatic reactions in all organs and
tissues. It exerts a modifying influence on calcium levels, a buffering effect on acid-base
equilibrium, and has a primary role in the renal excretion of hydrogen ions.
It is thought that the acetate from Iysine acetate and acetic acid, under the conditions of
parenteral nutrition, does not impact net acid-base balance when renal and respiratory functions
are normal. Clinical evidence seems to support this thinking; however, confirmatory
experimental evidence is not available.
The amounts of sodium and chloride present are not of clinical significance.
INDICATIONS AND USAGE
HepatAmine is indicated for the treatment of hepatic encephalopathy in patients with cirrhosis or
hepatitis. HepatAmine provides nutritional support for patients with these diseases of the liver
who require parenteral nutrition and are intolerant of general purpose amino acid injections,
which are contraindicated in patients with hepatic coma.
CONTRAINDICATIONS
HepatAmine is contraindicated in patients with anuria, inborn errors of amino acid metabolism,
especially those involving branched chain amino acid metabolism such as Maple Syrup Urine
Disease and Isovaleric Acidemia, or hypersensitivity to one or more amino acids present
in the solution.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-676/S-022
Page 7
WARNINGS
This product contains sodium bisulfite, a sulfite that may cause allergic-type reactions including
anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain
susceptible people. The overall prevalence of sulfite sensitivity in the general population is
unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in
nonasthmatic people.
WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic
levels with prolonged parenteral administration if kidney function is impaired. Premature
neonates are particularly at risk because their kidneys are immature, and they require large
amounts of calcium and phosphate solutions, which contain aluminum.
Research indicates that patients with impaired kidney function, including premature neonates,
who receive parenteral levels of aluminum at greater than 4 to 5 µg/kg/day accumulate
aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may
occur at even lower rates of administration.
Safe, effective use of parenteral nutrition requires a knowledge of nutrition as well as clinical
expertise in recognition and treatment of the complications which can occur. Frequent clinical
evaluation and laboratory determinations are necessary for proper monitoring of
parenteral nutrition. Studies should include blood sugar, serum proteins, kidney and liver
function tests, electrolytes, hemogram, carbon dioxide content, serum osmolarities, blood
cultures, and blood ammonia levels.
Administration of amino acids in the presence of impaired renal function or gastrointestinal
bleeding may augment an already elevated blood urea nitrogen. Patients with azotemia from any
cause should not be infused with amino acids without regard to total nitrogen intake.
Administration of intravenous solutions can cause fluid and/or solute overload resulting in
dilution of serum electrolyte concentrations, over-hydration, congested states, or pulmonary
edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of
the solutions. The risk of solute overload causing congested states with peripheral and pulmonary
edema is directly proportional to the electrolyte concentrations of the solutions.
PRECAUTIONS
General
Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in
fluid balance, electrolyte concentrations, and acid-base balance during prolonged parenteral
therapy or whenever the condition of the patient warrants such evaluation. Significant deviations
from normal concentrations may require the use of additional electrolyte supplements.
Strongly hypertonic nutrient solutions should be administered through an indwelling intravenous
catheter with the tip located in the superior vena cava.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-676/S-022
Page 8
Special care must be taken when giving hypertonic dextrose to a diabetic or prediabetic patient.
To prevent severe hyperglycemia in such patients, insulin may be required.
Peripheral intravenous administration of HepatAmine® (8% Amino Acid Injection) requires
appropriate dilution and provision of adequate calories. Care should be taken to assure proper
placement of the needle within the lumen of the vein. The venipuncture site should be inspected
frequently for signs of infiltration. If venous thrombosis or phlebitis occurs, discontinue
infusions or change infusion site and initiate appropriate treatment.
Care should be taken to avoid circulatory overload, particularly in patients with cardiac
insufficiency.
In patients with myocardial infarct, infusion of amino acids should always be accompanied by
dextrose since in anoxia, free fatty acids cannot be utilized by the myocardium and energy must
be produced anaerobically from glycogen or glucose.
Infusion of HepatAmine may not affect the clinical course of patients with fulminant hepatitis
who have a poor prognosis and are generally unresponsive to treatment. It has been shown that
the abnormal plasma amino acid pattern in fulminant hepatitis differs from that in chronic liver
disease.
Extraordinary electrolyte losses such as may occur during protracted nasogastric suction,
vomiting, diarrhea, or gastrointestinal fistula drainage may necessitate additional electrolyte
supplementation.
Administration of glucose at a rate exceeding the patient’s utilization rate may lead to
hyperglycemia, coma, and death.
Metabolic acidosis can be prevented or readily controlled by adding a portion of the cations in
the electrolyte mixture as acetate salts and in the case of hyperchloremic acidosis, by keeping the
total chloride content of the infusate to a minimum.
HepatAmine contains less than 3 mEq chloride per liter.
HepatAmine contains 10 mmole/liter of phosphate. Some patients, especially those with
hypophosphatemia, may require additional phosphate. To prevent hypocalcemia, calcium
supplementation should always accompany phosphate administration. To assure adequate intake,
serum levels should be monitored frequently.
HepatAmine has not been adequately studied in pregnant women and pediatric patients;
therefore, its safe use in such patients has not been demonstrated.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-676/S-022
Page 9
To minimize the risk of possible incompatibilities arising from mixing this solution with other
additives that may be prescribed, the final infusate should be inspected for cloudiness or
precipitation immediately after mixing, prior to administration, and periodically during
administration.
Use HepatAmine only if solution is clear, the seal unbroken, and vacuum is present.
Drug product contains no more than 25 µg/L of aluminum.
Laboratory Tests
Frequent clinical evaluation and laboratory determinations are necessary for proper
monitoring during administration.
laboratory tests should include measurement of blood sugar, electrolyte, and serum protein
concentrations; kidney and liver function tests; and evaluation of acid-base balance and fluid
balance. other laboratory tests may be suggested by the patient’s condition.
Drug Interactions
Some additives may be incompatible. Consult with pharmacist. When introducing additives, use
aseptic techniques. Mix thoroughly. Do not store.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No in vitro or in vivo carcinogenesis, mutagenesis, or fertility studies have been conducted with
HepatAmine® (8% Amino Acid Injection).
Pregnancy - Teratogenic Effects - Pregnancy Category C.
Pregnancy Category C. Animal reproduction studies have not been conducted with HepatAmine
(8% Amino Acid Injection). It is also not known whether HepatAmine can cause fetal harm
when administered to a pregnant woman or can affect reproduction capacity. HepatAmine should
be given to a pregnant woman only if clearly needed.
Labor and Delivery
Information is unknown.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in
human milk, caution should be exercised when HepatAmine is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of amino acid injections in pediatric patients have not been established
by adequate and well-controlled studies. However, the use of amino acid injections in pediatric
patients as an adjunct in the offsetting of nitrogen loss or in the treatment of negative nitrogen
balance is well established in the medical literature. See WARNINGS and DOSAGE AND
ADMINISTRATION.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-676/S-022
Page 10
Geriatric Use
Clinical studies of HepatAmine did not include sufficient numbers of subjects age 65 years and
over to determine whether they respond differently from younger subjects. Other reported
clinical experience has not identified differences in responses between the elderly and younger
patients. In general, dose selection for an elderly patient should be cautious, usually starting at
the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose selection, and it may
be useful to monitor renal function. See WARNINGS.
Special Precautions for Central Venous Nutrition
Administration by central venous catheter should be used only by those familiar with this
technique and its complications.
Central venous nutrition may be associated with complications which can be prevented or
minimized by careful attention to all aspects of the procedure, including solution preparation,
administration, and patient monitoring. It is essential that a carefully prepared protocol, based on
current medical practices, be followed, preferably by an experienced team.
Although a detailed discussion of the complications is beyond the scope of this insert, the
following summary lists those based on current literature.
Technical. The placement of a central venous catheter should be regarded as a surgical
procedure. One should be fully acquainted with various techniques of catheter insertion as well
as recognition and treatment of complications. For details of techniques and placement sites,
consult the medical literature. X-ray is the best means of verifying catheter placement.
Complications known to occur from the placement of central venous catheters are
pneumothorax, hemothorax, hydrothorax, artery puncture and transection, injury to the brachial
plexus, malposition of the catheter, formation of arterio-venous fistula, phlebitis, thrombosis,
pericardial tamponade, and air and catheter embolus.
Septic. The constant risk of sepsis is present during total parenteral nutrition. Since contaminated
solutions and infusion catheters are potential sources of infection, it is imperative that the
preparation of solutions and the placement and care of catheters be accomplished under
controlled aseptic conditions.
Solutions should ideally be prepared in the hospital pharmacy in a laminar flow hood. The key
factor in their preparation is careful aseptic technique to avoid inadvertent touch contamination
during mixing of solutions and subsequent admixtures.
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NDA 18-676/S-022
Page 11
Solutions should be used promptly after mixing. Any storage should be under refrigeration for as
brief a time as possible. Administration time for a single bottle and set should never exceed 24
hours.
Consult the medical literature for a discussion of the management of sepsis. In brief, typical
management includes replacing the solution being administered with a fresh container and set,
and culturing the contents for bacterial or fungal contamination. If sepsis persists and another
source of infection is not identified, the catheter is removed, the proximal tip cultured, and a new
catheter reinserted when the fever has subsided. Non-specific, prophylactic antibiotic treatment
is not recommended.
Clinical experience indicates that the catheter is likely to be the prime source of infection as
opposed to aseptically prepared and properly stored solutions.
Metabolic. The following metabolic complications have been reported during the use of central
venous nutrition; metabolic acidosis, hypophosphatemia, alkalosis, hyperglycemia and
glycosuria, osmotic diuresis and dehydration, rebound hypoglycemia, elevated liver enzymes,
hypo- and hyper-vitaminosis, electrolyte imbalances and hyperammonemia in pediatric patients.
Frequent clinical evaluation and laboratory determinations are necessary, especially during the
first few days of therapy to prevent or minimize these complications.
ADVERSE REACTIONS
See WARNINGS and Special Precautions for Central Venous Nutrition.
Reactions reported in clinical studies as a result of infusion of the parenteral fluid were water
weight gain, edema, increase in BUN, and dilutional hyponatremia. Asterixis was reported to
have worsened in one patient during infusion of hepatamine® (8% Amino Acid Injection).
Reactions which may occur because of the solution or the technique of administration include
febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from
the site of injection, extravasation and hypervolemia.
Symptoms may result from an excess or deficit of one or more of the ions present in the solution;
therefore, frequent monitoring of electrolyte levels is essential.
Phosphorus deficiency may lead to impaired tissue oxygenation and acute hemolytic anemia.
Relative to calcium, excessive phosphorus intake can precipitate hypocalcemia with cramps,
tetany and muscular hyperexcitability.
If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute
appropriate therapeutic countermeasures and save the remainder of the fluid for examination if
deemed necessary.
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NDA 18-676/S-022
Page 12
OVERDOSAGE
In the event of a fluid or solute overload during parenteral therapy, reevaluate the patient’s
condition and institute appropriate corrective treatment.
DOSAGE AND ADMINISTRATION
The objective of nutritional management of patients with liver disease is the provision of
sufficient amino acid and caloric support for protein synthesis without exacerbating hepatic
encephalopathy.
The total daily dose of HepatAmine depends on daily protein requirements and on the patient’s
metabolic and clinical response. The determination of nitrogen balance and accurate daily body
weights, corrected for fluid balance, are probably the best means of assessing individual protein
requirements. Dosage should also be guided by the patient’s fluid intake limits and glucose and
nitrogen tolerances, as well as by metabolic and clinical response.
The recommended dosage is 80-120 grams of amino acids (12-18 grams of nitrogen) as
HepatAmine per day. Typically, 500 mL of 8% HepatAmine® (8% Amino Acid Injection)
appropriately mixed with 500 mL of 50% dextrose supplemented with electrolytes and vitamins
is administered over an 8-12 hour period. This results in a total daily fluid intake of
approximately 2-3 liters. Patients with fluid restrictions may only tolerate 1-2 liters. Although
nitrogen requirements may be higher in severely hypercatabolic or depleted patients, provision of
additional nitrogen may not be possible due to fluid intake limits, nitrogen, or glucose
intolerance.
In many patients, provision of adequate calories in the form of hypertonic dextrose may require
the administration of exogenous insulin to prevent hyperglycemia and glycosuria. To prevent
rebound hypoglycemia, a solution containing 5% dextrose should be administered when
hypertonic dextrose solutions are abruptly discontinued.
Fat emulsion coadministration should be considered when prolonged (more than 5 days)
parenteral nutrition is required in order to prevent essential fatty acid deficiency (E.F.A.D.).
Serum lipids should be monitored for evidence of E.F.A.D. in patients maintained on fat free
TPN.
The provision of sufficient intracellular electrolytes, principally potassium, magnesium, and
phosphate, is required for optimum utilization of amino acids. Approximately 60-180 mEq of
potassium, 10-30 mEq of magnesium, and 10-40 mmole of phosphate per day appear necessary
to achieve optimum metabolic response. In addition, sufficient quantities of the major
extracellular electrolytes sodium, calcium, and chloride, must be given. In patients with
hyperchloremic or other metabolic acidoses, sodium and potassium may be added as the acetate
salts to provide bicarbonate precursor. The electrolyte content of HepatAmine must be
considered when calculating daily electrolyte intake. Serum electrolytes, including magnesium
and phosphorus, should be monitored frequently.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-676/S-022
Page 13
Pediatric Use
Use of HepatAmine in pediatric patients is governed by the same considerations that affect the
use of any amino acid solution in pediatrics. The amount administered is dosed on the basis of
grams of amino acids/kg of body weight/day. Two to three g/kg of body weight for infants with
adequate calories are generally sufficient to satisfy protein needs and promote positive nitrogen
balance. Solutions administered by peripheral vein should not exceed twice normal serum
osmolarity (718 mOsmol/L).
Hypertonic mixtures of amino acids and dextrose may be safely administered by continuous
infusion through a central venous catheter with the tip located in the superior vena cava. Initial
infusion rates should be slow, and gradually increased to the recommended 60-125 mL/hr. If
administration rate should fall behind schedule, no attempt to “catch up” to planned intake
should be made. In addition to meeting protein needs, the rate of administration, particularly
during the first few days of therapy, is governed by the patient’s glucose tolerance. Daily intake
of amino acids and dextrose should be increased gradually to the maximum required dose as
indicated by frequent determinations of glucose levels in blood and urine.
For patients in whom the central venous route is not indicated and who can consume adequate
calories enterally, 8% HepatAmine may be administered by peripheral vein with or without
parenteral carbohydrate calories. Such infusates can be prepared by dilution of 8% HepatAmine
with Sterile Water for Injection or 5%-10% dextrose to prepare isotonic or slightly hypertonic
solutions for peripheral infusion.
It is essential that peripheral infusion be accompanied by adequate caloric supplementation. In
pediatric patients, the final solution should not exceed twice normal serum osmolarity (718
mOsmol/L).
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit.
Care must be taken to avoid incompatible admixtures. Consult with pharmacist.
HOW SUPPLIED
HepatAmine® (8% Amino Acid Injection) is supplied sterile and nonpyrogenic in glass
containers with solid stoppers packaged 6 per case.
NDC
Cat. No.
Size
HEPATAMINE (8% AMINO ACID INJECTION)
0264-9371-55
S9371-SS
500 mL
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect
from freezing. It is recommended that the product be stored at room temperature (25°C);
however, brief exposure up to 40°C does not adversely affect the product.
PROTECT FROM LIGHT UNTIL USE.
Revised: May 2003
HepatAmine is a registered trademark of B. Braun Medical Inc.
Made in USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-676/S-022
Page 14
Directions for Use of B. Braun Glass Containers with Solid Stoppers
Designed for use with a vented set.
Before use, perform the following checks:
1. Inspect each container. Read the label. Ensure solution is the one ordered and is within the
expiration date. Check the security of bail and band.
2. Invert container and carefully inspect the solution in good light for cloudiness, haze, or
particulate matter; check the bottle for cracks or other damage. In checking for cracks, do not be
confused by normal surface marks and seams on the bottom and sides of the bottle. These are not
flaws. Look for bright reflections that have depth and penetrate into the wall of the bottle. Reject
any such bottle.
3. To remove the outer closure, lift the tear tab and pull up, over, and down until it is below the
stopper (See Figure 1). Use a circular pulling motion on the tab until it breaks away.
4. Grasp and remove the metal disk, exercising caution not to touch the exposed sterile stopper
surface.
Warning: Some additives may be incompatible. Consult with pharmacist. When introducing
additives, use aseptic techniques. Mix thoroughly. Do not store.
5. Refer to Directions for Use of the set being used. Insert the set spike into the large round outlet
port of the stopper and hang container.
6. After admixture and during administration, reinspect the solution frequently. If any evidence
of solution contamination or instability is found or if the patient exhibits any signs of fever, chills
or other reactions not readily explainable, discontinue administration immediately and notify the
physician.
7. When adding medication to the container during administration, swab the triangular
medication site, inject medication and mix thoroughly by gentle agitation.
8. Spiking, additions, or transfers should be made immediately after exposing the sterile stopper
surface. Check for vacuum at first puncture of stopper. Admixture by needle or syringe should be
made through the triangular ( ∇ ) medication site; contents should be drawn by vacuum into the
bottle. Admixture by spiked vial should be through the outlet port (See Figure 2). If contents of
initial addition are not drawn into the bottle, vacuum is not present and the unit should be
discarded. Each addition/transfer will reduce the vacuum remaining in the bottle.
9. If the first puncture of the stopper is the administration set spike, insert the spike fully into the
outlet port of the stopper and promptly invert the bottle. Verify vacuum by observing rising air
bubbles. Do not use the bottle if vacuum is not present.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-676/S-022
Page 15
10. If admixture or set insertion is not performed immediately following removal of protective
metal disk, swab stopper surface.
B. BRAUN MEDICAL INC.
IRVINE CA USA 92614-5895
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:50.777670
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/18676scs022_hepatamine_lbl.pdf', 'application_number': 18676, 'submission_type': 'SUPPL ', 'submission_number': 22}
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NDA 18-662/S054
Page 3
ACCUTANE
(isotretinoin)
CAPSULES
Rx only
CAUSES BIRTH
DEFECTS
DO NOT GET
PREGNANT
CONTRAINDICATIONS AND WARNINGS
Accutane must not be used by females who are pregnant. Although not every fetus exposed to
Accutane has resulted in a deformed child, there is an extremely high risk that a deformed infant
can result if pregnancy occurs while taking Accutane in any amount even for short periods of
time. Potentially any fetus exposed during pregnancy can be affected. Presently, there are no
accurate means of determining, after Accutane exposure, which fetus has been affected and
which fetus has not been affected.
Major human fetal abnormalities related to Accutane administration in females have been
documented. There is an increased risk of spontaneous abortion. In addition, premature births
have been reported.
Documented external abnormalities include: skull abnormality; ear abnormalities (including
anotia, micropinna, small or absent external auditory canals); eye abnormalities (including
microphthalmia); facial dysmorphia; cleft palate. Documented internal abnormalities include:
CNS abnormalities (including cerebral abnormalities, cerebellar malformation, hydrocephalus,
microcephaly, cranial nerve deficit); cardiovascular abnormalities; thymus gland abnormality;
parathyroid hormone deficiency. In some cases death has occurred with certain of the
abnormalities previously noted.
Cases of IQ scores less than 85 with or without obvious CNS abnormalities have also been
reported.
Accutane is contraindicated in females of childbearing potential unless the patient meets all of
the following conditions:
• Must NOT be pregnant or breast feeding.
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NDA 18-662/S054
Page 4
• Must be capable of complying with the mandatory contraceptive measures required for
Accutane therapy and understand behaviors associated with an increased risk of pregnancy.
• Must be reliable in understanding and carrying out instructions.
Accutane must be prescribed under the System to Manage Accutane Related Teratogenicity
(S.M.A.R.T.).
To prescribe Accutane, the prescriber must obtain a supply of yellow self-adhesive Accutane
Qualification Stickers. To obtain these stickers:
1) Read the booklet entitled System to Manage Accutane Related Teratogenicity (S.M.A.R.T.)
Guide to Best Practices.
2) Sign and return the completed S.M.A.R.T. Letter of Understanding containing the following
Prescriber Checklist:
• I know the risk and severity of fetal injury/birth defects from Accutane
• I know how to diagnose and treat the various presentations of acne
• I know the risk factors for unplanned pregnancy and the effective measures for avoidance of
unplanned pregnancy
• It is the informed patient’s responsibility to avoid pregnancy during Accutane therapy and
for 1 month after stopping Accutane. To help patients have the knowledge and tools to do so:
Before beginning treatment of female patients with Accutane I will refer for expert, detailed
pregnancy prevention counseling and prescribing, reimbursed by the manufacturer, OR I
have the expertise to perform this function and elect to do so
• I understand, and will properly use throughout the Accutane treatment course, the
S.M.A.R.T. procedures for Accutane, including monthly pregnancy avoidance counseling,
pregnancy testing and use of the yellow self-adhesive Accutane Qualification Stickers
3) To use the yellow self-adhesive Accutane Qualification Sticker: Accutane should not be
prescribed or dispensed to any patient (male or female) without a yellow self-adhesive
Accutane Qualification Sticker.
For female patients, the yellow self-adhesive Accutane Qualification Sticker signifies that she:
• Must have had 2 negative urine or serum pregnancy tests with a sensitivity of at least 25
mIU/mL before receiving the initial Accutane prescription. The first test (a screening test) is
obtained by the prescriber when the decision is made to pursue qualification of the patient
for Accutane. The second pregnancy test (a confirmation test) should be done during the first
5 days of the menstrual period immediately preceding the beginning of Accutane therapy.
For patients with amenorrhea, the second test should be done at least 11 days after the last
act of unprotected sexual intercourse (without using 2 effective forms of contraception). Each
month of therapy, the patient must have a negative result from a urine or serum pregnancy
test. A pregnancy test must be repeated every month prior to the female patient receiving
each prescription.
• Must have selected and have committed to use 2 forms of effective contraception
simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the
chosen method, or the patient has undergone a hysterectomy. Patients must use 2 forms of
effective contraception for at least 1 month prior to initiation of Accutane therapy, during
Accutane therapy, and for 1 month after discontinuing Accutane therapy. Counseling about
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S054
Page 5
contraception and behaviors associated with an increased risk of pregnancy must be repeated
on a monthly basis.
Effective forms of contraception include both primary and secondary forms of contraception.
Primary forms of contraception include: tubal ligation, partner’s vasectomy, intrauterine
devices, birth control pills, and topical/injectable/implantable/insertable hormonal birth control
products. Secondary forms of contraception include diaphragms, latex condoms, and cervical
caps; each must be used with a spermicide.
Any birth control method can fail. Therefore, it is critically important that women of
childbearing potential use 2 effective forms of contraception simultaneously. A drug interaction
that decreases effectiveness of hormonal contraceptives has not been entirely ruled out for
Accutane (See PRECAUTIONS: Drug Interactions). Although hormonal contraceptives are
highly effective, there have been reports of pregnancy from women who have used oral
contraceptives, as well as topical/injectable/implantable/insertable hormonal birth control
products. These reports occurred while these patients were taking Accutane. These reports are
more frequent for women who use only a single method of contraception. Patients must receive
written warnings about the rates of possible contraception failure (included in patient education
kits).
Prescribers are advised to consult the package insert of any medication administered
concomitantly with hormonal contraceptives, since some medications may decrease the
effectiveness of these birth control products. Patients should be prospectively cautioned not to
self-medicate with the herbal supplement St. John’s Wort because a possible interaction has been
suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral
contraceptives shortly after starting St. John's Wort. Pregnancies have been reported by users
of combined hormonal contraceptives who also used some form of St. John's Wort (see
PRECAUTIONS).
• Must have signed a Patient Information/Consent form that contains warnings about the risk
of potential birth defects if the fetus is exposed to isotretinoin.
• Must have been informed of the purpose and importance of participating in the Accutane
Survey and have been given the opportunity to enroll (see PRECAUTIONS).
The yellow self-adhesive Accutane Qualification Sticker documents that the female patient is
qualified, and includes the date of qualification, patient gender, cut-off date for filling the
prescription, and up to a 30-day supply limit with no refills.
These yellow self-adhesive Accutane Qualification Stickers should also be used for male patients.
Table 1. Use of Pregnancy Tests and Accutane Qualification Stickers for Patients
Patient Type
Pregnancy
Test Required
Qualification Date
Accutane
Qualification Sticker
Necessary
Dispense Within
7 Days of
Qualification Date
All Males
No
Date Prescription
Written
Yes
Yes
Females of
Childbearing
Potential
Yes
Date Sample Taken for
Confirmatory Negative
Pregnancy Test
Yes
Yes
Females* Not of
Childbearing
No
Date Prescription
Written
Yes
Yes
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NDA 18-662/S054
Page 6
Potential
*Females who have had a hysterectomy or who are postmenopausal are not considered to be of
childbearing potential.
If a pregnancy does occur during treatment of a woman with Accutane, the prescriber and
patient should discuss the desirability of continuing the pregnancy. Prescribers are strongly
encouraged to report all cases of pregnancy to Roche @ 1-800-526-6367 where a Roche
Pregnancy Prevention Program Specialist will be available to discuss Roche pregnancy
information, or prescribers may contact the Food and Drug Administration MedWatch Program
@ 1-800-FDA-1088.
Accutane should be prescribed only by prescribers who have demonstrated special competence
in the diagnosis and treatment of severe recalcitrant nodular acne, are experienced in the use of
systemic retinoids, have read the S.M.A.R.T. Guide to Best Practices, signed and returned the
completed S.M.A.R.T. Letter of Understanding, and obtained yellow self-adhesive Accutane
Qualification Stickers. Accutane should not be prescribed or dispensed without a yellow self-
adhesive Accutane Qualification Sticker.
INFORMATION FOR PHARMACISTS:
ACCUTANE MUST ONLY BE DISPENSED:
• IN NO MORE THAN A 30-DAY SUPPLY
• ONLY ON PRESENTATION OF AN ACCUTANE PRESCRIPTION WITH A YELLOW
SELF-ADHESIVE ACCUTANE QUALIFICATION STICKER
• WITHIN 7 DAYS OF THE QUALIFICATION DATE
• REFILLS REQUIRE A NEW PRESCRIPTION WITH A YELLOW SELF-ADHESIVE
ACCUTANE QUALIFICATION STICKER
• NO TELEPHONE OR COMPUTERIZED PRESCRIPTIONS ARE PERMITTED.
AN ACCUTANE MEDICATION GUIDE MUST BE GIVEN TO THE PATIENT EACH TIME
ACCUTANE IS DISPENSED, AS REQUIRED BY LAW. THIS ACCUTANE MEDICATION
GUIDE IS AN IMPORTANT PART OF THE RISK MANAGEMENT PROGRAM FOR THE
PATIENT.
DESCRIPTION
Isotretinoin, a retinoid, is available as Accutane in 10-mg, 20-mg and 40-mg soft gelatin capsules for
oral administration. Each capsule contains beeswax, butylated hydroxyanisole, edetate disodium,
hydrogenated soybean oil flakes, hydrogenated vegetable oil, and soybean oil. Gelatin capsules contain
glycerin and parabens (methyl and propyl), with the following dye systems: 10 mg — iron oxide (red)
and titanium dioxide; 20 mg — FD&C Red No. 3, FD&C Blue No. 1, and titanium dioxide; 40 mg —
FD&C Yellow No. 6, D&C Yellow No. 10, and titanium dioxide.
Chemically, isotretinoin is 13-cis-retinoic acid and is related to both retinoic acid and retinol (vitamin
A). It is a yellow to orange crystalline powder with a molecular weight of 300.44. The structural
formula is:
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S054
Page 7
CLINICAL PHARMACOLOGY
Isotretinoin is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1.0 mg/kg/day
(see DOSAGE AND ADMINISTRATION), inhibits sebaceous gland function and keratinization. The
exact mechanism of action of isotretinoin is unknown.
Nodular Acne
Clinical improvement in nodular acne patients occurs in association with a reduction in sebum
secretion. The decrease in sebum secretion is temporary and is related to the dose and duration of
treatment with Accutane, and reflects a reduction in sebaceous gland size and an inhibition of
sebaceous gland differentiation.1
Pharmacokinetics
Absorption
Due to its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a high-fat
meal. In a crossover study, 74 healthy adult subjects received a single 80 mg oral dose (2 x 40 mg
capsules) of Accutane under fasted and fed conditions. Both peak plasma concentration (Cmax) and the
total exposure (AUC) of isotretinoin were more than doubled following a standardized high-fat meal
when compared with Accutane given under fasted conditions (see Table 2 below). The observed
elimination half-life was unchanged. This lack of change in half-life suggests that food increases the
bioavailability of isotretinoin without altering its disposition. The time to peak concentration (Tmax)
was also increased with food and may be related to a longer absorption phase. Therefore, Accutane
capsules should always be taken with food (see DOSAGE AND ADMINISTRATION). Clinical
studies have shown that there is no difference in the pharmacokinetics of isotretinoin between patients
with nodular acne and healthy subjects with normal skin.
Table 2. Pharmacokinetic Parameters of Isotretinoin Mean (%CV), N=74
Accutane
2 x 40 mg
Capsules
AUC0-∞
(ng⋅hr/mL)
Cmax
(ng/mL)
Tmax
(hr)
t1/2
(hr)
Fed*
10,004 (22%)
862 (22%)
5.3 (77%)
21 (39%)
Fasted
3,703 (46%)
301 (63%)
3.2 (56%)
21 (30%)
*Eating a standardized high-fat meal
Distribution
Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.
Metabolism
Following oral administration of isotretinoin, at least three metabolites have been identified in human
plasma: 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). Retinoic
acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion. The
administration of one isomer will give rise to the other. Isotretinoin is also irreversibly oxidized to
4-oxo-isotretinoin, which forms its geometric isomer 4-oxo-tretinoin.
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Page 8
After a single 80 mg oral dose of Accutane to 74 healthy adult subjects, concurrent administration of
food increased the extent of formation of all metabolites in plasma when compared to the extent of
formation under fasted conditions.
All of these metabolites possess retinoid activity that is in some in vitro models more than that of the
parent isotretinoin. However, the clinical significance of these models is unknown. After multiple oral
dose administration of isotretinoin to adult cystic acne patients (≥18 years), the exposure of patients to
4-oxo-isotretinoin at steady-state under fasted and fed conditions was approximately 3.4 times higher
than that of isotretinoin.
In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are 2C8,
2C9, 3A4, and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are
then excreted in urine and feces.
Elimination
Following oral administration of an 80 mg dose of 14C-isotretinoin as a liquid suspension, 14C-activity
in blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are
ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%). After a
single 80 mg oral dose of Accutane to 74 healthy adult subjects under fed conditions, the mean ± SD
elimination half-lives (t1/2) of isotretinoin and 4-oxo-isotretinoin were 21.0 ± 8.2 hours and 24.0 ± 5.3
hours, respectively. After both single and multiple doses, the observed accumulation ratios of
isotretinoin ranged from 0.90 to 5.43 in patients with cystic acne.
Special Patient Populations
Pediatric Patients
The pharmacokinetics of isotretinoin were evaluated after single and multiple doses in 38 pediatric
patients (12 to 15 years) and 19 adult patients (≥18 years) who received Accutane for the treatment of
severe recalcitrant nodular acne. In both age groups, 4-oxo-isotretinoin was the major metabolite;
tretinoin and 4-oxo-tretinoin were also observed. The dose-normalized pharmacokinetic parameters for
isotretinoin following single and multiple doses are summarized in Table 3 for pediatric patients. There
were no statistically significant differences in the pharmacokinetics of isotretinoin between pediatric
and adult patients.
Table 3. Pharmacokinetic Parameters of Isotretinoin Following Single and Multiple Dose
Administration in Pediatric Patients, 12 to 15 Years of Age
Mean (± SD), N=38*
Parameter
Isotretinoin
(Single Dose)
Isotretinoin
(Steady-State)
Cmax (ng/mL)
573.25 (278.79)
731.98 (361.86)
AUC(0-12) (ng⋅hr/mL)
3033.37 (1394.17)
5082.00 (2184.23)
AUC(0-24) (ng⋅hr/mL)
6003.81 (2885.67)
–
Tmax (hr)†
6.00 (1.00-24.60)
4.00 (0-12.00)
Cssmin (ng/mL)
–
352.32 (184.44)
T1/2 (hr)
–
15.69 (5.12)
CL/F (L/hr)
–
17.96 (6.27)
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*The single and multiple dose data in this table were obtained following a
non-standardized meal that is not comparable to the high-fat meal that was used in the
study in Table 2.
†Median (range)
In pediatric patients (12 to 15 years), the mean ± SD elimination half-lives (t1/2) of isotretinoin and 4-
oxo-isotretinoin were 15.7 ± 5.1 hours and 23.1 ± 5.7 hours, respectively. The accumulation ratios of
isotretinoin ranged from 0.46 to 3.65 for pediatric patients.
INDICATIONS AND USAGE
Severe Recalcitrant Nodular Acne
Accutane is indicated for the treatment of severe recalcitrant nodular acne. Nodules are inflammatory
lesions with a diameter of 5 mm or greater. The nodules may become suppurative or hemorrhagic.
“Severe,” by definition,2 means “many” as opposed to “few or several” nodules. Because of significant
adverse effects associated with its use, Accutane should be reserved for patients with severe nodular
acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition,
Accutane is indicated only for those females who are not pregnant, because Accutane can cause severe
birth defects (see boxed CONTRAINDICATIONS AND WARNINGS).
A single course of therapy for 15 to 20 weeks has been shown to result in complete and prolonged
remission of disease in many patients.1,3,4 If a second course of therapy is needed, it should not be
initiated until at least 8 weeks after completion of the first course, because experience has shown that
patients may continue to improve while off Accutane. The optimal interval before retreatment has not
been defined for patients who have not completed skeletal growth (see WARNINGS: Skeletal: Bone
Mineral Density, Hyperostosis, and Premature Epiphyseal Closure).
CONTRAINDICATIONS
Pregnancy: Category X. See boxed CONTRAINDICATIONS AND WARNINGS.
Allergic Reactions
Accutane is contraindicated in patients who are hypersensitive to this medication or to any of its
components. Accutane should not be given to patients who are sensitive to parabens, which are used as
preservatives in the gelatin capsule (see PRECAUTIONS: Hypersensitivity).
WARNINGS
Psychiatric Disorders
Accutane may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts,
suicide, and aggressive and/or violent behaviors. Discontinuation of Accutane therapy may be
insufficient; further evaluation may be necessary. No mechanism of action has been established
for these events (see ADVERSE REACTIONS: Psychiatric). Prescribers should read the
brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for
Prescribers of Accutane (isotretinoin).
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Pseudotumor Cerebri
Accutane use has been associated with a number of cases of pseudotumor cerebri (benign
intracranial hypertension), some of which involved concomitant use of tetracyclines.
Concomitant treatment with tetracyclines should therefore be avoided. Early signs and
symptoms of pseudotumor cerebri include papilledema, headache, nausea and vomiting, and
visual disturbances. Patients with these symptoms should be screened for papilledema and, if
present, they should be told to discontinue Accutane immediately and be referred to a
neurologist for further diagnosis and care (see ADVERSE REACTIONS: Neurological).
Pancreatitis
Acute pancreatitis has been reported in patients with either elevated or normal serum triglyceride
levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. Accutane should be
stopped if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of
pancreatitis occur.
Lipids
Elevations of serum triglycerides in excess of 800 mg/dL have been reported in patients treated with
Accutane. Marked elevations of serum triglycerides were reported in approximately 25% of patients
receiving Accutane in clinical trials. In addition, approximately 15% developed a decrease in high-
density lipoproteins and about 7% showed an increase in cholesterol levels. In clinical trials, the
effects on triglycerides, HDL, and cholesterol were reversible upon cessation of Accutane therapy.
Some patients have been able to reverse triglyceride elevation by reduction in weight, restriction of
dietary fat and alcohol, and reduction in dose while continuing Accutane.5
Blood lipid determinations should be performed before Accutane is given and then at intervals until the
lipid response to Accutane is established, which usually occurs within 4 weeks. Especially careful
consideration must be given to risk/benefit for patients who may be at high risk during Accutane
therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial
history of lipid metabolism disorder). If Accutane therapy is instituted, more frequent checks of serum
values for lipids and/or blood sugar are recommended (see PRECAUTIONS: Laboratory Tests).
The cardiovascular consequences of hypertriglyceridemia associated with Accutane are unknown.
Animal Studies: In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 to 5.3 times the recommended
clinical dose of 1.0 mg/kg/day after normalization for total body surface area) for 18 months or longer,
the incidences of focal calcification, fibrosis and inflammation of the myocardium, calcification of
coronary, pulmonary and mesenteric arteries, and metastatic calcification of the gastric mucosa were
greater than in control rats of similar age. Focal endocardial and myocardial calcifications associated
with calcification of the coronary arteries were observed in two dogs after approximately 6 to 7 months
of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day (30 to 60 times the recommended
clinical dose of 1.0 mg/kg/day, respectively, after normalization for total body surface area).
Hearing Impairment
Impaired hearing has been reported in patients taking Accutane; in some cases, the hearing impairment
has been reported to persist after therapy has been discontinued. Mechanism(s) and causality for this
event have not been established. Patients who experience tinnitus or hearing impairment should
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discontinue Accutane treatment and be referred for specialized care for further evaluation (see
ADVERSE REACTIONS: Special Senses).
Hepatotoxicity
Clinical hepatitis considered to be possibly or probably related to Accutane therapy has been reported.
Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15%
of individuals treated during clinical trials, some of which normalized with dosage reduction or
continued administration of the drug. If normalization does not readily occur or if hepatitis is suspected
during treatment with Accutane, the drug should be discontinued and the etiology further investigated.
Inflammatory Bowel Disease
Accutane has been associated with inflammatory bowel disease (including regional ileitis) in patients
without a prior history of intestinal disorders. In some instances, symptoms have been reported to
persist after Accutane treatment has been stopped. Patients experiencing abdominal pain, rectal
bleeding or severe diarrhea should discontinue Accutane immediately (see ADVERSE REACTIONS:
Gastrointestinal).
Skeletal
Bone Mineral Density
Effects of multiple courses of Accutane on the developing musculoskeletal system are unknown.
There is some evidence that long-term, high-dose, or multiple courses of therapy with isotretinoin have
more of an effect than a single course of therapy on the musculoskeletal system. In an open-label
clinical trial (N=217) of a single course of therapy with Accutane for severe recalcitrant nodular acne,
bone density measurements at several skeletal sites were not significantly decreased (lumbar spine
change >-4% and total hip change >-5%) or were increased in the majority of patients. One patient
had a decrease in lumbar spine bone mineral density >4% based on unadjusted data. Sixteen (7.9%)
patients had decreases in lumbar spine bone mineral density >4%, and all the other patients (92%) did
not have significant decreases or had increases (adjusted for body mass index). Nine patients (4.5%)
had a decrease in total hip bone mineral density >5% based on unadjusted data. Twenty-one (10.6%)
patients had decreases in total hip bone mineral density >5%, and all the other patients (89%) did not
have significant decreases or had increases (adjusted for body mass index). Follow-up studies
performed in 8 of the patients with decreased bone mineral density for up to 11 months thereafter
demonstrated increasing bone density in 5 patients at the lumbar spine, while the other 3 patients had
lumbar spine bone density measurements below baseline values. Total hip bone mineral densities
remained below baseline (range –1.6% to -7.6%) in 5 of 8 patients (62.5%).
In a separate open-label extension study of 10 patients, ages 13-18 years, who started a second course
of Accutane 4 months after the first course, two patients showed a decrease in mean lumbar spine bone
mineral density up to 3.25% (see PRECAUTIONS: Pediatric Use).
Spontaneous reports of osteoporosis, osteopenia, bone fractures, and delayed healing of bone fractures
have been seen in the Accutane population. While causality to Accutane has not been established, an
effect cannot be ruled out. Longer term effects have not been studied. It is important that Accutane be
given at the recommended doses for no longer than the recommended duration.
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Hyperostosis
A high prevalence of skeletal hyperostosis was noted in clinical trials for disorders of keratinization
with a mean dose of 2.24 mg/kg/day. Additionally, skeletal hyperostosis was noted in 6 of 8 patients in
a prospective study of disorders of keratinization.6 Minimal skeletal hyperostosis and calcification of
ligaments and tendons have also been observed by x-ray in prospective studies of nodular acne patients
treated with a single course of therapy at recommended doses. The skeletal effects of multiple
Accutane treatment courses for acne are unknown.
In a clinical study of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne,
hyperostosis was not observed after 16 to 20 weeks of treatment with approximately 1 mg/kg/day of
Accutane given in two divided doses. Hyperostosis may require a longer time frame to appear. The
clinical course and significance remain unknown.
Premature Epiphyseal Closure
There are spontaneous reports of premature epiphyseal closure in acne patients receiving
recommended doses of Accutane. The effect of multiple courses of Accutane on epiphyseal closure is
unknown.
Vision Impairment
Visual problems should be carefully monitored. All Accutane patients experiencing visual difficulties
should discontinue Accutane treatment and have an ophthalmological examination (see ADVERSE
REACTIONS: Special Senses).
Corneal Opacities
Corneal opacities have occurred in patients receiving Accutane for acne and more frequently when
higher drug dosages were used in patients with disorders of keratinization. The corneal opacities that
have been observed in clinical trial patients treated with Accutane have either completely resolved or
were resolving at follow-up 6 to 7 weeks after discontinuation of the drug (see ADVERSE
REACTIONS: Special Senses).
Decreased Night Vision
Decreased night vision has been reported during Accutane therapy and in some instances the event has
persisted after therapy was discontinued. Because the onset in some patients was sudden, patients
should be advised of this potential problem and warned to be cautious when driving or operating any
vehicle at night.
PRECAUTIONS
The Accutane Pregnancy Prevention and Risk Management Programs consist of the System to Manage
Accutane Related Teratogenicity (S.M.A.R.T.) and the Accutane Pregnancy Prevention Program
(PPP). S.M.A.R.T. should be followed for prescribing Accutane with the goal of preventing fetal
exposure to isotretinoin. It consists of: 1) reading the booklet entitled System to Manage Accutane
Related Teratogenicity (S.M.A.R.T.) Guide to Best Practices, 2) signing and returning the completed
S.M.A.R.T. Letter of Understanding containing the Prescriber Checklist, 3) a yellow self-adhesive
Accutane Qualification Sticker to be affixed to the prescription page. In addition, the patient
educational material, Be Smart, Be Safe, Be Sure, should be used with each patient.
The following further describes each component:
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1) The S.M.A.R.T. Guide to Best Practices includes: Accutane teratogenic potential, information on
pregnancy testing, specific information about effective contraception, the limitations of
contraceptive methods and behaviors associated with an increased risk of contraceptive failure and
pregnancy, the methods to evaluate pregnancy risk, and the method to complete a qualified
Accutane prescription.
2) The S.M.A.R.T. Letter of Understanding attests that Accutane prescribers understand that
Accutane is a teratogen, have read the S.M.A.R.T. Guide to Best Practices, understand their
responsibilities in preventing exposure of pregnant females to Accutane and the procedures for
qualifying female patients as defined in the boxed CONTRAINDICATIONS AND WARNINGS.
The Prescriber Checklist attests that Accutane prescribers know the risk and severity of injury/birth
defects from Accutane; know how to diagnose and treat the various presentations of acne; know
the risk factors for unplanned pregnancy and the effective measures for avoidance; will refer the
patient for, or provide, detailed pregnancy prevention counseling to help the patient have
knowledge and tools needed to fulfill their ultimate responsibility to avoid becoming pregnant;
understand and properly use throughout the Accutane treatment course, the revised risk
management procedures, including monthly pregnancy avoidance counseling, pregnancy testing,
and use of qualified prescriptions with the yellow self-adhesive Accutane Qualification Sticker.
3) The yellow self-adhesive Accutane Qualification Sticker is used as documentation that the
prescriber has qualified the female patient according to the qualification criteria (see boxed
CONTRAINDICATIONS AND WARNINGS).
4) Accutane Pregnancy Prevention Program (PPP) is a systematic approach to comprehensive patient
education about their responsibilities and includes education for contraception compliance and
reinforcement of educational messages. The PPP includes information on the risks and benefits of
Accutane which is linked to the Accutane Medication Guide dispensed by pharmacists with each
prescription.
Male and female patients are provided with separate booklets. Each booklet contains information
on Accutane therapy, including precautions and warnings, an Informed Consent/Patient Agreement
form, and a toll-free line which provides Accutane information in 13 languages.
The booklet for male patients, Be Smart, Be Safe, Be Sure, Accutane Risk Management Program
for Men, also includes information about male reproduction, a warning not to share Accutane with
others or to donate blood during Accutane therapy and for 1 month following discontinuation of
Accutane.
The booklet for female patients, Be Smart, Be Safe, Be Sure, Accutane Pregnancy Prevention and
Risk Management Program for Women, also includes a referral program that offers females free
contraception counseling, reimbursed by the manufacturer, by a reproductive specialist; a second
Patient Information/Consent form concerning birth defects, obtaining her consent to be treated
within this agreement; an enrollment form for the Accutane Survey; and a qualification checklist
affirming the conditions under which female patients may receive Accutane. In addition, there is
information on the types of contraceptive methods, the selection and use of appropriate, effective
contraception, and the rates of possible contraceptive failure; a toll-free contraception counseling
line; and patient education videos — the video “Be Prepared, Be Protected” and the video “Be
Aware: The Risk of Pregnancy While on Accutane”.
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General
Although an effect of Accutane on bone loss is not established, physicians should use caution when
prescribing Accutane to patients with a genetic predisposition for age-related osteoporosis, a history of
childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism. This would
include patients diagnosed with anorexia nervosa and those who are on chronic drug therapy that
causes drug-induced osteoporosis/osteomalacia and/or affects vitamin D metabolism, such as systemic
corticosteroids and any anticonvulsant.
Patients may be at increased risk when participating in sports with repetitive impact where the risks of
spondylolisthesis with and without pars fractures and hip growth plate injuries in early and late
adolescence are known. There are spontaneous reports of fractures and/or delayed healing in patients
while on treatment with Accutane or following cessation of treatment with Accutane while involved in
these activities. While causality to Accutane has not been established, an effect cannot be ruled out.
Information for Patients and Prescribers
• Patients should be instructed to read the Medication Guide supplied as required by law when
Accutane is dispensed. The complete text of the Medication Guide is reprinted at the end of this
document. For additional information, patients should also read the Patient Product Information,
Important Information Concerning Your Treatment with Accutane (isotretinoin). All patients
should sign the Informed Consent/Patient Agreement.
• Females of childbearing potential should be instructed that they must not be pregnant when
Accutane therapy is initiated, and that they should use 2 forms of effective contraception 1 month
before starting Accutane, while taking Accutane, and for 1 month after Accutane has been stopped.
They should also sign a consent form prior to beginning Accutane therapy. They should be given
an opportunity to enroll in the Accutane Survey and to review the patient videotapes provided by
the manufacturer to the prescriber. The videos include information about contraception, the most
common reasons that contraception fails, and the importance of using 2 forms of effective
contraception when taking teratogenic drugs and comprehensive information about types of
potential birth defects which could occur if a woman who is pregnant takes Accutane at any time
during pregnancy. Female patients should be seen by their prescribers monthly and have a urine or
serum pregnancy test performed each month during treatment to confirm negative pregnancy status
before another Accutane prescription is written (see boxed CONTRAINDICATIONS AND
WARNINGS).
• Accutane is found in the semen of male patients taking Accutane, but the amount delivered to a
female partner would be about 1 million times lower than an oral dose of 40 mg. While the no-
effect limit for isotretinoin-induced embryopathy is unknown, 20 years of postmarketing reports
include 4 with isolated defects compatible with features of retinoid exposed fetuses. None of these
cases had the combination of malformations characteristic of retinoid exposure, and all had other
possible explanations for the defects observed.
• Patients may report mental health problems or family history of psychiatric disorders. These
reports should be discussed with the patient and/or the patient’s family. A referral to a mental
health professional may be necessary. The physician should consider whether or not Accutane
therapy is appropriate in this setting (see WARNINGS: Psychiatric Disorders).
• Patients should be informed that they must not share Accutane with anyone else because of the risk
of birth defects and other serious adverse events.
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• Patients should not donate blood during therapy and for 1 month following discontinuance of the
drug because the blood might be given to a pregnant woman whose fetus must not be exposed to
Accutane.
• Patients should be reminded to take Accutane with a meal (see DOSAGE AND
ADMINISTRATION). To decrease the risk of esophageal irritation, patients should swallow the
capsules with a full glass of liquid.
• Patients should be informed that transient exacerbation (flare) of acne has been seen, generally
during the initial period of therapy.
• Wax epilation and skin resurfacing procedures (such as dermabrasion, laser) should be avoided
during Accutane therapy and for at least 6 months thereafter due to the possibility of scarring (see
ADVERSE REACTIONS: Skin and Appendages).
• Patients should be advised to avoid prolonged exposure to UV rays or sunlight.
• Patients should be informed that they may experience decreased tolerance to contact lenses during
and after therapy.
• Patients should be informed that approximately 16% of patients treated with Accutane in a clinical
trial developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these
symptoms were mild to moderate, but occasionally required discontinuation of the drug. Transient
pain in the chest has been reported less frequently. In the clinical trial, these symptoms generally
cleared rapidly after discontinuation of Accutane, but in some cases persisted (see ADVERSE
REACTIONS: Musculoskeletal). There have been rare postmarketing reports of rhabdomyolysis,
some associated with strenuous physical activity (see Laboratory Tests: CPK).
• Pediatric patients and their caregivers should be informed that approximately 29% (104/358) of
pediatric patients treated with Accutane developed back pain. Back pain was severe in 13.5%
(14/104) of the cases and occurred at a higher frequency in female than male patients. Arthralgias
were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in 7.6% (6/79) of
patients. Appropriate evaluation of the musculoskeletal system should be done in patients who
present with these symptoms during or after a course of Accutane. Consideration should be given
to discontinuation of Accutane if any significant abnormality is found.
• Neutropenia and rare cases of agranulocytosis have been reported. Accutane should be
discontinued if clinically significant decreases in white cell counts occur.
Hypersensitivity
Anaphylactic reactions and other allergic reactions have been reported. Cutaneous allergic reactions
and serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities
and extracutaneous involvement (including renal) have been reported. Severe allergic reaction
necessitates discontinuation of therapy and appropriate medical management.
Drug Interactions
• Vitamin A: Because of the relationship of Accutane to vitamin A, patients should be advised
against taking vitamin supplements containing vitamin A to avoid additive toxic effects.
• Tetracyclines: Concomitant treatment with Accutane and tetracyclines should be avoided because
Accutane use has been associated with a number of cases of pseudotumor cerebri (benign
intracranial hypertension), some of which involved concomitant use of tetracyclines.
• Micro-dosed Progesterone Preparations: Micro-dosed progesterone preparations (“minipills” that
do not contain an estrogen) may be an inadequate method of contraception during Accutane
therapy. Although other hormonal contraceptives are highly effective, there have been reports of
pregnancy from women who have used combined oral contraceptives, as well as
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topical/injectable/implantable/insertable hormonal birth control products. These reports are more
frequent for women who use only a single method of contraception. It is not known if hormonal
contraceptives differ in their effectiveness when used with Accutane. Therefore, it is critically
important for women of childbearing potential to select and commit to use 2 forms of effective
contraception simultaneously, at least 1 of which must be a primary form, unless absolute
abstinence is the chosen method, or the patient has undergone a hysterectomy (see boxed
CONTRAINDICATIONS AND WARNINGS).
• Norethindrone/ethinyl estradiol: In a study of 31 premenopausal women with severe recalcitrant
nodular acne receiving OrthoNovum 7/7/7 Tablets as an oral contraceptive agent, Accutane at the
recommended dose of 1 mg/kg/day, did not induce clinically relevant changes in the
pharmacokinetics of ethinyl estradiol and norethindrone and in the serum levels of progesterone,
follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
• Phenytoin: Accutane has not been shown to alter the pharmacokinetics of phenytoin in a study in
seven healthy volunteers. These results are consistent with the in vitro finding that neither
isotretinoin nor its metabolites induce or inhibit the activity of the CYP 2C9 human hepatic P450
enzyme. Phenytoin is known to cause osteomalacia. No formal clinical studies have been
conducted to assess if there is an interactive effect on bone loss between phenytoin and Accutane.
Therefore, caution should be exercised when using these drugs together.
• Systemic Corticosteroids: Systemic corticosteroids are known to cause osteoporosis. No formal
clinical studies have been conducted to assess if there is an interactive effect on bone loss between
systemic corticosteroids and Accutane. Therefore, caution should be exercised when using these
drugs together.
Prescribers are advised to consult the package insert of medication administered concomitantly with
hormonal contraceptives, since some medications may decrease the effectiveness of these birth control
products. Accutane use is associated with depression in some patients (see WARNINGS:
Psychiatric Disorders and ADVERSE REACTIONS: Psychiatric). Patients should be prospectively
cautioned not to self-medicate with the herbal supplement St. John’s Wort because a possible
interaction has been suggested with hormonal contraceptives based on reports of breakthrough
bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies have been reported
by users of combined hormonal contraceptives who also used some form of St. John's Wort.
Laboratory Tests
Pregnancy Test
Female patients of childbearing potential must have negative results from 2 urine or serum pregnancy
tests with a sensitivity of at least 25 mIU/mL before receiving the initial Accutane prescription. The
first test is obtained by the prescriber when the decision is made to pursue qualification of the patient
for Accutane (a screening test). The second pregnancy test (a confirmation test) should be done during
the first 5 days of the menstrual period immediately preceding the beginning of Accutane therapy. For
patients with amenorrhea, the second test should be done at least 11 days after the last act of
unprotected sexual intercourse (without using 2 effective forms of contraception).
Each month of therapy, the patient must have a negative result from a urine or serum pregnancy test. A
pregnancy test must be repeated each month prior to the female patient receiving each prescription.
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• Lipids: Pretreatment and follow-up blood lipids should be obtained under fasting conditions. After
consumption of alcohol, at least 36 hours should elapse before these determinations are made. It is
recommended that these tests be performed at weekly or biweekly intervals until the lipid response
to Accutane is established. The incidence of hypertriglyceridemia is 1 patient in 4 on Accutane
therapy (see WARNINGS: Lipids).
• Liver Function Tests: Since elevations of liver enzymes have been observed during clinical trials,
and hepatitis has been reported, pretreatment and follow-up liver function tests should be
performed at weekly or biweekly intervals until the response to Accutane has been established (see
WARNINGS: Hepatotoxicity).
• Glucose: Some patients receiving Accutane have experienced problems in the control of their
blood sugar. In addition, new cases of diabetes have been diagnosed during Accutane therapy,
although no causal relationship has been established.
• CPK: Some patients undergoing vigorous physical activity while on Accutane therapy have
experienced elevated CPK levels; however, the clinical significance is unknown. There have been
rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity. In
a clinical trial of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne,
transient elevations in CPK were observed in 12% of patients, including those undergoing
strenuous physical activity in association with reported musculoskeletal adverse events such as
back pain, arthralgia, limb injury, or muscle sprain. In these patients, approximately half of the
CPK elevations returned to normal within 2 weeks and half returned to normal within 4 weeks. No
cases of rhabdomyolysis were reported in this trial.
Carcinogenesis, Mutagenesis and Impairment of Fertility
In male and female Fischer 344 rats given oral isotretinoin at dosages of 8 or 32 mg/kg/day (1.3 to 5.3
times the recommended clinical dose of 1.0 mg/kg/day, respectively, after normalization for total body
surface area) for greater than 18 months, there was a dose-related increased incidence of
pheochromocytoma relative to controls. The incidence of adrenal medullary hyperplasia was also
increased at the higher dosage in both sexes. The relatively high level of spontaneous
pheochromocytomas occurring in the male Fischer 344 rat makes it an equivocal model for study of
this tumor; therefore, the relevance of this tumor to the human population is uncertain.
The Ames test was conducted with isotretinoin in two laboratories. The results of the tests in one
laboratory were negative while in the second laboratory a weakly positive response (less than 1.6 x
background) was noted in S. typhimurium TA100 when the assay was conducted with metabolic
activation. No dose-response effect was seen and all other strains were negative. Additionally, other
tests designed to assess genotoxicity (Chinese hamster cell assay, mouse micronucleus test, S.
cerevisiae D7 assay, in vitro clastogenesis assay with human-derived lymphocytes, and unscheduled
DNA synthesis assay) were all negative.
In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were
observed at oral dosages of isotretinoin of 2, 8, or 32 mg/kg/day (0.3, 1.3, or 5.3 times the
recommended clinical dose of 1.0 mg/kg/day, respectively, after normalization for total body surface
area).
In dogs, testicular atrophy was noted after treatment with oral isotretinoin for approximately 30 weeks
at dosages of 20 or 60 mg/kg/day (10 or 30 times the recommended clinical dose of 1.0 mg/kg/day,
respectively, after normalization for total body surface area). In general, there was microscopic
evidence for appreciable depression of spermatogenesis but some sperm were observed in all testes
examined and in no instance were completely atrophic tubules seen. In studies of 66 men, 30 of whom
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Page 18
were patients with nodular acne under treatment with oral isotretinoin, no significant changes were
noted in the count or motility of spermatozoa in the ejaculate. In a study of 50 men (ages 17 to 32
years) receiving Accutane (isotretinoin) therapy for nodular acne, no significant effects were seen on
ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose.
Pregnancy: Category X. See boxed CONTRAINDICATIONS AND
WARNINGS.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because of the potential for adverse
effects, nursing mothers should not receive Accutane.
Pediatric Use
The use of Accutane in pediatric patients less than 12 years of age has not been studied. The use of
Accutane for the treatment of severe recalcitrant nodular acne in pediatric patients ages 12 to 17 years
should be given careful consideration, especially for those patients where a known metabolic or
structural bone disease exists (see PRECAUTIONS: General). Use of Accutane in this age group for
severe recalcitrant nodular acne is supported by evidence from a clinical study comparing 103 pediatric
patients (13 to 17 years) to 197 adult patients (≥18 years). Results from this study demonstrated that
Accutane, at a dose of 1 mg/kg/day given in two divided doses, was equally effective in treating severe
recalcitrant nodular acne in both pediatric and adult patients.
In studies with Accutane, adverse reactions reported in pediatric patients were similar to those
described in adults except for the increased incidence of back pain and arthralgia (both of which were
sometimes severe) and myalgia in pediatric patients (see ADVERSE REACTIONS).
In an open-label clinical trial (N=217) of a single course of therapy with Accutane for severe
recalcitrant nodular acne, bone density measurements at several skeletal sites were not significantly
decreased (lumbar spine change >-4% and total hip change >-5%) or were increased in the majority of
patients. One patient had a decrease in lumbar spine bone mineral density >4% based on unadjusted
data. Sixteen (7.9%) patients had decreases in lumbar spine bone mineral density >4%, and all the
other patients (92%) did not have significant decreases or had increases (adjusted for body mass
index). Nine patients (4.5%) had a decrease in total hip bone mineral density >5% based on
unadjusted data. Twenty-one (10.6%) patients had decreases in total hip bone mineral density >5%,
and all the other patients (89%) did not have significant decreases or had increases (adjusted for body
mass index). Follow-up studies performed in 8 of the patients with decreased bone mineral density for
up to 11 months thereafter demonstrated increasing bone density in 5 patients at the lumbar spine,
while the other 3 patients had lumbar spine bone density measurements below baseline values. Total
hip bone mineral densities remained below baseline (range –1.6% to -7.6%) in 5 of 8 patients (62.5%).
In a separate open-label extension study of 10 patients, ages 13-18 years, who started a second course
of Accutane 4 months after the first course, two patients showed a decrease in mean lumbar spine bone
mineral density up to 3.25% (see WARNINGS: Skeletal: Bone Mineral Density).
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Geriatric Use
Clinical studies of isotretinoin did not include sufficient numbers of subjects aged 65 years and over to
determine whether they respond differently from younger subjects. Although reported clinical
experience has not identified differences in responses between elderly and younger patients, effects of
aging might be expected to increase some risks associated with isotretinoin therapy (see WARNINGS
and PRECAUTIONS).
ADVERSE REACTIONS
Clinical Trials and Postmarketing Surveillance
The adverse reactions listed below reflect the experience from investigational studies of Accutane, and
the postmarketing experience. The relationship of some of these events to Accutane therapy is
unknown. Many of the side effects and adverse reactions seen in patients receiving Accutane are
similar to those described in patients taking very high doses of vitamin A (dryness of the skin and
mucous membranes, eg, of the lips, nasal passage, and eyes).
Dose Relationship
Cheilitis and hypertriglyceridemia are usually dose related. Most adverse reactions reported in clinical
trials were reversible when therapy was discontinued; however, some persisted after cessation of
therapy (see WARNINGS and ADVERSE REACTIONS).
Body as a Whole
allergic
reactions,
including
vasculitis,
systemic
hypersensitivity
(see
PRECAUTIONS:
Hypersensitivity), edema, fatigue, lymphadenopathy, weight loss
Cardiovascular
palpitation, tachycardia, vascular thrombotic disease, stroke
Endocrine/Metabolic
hypertriglyceridemia (see WARNINGS: Lipids), alterations in blood sugar levels (see
PRECAUTIONS: Laboratory Tests)
Gastrointestinal
inflammatory bowel disease (see WARNINGS: Inflammatory Bowel Disease), hepatitis (see
WARNINGS: Hepatotoxicity), pancreatitis (see WARNINGS: Lipids), bleeding and inflammation of
the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea, other nonspecific gastrointestinal
symptoms
Hematologic
allergic reactions (see PRECAUTIONS: Hypersensitivity), anemia, thrombocytopenia, neutropenia,
rare reports of agranulocytosis (see PRECAUTIONS: Information for Patients and Prescribers). See
PRECAUTIONS: Laboratory Tests for other hematological parameters.
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Page 20
Musculoskeletal
skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, decreases
in bone mineral density (see WARNINGS: Skeletal), musculoskeletal symptoms (sometimes severe)
including back pain and arthralgia (see PRECAUTIONS: Information for Patients and Prescribers),
transient pain in the chest (see PRECAUTIONS: Information for Patients and Prescribers), arthritis,
tendonitis, other types of bone abnormalities, elevations of CPK/rare reports of rhabdomyolysis (see
PRECAUTIONS: Laboratory Tests).
Neurological
pseudotumor cerebri (see WARNINGS: Pseudotumor Cerebri), dizziness, drowsiness, headache,
insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness
Psychiatric
suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors (see
WARNINGS: Psychiatric Disorders), emotional instability
Of the patients reporting depression, some reported that the depression subsided with discontinuation
of therapy and recurred with reinstitution of therapy.
Reproductive System
abnormal menses
Respiratory
bronchospasms (with or without a history of asthma), respiratory infection, voice alteration
Skin and Appendages
acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry
nose, dry skin, epistaxis, eruptive xanthomas,7 flushing, fragility of skin, hair abnormalities, hirsutism,
hyperpigmentation and hypopigmentation, infections (including disseminated herpes simplex), nail
dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus,
pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), sunburn susceptibility
increased, sweating, urticaria, vasculitis (including Wegener’s granulomatosis; see PRECAUTIONS:
Hypersensitivity), abnormal wound healing (delayed healing or exuberant granulation tissue with
crusting; see PRECAUTIONS: Information for Patients and Prescribers)
Special Senses
Hearing
hearing impairment (see WARNINGS: Hearing Impairment), tinnitus.
Vision
corneal opacities (see WARNINGS: Corneal Opacities), decreased night vision which may persist (see
WARNINGS: Decreased Night Vision), cataracts, color vision disorder, conjunctivitis, dry eyes, eyelid
inflammation, keratitis, optic neuritis, photophobia, visual disturbances
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Urinary System
glomerulonephritis (see PRECAUTIONS: Hypersensitivity), nonspecific urogenital findings (see
PRECAUTIONS: Laboratory Tests for other urological parameters)
Laboratory
Elevation of plasma triglycerides (see WARNINGS: Lipids), decrease in serum high-density
lipoprotein (HDL) levels, elevations of serum cholesterol during treatment
Increased alkaline phosphatase, SGOT (AST), SGPT (ALT), GGTP or LDH (see WARNINGS:
Hepatotoxicity)
Elevation of fasting blood sugar, elevations of CPK (see PRECAUTIONS: Laboratory Tests),
hyperuricemia
Decreases in red blood cell parameters, decreases in white blood cell counts (including severe
neutropenia and rare reports of agranulocytosis; see PRECAUTIONS: Information for Patients and
Prescribers), elevated sedimentation rates, elevated platelet counts, thrombocytopenia
White cells in the urine, proteinuria, microscopic or gross hematuria
OVERDOSAGE
The oral LD50 of isotretinoin is greater than 4000 mg/kg in rats and mice (>600 times the
recommended clinical dose of 1.0 mg/kg/day after normalization of the rat dose for total body surface
area and >300 times the recommended clinical dose of 1.0 mg/kg/day after normalization of the mouse
dose for total body surface area) and is approximately 1960 mg/kg in rabbits (653 times the
recommended clinical dose of 1.0 mg/kg/day after normalization for total body surface area). In
humans, overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain,
headache, dizziness, and ataxia. All symptoms quickly resolved without apparent residual effects.
Accutane causes serious birth defects at any dosage (see boxed CONTRAINDICATIONS AND
WARNINGS). Females of childbearing potential who present with isotretinoin overdose must be
evaluated for pregnancy. Patients who are pregnant should receive counseling about the risks to the
fetus, as described in the boxed CONTRAINDICATIONS AND WARNINGS. Non-pregnant patients
must be warned to avoid pregnancy for at least one month and receive contraceptive counseling as
described in the boxed CONTRAINDICATIONS AND WARNINGS. Educational materials for such
patients can be obtained by calling the manufacturer. Because an overdose would be expected to result
in higher levels of isotretinoin in semen than found during a normal treatment course, male patients
should use a condom, or avoid reproductive sexual activity with a female who is or might become
pregnant, for 30 days after the overdose. All patients with isotretinoin overdose should not donate
blood for at least 30 days.
DOSAGE AND ADMINISTRATION
Accutane should be administered with a meal (see PRECAUTIONS: Information for Patients and
Prescribers).
The recommended dosage range for Accutane is 0.5 to 1.0 mg/kg/day given in two divided doses with
food for 15 to 20 weeks. In studies comparing 0.1, 0.5, and 1.0 mg/kg/day,8 it was found that all
dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower
dosages. During treatment, the dose may be adjusted according to response of the disease and/or the
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NDA 18-662/S054
Page 22
appearance of clinical side effects — some of which may be dose related. Adult patients whose disease
is very severe with scarring or is primarily manifested on the trunk may require dose adjustments up to
2.0 mg/kg/day, as tolerated. Failure to take Accutane with food will significantly decrease absorption.
Before upward dose adjustments are made, the patients should be questioned about their compliance
with food instructions.
The safety of once daily dosing with Accutane has not been established. Once daily dosing is not
recommended.
If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of
treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and if
warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated.
The optimal interval before retreatment has not been defined for patients who have not completed
skeletal growth. Long-term use of Accutane, even in low doses, has not been studied, and is not
recommended. It is important that Accutane be given at the recommended doses for no longer than the
recommended duration. The effect of long-term use of Accutane on bone loss is unknown (see
WARNINGS: Skeletal: Bone Mineral Density, Hyperostosis, and Premature Epiphyseal Closure).
Contraceptive measures must be followed for any subsequent course of therapy (see boxed
CONTRAINDICATIONS AND WARNINGS).
Table 4. Accutane Dosing by Body Weight (Based on Administration With Food)
Body Weight
Total mg/day
kilograms
pounds
0.5 mg/kg
1 mg/kg
2 mg/kg*
40
88
20
40
80
50
110
25
50
100
60
132
30
60
120
70
154
35
70
140
80
176
40
80
160
90
198
45
90
180
100
220
50
100
200
*See DOSAGE AND ADMINISTRATION: the recommended dosage range is 0.5 to 1.0 mg/kg/day.
Information for Pharmacists
Accutane must only be dispensed in no more than a 30-day supply and only on presentation of an
Accutane prescription with a yellow self-adhesive Accutane Qualification Sticker within 7 days of the
qualification date. REFILLS REQUIRE A NEW WRITTEN PRESCRIPTION WITH A
YELLOW SELF-ADHESIVE ACCUTANE QUALIFICATION STICKER WITHIN 7 DAYS
OF THE QUALIFICATION DATE. No telephone or computerized prescriptions are permitted.
An Accutane Medication Guide must be given to the patient each time Accutane is dispensed, as
required by law. This Accutane Medication Guide is an important part of the risk management
program for the patient.
HOW SUPPLIED
Soft gelatin capsules, 10 mg (light pink), imprinted ACCUTANE 10 ROCHE. Boxes of 100 containing
10 Prescription Paks of 10 capsules (NDC 0004-0155-49).
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Soft gelatin capsules, 20 mg (maroon), imprinted ACCUTANE 20 ROCHE. Boxes of 100 containing
10 Prescription Paks of 10 capsules (NDC 0004-0169-49).
Soft gelatin capsules, 40 mg (yellow), imprinted ACCUTANE 40 ROCHE. Boxes of 100 containing
10 Prescription Paks of 10 capsules (NDC 0004-0156-49).
Storage
Store at controlled room temperature (59° to 86°F, 15° to 30°C). Protect from light.
REFERENCES
1. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and conglobate acne with 13-
cis-retinoic acid. N Engl J Med 300:329-333, 1979. 2. Pochi PE, Shalita AR, Strauss JS, Webster SB.
Report of the consensus conference on acne classification. J Am Acad Dermatol 24:495-500, 1991. 3.
Farrell LN, Strauss JS, Stranieri AM. The treatment of severe cystic acne with 13-cis-retinoic acid:
evaluation of sebum production and the clinical response in a multiple-dose trial. J Am Acad Dermatol
3:602-611, 1980. 4. Jones H, Blanc D, Cunliffe WJ. 13-cis-retinoic acid and acne. Lancet 2:1048-1049,
1980. 5. Katz RA, Jorgensen H, Nigra TP. Elevation of serum triglyceride levels from oral isotretinoin
in disorders of keratinization. Arch Dermatol 116:1369-1372, 1980. 6. Ellis CN, Madison KC, Pennes
DR, Martel W, Voorhees JJ. Isotretinoin therapy is associated with early skeletal radiographic changes.
J Am Acad Dermatol 10:1024-1029, 1984. 7. Dicken CH, Connolly SM. Eruptive xanthomas
associated with isotretinoin (13-cis-retinoic acid). Arch Dermatol 116:951-952, 1980. 8. Strauss JS,
Rapini RP, Shalita AR, et al. Isotretinoin therapy for acne: results of a multicenter dose-response
study. J Am Acad Dermatol 10:490-496, 1984.
OrthoNovum 7/7/7 is a registered trademark of Ortho-McNeil Pharmaceutical, Inc.
Revised: August 2004
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Page 24
PATIENT INFORMATION/CONSENT (for female patients concerning birth defects)
To be completed by the patient, her parent/guardian*
and signed by her prescriber.
Read each item below and initial in the space provided to show that you understand each item and
agree to follow your prescriber's instructions. Do not sign this consent and do not take Accutane if
there is anything that you do not understand.
*A parent or guardian of a minor patient (under age 18) must also read and initial each item before
signing the consent.
________________________________________________________________________
(Patient’s Name)
1. I understand that there is a very high risk that my unborn baby could have severe birth defects if I
am pregnant or become pregnant while taking Accutane in any amount even for short periods of
time. This is why I must not be pregnant while taking Accutane.
Initial: ______
2. I understand that I must not take Accutane (isotretinoin) if I am pregnant.
Initial: ______
3. I understand that I must not get pregnant during the entire time of my treatment and for 1 month
after the end of my treatment with Accutane.
Initial: ______
4. I understand that I must avoid sexual intercourse completely, or I must use 2 separate, effective
forms of birth control (contraception) at the same time. The only exception is if I have had
surgery to remove the womb (a hysterectomy).
Initial: ______
5. I understand that birth control pills and topical/injectable/implantable/insertable hormonal birth
control products are among the most effective forms of birth control. However, any form of birth
control can fail. Therefore, I must use 2 different methods at the same time, every time I have
sexual intercourse, even if 1 of the methods I choose is birth control pills or
topical/injectable/implantable/insertable hormonal birth control.
Initial: ______
6. I will talk with my prescriber about any drugs or herbal products I plan to take during my Accutane
treatment because hormonal birth control methods (for example, birth control pills) may not work
if I am taking certain drugs or herbal products (for example, St. John’s Wort).
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Initial: ______
7. I understand that the following are considered effective forms of birth control:
Primary:
Tubal ligation (tying my tubes), partner’s vasectomy, birth control pills,
topical/injectable/implantable/insertable hormonal birth control products, and an IUD
(intrauterine device).
Secondary: Diaphragms, latex condoms, and cervical caps. Each must be used with a spermicide,
which is a special cream or jelly that kills sperm.
I understand that at least 1 of my 2 methods of birth control must be a primary method.
Initial: ______
8. I understand that I may receive a free contraceptive (birth control) counseling session from a doctor
or other family planning expert. My Accutane prescriber can give me an Accutane Patient Referral
Form for this free consultation.
Initial: ______
9. I understand that I must begin using the birth control methods I have chosen as described above at
least 1 month before I start taking Accutane.
Initial: ______
10. I understand that I cannot get a prescription for Accutane unless I have 2 negative pregnancy test
results. The first pregnancy test should be done when my prescriber decides to prescribe Accutane.
The second pregnancy test should be done during the first 5 days of my menstrual period right
before starting Accutane therapy, or as instructed by my prescriber. I will then have 1 pregnancy
test every month during my Accutane therapy.
Initial: ______
11. I understand that I should not start taking Accutane until I am sure that I am not pregnant and have
negative results from 2 pregnancy tests.
Initial: ______
12. I have read and understand the materials my prescriber has given to me, including the Patient
Product Information, Important Information Concerning Your Treatment with Accutane
(isotretinoin). My prescriber gave me and asked me to watch the videos about contraception. I was
told about a confidential counseling line that I may call for more information about birth control. I
have received information on emergency contraception (birth control).
Initial: ______
13. I understand that I must stop taking Accutane right away and inform my prescriber if I get
pregnant, miss my menstrual period, stop using birth control, or have sexual intercourse without
using my 2 birth control methods at any time.
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Initial: ______
14. My prescriber gave me information about the confidential Accutane Survey and explained to me
how important it is to take part in the Accutane Survey.
Initial: ______
15. I understand that the yellow self-adhesive Accutane Qualification Sticker on my prescription for
Accutane means that I am qualified to receive an Accutane prescription, because I:
• have had 2 negative urine or serum pregnancy tests before receiving the initial Accutane
prescription. I must have a negative result from a urine or serum pregnancy test repeated each
month prior to my receiving each subsequent prescription.
• have selected and committed to use 2 forms of effective contraception simultaneously, at least 1 of
which must be a primary form, unless absolute abstinence is the chosen method, or I have
undergone a hysterectomy. I must use 2 forms of contraception for at least 1 month prior to
initiation of Accutane therapy, during therapy, and for 1 month after discontinuing therapy. I must
receive counseling, repeated on a monthly basis, about contraception and behaviors associated with
an increased risk of pregnancy.
• have signed a Patient Information/Consent form that contains warnings about the risk of potential
birth defects if I am pregnant or become pregnant and my unborn baby is exposed to isotretinoin.
• have been informed of the purpose and importance of participating in the Accutane Survey and
given the opportunity to enroll.
Initial: ______
My prescriber has answered all my questions about Accutane and I understand that it is my
responsibility not to get pregnant during Accutane treatment or for 1 month after I stop taking
Accutane.
Initial: ______
I now authorize my prescriber ________________ to begin my treatment with Accutane.
Patient Signature:________________________________ Date:____________________
Parent/Guardian Signature (if under age 18):____________________ Date:___________
Please print: Patient Name and Address________________________________________
_______________________________________ Telephone _______________________
I have fully explained to the patient, __________________, the nature and purpose of the treatment
described above and the risks to females of childbearing potential. I have asked the patient if she has
any questions regarding her treatment with Accutane and have answered those questions to the best of
my ability.
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Prescriber Signature: ______________________________ Date:__________________
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INFORMED CONSENT/PATIENT AGREEMENT (for all patients):
To be completed by patient (parent or guardian if patient is under age 18) and signed by the prescriber.
Read each item below and initial in the space provided if you understand each item and agree to follow
your prescriber’s instructions. A parent or guardian of a patient under age 18 must also read and
understand each item before signing the agreement.
Do not sign this agreement and do not take Accutane if there is anything that you do not
understand about all the information you have received about using Accutane.
1. I, ____________________________________________________________,
(Patient’s Name)
understand that Accutane is a medicine used to treat severe nodular acne that cannot be cleared up
by any other acne treatments, including antibiotics. In severe nodular acne, many red, swollen,
tender lumps form in the skin. If untreated, severe nodular acne can lead to permanent scars.
Initials: ______
2. My prescriber has told me about my choices for treating my acne.
Initials: ______
3. I understand that there are serious side effects that may happen while I am taking Accutane. These
have been explained to me. These side effects include serious birth defects in babies of pregnant
females. (Note: There is a second Informed Consent form for female patients concerning birth
defects.)
Initials: ______
4. I understand that some patients, while taking Accutane or soon after stopping Accutane, have
become depressed or developed other serious mental problems. Symptoms of these problems
include sad, “anxious” or empty mood, irritability, anger, loss of pleasure or interest in social or
sports activities, sleeping too much or too little, changes in weight or appetite, school or work
performance going down, or trouble concentrating. Some patients taking Accutane have had
thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some
people tried to end their own lives. And some people have ended their own lives. There were
reports that some of these people did not appear depressed. There have been reports of patients on
Accutane becoming aggressive or violent. No one knows if Accutane caused these behaviors or if
they would have happened even if the person did not take Accutane. Some people have had other
signs of depression while taking Accutane (see #7 below).
Initials: ______
5. Before I start taking Accutane, I agree to tell my prescriber if, to the best of my knowledge, I have
ever had symptoms of depression (see #7 below), been psychotic, attempted suicide, had any other
mental problems, or take medicine for any of these problems. Being psychotic means having a loss
of contact with reality, such as hearing voices or seeing things that are not there.
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Initials: ______
6. Before I start taking Accutane, I agree to tell my prescriber if, to the best of my knowledge, anyone
in my family has ever had symptoms of depression, been psychotic, attempted suicide, or had any
other serious mental problems.
Initials: ______
7. Once I start taking Accutane, I agree to stop using Accutane and tell my prescriber right away if
any of the following happen. I:
• Start to feel sad or have crying spells
• Lose interest in activities I once enjoyed
• Sleep too much or have trouble sleeping
• Become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of
violence)
• Have a change in my appetite or body weight
• Have trouble concentrating
• Withdraw from my friends or family
• Feel like I have no energy
• Have feelings of worthlessness or inappropriate guilt
• Start having thoughts about hurting myself or taking my own life (suicidal thoughts)
Initials: ______
8. I agree to return to see my prescriber every month I take Accutane to get a new prescription
for Accutane, to check my progress, and to check for signs of side effects.
Initials: ______
9. Accutane will be prescribed just for me—I will not share Accutane with other people because it
may cause serious side effects, including birth defects.
Initials: ______
10. I will not give blood while taking Accutane or for 1 month after I stop taking Accutane. I
understand that if someone who is pregnant gets my donated blood, her baby may be exposed to
Accutane and may be born with serious birth defects.
Initials: ______
11. I have read the Patient Product Information, Important Information Concerning Your Treatment
with Accutane (isotretinoin), and other materials my provider gave me containing important
safety information about Accutane. I understand all the information I received.
Initials: ______
12. My prescriber and I have decided I should take Accutane. I understand that each of my Accutane
prescriptions must have a yellow self-adhesive Accutane Qualification Sticker on it. I understand
that I can stop taking Accutane at any time. I agree to tell my prescriber if I stop taking Accutane.
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Initials: ______
I now authorize my prescriber ___________________________ to begin my treatment with Accutane.
Patient Signature: __________________________________________ Date: _________
Parent/Guardian Signature (if under age 18): _____________________ Date: _________
Patient Name (print) ___________________________________
Patient Address ____________________________________ Telephone (___.___.___)
____________________________________
I have:
• fully explained to the patient, __________________, the nature and purpose of Accutane
treatment, including its benefits and risks
• given the patient the appropriate educational materials, Be Smart, Be Safe, Be Sure, for Accutane
and asked the patient if he/she has any questions regarding his/her treatment with Accutane
• answered those questions to the best of my ability
• placed the yellow self-adhesive Accutane Qualification Sticker on the prescription.
Prescriber Signature: ___________________________________ Date:______________
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MEDICATION GUIDE
Read this Medication Guide every time you get a prescription or a refill for Accutane (ACK-u-tane).
There may be new information. This information does not take the place of talking with your
prescriber (doctor or other health care provider).
What is the most important information I should know about Accutane?
Accutane is used to treat a type of severe acne (nodular acne) that has not been helped by other
treatments, including antibiotics. However, Accutane can cause serious side effects. Before starting
Accutane, discuss with your prescriber how bad your acne is, the possible benefits of Accutane, and its
possible side effects, to decide if Accutane is right for you. Your prescriber will ask you to read and
sign a form or forms indicating you understand some of the serious risks of Accutane.
Possible serious side effects of taking Accutane include birth defects and mental disorders.
1. Birth defects. Accutane can cause birth defects (deformed babies) if taken by a pregnant
woman. It can also cause miscarriage (losing the baby before birth), premature (early) birth, or
death of the baby. Do not take Accutane if you are pregnant or plan to become pregnant while you
are taking Accutane. Do not get pregnant for 1 month after you stop taking Accutane. Also, if you
get pregnant while taking Accutane, stop taking it right away and call your prescriber.
All females should read the section in this Medication Guide "What are the important warnings for
females taking Accutane?"
2. Mental problems and suicide. Some patients, while taking Accutane or soon after stopping
Accutane, have become depressed or developed other serious mental problems. Symptoms of these
problems include sad, “anxious” or empty mood, irritability, anger, loss of pleasure or interest in
social or sports activities, sleeping too much or too little, changes in weight or appetite, school or
work performance going down, or trouble concentrating. Some patients taking Accutane have had
thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some
people tried to end their own lives. And some people have ended their own lives. There were
reports that some of these people did not appear depressed. There have been reports of patients on
Accutane becoming aggressive or violent. No one knows if Accutane caused these behaviors or if
they would have happened even if the person did not take Accutane.
All patients should read the section in this Medication Guide "What are the signs of mental
problems?"
For other possible serious side effects of Accutane, see "What are the possible side effects of
Accutane?" in this Medication Guide.
What are the important warnings for females taking Accutane?
You must not become pregnant while taking Accutane, or for 1 month after you stop taking Accutane.
Accutane can cause severe birth defects in babies of women who take it while they are pregnant, even
if they take Accutane for only a short time. There is an extremely high risk that your baby will be
deformed or will die if you are pregnant while taking Accutane. Taking Accutane also increases the
chance of miscarriage and premature births.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S054
Page 32
Female patients will not get their first prescription for Accutane unless there is proof they have had 2
negative pregnancy tests. The first test must be done when your prescriber decides to prescribe
Accutane. The second pregnancy test must be done during the first 5 days of the menstrual period right
before starting Accutane therapy, or as instructed by your prescriber. Each month of treatment, you
must have a negative result from a urine or serum pregnancy test. Female patients cannot get another
prescription for Accutane unless there is proof that they have had a negative pregnancy test.
A yellow self-adhesive Accutane Qualification Sticker on your prescription indicates to the pharmacist
that you are qualified by your prescriber to get Accutane.
While you are taking Accutane, you must use effective birth control. You must use 2 separate
effective forms of birth control at the same time for at least 1 month before starting Accutane, while
you take it, and for 1 month after you stop taking it. You can either discuss effective birth control
methods with your prescriber or go for a free visit to discuss birth control with another physician or
family planning expert. Your prescriber can arrange this free visit, which will be paid for by the
manufacturer.
You must use 2 separate forms of effective birth control because any method, including birth control
pills and sterilization, can fail. There are only 2 reasons you would not need to use 2 separate methods
of effective birth control:
1. You have had your womb removed by surgery (a hysterectomy).
2. You are absolutely certain you will not have genital-to-genital sexual contact with a male before,
during, and for 1 month after Accutane treatment.
If you have sex at any time without using 2 forms of effective birth control, get pregnant, or miss
your period, stop using Accutane and call your prescriber right away.
All patients should read the rest of this Medication Guide.
What are the signs of mental problems?
Tell your prescriber if, to the best of your knowledge, you or someone in your family has ever had any
mental illness, including depression, suicidal behavior, or psychosis. Psychosis means a loss of contact
with reality, such as hearing voices or seeing things that are not there. Also, tell your prescriber if you
take medicines for any of these problems.
Stop using Accutane and tell your provider right away if you:
• Start to feel sad or have crying spells
• Lose interest in activities you once enjoyed
• Sleep too much or have trouble sleeping
• Become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of
violence)
• Have a change in your appetite or body weight
• Have trouble concentrating
• Withdraw from your friends or family
• Feel like you have no energy
• Have feelings of worthlessness or inappropriate guilt
• Start having thoughts about hurting yourself or taking your own life (suicidal thoughts)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S054
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What is Accutane?
Accutane is used to treat the most severe form of acne (nodular acne) that cannot be cleared up by any
other acne treatments, including antibiotics. In severe nodular acne, many red, swollen, tender lumps
form in the skin. These can be the size of pencil erasers or larger. If untreated, nodular acne can lead to
permanent scars. However, because Accutane can have serious side effects, you should talk with your
prescriber about all of the possible treatments for your acne, and whether Accutane’s possible benefits
outweigh its possible risks.
Who should not take Accutane?
• Do not take Accutane if you are pregnant, plan to become pregnant, or become pregnant
during Accutane treatment. Accutane causes severe birth defects. All females should read the
section “What are the important warnings for females taking Accutane?” for more information and
warnings about Accutane and pregnancy.
• Do not take Accutane unless you completely understand its possible risks and are willing to follow
all of the instructions in this Medication Guide.
Tell your prescriber if you or someone in your family has had any kind of mental problems, asthma,
liver disease, diabetes, heart disease, osteoporosis (bone loss), weak bones, anorexia nervosa (an eating
disorder where people eat too little), or any other important health problems. Tell your prescriber about
any food or drug allergies you have had in the past. These problems do not necessarily mean you
cannot take Accutane, but your prescriber needs this information to discuss if Accutane is right for
you.
How should I take Accutane?
• You will get no more than a 30-day supply of Accutane at a time, to be sure you check in with your
prescriber each month to discuss side effects.
• Your prescription should have a special yellow self-adhesive sticker attached to it. The sticker is
YELLOW. If your prescription does not have this yellow self-adhesive sticker, call your prescriber.
The pharmacy should not fill your prescription unless it has the yellow self-adhesive sticker.
• The amount of Accutane you take has been specially chosen for you and may change during
treatment.
• You will take Accutane 2 times a day with a meal, unless your prescriber tells you otherwise.
Swallow your Accutane capsules with a full glass of liquid. This will help prevent the medication
inside the capsule from irritating the lining of your esophagus (connection between mouth and
stomach). For the same reason, do not chew or suck on the capsule.
• If you miss a dose, just skip that dose. Do not take 2 doses the next time.
• You should return to your prescriber as directed to make sure you don’t have signs of serious side
effects. Because some of Accutane’s serious side effects show up in blood tests, some of these
visits may involve blood tests (monthly visits for female patients should always include a urine or
serum pregnancy test).
What should I avoid while taking Accutane?
• Do not get pregnant while taking Accutane. See “What is the most important information I should
know about Accutane?” and “What are the important warnings for females taking Accutane?”
• Do not breast feed while taking Accutane and for 1 month after stopping Accutane. We do not
know if Accutane can pass through your milk and harm the baby.
This label may not be the latest approved by FDA.
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NDA 18-662/S054
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• Do not give blood while you take Accutane and for 1 month after stopping Accutane. If someone
who is pregnant gets your donated blood, her baby may be exposed to Accutane and may be born
with birth defects.
• Do not take vitamin A supplements. Vitamin A in high doses has many of the same side effects as
Accutane. Taking both together may increase your chance of getting side effects.
• Do not have cosmetic procedures to smooth your skin, including waxing, dermabrasion, or
laser procedures, while you are using Accutane and for at least 6 months after you stop.
Accutane can increase your chance of scarring from these procedures. Check with your prescriber
for advice about when you can have cosmetic procedures.
• Avoid sunlight and ultraviolet lights as much as possible. Tanning machines use ultraviolet
lights. Accutane may make your skin more sensitive to light.
• Do not use birth control pills that do not contain estrogen (“minipills”). They may not work
while you take Accutane. Ask your prescriber or pharmacist if you are not sure what type you are
using.
• Talk with your doctor if you plan to take other drugs or herbal products. This is especially
important for patients using birth control pills and other hormonal types of birth control because
the birth control may not work as effectively if you are taking certain drugs or herbal products. You
should not take the herbal supplement St. John’s Wort because this herbal supplement may make
birth control pills not work as effectively.
• Talk with your doctor if you are currently taking an oral or injected corticosteroid or
anticonvulsant (seizure) medication prior to using Accutane. These drugs may weaken your
bones.
• Do not share Accutane with other people. It can cause birth defects and other serious health
problems.
• Do not take Accutane with antibiotics unless you talk to your prescriber. For some antibiotics,
you may have to stop taking Accutane until the antibiotic treatment is finished. Use of both drugs
together can increase the chances of getting increased pressure in the brain.
What are the possible side effects of Accutane?
Accutane has possible serious side effects
• Accutane can cause birth defects, premature births, and death in babies whose mothers took
Accutane while they were pregnant. See “What is the most important information I should know
about Accutane?” and “What are the important warnings for females taking Accutane?”
• Serious mental health problems. See “What is the most important information I should know
about Accutane?”
• Serious brain problems. Accutane can increase the pressure in your brain. This can lead to
permanent loss of sight, or in rare cases, death. Stop taking Accutane and call your prescriber right
away if you get any of these signs of increased brain pressure: bad headache, blurred vision,
dizziness, nausea, or vomiting. Also, some patients taking Accutane have had seizures
(convulsions) or stroke.
• Abdomen (stomach area) problems. Certain symptoms may mean that your internal organs are
being damaged. These organs include the liver, pancreas, bowel (intestines), and esophagus
(connection between mouth and stomach). If your organs are damaged, they may not get better
even after you stop taking Accutane. Stop taking Accutane and call your prescriber if you get
severe stomach, chest or bowel pain, trouble swallowing or painful swallowing, new or worsening
heartburn, diarrhea, rectal bleeding, yellowing of your skin or eyes, or dark urine.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S054
Page 35
• Bone and muscle problems. Accutane may affect bones, muscles, and ligaments and cause pain in
your joints or muscles. Tell your prescriber if you plan vigorous physical activity during treatment
with Accutane. Tell your prescriber if you develop pain, particularly back pain or joint pain. There
are reports that some patients have had stunted growth after taking Accutane for acne as directed.
There are also some reports of broken bones or reduced healing of broken bones after taking
Accutane for acne as directed. No one knows if taking Accutane for acne will affect your bones. If
you have a broken bone, tell your provider that you are taking Accutane. Muscle weakness with or
without pain can be a sign of serious muscle damage. If this happens, stop taking Accutane and call
your prescriber right away.
• Hearing problems. Some people taking Accutane have developed hearing problems. It is possible
that hearing loss can be permanent. Stop using Accutane and call your prescriber if your hearing
gets worse or if you have ringing in your ears.
• Vision problems. While taking Accutane you may develop a sudden inability to see in the dark, so
driving at night can be dangerous. This condition usually clears up after you stop taking Accutane,
but it may be permanent. Other serious eye effects can occur. Stop taking Accutane and call your
prescriber right away if you have any problems with your vision or dryness of the eyes that is
painful or constant.
• Lipid (fats and cholesterol in blood) problems. Many people taking Accutane develop high
levels of cholesterol and other fats in their blood. This can be a serious problem. Return to your
prescriber for blood tests to check your lipids and to get any needed treatment. These problems
generally go away when Accutane treatment is finished.
• Allergic reactions. In some people, Accutane can cause serious allergic reactions. Stop taking
Accutane and get emergency care right away if you develop hives, a swollen face or mouth, or
have trouble breathing. Stop taking Accutane and call your prescriber if you develop a fever, rash,
or red patches or bruises on your legs.
• Signs of other possibly serious problems. Accutane may cause other problems. Tell your
prescriber if you have trouble breathing (shortness of breath), are fainting, are very thirsty or
urinate a lot, feel weak, have leg swelling, convulsions, slurred speech, problems moving, or any
other serious or unusual problems. Frequent urination and thirst can be signs of blood sugar
problems.
Serious permanent problems do not happen often. However, because the symptoms listed above may
be signs of serious problems, if you get these symptoms, stop taking Accutane and call your prescriber.
If not treated, they could lead to serious health problems. Even if these problems are treated, they may
not clear up after you stop taking Accutane.
Accutane has less serious possible side effects
The common less serious side effects of Accutane are dry skin, chapped lips, dry eyes, and dry nose
that may lead to nosebleeds. People who wear contact lenses may have trouble wearing them while
taking Accutane and after therapy. Sometimes, people’s acne may get worse for a while. They should
continue taking Accutane unless told to stop by their prescriber.
These are not all of Accutane’s possible side effects. Your prescriber or pharmacist can give you more
detailed information that is written for health care professionals.
This Medication Guide is only a summary of some important information about Accutane. Medicines
are sometimes prescribed for purposes other than those listed in a Medication Guide. If you have any
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S054
Page 36
concerns or questions about Accutane, ask your prescriber. Do not use Accutane for a condition for
which it was not prescribed.
Active Ingredient: Isotretinoin.
Inactive Ingredients: beeswax, butylated hydroxyanisole, edetate disodium, hydrogenated soybean oil
flakes, hydrogenated vegetable oil, and soybean oil. Gelatin capsules contain glycerin and parabens
(methyl and propyl), with the following dye systems: 10 mg — iron oxide (red) and titanium dioxide;
20 mg — FD&C Red No. 3, FD&C Blue No. 1, and titanium dioxide; 40 mg — FD&C Yellow No. 6,
D&C Yellow No. 10, and titanium dioxide.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Medication Guide Revised: June 2002
xxxxxxxx
Copyright © 2000-xxxx by Roche Laboratories Inc. All rights reserved.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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2025-02-12T13:44:50.812734
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ACCUTANE®
(isotretinoin capsules)
Rx only
CAUSES BIRTH
DEFECTS
DO NOT GET
PREGNANT
CONTRAINDICATIONS AND WARNINGS
Accutane must not be used by female patients who are or may become pregnant. There is an
extremely high risk that severe birth defects will result if pregnancy occurs while taking
Accutane in any amount, even for short periods of time. Potentially any fetus exposed during
pregnancy can be affected. There are no accurate means of determining whether an exposed
fetus has been affected.
Birth defects which have been documented following Accutane exposure include abnormalities of
the face, eyes, ears, skull, central nervous system, cardiovascular system, and thymus and
parathyroid glands. Cases of IQ scores less than 85 with or without other abnormalities have
been reported. There is an increased risk of spontaneous abortion, and premature births have
been reported.
Documented external abnormalities include: skull abnormality; ear abnormalities (including
anotia, micropinna, small or absent external auditory canals); eye abnormalities (including
microphthalmia); facial dysmorphia; cleft palate. Documented internal abnormalities include:
CNS abnormalities (including cerebral abnormalities, cerebellar malformation, hydrocephalus,
microcephaly, cranial nerve deficit); cardiovascular abnormalities; thymus gland abnormality;
parathyroid hormone deficiency. In some cases death has occurred with certain of the
abnormalities previously noted.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
Page 12
If pregnancy does occur during treatment of a female patient who is taking Accutane, Accutane
must be discontinued immediately and she should be referred to an Obstetrician-Gynecologist
experienced in reproductive toxicity for further evaluation and counseling.
Special Prescribing Requirements
Because of Accutane’s teratogenicity and to minimize fetal exposure, Accutane is approved for
marketing only under a special restricted distribution program approved by the Food and Drug
Administration. This program is called iPLEDGE™. Accutane must only be prescribed by
prescribers who are registered and activated with the iPLEDGE program. Accutane must only be
dispensed by a pharmacy registered and activated with iPLEDGE, and must only be dispensed to
patients who are registered and meet all the requirements of iPLEDGE (see PRECAUTIONS).
Table 1
Monthly Required iPLEDGE Interactions
Female Patients Of
Childbearing Potential
Male Patients, And Female
Patients Not Of Childbearing
Potential
PRESCRIBER
Confirms patient counseling
X
X
Enters the 2 contraception methods
chosen by the patient
X
Enters pregnancy test results
X
PATIENT
Answers educational questions before
every prescription
X
Enters 2 forms of contraception
X
PHARMACIST
Calls system to get an authorization
X
X
DESCRIPTION
Isotretinoin, a retinoid, is available as Accutane in 10-mg, 20-mg and 40-mg soft gelatin capsules for
oral administration. Each capsule contains beeswax, butylated hydroxyanisole, edetate disodium,
hydrogenated soybean oil flakes, hydrogenated vegetable oil, and soybean oil. Gelatin capsules contain
glycerin and parabens (methyl and propyl), with the following dye systems: 10 mg — iron oxide (red)
and titanium dioxide; 20 mg — FD&C Red No. 3, FD&C Blue No. 1, and titanium dioxide; 40 mg —
FD&C Yellow No. 6, D&C Yellow No. 10, and titanium dioxide.
Chemically, isotretinoin is 13-cis-retinoic acid and is related to both retinoic acid and retinol (vitamin
A). It is a yellow to orange crystalline powder with a molecular weight of 300.44. The structural
formula is:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
Page 13
CLINICAL PHARMACOLOGY
Isotretinoin is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1.0 mg/kg/day
(see DOSAGE AND ADMINISTRATION), inhibits sebaceous gland function and keratinization.
The exact mechanism of action of isotretinoin is unknown.
Nodular Acne
Clinical improvement in nodular acne patients occurs in association with a reduction in sebum
secretion. The decrease in sebum secretion is temporary and is related to the dose and duration of
treatment with Accutane, and reflects a reduction in sebaceous gland size and an inhibition of
sebaceous gland differentiation.1
Pharmacokinetics
Absorption
Due to its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a high-fat
meal. In a crossover study, 74 healthy adult subjects received a single 80 mg oral dose (2 x 40 mg
capsules) of Accutane under fasted and fed conditions. Both peak plasma concentration (Cmax) and the
total exposure (AUC) of isotretinoin were more than doubled following a standardized high-fat meal
when compared with Accutane given under fasted conditions (see Table 2). The observed elimination
half-life was unchanged. This lack of change in half-life suggests that food increases the bioavailability
of isotretinoin without altering its disposition. The time to peak concentration (Tmax) was also increased
with food and may be related to a longer absorption phase. Therefore, Accutane capsules should
always be taken with food (see DOSAGE AND ADMINISTRATION). Clinical studies have shown
that there is no difference in the pharmacokinetics of isotretinoin between patients with nodular acne
and healthy subjects with normal skin.
Table 2
Pharmacokinetic Parameters of Isotretinoin Mean (%CV), N=74
Accutane
2 x 40 mg
Capsules
AUC0-∞
(ng⋅hr/mL)
Cmax
(ng/mL)
Tmax
(hr)
t1/2
(hr)
Fed*
10,004 (22%)
862 (22%)
5.3 (77%)
21 (39%)
Fasted
3,703 (46%)
301 (63%)
3.2 (56%)
21 (30%)
*Eating a standardized high-fat meal
Distribution
Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.
Metabolism
Following oral administration of isotretinoin, at least three metabolites have been identified in human
plasma: 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). Retinoic
acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion. The
administration of one isomer will give rise to the other. Isotretinoin is also irreversibly oxidized to
4-oxo-isotretinoin, which forms its geometric isomer 4-oxo-tretinoin.
After a single 80 mg oral dose of Accutane to 74 healthy adult subjects, concurrent administration of
food increased the extent of formation of all metabolites in plasma when compared to the extent of
formation under fasted conditions.
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NDA 18-662/S-056
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All of these metabolites possess retinoid activity that is in some in vitro models more than that of the
parent isotretinoin. However, the clinical significance of these models is unknown. After multiple oral
dose administration of isotretinoin to adult cystic acne patients (≥18 years), the exposure of patients to
4-oxo-isotretinoin at steady-state under fasted and fed conditions was approximately 3.4 times higher
than that of isotretinoin.
In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are 2C8,
2C9, 3A4, and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are
then excreted in urine and feces.
Elimination
Following oral administration of an 80 mg dose of 14C-isotretinoin as a liquid suspension, 14C-activity
in blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are
ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%). After a
single 80 mg oral dose of Accutane to 74 healthy adult subjects under fed conditions, the mean ± SD
elimination half-lives (t1/2) of isotretinoin and 4-oxo-isotretinoin were 21.0 ± 8.2 hours and 24.0 ± 5.3
hours, respectively. After both single and multiple doses, the observed accumulation ratios of
isotretinoin ranged from 0.90 to 5.43 in patients with cystic acne.
Special Patient Populations
Pediatric Patients
The pharmacokinetics of isotretinoin were evaluated after single and multiple doses in 38 pediatric
patients (12 to 15 years) and 19 adult patients (≥18 years) who received Accutane for the treatment of
severe recalcitrant nodular acne. In both age groups, 4-oxo-isotretinoin was the major metabolite;
tretinoin and 4-oxo-tretinoin were also observed. The dose-normalized pharmacokinetic parameters for
isotretinoin following single and multiple doses are summarized in Table 3 for pediatric patients.
There were no statistically significant differences in the pharmacokinetics of isotretinoin between
pediatric and adult patients.
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NDA 18-662/S-056
Page 15
Table 3
Pharmacokinetic Parameters of Isotretinoin Following Single and
Multiple Dose Administration in Pediatric Patients, 12 to 15 Years of
Age
Mean (± SD), N=38*
Parameter
Isotretinoin
(Single Dose)
Isotretinoin
(Steady-State)
Cmax (ng/mL)
573.25 (278.79)
731.98 (361.86)
AUC(0-12) (ng⋅hr/mL)
3033.37 (1394.17)
5082.00 (2184.23)
AUC(0-24) (ng⋅hr/mL)
6003.81 (2885.67)
–
Tmax (hr)†
6.00 (1.00-24.60)
4.00 (0-12.00)
Cssmin (ng/mL)
–
352.32 (184.44)
T1/2 (hr)
–
15.69 (5.12)
CL/F (L/hr)
–
17.96 (6.27)
*The single and multiple dose data in this table were obtained following a
non-standardized meal that is not comparable to the high-fat meal that was used in the
study in Table 2.
†Median (range)
In pediatric patients (12 to 15 years), the mean ± SD elimination half-lives (t1/2) of isotretinoin and 4-
oxo-isotretinoin were 15.7 ± 5.1 hours and 23.1 ± 5.7 hours, respectively. The accumulation ratios of
isotretinoin ranged from 0.46 to 3.65 for pediatric patients.
INDICATIONS AND USAGE
Severe Recalcitrant Nodular Acne
Accutane is indicated for the treatment of severe recalcitrant nodular acne. Nodules are inflammatory
lesions with a diameter of 5 mm or greater. The nodules may become suppurative or hemorrhagic.
“Severe,” by definition,2 means “many” as opposed to “few or several” nodules. Because of significant
adverse effects associated with its use, Accutane should be reserved for patients with severe nodular
acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition,
Accutane is indicated only for those female patients who are not pregnant, because Accutane can cause
severe birth defects (see Boxed CONTRAINDICATIONS AND WARNINGS).
A single course of therapy for 15 to 20 weeks has been shown to result in complete and prolonged
remission of disease in many patients.1,3,4 If a second course of therapy is needed, it should not be
initiated until at least 8 weeks after completion of the first course, because experience has shown that
patients may continue to improve while off Accutane. The optimal interval before retreatment has not
been defined for patients who have not completed skeletal growth (see WARNINGS: Skeletal: Bone
Mineral Density, Hyperostosis, and Premature Epiphyseal Closure).
CONTRAINDICATIONS
Pregnancy: Category X. See Boxed CONTRAINDICATIONS AND WARNINGS.
Allergic Reactions
Accutane is contraindicated in patients who are hypersensitive to this medication or to any of its
components. Accutane should not be given to patients who are sensitive to parabens, which are used as
preservatives in the gelatin capsule (see PRECAUTIONS: Hypersensitivity).
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
Page 16
WARNINGS
Psychiatric Disorders
Accutane may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts,
suicide, and aggressive and/or violent behaviors. No mechanism of action has been established
for these events (see ADVERSE REACTIONS: Psychiatric). Prescribers should read the
brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for
Prescribers of Isotretinoin. Prescribers should be alert to the warning signs of psychiatric
disorders to guide patients to receive the help they need. Therefore, prior to initiation of
Accutane therapy, patients and family members should be asked about any history of psychiatric
disorder, and at each visit during therapy patients should be assessed for symptoms of
depression, mood disturbance, psychosis, or aggression to determine if further evaluation may be
necessary. Signs and symptoms of depression, as described in the brochure (“Recognizing
Psychiatric Disorders in Adolescents and Young Adults”), include sad mood, hopelessness,
feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue,
difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts
or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical
symptoms unresponsive to treatment. Patients should stop Accutane and the patient or a family
member should promptly contact their prescriber if the patient develops depression, mood
disturbance, psychosis, or aggression, without waiting until the next visit. Discontinuation of
Accutane therapy may be insufficient; further evaluation may be necessary. While such
monitoring may be helpful, it may not detect all patients at risk. Patients may report mental
health problems or family history of psychiatric disorders. These reports should be discussed
with the patient and/or the patient’s family. A referral to a mental health professional may be
necessary. The physician should consider whether Accutane therapy is appropriate in this
setting; for some patients the risks may outweigh the benefits of Accutane therapy.
Pseudotumor Cerebri
Accutane use has been associated with a number of cases of pseudotumor cerebri (benign
intracranial hypertension), some of which involved concomitant use of tetracyclines.
Concomitant treatment with tetracyclines should therefore be avoided. Early signs and
symptoms of pseudotumor cerebri include papilledema, headache, nausea and vomiting, and
visual disturbances. Patients with these symptoms should be screened for papilledema and, if
present, they should be told to discontinue Accutane immediately and be referred to a
neurologist for further diagnosis and care (see ADVERSE REACTIONS: Neurological).
Pancreatitis
Acute pancreatitis has been reported in patients with either elevated or normal serum triglyceride
levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. Accutane should be
stopped if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of
pancreatitis occur.
Lipids
Elevations of serum triglycerides in excess of 800 mg/dL have been reported in patients treated with
Accutane. Marked elevations of serum triglycerides were reported in approximately 25% of patients
receiving Accutane in clinical trials. In addition, approximately 15% developed a decrease in high-
density lipoproteins and about 7% showed an increase in cholesterol levels. In clinical trials, the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
Page 17
effects on triglycerides, HDL, and cholesterol were reversible upon cessation of Accutane therapy.
Some patients have been able to reverse triglyceride elevation by reduction in weight, restriction of
dietary fat and alcohol, and reduction in dose while continuing Accutane.5
Blood lipid determinations should be performed before Accutane is given and then at intervals until the
lipid response to Accutane is established, which usually occurs within 4 weeks. Especially careful
consideration must be given to risk/benefit for patients who may be at high risk during Accutane
therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial
history of lipid metabolism disorder). If Accutane therapy is instituted, more frequent checks of serum
values for lipids and/or blood sugar are recommended (see PRECAUTIONS: Laboratory Tests).
The cardiovascular consequences of hypertriglyceridemia associated with Accutane are unknown.
Animal Studies: In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 to 5.3 times the recommended
clinical dose of 1.0 mg/kg/day after normalization for total body surface area) for 18 months or longer,
the incidences of focal calcification, fibrosis and inflammation of the myocardium, calcification of
coronary, pulmonary and mesenteric arteries, and metastatic calcification of the gastric mucosa were
greater than in control rats of similar age. Focal endocardial and myocardial calcifications associated
with calcification of the coronary arteries were observed in two dogs after approximately 6 to 7 months
of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day (30 to 60 times the recommended
clinical dose of 1.0 mg/kg/day, respectively, after normalization for total body surface area).
Hearing Impairment
Impaired hearing has been reported in patients taking Accutane; in some cases, the hearing impairment
has been reported to persist after therapy has been discontinued. Mechanism(s) and causality for this
event have not been established. Patients who experience tinnitus or hearing impairment should
discontinue Accutane treatment and be referred for specialized care for further evaluation (see
ADVERSE REACTIONS: Special Senses).
Hepatotoxicity
Clinical hepatitis considered to be possibly or probably related to Accutane therapy has been reported.
Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15%
of individuals treated during clinical trials, some of which normalized with dosage reduction or
continued administration of the drug. If normalization does not readily occur or if hepatitis is suspected
during treatment with Accutane, the drug should be discontinued and the etiology further investigated.
Inflammatory Bowel Disease
Accutane has been associated with inflammatory bowel disease (including regional ileitis) in patients
without a prior history of intestinal disorders. In some instances, symptoms have been reported to
persist after Accutane treatment has been stopped. Patients experiencing abdominal pain, rectal
bleeding or severe diarrhea should discontinue Accutane immediately (see ADVERSE REACTIONS:
Gastrointestinal).
Skeletal
Bone Mineral Density
Effects of multiple courses of Accutane on the developing musculoskeletal system are unknown.
There is some evidence that long-term, high-dose, or multiple courses of therapy with isotretinoin have
more of an effect than a single course of therapy on the musculoskeletal system. In an open-label
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NDA 18-662/S-056
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clinical trial (N=217) of a single course of therapy with Accutane for severe recalcitrant nodular acne,
bone density measurements at several skeletal sites were not significantly decreased (lumbar spine
change >–4% and total hip change >–5%) or were increased in the majority of patients. One patient
had a decrease in lumbar spine bone mineral density >4% based on unadjusted data. Sixteen (7.9%)
patients had decreases in lumbar spine bone mineral density >4%, and all the other patients (92%) did
not have significant decreases or had increases (adjusted for body mass index). Nine patients (4.5%)
had a decrease in total hip bone mineral density >5% based on unadjusted data. Twenty-one (10.6%)
patients had decreases in total hip bone mineral density >5%, and all the other patients (89%) did not
have significant decreases or had increases (adjusted for body mass index). Follow-up studies
performed in 8 of the patients with decreased bone mineral density for up to 11 months thereafter
demonstrated increasing bone density in 5 patients at the lumbar spine, while the other 3 patients had
lumbar spine bone density measurements below baseline values. Total hip bone mineral densities
remained below baseline (range –1.6% to –7.6%) in 5 of 8 patients (62.5%).
In a separate open-label extension study of 10 patients, ages 13-18 years, who started a second course
of Accutane 4 months after the first course, two patients showed a decrease in mean lumbar spine bone
mineral density up to 3.25% (see PRECAUTIONS: Pediatric Use).
Spontaneous reports of osteoporosis, osteopenia, bone fractures, and delayed healing of bone fractures
have been seen in the Accutane population. While causality to Accutane has not been established, an
effect cannot be ruled out. Longer term effects have not been studied. It is important that Accutane be
given at the recommended doses for no longer than the recommended duration.
Hyperostosis
A high prevalence of skeletal hyperostosis was noted in clinical trials for disorders of keratinization
with a mean dose of 2.24 mg/kg/day. Additionally, skeletal hyperostosis was noted in 6 of 8 patients in
a prospective study of disorders of keratinization.6 Minimal skeletal hyperostosis and calcification of
ligaments and tendons have also been observed by x-ray in prospective studies of nodular acne patients
treated with a single course of therapy at recommended doses. The skeletal effects of multiple
Accutane treatment courses for acne are unknown.
In a clinical study of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne,
hyperostosis was not observed after 16 to 20 weeks of treatment with approximately 1 mg/kg/day of
Accutane given in two divided doses. Hyperostosis may require a longer time frame to appear. The
clinical course and significance remain unknown.
Premature Epiphyseal Closure
There are spontaneous reports of premature epiphyseal closure in acne patients receiving
recommended doses of Accutane. The effect of multiple courses of Accutane on epiphyseal closure is
unknown.
Vision Impairment
Visual problems should be carefully monitored. All Accutane patients experiencing visual difficulties
should discontinue Accutane treatment and have an ophthalmological examination (see ADVERSE
REACTIONS: Special Senses).
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NDA 18-662/S-056
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Corneal Opacities
Corneal opacities have occurred in patients receiving Accutane for acne and more frequently when
higher drug dosages were used in patients with disorders of keratinization. The corneal opacities that
have been observed in clinical trial patients treated with Accutane have either completely resolved or
were resolving at follow-up 6 to 7 weeks after discontinuation of the drug (see ADVERSE
REACTIONS: Special Senses).
Decreased Night Vision
Decreased night vision has been reported during Accutane therapy and in some instances the event has
persisted after therapy was discontinued. Because the onset in some patients was sudden, patients
should be advised of this potential problem and warned to be cautious when driving or operating any
vehicle at night.
PRECAUTIONS
Accutane must only be prescribed by prescribers who are registered and activated with the iPLEDGE
program. Accutane must only be dispensed by a pharmacy registered and activated with iPLEDGE,
and must only be dispensed to patients who are registered and meet all the requirements of iPLEDGE.
Registered and activated pharmacies must receive Accutane only from wholesalers registered with
iPLEDGE.
iPLEDGE program requirements for wholesalers, prescribers, and pharmacists are described below:
Wholesalers:
For the purpose of the iPLEDGE program, the term wholesaler refers to wholesaler, distributor, and/or
chain pharmacy distributor. To distribute Accutane, wholesalers must be registered with iPLEDGE,
and agree to meet all iPLEDGE requirements for wholesale distribution of isotretinoin products.
Wholesalers must register with iPLEDGE by signing and returning the iPLEDGE wholesaler
agreement that affirms they will comply with all iPLEDGE requirements for distribution of
isotretinoin. These include:
• Registering prior to distributing isotretinoin and reregistering annually thereafter
• Distributing only FDA approved isotretinoin product
• Only shipping isotretinoin to
− wholesalers registered in the iPLEDGE program with prior written consent from the
manufacturer or
− pharmacies licensed in the US and registered and activated in the iPLEDGE program
• Notifying the isotretinoin manufacturer (or delegate) of any non-registered and/or non-activated
pharmacy or unregistered wholesaler that attempts to order isotretinoin
• Complying with inspection of wholesaler records for verification of compliance with the iPLEDGE
program by the isotretinoin manufacturer (or delegate)
• Returning to the manufacturer (or delegate) any undistributed product if registration is revoked by
the manufacturer or if the wholesaler chooses to not reregister annually
• Providing product flow data to manufacturer (or delegate) as detailed in the wholesalers agreement
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NDA 18-662/S-056
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Prescribers:
To prescribe isotretinoin, the prescriber must be registered and activated with the pregnancy risk
management program iPLEDGE. Prescribers can register by signing and returning the completed
registration form. Prescribers can only activate their registration by affirming that they meet
requirements and will comply with all iPLEDGE requirements by attesting to the following points:
• I know how to diagnose and treat the various presentations of acne.
• I know the risk and severity of fetal injury/birth defects from isotretinoin.
• I know the risk factors for unplanned pregnancy and the effective measures for avoidance of
unplanned pregnancy.
• I have the expertise to provide the patient with detailed pregnancy prevention counseling or I will
refer her to an expert for such counseling, reimbursed by the manufacturer.
• I will comply with the iPLEDGE program requirements described in the booklets entitled The
iPLEDGE Program Guide to Best Practices for Isotretinoin and The iPLEDGE Program
Prescriber Contraception Counseling Guide.
• Before beginning treatment of female patients of child bearing potential with isotretinoin and on a
monthly basis, the patient will be counseled to avoid pregnancy by using two forms of
contraception simultaneously and continuously one month before, during, and one month after
isotretinoin therapy, unless the patient commits to continuous abstinence.
• I will not prescribe isotretinoin to any female patient of childbearing potential until verifying she
has a negative screening pregnancy test and monthly negative CLIA-certified (Clinical Laboratory
Improvement Amendment) pregnancy tests. Patients should have a pregnancy test at the
completion of the entire course of isotretinoin and another pregnancy test 1 month later.
• I will report any pregnancy case that I become aware of while the female patient is on isotretinoin
or 1 month after the last dose to the pregnancy registry.
To prescribe isotretinoin, the Prescriber must access the iPLEDGE system via the internet
(www.ipledgeprogram.com) or telephone (1-866-495-0654) to:
1) Register each patient in the iPLEDGE program.
2) Confirm monthly that each patient has received counseling and education.
3) For female patients of childbearing potential:
• Enter patient’s two chosen forms of contraception each month.
• Enter monthly result from CLIA-certified laboratory conducted pregnancy test.
Isotretinoin must only be prescribed to female patients who are known not to be pregnant as confirmed
by a negative CLIA-certified laboratory conducted pregnancy test.
Isotretinoin must only be dispensed by a pharmacy registered and activated with the pregnancy risk
management program iPLEDGE and only when the registered patient meets all the requirements of the
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NDA 18-662/S-056
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iPLEDGE program. Meeting the requirements for a female patient of childbearing potential signifies
that she:
• Has been counseled and has signed a Patient Information/Informed Consent About Birth
Defects (for female patients who can get pregnant) form that contains warnings about the risk
of potential birth defects if the fetus is exposed to isotretinoin. The patient must sign the
informed consent form before starting treatment and patient counseling must also be done at
that time and on a monthly basis thereafter.
• Has had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL
before receiving the initial isotretinoin prescription. The first test (a screening test) is obtained
by the prescriber when the decision is made to pursue qualification of the patient
forisotretinoin. The second pregnancy test (a confirmation test) must be done in a CLIA-
certified laboratory. The interval between the 2 tests should be at least 19 days.
− For patients with regular menstrual cycles, the second pregnancy test should be done during
the first 5 days of the menstrual period and within 7 days of the office visit, immediately
preceding the beginning of isotretinoin therapy and after the patient has used 2 forms of
contraception for 1 month.
− For patients with amenorrhea, irregular cycles, or using a contraceptive method that
precludes withdrawal bleeding, the second pregnancy test must be done within 7 days
following the office visit, immediately preceding the beginning of isotretinoin therapy and
after the patient has used 2 forms of contraception for 1 month.
• Has had a negative result from a urine or serum pregnancy test in a CLIA- certified laboratory
before receiving each subsequent course of isotretinoin. A pregnancy test must be repeated
every month, in a CLIA-certified laboratory, prior to the female patient receiving each
prescription.
• Has selected and has committed to use 2 forms of effective contraception simultaneously, at
least 1 of which must be a primary form, unless the patient commits to continuous abstinence
from heterosexual contact, or the patient has undergone a hysterectomy or bilateral
oophorectomy, or has been medically confirmed to be post-menopausal. Patients must use 2
forms of effective contraception for at least 1 month prior to initiation of isotretinoin therapy,
during isotretinoin therapy, and for 1 month after discontinuing isotretinoin therapy.
Counseling about contraception and behaviors associated with an increased risk of pregnancy
must be repeated on a monthly basis.
If the patient has unprotected heterosexual intercourse at any time 1 month before, during, or 1
month after therapy, she must:
1. Stop taking Accutane immediately, if on therapy
2. Have a pregnancy test at least 19 days after the last act of unprotected heterosexual
intercourse
3. Start using 2 forms of effective contraception simultaneously again for 1 month before
resuming Accutane therapy
4. Have a second pregnancy test after using 2 forms of effective contraception for 1 month
as described above depending on whether she has regular menses or not.
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NDA 18-662/S-056
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Effective forms of contraception include both primary and secondary forms of contraception:
Primary forms
• tubal sterilization
• partner’s vasectomy
• intrauterine device
• hormonal (combination
oral contraceptives,
transdermal patch,
injectables,
implantables, or vaginal
ring)
Secondary forms
Barrier forms (always used with
spermicide):
• male latex condom
• diaphragm
• cervical cap
Others:
• vaginal sponge (contains
spermicide)
Any birth control method can fail. There have been reports of pregnancy from female patients who
have used oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring
hormonal birth control products; these pregnancies occurred while these patients were taking
Accutane. These reports are more frequent for female patients who use only a single method of
contraception. Therefore, it is critically important that female patients of childbearing potential use 2
effective forms of contraception simultaneously. Patients must receive written warnings about the rates
of possible contraception failure (included in patient education kits).
Using two forms of contraception simultaneously substantially reduces the chances that a female will
become pregnant over the risk of pregnancy with either form alone. A drug interaction that decreases
effectiveness of hormonal contraceptives has not been entirely ruled out for Accutane (see
PRECAUTIONS: Drug Interactions). Although hormonal contraceptives are highly effective,
Prescribers are advised to consult the package insert of any medication administered concomitantly
with hormonal contraceptives, since some medications may decrease the effectiveness of these birth
control products.
Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John’s
Wort because a possible interaction has been suggested with hormonal contraceptives based on reports
of breakthrough bleeding on oral contraceptives shortly after starting St. John’s Wort. Pregnancies
have been reported by users of combined hormonal contraceptives who also used some form of St.
John’s Wort.
If a pregnancy does occur during isotretinoin treatment, isotretinoin must be discontinued immediately.
The patient should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for
further evaluation and counseling. Any suspected fetal exposure during or 1 month after isotretinoin
therapy must be reported immediately to the FDA via the MedWatch number 1-800-FDA-1088 and
also
to
the
iPLEDGE
pregnancy
registry
at
1-866-495-0654
or
via
the
internet
(www.ipledgeprogram.com).
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NDA 18-662/S-056
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All Patients
Isotretinoin is contraindicated in female patients who are pregnant. To receive isotretinoin all patients
must meet all of the following conditions:
• Must be registered with the iPLEDGE program by the prescriber
• Must understand that severe birth defects can occur with the use of isotretinoin by female patients
• Must be reliable in understanding and carrying out instructions
• Must sign a Patient Information/Informed Consent (for all patients) form that contains warnings
about the potential risks associated with isotretinoin
• Must fill the prescription within 7 days of the office visit
• Must not donate blood while on isotretinoin and for 1 month after treatment has ended
• Must not share isotretinoin with anyone, even someone who has similar symptoms
Female Patients of Childbearing Potential
Isotretinoin is contraindicated in female patients who are pregnant. In addition to the requirements for
all patients described above, female patients of childbearing potential must meet the following
conditions:
• Must NOT be pregnant or breast-feeding
• Must comply with the required pregnancy testing at a CLIA-certified laboratory
• Must be capable of complying with the mandatory contraceptive measures required for isotretinoin
therapy, or commit to continuous abstinence from heterosexual intercourse, and understand
behaviors associated with an increased risk of pregnancy
• Must understand that it is her responsibility to avoid pregnancy one month before, during and one
month after isotretinoin therapy
• Must have signed an additional Patient Information/Informed Consent About Birth Defects (for
female patients who can get pregnant) form, before starting isotretinoin, that contains warnings
about the risk of potential birth defects if the fetus is exposed to isotretinoin
• Must access the iPLEDGE program via the internet (www.ipledgeprogram.com) or telephone (1-
866-495-0654), before starting isotretinoin, on a monthly basis during therapy, and 1 month after
the last dose to answer questions on the program requirements and to enter the patient’s two chosen
forms of contraception
• Must have been informed of the purpose and importance of providing information to the iPLEDGE
program should she become pregnant while taking isotretinoin or within 1 month of the last dose
Pharmacists:
To dispense isotretinoin, pharmacies must be registered and activated with the pregnancy risk
management program iPLEDGE.
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NDA 18-662/S-056
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The Responsible Site Pharmacist must register the pharmacy by signing and returning the completed
registration form. After registration, the Responsible Site Pharmacist can only activate the pharmacy
registration by affirming that they meet requirements and will comply with all iPLEDGE requirements
by attesting to the following points:
• I know the risk and severity of fetal injury/birth defects from isotretinoin.
• I will train all pharmacists, who participate in the filling and dispensing of isotretinoin prescription,
on the iPLEDGE program requirements.
• I will comply and seek to ensure all pharmacists who participate in the filling and dispensing of
isotretinoin prescriptions comply with the iPLEDGE program requirements described in the
booklet entitled The iPLEDGE Program Pharmacist Guide for Isotretinoin.
• I will obtain Accutane product only from iPLEDGE registered wholesalers.
• I will not sell, buy, borrow, loan or otherwise transfer isotretinoin in any manner to or from another
pharmacy.
• I will return to the manufacturer (or delegate) any unused product if registration is revoked by the
manufacturer or if the pharmacy chooses to not reactivate annually.
• I will not fill isotretinoin for any party other than a qualified patient.
To dispense isotretinoin, the pharmacist must:
1) be trained by the Responsible Site Pharmacist concerning the iPLEDGE program requirements.
2) obtain authorization from the iPLEDGE program via the internet (www.ipledgeprogram.com) or
telephone (1-866-495-0654) for every isotretinoin prescription. Authorization signifies that the
patient has met all program requirements and is qualified to receive isotretinoin.
3) write the Risk Management Authorization (RMA) number on the prescription.
Accutane must only be dispensed:
• in no more than a 30-day supply
• with an Accutane Medication Guide
• after authorization from the iPLEDGE program
• prior to the “do not dispense to patient after” date provided by the iPLEDGE system (within 7 days
of the office visit)
• with a new prescription for refills and another authorization from the iPLEDGE program (No
automatic refills are allowed)
An Accutane Medication Guide must be given to the patient each time Accutane is dispensed, as
required by law. This Accutane Medication Guide is an important part of the risk management
program for the patients.
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NDA 18-662/S-056
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Accutane must not be prescribed, dispensed or otherwise obtained through the internet or any other
means outside of the iPLEDGE program. Only FDA-approved Accutane products must be distributed,
prescribed, dispensed, and used. Patients must fill Accutane prescriptions only at US licensed
pharmacies.
A description of the iPLEDGE program educational materials available with iPLEDGE is provided
below. The main goal of these educational materials is to explain the iPLEDGE program requirements
and to reinforce the educational messages.
1) The iPLEDGE Program Guide to Best Practices for Isotretinoin includes: isotretinoin teratogenic
potential, information on pregnancy testing, and the method to complete a qualified isotretinoin
prescription.
2) The iPLEDGE Program Prescriber Contraception Counseling Guide includes: specific
information about effective contraception, the limitations of contraceptive methods, behaviors
associated with an increased risk of contraceptive failure and pregnancy and the methods to
evaluate pregnancy risk.
3) The iPLEDGE Program Pharmacist Guide for Isotretinoin includes: isotretinoin teratogenic
potential and the method to obtain authorization to dispense an isotretinoin prescription.
4) The iPLEDGE program is a systematic approach to comprehensive patient education about their
responsibilities and includes education for contraception compliance and reinforcement of
educational messages. The iPLEDGE program includes information on the risks and benefits of
isotretinoin which is linked to the Medication Guide dispensed by pharmacists with each
isotretinoin prescription.
5) Female patients not of childbearing potential and male patients, and female patients of childbearing
potential are provided with separate booklets. Each booklet contains information on isotretinoin
therapy including precautions and warnings, a Patient Information/Informed Consent (for all
patients) form, and a toll-free line which provides isotretinoin information in 2 languages.
6) The booklet for female patients not of childbearing potential and male patients, The iPLEDGE
Program Guide to Isotretinoin for Male Patients & Female Patients Who Cannot Get Pregnant,
also includes information about male reproduction and a warning not to share isotretinoin with
others or to donate blood during isotretinoin therapy and for 1 month following discontinuation of
isotretinoin.
7) The booklet for female patients of childbearing potential, The iPLEDGE Program Guide to
Isotretinoin for Female Patients Who Can Get Pregnant, includes a referral program that offers
female patients free contraception counseling, reimbursed by the manufacturer, by a reproductive
specialist; and a second Patient Information/Informed Consent About Birth Defects (for female
patients who can get pregnant) form concerning birth defects.
8) The booklet, The iPLEDGE Program Birth Control Workbook includes information on the types of
contraceptive methods, the selection and use of appropriate, effective contraception, the rates of
possible contraceptive failure and a toll-free contraception counseling line.
9) In addition, there is a patient educational DVD with the following videos — “Be Prepared, Be
Protected” and “Be Aware: The Risk of Pregnancy While on Isotretinoin” (see Information for
Patients).
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
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General
Although an effect of Accutane on bone loss is not established, physicians should use caution when
prescribing Accutane to patients with a genetic predisposition for age-related osteoporosis, a history of
childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism. This would
include patients diagnosed with anorexia nervosa and those who are on chronic drug therapy that
causes drug-induced osteoporosis/osteomalacia and/or affects vitamin D metabolism, such as systemic
corticosteroids and any anticonvulsant.
Patients may be at increased risk when participating in sports with repetitive impact where the risks of
spondylolisthesis with and without pars fractures and hip growth plate injuries in early and late
adolescence are known. There are spontaneous reports of fractures and/or delayed healing in patients
while on therapy with Accutane or following cessation of therapy with Accutane while involved in
these activities. While causality to Accutane has not been established, an effect must not be ruled out.
Information for Patients
See PRECAUTIONS and Boxed CONTRAINDICATIONS AND WARNINGS.
• Patients must be instructed to read the Medication Guide supplied as required by law when
Accutane is dispensed. The complete text of the Medication Guide is reprinted at the end of this
document. For additional information, patients must also be instructed to read the iPLEDGE
program patient educational materials. All patients must sign the Patient Information/Informed
Consent (for all patients) form.
• Female patients of childbearing potential must be instructed that they must not be pregnant when
Accutane therapy is initiated, and that they should use 2 forms of effective contraception
simultaneously for 1 month before starting Accutane, while taking Accutane, and for 1 month after
Accutane has been stopped, unless they commit to continuous abstinence from heterosexual
intercourse. They should also sign a second Patient Information/Informed Consent About Birth
Defects (for female patients who can get pregnant) form prior to beginning Accutane therapy. They
should be given an opportunity to view the patient DVD provided by the manufacturer to the
prescriber. The DVD includes information about contraception, the most common reasons that
contraception fails, and the importance of using 2 forms of effective contraception when taking
teratogenic drugs and comprehensive information about types of potential birth defects which
could occur if a female patients who is pregnant takes Accutane at any time during pregnancy.
Female patients should be seen by their prescribers monthly and have a urine or serum pregnancy
test, in a CLIA-certified laboratory, performed each month during treatment to confirm negative
pregnancy
status
before
another
Accutane
prescription
is
written
(see
Boxed
CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS).
• Accutane is found in the semen of male patients taking Accutane, but the amount delivered to a
female partner would be about 1 million times lower than an oral dose of 40 mg. While the no-
effect limit for isotretinoin induced embryopathy is unknown, 20 years of postmarketing reports
include 4 with isolated defects compatible with features of retinoid exposed fetuses; however 2 of
these reports were incomplete, and 2 had other possible explanations for the defects observed.
• Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive
the help they need. Therefore, prior to initiation of Accutane treatment, patients and family
members should be asked about any history of psychiatric disorder, and at each visit during
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
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treatment patients should be assessed for symptoms of depression, mood disturbance, psychosis, or
aggression to determine if further evaluation may be necessary. Signs and symptoms of
depression include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness,
loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep
pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability,
acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment.
Patients should stop Accutane and the patient or a family member should promptly contact their
prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without
waiting until the next visit. Discontinuation of Accutane treatment may be insufficient; further
evaluation may be necessary. While such monitoring may be helpful, it may not detect all patients
at risk. Patients may report mental health problems or family history of psychiatric disorders. These
reports should be discussed with the patient and/or the patient’s family. A referral to a mental
health professional may be necessary. The physician should consider whether Accutane therapy is
appropriate in this setting; for some patients the risks may outweigh the benefits of Accutane
therapy.
• Patients must be informed that some patients, while taking Accutane or soon after stopping
Accutane, have become depressed or developed other serious mental problems. Symptoms of
depression include sad, “anxious” or empty mood, irritability, acting on dangerous impulses, anger,
loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in
weight or appetite, school or work performance going down, or trouble concentrating. Some
patients taking Accutane have had thoughts about hurting themselves or putting an end to their own
lives (suicidal thoughts). Some people tried to end their own lives. And some people have ended
their own lives. There were reports that some of these people did not appear depressed. There have
been reports of patients on Accutane becoming aggressive or violent. No one knows if Accutane
caused these behaviors or if they would have happened even if the person did not take Accutane.
Some people have had other signs of depression while taking Accutane.
• Patients must be informed that they must not share Accutane with anyone else because of the risk
of birth defects and other serious adverse events.
• Patients must be informed not to donate blood during therapy and for 1 month following
discontinuation of the drug because the blood might be given to a pregnant female patient whose
fetus must not be exposed to Accutane.
• Patients should be reminded to take Accutane with a meal (see DOSAGE AND
ADMINISTRATION). To decrease the risk of esophageal irritation, patients should swallow the
capsules with a full glass of liquid.
• Patients should be informed that transient exacerbation (flare) of acne has been seen, generally
during the initial period of therapy.
• Wax epilation and skin resurfacing procedures (such as dermabrasion, laser) should be avoided
during Accutane therapy and for at least 6 months thereafter due to the possibility of scarring (see
ADVERSE REACTIONS: Skin and Appendages).
• Patients should be advised to avoid prolonged exposure to UV rays or sunlight.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
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• Patients should be informed that they may experience decreased tolerance to contact lenses during
and after therapy.
• Patients should be informed that approximately 16% of patients treated with Accutane in a clinical
trial developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these
symptoms were mild to moderate, but occasionally required discontinuation of the drug. Transient
pain in the chest has been reported less frequently. In the clinical trial, these symptoms generally
cleared rapidly after discontinuation of Accutane, but in some cases persisted (see ADVERSE
REACTIONS: Musculoskeletal). There have been rare postmarketing reports of rhabdomyolysis,
some associated with strenuous physical activity (see Laboratory Tests: CPK).
• Pediatric patients and their caregivers should be informed that approximately 29% (104/358) of
pediatric patients treated with Accutane developed back pain. Back pain was severe in 13.5%
(14/104) of the cases and occurred at a higher frequency in female patients than male patients.
Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in
7.6% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be done in
patients who present with these symptoms during or after a course of Accutane. Consideration
should be given to discontinuation of Accutane if any significant abnormality is found.
• Neutropenia and rare cases of agranulocytosis have been reported. Accutane should be
discontinued if clinically significant decreases in white cell counts occur.
Hypersensitivity
Anaphylactic reactions and other allergic reactions have been reported. Cutaneous allergic reactions
and serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities
and extracutaneous involvement (including renal) have been reported. Severe allergic reaction
necessitates discontinuation of therapy and appropriate medical management.
Drug Interactions
• Vitamin A: Because of the relationship of Accutane to vitamin A, patients should be advised
against taking vitamin supplements containing vitamin A to avoid additive toxic effects.
• Tetracyclines: Concomitant treatment with Accutane and tetracyclines should be avoided because
Accutane use has been associated with a number of cases of pseudotumor cerebri (benign
intracranial hypertension), some of which involved concomitant use of tetracyclines.
• Micro-dosed Progesterone Preparations: Micro-dosed progesterone preparations (“minipills” that
do not contain an estrogen) may be an inadequate method of contraception during Accutane
therapy. Although other hormonal contraceptives are highly effective, there have been reports of
pregnancy from female patients who have used combined oral contraceptives, as well as
transdermal patch/injectable/implantable/vaginal ring hormonal birth control products. These
reports are more frequent for female patients who use only a single method of contraception. It is
not known if hormonal contraceptives differ in their effectiveness when used with Accutane.
Therefore, it is critically important for female patients of childbearing potential to select and
commit to use 2 forms of effective contraception simultaneously, at least 1 of which must be a
primary form (see PRECAUTIONS).
• Norethindrone/ethinyl estradiol: In a study of 31 premenopausal female patients with severe
recalcitrant nodular acne receiving OrthoNovum® 7/7/7 Tablets as an oral contraceptive agent,
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Accutane at the recommended dose of 1 mg/kg/day, did not induce clinically relevant changes in
the pharmacokinetics of ethinyl estradiol and norethindrone and in the serum levels of
progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Prescribers are
advised to consult the package insert of medication administered concomitantly with hormonal
contraceptives, since some medications may decrease the effectiveness of these birth control
products.
• St. John’s Wort: Accutane use is associated with depression in some patients (see
WARNINGS: Psychiatric Disorders and ADVERSE REACTIONS: Psychiatric). Patients
should be prospectively cautioned not to self-medicate with the herbal supplement St. John’s Wort
because a possible interaction has been suggested with hormonal contraceptives based on reports of
breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies
have been reported by users of combined hormonal contraceptives who also used some form of St.
John's Wort.
• Phenytoin: Accutane has not been shown to alter the pharmacokinetics of phenytoin in a study in
seven healthy volunteers. These results are consistent with the in vitro finding that neither
isotretinoin nor its metabolites induce or inhibit the activity of the CYP 2C9 human hepatic P450
enzyme. Phenytoin is known to cause osteomalacia. No formal clinical studies have been
conducted to assess if there is an interactive effect on bone loss between phenytoin and Accutane.
Therefore, caution should be exercised when using these drugs together.
• Systemic Corticosteroids: Systemic corticosteroids are known to cause osteoporosis. No formal
clinical studies have been conducted to assess if there is an interactive effect on bone loss between
systemic corticosteroids and Accutane. Therefore, caution should be exercised when using these
drugs together.
Laboratory Tests
Pregnancy Test
− Female patients of childbearing potential must have had two negative urine or serum pregnancy
tests with a sensitivity of at least 25 mIU/mL before receiving the initial Accutane prescription.
The first test (a screening test) is obtained by the prescriber when the decision is made to pursue
qualification of the patient for Accutane. The second pregnancy test (a confirmation test) must be
done in a CLIA-certified laboratory. The interval between the two tests must be at least 19 days.
− For patients with regular menstrual cycles, the second pregnancy test must be done during the first
5 days of the menstrual period and within 7 days following the office visit, immediately preceding
the beginning of Accutane therapy and after the patient has used 2 forms of contraception for 1
month.
− For patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes
withdrawal bleeding, the second pregnancy test must be done within 7 days following the office
visit, immediately preceding the beginning of Accutane therapy and after the patient has used 2
forms of contraception for 1 month.
− Each month of therapy, patients must have a negative result from a urine or serum pregnancy test.
A pregnancy test must be repeated each month, in a CLIA-certified laboratory, prior to the female
patient receiving each prescription.
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• Lipids: Pretreatment and follow-up blood lipids should be obtained under fasting conditions. After
consumption of alcohol, at least 36 hours should elapse before these determinations are made. It is
recommended that these tests be performed at weekly or biweekly intervals until the lipid response
to Accutane is established. The incidence of hypertriglyceridemia is 1 patient in 4 on Accutane
therapy (see WARNINGS: Lipids).
• Liver Function Tests: Since elevations of liver enzymes have been observed during clinical trials,
and hepatitis has been reported, pretreatment and follow-up liver function tests should be
performed at weekly or biweekly intervals until the response to Accutane has been established (see
WARNINGS: Hepatotoxicity).
• Glucose: Some patients receiving Accutane have experienced problems in the control of their
blood sugar. In addition, new cases of diabetes have been diagnosed during Accutane therapy,
although no causal relationship has been established.
• CPK: Some patients undergoing vigorous physical activity while on Accutane therapy have
experienced elevated CPK levels; however, the clinical significance is unknown. There have been
rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity. In
a clinical trial of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne,
transient elevations in CPK were observed in 12% of patients, including those undergoing
strenuous physical activity in association with reported musculoskeletal adverse events such as
back pain, arthralgia, limb injury, or muscle sprain. In these patients, approximately half of the
CPK elevations returned to normal within 2 weeks and half returned to normal within 4 weeks. No
cases of rhabdomyolysis were reported in this trial.
Carcinogenesis, Mutagenesis and Impairment of Fertility
In male and female Fischer 344 rats given oral isotretinoin at dosages of 8 or 32 mg/kg/day (1.3 to 5.3
times the recommended clinical dose of 1.0 mg/kg/day, respectively, after normalization for total body
surface area) for greater than 18 months, there was a dose-related increased incidence of
pheochromocytoma relative to controls. The incidence of adrenal medullary hyperplasia was also
increased at the higher dosage in both sexes. The relatively high level of spontaneous
pheochromocytomas occurring in the male Fischer 344 rat makes it an equivocal model for study of
this tumor; therefore, the relevance of this tumor to the human population is uncertain.
The Ames test was conducted with isotretinoin in two laboratories. The results of the tests in one
laboratory were negative while in the second laboratory a weakly positive response (less than 1.6 x
background) was noted in S. typhimurium TA100 when the assay was conducted with metabolic
activation. No dose-response effect was seen and all other strains were negative. Additionally, other
tests designed to assess genotoxicity (Chinese hamster cell assay, mouse micronucleus test, S.
cerevisiae D7 assay, in vitro clastogenesis assay with human-derived lymphocytes, and unscheduled
DNA synthesis assay) were all negative.
In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were
observed at oral dosages of isotretinoin of 2, 8, or 32 mg/kg/day (0.3, 1.3, or 5.3 times the
recommended clinical dose of 1.0 mg/kg/day, respectively, after normalization for total body surface
area).
In dogs, testicular atrophy was noted after treatment with oral isotretinoin for approximately 30 weeks
at dosages of 20 or 60 mg/kg/day (10 or 30 times the recommended clinical dose of 1.0 mg/kg/day,
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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respectively, after normalization for total body surface area). In general, there was microscopic
evidence for appreciable depression of spermatogenesis but some sperm were observed in all testes
examined and in no instance were completely atrophic tubules seen. In studies of 66 men, 30 of whom
were patients with nodular acne under treatment with oral isotretinoin, no significant changes were
noted in the count or motility of spermatozoa in the ejaculate. In a study of 50 men (ages 17 to 32
years) receiving Accutane (isotretinoin) therapy for nodular acne, no significant effects were seen on
ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose.
Pregnancy: Category X. See Boxed CONTRAINDICATIONS AND WARNINGS.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because of the potential for adverse
effects, nursing mothers should not receive Accutane.
Pediatric Use
The use of Accutane in pediatric patients less than 12 years of age has not been studied. The use of
Accutane for the treatment of severe recalcitrant nodular acne in pediatric patients ages 12 to 17 years
should be given careful consideration, especially for those patients where a known metabolic or
structural bone disease exists (see PRECAUTIONS: General). Use of Accutane in this age group for
severe recalcitrant nodular acne is supported by evidence from a clinical study comparing 103 pediatric
patients (13 to 17 years) to 197 adult patients (≥18 years). Results from this study demonstrated that
Accutane, at a dose of 1 mg/kg/day given in two divided doses, was equally effective in treating severe
recalcitrant nodular acne in both pediatric and adult patients.
In studies with Accutane, adverse reactions reported in pediatric patients were similar to those
described in adults except for the increased incidence of back pain and arthralgia (both of which were
sometimes severe) and myalgia in pediatric patients (see ADVERSE REACTIONS).
In an open-label clinical trial (N=217) of a single course of therapy with Accutane for severe
recalcitrant nodular acne, bone density measurements at several skeletal sites were not significantly
decreased (lumbar spine change >−4% and total hip change >−5%) or were increased in the majority of
patients. One patient had a decrease in lumbar spine bone mineral density >4% based on unadjusted
data. Sixteen (7.9%) patients had decreases in lumbar spine bone mineral density >4%, and all the
other patients (92%) did not have significant decreases or had increases (adjusted for body mass
index). Nine patients (4.5%) had a decrease in total hip bone mineral density >5% based on
unadjusted data. Twenty-one (10.6%) patients had decreases in total hip bone mineral density >5%,
and all the other patients (89%) did not have significant decreases or had increases (adjusted for body
mass index). Follow-up studies performed in 8 of the patients with decreased bone mineral density for
up to 11 months thereafter demonstrated increasing bone density in 5 patients at the lumbar spine,
while the other 3 patients had lumbar spine bone density measurements below baseline values. Total
hip bone mineral densities remained below baseline (range −1.6% to −7.6%) in 5 of 8 patients (62.5%).
In a separate open-label extension study of 10 patients, ages 13 to 18 years, who started a second
course of Accutane 4 months after the first course, two patients showed a decrease in mean lumbar
spine bone mineral density up to 3.25% (see WARNINGS: Skeletal: Bone Mineral Density).
This label may not be the latest approved by FDA.
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Geriatric Use
Clinical studies of isotretinoin did not include sufficient numbers of subjects aged 65 years and over to
determine whether they respond differently from younger subjects. Although reported clinical
experience has not identified differences in responses between elderly and younger patients, effects of
aging might be expected to increase some risks associated with isotretinoin therapy (see WARNINGS
and PRECAUTIONS).
ADVERSE REACTIONS
Clinical Trials and Postmarketing Surveillance
The adverse reactions listed below reflect the experience from investigational studies of Accutane, and
the postmarketing experience. The relationship of some of these events to Accutane therapy is
unknown. Many of the side effects and adverse reactions seen in patients receiving Accutane are
similar to those described in patients taking very high doses of vitamin A (dryness of the skin and
mucous membranes, eg, of the lips, nasal passage, and eyes).
Dose Relationship
Cheilitis and hypertriglyceridemia are usually dose related. Most adverse reactions reported in clinical
trials were reversible when therapy was discontinued; however, some persisted after cessation of
therapy (see WARNINGS and ADVERSE REACTIONS).
Body as a Whole
allergic
reactions,
including
vasculitis,
systemic
hypersensitivity
(see
PRECAUTIONS:
Hypersensitivity), edema, fatigue, lymphadenopathy, weight loss
Cardiovascular
palpitation, tachycardia, vascular thrombotic disease, stroke
Endocrine/Metabolic
hypertriglyceridemia (see WARNINGS: Lipids), alterations in blood sugar levels (see
PRECAUTIONS: Laboratory Tests)
Gastrointestinal
inflammatory bowel disease (see WARNINGS: Inflammatory Bowel Disease), hepatitis (see
WARNINGS: Hepatotoxicity), pancreatitis (see WARNINGS: Lipids), bleeding and inflammation
of the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea, other nonspecific gastrointestinal
symptoms
Hematologic
allergic reactions (see PRECAUTIONS: Hypersensitivity), anemia, thrombocytopenia, neutropenia,
rare reports of agranulocytosis (see PRECAUTIONS: Information for Patients). See
PRECAUTIONS: Laboratory Tests for other hematological parameters.
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Musculoskeletal
skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, decreases
in bone mineral density (see WARNINGS: Skeletal), musculoskeletal symptoms (sometimes severe)
including back pain, myalgia, and arthralgia (see PRECAUTIONS: Information for Patients),
transient pain in the chest (see PRECAUTIONS: Information for Patients), arthritis, tendonitis,
other types of bone abnormalities, elevations of CPK/rare reports of rhabdomyolysis (see
PRECAUTIONS: Laboratory Tests).
Neurological
pseudotumor cerebri (see WARNINGS: Pseudotumor Cerebri), dizziness, drowsiness, headache,
insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness
Psychiatric
suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors (see
WARNINGS: Psychiatric Disorders), emotional instability
Of the patients reporting depression, some reported that the depression subsided with discontinuation
of therapy and recurred with reinstitution of therapy.
Reproductive System
abnormal menses
Respiratory
bronchospasms (with or without a history of asthma), respiratory infection, voice alteration
Skin and Appendages
acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry
nose, dry skin, epistaxis, eruptive xanthomas,7 flushing, fragility of skin, hair abnormalities, hirsutism,
hyperpigmentation and hypopigmentation, infections (including disseminated herpes simplex), nail
dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus,
pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), sunburn susceptibility
increased, sweating, urticaria, vasculitis (including Wegener’s granulomatosis; see PRECAUTIONS:
Hypersensitivity), abnormal wound healing (delayed healing or exuberant granulation tissue with
crusting; see PRECAUTIONS: Information for Patients)
Special Senses
Hearing
hearing impairment (see WARNINGS: Hearing Impairment), tinnitus.
Vision
corneal opacities (see WARNINGS: Corneal Opacities), decreased night vision which may persist
(see WARNINGS: Decreased Night Vision), cataracts, color vision disorder, conjunctivitis, dry eyes,
eyelid inflammation, keratitis, optic neuritis, photophobia, visual disturbances
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NDA 18-662/S-056
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Urinary System
glomerulonephritis (see PRECAUTIONS: Hypersensitivity), nonspecific urogenital findings (see
PRECAUTIONS: Laboratory Tests for other urological parameters)
Laboratory
Elevation of plasma triglycerides (see WARNINGS: Lipids), decrease in serum high-density
lipoprotein (HDL) levels, elevations of serum cholesterol during treatment
Increased alkaline phosphatase, SGOT (AST), SGPT (ALT), GGTP or LDH (see WARNINGS:
Hepatotoxicity)
Elevation of fasting blood sugar, elevations of CPK (see PRECAUTIONS: Laboratory Tests),
hyperuricemia
Decreases in red blood cell parameters, decreases in white blood cell counts (including severe
neutropenia and rare reports of agranulocytosis; see PRECAUTIONS: Information for Patients),
elevated sedimentation rates, elevated platelet counts, thrombocytopenia
White cells in the urine, proteinuria, microscopic or gross hematuria
OVERDOSAGE
The oral LD50 of isotretinoin is greater than 4000 mg/kg in rats and mice (>600 times the
recommended clinical dose of 1.0 mg/kg/day after normalization of the rat dose for total body surface
area and >300 times the recommended clinical dose of 1.0 mg/kg/day after normalization of the mouse
dose for total body surface area) and is approximately 1960 mg/kg in rabbits (653 times the
recommended clinical dose of 1.0 mg/kg/day after normalization for total body surface area). In
humans, overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain,
headache, dizziness, and ataxia. These symptoms quickly resolve without apparent residual effects.
Accutane causes serious birth defects at any dosage (see Boxed CONTRAINDICATIONS AND
WARNINGS). Female patients of childbearing potential who present with isotretinoin overdose must
be evaluated for pregnancy. Patients who are pregnant should receive counseling about the risks to the
fetus, as described in the boxed CONTRAINDICATIONS AND WARNINGS. Non-pregnant patients
must be warned to avoid pregnancy for at least one month and receive contraceptive counseling as
described in PRECAUTIONS. Educational materials for such patients can be obtained by calling the
manufacturer. Because an overdose would be expected to result in higher levels of isotretinoin in
semen than found during a normal treatment course, male patients should use a condom, or avoid
reproductive sexual activity with a female patient who is or might become pregnant, for 1 month after
the overdose. All patients with isotretinoin overdose should not donate blood for at least 1 month.
DOSAGE AND ADMINISTRATION
Accutane should be administered with a meal (see PRECAUTIONS: Information for Patients).
The recommended dosage range for Accutane is 0.5 to 1.0 mg/kg/day given in two divided doses with
food for 15 to 20 weeks. In studies comparing 0.1, 0.5, and 1.0 mg/kg/day,8 it was found that all
dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower
dosages. During treatment, the dose may be adjusted according to response of the disease and/or the
appearance of clinical side effects — some of which may be dose related. Adult patients whose disease
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
Page 35
is very severe with scarring or is primarily manifested on the trunk may require dose adjustments up to
2.0 mg/kg/day, as tolerated. Failure to take Accutane with food will significantly decrease absorption.
Before upward dose adjustments are made, the patients should be questioned about their compliance
with food instructions.
The safety of once daily dosing with Accutane has not been established. Once daily dosing is not
recommended.
If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of
treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and if
warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated.
The optimal interval before retreatment has not been defined for patients who have not completed
skeletal growth. Long-term use of Accutane, even in low doses, has not been studied, and is not
recommended. It is important that Accutane be given at the recommended doses for no longer than the
recommended duration. The effect of long-term use of Accutane on bone loss is unknown (see
WARNINGS: Skeletal: Bone Mineral Density, Hyperostosis, and Premature Epiphyseal
Closure).
Contraceptive measures must be followed for any subsequent course of therapy (see
PRECAUTIONS).
Table 4
Accutane Dosing by Body Weight (Based on Administration With Food)
Body Weight
Total mg/day
kilograms
pounds
0.5 mg/kg
1 mg/kg
2 mg/kg*
40
88
20
40
80
50
110
25
50
100
60
132
30
60
120
70
154
35
70
140
80
176
40
80
160
90
198
45
90
180
100
220
50
100
200
*See DOSAGE AND ADMINISTRATION: the recommended dosage range is 0.5 to 1.0 mg/kg/day.
INFORMATION FOR PHARMACISTS
Access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-
0654) to obtain an authorization and the “do not dispense to patient after” date. Accutane must only
be dispensed in no more than a 30-day supply.
REFILLS REQUIRE A NEW PRESCRIPTION AND A NEW AUTHORIZATION FROM THE
iPLEDGE SYSTEM.
An Accutane Medication Guide must be given to the patient each time Accutane is dispensed, as
required by law. This Accutane Medication Guide is an important part of the risk management
program for the patient.
HOW SUPPLIED
Soft gelatin capsules, 10 mg (light pink), imprinted ACCUTANE 10 ROCHE. Boxes of 100 containing
10 Prescription Paks of 10 capsules (NDC 0004-0155-49).
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
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Soft gelatin capsules, 20 mg (maroon), imprinted ACCUTANE 20 ROCHE. Boxes of 100 containing
10 Prescription Paks of 10 capsules (NDC 0004-0169-49).
Soft gelatin capsules, 40 mg (yellow), imprinted ACCUTANE 40 ROCHE. Boxes of 100 containing
10 Prescription Paks of 10 capsules (NDC 0004-0156-49).
Storage
Store at controlled room temperature (59° to 86°F, 15° to 30°C). Protect from light.
REFERENCES
1. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and conglobate acne with 13-
cis-retinoic acid. N Engl J Med 300:329-333, 1979. 2. Pochi PE, Shalita AR, Strauss JS, Webster SB.
Report of the consensus conference on acne classification. J Am Acad Dermatol 24:495-500, 1991.
3. Farrell LN, Strauss JS, Stranieri AM. The treatment of severe cystic acne with 13-cis-retinoic acid:
evaluation of sebum production and the clinical response in a multiple-dose trial. J Am Acad Dermatol
3:602-611, 1980. 4. Jones H, Blanc D, Cunliffe WJ. 13-cis-retinoic acid and acne. Lancet 2:1048-1049,
1980. 5. Katz RA, Jorgensen H, Nigra TP. Elevation of serum triglyceride levels from oral isotretinoin
in disorders of keratinization. Arch Dermatol 116:1369-1372, 1980. 6. Ellis CN, Madison KC, Pennes
DR, Martel W, Voorhees JJ. Isotretinoin therapy is associated with early skeletal radiographic changes.
J Am Acad Dermatol 10:1024-1029, 1984. 7. Dicken CH, Connolly SM. Eruptive xanthomas
associated with isotretinoin (13-cis-retinoic acid). Arch Dermatol 116:951-952, 1980. 8. Strauss JS,
Rapini RP, Shalita AR, et al. Isotretinoin therapy for acne: results of a multicenter dose-response
study. J Am Acad Dermatol 10:490-496, 1984.
OrthoNovum 7/7/7 is a registered trademark of Ortho-McNeil Pharmaceutical, Inc.
Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant)
To be completed by the patient (and her parent or guardian* if patient is under age 18) and signed by
her doctor.
Read each item below and initial in the space provided to show that you understand each item and
agree to follow your doctor's instructions. Do not sign this consent and do not take isotretinoin if
there is anything that you do not understand.
*A parent or guardian of a minor patient (under age 18) must also read and initial each item before
signing the consent.
______________________________________________________________
(Patient’s Name)
1. I understand that there is a very high chance that my unborn baby could have severe birth defects if
I am pregnant or become pregnant while taking isotretinoin. This can happen with any amount and
even if taken for short periods of time. This is why I must not be pregnant while taking isotretinoin.
Initial: ______
2. I understand that I must not get pregnant 1 month before, during the entire time of my treatment,
and for 1 month after the end of my treatment with isotretinoin.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
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Initial: ______
3. I understand that I must avoid sexual intercourse completely, or I must use 2 separate, effective
forms of birth control (contraception) at the same time. The only exceptions are if I have had
surgery to remove the uterus (a hysterectomy) or both of my ovaries (bilateral oophorectomy), or
my doctor has medically confirmed that I am post-menopausal.
Initial: ______
4. I understand that hormonal birth control products are among the most effective forms of birth
control. Combination birth control pills and other hormonal products include skin patches, shots,
under-the-skin implants, vaginal rings, and intrauterine devices (IUDs). Any form of birth control
can fail. That is why I must use 2 different birth control methods starting 1 month before, during,
and for 1 month after stopping therapy at the same time, every time I have sexual intercourse, even
if 1 of the methods I choose is hormonal birth control.
Initial: ______
5. I understand that the following are effective forms of birth control:
Primary forms
• tying my tubes (tubal
sterilization)
• partner’s vasectomy
• intrauterine device
• hormonal (combination
birth control pills, skin
patches, shots, under-
the-skin implants, or
vaginal ring)
Secondary forms
Barrier forms (always used with
spermicide):
• male latex condom
• diaphragm
• cervical cap
Others:
• vaginal sponge (contains
spermicide)
A diaphragm, condom, and cervical cap must each be used with spermicide, a special cream that
kills sperm
I understand that at least 1 of my 2 forms of birth control must be a primary method.
Initial: ______
6. I will talk with my doctor about any medicines including herbal products I plan to take during my
isotretinoin treatment because hormonal birth control methods may not work if I am taking certain
medicines or herbal products.
Initial: ______
7. I may receive a free birth control counseling session from a doctor or other family planning expert.
My isotretinoin doctor can give me an isotretinoin Patient Referral Form for this free consultation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
Page 38
Initial: ______
8. I must begin using the birth control methods I have chosen as described above at least 1 month
before I start taking isotretinoin.
Initial: ______
9. I can not get my first prescription for isotretinoin unless my doctor has told that I have 2 negative
pregnancy test results. The first pregnancy test should be done when my doctor decides to prescribe
isotretinoin. The second pregnancy test must be done in a lab during the first 5 days of my
menstrual period right before starting isotretinoin therapy treatment, or as instructed by my doctor.
I will then have 1 pregnancy test; in a lab.
• every month during treatment.
• at the end of treatment
• and 1 month after stopping treatment
I must not start taking isotretinoin until I am sure that I am not pregnant, have negative results from
2 pregnancy tests, and the second test has been done in a lab.
Initial: ______
10. I have read and understand the materials my doctor has given to me, including The iPLEDGE
Program Guide for Isotretinoin for Female Patients Who Can Get Pregnant, The iPLEDGE Birth
Control Workbook and The iPLEDGE Program Patient Introductory Brochure. .
My doctor gave me and asked me to watch the DVD containing a video about birth control and a
video about birth defects and isotretinoin.
I was told about a private counseling line that I may call for more information about birth control. I
have received information on emergency birth control.
Initial: ______
11. I must stop taking isotretinoin right away and call my doctor if I get pregnant, miss my expected
menstrual period, stop using birth control, or have sexual intercourse without using my 2 birth
control methods at any time.
Initial: ______
12. My doctor gave me information about the purpose and importance of providing information to the
iPLEDGE program should I become pregnant while taking isotretinoin or within 1 month of the
last dose. If I become pregnant, I agree to be contacted by the iPLEDGE program and be asked
questions about my pregnancy. I also understand that if I become pregnant, information about my
pregnancy, my health, and my baby’s health may be given to the maker of isotretinoin and
government health regulatory authorities.
Initial: ______
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
Page 39
13. I understand that being qualified to receive isotretinoin in the iPLEDGE program means that I:
•
have had 2 negative urine or blood pregnancy tests before receiving the first isotretinoin
prescription. The second test must be done in a lab. I must have a negative result from a urine or
blood pregnancy test done in a lab repeated each month before I receive another isotretinoin
prescription.
•
have chosen and agreed to use 2 forms of effective birth control at the same time. At least 1
method must be a primary form of birth control, unless I have chosen never to have sexual
contact with a male (abstinence), or I have undergone a hysterectomy. I must use 2 forms of
birth control for at least 1 month before I start isotretinoin therapy, during therapy, and for 1
month after stopping therapy. I must receive counseling, repeated on a monthly basis, about
birth control and behaviors associated with an increased risk of pregnancy.
•
have signed a Patient Information/Informed Consent About Birth Defects (for female patients
who can get pregnant) that contains warnings about the chance of possible birth defects if I am
pregnant or become pregnant and my unborn baby is exposed to isotretinoin.
•
have been informed of and understand the purpose and importance of providing information to
the iPLEDGE program should I become pregnant while taking isotretinoin or within 1 month of
the last dose. I agree to be contacted by the iPLEDGE program and be asked questions about my
pregnancy.
•
have interacted with the iPLEDGE program before starting isotretinoin and on a monthly basis
to answer questions on the program requirements and to enter my two chosen forms of birth
control.
Initial: ______
My doctor has answered all my questions about isotretinoin and I understand that it is my
responsibility not to get pregnant 1 month before, during isotretinoin treatment, or for 1 month
after I stop taking isotretinoin.
Initial: ______
I now authorize my doctor ________________ to begin my treatment with isotretinoin.
Patient Signature:_____________________________________ Date: ______
Parent/Guardian Signature (if under age 18):________________ Date:______
Please print: Patient Name and Address_______________________________
______________________________ Telephone _______________________
I have fully explained to the patient, __________________, the nature and purpose of the treatment
described above and the risks to female patients of childbearing potential. I have asked the patient if
she has any questions regarding her treatment with isotretinoin and have answered those questions to
the best of my ability.
Doctor Signature: __________________________________ Date: ______
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
Page 40
PLACE THE ORIGINAL SIGNED DOCUMENTS IN THE PATIENT’S MEDICAL RECORD.
PLEASE PROVIDE A COPY TO THE PATIENT.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
Page 41
Patient Information/Informed Consent (for all patients):
To be completed by patient (and parent or guardian if patient is under age 18) and signed by the doctor.
Read each item below and initial in the space provided if you understand each item and agree to follow
your doctor’s instructions. A parent or guardian of a patient under age 18 must also read and
understand each item before signing the agreement.
Do not sign this agreement and do not take isotretinoin if there is anything that you do not
understand about all the information you have received about using isotretinoin.
1. I, ______________________________________________________,
(Patient’s Name)
understand that isotretinoin is a medicine used to treat severe nodular acne that cannot be cleared
up by any other acne treatments, including antibiotics. In severe nodular acne, many red, swollen,
tender lumps form in the skin. If untreated, severe nodular acne can lead to permanent scars.
Initials: ______
2. My doctor has told me about my choices for treating my acne.
Initials: ______
3. I understand that there are serious side effects that may happen while I am taking isotretinoin.
These have been explained to me. These side effects include serious birth defects in babies of
pregnant patients. (Note: There is a second Patient Information/Informed Consent About Birth
Defects (for female patients who can get pregnant)
Initials: ______
4. I understand that some patients, while taking isotretinoin or soon after stopping isotretinoin, have
become depressed or developed other serious mental problems. Symptoms of depression include
sad, “anxious” or empty mood, irritability, acting on dangerous impulses, anger, loss of pleasure or
interest in social or sports activities, sleeping too much or too little, changes in weight or appetite,
school or work performance going down, or trouble concentrating. Some patients taking
isotretinoin have had thoughts about hurting themselves or putting an end to their own lives
(suicidal thoughts). Some people tried to end their own lives. And some people have ended their
own lives. There were reports that some of these people did not appear depressed. There have been
reports of patients on isotretinoin becoming aggressive or violent. No one knows if isotretinoin
caused these behaviors or if they would have happened even if the person did not take isotretinoin.
Some people have had other signs of depression while taking isotretinoin (see #7 below).
Initials: ______
5. Before I start taking isotretinoin, I agree to tell my doctor if I have ever had symptoms of
depression (see #7 below), been psychotic, attempted suicide, had any other mental problems, or
take medicine for any of these problems. Being psychotic means having a loss of contact with
reality, such as hearing voices or seeing things that are not there.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
Page 42
Initials: ______
6. Before I start taking isotretinoin, I agree to tell my doctor if, to the best of my knowledge, anyone
in my family has ever had symptoms of depression, been psychotic, attempted suicide, or had any
other serious mental problems.
Initials: ______
7. Once I start taking isotretinoin, I agree to stop using isotretinoin and tell my doctor right away if
any of the following signs and symptoms of depression or psychosis happen. I:
•
Start to feel sad or have crying spells
•
Lose interest in activities I once enjoyed
•
Sleep too much or have trouble sleeping
•
Become more irritable, angry, or aggressive than usual (for example, temper outbursts,
thoughts of violence)
•
Have a change in my appetite or body weight
•
Have trouble concentrating
•
Withdraw from my friends or family
•
Feel like I have no energy
•
Have feelings of worthlessness or guilt
•
Start having thoughts about hurting myself or taking my own life (suicidal thoughts)
•
Start acting on dangerous impulses
•
Start seeing or hearing things that are not real
Initials: ______
8. I agree to return to see my doctor every month I take isotretinoin to get a new prescription
for isotretinoin, to check my progress, and to check for signs of side effects.
Initials: ______
9. Isotretinoin will be prescribed just for me — I will not share isotretinoin with other people because
it may cause serious side effects, including birth defects.
Initials: ______
10. I will not give blood while taking isotretinoin or for 1 month after I stop taking isotretinoin. I
understand that if someone who is pregnant gets my donated blood, her baby may be exposed to
isotretinoin and may be born with serious birth defects.
Initials: ______
11. I have read The iPLEDGE Program Patient Introductory Brochure, and other materials my
provider gave me containing important safety information about isotretinoin. I understand all the
information I received.
Initials: ______
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
Page 43
12. My doctor and I have decided I should take isotretinoin. I understand that I must be qualified in the
iPLEDGE program to have my prescription filled each month. I understand that I can stop taking
isotretinoin at any time. I agree to tell my doctor if I stop taking isotretinoin.
Initials: ______
I now allow my doctor ___________________________ to begin my treatment with isotretinoin.
Patient Signature: ____________________________________ Date: ______
Parent/Guardian Signature (if under age 18): _______________ Date: ______
Patient Name (print) ___________________________________
Patient Address ___________________________ Telephone (___.___.___)
____________________________________
I have:
• fully explained to the patient, __________________, the nature and purpose of isotretinoin
treatment, including its benefits and risks
• given the patient the appropriate educational materials, The iPLEDGE Program Patient
Introductory Brochure and asked the patient if he/she has any questions regarding his/her treatment
with isotretinoin
• answered those questions to the best of my ability
Doctor Signature: _________________________________ Date: ______
PLACE THE ORIGINAL SIGNED DOCUMENTS IN THE PATIENT’S MEDICAL RECORD.
PLEASE PROVIDE A COPY TO THE PATIENT.
MEDICATION GUIDE
ACCUTANE (ACK-U-TANE)
(isotretinoin capsules)
Read the Medication Guide that comes with Accutane before you start taking it and each time you get
a prescription. There may be new information. This information does not take the place of talking with
your doctor about your medical condition or your treatment.
What is the most important information I should know about Accutane?
• Accutane is used to treat a type of severe acne (nodular acne) that has not been helped by other
treatments, including antibiotics.
• Because Accutane can cause birth defects, Accutane is only for patients who can understand
and agree to carry out all of the instructions in the iPLEDGE program.
• Accutane may cause serious mental health problems.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
Page 44
1. Birth defects (deformed babies), loss of a baby before birth (miscarriage), death of the baby,
and early (premature) births. Female patients who are pregnant or who plan to become pregnant
must not take Accutane. Female patients must not get pregnant:
• for 1 month before starting Accutane
• while taking Accutane
• for 1 month after stopping Accutane.
If you get pregnant while taking Accutane, stop taking it right away and call your doctor.
Doctors and patients should report all cases of pregnancy to:
• FDA MedWatch at 1-800-FDA-1088, and
• the iPLEDGE pregnancy registry at 1-800-495-0654
2. Serious mental health problems. Accutane may cause:
• depression
• psychosis (seeing or hearing things that are not real)
• suicide. Some patients taking Accutane have had thoughts about hurting themselves or
putting an end to their own lives (suicidal thoughts). Some people tried to end their own
lives. And some people have ended their own lives.
Stop Accutane and call your doctor right away if you or a family member notices that you
have any of the following signs and symptoms of depression or psychosis:
• start to feel sad or have crying spells
• lose interest in activities you once enjoyed
• sleep too much or have trouble sleeping
• become more irritable, angry, or aggressive than usual (for example, temper outbursts,
thoughts of violence)
• have a change in your appetite or body weight
• have trouble concentrating
• withdraw from your friends or family
• feel like you have no energy
• have feelings of worthlessness or guilt
• start having thoughts about hurting yourself or taking your own life (suicidal thoughts)
• start acting on dangerous impulses
• start seeing or hearing things that are not real
After stopping Accutane, you may also need follow-up mental health care if you had any of these
symptoms.
What is Accutane?
Accutane is a medicine taken by mouth to treat the most severe form of acne (nodular acne) that cannot
be cleared up by any other acne treatments, including antibiotics. Accutane can cause serious side
effects (see “What is the most important information I should know about Accutane?”). Accutane
can only be:
• prescribed by doctors that are registered in the iPLEDGE program
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
Page 45
• dispensed by a pharmacy that is registered with the iPLEDGE program
• given to patients who are registered in the iPLEDGE program and agree to do everything
required in the program
What is severe nodular acne?
Severe nodular acne is when many red, swollen, tender lumps form in the skin. These can be the size
of pencil erasers or larger. If untreated, nodular acne can lead to permanent scars.
Who should not take Accutane?
• Do not take Accutane if you are pregnant, plan to become pregnant, or become pregnant
during Accutane treatment. Accutane causes severe birth defects. See “What is the most
important information I should know about Accutane?”
• Do not take Accutane if you are allergic to anything in it. Accutane contains parabens as the
preservative. See the end of this Medication Guide for a complete list of ingredients in Accutane.
What should I tell my doctor before taking Accutane?
Tell your doctor if you or a family member has any of the following health conditions:
• mental problems
• asthma
• liver disease
• diabetes
• heart disease
• bone loss (osteoporosis) or weak bones
• an eating problem called anorexia nervosa (where people eat too little),
• food or medicine allergies
Tell your doctor if you are pregnant or breastfeeding. Accutane must not be used by women
who are pregnant or breastfeeding.
Tell your doctor about all of the medicines you take including prescription and non-prescription
medicines, vitamins and herbal supplements. Accutane and certain other medicines can interact with
each other, sometimes causing serious side effects. Especially tell your doctor if you take:
• Vitamin A supplements. Vitamin A in high doses has many of the same side effects as Accutane.
Taking both together may increase your chance of getting side effects.
• Tetracycline antibiotics. Tetracycline antibiotics taken with Accutane can increase the chances
of getting increased pressure in the brain.
• Progestin-only birth control pills (mini-pills). They may not work while you take Accutane. Ask
your doctor or pharmacist if you are not sure what type you are using.
• Dilantin (phenytoin). This medicine taken with Accutane may weaken your bones.
• Corticosteroid medicines. These medicines taken with Accutane may weaken your bones.
• St. John’s Wort. This herbal supplement may make birth control pills work less effectively.
These medicines should not be used with Accutane unless your doctor tells you it is okay.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
Page 46
Know the medicines you take. Keep a list of them to show to your doctor and pharmacist. Do not take
any new medicine without talking with your doctor.
How should I take Accutane?
• You must take Accutane exactly as prescribed. You must also follow all the instructions of the
iPLEDGE program. Before prescribing Accutane, your doctor will:
• explain the iPLEDGE program to you
• have you sign the Patient Information/Informed Consent (for all patients). Female patients who
can get pregnant must also sign another consent form.
You will not be prescribed Accutane if you can not agree to or follow all the instructions of
the iPLEDGE program.
• You will get no more than a 30-day supply of Accutane at a time. This is to make sure you are
following the Accutane iPLEDGE program. You should talk with your doctor each month about
side effects.
• The amount of Accutane you take has been specially chosen for you. It is based on your body
weight, and may change during treatment.
• Take Accutane 2 times a day with a meal, unless your doctor tells you otherwise. Swallow your
Accutane capsules whole with a full glass of liquid. Do not chew or suck on the capsule.
Accutane can hurt the tube that connects your mouth to your stomach (esophagus) if it is not
swallowed whole.
• If you miss a dose, just skip that dose. Do not take 2 doses at the same time.
• If you take too much Accutane or overdose, call your doctor or poison control center right away.
• Your acne may get worse when you first start taking Accutane. This should last only a short while.
Talk with your doctor if this is a problem for you.
• You must return to your doctor as directed to make sure you don’t have signs of serious side
effects. Your doctor may do blood tests to check for serious side effects from Accutane. Female
patients who can get pregnant will get a pregnancy test each month.
• Female patients who can become pregnant must agree to use 2 separate forms of effective birth
control at the same time 1 month before, while taking, and for 1 month after taking Accutane. You
must access the iPLEDGE system to answer questions about the program requirements and
to enter your 2 chosen forms of birth control. To access the iPLEDGE system, go to
www.ipledgeprogram.com or call 1-866-495-0654.
You must talk about effective birth control methods with your doctor or go for a free visit to talk
about birth control with another doctor or family planning expert. Your doctor can arrange this free
visit, which will be paid for by the company that makes Accutane.
If you have sex at any time without using 2 forms of effective birth control, get pregnant, or
miss your expected period, stop using Accutane and call your doctor right away.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
Page 47
What should I avoid while taking Accutane?
• Do not get pregnant while taking Accutane and for 1 month after stopping Accutane. See “What
is the most important information I should know about Accutane?”
• Do not breast feed while taking Accutane and for 1 month after stopping Accutane. We do not
know if Accutane can pass through your milk and harm the baby.
• Do not give blood while you take Accutane and for 1 month after stopping Accutane. If someone
who is pregnant gets your donated blood, her baby may be exposed to Accutane and may be born
with birth defects.
• Do not take other medicines or herbal products with Accutane unless you talk to your doctor.
See “What should I tell my doctor before taking Accutane?”.
• Do not drive at night until you know if Accutane has affected your vision. Accutane may
decrease your ability to see in the dark.
• Do not have cosmetic procedures to smooth your skin, including waxing, dermabrasion, or
laser procedures, while you are using Accutane and for at least 6 months after you stop.
Accutane can increase your chance of scarring from these procedures. Check with your doctor for
advice about when you can have cosmetic procedures.
• Avoid sunlight and ultraviolet lights as much as possible. Tanning machines use ultraviolet
lights. Accutane may make your skin more sensitive to light.
• Do not share Accutane with other people. It can cause birth defects and other serious health
problems.
What are the possible side effects of Accutane?
• Accutane can cause birth defects (deformed babies), loss of a baby before birth (miscarriage),
death of the baby, and early (premature) births. See “What is the most important
information I should know about Accutane?”
• Accutane may cause serious mental health problems. See “What is the most important
information I should know about Accutane?”
• serious brain problems. Accutane can increase the pressure in your brain. This can lead to
permanent loss of eyesight and, in rare cases, death. Stop taking Accutane and call your doctor
right away if you get any of these signs of increased brain pressure:
• bad headache
• blurred vision
• dizziness
• nausea, or vomiting
• seizures (convulsions)
• stroke
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
Page 48
• stomach area (abdomen) problems. Certain symptoms may mean that your internal organs are
being damaged. These organs include the liver, pancreas, bowel (intestines), and esophagus
(connection between mouth and stomach). If your organs are damaged, they may not get better
even after you stop taking Accutane. Stop taking Accutane and call your doctor if you get:
• severe stomach, chest or bowel pain
• trouble swallowing or painful swallowing
• new or worsening heartburn
• diarrhea
• rectal bleeding
• yellowing of your skin or eyes
• dark urine
• bone and muscle problems. Accutane may affect bones, muscles, and ligaments and cause pain in
your joints or muscles. Tell your doctor if you plan hard physical activity during treatment with
Accutane. Tell your doctor if you get:
• back pain
• joint pain
• broken bone. Tell all healthcare providers that you take Accutane if you break a bone.
Stop Accutane and call your doctor right away if you have muscle weakness. Muscle
weakness with or without pain can be a sign of serious muscle damage.
Accutane may stop long bone growth in teenagers who are still growing.
• hearing problems. Stop using Accutane and call your doctor if your hearing gets worse or if you
have ringing in your ears. Your hearing loss may be permanent.
• vision problems. Accutane may affect your ability to see in the dark. This condition usually clears
up after you stop taking Accutane, but it may be permanent. Other serious eye effects can occur.
Stop taking Accutane and call your doctor right away if you have any problems with your vision or
dryness of the eyes that is painful or constant. If you wear contact lenses, you may have trouble
wearing them while taking Accutane and after treatment.
• lipid (fats and cholesterol in blood) problems. Accutane can raise the level of fats and
cholesterol in your blood. This can be a serious problem. Return to your doctor for blood tests to
check your lipids and to get any needed treatment. These problems usually go away when
Accutane treatment is finished.
• serious allergic reactions. Stop taking Accutane and get emergency care right away if you
develop hives, a swollen face or mouth, or have trouble breathing. Stop taking Accutane and call
your doctor if you get a fever, rash, or red patches or bruises on your legs.
• blood sugar problems. Accutane may cause blood sugar problems including diabetes. Tell your
doctor if you are very thirsty or urinate a lot.
• decreased red and white blood cells. Call your doctor if you have trouble breathing, faint, or feel
weak.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
Page 49
The common, less serious side effects of Accutane are dry skin, chapped lips, dry eyes, and dry nose
that may lead to nosebleeds. Call your doctor if you get any side effect that bothers you or that does
not go away.
These are not all of the possible side effects with Accutane. Your doctor or pharmacist can give you
more detailed information.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
Page 50
How should I store Accutane?
• Store Accutane at room temperature, between 59° and 86°F. Protect from light.
• Keep Accutane and all medicines out of the reach of children.
General Information about Accutane.
Medicines are sometimes prescribed for conditions that are not mentioned in Medication Guides. Do
not use Accutane for a condition for which it was not prescribed. Do not give Accutane to other
people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about Accutane. If you would like
more information, talk with your doctor. You can ask your doctor or pharmacist for information about
Accutane that is written for health care professionals. You can also call iPLEDGE program at 1-800-
495-0654 or visit www.ipledgeprogram.com.
What are the ingredients in Accutane?
Active Ingredient: Isotretinoin
Inactive Ingredients: beeswax, butylated hydroxyanisole, edetate disodium, hydrogenated soybean oil
flakes, hydrogenated vegetable oil, and soybean oil. Gelatin capsules contain glycerin and parabens
(methyl and propyl), with the following dye systems: 10 mg — iron oxide (red) and titanium dioxide;
20 mg — FD&C Red No. 3, FD&C Blue No. 1, and titanium dioxide; 40 mg — FD&C Yellow No. 6,
D&C Yellow No. 10, and titanium dioxide.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Dilantin is a registered trademark of Warner-Lambert Company LLC.
Distributed by:
27898954
Revised: August 2005
Copyright © 2000-2005 by Roche Laboratories Inc. All rights reserved.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
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[text printed on 'prescription pak' blister cards]
Accutane (isotretinoin capsules)
IMPORTANT INFORMATION FOR ALL PATIENTS:
It is important for your health that you read all the information you received with
this prescription and from your doctor
This package provides reminders of important safety facts about Accutane, but it does not contain all
the information you need to know. It is important for you to know how to take Accutane correctly and
what side effects to watch for.
Read all the information you get about Accutane from your doctor and pharmacist, including the
Medication Guide provided with this package.
You should read, understand and sign a Patient Information/Informed Consent form before you
take Accutane. Contact your doctor if you have not signed this form (male patients and female
patients who cannot get pregnant must sign 1 form and female patients who can get pregnant
must sign 2 forms).
Never share Accutane because it can cause serious side effects
including severe birth defects.
Before you start taking Accutane, tell your doctor if you:
• Are currently taking an oral or injected corticosteroid or an anticonvulsant (seizure) medication.
• Take part in sports where you are more likely to break a bone.
• Have mental problems, anorexia nervosa (a type of eating disorder), back pain, a history of
problems with healing of bone fractures, or problems with bone metabolism.
Special Warning for Female Patients
CAUSES BIRTH DEFECTS
DO NOT GET PREGNANT
Accutane causes serious birth defects. Do NOT take Accutane if you are pregnant.
It is very important for you to read and understand the information about preventing pregnancy
found in this package, the Medication Guide, and the materials given to you by your doctor. It is
very important for you to interact with the iPLEDGE system to answer questions about program
requirements and view the DVD at your doctor’s office. If you do not have the Medication
Guide, and the patient booklets about pregnancy prevention, don’t start taking Accutane. Call
your doctor.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
Page 52
Most people have further questions after reading so much important information about pregnancy
prevention and birth defects. If there is anything you are not sure about, do not take Accutane until
your questions have been answered by your doctor.
Mental problems and suicide
Some patients have become depressed or developed other serious mental problems while they were
taking Accutane or shortly after stopping Accutane. Some patients taking Accutane have had thoughts
of ending their own lives (suicidal thoughts). Some people have tried to end their own lives (attempted
suicide) and some people have ended their own lives (committed suicide). There have been reports of
patients on Accutane becoming aggressive or violent. No one knows if Accutane caused these
problems or behaviors or if they would have happened even if the person did not take Accutane.
Stop taking Accutane and call your doctor right away if you or a family member
notices that you have any of the following signs and symptoms of depression or
psychosis:
• Start to feel sad or have crying spells.
• Lose interest in activities you once enjoyed.
• Sleep too much or have trouble sleeping.
• Become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of
violence).
• Have a change in your appetite or body weight.
• Have trouble concentrating.
• Withdraw from your friends or family.
• Feel like you have no energy.
• Have feelings of worthlessness or guilt.
• Start having thoughts about hurting yourself or taking your own life (suicidal thoughts).
• Start acting on dangerous impulses.
• Start seeing or hearing things that are not real.
Tell your doctor if you or someone in your family has ever had a mental illness or if you take any
medicines for a mental illness (for example, depression).
Other serious side effects to watch for
Stop taking Accutane and call your doctor if you develop any of the problems on this list or any
other unusual or severe problems. If not treated, they could lead to serious health problems. Serious
permanent problems do not happen often.
• Headaches, nausea, vomiting, blurred vision (increased brain pressure).
• Severe stomach pain, diarrhea, rectal bleeding, or trouble swallowing.
• Yellowing of your skin or eyes and/or dark urine.
• Changes in hearing.
• Allergic reactions (if you know you are sensitive to “parabens”, tell your doctor because it is a
preservative in the gelatin capsule of Accutane).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
Page 53
• Bone or muscle pain.
• Vision changes, including trouble seeing at night (this can start suddenly, so be very careful when
driving or operating any vehicle at night).
• Persistent fever, chills, or sore throat.
Other Important Information is found in the Medication Guide and in the booklets from your
doctor:
• Common side effects that are not serious but that you should tell your doctor about.
• How to take Accutane.
• Things to avoid during Accutane treatment.
• Ways to get more information if you need it.
Accutane Causes Serious Birth Defects
[text appearing on main back panel outside of card]
Highlights of Warning to Female Patients. (It is important to watch the DVD and read all
information in the materials given to you by your doctor.)
• You MUST NOT take Accutane if you are pregnant because any amount can cause severe birth
defects, even if taken for short periods during pregnancy.
• You MUST NOT become pregnant 1 month before, during, and for 1 month after you stop taking
Accutane.
• You will not get your first prescription for Accutane until there is proof you have had 2 negative
pregnancy tests as instructed by your doctor (a negative test means that it does not show
pregnancy) and you have interacted with the iPLEDGE system to answer questions about program
requirements.
• You cannot get monthly refills for Accutane unless there is proof that you have had a negative
pregnancy test conducted in a lab every month during Accutane treatment.
• Even the best methods of birth control can fail. Therefore, 2 separate, effective forms of birth
control must be used at the same time for at least 1 month before, during, and for 1 month after you
stop taking Accutane.
• Stop taking Accutane right away and call your doctor immediately if you have sex without birth
control, miss your period or think you are pregnant while you are taking Accutane. If you think you
are pregnant in the month after you have stopped Accutane treatment, call your doctor
immediately.
Very severe birth defects have occurred with Accutane use including:
• Severe Internal Defects: defects that you cannot see—involving the brain (including lower IQ
scores), heart, glands and nervous system.
• Severe External Defects: defects that you can see—such as low-set, deformed or absent ears, wide-
set eyes, depressed bridge of nose, enlarged head and small chin.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
Page 54
[illustration of how to remove capsules]
Figure A
Store at controlled room temperature (59° to 86°F, 15° to 30°C). Protect from light.
[binder copy]
FEMALE PATIENTS:
xx MG
DO NOT GET PREGNANT
27898956
27898958
27898960
Copyright © 2005 by Roche Laboratories Inc. All rights reserved.
Revised: August 2005
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-662/S-056
Page 55
Accutane Revised Text for Blue Boxes on Outer Cartons
Accutane (isotretinoin capsules)
Special Instructions to Pharmacists:
• Only fill Accutane after authorization from the iPLEDGE program by calling 1-866-495-0654
or visiting www.ipledgeprogram.com
• Dispense no more than a 30-day supply
• An Accutane Medication Guide is included in each Prescription Pak
• Dispense Prescription Paks intact
• Do not remove Prescription Paks from carton until dispensed
Reminders for Pharmacists:
• Dispense isotretinoin only for registered patients after obtaining authorization from the
iPLEDGE program by calling 1-866-495-0654 or visiting www.ipledgeprogram.com
• Write Risk Management Authorization number on the prescription
• Dispense no more than a 30-day supply. No refills.
• Dispense Prescription Paks intact
• Do not dispense after the “Do not dispense to Patient After” date
• A Medication Guide is included in each Prescription Pak
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:51.007416
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/018662s056lbl.pdf', 'application_number': 18662, 'submission_type': 'SUPPL ', 'submission_number': 56}
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To reduce the development of drug-
resistant bacteria and maintain
the effectiveness of trimethoprim
tablets, USP and other antibacterial
drugs, trimethoprim tablets, USP
should be used only to treat or
prevent infections that are proven
or strongly suspected to be caused
by bacteria.
DESCRIPTION
Trimethoprim
is
a
synthetic
antibacterial available in tablet
form
for
oral
administration.
Each scored white tablet contains
100 mg trimethoprim or 200 mg
trimethoprim.
Tr i m e t h o p r i m
i s
5-[(3,4,5-trimethoxyphenyl)
methyl]-2,4-pyrimidinediamine. It is
a white to light yellow, odorless,
bitter compound with a molecular
weight of 290.32 and the molecular
formula C14H18N4O3. The structural
formula is:
OCH3
NH2
NH2
N
N
CH3O
CH2
OCH3
Inactive Ingredients
Colloidal silicon dioxide, dibasic
calcium
phosphate
dihydrate,
magnesium stearate, microcrystalline
cellulose, pregelatinized starch, and
sodium starch glycolate.
CLINICAL PHARMACOLOGY
Trimethoprim is rapidly absorbed
following oral administration. It
exists in the blood as unbound,
protein-bound, and metabolized
forms. Ten to twenty percent of
trimethoprim
is
metabolized,
primarily in the liver; the remainder
is excreted unchanged in the
urine. The principal metabolites
of trimethoprim are the 1- and
3-oxides and the 3ʹ- and 4ʹ-hydroxy
derivatives. The free form is
considered to be the therapeutically
active form. Approximately 44% of
trimethoprim is bound to plasma
proteins.
Mean peak serum concentrations
of approximately 1.0 mcg/mL occur
1 to 4 hours after oral administration
of a single 100 mg dose. A single
200 mg dose will result in serum
levels approximately twice as high.
The half-life of trimethoprim ranges
from 8 to 10 hours. However,
patients with severely impaired
renal function exhibit an increase in
the half-life of trimethoprim, which
requires either dosage regimen
adjustment or not using the drug
in such patients (see DOSAGE
AND ADMINISTRATION). During
a 13 week study of trimethoprim
administered at a daily dosage of
200 mg (50 mg q.i.d.), the mean
minimum steady-state concentration
of the drug was 1.1 mcg/mL. Steady-
state concentrations were achieved
within 2 to 3 days of chronic
administration and were maintained
throughout the experimental period.
Excretion of trimethoprim is primarily
by the kidneys through glomerular
filtration and tubular secretion. Urine
concentrations of trimethoprim are
considerably higher than are the
concentrations in the blood. After a
single oral dose of 100 mg, urine
concentrations
of
trimethoprim
ranged from 30 to 160 mcg/mL
during the 0 to 4 hour period and
declined to approximately 18 to
91 mcg/mL during the 8 to 24 hour
period. A 200 mg single oral dose
will result in trimethoprim urine levels
approximately twice as high. After
oral administration, 50% to 60%
of trimethoprim is excreted in the
urine within 24 hours, approximately
80% of this being unmetabolized
trimethoprim.
Since normal vaginal and fecal
flora are the source of most
pathogens causing urinary tract
infections, it is relevant to consider
the distribution of trimethoprim
into these sites. Concentrations of
trimethoprim in vaginal secretions
are
consistently
greater
than
those found simultaneously in the
serum, being typically 1.6 times the
concentrations of simultaneously
obtained serum samples. Sufficient
trimethoprim is excreted in the feces
to markedly reduce or eliminate
trimethoprim-susceptible organisms
from the fecal flora.
Trimethoprim also passes the
placental barrier and is excreted in
human milk.
Microbiology
Trimethoprim blocks the production
of
tetrahydrofolic
acid
from
dihydrofolic acid by binding to and
reversibly inhibiting the required
enzyme, dihydrofolate reductase.
This binding is much stronger for
the bacterial enzyme than for the
corresponding mammalian enzyme.
Thus,
trimethoprim
selectively
interferes with bacterial biosynthesis
of nucleic acids and proteins.
In vitro serial dilution tests have
shown that the spectrum of
antibacterial activity of trimethoprim
includes the common urinary tract
pathogens with the exception of
Pseudomonas aeruginosa.
The dominant non-Enterobacteriaceae
fecal organisms, Bacteroides spp. and
Lactobacillus spp., are not susceptible
to
trimethoprim
concentrations
obtained with the recommended
dosage.
Trimethoprim has been shown to
be active against most strains of
the following microorganisms, both
in vitro and in clinical infections as
described in the INDICATIONS AND
USAGE section.
Aerobic gram-positive microorganisms
Staphylococcus species (coagulase-
negative
strains,
including
S. saprophyticus)
Aerobic gram-negative microorganisms
Enterobacter species
Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis
Susceptibility Testing Methods
Dilution techniques
Quantitative methods are used to
determine antimicrobial minimum
inhibitory concentrations (MICs).
These MICs provide estimates of
the susceptibility of bacteria to
antimicrobial
compounds.
The
MICs should be determined using a
standardized procedure. Standardized
procedures are based on a dilution
method1,7 (broth or agar) or
equivalent with standardized inoculum
concentrations
and
standardized
concentrations
of
trimethoprim
powder. The MIC values should be
interpreted according to the following
criteria:
For testing Enterobacteriaceae and
Staphylococcus spp.:
MIC (mcg/mL)
Interpretation
≤ 8
Susceptible (S)
≥ 16
Resistant (R)
A report of “Susceptible” indicates
that the pathogen is likely to be
inhibited
if
the
antimicrobial
compound in the blood reaches the
concentrations usually achievable.
A report of “Intermediate” indicates
that the result should be considered
equivocal, and, if the microorganism
is not fully susceptible to alternative,
clinically feasible drugs, the test
should be repeated. This category
implies possible clinical applicability
in body sites where the drug is
physiologically concentrated or in
situations where high dosage of
drug can be used. This category
also provides a buffer zone which
prevents
small
uncontrolled
technical factors from causing major
discrepancies
in
interpretation.
A report of “Resistant” indicates
that the pathogen is not likely to
be inhibited if the antimicrobial
compound in the blood reaches the
concentrations usually achievable;
other therapy should be selected.
Standardized susceptibility test
procedures require the use of
laboratory control microorganisms
to control the technical aspects of
the laboratory procedures. Standard
trimethoprima
powder
should
provide the following MIC values:
Staphylococcus
aureus
Escherichia coli
Microorganism
ATCC
29213
ATCC
25922
1 to 4
0.5 to 2
MIC (mcg/mL)
a Very medium-dependent.
Diffusion techniques
Quantitative methods that require
measurement of zone diameters
also provide reproducible estimates
of the susceptibility of bacteria to
antimicrobial compounds. One such
standardized procedure2,7 requires
the use of standardized inoculum
concentrations. This procedure
uses paper disks impregnated with
5 mcg trimethoprim to test the
susceptibility of microorganisms to
trimethoprim.
Reports
from
the
laboratory
providing results of the standard
single-disk susceptibility test with
a 5 mcg trimethoprim disk should
be interpreted according to the
following criteria:
For testing Enterobacteriaceae and
Staphylococcus spp.:
≤ 10
11 to 15
≥ 16
Zone Diameter
(mm)
Resistant (R)
Intermediate (I)
Susceptible (S)
Interpretation
≥ 16
-
≤ 4
MIC
(mcg/mL)
Interpretation should be as stated
above for results using dilution
techniques. Interpretation involves
correlation of the diameter obtained
in the disk test with the MIC of
trimethoprim.
As
with
standardized
dilution
techniques,
diffusion
methods
require the use of the laboratory
control microorganisms that are
used to control the technical aspects
of the laboratory procedures. For
the diffusion technique, the 5 mcg
trimethoprimb disk should provide
the following zone diameters in these
laboratory test quality control stains:
Staphylococcus
aureus
Escherichia coli
Microorganism
ATCC 25923
ATCC 25922
19 to 26
21 to 28
Zone
Diameter
(mm)
b Mueller-Hinton agar should be
checked for excessive levels
of thymidine. To determine
whether Mueller-Hinton medium
has sufficiently low levels of
thymidine and thymine, an
Enterococcus faecalis (ATCC
29212 or ATCC 33186) may
be tested with trimethoprim/
sulfamethoxazole disks. A zone
of inhibition ≥ 20 mm that is
essentially free of fine colonies
indicates a sufficiently low level
of thymidine and thymine.
INDICATIONS AND USAGE
To reduce the development of drug-
resistant bacteria and maintain
the effectiveness of trimethoprim
tablets, USP and other antibacterial
drugs, trimethoprim tablets, USP
should be used only to treat or
prevent infections that are proven or
strongly suspected to be caused by
susceptible bacteria. When culture
and susceptibility information are
available, they should be considered
in selecting or modifying antibacterial
therapy. In the absence of such data,
local epidemiology and susceptibility
patterns may contribute to the empiric
selection of therapy.
For the treatment of initial episodes
of uncomplicated urinary tract
infections
due
to
susceptible
strains of the following organisms:
Escherichia coli, Proteus mirabilis,
Klebsiella pneumoniae, Enterobacter
species, and coagulase-negative
Staphylococcus species, including
S. saprophyticus.
Cultures and susceptibility tests
should be performed to determine
the susceptibility of the bacteria
to trimethoprim. Therapy may be
initiated prior to obtaining the results
of these tests.
CONTRAINDICATIONS
Trimethoprim is contraindicated
in individuals hypersensitive to
trimethoprim and in those with
documented megaloblastic anemia
due to folate deficiency.
WARNINGS
Serious hypersensitivity reactions
have
been
reported
rarely
in
patients on trimethoprim therapy.
Trimethoprim has been reported
rarely to interfere with hematopoiesis,
especially when administered in large
doses and/or for prolonged periods.
The presence of clinical signs such as
sore throat, fever, pallor, or purpura
may be early indications of serious
blood disorders (see OVERDOSAGE,
Chronic).
Complete blood counts should be
obtained if any of these signs are noted
in a patient receiving trimethoprim and
the drug discontinued if a significant
reduction in the count of any formed
blood element is found.
Clostridium
difficile
associated
diarrhea (CDAD) has been reported
with use of nearly all antibacterial
agents, including trimethoprim tablets,
USP, and may range in severity from
mild diarrhea to fatal colitis. Treatment
with antibacterial agents alters the
normal flora of the colon leading to
overgrowth of C. difficile.
C. difficile produces toxins A and B
which contribute to the development
of CDAD. Hypertoxin producing
strains of C. difficile cause increased
morbidity and mortality, as these
infections can be refractory to
antimicrobial therapy and may
require colectomy. CDAD must be
considered in all patients who present
with diarrhea following antibiotic use.
Careful medical history is necessary
since CDAD has been reported to
occur over two months after the
administration of antibacterial agents.
If CDAD is suspected or confirmed,
ongoing antiobiotic use not directed
against C. difficile may need to be
discontinued.
Appropriate
fluid
and
electrolyte
management,
protein supplementation, antibiotic
treatment of C. difficile, and surgical
evaluation should be instituted as
clinically indicated.
PRECAUTIONS
General
Prescribing trimethoprim tablets,
USP in the absence of a proven or
strongly suspected bacterial infection
or a prophylactic indication is unlikely
to provide benefit to the patient and
increases the risk of the development
of drug-resistant bacteria.
Trimethoprim should be given with
caution to patients with possible
folate deficiency. Folates may be
administered concomitantly without
interfering with the antibacterial
action of trimethoprim. Trimethoprim
should also be given with caution
to patients with impaired renal or
hepatic function (see CLINICAL
PHARMACOLOGY and DOSAGE AND
ADMINISTRATION).
Information for Patients
Patients should be counseled
that antibacterial drugs including
trimethoprim tablets, USP should
only be used to treat bacterial
infections. They do not treat viral
infections (e.g., the common cold).
When trimethoprim tablets, USP
are prescribed to treat a bacterial
infection, patients should be told that
although it is common to feel better
early in the course of therapy, the
medication should be taken exactly
as directed. Skipping doses or not
completing the full course of therapy
may (1) decrease the effectiveness
of the immediate treatment and (2)
increase the likelihood that bacteria
will develop resistance and will not
be treatable by trimethoprim tablets,
USP or other antibacterial drugs
in the future.
TRIMETHOPRIM
TABLETS, USP
Rev. I 1/2012
2158
2159
only
Reference ID: 31
not be the latest ap
ion, please visit htt
Diarrhea is a common problem
caused
by
antibiotics
which
usually ends when the antibiotic
is discontinued. Sometimes after
starting treatment with antibiotics,
patients can develop watery and
bloody stools (with and without
stomach cramps and fever) even
as late as two or more months after
having taken the last dose of the
antibiotic. If this occurs, patients
should contact their physician as
soon as possible.
Drug Interactions
Trimethoprim
may
inhibit
the
hepatic metabolism of phenytoin.
Trimethoprim, given at a common
clinical dosage, increased the
phenytoin
half-life
by
51%
and
decreased
the
phenytoin
metabolic clearance rate by 30%.
When administering these drugs
concurrently, one should be alert for
possible excessive phenytoin effect.
Drug/Laboratory Test Interactions
Trimethoprim can interfere with
a serum methotrexate assay as
determined by the Competitive
Binding Protein Technique (CBPA)
when
a
bacterial
dihydrofolate
reductase is used as the binding
protein. No interference occurs,
however, if methotrexate is measured
by a radioimmunoassay (RIA).
The presence of trimethoprim may
also interfere with the Jaffé alkaline
picrate reaction assay for creatinine,
resulting in overestimations of about
10% in the range of normal values.
Carcinogenesis, Mutagenesis,
Impairment of Fertility
Carcinogenesis
Long-term studies in animals to
evaluate carcinogenic potential have
not been conducted with trimethoprim.
Mutagenesis
Trimethoprim was demonstrated to
be nonmutagenic in the Ames assay.
In studies at two laboratories, no
chromosomal damage was detected
in
cultured
Chinese
hamster
ovary
cells
at
concentrations
approximately 500 times human
plasma levels; at concentrations
approximately 1000 times human
plasma levels in these same
cells, a low level of chromosomal
damage was induced at one of
the laboratories. No chromosomal
abnormalities were observed in
cultured human leukocytes at
concentrations of trimethoprim up
to 20 times human steady-state
plasma levels. No chromosomal
effects were detected in peripheral
lymphocytes of human subjects
receiving 320 mg of trimethoprim in
combination with up to 1600 mg of
sulfamethoxazole per day for as long
as 112 weeks.
Impairment of Fertility
No adverse effects on fertility or
general reproductive performance
were observed in rats given
trimethoprim in oral dosages as
high as 70 mg/kg/day for males and
14 mg/kg/day for females.
Pregnancy
Teratogenic Effects
Pregnancy category C
Trimethoprim has been shown
to be teratogenic in the rat when
given in doses 40 times the human
dose. In some rabbit studies, the
overall increase in fetal loss (dead
and
resorbed
and
malformed
conceptuses)
was
associated
with doses six times the human
therapeutic dose.
While there are no large, well-
controlled studies on the use
of
trimethoprim
in
pregnant
women, Brumfitt and Pursell,3
in a retrospective study, reported
the outcome of 186 pregnancies
during which the mother received
either placebo or trimethoprim in
combination with sulfamethoxazole.
The
incidence
of
congenital
abnormalities was 4.5% (3 of 66)
in those who received placebo and
3.3% (4 of 120) in those receiving
trimethoprim and sulfamethoxazole.
There were no abnormalities in the
10 children whose mothers received
the drug during the first trimester.
In a separate survey, Brumfitt and
Pursell also found no congenital
abnormalities in 35 children whose
mothers had received trimethoprim
and sulfamethoxazole at the time
of conception or shortly thereafter.
Because
trimethoprim
may
interfere with folic acid metabolism,
trimethoprim should be used during
pregnancy only if the potential
benefit justifies the potential risk
to the fetus.
Nonteratogenic Effects
The
oral
administration
of
trimethoprim to rats at a dose of
70 mg/kg/day commencing with
the last third of gestation and
continuing through parturition and
lactation caused no deleterious
effects on gestation or pup growth
and survival.
Nursing Mothers
Trimethoprim is excreted in human
milk. Because trimethoprim may
interfere with folic acid metabolism,
caution should be exercised when
trimethoprim is administered to a
nursing woman.
Pediatric Use
Safety and effectiveness in pediatric
patients below the age of 2 months
have not been established. The
effectiveness
of
trimethoprim
as a single agent has not been
established in pediatric patients
under 12 years of age.
Geriatric Use
Clinical studies of trimethoprim
tablets did not include sufficient
numbers of subjects aged 65 and
over to determine whether they
respond differently from younger
subjects. Other reported clinical
experience4,5 has not identified
differences in response between
the elderly and younger patients.
In general, dose selection for an
elderly patient should be cautious,
usually starting at the low end of the
dosing range, reflecting the greater
frequency of decreased hepatic,
renal or cardiac function, and of
concomitant disease or other drug
therapy.
Case
reports
of
hyperkalemia
in
elderly
patients
receiving
trimethoprim-sulfamethoxazole have
been published.6 Trimethoprim is
known to be substantially excreted
by the kidney, and the risk of toxic
reactions to this drug may be greater
in patients with impaired renal
function. Because elderly patients
are more likely to have decreased
renal function, care should be
taken in dose selection, and it may
be useful to monitor potassium
concentrations and to monitor renal
function by calculating creatinine
clearance.
ADVERSE REACTIONS
The adverse effects encountered
most often with trimethoprim were
rash and pruritus.
Dermatologic
Rash, pruritus, and phototoxic skin
eruptions. At the recommended
dosage regimens of 100 mg b.i.d.
or 200 mg q.d., each for 10 days, the
incidence of rash is 2.9% to 6.7%.
In clinical studies which employed
high doses of trimethoprim, an
elevated incidence of rash was noted.
These rashes were maculopapular,
morbilliform, pruritic, and generally
mild to moderate, appearing 7 to
14 days after the initiation of therapy.
Hypersensitivity
Rare reports of exfoliative dermatitis,
erythema
multiforme,
Stevens-
Johnson syndrome, toxic epidermal
necrolysis (Lyell Syndrome), and
anaphylaxis have been received.
Gastrointestinal
Epigastric distress, nausea, vomiting,
and glossitis. Elevation of serum
transaminase and bilirubin has been
noted, but the significance of this
finding is unknown. Cholestatic
jaundice has been rarely reported.
Hematologic
Thrombocytopenia,
leukopenia,
neutropenia, megaloblastic anemia,
and methemoglobinemia.
Metabolic
Hyperkalemia, hyponatremia.
Neurologic
Aseptic meningitis has been rarely
reported.
Miscellaneous
Fever, and increases in BUN and
serum creatinine levels.
OVERDOSAGE
Acute
Signs of acute overdosage with
trimethoprim may appear following
ingestion of 1 gram or more of the drug
and include nausea, vomiting, dizziness,
headaches,
mental
depression,
confusion, and bone marrow depression
(see Chronic subsection).
Treatment
consists
of
gastric
lavage and general supportive
measures. Acidification of the urine
will increase renal elimination of
trimethoprim. Peritoneal dialysis
is not effective and hemodialysis
is only moderately effective in
eliminating the drug.
Chronic
Use of trimethoprim at high doses
and/or for extended periods of time
may cause bone marrow depression
manifested as thrombocytopenia,
leukopenia, and/or megaloblastic
anemia. If signs of bone marrow
depression
occur,
trimethoprim
should be discontinued and the
patient should be given leucovorin;
5 to 15 mg leucovorin daily has been
recommended by some investigators.
DOSAGE AND ADMINISTRATION
The usual oral adult dosage is 100 mg
of trimethoprim every 12 hours or
200 mg of trimethoprim every
24 hours, each for 10 days. The
use of trimethoprim in patients with
a creatinine clearance of less than
15 mL/min is not recommended. For
patients with a creatinine clearance of
15 to 30 mL/min, the dose should be
50 mg every 12 hours.
HOW SUPPLIED
Trimethoprim tablets, USP, 100 mg:
White, round, convex tablet, debossed
“9”, scored, “3” on one side and
debossed “2158” on the other, in
bottles of 100.
Trimethoprim tablets, USP, 200 mg:
White, round, scored, convex tablet,
debossed “93” above the score and
debossed “2159” below the score
on one side and plain on the other,
in bottles of 100.
Store at 20° to 25°C (68° to 77°F) [See
USP Controlled Room Temperature].
Dispense in a tight, light-resistant
container as defined in the USP with
a child-resistant closure (as required).
REFERENCES
1. Clinical and Laboratory Standards
Institute. Methods for Dilution
Antimicrobial Susceptibility Tests
for Bacteria that Grow Aerobically;
Approved Standard-Ninth Edition.
CLSI Document M07-A9, Vol. 32, No.
2, CLSI, Wayne, PA, January, 2012.
2. Clinical and Laboratory Standards
Institute. Performance Standards
for Antimicrobial Disk Susceptibility
Tests; Approved Standard-Eleventh
Edition. CLSI Document M02-A11,
Vol. 32, No. 1, CLSI, Wayne, PA,
January, 2012.
3. Brumfitt W, Pursell R. Trimethoprim-
sulfamethoxazole in the treatment of
bacteriuria in women. J Infect Dis.
1973;128(suppl): S657-S663.
4. Lacey RW, Simpson MHC, Fawcett
C, et al. Comparison of single-dose
trimethoprim with a five-day course
for the treatment of urinary tract
infections in the elderly. Age and
Ageing 10: 179-185, 1981.
5. Ewer TC, Bailey RR, Gilchrist
NL, et al. Comparative study of
norfloxacin and trimethoprim for
the treatment of elderly patients
with urinary tract infection. NZ
Med J 101: 537-539, 1988.
6. Marinella MA. Trimethoprim-
induced
hyperkalemia:
An
analysis of reported cases.
Gerontology 45: 209-212, 1999.
7. Clinical
Laboratory
Standards
Institute. Performance Standards
for Antimicrobial Susceptibility
Testing;
Twenty-Second
Informational Supplement. CLSI
Document M100-S22, Vol. 32, No.
3, CLSI, Wayne, PA, January 2012.
Manufactured In Canada By:
TEVA CANADA LIMITED
Toronto, Canada M1B 2K9
Manufactured For:
TEVA PHARMACEUTICALS USA
Sellersville, PA 18960
Rev. I 1/2012
Reference ID: 31
not be the latest ap
ion, please visit htt
|
custom-source
|
2025-02-12T13:44:51.180242
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/018679s040lbl.pdf', 'application_number': 18679, 'submission_type': 'SUPPL ', 'submission_number': 40}
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Page 3
PROPOSED PRESCRIBING INFORMATION
ParaGard® T 380A Intrauterine Copper Contraceptive
Prescribing Information
Patients should be counseled that this product does not protect against HIV infection (AIDS) and
other sexually transmitted diseases.
ParaGard® T 380A Intrauterine Copper Contraceptive should be placed and removed only by
healthcare professionals who are experienced with these procedures.
DESCRIPTION
ParaGard® T 380A Intrauterine Copper Contraceptive (ParaGard®) is a T-shaped intrauterine device
(IUD), measuring 32 mm horizontally and 36 mm vertically, with a 3 mm diameter bulb at the tip of
the vertical stem. A monofilament polyethylene thread is tied through the tip, resulting in two white
threads, each at least 10.5 cm in length, to aid in detection and removal of the device. The T-frame is
made of polyethylene with barium sulfate to aid in detecting the device under x-ray. ParaGard® also
contains copper: approximately 176 mg of wire coiled along the vertical stem and a 68.7 mg collar on
each side of the horizontal arm. The total exposed copper surface area is 380 + 23 mm². One
ParaGard® weighs less than one (1) gram. No component of ParaGard® or its packaging contains latex.
ParaGard® is packaged together with an insertion tube and solid white rod in a Tyvek® polyethylene
pouch that is then sterilized. A moveable flange on the insertion tube aids in gauging the depth of
insertion through the cervical canal and into the uterine cavity.
CLINICAL PHARMACOLOGY
The contraceptive effectiveness of ParaGard® is enhanced by copper continuously released into the
uterine cavity. Possible mechanism(s) by which copper enhances contraceptive efficacy include
interference with sperm transport or fertilization, and prevention of implantation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-680/S-060
Page 4
INDICATIONS AND USAGE
ParaGard® is indicated for intrauterine contraception for up to 10 years. The pregnancy rate in clinical
studies has been less than 1 pregnancy per 100 women each year.
Table 1: Percentage of women experiencing an unintended pregnancy during the first year of typical
use and first year of perfect use of contraception and the percentage continuing use at the end of the
first year: United States
% of Women Experiencing
% of Women
an Accidental Pregnancy
Continuing Use at
within the First Year of Use
One Year3
Method
Typical Use1 Perfect Use2
(1)
(2)
(3)
(4)
Chance4
85
85
Spermicides5
26
6
40
Periodic abstinence
25
63
Calendar
9
Ovulation method
3
Sympto-thermal6
2
Post-ovulation
1
Cap7
Parous women
40
26
42
Nulliparous women
20
9
56
Sponge
Parous women
40
20
42
Nulliparous women
20
9
56
Diaphragm7
20
6
56
Withdrawal
19
4
Condom8
Female (Reality)
21
5
56
Male
14
3
61
Pill
5
71
Progestin only
0.5
Combined
0.1
IUD
Progesterone T
2.0
1.5
81
Copper T 380A
0.8
0.6
78
LNg 20
0.1
0.1
81
Depo Provera
0.3
0.3
70
Norplant and Norplant-2
0.05
0.05
88
Female sterilization
0.5
0.5
100
Male sterilization
0.15
0.10
100
EMERGENCY CONTRACEPTIVE PILLS: TREATMENT INITIATED WITHIN 72 HOURS AFTER UNPROTECTED
INTERCOURSE REDUCES THE RISK OF PREGNANCY BY AT LEAST 75%.9
Lactational Amenorrhea Method: LAM is a highly effective temporary method of contraception.10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-680/S-060
Page 5
Footnotes to Table 4
Source: Trussell J, Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK,
Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington
Publishers, 1998.
1 Among typical couples who initiate use of a method (not necessarily for the first time), the
percentage who experience an accidental pregnancy during the first year if they do not stop use for
any other reason.
2 Among couples who initiate use of a method (not necessarily for the first time) and who use it
perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy
during the first year if they do not stop use for any reason.
3 Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one
year.
4 The percents becoming pregnant in columns (2) and (3) are based on data from populations where
contraception is not used and from women who cease using contraception in order to become
pregnant. Among such populations, about 89% become pregnant within one year. This estimate was
lowered slightly (to 85%) to represent the percentage who would become pregnant within one year
among women now relying on reversible methods of contraception if they abandoned contraception
altogether.
5 Foams, creams, gels, vaginal suppositories, and vaginal film.
6 Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body
temperature in the post-ovulatory phases.
7 With spermicidal cream or jelly.
8 Without spermicides.
9 The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose
12 hours after the first dose. Preven is the only dedicated product specifically marketed for
emergency contraception. The Food and Drug Administration has also declared the following brands
of oral contraceptive to be safe and effective for emergency contraception: Ovral (1 dose is 2 white
pills), Alesse (1 dose is 5 pink pills), Nordette or Levlen (1 dose is 4 light-orange pills), Lo/Ovral (1
dose is 4 white pills), Triphasil or Tri-Levlen (1 dose is 4 yellow pills).
10 However, to maintain effective protection against pregnancy, another method of contraception must
be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle
feeds are introduced or the baby reaches 6 months of age.
CONTRAINDICATIONS
ParaGard® should not be placed when one or more of the following conditions exist:
1.
Pregnancy or suspicion of pregnancy
2.
Abnormalities of the uterus resulting in distortion of the uterine cavity
3.
Acute pelvic inflammatory disease, or current behavior suggesting a high risk for pelvic
inflammatory disease
4.
Postpartum endometritis or postabortal endometritis in the past 3 months
5.
Known or suspected uterine or cervical malignancy
6.
Genital bleeding of unknown etiology
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-680/S-060
Page 6
7.
Mucopurulent cervicitis
8.
Wilson’s disease
9.
Allergy to any component of ParaGard®
10. A previously placed IUD that has not been removed
WARNINGS
1. Intrauterine Pregnancy
If intrauterine pregnancy occurs with ParaGard® in place and the string is visible, ParaGard®
should be removed because of the risk of spontaneous abortion, premature delivery, sepsis, septic
shock, and, rarely, death. Removal may be followed by pregnancy loss.
If the string is not visible, and the woman decides to continue her pregnancy, check if the
ParaGard® is in her uterus (for example, by ultrasound). If ParaGard® is in her uterus, warn her
that there is an increased risk of spontaneous abortion and sepsis, septic shock, and rarely, death.1
In addition, the risk of premature labor and delivery is increased.1
Human data about risk of birth defects from copper exposure are limited. However, studies have
not detected a pattern of abnormalities, and published reports do not suggest a risk that is higher
than the baseline risk for birth defects.
2. Ectopic Pregnancy
Women who become pregnant while using ParaGard® should be evaluated for ectopic pregnancy.
A pregnancy that occurs with ParaGard® in place is more likely to be ectopic than a pregnancy in
the general population. However, because ParaGard® prevents most pregnancies, women who use
ParaGard® have a lower risk of an ectopic pregnancy than sexually active women who do not use
any contraception.2-3
3. Pelvic Infection
Although pelvic inflammatory disease (PID) in women using IUDs is uncommon, IUDs may be
associated with an increased relative risk of PID compared to other forms of contraception and to
no contraception. The highest incidence of PID occurs within 20 days following insertion.
Therefore, the visit following the first post-insertion menstrual period is an opportunity to assess
the patient for infection, as well as to check that the IUD is in place. (See INSTRUCTIONS FOR
USE, Continuing Care.) Since pelvic infection is most frequently associated with sexually
transmitted organisms, IUDs are not recommended for women at high risk for sexual infection.
Prophylactic antibiotics at the time of insertion do not appear to lower the incidence of PID. 4
PID can have serious consequences, such as tubal damage (leading to ectopic pregnancy or
infertility), hysterectomy, sepsis, and, rarely, death. It is therefore important to promptly assess
and treat any woman who develops signs or symptoms of PID.
Guidelines for treatment of PID are available from the Centers for Disease Control and Prevention
(CDC), Atlanta, Georgia at www.cdc.gov or 1-800-311-3435. Antibiotics are the mainstay of
therapy. Most healthcare professionals also remove the IUD.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-680/S-060
Page 7
The significance of actinomyces-like organisms on Papanicolaou smear in an asymptomatic IUD-
user is unknown,5-6 and so this finding alone does not always require IUD removal and treatment.
However, because pelvic actinomycosis is a serious infection, a woman who has symptoms of
pelvic infection possibly due to actinomyces should be treated and have her IUD removed.
4. Immunocompromise
Women with AIDS should not have IUDs inserted unless they are clinically stable on antiretroviral
therapy. Limited data suggest that asymptomatic women infected with human immunodeficiency
virus may use intrauterine devices. Little is known about the use of IUDs in women who have
illnesses causing serious immunocompromise. Therefore these women should be carefully
monitored for infection if they choose to use an IUD. The risk of pregnancy should be weighed
against the theoretical risk of infection.
5. Embedment
Partial penetration or embedment of ParaGard® in the myometrium can make removal difficult. In
some cases, surgical removal may be necessary.
6. Perforation
Partial or total perforation of the uterine wall or cervix may occur rarely during placement,
although it may not be detected until later. Spontaneous migration has also been reported. If
perforation does occur, remove ParaGard® promptly, since the copper can lead to intraperitoneal
adhesions. Intestinal penetration, intestinal obstruction, and/or damage to adjacent organs may
result if an IUD is left in the peritoneal cavity. Pre-operative imaging followed by laparoscopy or
laparotomy is often required to remove an IUD from the peritoneal cavity.
7. Expulsion
Expulsion can occur, usually during the menses and usually in the first few months after insertion.
There is an increased risk of expulsion in the nulliparous patient. If unnoticed, an unintended
pregnancy could occur.
8. Wilson’s Disease
Theoretically, ParaGard® can exacerbate Wilson’s disease, a rare genetic disease affecting copper
excretion.
PRECAUTIONS
Patients should be counseled that this product does not protect against HIV infection (AIDS)
and other sexually transmitted diseases.
1. Information for patients
Before inserting ParaGard® discuss the Patient Package Insert with the patient, and give her time to
read the information. Discuss any questions she may have concerning ParaGard® as well as other
methods of contraception. Instruct her to promptly report symptoms of infection, pregnancy, or
missing strings.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-680/S-060
Page 8
2. Insertion precautions, continuing care, and removal.
(See INSTRUCTIONS FOR USE.)
3. Vaginal bleeding
In the 2 largest clinical trials with ParaGard® (see ADVERSE REACTIONS, Table 2), menstrual
changes were the most common medical reason for discontinuation of ParaGard®. Discontinuation
rates for pain and bleeding combined are highest in the first year of use and diminish thereafter.
The percentage of women who discontinued ParaGard® because of bleeding problems or pain
during these studies ranged from 11.9% in the first year to 2.2 % in year 9. Women complaining of
heavy vaginal bleeding should be evaluated and treated, and may need to discontinue ParaGard®.
(See ADVERSE REACTIONS.)
4. Vasovagal reactions, including fainting
Some women have vasovagal reactions immediately after insertion. Hence, patients should remain
supine until feeling well and should be cautious when getting up.
5. Expulsion following placement after a birth or abortion
ParaGard® has been placed immediately after delivery, although risk of expulsion may be higher
than when ParaGard® is placed at times unrelated to delivery.7 However, unless done immediately
postpartum, insertion should be delayed to the second postpartum month because insertion during
the first postpartum month (except for immediately after delivery) has been associated with
increased risk of perforation.8
ParaGard® can be placed immediately after abortion, although immediate placement has a slightly
higher risk of expulsion than placement at other times.9 Placement after second trimester abortion
is associated with a higher risk of expulsion than placement after the first trimester abortion.9
6. Magnetic resonance imaging (MRI)
Limited data suggest that MRI at the level of 1.5 Tesla is acceptable in women using ParaGard®.
One study examined the effect of MRI on the CU-7® Intrauterine Copper Contraceptive and Lippes
LoopTM intrauterine devices. Neither device moved under the influence of the magnetic field or
heated during the spin-echo sequences usually employed for pelvic imaging.10 An in vitro study did
not detect movement or temperature change when ParaGard® was subjected to MRI.11
7. Medical diathermy
Theoretically, medical (non-surgical) diathermy (short-wave and microwave heat therapy) in a
patient with a metal-containing IUD may cause heat injury to the surrounding tissue. However, a
small study of eight women did not detect a significant elevation of intrauterine temperature when
diathermy was performed in the presence of a copper IUD.12
8. Pregnancy
ParaGard® is contraindicated during pregnancy. (See CONTRAINDICATIONS and
WARNINGS.)
9. Nursing mothers
Nursing mothers may use ParaGard®. No difference has been detected in concentration of copper
in human milk before and after insertion of copper IUDs. The literature is conflicting, but limited
data suggest that there may be an increased risk of perforation and expulsion if a woman is
lactating. 13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-680/S-060
Page 9
10. Pediatric use
ParaGard® is not indicated before menarche. Safety and efficacy have been established in women
over 16 years old.
ADVERSE REACTIONS
The most serious adverse events associated with intrauterine contraception are discussed in
WARNINGS and PRECAUTIONS. These include:
Intrauterine pregnancy
Septic abortion
Ectopic pregnancy
Pelvic infection
Perforation
Embedment
Table 2 shows discontinuation rates from two clinical studies by adverse event and year.
Table 2. Summary of Rates (No. per 100 Subjects) by Year for Adverse Events Causing
Discontinuation
Year
Adverse Event
1
2
3
4
5
6
7
8
9
10
Pregnancy
0.7
0.3
0.6
0.2
0.3
0.2
0.0
0.4
0.0
0.0
Expulsion
5.7
2.5
1.6
1.2
0.3
0.0
0.6
1.7
0.2
0.4
Bleeding/Pain
11.9
9.8
7.0
3.5
3.7
2.7
3.0
2.5
2.2
3.7
Other Medical Event
2.5
2.1
1.6
1.7
0.1
0.3
1.0
0.4
0.7
0.3
No. of Women at Start of Year 4932
3149
2018
1121
872
621 563 483 423
325
*Rates were calculated by weighting the annual rates by the number of subjects starting each year for each of the
Population Council (3,536 subjects) and the World Health Organization (1,396 subjects) trials.
The following adverse events have also been observed. These are listed alphabetically and not by
order of frequency or severity.
Anemia
Backache
Dysmenorrhea
Dyspareunia
Expulsion, complete or partial
Leukorrhea
Menstrual flow, prolonged
Menstrual spotting
Pain and cramping
Urticarial allergic skin reaction
Vaginitis
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-680/S-060
Page 10
INSTRUCTIONS FOR USE
The placement technique for ParaGard® is different from that used for other IUDs. Therefore, the
clinician should be familiar with the following instructions.
ParaGard® may be placed at any time during the cycle when the clinician is reasonably certain the
patient is not pregnant. For information about timing of postpartum and postabortion insertions, see
PRECAUTIONS.
A single ParaGard® should be placed at the fundus of the uterine cavity. ParaGard® should be
removed on or before 10 years from the date of insertion.
Before Placement:
1. Make sure that the patient is an appropriate candidate for ParaGard® and that she has read the
Patient Package Insert.
2. Use of an analgesic before insertion is at the discretion of the patient and the clinician.
3. Establish the size and position of the uterus by pelvic examination.
4. Insert a speculum and cleanse the vagina and cervix with an antiseptic solution.
5. Apply a tenaculum to the cervix and use gentle traction to align the cervical canal with the
uterine cavity.
6. Gently insert a sterile sound to measure the depth of the uterine cavity.
7. The uterus should sound to a depth of 6 to 9 cm except when inserting ParaGard® immediately
post-abortion or post-partum. Insertion of ParaGard® into a uterine cavity measuring less than 6 cm
may increase the incidence of expulsion, bleeding, pain, and perforation. If you encounter cervical
stenosis, avoid undue force. Dilators may be helpful in this situation.
How to Load and Place ParaGard:®
Do not bend the arms of ParaGard® earlier than 5 minutes before it is to be placed in the uterus.
Use aseptic technique when handling ParaGard® and the part of the insertion tube that will enter
the uterus.
STEP 1
Load ParaGard into the insertion tube by folding the two horizontal arms of ParaGard against the
stem and push the tips of the arms securely into the inserter tube.
If you do not have sterile gloves, you can do STEPS 1 and 2 while ParaGard® is in the sterile
package. First, place the package face up on a clean surface. Next, open at the bottom end (where
arrow says OPEN). Pull the solid white rod partially from the package so it will not interfere with
assembly. Place thumb and index finger on top of package on ends of the horizontal arms. Use
other hand to push insertion tube against arms of ParaGard® (shown by arrow in Fig. 1). This will
start bending the T arms.
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NDA 18-680/S-060
Page 11
STEP 2
Bring the thumb and index finger closer together to continue bending the arms until they are
alongside the stem. Use the other hand to withdraw the insertion tube just enough so that the
insertion tube can be pushed and rotated onto the tips of the arms. Your goal is to secure the tips of
the arms inside the tube (Fig. 2). Insert the arms no further than necessary to insure retention.
Introduce the solid white rod into the insertion tube from the bottom, alongside the threads, until it
touches the bottom of the ParaGard®.
STEP 3
Grasp the insertion tube at the open end of the package; adjust the blue flange so that the distance
from the top of the ParaGard® (where it protrudes from the inserter) to the blue flange is the same
as the uterine depth that you measured with the sound. Rotate the insertion tube so that the
horizontal arms of the T and the long axis of the blue flange lie in the same horizontal plane (Fig.
3). Now pass the loaded insertion tube through the cervical canal until ParaGard® just touches the
fundus of the uterus. The blue flange should be at the cervix in the horizontal plane.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-680/S-060
Page 12
STEP 4
To release the arms of ParaGard®, hold the solid white rod steady and withdraw the insertion tube
no more than one centimeter This releases the arms of ParaGard® high in the uterine fundus (Fig.
4).
STEP 5
Gently and carefully move the insertion tube upward toward the top of the uterus, until slight
resistance is felt. This will ensure placement of the T at the highest possible position within the
uterus (Fig. 5).
STEP 6
Hold the insertion tube steady and withdraw the solid white rod (Fig. 6).
STEP 7
Gently and slowly withdraw the insertion tube from the cervical canal. Only the threads should be
visible protruding from the cervix. (Fig. 7). Trim the threads so that 3 to 4 cm protrude into the
vagina. Note the length of the threads in the patient’s records.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-680/S-060
Page 13
If you suspect that ParaGard® is not in the correct position, check placement (with ultrasound, if
necessary). If ParaGard® is not positioned completely within the uterus, remove it and replace it
with a new ParaGard®. Do not reinsert an expelled or partially expelled ParaGard®.
CAUTION
Instrumentation of the cervical os may result in vasovagal reactions, including fainting. Have the
patient remain supine until she feels well, and have her get up with caution.
Continuing Care:
Following placement, examine the patient after her first menses to confirm that ParaGard® is still in
place. You should be able to see or feel only the threads. If ParaGard® has been partially or
completely expelled, remove it. You can place a new ParaGard® if the patient desires and if she is
not pregnant. Do not reinsert a used ParaGard®.
Evaluate the patient promptly if she complains of any of the following:
• Abdominal or pelvic pain, cramping, or tenderness; malodorous discharge; bleeding;
fever
• A missed period
(See WARNINGS, Pelvic Infection, Intrauterine Pregnancy and Ectopic Pregnancy.)
The length of the visible threads may change with time. However, no action is needed unless you
suspect partial expulsion, perforation, or pregnancy.
If you cannot find the threads in the vagina, check that ParaGard® is still in the uterus. The
threads can retract into the uterus or break, or ParaGard® can break, perforate the uterus, or be
expelled. Gentle probing of the cavity, radiography, or sonography may be required to locate the
IUD.
If there is evidence of partial expulsion, perforation, or breakage, remove ParaGard®.
How to Remove ParaGard®
Remove ParaGard® with forceps, pulling gently on the exposed threads. The arms of ParaGard®
will fold upwards as it is withdrawn from the uterus. You may immediately insert a new ParaGard®
if the patient requests it and has no contraindications.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-680/S-060
Page 14
Embedment or breakage of ParaGard® in the myometrium can make removal difficult. Analgesia,
paracervical anesthesia, and cervical dilation may assist in removing an embedded ParaGard®. An
alligator forceps or other grasping instrument may be helpful. Hysteroscopy may also be helpful.
HOW SUPPLIED
ParaGard® is available in cartons of 1 (one) sterile unit (NDC 50907-0380-6) or cartons of 5 (five)
sterile units (NDC 50907-0380-7). Each ParaGard® is packaged together with an insertion tube and
solid white rod in a Tyvek® polyethylene pouch.
REFERENCES
1.Tatum HJ, Schmidt FH, Jain AK. Management and outcome of pregnancies associated with the
Copper T intrauterine contraceptive device. Am J Obstet Gynecol. 1976;126:869-879.
2.Sivin I. Dose- and age-dependent ectopic pregnancy risks with intrauterine contraception. Obstet
Gynecol. 1999;78:291-298.
3.Franks AL, Beral V, Cates W Jr, Hogue CJR. Contraception and ectopic pregnancy risk. Am J
Obstet Gynecol. 1990;163:1120-1123.
4.Grimes DA, Schulz KF. Prophylactic antibiotics for intrauterine device insertion: a metaanalysis
of the randomized controlled trials. Contraception. 1999;60:57-63.
5.Lippes J. Pelvic actinomycosis: a review and preliminary look at prevalence. Am J Obstet
Gynecol. 1999;180:265-269.
6. Petitti DB, Yamamoto D, Morgenstern N. Factors associated with actinomyces-like organisms
on Papanicolaou smear in users of intrauterine contraceptive devices. Am
J Obstet Gynecol. 1983;145:338-341.
7.Grimes D, Schulz K, van Vliet H, Stanwood N. Immediate post-partum insertion of intrauterine
devices: a Cochrane review. Hum Reprod. 2002;17:549-554.
8.Cole LP, Edelman DA, Potts DM, Wheeler RG, Laufe LE. Postpartum insertion of modified
intrauterine devices. J Reprod Med. 1984;29:677-682.
9.Grimes DA, Schulz KF, Stanwood N. Immediate post-abortal insertion of intrauterine devices.
(Cochrane Review). In: The Cochrane Library, Issue 2, 2003. Oxford: Update Software.
10.Hess T, Stepanow B, Knopp MV. Magnetic resonance imaging: safety of intrauterine
contraceptive devices during MR imaging. Eur Radiol. 1996;6:66-68.
11.Mark AS, Hricak H. Intrauterine contraceptive devices: MR imaging. Radiology. 1987;
162:311-314.
12 Heick A., Espersen T., Pedersen HL, Raahauge J: Is diathermy safe in women with copper-
bearing IUDs? Acta Obstet Gynecol Scand. 1991;70(2):153-5.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-680/S-060
Page 15
13 Rodrigues da Cunha AC, Dorea JG, Cantuaria AA. Intrauterine device and maternal copper
metabolism during lactation. Contraception 2001;63:37-9.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-680/S-060
Page 16
(Cover Page)
INFORMATION FOR PATIENTS
ParaGard® T 380A
Intrauterine Copper Contraceptive
(Inner Pages)
ParaGard® T 380A Intrauterine Copper Contraceptive is used to prevent pregnancy. It does not
protect against HIV infection (AIDS) and other sexually transmitted diseases.
It is important for you to understand this brochure and discuss it with your healthcare provider before
choosing ParaGard® T 380A Intrauterine Copper Contraceptive (ParaGard®). You should also learn
about other birth control methods that may be an option for you.
What is ParaGard®?
ParaGard® is a copper-releasing device that is placed in your uterus to prevent pregnancy for up to 10
years.
ParaGard® is made of white plastic in the shape of a “T.” Copper is wrapped around the stem and arms
of the “T”. Two white threads are attached to the stem of the “T”. The threads are the only part of
ParaGard® that you can feel when ParaGard® is in your uterus. ParaGard® and its components do not
contain latex.
How long can I keep ParaGard® in place?
You can keep ParaGard® in your uterus for up to 10 years. After 10 years, you should have ParaGard®
removed by your healthcare provider. If you wish and if it is still right for you, you may get a new
ParaGard® during the same visit.
What if I change my mind and want to become pregnant?
Your healthcare provider can remove ParaGard® at any time. After discontinuation of ParaGard®, its
contraceptive effect is reversed.
How does ParaGard® work?
Ideas about how ParaGard® works include preventing sperm from reaching the egg, preventing sperm
from fertilizing the egg, and preventing the egg from attaching (implanting) in the uterus. ParaGard®
does not stop your ovaries from making an egg (ovulating) each month.
How well does ParaGard® work?
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-680/S-060
Page 17
Fewer than 1 in 100 women become pregnant each year while using ParaGard®.
The table below shows the chance of getting pregnant using different types of birth control. The
numbers show typical use, which includes people who don't always use birth control correctly.
Number of women out of 100 women who are likely to get pregnant over one year
Method of birth control
Pregnancies per 100 women over one year
No method
85
Spermicides
26
Periodic abstinence
25
Cap with Spermicides
20
Vaginal Sponge
20 to 40
Diaphragm with Spermicides
20
Withdrawal
19
Condom without spermicides (female)
21
Condom without spermicides (male)
14
Oral Contraceptives
5
IUDs, Depo-Provera, implants, sterilization
less than 1
Who might use ParaGard®?
You might choose ParaGard® if you
•
need birth control that is very effective
•
need birth control that stops working when you stop using it
•
need birth control that is easy to use
Who should not use ParaGard®?
You should not use ParaGard® if you
• Might be pregnant
• Have a uterus that is abnormally shaped inside
• Have a pelvic infection called pelvic inflammatory disease (PID) or have current behavior that
puts you at high risk of PID (for example, because you are having sex with several men, or your
partner is having sex with other women)
• Have had an infection in your uterus after a pregnancy or abortion in the past 3 months
• Have cancer of the uterus or cervix
• Have unexplained bleeding from your vagina
• Have an infection in your cervix
• Have Wilson’s disease (a disorder in how the body handles copper)
• Are allergic to anything in ParaGard®
• Already have an intrauterine contraceptive in your uterus
How is ParaGard® placed in the uterus?
ParaGard® is placed in your uterus during an office visit. Your healthcare provider first examines you
to find the position of your uterus. Next, he or she will cleanse your vagina and cervix, measure your
uterus, and then slide a plastic tube containing ParaGard® into your uterus. The tube is removed,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-680/S-060
Page 18
leaving ParaGard® inside your uterus. Two white threads extend into your vagina. The threads are
trimmed so they are just long enough for you to feel with your fingers when doing a self-check. As
ParaGard® goes in, you may feel cramping or pinching. Some women feel faint, nauseated, or dizzy for
a few minutes afterwards. Your healthcare provider may ask you to lie down for a while and to get up
slowly.
How do I check that ParaGard® is in my uterus ?
Visit your healthcare provider for a check-up about one month after placement to make sure ParaGard®
is still in your uterus.
You can also check to make sure that ParaGard® is still in your uterus by reaching up to the top of your
vagina with clean fingers to feel the two threads. Do not pull on the threads.
If you cannot feel the threads, ask your healthcare provider to check if ParaGard® is in the right place.
If you can feel more of ParaGard® than just the threads, ParaGard® is not in the right place. If you can’t
see your healthcare provider right away, use an additional birth control method. If ParaGard® is in the
wrong place, your chances of getting pregnant are increased. It is a good habit for you to check that
ParaGard® is in place once a month.
You may use tampons when you are using ParaGard®.
What if I become pregnant while using ParaGard®?
If you think you are pregnant, contact your healthcare professional right away. If you are pregnant and
ParaGard® is in your uterus, you may get a severe infection or shock, have a miscarriage or premature
labor and delivery, or even die. Because of these risks, your healthcare provider will recommend that
you have ParaGard® removed, even though removal may cause miscarriage.
If you continue a pregnancy with ParaGard® in place, see your healthcare provider regularly. Contact
your healthcare provider right away if you get fever, chills, cramping, pain, bleeding, flu-like
symptoms, or an unusual, bad smelling vaginal discharge.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-680/S-060
Page 19
A pregnancy with ParaGard® in place has a greater than usual chance of being ectopic (outside your
uterus). Ectopic pregnancy is an emergency that may require surgery. An ectopic pregnancy can cause
internal bleeding, infertility, and death. Unusual vaginal bleeding or abdominal pain may be signs of an
ectopic pregnancy.
Copper in ParaGard® does not seem to cause birth defects.
What side effects can I expect with ParaGard®?
The most common side effects of ParaGard® are heavier, longer periods and spotting between periods;
most of these side effects diminish after 2-3 months. However, if your menstrual flow continues to be
heavy or long, or spotting continues, contact your healthcare provider.
Infrequently, serious side effects may occur:
• Pelvic inflammatory disease (PID): Uncommonly, ParaGard® and other IUDs are associated with
PID. PID is an infection of the uterus, tubes, and nearby organs. PID is most likely to occur in the
first 20 days after placement. You have a higher chance of getting PID if you or your partner have
sex with more than one person. PID is treated with antibiotics. However, PID can cause serious
problems such as infertility, ectopic pregnancy, and chronic pelvic pain. Rarely, PID may even
cause death. More serious cases of PID require surgery or a hysterectomy (removal of the uterus).
Contact your healthcare provider right away if you have any of the signs of PID: abdominal or
pelvic pain, painful sex, unusual or bad smelling vaginal discharge, chills, heavy bleeding, or fever.
• Difficult removals: Occasionally ParaGard® may be hard to remove because it is stuck in the
uterus. Surgery may sometimes be needed to remove ParaGard®.
• Perforation: Rarely, ParaGard® goes through the wall of the uterus, especially during placement.
This is called perforation. If ParaGard® perforates the uterus, it should be removed. Surgery may be
needed. Perforation can cause infection, scarring, or damage to other organs. If ParaGard®
perforates the uterus, you are not protected from pregnancy.
• Expulsion: ParaGard® may partially or completely fall out of the uterus. This is called expulsion.
Women who have never been pregnant may be more likely to expel ParaGard® than women who
have been pregnant before. If you think that ParaGard® has partly or completely fallen out, use an
additional birth control method, such as a condom and call your healthcare provider.
You may have other side effects with ParaGard®. For example, you may have anemia (low blood
count), backache, pain during sex, menstrual cramps, allergic reaction, vaginal infection, vaginal
discharge, faintness, or pain. This is not a complete list of possible side effects. If you have questions
about a side effect, check with your healthcare provider.
When should I call my healthcare provider?
Call your healthcare provider if you have any concerns about ParaGard®. Be sure to call if you
• Think you are pregnant
• Have pelvic pain or pain during sex
• Have unusual vaginal discharge or genital sores
• Have unexplained fever
• Might be exposed to sexually transmitted diseases (STDs)
• Cannot feel ParaGard®’s threads or can feel the threads are much longer
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18-680/S-060
Page 20
• Can feel any other part of the ParaGard® besides the threads
• Become HIV positive or your partner becomes HIV positive
• Have severe or prolonged vaginal bleeding
• Miss a menstrual period
General advice about prescription medicines
This brochure summarizes the most important information about ParaGard®. If you would like more
information, talk with your healthcare provider. You can ask your healthcare provider for information
about ParaGard® that is written for healthcare professionals.
Checklist
This checklist will help you and your healthcare provider discuss the pros and cons of ParaGard® for
you. Do you have any of the following conditions?
Yes
No
Don’t know
Abnormal Pap smear
Abnormalities of the uterus
Allergy to copper
Anemia or blood clotting problems
Bleeding between periods
Cancer of the uterus or cervix
Fainting attacks
Genital sores
Heavy menstrual flow
HIV or AIDS
Infection of the uterus or cervix
IUD in place now or in the past
More than one sexual partner
Pelvic infection (PID)
Possible pregnancy
Repeated episodes of pelvic infection (PID)
Serious infection following a pregnancy or
abortion in the past 3 months
Severe menstrual cramps
Sexual partner who has more than
one sexual partner
Sexually transmitted disease (STD)
such as gonorrhea or chlamydia
Wilson’s disease
(Back Page)
[FEI LOGO]
Manufactured by FEI Products LLC
N. Tonawanda, New York 14120
© FEI 2005 FEI Women’s Health LLC
Printed in USA
ECR #1480 September 2005
Revision: September 2005
1019100
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/018680s060lbl.pdf', 'application_number': 18680, 'submission_type': 'SUPPL ', 'submission_number': 60}
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NDA 18681/S-027
Page 5
LD-442-1 Y36-002-845
Package Insert
Lactated Ringer's Irrigation
FOR ALL GENERAL IRRIGATION, WASHING AND RINSING PURPOSES
Not For Injection By Usual Parenteral Routes
Flexible Irrigation Container
Rx only
DESCRIPTION
Lactated Ringer’s Irrigation is a sterile, nonpyrogenic solution of electrolytes in water for injection intended only for sterile
irrigation, washing and rinsing purposes. The composition is based on a modification of the injectable formula originally known as
Hartmann’s Solution.
Each 100 mL of Lactated Ringer’s Irrigation contains: Sodium chloride 600 mg; sodium lactate, anhydrous 310 mg; potassium
chloride 30 mg; calcium chloride, dihydrate 20 mg. The pH is 6.75 (6.0 — 7.5). The solution is isotonic (273 mOsmol/liter, calc.)
and has the following electrolyte content (mEq/liter): Sodium (Na+) 130; potassium (K+) 4; calcium (Ca++) 3; chloride (Cl¯) 109
and lactate (CH3CH(OH)COO¯) 28. Contains sodium hydroxide and may contain hydrochloric acid for pH adjustment.
The solution contains no bacteriostatic or antimicrobial agent or added buffer and is intended only for use as a single-dose or
short procedure irrigation. When smaller volumes are required, the unused portion should be discarded. Lactated Ringer’s
Irrigation may be classified as a sterile irrigant, wash, rinse and pharmaceutical vehicle.
Calcium Chloride, USP is chemically designated calcium chloride, dihydrate (CaCl2 • 2H2O), white fragments or granules freely
soluble in water.
Potassium Chloride, USP is chemically designated KCl, a white granular powder freely soluble in water.
Sodium Chloride, USP is chemically designated NaCl, a white crystalline powder freely soluble in water.
Sodium Lactate, USP is chemically designated C3H5NaO3, a 60% aqueous solution miscible in water.
It has the following structural formula: structural formula
Water for Injection, USP is chemically designated H2O.
Reference ID: 3620110
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18681/S-027
Page 6
The plastic container is made from a multilayered film specifically developed for parenteral drugs. It contains no plasticizers and
exhibits virtually no leachables. The solution contact layer is a rubberized copolymer of ethylene and propylene. The container is
nontoxic and biologically inert. The container-solution unit is a closed system and is not dependent upon entry of external air
during administration. The container is overwrapped to provide protection from the physical environment and to provide an
additional moisture barrier when necessary.
Not made with natural rubber latex, PVC or DEHP.
CLINICAL PHARMACOLOGY
Lactated Ringer’s Irrigation exerts a mechanical cleansing action for sterile irrigation of body cavities, tissues or wounds,
indwelling urethral catheters and surgical drainage tubes, and for washing, rinsing or soaking surgical dressings, instruments and
laboratory specimens. It also serves as a vehicle for drugs used for irrigation or other pharmaceutical preparations.
Lactated Ringer’s Irrigation provides an isotonic irrigation with the same ionic constituents as Lactated Ringer’s Injection, USP,
a modification of Hartmann’s Solution.
Lactated Ringer’s Irrigation is considered generally compatible with living tissues and organs.
Calcium chloride in water dissociates to provide calcium (Ca++) and chloride (Cl¯) ions. They are normal constituents of the body
fluids and are dependent on various physiologic mechanisms for maintenance of balance between intake and output.
Approximately 80% of body calcium is excreted in the feces as insoluble salts; urinary excretion accounts for the remaining 20%.
Potassium chloride in water dissociates to provide potassium (K+) and chloride (Cl¯) ions. Potassium is the chief cation of body
cells (160 mEq/liter of intracellular water). It is found in low concentration in plasma and extracellular fluids (3.5 to 5.0 mEq/liter in
a healthy adult). Potassium plays an important role in electrolyte balance.
Normally about 80 to 90% of the potassium intake is excreted in the urine; the remainder in the stools and to a small extent, in
the perspiration. The kidney does not conserve potassium well so that during fasting or in patients on a potassium-free diet,
potassium loss from the body continues resulting in potassium depletion.
Sodium chloride in water dissociates to provide sodium (Na+) and chloride (Cl¯) ions. Sodium (Na+) is the principal cation of the
extracellular fluid and plays a large part in the therapy of fluid and electrolyte disturbances. Chloride (Cl¯) has an integral role in
buffering action when oxygen and carbon dioxide exchange occurs in the red blood cells. The distribution and excretion of
sodium (Na+) and chloride (Cl¯) are largely under the control of the kidney which maintains a balance between intake and output.
Sodium lactate in water dissociates to provide sodium (Na+) and lactate (C3H5O3¯) ions. The lactate anion provides an alkalizing
effect resulting from simultaneous removal by the liver of lactate and hydrogen ions. In the liver, the lactate is metabolized to
glycogen which is ultimately converted to carbon dioxide and water by oxidative metabolism.
The lactate anion acts as a source (alternate) of bicarbonate when normal production and utilization of lactic acid is not impaired
as a result of disordered lactate metabolism. Since metabolic conversion is dependent on the integrity of cellular oxidative
processes, lactate may be inadequate or ineffective as a source of bicarbonate in patients suffering from acidosis associated
Reference ID: 3620110
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18681/S-027
Page 7
with shock or other disorders involving reduced perfusion of body tissues. When oxidative activity is intact, one to two hours time
is required for metabolism of lactate.
Water is an essential constituent of all body tissues and accounts for approximately 70% of total body weight. Average normal
adult daily requirement ranges from two to three liters (1 to 1.5 liters each for insensible water loss by perspiration and urine
production).
Water balance is maintained by various regulatory mechanisms. Water distribution depends primarily on the concentration of
electrolytes in the body compartments and sodium (Na+) plays a major role in maintaining physiologic equilibrium.
INDICATIONS AND USAGE
Lactated Ringer’s Irrigation is indicated for all general irrigation, washing and rinsing purposes which permit use of a sterile,
nonpyrogenic electrolyte solution.
CONTRAINDICATIONS
NOT FOR INJECTION BY USUAL PARENTERAL ROUTES.
An electrolyte solution should not be used for irrigation during electrosurgical procedures.
WARNINGS
FOR IRRIGATION ONLY. NOT FOR INJECTION.
Irrigating fluids have been demonstrated to enter the systemic circulation in relatively large volumes; thus this irrigation must be
regarded as a systemic drug. Absorption of large amounts can cause fluid and/or solute overloading resulting in dilution of serum
electrolyte concentrations, overhydration, congested states or pulmonary edema.
The risk of dilutional states is inversely proportional to the electrolyte concentrations of administered parenteral solutions. The
risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte
concentrations of such solutions.
PRECAUTIONS
Do not use for irrigation that may result in absorption into the blood.
Caution should be observed when the solution is used for continuous irrigation or allowed to “dwell” inside body cavities because
of possible absorption into the blood stream and the production of circulatory overload.
Aseptic technique is essential with the use of sterile solutions for irrigation of body cavities, wounds and urethral catheters or for
wetting dressings that come in contact with body tissues.
The flexible container is designed for use with nonvented irrigation sets. When used for irrigation via irrigation equipment, the
administration set should be attached promptly. Unused portions should be discarded and a fresh container of appropriate size
used for the start-up of each cycle or repeat procedure. For repeated irrigations of urethral catheters, a separate container
should be used for each patient.
Reference ID: 3620110
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18681/S-027
Page 8
Do not administer unless solution is clear and container is undamaged. Discard unused portion.
Pregnancy Category C.
Animal reproduction studies have not been conducted with Lactated Ringer’s Irrigation. It is also not known whether it can cause
fetal harm when administered to a pregnant woman or can affect reproduction capacity. It should be given to a pregnant woman
only if clearly needed.
Pediatric Use:
The safety and effectiveness of Lactated Ringer’s Irrigation have not been established. Its limited use in pediatric patients has
been inadequate to fully define proper dosage and limitations for use.
ADVERSE REACTIONS
Possible adverse effects arising from the irrigation of body cavities, tissues, or indwelling catheters and tubes are usually
avoidable when proper procedures are followed. Displaced catheters or drainage tubes can lead to irrigation or infiltration of
unintended structures or cavities. Excessive volume or pressure during irrigation of closed cavities may cause undue distension
or disruption of tissues. Accidental contamination from careless technique may transmit infection.
Should any adverse reaction occur, discontinue the irrigant, evaluate the patient, institute appropriate therapeutic
countermeasures and save the remainder of the fluid for examination if deemed necessary.
OVERDOSAGE
In the event of overhydration or solute overload, re-evaluate the patient and institute appropriate corrective measures. (See
WARNINGS, PRECAUTIONS and ADVERSE REACTIONS.)
DOSAGE AND ADMINISTRATION
The dose is dependent upon the capacity or surface area of the structure to be irrigated and the nature of the procedure. When
used as a vehicle for other drugs, the manufacturer’s recommendations should be followed.
Drug Interactions
Additives may be incompatible. Consult with pharmacist, if available. When introducing additives, use aseptic technique, mix
thoroughly and do not store.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever
solution container permits. (See PRECAUTIONS.)
HOW SUPPLIED
Lactated Ringer's Irrigation is supplied sterile and nonpyrogenic in single-dose 3000 mL flexible irrigation container packaged
4 per case.
NDC
REF
SIZE
0264-7389-60
R8306
3000 mL
Reference ID: 3620110
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18681/S-027
Page 9
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. It is
recommended that the product be stored at room temperature (25°C); however, brief exposure up to 40°C does not adversely
affect the product.
Initiated: August 2013
Directions for Use of Plastic Container
Not for injection.
Aseptic technique is required. usage illustration
•
Inspect irrigation bag: overwrap and primary bag.
•
Do not use if overwrap has been damaged.
•
Do not use unless solution is clear and closure is intact.
1. To open: Tear overwrap starting from the tear notches. (Figure 1) usage illustration
Reference ID: 3620110
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18681/S-027
Page 10
2. Prepare medication port by removal of aluminum foil. (Figure 2a)
• Puncture resealable medication port by using 19 – 22 gauge needle and inject additive(s). (Figure 2b) usage illustration
• Mix solution and medication thoroughly. (Figure 3a)
• Medication port must be swabbed with disinfection agent before re-puncturing.
• Check admixture visually for particulate matter. (Figure 3b) usage illustration
3. Remove aluminum foil from outlet/set port at the bottom of container (Figure 4a) and attach administration set (Figure 4b):
use non-vented infusion set or close air vent on a vented set. Refer to directions for use accompanying the administration
set. usage illustration
Reference ID: 3620110
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 18681/S-027
Page 11
4. Hang bag on IV Pole. (Figure 5) usage illustration
B. Braun Medical Inc.
Irvine, CA 92614-5895 USA
1-800-227-2862
www.bbraun.com
Made in USA
Reference ID: 3620110
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018681s027lbl.pdf', 'application_number': 18681, 'submission_type': 'SUPPL ', 'submission_number': 27}
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TRIMETHOPRIM TABLETS, USP
2158
Rx only
To reduce the development of drug-resistant bacteria and maintain the effectiveness of trimethoprim
tablets, USP and other antibacterial drugs, trimethoprim tablets, USP should be used only to treat or
prevent infections that are proven or strongly suspected to be caused by bacteria.
DESCRIPTION
Trimethoprim is a synthetic antibacterial available in tablet form for oral administration. Each scored
white tablet contains 100 mg trimethoprim.
Trimethoprim is 5-[(3,4,5-trimethoxyphenyl)methyl]-2,4-pyrimidinediamine. It is a white to light yellow,
odorless, bitter compound with a molecular weight of 290.32 and the molecular formula C14H18N4O3. The
structural formula is: structural formula
Inactive Ingredients
Colloidal silicon dioxide, dibasic calcium phosphate dihydrate, magnesium stearate, microcrystalline
cellulose, pregelatinized starch, and sodium starch glycolate.
CLINICAL PHARMACOLOGY
Trimethoprim is rapidly absorbed following oral administration. It exists in the blood as unbound,
protein-bound, and metabolized forms. Ten to twenty percent of trimethoprim is metabolized, primarily in
the liver; the remainder is excreted unchanged in the urine. The principal metabolites of trimethoprim are
the 1- and 3-oxides and the 3'- and 4'-hydroxy derivatives. The free form is considered to be the
therapeutically active form. Approximately 44% of trimethoprim is bound to plasma proteins.
Mean peak serum concentrations of approximately 1.0 mcg/mL occur 1 to 4 hours after oral
administration of a single 100 mg dose. A single 200 mg dose will result in serum levels approximately
twice as high. The half-life of trimethoprim ranges from 8 to 10 hours. However, patients with severely
impaired renal function exhibit an increase in the half-life of trimethoprim, which requires either dosage
regimen adjustment or not using the drug in such patients (see DOSAGE AND ADMINISTRATION).
During a 13 week study of trimethoprim administered at a daily dosage of 200 mg (50 mg q.i.d.), the
mean minimum steady-state concentration of the drug was 1.1 mcg/mL.
Reference ID: 3945144
Steady-state concentrations were achieved within 2 to 3 days of chronic administration and were
maintained throughout the experimental period.
Excretion of trimethoprim is primarily by the kidneys through glomerular filtration and tubular secretion.
Urine concentrations of trimethoprim are considerably higher than are the concentrations in the blood.
After a single oral dose of 100 mg, urine concentrations of trimethoprim ranged from 30 to 160 mcg/mL
during the 0 to 4 hour period and declined to approximately 18 to 91 mcg/mL during the 8 to 24 hour
period. A 200 mg single oral dose will result in trimethoprim urine levels approximately twice as high.
After oral administration, 50% to 60% of trimethoprim is excreted in the urine within 24 hours,
approximately 80% of this being unmetabolized trimethoprim.
Since normal vaginal and fecal flora are the source of most pathogens causing urinary tract infections, it is
relevant to consider the distribution of trimethoprim into these sites. Concentrations of trimethoprim in
vaginal secretions are consistently greater than those found simultaneously in the serum, being typically
1.6 times the concentrations of simultaneously obtained serum samples. Sufficient trimethoprim is
excreted in the feces to markedly reduce or eliminate trimethoprim-susceptible organisms from the fecal
flora.
Trimethoprim also passes the placental barrier and is excreted in human milk.
Microbiology
Mechanism of Action
Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and
reversibly inhibiting the required enzyme, dihydrofolate reductase. This binding is very much stronger for
the bacterial enzyme than for the corresponding mammalian enzyme. Thus, trimethoprim selectively
interferes with bacterial biosynthesis of nucleic acids and proteins.
Resistance
Resistance to trimethoprim may be conferred by a variety of mechanisms including cell wall
impermeability, overproduction of the chromosomal dihydrofolate reductase (DHFR) enzyme, production
of a resistant chromosomal DHFR enzyme or production of a plasmid-mediated trimethoprim-resistant
DHFR enzyme. Acinetobacter baumannii/Acinetobacter calcoaceticus complex, Burkholderia cepacia
complex, Pseudomonas aeruginosa, Stenotrophomonas maltophilia are intrinsically resistant to
trimethoprim. Non-Enterobacteriaceae fecal organisms, Bacteroides spp. and Lactobacillus spp. are not
susceptible to trimethoprim at the concentrations obtained with the recommended dosage. Enterococcus
spp, (E. faecalis, E. faecium, E. gallinarum/E. casseliflavus) may appear active in vitro to trimethoprim
but are not effective clinically and should not be reported as susceptible. Moraxella catarrhalis isolates
were found consistently resistant to trimethoprim.
Antimicrobial Activity
Trimethoprim has been shown to be active against most strains of the following microorganisms, both in
vitro and in clinical infections as described in the INDICATIONS AND USAGE section.
Reference ID: 3945144
Aerobic gram-positive bacteria
Staphylococcus species (coagulase-negative strains, including S. saprophyticus)
Aerobic gram-negative bacteria
Enterobacter species
Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis
Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide cumulative reports of in vitro
susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician
as periodic reports that describe the susceptibility profile of nosocomial and community-acquired
pathogens. These reports should aid the physician in selecting an antibacterial drug for treatment.
Dilution techniques
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MIC’s).
These MIC’s provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC’s
should be determined using a standardized procedure (broth and/or agar)1,7. The MIC values should be
interpreted according to the criteria provided in Table 1.
Diffusion techniques
Quantitative methods that require measurement of zone diameters can also provide reproducible estimates
of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a
standardized test method.2,7 This procedure uses paper disks impregnated with 5 mcg trimethoprim to test
the susceptibility of bacteria to trimethoprim. The disc diffusion breakpoints are provided in Table 1.
Table 1. Susceptibility Test Interpretive Criteria for Trimethoprim
Pathogen
Minimum
Inhibitory Concentrations
(mcg/mL)
Zone Diameters
(mm)
S
I
R
S
I
R
Enterobacteriaceae
≤ 8
-
≥ 16
≥ 16
11-15
≤ 10
Coagulase negative
staphylococci
(including S. saprophyticus)
≤ 8
-
≥ 16
≥ 16
11-15
≤ 10
A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen
if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of
Intermediate (I) indicates that the result should be considered equivocal, and, if the microorganism is not
Reference ID: 3945144
fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies
possible clinical applicability in body sites where the drug is physiologically concentrated or in situations
where a high dosage of the drug can be used. This category also provides a buffer zone that prevents
small uncontrolled technical factors from causing major discrepancies in interpretation. A report of
Resistant (R) indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the
antimicrobial drug reaches the concentration usually achievable at the infection site; other therapy should
be selected.
Quality Control
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure
the accuracy and precision of supplies and reagents used in the assay, and the techniques of the
individuals performing the test1,2,7. Standard trimethoprim powder should provide the following range of
MIC values noted in Table 2. For the diffusion technique using the 5 mcg disk, the criteria in Table 2
should be achieved.
Table 2: Quality Control Parameters for Trimethoprim
QC Strain
Minimum
Inhibitory Concentrations
(mcg/mL)
Zone Diameters
(mm)
Enterococcus faecalis ATCC
29212
0.12 - 0.5
--
Escherichia coli ATCC 25922
0.5 - 2
21 - 28
Haemophilus influenzae ATCC
49247
0.06 - 0.5
27 - 33
Staphylococcus aureus ATCC
29213
1 - 4
--
Staphylococcus aureus ATCC
25923
--
19 - 26
Streptococcus pneumoniae
ATCC 49619
1 - 4
--
Pseudomonas aeruginosa ATCC
27853
> 64
--
INDICATIONS AND USAGE
To reduce the development of drug-resistant bacteria and maintain the effectiveness of trimethoprim
tablets, USP and other antibacterial drugs, trimethoprim tablets, USP should be used only to treat or
prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When
culture and susceptibility information are available, they should be considered in selecting or modifying
Reference ID: 3945144
antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may
contribute to the empiric selection of therapy.
For the treatment of initial episodes of uncomplicated urinary tract infections due to susceptible strains of
the following organisms: Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Enterobacter
species, and coagulase-negative Staphylococcus species, including S. saprophyticus.
Cultures and susceptibility tests should be performed to determine the susceptibility of the bacteria to
trimethoprim. Therapy may be initiated prior to obtaining the results of these tests.
CONTRAINDICATIONS
Trimethoprim is contraindicated in individuals hypersensitive to trimethoprim and in those with
documented megaloblastic anemia due to folate deficiency.
WARNINGS
Serious hypersensitivity reactions have been reported rarely in patients on trimethoprim therapy.
Trimethoprim has been reported rarely to interfere with hematopoiesis, especially when administered in
large doses and/or for prolonged periods.
The presence of clinical signs such as sore throat, fever, pallor, or purpura may be early indications of
serious blood disorders (see OVERDOSAGE, Chronic).
Complete blood counts should be obtained if any of these signs are noted in a patient receiving
trimethoprim and the drug discontinued if a significant reduction in the count of any formed blood
element is found.
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial
agents, including trimethoprim tablets, USP, and may range in severity from mild diarrhea to fatal colitis.
Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C.
difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin
producing strains of C. difficile cause increased morbidity and mortality, as these infections can be
refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients
who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has
been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antiobiotic use not directed against C. difficile may need to
be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic
treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Reference ID: 3945144
PRECAUTIONS
General
Prescribing trimethoprim tablets, USP in the absence of a proven or strongly suspected bacterial infection
or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.
Trimethoprim should be given with caution to patients with possible folate deficiency. Folates may be
administered concomitantly without interfering with the antibacterial action of trimethoprim.
Trimethoprim should also be given with caution to patients with impaired renal or hepatic function (see
CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Information for Patients
Patients should be counseled that antibacterial drugs including trimethoprim tablets, USP should only be
used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When
trimethoprim tablets, USP are prescribed to treat a bacterial infection, patients should be told that
although it is common to feel better early in the course of therapy, the medication should be taken exactly
as directed. Skipping doses or not completing the full course of therapy may (1) decrease the
effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop
resistance and will not be treatable by trimethoprim tablets, USP or other antibacterial drugs in the future.
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is
discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody
stools (with and without stomach cramps and fever) even as late as two or more months after having taken
the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
Drug Interactions
Trimethoprim may inhibit the hepatic metabolism of phenytoin. Trimethoprim, given at a common
clinical dosage, increased the phenytoin half-life by 51% and decreased the phenytoin metabolic
clearance rate by 30%. When administering these drugs concurrently, one should be alert for possible
excessive phenytoin effect.
Drug/Laboratory Test Interactions
Trimethoprim can interfere with a serum methotrexate assay as determined by the Competitive Binding
Protein Technique (CBPA) when a bacterial dihydrofolate reductase is used as the binding protein. No
interference occurs, however, if methotrexate is measured by a radioimmunoassay (RIA).
The presence of trimethoprim may also interfere with the Jaffé alkaline picrate reaction assay for
creatinine, resulting in overestimations of about 10% in the range of normal values.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Long-term studies in animals to evaluate carcinogenic potential have not been conducted with
trimethoprim.
Reference ID: 3945144
Mutagenesis
Trimethoprim was demonstrated to be nonmutagenic in the Ames assay. In studies at two laboratories, no
chromosomal damage was detected in cultured Chinese hamster ovary cells at concentrations
approximately 500 times human plasma levels; at concentrations approximately 1000 times human
plasma levels in these same cells, a low level of chromosomal damage was induced at one of the
laboratories. No chromosomal abnormalities were observed in cultured human leukocytes at
concentrations of trimethoprim up to 20 times human steady-state plasma levels. No chromosomal effects
were detected in peripheral lymphocytes of human subjects receiving 320 mg of trimethoprim in
combination with up to 1600 mg of sulfamethoxazole per day for as long as 112 weeks.
Impairment of Fertility
No adverse effects on fertility or general reproductive performance were observed in rats given
trimethoprim in oral dosages as high as 70 mg/kg/day for males and 14 mg/kg/day for females.
Pregnancy
Teratogenic Effects
Pregnancy category C
Trimethoprim has been shown to be teratogenic in the rat when given in doses 40 times the human dose.
In some rabbit studies, the overall increase in fetal loss (dead and resorbed and malformed conceptuses)
was associated with doses six times the human therapeutic dose.
While there are no large, well-controlled studies on the use of trimethoprim in pregnant women, Brumfitt
and Pursell,3 in a retrospective study, reported the outcome of 186 pregnancies during which the mother
received either placebo or trimethoprim in combination with sulfamethoxazole. The incidence of
congenital abnormalities was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) in those
receiving trimethoprim and sulfamethoxazole. There were no abnormalities in the 10 children whose
mothers received the drug during the first trimester. In a separate survey, Brumfitt and Pursell also found
no congenital abnormalities in 35 children whose mothers had received trimethoprim and
sulfamethoxazole at the time of conception or shortly thereafter.
Because trimethoprim may interfere with folic acid metabolism, trimethoprim should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects
The oral administration of trimethoprim to rats at a dose of 70 mg/kg/day commencing with the last third
of gestation and continuing through parturition and lactation caused no deleterious effects on gestation or
pup growth and survival.
Nursing Mothers
Trimethoprim is excreted in human milk. Because trimethoprim may interfere with folic acid metabolism,
caution should be exercised when trimethoprim is administered to a nursing woman.
Reference ID: 3945144
Pediatric Use
Safety and effectiveness in pediatric patients below the age of 2 months have not been established. The
effectiveness of trimethoprim as a single agent has not been established in pediatric patients under 12
years of age.
Geriatric Use
Clinical studies of trimethoprim tablets did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other reported clinical experience4,5
has not identified differences in response between the elderly and younger patients. In general, dose
selection for an elderly patient should be cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant
disease or other drug therapy.
Case reports of hyperkalemia in elderly patients receiving trimethoprim-sulfamethoxazole have been
published.6 Trimethoprim is known to be substantially excreted by the kidney, and the risk of toxic
reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose selection, and it may be useful
to monitor potassium concentrations and to monitor renal function by calculating creatinine clearance.
ADVERSE REACTIONS
The adverse effects encountered most often with trimethoprim were rash and pruritus.
Dermatologic
Rash, pruritus, and phototoxic skin eruptions. At the recommended dosage regimens of 100 mg b.i.d. or
200 mg q.d., each for 10 days, the incidence of rash is 2.9% to 6.7%. In clinical studies which employed
high doses of trimethoprim, an elevated incidence of rash was noted. These rashes were maculopapular,
morbilliform, pruritic, and generally mild to moderate, appearing 7 to 14 days after the initiation of
therapy.
Hypersensitivity
Rare reports of exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal
necrolysis (Lyell Syndrome), and anaphylaxis have been received.
Gastrointestinal
Epigastric distress, nausea, vomiting, and glossitis. Elevation of serum transaminase and bilirubin has
been noted, but the significance of this finding is unknown. Cholestatic jaundice has been rarely reported.
Hematologic
Thrombocytopenia, leukopenia, neutropenia, megaloblastic anemia, and methemoglobinemia.
Metabolic
Hyperkalemia, hyponatremia.
Reference ID: 3945144
Neurologic
Aseptic meningitis has been rarely reported.
Miscellaneous
Fever, and increases in BUN and serum creatinine levels.
OVERDOSAGE
Acute
Signs of acute overdosage with trimethoprim may appear following ingestion of 1 gram or more of the
drug and include nausea, vomiting, dizziness, headaches, mental depression, confusion, and bone marrow
depression (see Chronic subsection).
Treatment consists of gastric lavage and general supportive measures. Acidification of the urine will
increase renal elimination of trimethoprim. Peritoneal dialysis is not effective and hemodialysis is only
moderately effective in eliminating the drug.
Chronic
Use of trimethoprim at high doses and/or for extended periods of time may cause bone marrow depression
manifested as thrombocytopenia, leukopenia, and/or megaloblastic anemia. If signs of bone marrow
depression occur, trimethoprim should be discontinued and the patient should be given leucovorin; 5 to
15 mg leucovorin daily has been recommended by some investigators.
DOSAGE AND ADMINISTRATION
The usual oral adult dosage is 100 mg of trimethoprim every 12 hours or 200 mg of trimethoprim every
24 hours, each for 10 days. The use of trimethoprim in patients with a creatinine clearance of less than 15
mL/min is not recommended. For patients with a creatinine clearance of 15 to 30 mL/min, the dose
should be 50 mg every 12 hours.
HOW SUPPLIED
Trimethoprim tablets, USP, 100 mg: White, round, convex tablet, debossed “9”, scored, “3” on one side
and debossed “2158” on the other, in bottles of 100.
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Dispense in a tight, light-resistant container as defined in the USP with a child-resistant closure (as
required).
REFERENCES
1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial
Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard-Tenth Edition. CLSI
document M07-A10 [2015], Clinical and Laboratory Standards Institute, 950 West Valley Road,
Suite 2500, Wayne, Pennsylvania 19087, USA.
Reference ID: 3945144
2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial
Disk Diffusion Susceptibility Tests; Approved Standard-Twelfth Edition. CLSI document M02
A12 [2015], Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500,
Wayne, Pennsylvania 19087, USA.
3. Brumfitt W, Pursell R. Trimethoprim-sulfamethoxazole in the treatment of bacteriuria in women.
J Infect Dis. 1973;128(suppl): S657-S663.
4. Lacey RW, Simpson MHC, Fawcett C, et al. Comparison of single-dose trimethoprim with a five-
day course for the treatment of urinary tract infections in the elderly. Age and Ageing 10: 179
185, 1981.
5. Ewer TC, Bailey RR, Gilchrist NL, et al. Comparative study of norfloxacin and trimethoprim for
the treatment of elderly patients with urinary tract infection. NZ Med J 101: 537-539, 1988.
6. Marinella MA. Trimethoprim-induced hyperkalemia: An analysis of reported cases. Gerontology
45: 209-212, 1999.
7. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial
Susceptibility Testing; Twenty-sixth Informational Supplement, CLSI document M100-S26
[2016], Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne,
Pennsylvania 19087, USA.
Manufactured In Canada By:
TEVA CANADA LIMITED
Toronto, Canada M1B 2K9
Manufactured For:
TEVA PHARMACEUTICALS USA
Sellersville, PA 18960
Rev. J 4/2016
Reference ID: 3945144
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/018679s044lbl.pdf', 'application_number': 18679, 'submission_type': 'SUPPL ', 'submission_number': 44}
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Maternal hypotension has resulted from regional
anesthesia. Local anesthetics produce vasodilation by
blocking sympathetic nerves. Elevating the patient’s legs
and positioning her on her left side will help prevent
decreases in blood pressure. The fetal heart rate also
should be monitored continuously and electronic fetal
monitoring is highly advisable.
It is extremely important to avoid aortocaval
compression by the gravid uterus during administrations
of regional block to parturients. To do this, the patient
must be maintained in the left lateral decubitus position
or a blanket roll or sandbag may be placed beneath the
right hip and the gravid uterus displaced to the left.
Spinal anesthesia may alter the forces of parturition
through changes in uterine contractility or maternal
expulsive efforts. Spinal anesthesia has also been
reported to prolong the second stage of labor by
removing the parturient’s reflex urge to bear down or by
interfering with motor function. The use of obstetrical
anesthesia may increase the need for forceps
assistance.
The use of some local anesthetic drug products
during labor and delivery may be followed by diminished
muscle strength and tone for the first day or two of life.
This has not been reported with bupivacaine.
There have been reports of cardiac arrest during use
of MARCAINE 0.75% solution for epidural anesthesia in
obstetrical patients. The package insert for MARCAINE
hydrochloride for epidural, nerve block, etc., has a more
complete
discussion
of
preparation for,
and
management of, this problem. These cases are
compatible with systemic toxicity following unintended
intravascular injection of the much larger doses
recommended for epidural anesthesia and have not
occurred within the dose range of bupivacaine
hydrochloride
0.75%
recommended
for
spinal
anesthesia in obstetrics. The 0.75% concentration of
MARCAINE is therefore not recommended for
obstetrical epidural anesthesia. MARCAINE Spinal
(bupivacaine hydrochloride in dextrose injection) is
recommended for spinal anesthesia in obstetrics.
Nursing Mothers: Bupivacaine has been reported to be
excreted in human milk suggesting that the nursing
infant could be theoretically exposed to a dose of the
drug. Because of the potential for serious adverse
reactions in nursing infants from bupivacaine, a decision
should be made whether to discontinue nursing or not
administer bupivacaine, taking into account the
importance of the drug to the mother.
Pediatric Use: Until further experience is gained
in patients younger than 18 years, administration of
MARCAINE Spinal in this age group is not
recommended.
Geriatric Use: Patients over 65 years, particularly those
with hypertension, may be at increased risk for
developing hypotension while undergoing spinal
anesthesia
with
MARCAINE
Spinal.
(See
PRECAUTIONS, General and ADVERSE REACTIONS,
Cardiovascular System.)
Elderly patients may require lower doses of
MARCAINE Spinal. (See PRECAUTIONS, General and
DOSAGE AND ADMINISTRATION.)
In
clinical
studies,
differences
in
various
pharmacokinetic parameters have been observed
between elderly and younger patients. (See CLINICAL
PHARMACOLOGY, Pharmacokinetics.)
This product is known to be substantially excreted by
the kidney, and the risk of toxic reactions to this drug
may be greater in patients with impaired renal function.
Because elderly patients are more likely to have
decreased renal function, care should be taken in dose
selection, and it may be useful to monitor renal function.
(See CLINICAL PHARMACOLOGY, Pharmacokinetics.)
ADVERSE REACTIONS
Reactions to bupivacaine are characteristic of those
associated with other amide-type local anesthetics.
The
most
commonly
encountered
acute
adverse experiences which demand immediate
countermeasures following the administration of spinal
anesthesia are hypotension due to loss of sympathetic
tone and respiratory paralysis or underventilation due to
cephalad extension of the motor level of anesthesia.
These may lead to cardiac arrest if untreated. In
addition, dose-related convulsions and cardiovascular
collapse may result from diminished tolerance, rapid
absorption from the injection site, or from unintentional
intravascular injection of a local anesthetic solution.
Factors influencing plasma protein binding, such as
acidosis, systemic diseases which alter protein
production, or competition of other drugs for protein
binding sites, may diminish individual tolerance.
Respiratory System: Respiratory paralysis or
underventilation may be noted as a result of upward
extension of the level of spinal anesthesia and may lead
to secondary hypoxic cardiac arrest if untreated.
Preanesthetic medication, intraoperative analgesics
and sedatives, as well as surgical manipulation, may
contribute to underventilation. This will usually be noted
within minutes of the injection of spinal anesthetic
solution, but because of differing maximal onset times,
differing intercurrent drug usage and differing surgical
manipulation, it may occur at any time during surgery or
the immediate recovery period.
Cardiovascular System: Hypotension due to loss of
sympathetic tone is a commonly encountered extension
of the clinical pharmacology of spinal anesthesia. This is
more commonly observed in elderly patients,
particularly those with hypertension, and patients with
shrunken blood volume, shrunken interstitial fluid
volume, cephalad spread of the local anesthetic, and/or
mechanical obstruction of venous return. Nausea and
vomiting are frequently associated with hypotensive
episodes following the administration of spinal
anesthesia. High doses, or inadvertent intravascular
injection, may lead to high plasma levels and related
depression of the myocardium, decreased cardiac
output,
bradycardia,
heart
block,
ventricular
arrhythmias, and, possibly, cardiac arrest. (See
WARNINGS,
PRECAUTIONS,
and
OVERDOSAGE
sections.)
Central Nervous System: Respiratory paralysis or
underventilation secondary to cephalad spread of the
level of spinal anesthesia (see Respiratory System) and
hypotension for the same reason (see Cardiovascular
System) are the two most commonly encountered
central nervous system-related adverse observations
which demand immediate countermeasures.
High doses or inadvertent intravascular injection may
lead to high plasma levels and related central nervous
system toxicity characterized by excitement and/or
depression. Restlessness, anxiety, dizziness, tinnitus,
blurred vision, or tremors may occur, possibly
proceeding to convulsions. However, excitement may be
transient or absent, with depression being the first
manifestation of an adverse reaction. This may quickly
be
followed
by
drowsiness
merging
into
unconsciousness and respiratory arrest.
Neurologic: The incidences of adverse neurologic
reactions associated with the use of local anesthetics
may be related to the total dose of local anesthetic
administered and are also dependent upon the
particular drug used, the route of administration, and the
physical status of the patient. Many of these effects may
be related to local anesthetic techniques, with or
without a contribution from the drug.
Neurologic effects following spinal anesthesia may
include loss of perineal sensation and sexual function;
persistent anesthesia, paresthesia, weakness and
paralysis of the lower extremities, and loss of sphincter
control all of which may have slow, incomplete, or no
recovery; hypotension, high or total spinal block; urinary
retention; headache; backache; septic meningitis,
meningismus; arachnoiditis; slowing of labor; increased
incidence of forceps delivery; shivering; cranial nerve
palsies due to traction on nerves from loss of
cerebrospinal fluid; and fecal and urinary incontinence.
Allergic: Allergic-type reactions are rare and may
occur as a result of sensitivity to the local anesthetic.
These reactions are characterized by signs such as
urticaria, pruritus, erythema, angioneurotic edema
(including laryngeal edema), tachycardia, sneezing,
nausea, vomiting, dizziness, syncope, excessive
sweating, elevated temperature, and, possibly,
anaphylactoid-like symptomatology (including severe
hypotension). Cross sensitivity among members of the
amide-type local anesthetic group has been reported.
The usefulness of screening for sensitivity has not been
definitely established.
Other: Nausea and vomiting may occur during spinal
anesthesia.
OVERDOSAGE
Acute emergencies from local anesthetics are generally
related to high plasma levels encountered during
therapeutic use or to underventilation (and perhaps
apnea) secondary to upward extension of spinal
anesthesia. Hypotension is commonly encountered
during the conduct of spinal anesthesia due to
relaxation of sympathetic tone, and sometimes,
contributory mechanical obstruction of venous return.
Management of Local Anesthetic Emergencies: The first
consideration is prevention, best accomplished by
careful and constant monitoring of cardiovascular and
respiratory vital signs and the patient’s state of
consciousness after each local anesthetic injection. At
the first sign of change, oxygen should be administered.
The first step in the management of systemic toxic
reactions, as well as underventilation or apnea due to a
high or total spinal, consists of immediate attention to
the establishment and maintenance of a patent airway
and effective assisted or controlled ventilation with
100% oxygen with a delivery system capable of
permitting immediate positive airway pressure by mask.
This may prevent convulsions if they have not already
occurred.
If necessary, use drugs to control the convulsions.
A 50 mg to 100 mg bolus IV injection of succinylcholine
will paralyze the patient without depressing the central
nervous or cardiovascular systems and facilitate
ventilation. A bolus IV dose of 5 mg to 10 mg of diazepam
or 50 mg to 100 mg of thiopental will permit ventilation
and counteract central nervous system stimulation, but
these drugs also depress central nervous system,
respiratory and cardiac function, add to postictal
depression and may result in apnea. Intravenous
barbiturates, anticonvulsant agents, or muscle relaxants
should only be administered by those familiar with their
use. Immediately after the institution of these ventilatory
measures, the adequacy of the circulation should be
evaluated.
Supportive
treatment
of
circulatory
depression may require administration of intravenous
fluids, and, when appropriate, a vasopressor dictated by
the clinical situation (such as ephedrine or epinephrine
to enhance myocardial contractile force).
Hypotension due to sympathetic relaxation may be
managed by giving intravenous fluids (such as isotonic
saline or lactated Ringer’s solution), in an attempt to
relieve mechanical obstruction of venous return, or by
using vasopressors (such as ephedrine which increases
the force of myocardial contractions) and, if indicated,
by giving plasma expanders or whole blood.
Endotracheal intubation, employing drugs and
techniques familiar to the clinician, may be indicated
after initial administration of oxygen by mask if difficulty
is encountered in the maintenance of a patent airway,
or if prolonged ventilatory support (assisted or
controlled) is indicated.
Recent clinical data from patients experiencing local
anesthetic-induced convulsions demonstrated rapid
development of hypoxia, hypercarbia, and acidosis with
bupivacaine within a minute of the onset of convulsions.
These observations suggest that oxygen consumption
and carbon dioxide production are greatly increased
during local anesthetic convulsions and emphasize the
importance of immediate and effective ventilation with
oxygen which may avoid cardiac arrest.
If not treated immediately, convulsions with
simultaneous hypoxia, hypercarbia, and acidosis plus
myocardial depression from the direct effects of the
local anesthetic may result in cardiac arrhythmias,
bradycardia, asystole, ventricular fibrillation, or cardiac
arrest. Respiratory abnormalities, including apnea, may
occur. Underventilation or apnea due to a high or total
spinal may produce these same signs and also lead to
cardiac arrest if ventilatory support is not instituted. If
cardiac arrest should occur, standard cardiopulmonary
resuscitative measures should be instituted and
maintained for a prolonged period if necessary.
Recovery has been reported after prolonged
resuscitative efforts.
The supine position is dangerous in pregnant women
at term because of aortocaval compression by the
gravid uterus. Therefore during treatment of systemic
toxicity, maternal hypotension, or fetal bradycardia
following regional block, the parturient should be
maintained in the left lateral decubitus position if
possible, or manual displacement of the uterus off the
great vessels be accomplished.
The mean seizure dosage of bupivacaine in rhesus
monkeys was found to be 4.4 mg/kg with mean arterial
plasma concentration of 4.5 mcg/mL. The intravenous
and subcutaneous LD50 in mice is 6 mg/kg to 8 mg/kg and
38 mg/kg to 54 mg/kg respectively.
DOSAGE AND ADMINISTRATION
The dose of any local anesthetic administered varies
with the anesthetic procedure, the area to be
anesthetized, the vascularity of the tissues, the number
of neuronal segments to be blocked, the depth of
anesthesia and degree of muscle relaxation required,
the duration of anesthesia desired, individual tolerance,
and the physical condition of the patient. The smallest
dose and concentration required to produce the desired
result should be administered. Dosages of MARCAINE
Spinal should be reduced for elderly and debilitated
patients and patients with cardiac and/or liver disease.
For specific techniques and procedures, refer to
standard textbooks.
There have been adverse event reports of
chondrolysis in patients receiving intra-articular
infusions of local anesthetics following arthroscopic and
other surgical procedures. MARCAINE Spinal is not
approved for this use (see WARNINGS and DOSAGE
AND ADMINISTRATION).
The extent and degree of spinal anesthesia depend
upon several factors including dosage, specific gravity
of the anesthetic solution, volume of solution used, force
of injection, level of puncture, and position of the patient
during and immediately after injection.
Seven and one-half mg (7.5 mg or 1 mL) MARCAINE
Spinal has generally proven satisfactory for spinal
anesthesia for lower extremity and perineal procedures
including TURP and vaginal hysterectomy. Twelve mg
(12 mg or 1.6 mL) has been used for lower abdominal
procedures such as abdominal hysterectomy, tubal
ligation, and appendectomy. These doses are
recommended as a guide for use in the average adult
and may be reduced for the elderly or debilitated
patients. Because experience with MARCAINE Spinal is
limited in patients below the age of 18 years, dosage
recommendations in this age group cannot be made.
Obstetrical Use: Doses as low as 6 mg bupivacaine
hydrochloride have been used for vaginal delivery under
spinal anesthesia. The dose range of 7.5 mg to 10.5 mg
(1 mL to 1.4 mL) bupivacaine hydrochloride has been
used for Cesarean section under spinal anesthesia.
In recommended doses, MARCAINE Spinal produces
complete motor and sensory block.
Unused portions of solutions should be discarded
following initial use.
MARCAINE Spinal should be inspected visually for
discoloration
and
particulate
matter
prior
to
administration; solutions which are discolored or which
contain particulate matter should not be administered.
HOW SUPPLIED
Single-dose ampuls of 2 mL (15 mg bupivacaine
hydrochloride with 165 mg dextrose), is supplied as
follows:
NDC No.
Container
Fill
Quantity
0409-1761-02 Uni-Amp™
2 mL
package of 10
0409-1761-62 Uni-Amp™
2 mL
bulk package of 800
Store at 20 to 25°C (68 to 77°F). [See USP Controlled
Room Temperature.]
MARCAINE Spinal solution may be autoclaved once at
15 pound pressure, 121°C (250°F) for 15 minutes. Do not
administer any solution which is discolored or contains
particulate matter.
Revised: November, 2009
Printed in USA
Hospira, Inc., Lake Forest, IL 60045 USA
EN-2313
Marcaine™
Spinal
bupivacaine hydrochloride in dextrose injection, USP
STERILE HYPERBARIC SOLUTION
FOR SPINAL ANESTHESIA
Rx only
DESCRIPTION
Bupivacaine hydrochloride is 2-Piperidinecarboxamide,
1-butyl-N-(2,6-dimethylphenyl)-, monohydrochloride,
monohydrate, a white crystalline powder that is freely
soluble in 95 percent ethanol, soluble in water, and
slightly soluble in chloroform or acetone. It has the
following structural formula:
Dextrose is D-glucopyranose monohydrate and has
the following structural formula:
MARCAINE™ Spinal is available in sterile hyperbaric
solution for subarachnoid injection (spinal block).
Bupivacaine hydrochloride is related chemically and
pharmacologically to the aminoacyl local anesthetics. It
is a homologue of mepivacaine and is chemically related
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Approved for FDA Submission
L Kindwald 12-02-09
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Document Name: QEN-2313v3.qxp
to lidocaine. All three of these anesthetics contain an
amide linkage between the aromatic nucleus and the
amino or piperidine group. They differ in this respect
from the procaine-type local anesthetics, which have an
ester linkage.
Each mL of MARCAINE Spinal contains 7.5 mg
bupivacaine hydrochloride (anhydrous) and 82.5 mg
dextrose (anhydrous). The pH of this solution is adjusted
to between 4.0 and 6.5 with sodium hydroxide or
hydrochloric acid.
The specific gravity of MARCAINE Spinal is between
1.030 and 1.035 at 25°C and 1.03 at 37°C.
MARCAINE
Spinal
does
not
contain
any
preservatives.
CLINICAL PHARMACOLOGY
Local anesthetics block the generation and the
conduction of nerve impulses, presumably by increasing
the threshold for electrical excitation in the nerve, by
slowing the propagation of the nerve impulse, and by
reducing the rate of rise of the action potential. In
general, the progression of anesthesia is related to the
diameter, myelination, and conduction velocity of
affected nerve fibers. Clinically, the order of loss of
nerve function is as follows: (1) pain, (2) temperature,
(3) touch, (4) proprioception, and (5) skeletal muscle
tone.
Systemic absorption of local anesthetics produces
effects on the cardiovascular and central nervous
systems (CNS). At blood concentrations achieved with
normal therapeutic doses, changes in cardiac
conduction, excitability, refractoriness, contractility, and
peripheral vascular resistance are minimal. However,
toxic blood concentrations depress cardiac conduction
and excitability, which may lead to atrioventricular
block, ventricular arrhythmias, and cardiac arrest,
sometimes resulting in fatalities. In addition, myocardial
contractility is depressed and peripheral vasodilation
occurs, leading to decreased cardiac output and arterial
blood pressure. Recent clinical reports and animal
research suggest that these cardiovascular changes
are more likely to occur after unintended direct
intravascular injection of bupivacaine. Therefore, when
epidural anesthesia with bupivacaine is considered,
incremental dosing is necessary.
Following systemic absorption, local anesthetics can
produce central nervous system stimulation, depression,
or both. Apparent central stimulation is manifested as
restlessness, tremors and shivering, progressing to
convulsions, followed by depression and coma
progressing ultimately to respiratory arrest. However,
the local anesthetics have a primary depressant effect
on the medulla and on higher centers. The depressed
stage may occur without a prior excited stage.
Pharmacokinetics: The rate of systemic absorption of
local anesthetics is dependent upon the total dose and
concentration of drug administered, the route of
administration, the vascularity of the administration site,
and the presence or absence of epinephrine in
the anesthetic solution. A dilute concentration of
epinephrine (1:200,000 or 5 mcg/mL) usually reduces the
rate of absorption and peak plasma concentration of
MARCAINE, permitting the use of moderately larger total
doses and sometimes prolonging the duration of action.
The onset of action with MARCAINE is rapid and
anesthesia is long lasting. The duration of anesthesia is
significantly longer with MARCAINE than with any other
commonly used local anesthetic. It has also been noted
that there is a period of analgesia that persists after the
return of sensation, during which time the need for
strong analgesics is reduced.
The onset of sensory blockade following spinal block
with MARCAINE Spinal is very rapid (within one minute);
maximum motor blockade and maximum dermatome
level are achieved within 15 minutes in most cases.
Duration of sensory blockade (time to return of
complete sensation in the operative site or regression
of two dermatomes) following a 12 mg dose averages
2 hours with or without 0.2 mg epinephrine. The time to
return of complete motor ability with 12 mg MARCAINE
Spinal averages 3 1/2 hours without the addition of
epinephrine and 4 1/2 hours if 0.2 mg epinephrine is
added. When compared to equal milligram doses of
hyperbaric tetracaine, the duration of sensory blockade
was the same but the time to complete motor recovery
was significantly longer for tetracaine. Addition of
0.2 mg epinephrine significantly prolongs the motor
blockade and time to first postoperative narcotic with
MARCAINE Spinal.
Local anesthetics appear to cross the placenta by
passive diffusion. The rate and degree of diffusion is
governed by (1) the degree of plasma protein binding,
(2) the degree of ionization, and (3) the degree of lipid
solubility. Fetal/maternal ratios of local anesthetics
appear to be inversely related to the degree of plasma
protein binding, because only the free, unbound drug is
available for placental transfer. MARCAINE with a high
protein binding capacity (95%) has a low fetal/maternal
ratio (0.2 to 0.4). The extent of placental transfer is also
determined by the degree of ionization and lipid solubility
of the drug. Lipid soluble, nonionized drugs readily enter
the fetal blood from the maternal circulation.
Depending upon the route of administration, local
anesthetics are distributed to some extent to all body
tissues, with high concentrations found in highly
perfused organs such as the liver, lungs, heart, and
brain.
Pharmacokinetic studies on the plasma profiles of
MARCAINE after direct intravenous injection suggest a
three-compartment open model. The first compartment
is represented by the rapid intravascular distribution of
the drug. The second compartment represents the
equilibration of the drug throughout the highly perfused
organs such as the brain, myocardium, lungs, kidneys,
and liver. The third compartment represents an
equilibration of the drug with poorly perfused tissues,
such as muscle and fat. The elimination of drug from
tissue distribution depends largely upon the ability of
binding sites in the circulation to carry it to the liver
where it is metabolized.
Various pharmacokinetic parameters of the local
anesthetics can be significantly altered by the presence
of hepatic or renal disease, addition of epinephrine,
factors affecting urinary pH, renal blood flow, the route
of drug administration, and the age of the patient. The
half-life of MARCAINE in adults is 2.7 hours and in
neonates 8.1 hours. In clinical studies, elderly patients
exhibited a greater spread and higher maximal level of
analgesia than younger patients. Elderly patients also
reached the maximal level of analgesia more rapidly
than younger patients, and exhibited a faster onset of
motor blockade. The total plasma clearance was
decreased and the terminal half-life was lengthened in
these patients.
Amide-type local anesthetics such as MARCAINE are
metabolized primarily in the liver via conjugation with
glucuronic acid. Patients with hepatic disease,
especially those with severe hepatic disease, may be
more susceptible to the potential toxicities of the amide-
type local anesthetics. Pipecolylxylidine is the major
metabolite of MARCAINE.
The kidney is the main excretory organ for most local
anesthetics and their metabolites. Urinary excretion is
affected by urinary perfusion and factors affecting
urinary pH. Only 6% of bupivacaine is excreted
unchanged in the urine.
When administered in recommended doses and
concentrations, MARCAINE does not ordinarily produce
irritation or tissue damage and does not cause
methemoglobinemia.
INDICATIONS AND USAGE
MARCAINE Spinal is indicated for the production of
subarachnoid block (spinal anesthesia).
Standard textbooks should be consulted to determine
the accepted procedures and techniques for the
administration of spinal anesthesia.
CONTRAINDICATIONS
MARCAINE Spinal is contraindicated in patients with a
known hypersensitivity to it or to any local anesthetic
agent of the amide-type.
The following conditions preclude the use of spinal
anesthesia:
1. Severe hemorrhage, severe hypotension or shock
and arrhythmias, such as complete heart block,
which severely restrict cardiac output.
2. Local infection at the site of proposed lumbar
puncture.
3. Septicemia.
WARNINGS
LOCAL ANESTHETICS SHOULD ONLY BE EMPLOYED BY
CLINICIANS WHO ARE WELL VERSED IN DIAGNOSIS
AND MANAGEMENT OF DOSE-RELATED TOXICITY AND
OTHER ACUTE EMERGENCIES WHICH MIGHT ARISE
FROM THE BLOCK TO BE EMPLOYED, AND THEN ONLY
AFTER INSURING THE IMMEDIATE AVAILABILITY
OF
OXYGEN,
OTHER
RESUSCITATIVE
DRUGS,
CARDIOPULMONARY RESUSCITATIVE EQUIPMENT,
AND THE PERSONNEL RESOURCES NEEDED FOR
PROPER MANAGEMENT OF TOXIC REACTIONS AND
RELATED
EMERGENCIES.
(See
also
ADVERSE
REACTIONS and PRECAUTIONS.) DELAY IN PROPER
MANAGEMENT
OF
DOSE-RELATED
TOXICITY,
UNDERVENTILATION FROM ANY CAUSE AND/OR
ALTERED
SENSITIVITY
MAY
LEAD
TO
THE
DEVELOPMENT OF ACIDOSIS, CARDIAC ARREST, AND,
POSSIBLY, DEATH.
Intra-articular infusions of local anesthetics following
arthroscopic and other surgical procedures is an
unapproved use, and there have been post-marketing
reports of chondrolysis in patients receiving such
infusions. The majority of reported cases of chondrolysis
have involved the shoulder joint; cases of gleno-humeral
chondrolysis have been described in pediatric and adult
patients following intra-articular infusions of local
anesthetics with and without epinephrine for periods of
48 to 72 hours. There is insufficient information to
determine whether shorter infusion periods are not
associated with these findings. The time of onset of
symptoms, such as joint pain, stiffness and loss of
motion can be variable, but may begin as early as the
2nd month after surgery. Currently, there is no effective
treatment for chondrolysis; patients who experienced
chondrolysis have required additional diagnostic and
therapeutic procedures and some required arthroplasty
or shoulder replacement.
Spinal anesthetics should not be injected during
uterine contractions, because spinal fluid current may
carry the drug further cephalad than desired.
A free flow of cerebrospinal fluid during the
performance of spinal anesthesia is indicative of entry
into the subarachnoid space. However, aspiration
should be performed before the anesthetic solution is
injected to confirm entry into the subarachnoid space
and to avoid intravascular injection.
MARCAINE solutions containing epinephrine or other
vasopressors should not be used concomitantly with
ergot-type oxytocic drugs, because a severe persistent
hypertension may occur. Likewise, solutions of
MARCAINE containing a vasoconstrictor, such as
epinephrine, should be used with extreme caution in
patients receiving monoamine oxidase inhibitors (MAOI)
or antidepressants of the triptyline or imipramine types,
because severe prolonged hypertension may result.
Until further experience is gained in patients younger
than 18 years, administration of MARCAINE in this age
group is not recommended.
Mixing or the prior or intercurrent use of any other
local
anesthetic
with
MARCAINE
cannot
be
recommended because of insufficient data on the
clinical use of such mixtures.
PRECAUTIONS
General: The safety and effectiveness of spinal
anesthetics depend on proper dosage, correct
technique, adequate precautions, and readiness for
emergencies. Resuscitative equipment, oxygen, and
other resuscitative drugs should be available for
immediate use. (See WARNINGS and ADVERSE
REACTIONS.) The patient should have IV fluids running
via an indwelling catheter to assure a functioning
intravenous pathway. The lowest dosage of local
anesthetic that results in effective anesthesia should be
used. Aspiration for blood should be performed before
injection and injection should be made slowly. Tolerance
varies with the status of the patient. Elderly patients and
acutely ill patients may require reduced doses. Reduced
doses may also be indicated in patients with increased
intra-abdominal
pressure
(including
obstetrical
patients), if otherwise suitable for spinal anesthesia.
There should be careful and constant monitoring of
cardiovascular and respiratory (adequacy of ventilation)
vital signs and the patient’s state of consciousness after
local anesthetic injection. Restlessness, anxiety,
incoherent speech, lightheadedness, numbness and
tingling of the mouth and lips, metallic taste, tinnitus,
dizziness, blurred vision, tremors, depression, or
drowsiness may be early warning signs of central
nervous system toxicity.
Spinal anesthetics should be used with caution in
patients with severe disturbances of cardiac rhythm,
shock, or heart block.
Sympathetic blockade occurring during spinal
anesthesia may result in peripheral vasodilation and
hypotension, the extent depending on the number of
dermatomes blocked. Patients over 65 years,
particularly those with hypertension, may be at
increased risk for experiencing the hypotensive effects
of MARCAINE Spinal. Blood pressure should, therefore,
be carefully monitored especially in the early phases of
anesthesia. Hypotension may be controlled by
vasoconstrictors in dosages depending on the severity
of hypotension and response of treatment. The level of
anesthesia should be carefully monitored because it is
not always controllable in spinal techniques.
Because amide-type local anesthetics such as
MARCAINE are metabolized by the liver, these drugs,
especially repeat doses, should be used cautiously in
patients with hepatic disease. Patients with severe
hepatic disease, because of their inability to metabolize
local anesthetics normally, are at a greater risk of
developing toxic plasma concentrations. Local
anesthetics should also be used with caution in patients
with impaired cardiovascular function because they
may be less able to compensate for functional changes
associated with the prolongation of AV conduction
produced
by
these
drugs.
However,
dosage
recommendations for spinal anesthesia are much
lower than dosage recommendations for other major
blocks and most experience regarding hepatic and
cardiovascular disease dose-related toxicity is derived
from these other major blocks.
Serious dose-related cardiac arrhythmias may occur
if preparations containing a vasoconstrictor such as
epinephrine are employed in patients during or following
the administration of potent inhalation agents. In
deciding whether to use these products concurrently in
the same patient, the combined action of both agents
upon the myocardium, the concentration and volume of
vasoconstrictor used, and the time since injection, when
applicable, should be taken into account.
Many drugs used during the conduct of anesthesia
are considered potential triggering agents for familial
malignant hyperthermia. Because it is not known
whether amide-type local anesthetics may trigger this
reaction and because the need for supplemental
general anesthesia cannot be predicted in advance, it is
suggested that a standard protocol for management
should be available. Early unexplained signs of
tachycardia, tachypnea, labile blood pressure, and
metabolic acidosis may precede temperature elevation.
Successful outcome is dependent on early diagnosis,
prompt discontinuance of the suspect triggering
agent(s) and institution of treatment, including oxygen
therapy, indicated supportive measures, and dantrolene.
(Consult dantrolene sodium intravenous package insert
before using.)
The following conditions may preclude the use of
spinal anesthesia, depending upon the physician’s
evaluation of the situation and ability to deal with the
complications or complaints which may occur:
• Pre-existing diseases of the central nervous
system, such as those attributable to pernicious
anemia, poliomyelitis, syphilis, or tumor.
• Hematological
disorders
predisposing
to
coagulopathies or patients on anti coagulant
therapy. Trauma to a blood vessel during the
conduct of spinal anesthesia may, in some
instances, result in uncontrollable central nervous
system hemorrhage or soft tissue hemorrhage.
• Chronic backache and preoperative headache.
• Hypotension and hypertension.
• Technical problems (persistent paresthesias,
persistent bloody tap).
• Arthritis or spinal deformity.
• Extremes of age.
• Psychosis or other causes of poor cooperation by
the patient.
Information for Patients: When appropriate, patients
should be informed in advance that they may experience
temporary loss of sensation and motor activity, usually in
the lower half of the body, following proper
administration of spinal anesthesia. Also, when
appropriate, the physician should discuss other
information including adverse reactions in the
MARCAINE Spinal package insert.
Clinically
Significant
Drug
Interactions:
The
administration of local anesthetic solutions containing
epinephrine or norepinephrine to patients receiving
monoamine
oxidase
inhibitors
or
tricyclic
antidepressants may produce severe, prolonged
hypertension. Concurrent use of these agents should
generally be avoided. In situations when concurrent
therapy is necessary, careful patient monitoring is
essential.
Concurrent administration of vasopressor drugs and
of ergot-type oxytocic drugs may cause severe
persistent hypertension or cerebrovascular accidents.
Phenothiazines and butyrophenones may reduce or
reverse the pressor effect of epinephrine.
Carcinogenesis, Mutagenesis, and Impairment of
Fertility: Long-term studies in animals of most local
anesthetics including bupivacaine to evaluate the
carcinogenic potential have not been conducted.
Mutagenic potential or the effect on fertility have not
been determined. There is no evidence from human data
that MARCAINE Spinal may be carcinogenic or
mutagenic or that it impairs fertility.
Pregnancy Category C: Decreased pup survival in rats
and an embryocidal effect in rabbits have been
observed when bupivacaine hydrochloride was
administered to these species in doses comparable to
230 and 130 times respectively the maximum
recommended human spinal dose. There are no
adequate and well-controlled studies in pregnant
women of the effect of bupivacaine on the developing
fetus. Bupivacaine hydrochloride should be used during
pregnancy only if the potential benefit justifies the
potential risk to the fetus. This does not exclude the use
of MARCAINE Spinal at term for obstetrical anesthesia.
(See Labor and Delivery.)
Labor and Delivery: Spinal anesthesia has a recognized
use
during
labor
and
delivery.
Bupivacaine
hydrochloride, when administered properly, via the
epidural route in doses 10 to 12 times the amount used in
spinal anesthesia has been used for obstetrical
analgesia and anesthesia without evidence of adverse
effects on the fetus.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:51.560339
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018692s014lbl.pdf', 'application_number': 18692, 'submission_type': 'SUPPL ', 'submission_number': 14}
|
11,278
|
MarcaineTM
Bupivacaine Hydrochloride Injection, USP
MarcaineTM
With Epinephrine 1:200,000 (as bitartrate)
Bupivacaine Hydrochloride and Epinephrine Injection, USP
Rx only
DESCRIPTION
Bupivacaine hydrochloride is 2-Piperidinecarboxamide, 1-butyl-N-(2,6-dimethylphenyl)-,
monohydrochloride, monohydrate, a white crystalline powder that is freely soluble in 95 percent ethanol,
soluble in water, and slightly soluble in chloroform or acetone. It has the following structural formula: structural formula
Epinephrine is (-)-3,4-Dihydroxy-α-[(methylamino)methyl] benzyl alcohol. It has the following structural
formula: structural formula
MARCAINE is available in sterile isotonic solutions with and without epinephrine (as bitartrate)
1:200,000 for injection via local infiltration, peripheral nerve block, and caudal and lumbar epidural
blocks. Solutions of MARCAINE may be autoclaved if they do not contain epinephrine. Solutions are
clear and colorless.
Bupivacaine is related chemically and pharmacologically to the aminoacyl local anesthetics. It is a
homologue of mepivacaine and is chemically related to lidocaine. All three of these anesthetics contain an
amide linkage between the aromatic nucleus and the amino, or piperidine group. They differ in this
respect from the procaine-type local anesthetics, which have an ester linkage.
MARCAINE — Sterile isotonic solutions containing sodium chloride. In multiple-dose vials, each mL also
contains 1 mg methylparaben as antiseptic preservative. The pH of these solutions is adjusted to between
4 and 6.5 with sodium hydroxide or hydrochloric acid.
MARCAINE with epinephrine 1:200,000 (as bitartrate)—Sterile isotonic solutions containing sodium
chloride. Each mL contains bupivacaine hydrochloride and 0.0091 mg epinephrine bitartrate, with 0.5 mg
sodium metabisulfite, 0.001 mL monothioglycerol, and 2 mg ascorbic acid as antioxidants, 0.0017 mL
60% sodium lactate buffer, and 0.1 mg edetate calcium disodium as stabilizer. In multiple-dose vials, each
mL also contains 1 mg methylparaben as antiseptic preservative. The pH of these solutions is adjusted to
between 3.4 and 4.5 with sodium hydroxide or hydrochloric acid. The specific gravity of MARCAINE
0.5% with epinephrine 1:200,000 (as bitartrate) at 25°C is 1.008 and at 37°C is 1.008.
CLINICAL PHARMACOLOGY
Local anesthetics block the generation and the conduction of nerve impulses, presumably by increasing
the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and
wEN-2916v03
Page 1 of 14
Reference ID: 3079122
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to
the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of
nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal
muscle tone.
Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous
systems (CNS). At blood concentrations achieved with normal therapeutic doses, changes in cardiac
conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal.
However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to
atrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. In
addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased
cardiac output and arterial blood pressure. Recent clinical reports and animal research suggest that these
cardiovascular changes are more likely to occur after unintended intravascular injection of bupivacaine.
Therefore, incremental dosing is necessary.
Following systemic absorption, local anesthetics can produce central nervous system stimulation,
depression, or both. Apparent central stimulation is manifested as restlessness, tremors and shivering
progressing to convulsions, followed by depression and coma progressing ultimately to respiratory arrest.
However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The
depressed stage may occur without a prior excited state.
Pharmacokinetics: The rate of systemic absorption of local anesthetics is dependent upon the total dose
and concentration of drug administered, the route of administration, the vascularity of the administration
site, and the presence or absence of epinephrine in the anesthetic solution. A dilute concentration of
epinephrine (1:200,000 or 5 mcg/mL) usually reduces the rate of absorption and peak plasma
concentration of MARCAINE, permitting the use of moderately larger total doses and sometimes
prolonging the duration of action.
The onset of action with MARCAINE is rapid and anesthesia is long lasting. The duration of anesthesia is
significantly longer with MARCAINE than with any other commonly used local anesthetic. It has also
been noted that there is a period of analgesia that persists after the return of sensation, during which time
the need for strong analgesics is reduced.
The onset of action following dental injections is usually 2 to 10 minutes and anesthesia may last two or
three times longer than lidocaine and mepivacaine for dental use, in many patients up to 7 hours. The
duration of anesthetic effect is prolonged by the addition of epinephrine 1:200,000.
Local anesthetics are bound to plasma proteins in varying degrees. Generally, the lower the plasma
concentration of drug the higher the percentage of drug bound to plasma proteins.
Local anesthetics appear to cross the placenta by passive diffusion. The rate and degree of diffusion is
governed by (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of
lipid solubility. Fetal/ maternal ratios of local anesthetics appear to be inversely related to the degree of
plasma protein binding, because only the free, unbound drug is available for placental transfer.
MARCAINE with a high protein binding capacity (95%) has a low fetal/maternal ratio (0.2 to 0.4). The
extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug.
Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation.
Depending upon the route of administration, local anesthetics are distributed to some extent to all body
tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain.
Pharmacokinetic studies on the plasma profile of MARCAINE after direct intravenous injection suggest a
three-compartment open model. The first compartment is represented by the rapid intravascular
distribution of the drug. The second compartment represents the equilibration of the drug throughout the
wEN-2916v03
Page 2 of 14
Reference ID: 3079122
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
highly perfused organs such as the brain, myocardium, lungs, kidneys, and liver. The third compartment
represents an equilibration of the drug with poorly perfused tissues, such as muscle and fat. The
elimination of drug from tissue distribution depends largely upon the ability of binding sites in the
circulation to carry it to the liver where it is metabolized.
After injection of MARCAINE for caudal, epidural, or peripheral nerve block in man, peak levels of
bupivacaine in the blood are reached in 30 to 45 minutes, followed by a decline to insignificant levels
during the next three to six hours.
Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence
of hepatic or renal disease, addition of epinephrine, factors affecting urinary pH, renal blood flow, the
route of drug administration, and the age of the patient. The half-life of MARCAINE in adults is 2.7 hours
and in neonates 8.1 hours.
In clinical studies, elderly patients reached the maximal spread of analgesia and maximal motor blockade
more rapidly than younger patients. Elderly patients also exhibited higher peak plasma concentrations
following administration of this product. The total plasma clearance was decreased in these patients.
Amide-type local anesthetics such as MARCAINE are metabolized primarily in the liver via conjugation
with glucuronic acid. Patients with hepatic disease, especially those with severe hepatic disease, may be
more susceptible to the potential toxicities of the amide-type local anesthetics. Pipecoloxylidine is the
major metabolite of MARCAINE.
The kidney is the main excretory organ for most local anesthetics and their metabolites. Urinary excretion
is affected by urinary perfusion and factors affecting urinary pH. Only 6% of bupivacaine is excreted
unchanged in the urine.
When administered in recommended doses and concentrations, MARCAINE does not ordinarily produce
irritation or tissue damage and does not cause methemoglobinemia.
INDICATIONS AND USAGE
MARCAINE is indicated for the production of local or regional anesthesia or analgesia for surgery, dental
and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. Only
the 0.25% and 0.5% concentrations are indicated for obstetrical anesthesia. (See WARNINGS.)
Experience with nonobstetrical surgical procedures in pregnant patients is not sufficient to recommend
use of 0.75% concentration of MARCAINE in these patients.
MARCAINE is not recommended for intravenous regional anesthesia (Bier Block). See WARNINGS.
The routes of administration and indicated MARCAINE concentrations are:
∙ local infiltration
0.25%
∙ peripheral nerve block
0.25% and 0.5%
∙ retrobulbar block
0.75%
∙ sympathetic block
0.25%
∙ lumbar epidural
0.25%, 0.5%, and 0.75%
(0.75% not for obstetrical anesthesia)
∙ caudal
0.25% and 0.5%
∙ epidural test dose
0.5% with epinephrine 1:200,000
∙ dental blocks
0.5% with epinephrine 1:200,000
(See DOSAGE AND ADMINISTRATION for additional information.)
Standard textbooks should be consulted to determine the accepted procedures and techniques for the
administration of MARCAINE.
wEN-2916v03
Page 3 of 14
Reference ID: 3079122
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CONTRAINDICATIONS
MARCAINE is contraindicated in obstetrical paracervical block anesthesia. Its use in this technique has
resulted in fetal bradycardia and death.
MARCAINE is contraindicated in patients with a known hypersensitivity to it or to any local anesthetic
agent of the amide-type or to other components of MARCAINE solutions.
WARNINGS
THE 0.75% CONCENTRATION OF MARCAINE IS NOT RECOMMENDED FOR
OBSTETRICAL ANESTHESIA. THERE HAVE BEEN REPORTS OF CARDIAC ARREST
WITH DIFFICULT RESUSCITATION OR DEATH DURING USE OF MARCAINE FOR
EPIDURAL ANESTHESIA IN OBSTETRICAL PATIENTS. IN MOST CASES, THIS HAS
FOLLOWED USE OF THE 0.75% CONCENTRATION. RESUSCITATION HAS BEEN
DIFFICULT OR IMPOSSIBLE DESPITE APPARENTLY ADEQUATE PREPARATION
AND APPROPRIATE MANAGEMENT. CARDIAC ARREST HAS OCCURRED AFTER
CONVULSIONS RESULTING FROM SYSTEMIC TOXICITY, PRESUMABLY
FOLLOWING UNINTENTIONAL INTRAVASCULAR INJECTION. THE 0.75%
CONCENTRATION SHOULD BE RESERVED FOR SURGICAL PROCEDURES WHERE A
HIGH DEGREE OF MUSCLE RELAXATION AND PROLONGED EFFECT ARE
NECESSARY.
LOCAL ANESTHETICS SHOULD ONLY BE EMPLOYED BY CLINICIANS WHO ARE WELL
VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE-RELATED TOXICITY AND OTHER
ACUTE EMERGENCIES WHICH MIGHT ARISE FROM THE BLOCK TO BE EMPLOYED, AND
THEN ONLY AFTER INSURING THE IMMEDIATE AVAILABILITY OF OXYGEN, OTHER
RESUSCITATIVE DRUGS, CARDIOPULMONARY RESUSCITATIVE EQUIPMENT, AND THE
PERSONNEL RESOURCES NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS
AND RELATED EMERGENCIES. (See also ADVERSE REACTIONS, PRECAUTIONS, and
OVERDOSAGE.) DELAY IN PROPER MANAGEMENT OF DOSE-RELATED TOXICITY,
UNDERVENTILATION FROM ANY CAUSE, AND/OR ALTERED SENSITIVITY MAY LEAD TO
THE DEVELOPMENT OF ACIDOSIS, CARDIAC ARREST AND, POSSIBLY, DEATH.
Local anesthetic solutions containing antimicrobial preservatives, i.e., those supplied in multiple-dose
vials, should not be used for epidural or caudal anesthesia because safety has not been established with
regard to intrathecal injection, either intentionally or unintentionally, of such preservatives.
Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an
unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such
infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno
humeral chondrolysis have been described in pediatric and adult patients following intra-articular
infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is
insufficient information to determine whether shorter infusion periods are not associated with these
findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable,
but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for
chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic
procedures and some required arthroplasty or shoulder replacement.
It is essential that aspiration for blood or cerebrospinal fluid (where applicable) be done prior to injecting
any local anesthetic, both the original dose and all subsequent doses, to avoid intravascular or
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subarachnoid injection. However, a negative aspiration does not ensure against an intravascular or
subarachnoid injection.
MARCAINE with epinephrine 1:200,000 or other vasopressors should not be used concomitantly with
ergot-type oxytocic drugs, because a severe persistent hypertension may occur. Likewise, solutions of
MARCAINE containing a vasoconstrictor, such as epinephrine, should be used with extreme caution in
patients receiving monoamineoxidase inhibitors (MAOI) or antidepressants of the triptyline or
imipramine types, because severe prolonged hypertension may result.
Until further experience is gained in pediatric patients younger than 12 years, administration of
MARCAINE in this age group is not recommended.
Mixing or the prior or intercurrent use of any other local anesthetic with MARCAINE cannot be
recommended because of insufficient data on the clinical use of such mixtures.
There have been reports of cardiac arrest and death during the use of MARCAINE for intravenous
regional anesthesia (Bier Block). Information on safe dosages and techniques of administration of
MARCAINE in this procedure is lacking. Therefore, MARCAINE is not recommended for use in this
technique.
MARCAINE with epinephrine 1:200,000 contains sodium metabisulfite, a sulfite that may cause allergic-
type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in
certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is
unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic
people. Single-dose ampuls and single-dose vials of MARCAINE without epinephrine do not contain
sodium metabisulfite.
PRECAUTIONS
General: The safety and effectiveness of local anesthetics depend on proper dosage, correct technique,
adequate precautions, and readiness for emergencies. Resuscitative equipment, oxygen, and other
resuscitative drugs should be available for immediate use. (See WARNINGS, ADVERSE
REACTIONS, and OVERDOSAGE.) During major regional nerve blocks, the patient should have IV
fluids running via an indwelling catheter to assure a functioning intravenous pathway. The lowest dosage
of local anesthetic that results in effective anesthesia should be used to avoid high plasma levels and
serious adverse effects. The rapid injection of a large volume of local anesthetic solution should be
avoided and fractional (incremental) doses should be used when feasible.
Epidural Anesthesia: During epidural administration of MARCAINE, 0.5% and 0.75% solutions should
be administered in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic
manifestations of unintentional intravascular or intrathecal injection. Injections should be made slowly,
with frequent aspirations before and during the injection to avoid intravascular injection. Syringe
aspirations should also be performed before and during each supplemental injection in continuous
(intermittent) catheter techniques. An intravascular injection is still possible even if aspirations for blood
are negative.
During the administration of epidural anesthesia, it is recommended that a test dose be administered
initially and the effects monitored before the full dose is given. When using a “continuous” catheter
technique, test doses should be given prior to both the original and all reinforcing doses, because plastic
tubing in the epidural space can migrate into a blood vessel or through the dura. When clinical conditions
permit, the test dose should contain epinephrine (10 mcg to 15 mcg has been suggested) to serve as a
warning of unintended intravascular injection. If injected into a blood vessel, this amount of epinephrine
is likely to produce a transient “epinephrine response” within 45 seconds, consisting of an increase in
heart rate and/or systolic blood pressure, circumoral pallor, palpitations, and nervousness in the unsedated
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patient. The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15
or more seconds. Therefore, following the test dose, the heart rate should be monitored for a heart rate
increase. Patients on beta-blockers may not manifest changes in heart rate, but blood pressure monitoring
can detect a transient rise in systolic blood pressure. The test dose should also contain 10 mg to 15 mg of
MARCAINE or an equivalent amount of another local anesthetic to detect an unintended intrathecal
administration. This will be evidenced within a few minutes by signs of spinal block (e.g., decreased
sensation of the buttocks, paresis of the legs, or, in the sedated patient, absent knee jerk). The Test Dose
formulation of MARCAINE contains 15 mg of bupivacaine and 15 mcg of epinephrine in a volume of
3 mL. An intravascular or subarachnoid injection is still possible even if results of the test dose are
negative. The test dose itself may produce a systemic toxic reaction, high spinal or epinephrine-induced
cardiovascular effects.
Injection of repeated doses of local anesthetics may cause significant increases in plasma levels with each
repeated dose due to slow accumulation of the drug or its metabolites, or to slow metabolic degradation.
Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly patients and
acutely ill patients should be given reduced doses commensurate with their age and physical status. Local
anesthetics should also be used with caution in patients with hypotension or heartblock.
Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs
and the patient’s state of consciousness should be performed after each local anesthetic injection. It should
be kept in mind at such times that restlessness, anxiety, incoherent speech, lightheadedness, numbness
and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching,
depression, or drowsiness may be early warning signs of central nervous system toxicity.
Local anesthetic solutions containing a vasoconstrictor should be used cautiously and in carefully
restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood
supply such as digits, nose, external ear, or penis. Patients with hypertensive vascular disease may exhibit
exaggerated vasoconstrictor response. Ischemic injury or necrosis may result.
Because amide-local anesthetics such as MARCAINE are metabolized by the liver, these drugs,
especially repeat doses, should be used cautiously in patients with hepatic disease. Patients with severe
hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of
developing toxic plasma concentrations. Local anesthetics should also be used with caution in patients
with impaired cardiovascular function because they may be less able to compensate for functional
changes associated with the prolongation of AV conduction produced by these drugs.
Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as
epinephrine are employed in patients during or following the administration of potent inhalation
anesthetics. In deciding whether to use these products concurrently in the same patient, the combined
action of both agents upon the myocardium, the concentration and volume of vasoconstrictor used, and
the time since injection, when applicable, should be taken into account.
Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial
malignant hyperthermia. Because it is not known whether amide-type local anesthetics may trigger this
reaction and because the need for supplemental general anesthesia cannot be predicted in advance, it is
suggested that a standard protocol for management should be available. Early unexplained signs of
tachycardia, tachypnea, labile blood pressure, and metabolic acidosis may precede temperature elevation.
Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect triggering
agent(s) and prompt institution of treatment, including oxygen therapy, indicated supportive measures and
dantrolene. (Consult dantrolene sodium intravenous package insert before using.)
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Use in Head and Neck Area: Small doses of local anesthetics injected into the head and neck area,
including retrobulbar, dental, and stellate ganglion blocks, may produce adverse reactions similar to
systemic toxicity seen with unintentional intravascular injections of larger doses. The injection procedures
require the utmost care. Confusion, convulsions, respiratory depression, and/or respiratory arrest, and
cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial
injection of the local anesthetic with retrograde flow to the cerebral circulation. They may also be due to
puncture of the dural sheath of the optic nerve during retrobulbar block with diffusion of any local
anesthetic along the subdural space to the midbrain. Patients receiving these blocks should have their
circulation and respiration monitored and be constantly observed. Resuscitative equipment and personnel
for treating adverse reactions should be immediately available. Dosage recommendations should not be
exceeded. (See DOSAGE AND ADMINISTRATION.)
Use in Ophthalmic Surgery: Clinicians who perform retrobulbar blocks should be aware that there have
been reports of respiratory arrest following local anesthetic injection. Prior to retrobulbar block, as with
all other regional procedures, the immediate availability of equipment, drugs, and personnel to manage
respiratory arrest or depression, convulsions, and cardiac stimulation or depression should be assured (see
also WARNINGS and Use In Head and Neck Area, above). As with other anesthetic procedures, patients
should be constantly monitored following ophthalmic blocks for signs of these adverse reactions, which
may occur following relatively low total doses.
A concentration of 0.75% bupivacaine is indicated for retrobulbar block; however, this concentration is
not indicated for any other peripheral nerve block, including the facial nerve, and not indicated for local
infiltration, including the conjunctiva (see INDICATIONS AND USAGE and PRECAUTIONS,
General). Mixing MARCAINE with other local anesthetics is not recommended because of insufficient
data on the clinical use of such mixtures.
When MARCAINE 0.75% is used for retrobulbar block, complete corneal anesthesia usually precedes
onset of clinically acceptable external ocular muscle akinesia. Therefore, presence of akinesia rather than
anesthesia alone should determine readiness of the patient for surgery.
Use in Dentistry: Because of the long duration of anesthesia, when MARCAINE 0.5% with epinephrine is
used for dental injections, patients should be cautioned about the possibility of inadvertent trauma to
tongue, lips, and buccal mucosa and advised not to chew solid foods or test the anesthetized area by biting
or probing.
Information for Patients: When appropriate, patients should be informed in advance that they may
experience temporary loss of sensation and motor activity, usually in the lower half of the body, following
proper administration of caudal or epidural anesthesia. Also, when appropriate, the physician should
discuss other information including adverse reactions in the package insert of MARCAINE.
Patients receiving dental injections of MARCAINE should be cautioned not to chew solid foods or test
the anesthetized area by biting or probing until anesthesia has worn off (up to 7 hours).
Clinically Significant Drug Interactions: The administration of local anesthetic solutions containing
epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors or tricyclic
antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should
generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is
essential.
Concurrent administration of vasopressor drugs and of ergot-type oxytocic drugs may cause severe,
persistent hypertension or cerebrovascular accidents.
Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine.
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Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals to evaluate the
carcinogenic potential of bupivacaine hydrochloride have not been conducted. The mutagenic potential
and the effect on fertility of bupivacaine hydrochloride have not been determined.
Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women.
MARCAINE should be used during pregnancy only if the potential benefit justifies the potential risk to
the fetus. Bupivacaine hydrochloride produced developmental toxicity when administered subcutaneously
to pregnant rats and rabbits at clinically relevant doses. This does not exclude the use of MARCAINE at
term for obstetrical anesthesia or analgesia. (See Labor and Delivery)
Bupivacaine hydrochloride was administered subcutaneously to rats at doses of 4.4, 13.3, & 40 mg/kg and
to rabbits at doses of 1.3, 5.8, & 22.2 mg/kg during the period of organogenesis (implantation to closure
of the hard palate). The high doses are comparable to the daily maximum recommended human dose
(MRHD) of 400 mg/day on a mg/m2 body surface area (BSA) basis. No embryo-fetal effects were
observed in rats at the high dose which caused increased maternal lethality. An increase in embryo-fetal
deaths was observed in rabbits at the high dose in the absence of maternal toxicity with the fetal No
Observed Adverse Effect Level representing approximately 1/5th the MRHD on a BSA basis.
In a rat pre- and post-natal development study (dosing from implantation through weaning) conducted at
subcutaneous doses of 4.4, 13.3, & 40 mg/kg mg/kg/day, decreased pup survival was observed at the high
dose. The high dose is comparable to the daily MRHD of 400 mg/day on a BSA basis.
Labor and Delivery: SEE BOXED WARNING REGARDING OBSTETRlCAL USE OF
0.75% MARCAINE.
MARCAINE is contraindicated for obstetrical paracervical block anesthesia.
Local anesthetics rapidly cross the placenta, and when used for epidural, caudal, or pudendal block
anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity. (See CLINICAL
PHARMACOLOGY, Pharmacokinetics.) The incidence and degree of toxicity depend upon the
procedure performed, the type, and amount of drug used, and the technique of drug administration.
Adverse reactions in the parturient, fetus, and neonate involve alterations of the central nervous system,
peripheral vascular tone, and cardiac function.
Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by
blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help
prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously and
electronic fetal monitoring is highly advisable.
Epidural, caudal, or pudendal anesthesia may alter the forces of parturition through changes in uterine
contractility or maternal expulsive efforts. Epidural anesthesia has been reported to prolong the second
stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function.
The use of obstetrical anesthesia may increase the need for forceps assistance.
The use of some local anesthetic drug products during labor and delivery may be followed by diminished
muscle strength and tone for the first day or two of life. This has not been reported with bupivacaine.
It is extremely important to avoid aortocaval compression by the gravid uterus during administration of
regional block to parturients. To do this, the patient must be maintained in the left lateral decubitus
position or a blanket roll or sandbag may be placed beneath the right hip and gravid uterus displaced to
the left.
Nursing Mothers: Bupivacaine has been reported to be excreted in human milk suggesting that the
nursing infant could be theoretically exposed to a dose of the drug. Because of the potential for serious
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adverse reactions in nursing infants from bupivacaine, a decision should be made whether to discontinue
nursing or not administer bupivacaine, taking into account the importance of the drug to the mother.
Pediatric Use: Until further experience is gained in pediatric patients younger than 12 years,
administration of MARCAINE in this age group is not recommended. Continuous infusions of
bupivacaine in children have been reported to result in high systemic levels of bupivacaine and seizures;
high plasma levels may also be associated with cardiovascular abnormalities. (See WARNINGS,
PRECAUTIONS, and OVERDOSAGE.)
Geriatric Use: Patients over 65 years, particularly those with hypertension, may be at increased risk for
developing hypotension while undergoing anesthesia with MARCAINE. (See ADVERSE
REACTIONS.)
Elderly patients may require lower doses of MARCAINE. (See PRECAUTIONS, Epidural Anesthesia
and DOSAGE AND ADMINISTRATION.)
In clinical studies, differences in various pharmacokinetic parameters have been observed between elderly
and younger patients. (See CLINICAL PHARMACOLOGY.)
This product is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely to
have decreased renal function, care should be taken in dose selection, and it may be useful to monitor
renal function. (See CLINICAL PHARMACOLOGY.)
ADVERSE REACTIONS
Reactions to MARCAINE are characteristic of those associated with other amide-type local anesthetics. A
major cause of adverse reactions to this group of drugs is excessive plasma levels, which may be due to
overdosage, unintentional intravascular injection, or slow metabolic degradation.
The most commonly encountered acute adverse experiences which demand immediate counter-measures
are related to the central nervous system and the cardiovascular system. These adverse experiences are
generally dose related and due to high plasma levels which may result from overdosage, rapid absorption
from the injection site, diminished tolerance, or from unintentional intravascular injection of the local
anesthetic solution. In addition to systemic dose-related toxicity, unintentional subarachnoid injection of
drug during the intended performance of caudal or lumbar epidural block or nerve blocks near the
vertebral column (especially in the head and neck region) may result in underventilation or apnea (“Total
or High Spinal”). Also, hypotension due to loss of sympathetic tone and respiratory paralysis or
underventilation due to cephalad extension of the motor level of anesthesia may occur. This may lead to
secondary cardiac arrest if untreated. Patients over 65 years, particularly those with hypertension, may be
at increased risk for experiencing the hypotensive effects of MARCAINE. Factors influencing plasma
protein binding, such as acidosis, systemic diseases which alter protein production, or competition of
other drugs for protein binding sites, may diminish individual tolerance.
Central Nervous System Reactions: These are characterized by excitation and/or depression.
Restlessness, anxiety, dizziness, tinnitus, blurred vision, or tremors may occur, possibly proceeding to
convulsions. However, excitement may be transient or absent, with depression being the first
manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into
unconsciousness and respiratory arrest. Other central nervous system effects may be nausea, vomiting,
chills, and constriction of the pupils.
The incidence of convulsions associated with the use of local anesthetics varies with the procedure used
and the total dose administered. In a survey of studies of epidural anesthesia, overt toxicity progressing to
convulsions occurred in approximately 0.1% of local anesthetic administrations.
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Cardiovascular System Reactions: High doses or unintentional intravascular injection may lead to high
plasma levels and related depression of the myocardium, decreased cardiac output, heartblock,
hypotension, bradycardia, ventricular arrhythmias, including ventricular tachycardia and ventricular
fibrillation, and cardiac arrest. (See WARNINGS, PRECAUTIONS, and OVERDOSAGE.)
Allergic: Allergic-type reactions are rare and may occur as a result of sensitivity to the local anesthetic or
to other formulation ingredients, such as the antimicrobial preservative methylparaben contained in
multiple-dose vials or sulfites in epinephrine-containing solutions. These reactions are characterized by
signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia,
sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly,
anaphylactoid-like symptomatology (including severe hypotension). Cross sensitivity among members of
the amide-type local anesthetic group has been reported. The usefulness of screening for sensitivity has
not been definitely established.
Neurologic: The incidences of adverse neurologic reactions associated with the use of local anesthetics
may be related to the total dose of local anesthetic administered and are also dependent upon the
particular drug used, the route of administration, and the physical status of the patient. Many of these
effects may be related to local anesthetic techniques, with or without a contribution from the drug.
In the practice of caudal or lumbar epidural block, occasional unintentional penetration of the
subarachnoid space by the catheter or needle may occur. Subsequent adverse effects may depend partially
on the amount of drug administered intrathecally and the physiological and physical effects of a dural
puncture. A high spinal is characterized by paralysis of the legs, loss of consciousness, respiratory
paralysis, and bradycardia.
Neurologic effects following epidural or caudal anesthesia may include spinal block of varying magnitude
(including high or total spinal block); hypotension secondary to spinal block; urinary retention; fecal and
urinary incontinence; loss of perineal sensation and sexual function; persistent anesthesia, paresthesia,
weakness, paralysis of the lower extremities and loss of sphincter control all of which may have slow,
incomplete, or no recovery; headache; backache; septic meningitis; meningismus; slowing of labor;
increased incidence of forceps delivery; and cranial nerve palsies due to traction on nerves from loss of
cerebrospinal fluid.
Neurologic effects following other procedures or routes of administration may include persistent
anesthesia, paresthesia, weakness, paralysis, all of which may have slow, incomplete, or no recovery.
OVERDOSAGE
Acute emergencies from local anesthetics are generally related to high plasma levels encountered during
therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution.
(See ADVERSE REACTIONS, WARNINGS, and PRECAUTIONS.)
Management of Local Anesthetic Emergencies: The first consideration is prevention, best
accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the
patient’s state of consciousness after each local anesthetic injection. At the first sign of change, oxygen
should be administered.
The first step in the management of systemic toxic reactions, as well as underventilation or apnea due to
unintentional subarachnoid injection of drug solution, consists of immediate attention to the
establishment and maintenance of a patent airway and effective assisted or controlled ventilation with
100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask.
This may prevent convulsions if they have not already occurred.
If necessary, use drugs to control the convulsions. A 50 mg to 100 mg bolus IV injection of
succinylcholine will paralyze the patient without depressing the central nervous or cardiovascular systems
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and facilitate ventilation. A bolus IV dose of 5 mg to 10 mg of diazepam or 50 mg to 100 mg of thiopental
will permit ventilation and counteract central nervous system stimulation, but these drugs also depress
central nervous system, respiratory, and cardiac function, add to postictal depression and may result in
apnea. Intravenous barbiturates, anticonvulsant agents, or muscle relaxants should only be administered
by those familiar with their use. Immediately after the institution of these ventilatory measures, the
adequacy of the circulation should be evaluated. Supportive treatment of circulatory depression may
require administration of intravenous fluids, and when appropriate, a vasopressor dictated by the clinical
situation (such as ephedrine or epinephrine to enhance myocardial contractile force).
Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated after
initial administration of oxygen by mask if difficulty is encountered in the maintenance of a patent
airway, or if prolonged ventilatory support (assisted or controlled) is indicated.
Recent clinical data from patients experiencing local anesthetic-induced convulsions demonstrated rapid
development of hypoxia, hypercarbia, and acidosis with bupivacaine within a minute of the onset of
convulsions. These observations suggest that oxygen consumption and carbon dioxide production are
greatly increased during local anesthetic convulsions and emphasize the importance of immediate and
effective ventilation with oxygen which may avoid cardiac arrest.
If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis plus
myocardial depression from the direct effects of the local anesthetic may result in cardiac arrhythmias,
bradycardia, asystole, ventricular fibrillation, or cardiac arrest. Respiratory abnormalities, including
apnea, may occur. Underventilation or apnea due to unintentional subarachnoid injection of local
anesthetic solution may produce these same signs and also lead to cardiac arrest if ventilatory support is
not instituted. If cardiac arrest should occur, successful outcome may require prolonged resuscitative
efforts.
The supine position is dangerous in pregnant women at term because of aortocaval compression by the
gravid uterus. Therefore during treatment of systemic toxicity, maternal hypotension or fetal bradycardia
following regional block, the parturient should be maintained in the left lateral decubitus position if
possible, or manual displacement of the uterus off the great vessels be accomplished.
The mean seizure dosage of bupivacaine in rhesus monkeys was found to be 4.4 mg/kg with mean arterial
plasma concentration of 4.5 mcg/mL. The intravenous and subcutaneous LD50 in mice is 6 mg/kg to
8 mg/kg and 38 mg/kg to 54 mg/kg respectively.
DOSAGE AND ADMINISTRATION
The dose of any local anesthetic administered varies with the anesthetic procedure, the area to be
anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of
anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual
tolerance, and the physical condition of the patient. The smallest dose and concentration required to
produce the desired result should be administered. Dosages of MARCAINE should be reduced for elderly
and/or debilitated patients and patients with cardiac and/or liver disease. The rapid injection of a large
volume of local anesthetic solution should be avoided and fractional (incremental) doses should be used
when feasible.
For specific techniques and procedures, refer to standard textbooks.
There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of
local anesthetics following arthroscopic and other surgical procedures. MARCAINE is not approved for
this use (see WARNINGS and DOSAGE AND ADMINISTRATION).
In recommended doses, MARCAINE produces complete sensory block, but the effect on motor function
differs among the three concentrations.
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0.25%―when used for caudal, epidural, or peripheral nerve block, produces incomplete motor block.
Should be used for operations in which muscle relaxation is not important, or when another
means of providing muscle relaxation is used concurrently. Onset of action may be slower than
with the 0.5% or 0.75% solutions.
0.5%― provides motor blockade for caudal, epidural, or nerve block, but muscle relaxation may be
inadequate for operations in which complete muscle relaxation is essential.
0.75%―produces complete motor block. Most useful for epidural block in abdominal operations
requiring complete muscle relaxation, and for retrobulbar anesthesia. Not for obstetrical
anesthesia.
The duration of anesthesia with MARCAINE is such that for most indications, a single dose is sufficient.
Maximum dosage limit must be individualized in each case after evaluating the size and physical status of
the patient, as well as the usual rate of systemic absorption from a particular injection site. Most
experience to date is with single doses of MARCAINE up to 225 mg with epinephrine 1:200,000 and
175 mg without epinephrine; more or less drug may be used depending on individualization of each case.
These doses may be repeated up to once every three hours. In clinical studies to date, total daily doses
have been up to 400 mg. Until further experience is gained, this dose should not be exceeded in 24 hours.
The duration of anesthetic effect may be prolonged by the addition of epinephrine.
The dosages in Table 1 have generally proved satisfactory and are recommended as a guide for use in the
average adult. These dosages should be reduced for elderly or debilitated patients. Until further
experience is gained, MARCAINE is not recommended for pediatric patients younger than 12 years.
MARCAINE is contraindicated for obstetrical paracervical blocks, and is not recommended for
intravenous regional anesthesia (Bier Block).
Use in Epidural Anesthesia: During epidural administration of MARCAINE, 0.5% and 0.75% solutions
should be administered in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect
toxic manifestations of unintentional intravascular or intrathecal injection. In obstetrics, only the 0.5% and
0.25% concentrations should be used; incremental doses of 3 mL to 5 mL of the 0.5% solution not
exceeding 50 mg to 100 mg at any dosing interval are recommended. Repeat doses should be preceded by
a test dose containing epinephrine if not contraindicated. Use only the single-dose ampuls and single-dose
vials for caudal or epidural anesthesia; the multiple-dose vials contain a preservative and therefore should
not be used for these procedures.
Test Dose for Caudal and Lumbar Epidural Blocks: The Test Dose of MARCAINE (0.5% bupivacaine
with 1:200,000 epinephrine in a 3 mL ampul) is recommended for use as a test dose when clinical
conditions permit prior to caudal and lumbar epidural blocks. This may serve as a warning of unintended
intravascular or subarachnoid injection. (See PRECAUTIONS.) The pulse rate and other signs should be
monitored carefully immediately following each test dose administration to detect possible intravascular
injection, and adequate time for onset of spinal block should be allotted to detect possible intrathecal
injection. An intravascular or subarachnoid injection is still possible even if results of the test dose are
negative. The test dose itself may produce a systemic toxic reaction, high spinal or cardiovascular effects
from the epinephrine. (See WARNINGS and OVERDOSAGE.)
Use in Dentistry: The 0.5% concentration with epinephrine is recommended for infiltration and block
injection in the maxillary and mandibular area when a longer duration of local anesthetic action is desired,
such as for oral surgical procedures generally associated with significant postoperative pain. The average
dose of 1.8 mL (9 mg) per injection site will usually suffice; an occasional second dose of 1.8 mL (9 mg)
may be used if necessary to produce adequate anesthesia after making allowance for 2 to 10 minutes onset
time. (See CLINICAL PHARMACOLOGY.) The lowest effective dose should be employed and time
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should be allowed between injections; it is recommended that the total dose for all injection sites, spread
out over a single dental sitting, should not ordinarily exceed 90 mg for a healthy adult patient (ten 1.8 mL
injections of 0.5% MARCAINE with epinephrine). Injections should be made slowly and with frequent
aspirations. Until further experience is gained, MARCAINE in dentistry is not recommended for pediatric
patients younger than 12 years.
Unused portions of solution not containing preservatives, i.e., those supplied in single-dose ampuls and
single-dose vials, should be discarded following initial use.
This product should be inspected visually for particulate matter and discoloration prior to administration
whenever solution and container permit. Solutions which are discolored or which contain particulate
matter should not be administered.
Table 1. Recommended Concentrations and Doses of MARCAINE
Type of
Block
Local
infiltration
Epidural
Conc.
0.25%4
0.75%2,4
0.5%4
0.25%4
(mL)
up to
max.
10-20
10-20
10-20
Each Dose
(mg)
up to
max.
75-150
50-100
25-50
Motor
Block1
―
complete
moderate
to complete
partial
to moderate
Caudal
0.5%4
0.25%4
15-30
15-30
75-150
37.5-75
moderate
to complete
moderate
Peripheral
nerves
0.5%4
0.25%4
5 to
max.
5 to
max.
25 to
max.
12.5 to
max.
moderate
to complete
moderate
to complete
Retrobulbar3
0.75%4
2-4
15-30
complete
Sympathetic
Dental3
0.25%
0.5%
w/epi
20-50
1.8-3.6
per site
50-125
9-18
per site
―
―
Epidural3
Test Dose
0.5%
w/epi
2-3
10-15
(10-15
micrograms
epinephrine)
―
1With continuous (intermittent) techniques, repeat doses increase the degree of motor block. The first repeat dose of 0.5% may
produce complete motor block. Intercostal nerve block with 0.25% may also produce complete motor block for intra
abdominal surgery.
2For single-dose use, not for intermittent epidural technique. Not for obstetrical anesthesia.
3See PRECAUTIONS.
4Solutions with or without epinephrine.
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HOW SUPPLIED
These solutions are not for spinal anesthesia.
Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.]
MARCAINE ―Solutions of MARCAINE that do not contain epinephrine may be autoclaved. Autoclave
at 15-pound pressure, 121°C (250°F) for 15 minutes.
NDC No.
Container
Fill
Quantity
0.25%―Contains 2.5 mg bupivacaine hydrochloride per mL.
0409-1559-10
Single-dose vials
10 mL
box of 10
0409-1559-30
Single-dose vials
30 mL
box of 10
0409-1587-50
Multiple-dose vials
50 mL
box of 1
0.5%―Contains 5 mg bupivacaine hydrochloride per mL.
0409-1560-10
Single-dose vials
10 mL
box of 10
0409-1560-29
Single-dose vials
30 mL
box of 10
0409-1610-50
Multiple-dose vials
50 mL
box of 1
0.75%―Contains 7.5 mg bupivacaine hydrochloride per mL.
0409-1582-10
Single-dose vials
10 mL
box of 10
0409-1582-29
Single-dose vials
30 mL
box of 10
MARCAINE with epinephrine 1:200,000 (as bitartrate)―Solutions of MARCAINE that contain
epinephrine should not be autoclaved and should be protected from light. Do not use the solution if its
color is pinkish or darker than slightly yellow or if it contains a precipitate.
NDC No.
Container
Fill
Quantity
0.25% with epinephrine 1:200,000—Contains 2.5 mg bupivacaine hydrochloride per mL.
0409-1746-10
Single-dose vials
10 mL
box of 10
0409-1746-30
Single-dose vials
30 mL
box of 10
0409-1752-50
Multiple-dose vials
50 mL
box of 1
0.5% with epinephrine 1:200,000—Contains 5 mg bupivacaine hydrochloride per mL.
0409-1749-03
Single-dose ampuls
3 mL
box of 10
0409-1749-10
Single-dose vials
10 mL
box of 10
0409-1749-29
Single-dose vials
30 mL
box of 10
0409-1755-50
Multiple-dose vials
50 mL
box of 1
Revised: 10/2011
Printed in USA
EN-2916
Hospira, Inc., Lake Forest, IL 60045 USA Hospira
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MarcaineTM
Spinal
bupivacaine hydrochloride in dextrose injection, USP
STERILE HYPERBARIC SOLUTION
FOR SPINAL ANESTHESIA
Rx only
DESCRIPTION
Bupivacaine hydrochloride is 2-Piperidinecarboxamide, 1-butyl-N-(2,6-dimethylphenyl)-,
monohydrochloride, monohydrate, a white crystalline powder that is freely soluble in 95 percent ethanol,
soluble in water, and slightly soluble in chloroform or acetone. It has the following structural formula: structural formula
Dextrose is D-glucopyranose monohydrate and has the following structural formula: structural formula
MARCAINE™ Spinal is available in sterile hyperbaric solution for subarachnoid injection (spinal block).
Bupivacaine hydrochloride is related chemically and pharmacologically to the aminoacyl local
anesthetics. It is a homologue of mepivacaine and is chemically related to lidocaine. All three of these
anesthetics contain an amide linkage between the aromatic nucleus and the amino or piperidine group.
They differ in this respect from the procaine-type local anesthetics, which have an ester linkage.
Each mL of MARCAINE Spinal contains 7.5 mg bupivacaine hydrochloride (anhydrous) and 82.5 mg
dextrose (anhydrous). The pH of this solution is adjusted to between 4.0 and 6.5 with sodium hydroxide
or hydrochloric acid.
The specific gravity of MARCAINE Spinal is between 1.030 and 1.035 at 25°C and 1.03 at 37°C.
MARCAINE Spinal does not contain any preservatives.
CLINICAL PHARMACOLOGY
Local anesthetics block the generation and the conduction of nerve impulses, presumably by increasing
the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and
by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to
the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of
nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal
muscle tone.
Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous
systems (CNS). At blood concentrations achieved with normal therapeutic doses, changes in cardiac
conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal.
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However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to
atrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. In
addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased
cardiac output and arterial blood pressure. Recent clinical reports and animal research suggest that these
cardiovascular changes are more likely to occur after unintended direct intravascular injection of
bupivacaine. Therefore, when epidural anesthesia with bupivacaine is considered, incremental dosing is
necessary.
Following systemic absorption, local anesthetics can produce central nervous system stimulation,
depression, or both. Apparent central stimulation is manifested as restlessness, tremors and shivering,
progressing to convulsions, followed by depression and coma progressing ultimately to respiratory arrest.
However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The
depressed stage may occur without a prior excited stage.
Pharmacokinetics: The rate of systemic absorption of local anesthetics is dependent upon the total dose
and concentration of drug administered, the route of administration, the vascularity of the administration
site, and the presence or absence of epinephrine in the anesthetic solution. A dilute concentration of
epinephrine (1:200,000 or 5 mcg/mL) usually reduces the rate of absorption and peak plasma
concentration of MARCAINE, permitting the use of moderately larger total doses and sometimes
prolonging the duration of action.
The onset of action with MARCAINE is rapid and anesthesia is long lasting. The duration of anesthesia is
significantly longer with MARCAINE than with any other commonly used local anesthetic. It has also
been noted that there is a period of analgesia that persists after the return of sensation, during which time
the need for strong analgesics is reduced.
The onset of sensory blockade following spinal block with MARCAINE Spinal is very rapid (within one
minute); maximum motor blockade and maximum dermatome level are achieved within 15 minutes in
most cases. Duration of sensory blockade (time to return of complete sensation in the operative site or
regression of two dermatomes) following a 12 mg dose averages 2 hours with or without 0.2 mg
epinephrine. The time to return of complete motor ability with 12 mg MARCAINE Spinal averages 3 1/2
hours without the addition of epinephrine and 4 1/2 hours if 0.2 mg epinephrine is added. When compared
to equal milligram doses of hyperbaric tetracaine, the duration of sensory blockade was the same but the
time to complete motor recovery was significantly longer for tetracaine. Addition of 0.2 mg epinephrine
significantly prolongs the motor blockade and time to first postoperative narcotic with MARCAINE
Spinal.
Local anesthetics appear to cross the placenta by passive diffusion. The rate and degree of diffusion is
governed by (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of
lipid solubility. Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of
plasma protein binding, because only the free, unbound drug is available for placental transfer.
MARCAINE with a high protein binding capacity (95%) has a low fetal/maternal ratio (0.2 to 0.4). The
extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug.
Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation.
Depending upon the route of administration, local anesthetics are distributed to some extent to all body
tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain.
Pharmacokinetic studies on the plasma profiles of MARCAINE after direct intravenous injection suggest
a three-compartment open model. The first compartment is represented by the rapid intravascular
distribution of the drug. The second compartment represents the equilibration of the drug throughout the
highly perfused organs such as the brain, myocardium, lungs, kidneys, and liver. The third compartment
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represents an equilibration of the drug with poorly perfused tissues, such as muscle and fat. The
elimination of drug from tissue distribution depends largely upon the ability of binding sites in the
circulation to carry it to the liver where it is metabolized.
Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence
of hepatic or renal disease, addition of epinephrine, factors affecting urinary pH, renal blood flow, the
route of drug administration, and the age of the patient. The half-life of MARCAINE in adults is 2.7 hours
and in neonates 8.1 hours. In clinical studies, elderly patients exhibited a greater spread and higher
maximal level of analgesia than younger patients. Elderly patients also reached the maximal level of
analgesia more rapidly than younger patients, and exhibited a faster onset of motor blockade. The total
plasma clearance was decreased and the terminal half-life was lengthened in these patients.
Amide-type local anesthetics such as MARCAINE are metabolized primarily in the liver via conjugation
with glucuronic acid. Patients with hepatic disease, especially those with severe hepatic disease, may be
more susceptible to the potential toxicities of the amide-type local anesthetics. Pipecolylxylidine is the
major metabolite of MARCAINE.
The kidney is the main excretory organ for most local anesthetics and their metabolites. Urinary excretion
is affected by urinary perfusion and factors affecting urinary pH. Only 6% of bupivacaine is excreted
unchanged in the urine.
When administered in recommended doses and concentrations, MARCAINE does not ordinarily produce
irritation or tissue damage and does not cause methemoglobinemia.
INDICATIONS AND USAGE
MARCAINE Spinal is indicated for the production of subarachnoid block (spinal anesthesia).
Standard textbooks should be consulted to determine the accepted procedures and techniques for the
administration of spinal anesthesia.
CONTRAINDICATIONS
MARCAINE Spinal is contraindicated in patients with a known hypersensitivity to it or to any local
anesthetic agent of the amide-type.
The following conditions preclude the use of spinal anesthesia:
1. Severe hemorrhage, severe hypotension or shock and arrhythmias, such as complete heart block,
which severely restrict cardiac output.
2. Local infection at the site of proposed lumbar puncture.
3. Septicemia.
WARNINGS
LOCAL ANESTHETICS SHOULD ONLY BE EMPLOYED BY CLINICIANS WHO ARE WELL
VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE-RELATED TOXICITY AND OTHER
ACUTE EMERGENCIES WHICH MIGHT ARISE FROM THE BLOCK TO BE EMPLOYED, AND
THEN ONLY AFTER INSURING THE IMMEDIATE AVAILABILITY OF OXYGEN, OTHER
RESUSCITATIVE DRUGS, CARDIOPULMONARY RESUSCITATIVE EQUIPMENT, AND THE
PERSONNEL RESOURCES NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS
AND RELATED EMERGENCIES. (See also ADVERSE REACTIONS and PRECAUTIONS.)
DELAY IN PROPER MANAGEMENT OF DOSE-RELATED TOXICITY, UNDERVENTILATION
FROM ANY CAUSE AND/OR ALTERED SENSITIVITY MAY LEAD TO THE DEVELOPMENT OF
ACIDOSIS, CARDIAC ARREST, AND, POSSIBLY, DEATH.
Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an
unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such
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infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno
humeral chondrolysis have been described in pediatric and adult patients following intra-articular
infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is
insufficient information to determine whether shorter infusion periods are not associated with these
findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable,
but may begin as early as the 2nd month after surgery. Currently, there is no effective treatment for
chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic
procedures and some required arthroplasty or shoulder replacement.
Spinal anesthetics should not be injected during uterine contractions, because spinal fluid current may
carry the drug further cephalad than desired.
A free flow of cerebrospinal fluid during the performance of spinal anesthesia is indicative of entry into
the subarachnoid space. However, aspiration should be performed before the anesthetic solution is
injected to confirm entry into the subarachnoid space and to avoid intravascular injection.
MARCAINE solutions containing epinephrine or other vasopressors should not be used concomitantly
with ergot-type oxytocic drugs, because a severe persistent hypertension may occur. Likewise, solutions
of MARCAINE containing a vasoconstrictor, such as epinephrine, should be used with extreme caution in
patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or
imipramine types, because severe prolonged hypertension may result.
Until further experience is gained in patients younger than 18 years, administration of MARCAINE in
this age group is not recommended.
Mixing or the prior or intercurrent use of any other local anesthetic with MARCAINE cannot be
recommended because of insufficient data on the clinical use of such mixtures.
PRECAUTIONS
General: The safety and effectiveness of spinal anesthetics depend on proper dosage, correct technique,
adequate precautions, and readiness for emergencies. Resuscitative equipment, oxygen, and other
resuscitative drugs should be available for immediate use. (See WARNINGS and ADVERSE
REACTIONS.) The patient should have IV fluids running via an indwelling catheter to assure a
functioning intravenous pathway. The lowest dosage of local anesthetic that results in effective anesthesia
should be used. Aspiration for blood should be performed before injection and injection should be made
slowly. Tolerance varies with the status of the patient. Elderly patients and acutely ill patients may require
reduced doses. Reduced doses may also be indicated in patients with increased intra-abdominal pressure
(including obstetrical patients), if otherwise suitable for spinal anesthesia.
There should be careful and constant monitoring of cardiovascular and respiratory (adequacy of
ventilation) vital signs and the patient’s state of consciousness after local anesthetic injection.
Restlessness, anxiety, incoherent speech, lightheadedness, numbness and tingling of the mouth and lips,
metallic taste, tinnitus, dizziness, blurred vision, tremors, depression, or drowsiness may be early warning
signs of central nervous system toxicity.
Spinal anesthetics should be used with caution in patients with severe disturbances of cardiac rhythm,
shock, or heart block.
Sympathetic blockade occurring during spinal anesthesia may result in peripheral vasodilation and
hypotension, the extent depending on the number of dermatomes blocked. Patients over 65 years,
particularly those with hypertension, may be at increased risk for experiencing the hypotensive effects of
MARCAINE Spinal. Blood pressure should, therefore, be carefully monitored especially in the early
phases of anesthesia. Hypotension may be controlled by vasoconstrictors in dosages depending on the
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severity of hypotension and response of treatment. The level of anesthesia should be carefully monitored
because it is not always controllable in spinal techniques.
Because amide-type local anesthetics such as MARCAINE are metabolized by the liver, these drugs,
especially repeat doses, should be used cautiously in patients with hepatic disease. Patients with severe
hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of
developing toxic plasma concentrations. Local anesthetics should also be used with caution in patients
with impaired cardiovascular function because they may be less able to compensate for functional
changes associated with the prolongation of AV conduction produced by these drugs. However, dosage
recommendations for spinal anesthesia are much lower than dosage recommendations for other major
blocks and most experience regarding hepatic and cardiovascular disease dose-related toxicity is derived
from these other major blocks.
Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as
epinephrine are employed in patients during or following the administration of potent inhalation agents. In
deciding whether to use these products concurrently in the same patient, the combined action of both
agents upon the myocardium, the concentration and volume of vasoconstrictor used, and the time since
injection, when applicable, should be taken into account.
Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial
malignant hyperthermia. Because it is not known whether amide-type local anesthetics may trigger this
reaction and because the need for supplemental general anesthesia cannot be predicted in advance, it is
suggested that a standard protocol for management should be available. Early unexplained signs of
tachycardia, tachypnea, labile blood pressure, and metabolic acidosis may precede temperature elevation.
Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect triggering
agent(s) and institution of treatment, including oxygen therapy, indicated supportive measures, and
dantrolene. (Consult dantrolene sodium intravenous package insert before using.)
The following conditions may preclude the use of spinal anesthesia, depending upon the physician’s
evaluation of the situation and ability to deal with the complications or complaints which may occur:
• Pre-existing diseases of the central nervous system, such as those attributable to pernicious anemia,
poliomyelitis, syphilis, or tumor.
• Hematological disorders predisposing to coagulopathies or patients on anticoagulant therapy. Trauma
to a blood vessel during the conduct of spinal anesthesia may, in some instances, result in
uncontrollable central nervous system hemorrhage or soft tissue hemorrhage.
• Chronic backache and preoperative headache.
• Hypotension and hypertension.
• Technical problems (persistent paresthesias, persistent bloody tap).
• Arthritis or spinal deformity.
• Extremes of age.
• Psychosis or other causes of poor cooperation by the patient.
Information for Patients: When appropriate, patients should be informed in advance that they may
experience temporary loss of sensation and motor activity, usually in the lower half of the body, following
proper administration of spinal anesthesia. Also, when appropriate, the physician should discuss other
information including adverse reactions in the MARCAINE Spinal package insert.
Clinically Significant Drug Interactions: The administration of local anesthetic solutions containing
epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors or tricyclic
antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should
generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is
essential.
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Concurrent administration of vasopressor drugs and of ergot-type oxytocic drugs may cause severe
persistent hypertension or cerebrovascular accidents.
Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: Long-term studies in animals to evaluate
the carcinogenic potential of bupivacaine hydrochloride have not been conducted. The mutagenic
potential and the effect on fertility of bupivacaine hydrochloride have not been determined.
Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women.
MARCAINE Spinal should be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus. Bupivacaine hydrochloride produced developmental toxicity when administered
subcutaneously to pregnant rats and rabbits at clinically relevant doses. This does not exclude the use of
MARCAINE Spinal at term for obstetrical anesthesia or analgesia. (See Labor and Delivery.)
Bupivacaine hydrochloride was administered subcutaneously to rats at doses of 4.4, 13.3, & 40 mg/kg and
to rabbits at doses of 1.3, 5.8, & 22.2 mg/kg during the period of organogenesis (implantation to closure
of the hard palate). The high doses are approximately 30-times the daily maximum recommended human
dose (MRHD) of 12 mg/day on a mg dose/m2 body surface area (BSA) basis. No embryo-fetal effects
were observed in rats at the high dose which caused increased maternal lethality. An increase in embryo-
fetal deaths was observed in rabbits at the high dose in the absence of maternal toxicity with the fetal No
Observed Adverse Effect Level being approximately 8-times the MRHD on a BSA basis.
In a rat pre- and post-natal development study (dosing from implantation through weaning) conducted at
subcutaneous doses of 4.4, 13.3, & 40 mg/kg mg/kg/day, decreased pup survival was observed at the high
dose. The high dose is approximately 30-times the daily MRHD of 12 mg/day on a BSA basis.
Labor and Delivery: Spinal anesthesia has a recognized use during labor and delivery. Bupivacaine
hydrochloride, when administered properly, via the epidural route in doses 10 to 12 times the amount
used in spinal anesthesia has been used for obstetrical analgesia and anesthesia without evidence of
adverse effects on the fetus.
Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by
blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help
prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously and
electronic fetal monitoring is highly advisable.
It is extremely important to avoid aortocaval compression by the gravid uterus during administrations of
regional block to parturients. To do this, the patient must be maintained in the left lateral decubitus
position or a blanket roll or sandbag may be placed beneath the right hip and the gravid uterus displaced
to the left.
Spinal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal
expulsive efforts. Spinal anesthesia has also been reported to prolong the second stage of labor by
removing the parturient’s reflex urge to bear down or by interfering with motor function. The use of
obstetrical anesthesia may increase the need for forceps assistance.
The use of some local anesthetic drug products during labor and delivery may be followed by diminished
muscle strength and tone for the first day or two of life. This has not been reported with bupivacaine.
There have been reports of cardiac arrest during use of MARCAINE 0.75% solution for epidural
anesthesia in obstetrical patients. The package insert for MARCAINE hydrochloride for epidural, nerve
block, etc., has a more complete discussion of preparation for, and management of, this problem. These
cases are compatible with systemic toxicity following unintended intravascular injection of the much
larger doses recommended for epidural anesthesia and have not occurred within the dose range of
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bupivacaine hydrochloride 0.75% recommended for spinal anesthesia in obstetrics. The 0.75%
concentration of MARCAINE is therefore not recommended for obstetrical epidural anesthesia.
MARCAINE Spinal (bupivacaine hydrochloride in dextrose injection) is recommended for spinal
anesthesia in obstetrics.
Nursing Mothers: Bupivacaine has been reported to be excreted in human milk suggesting that the
nursing infant could be theoretically exposed to a dose of the drug. Because of the potential for serious
adverse reactions in nursing infants from bupivacaine, a decision should be made whether to discontinue
nursing or not administer bupivacaine, taking into account the importance of the drug to the mother.
Pediatric Use: Until further experience is gained in patients younger than 18 years, administration of
MARCAINE Spinal in this age group is not recommended.
Geriatric Use: Patients over 65 years, particularly those with hypertension, may be at increased risk for
developing hypotension while undergoing spinal anesthesia with MARCAINE Spinal. (See
PRECAUTIONS, General and ADVERSE REACTIONS, Cardiovascular System.)
Elderly patients may require lower doses of MARCAINE Spinal. (See PRECAUTIONS, General and
DOSAGE AND ADMINISTRATION.)
In clinical studies, differences in various pharmacokinetic parameters have been observed between elderly
and younger patients. (See CLINICAL PHARMACOLOGY, Pharmacokinetics.)
This product is known to be substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Because elderly patients are more likely to
have decreased renal function, care should be taken in dose selection, and it may be useful to monitor
renal function. (See CLINICAL PHARMACOLOGY, Pharmacokinetics.)
ADVERSE REACTIONS
Reactions to bupivacaine are characteristic of those associated with other amide-type local anesthetics.
The most commonly encountered acute adverse experiences which demand immediate countermeasures
following the administration of spinal anesthesia are hypotension due to loss of sympathetic tone and
respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia. These
may lead to cardiac arrest if untreated. In addition, dose-related convulsions and cardiovascular collapse
may result from diminished tolerance, rapid absorption from the injection site, or from unintentional
intravascular injection of a local anesthetic solution. Factors influencing plasma protein binding, such as
acidosis, systemic diseases which alter protein production, or competition of other drugs for protein
binding sites, may diminish individual tolerance.
Respiratory System: Respiratory paralysis or underventilation may be noted as a result of upward
extension of the level of spinal anesthesia and may lead to secondary hypoxic cardiac arrest if untreated.
Preanesthetic medication, intraoperative analgesics and sedatives, as well as surgical manipulation, may
contribute to underventilation. This will usually be noted within minutes of the injection of spinal
anesthetic solution, but because of differing maximal onset times, differing intercurrent drug usage and
differing surgical manipulation, it may occur at any time during surgery or the immediate recovery period.
Cardiovascular System: Hypotension due to loss of sympathetic tone is a commonly encountered
extension of the clinical pharmacology of spinal anesthesia. This is more commonly observed in elderly
patients, particularly those with hypertension, and patients with shrunken blood volume, shrunken
interstitial fluid volume, cephalad spread of the local anesthetic, and/or mechanical obstruction of venous
return. Nausea and vomiting are frequently associated with hypotensive episodes following the
administration of spinal anesthesia. High doses, or inadvertent intravascular injection, may lead to high
plasma levels and related depression of the myocardium, decreased cardiac output, bradycardia, heart
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block, ventricular arrhythmias, and, possibly, cardiac arrest. (See WARNINGS, PRECAUTIONS, and
OVERDOSAGE sections.)
Central Nervous System: Respiratory paralysis or underventilation secondary to cephalad spread of the
level of spinal anesthesia (see Respiratory System) and hypotension for the same reason (see
Cardiovascular System) are the two most commonly encountered central nervous system-related adverse
observations which demand immediate countermeasures.
High doses or inadvertent intravascular injection may lead to high plasma levels and related central
nervous system toxicity characterized by excitement and/or depression. Restlessness, anxiety, dizziness,
tinnitus, blurred vision, or tremors may occur, possibly proceeding to convulsions. However, excitement
may be transient or absent, with depression being the first manifestation of an adverse reaction. This may
quickly be followed by drowsiness merging into unconsciousness and respiratory arrest.
Neurologic: The incidences of adverse neurologic reactions associated with the use of local anesthetics
may be related to the total dose of local anesthetic administered and are also dependent upon the
particular drug used, the route of administration, and the physical status of the patient. Many of these
effects may be related to local anesthetic techniques, with or without a contribution from the drug.
Neurologic effects following spinal anesthesia may include loss of perineal sensation and sexual function;
persistent anesthesia, paresthesia, weakness and paralysis of the lower extremities, and loss of sphincter
control all of which may have slow, incomplete, or no recovery; hypotension, high or total spinal block;
urinary retention; headache; backache; septic meningitis, meningismus; arachnoiditis; slowing of labor;
increased incidence of forceps delivery; shivering; cranial nerve palsies due to traction on nerves from
loss of cerebrospinal fluid; and fecal and urinary incontinence.
Allergic: Allergic-type reactions are rare and may occur as a result of sensitivity to the local anesthetic.
These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema
(including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive
sweating, elevated temperature, and, possibly, anaphylactoid-like symptomatology (including severe
hypotension). Cross sensitivity among members of the amide-type local anesthetic group has been
reported. The usefulness of screening for sensitivity has not been definitely established.
Other: Nausea and vomiting may occur during spinal anesthesia.
OVERDOSAGE
Acute emergencies from local anesthetics are generally related to high plasma levels encountered during
therapeutic use or to underventilation (and perhaps apnea) secondary to upward extension of spinal
anesthesia. Hypotension is commonly encountered during the conduct of spinal anesthesia due to
relaxation of sympathetic tone, and sometimes, contributory mechanical obstruction of venous return.
Management of Local Anesthetic Emergencies: The first consideration is prevention, best
accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the
patient’s state of consciousness after each local anesthetic injection. At the first sign of change, oxygen
should be administered.
The first step in the management of systemic toxic reactions, as well as underventilation or apnea due to a
high or total spinal, consists of immediate attention to the establishment and maintenance of a patent
airway and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable
of permitting immediate positive airway pressure by mask. This may prevent convulsions if they have not
already occurred.
If necessary, use drugs to control the convulsions. A 50 mg to 100 mg bolus IV injection of
succinylcholine will paralyze the patient without depressing the central nervous or cardiovascular systems
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and facilitate ventilation. A bolus IV dose of 5 mg to 10 mg of diazepam or 50 mg to 100 mg of thiopental
will permit ventilation and counteract central nervous system stimulation, but these drugs also depress
central nervous system, respiratory and cardiac function, add to postictal depression and may result in
apnea. Intravenous barbiturates, anticonvulsant agents, or muscle relaxants should only be administered
by those familiar with their use. Immediately after the institution of these ventilatory measures, the
adequacy of the circulation should be evaluated. Supportive treatment of circulatory depression may
require administration of intravenous fluids, and, when appropriate, a vasopressor dictated by the clinical
situation (such as ephedrine or epinephrine to enhance myocardial contractile force).
Hypotension due to sympathetic relaxation may be managed by giving intravenous fluids (such as
isotonic saline or lactated Ringer’s solution), in an attempt to relieve mechanical obstruction of venous
return, or by using vasopressors (such as ephedrine which increases the force of myocardial contractions)
and, if indicated, by giving plasma expanders or whole blood.
Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated after
initial administration of oxygen by mask if difficulty is encountered in the maintenance of a patent
airway, or if prolonged ventilatory support (assisted or controlled) is indicated.
Recent clinical data from patients experiencing local anesthetic-induced convulsions demonstrated rapid
development of hypoxia, hypercarbia, and acidosis with bupivacaine within a minute of the onset of
convulsions. These observations suggest that oxygen consumption and carbon dioxide production are
greatly increased during local anesthetic convulsions and emphasize the importance of immediate and
effective ventilation with oxygen which may avoid cardiac arrest.
If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis plus
myocardial depression from the direct effects of the local anesthetic may result in cardiac arrhythmias,
bradycardia, asystole, ventricular fibrillation, or cardiac arrest. Respiratory abnormalities, including
apnea, may occur. Underventilation or apnea due to a high or total spinal may produce these same signs
and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur,
standard cardiopulmonary resuscitative measures should be instituted and maintained for a prolonged
period if necessary. Recovery has been reported after prolonged resuscitative efforts.
The supine position is dangerous in pregnant women at term because of aortocaval compression by the
gravid uterus. Therefore during treatment of systemic toxicity, maternal hypotension, or fetal bradycardia
following regional block, the parturient should be maintained in the left lateral decubitus position if
possible, or manual displacement of the uterus off the great vessels be accomplished.
The mean seizure dosage of bupivacaine in rhesus monkeys was found to be 4.4 mg/kg with mean arterial
plasma concentration of 4.5 mcg/mL. The intravenous and subcutaneous LD50 in mice is 6 mg/kg to
8 mg/kg and 38 mg/kg to 54 mg/kg respectively.
DOSAGE AND ADMINISTRATION
The dose of any local anesthetic administered varies with the anesthetic procedure, the area to be
anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of
anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual
tolerance, and the physical condition of the patient. The smallest dose and concentration required to
produce the desired result should be administered. Dosages of MARCAINE Spinal should be reduced for
elderly and debilitated patients and patients with cardiac and/or liver disease.
For specific techniques and procedures, refer to standard textbooks.
There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of
local anesthetics following arthroscopic and other surgical procedures. MARCAINE Spinal is not
approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION).
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The extent and degree of spinal anesthesia depend upon several factors including dosage, specific gravity
of the anesthetic solution, volume of solution used, force of injection, level of puncture, and position of
the patient during and immediately after injection.
Seven and one-half mg (7.5 mg or 1 mL) MARCAINE Spinal has generally proven satisfactory for spinal
anesthesia for lower extremity and perineal procedures including TURP and vaginal hysterectomy.
Twelve mg (12 mg or 1.6 mL) has been used for lower abdominal procedures such as abdominal
hysterectomy, tubal ligation, and appendectomy. These doses are recommended as a guide for use in the
average adult and may be reduced for the elderly or debilitated patients. Because experience with
MARCAINE Spinal is limited in patients below the age of 18 years, dosage recommendations in this age
group cannot be made.
Obstetrical Use: Doses as low as 6 mg bupivacaine hydrochloride have been used for vaginal delivery
under spinal anesthesia. The dose range of 7.5 mg to 10.5 mg (1 mL to 1.4 mL) bupivacaine
hydrochloride has been used for Cesarean section under spinal anesthesia.
In recommended doses, MARCAINE Spinal produces complete motor and sensory block.
Unused portions of solutions should be discarded following initial use.
MARCAINE Spinal should be inspected visually for discoloration and particulate matter prior to
administration; solutions which are discolored or which contain particulate matter should not be
administered.
HOW SUPPLIED
Single-dose ampuls of 2 mL (15 mg bupivacaine hydrochloride with 165 mg dextrose), is supplied as
follows:
NDC No.
Container
Fill
Quantity
0409-1761-02
0409-1761-62
Uni-Amp™
Uni-Amp™
2 mL
2 mL
package of 10
bulk package of 800
Store at 20 to 25ºC (68 to 77ºF). [See USP Controlled Room Temperature.]
MARCAINE Spinal solution may be autoclaved once at 15 pound pressure, 121°C (250°F) for 15
minutes. Do not administer any solution which is discolored or contains particulate matter.
Revised: 10/2011
EN-2919
Hospira, Inc., Lake Forest, IL 60045 USA Hospira
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Bupivacaine HCl
0.5%
with
epinephrine
1:200,000 (as bitartrate)
(bupivacaine hydrochloride and epinephrine injection, USP)
THIS SOLUTION IS INTENDED FOR DENTAL USE.
Rx only
DESCRIPTION
Bupivacaine hydrochloride is (±) -1-Butyl-2´,6´-pipecoloxylidide monohydrochloride, monohydrate, a
white crystalline powder that is freely soluble in 95 percent ethanol, soluble in water, and slightly soluble
in chloroform or acetone. It has the following structural formula: structural formula
Epinephrine is (-)-3,4-Dihydroxy-α-[(methylamino)methyl] benzyl alcohol. It has the following structural
formula: structural formula
BUPIVACAINE HCl is available in a sterile isotonic solution with epinephrine (as bitartrate) 1:200,000.
Solutions of BUPIVACAINE HCl containing epinephrine may not be autoclaved.
BUPIVACAINE HCl is related chemically and pharmacologically to the aminoacyl local anesthetics. It is
a homologue of mepivacaine and is chemically related to lidocaine.
All three of these anesthetics contain an amide linkage between the aromatic nucleus and the amino or
piperidine group. They differ in this respect from the procaine-type local anesthetics, which have an ester
linkage.
CLINICAL PHARMACOLOGY
BUPIVACAINE HCl stabilizes the neuronal membrane and prevents the initiation and transmission of
nerve impulses, thereby effecting local anesthesia.
The onset of action following dental injections is usually 2 to 10 minutes and anesthesia may last two or
three times longer than lidocaine and mepivacaine for dental use, in many patients up to 7 hours. The
duration of anesthetic effect is prolonged by the addition of epinephrine 1:200,000.
It has also been noted that there is a period of analgesia that persists after the return of sensation, during
which time the need for strong analgesic is reduced.
After injection of BUPIVACAINE HCl for caudal, epidural or peripheral nerve block in man, peak levels
of BUPIVACAINE HCl in the blood are reached in 30 to 45 minutes, followed by a decline to
insignificant levels during the next three to six hours. Because of its amide structure, BUPIVACAINE
HCl is not detoxified by plasma esterases but is detoxified, via conjugation with glucuronic acid, in the
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liver. When administered in recommended doses and concentrations, BUPIVACAINE HCl does not
ordinarily produce irritation or tissue damage, and does not cause methemoglobinemia.
Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous
systems (CNS). At blood concentrations achieved with normal therapeutic doses, changes in cardiac
conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal.
However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to
atrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. In
addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased
cardiac output and arterial blood pressure. Recent clinical reports and animal research suggest that these
cardiovascular changes are more likely to occur after unintended intravascular injection of bupivacaine.
Therefore, incremental dosing is necessary.
Following systemic absorption, local anesthetics can produce central nervous system stimulation,
depression, or both. Apparent central stimulation is manifested as restlessness, tremors and shivering
progressing to convulsions, followed by depression and coma progressing ultimately to respiratory arrest.
However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The
depressed stage may occur without a prior excited state.
INDICATIONS AND USAGE
BUPIVACAINE HCl is indicated for the production of local anesthesia for dental procedures by
infiltration injection or nerve block in adults.
BUPIVACAINE HCl is not recommended for children.
CONTRAINDICATIONS
BUPIVACAINE HCl is contraindicated in patients with a known hypersensitivity to it or to any local
anesthetic agent of the amide-type or to other components of BUPIVACAINE HCl solutions.
WARNINGS
LOCAL ANESTHETICS SHOULD BE EMPLOYED ONLY BY CLINICIANS WHO ARE WELL
VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE-RELATED TOXICITY AND OTHER
ACUTE EMERGENCIES WHICH MIGHT ARISE FROM THE BLOCK TO BE EMPLOYED, AND
THEN ONLY AFTER INSURING THE IMMEDIATE AVAILABILITY OF OXYGEN, OTHER
RESUSCITATIVE DRUGS, CARDIOPULMONARY RESUSCITATIVE EQUIPMENT, AND THE
PERSONNEL RESOURCES NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS
AND RELATED EMERGENCIES. (See also ADVERSE REACTIONS and PRECAUTIONS.)
DELAY IN PROPER MANAGEMENT OF DOSE-RELATED TOXICITY, UNDERVENTILATION
FROM ANY CAUSE, AND/OR ALTERED SENSITIVITY MAY LEAD TO THE DEVELOPMENT
OF ACIDOSIS, CARDIAC ARREST AND, POSSIBLY, DEATH.
Small doses of local anesthetics injected into the head and neck area, as small as nine to eighteen
milligrams, may produce adverse reactions similar to systemic toxicity seen with unintentional
intravascular injections of larger doses. Confusion, convulsions, respiratory depression, and/or respiratory
arrest, cardiovascular stimulation or depression and cardiac arrest have been reported. Reactions resulting
in fatalities have occurred on rare occasions. In a few cases, resuscitation has been difficult or impossible
despite apparently adequate preparation and appropriate management. These reactions may be due to
intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. Patients
receiving these blocks should have their circulation and respiration monitored and be constantly observed.
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Resuscitative equipment and personnel for treating adverse reactions should be immediately available.
Dosage recommendations should not be exceeded (see DOSAGE AND ADMINISTRATION).
It is essential that aspiration for blood or cerebrospinal fluid (where applicable) be done prior to injecting
any local anesthetic, both the original dose and all subsequent doses, to avoid intravascular injection.
However, a negative aspiration does not ensure against an intravascular injection.
Reactions resulting in fatality have occurred on rare occasions with the use of local anesthetics, even in
the absence of a history of hypersensitivity.
This solution, which contains a vasoconstrictor, should be used with extreme caution for patients whose
medical history and physical evaluation suggest the existence of hypertension, arteriosclerotic heart
disease, cerebral vascular insufficiency, heart block, thyrotoxicosis and diabetes, etc., as well as patients
receiving drugs likely to produce alterations in blood pressure.
BUPIVACAINE HCl with epinephrine 1:200,000 or other vasopressors should not be used concomitantly
with ergot-type oxytocic drugs, because a severe persistent hypertension may occur. Likewise, solutions
of BUPIVACAINE HCl containing a vasoconstrictor, such as epinephrine, should be used with extreme
caution in patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the triptyline or
imipramine types, because severe prolonged hypertension may result.
Until further experience is gained in children younger than 12 years, administration of BUPIVACAINE
HCl in this age group is not recommended.
Contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic
symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall
prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity
is seen more frequently in asthmatic than in nonasthmatic people.
PRECAUTIONS
The safety and effectiveness of local anesthetics depend upon proper dosage, correct technique, adequate
precautions, and readiness for emergencies.
The lowest dosage that gives effective anesthesia should be used in order to avoid high plasma levels and
serious systemic side effects. Injection of repeated doses of BUPIVACAINE HCl may cause significant
increase in blood levels with each additional dose, due to accumulation of the drug or its metabolites or
due to slow metabolic degradation. Tolerance varies with the status of the patient. Debilitated, elderly
patients and acutely ill patients should be given reduced doses commensurate with age and physical
condition.
Because of the long duration of anesthesia, when BUPIVACAINE HCl 0.5% with epinephrine is used for
dental injections, patients should be cautioned about the possibility of inadvertent trauma to tongue, lips,
and buccal mucosa and advised not to chew solid foods or test the anesthetized area by biting or probing.
Changes in sensorium, such as excitation, disorientation, drowsiness, may be early indications of a high
blood level of the drug and may occur following inadvertent intravascular administration or rapid
absorption of BUPIVACAINE HCl.
Solutions containing a vasoconstrictor should be used cautiously in areas with limited blood supply, in the
presence of diseases that may adversely affect the patient's cardiovascular system, or in patients with
peripheral vascular disease.
Caution is advised in administration of repeat doses of BUPIVACAINE HCl to patients with severe liver
disease.
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Local anesthetic procedures should be used with caution when there is inflammation and/or sepsis in the
region of the proposed injection.
Drug Interactions: See WARNINGS concerning solutions containing a vasoconstrictor.
If sedatives are employed to reduce patient apprehension, use reduced doses, since local anesthetic agents,
like sedatives, are central nervous system depressants which in combination may have an additive effect.
BUPIVACAINE HCl should be used cautiously in persons with known drug allergies or sensitivities,
particularly to the amide-type local anesthetics.
Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as
epinephrine are employed in patients during or following the administration of chloroform, halothane,
cyclopropane, trichloroethylene, or other related agents. In deciding whether to use these products
concurrently in the same patient, the combined action of both agents upon the myocardium, the
concentration and volume of vasoconstrictor used, and the time since injection, when applicable, should
be taken into account.
Information for Patients: When appropriate, the dentist should discuss information including adverse
reactions in the package insert for BUPIVACAINE HCl.
Clinically Significant Drug Interactions: The administration of local anesthetic solutions containing
epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors or tricyclic
antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should
generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is
essential.
Concurrent administration of vasopressor drugs and of ergot-type oxytocic drugs may cause severe,
persistent hypertension or cerebrovascular accidents.
Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals to evaluate the
carcinogenic potential of bupivacaine hydrochloride have not been conducted. The mutagenic potential
and the effect on fertility of bupivacaine hydrochloride have not been determined.
Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women.
BUPIVACAINE HCl should be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus. Bupivacaine hydrochloride produced developmental toxicity when administered
subcutaneously to pregnant rats and rabbits at clinically relevant doses. This does not exclude the use of
BUPIVACAINE HCl at term for obstetrical anesthesia or analgesia.
Bupivacaine hydrochloride was administered subcutaneously to rats at doses of 4.4, 13.3, & 40 mg/kg and
to rabbits at doses of 1.3, 5.8, & 22.2 mg/kg during the period of organogenesis (implantation to closure
of the hard palate). The high doses are approximately 4-times the daily maximum recommended human
dose (MRHD) of 90 mg/day on a mg dose/m2 body surface area (BSA) basis. No embryo-fetal effects
were observed in rats at the high dose which caused increased maternal lethality. An increase in embryo-
fetal deaths was observed in rabbits at the high dose in the absence of maternal toxicity with the fetal No
Observed Adverse Effect Level being a comparable dose to the MRHD on a BSA basis.
In a rat pre- and post-natal development study (dosing from implantation through weaning) conducted at
subcutaneous doses of 4.4, 13.3, & 40 mg/kg mg/kg/day, decreased pup survival was observed at the high
dose. The high dose is approximately 4-times the daily MRHD of 90 mg/day on a BSA basis.
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Nursing Mothers: It is not known whether local anesthetic drugs are excreted in human milk. Because
many drugs are excreted in human milk, caution should be exercised when local anesthetics are
administered to a nursing woman.
Pediatric Use: Until further experience is gained in children younger than 12 years, administration of
BUPIVACAINE HCl in this age group is not recommended.
ADVERSE REACTIONS
Reactions to BUPIVACAINE HCl are characteristic of those associated with other amide-type local
anesthetics. A major cause of adverse reactions to this group of drugs is excessive plasma levels, which
may be due to overdosage, inadvertent intravascular injection, or slow metabolic degradation.
Excessive plasma levels of the amide-type local anesthetics cause systemic reactions involving the central
nervous system and the cardiovascular system. The central nervous system effects are characterized by
excitation or depression. The first manifestation may be nervousness, dizziness, blurred vision, or
tremors, followed by drowsiness, convulsions, unconsciousness, and possibly respiratory arrest. Since
excitement may be transient or absent, the first manifestation may be drowsiness, sometimes merging into
unconsciousness and respiratory arrest. Other central nervous system effects may be nausea, vomiting,
chills, constriction of the pupils, or tinnitus. The cardiovascular manifestations of excessive plasma levels
may include depression of the myocardium, blood pressure changes (usually hypotension), and cardiac
arrest. Allergic reactions, which may be due to hypersensitivity, idiosyncrasy, or diminished tolerance, are
characterized by cutaneous lesions (e.g., urticaria), edema, and other manifestations of allergy. Detection
of sensitivity by skin testing is of doubtful value.
Transient facial swelling and puffiness may occur near the injection site.
Treatment of Reactions: Toxic effects of local anesthetics require symptomatic treatment; there is no
specific cure. The dentist should be prepared to maintain an airway and to support ventilation with oxygen
and assisted or controlled respiration as required. Supportive treatment of the cardiovascular system
includes intravenous fluids and, when appropriate, vasopressors (preferably those that stimulate the
myocardium). Convulsions may be controlled with oxygen and intravenous administration, in small
increments, of a barbiturate, as follows: preferably, an ultra-short-acting barbiturate such as thiopental or
thiamylal; if this is not available, a short-acting barbiturate (e.g., secobarbital or pentobarbital) or
diazepam. Intravenous barbiturates or anticonvulsant agents should only be administered by those familiar
with their use.
DOSAGE AND ADMINISTRATION
As with all local anesthetics, the dosage varies and depends upon the area to be anesthetized, the
vascularity of the tissues, the number of neuronal segments to be blocked, individual tolerance, and the
technique of anesthesia. The lowest dosage needed to provide effective anesthesia should be administered.
For specific techniques and procedures, refer to standard textbooks.
The 0.5% concentration with epinephrine is recommended for infiltration and block injection in the
maxillary and mandibular area when a longer duration of local anesthetic action is desired, such as for
oral surgical procedures generally associated with significant postoperative pain. The average dose of
1.8 mL (9 mg) per injection site will usually suffice; an occasional second dose of 1.8 mL (9 mg) may be
used if necessary to produce adequate anesthesia after making allowance for 2 to 10 minutes onset time
(see CLINICAL PHARMACOLOGY). The lowest effective dose should be employed and time should
be allowed between injections; it is recommended that the total dose for all injection sites, spread out over
a single dental sitting, should not ordinarily exceed 90 mg for a healthy adult patient (ten 1.8 mL
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injections of 0.5% BUPIVACAINE HCl with epinephrine). Injections should be made slowly and with
frequent aspirations. Until further experience is gained, BUPIVACAINE HCl in dentistry is not
recommended for children younger than 12 years.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration, whenever solution and container permit.
HOW SUPPLIED
Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Protect from light.
0.5% Bupivacaine hydrochloride with epinephrine 1:200,000 (as bitartrate) – Sterile isotonic solutions
containing sodium chloride. Each 1 mL contains 5 mg bupivacaine hydrochloride and 0.0091 mg
epinephrine bitartrate, with 0.5 mg sodium metabisulfite, 0.001 mL monothioglycerol, and 2 mg ascorbic
acid as antioxidants, 0.0017 mL 60% sodium lactate buffer, and 0.1 mg edetate calcium disodium as
stabilizer. The pH of these solutions is adjusted with sodium hydroxide or hydrochloric acid. Solutions of
BUPIVACAINE HCl that contain epinephrine should not be autoclaved and should be protected from
light. Do not use the solution if its color is pinkish or darker than slightly yellow or if it contains a
precipitate. This product is latex-free.
NDC 0409-7600-01 1.8 mL cartridges, containers of 50, to fit the CarpuleTM aspirator.
Revised: 10/2011
EN-2920
Hospira, Inc., Lake Forest, IL 60045 USA Hospira
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|
custom-source
|
2025-02-12T13:44:51.704079
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/018692s015lbl.pdf', 'application_number': 18692, 'submission_type': 'SUPPL ', 'submission_number': 15}
|
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structural formula
HALDOL® Decanoate 50 (haloperidol)
HALDOL® Decanoate 100 (haloperidol)
For IM Injection Only
WARNING
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic
drugs are at an increased risk of death. Analyses of seventeen placebo-controlled
trials (modal duration of 10 weeks), largely in patients taking atypical
antipsychotic drugs, revealed a risk of death in drug-treated patients of between
1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a
typical 10-week controlled trial, the rate of death in drug-treated patients was
about 4.5%, compared to a rate of about 2.6% in the placebo group. Although
the causes of death were varied, most of the deaths appeared to be either
cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia)
in nature. Observational studies suggest that, similar to atypical antipsychotic
drugs, treatment with conventional antipsychotic drugs may increase mortality.
The extent to which the findings of increased mortality in observational studies
may be attributed to the antipsychotic drug as opposed to some characteristic(s)
of the patients is not clear. HALDOL Decanoate is not approved for the
treatment of patients with dementia-related psychosis (see WARNINGS).
DESCRIPTION
Haloperidol decanoate is the decanoate ester of the butyrophenone, HALDOL
(haloperidol). It has a markedly extended duration of effect. It is available in sesame
oil in sterile form for intramuscular (IM) injection. The structural formula of
haloperidol
decanoate,
4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-4
piperidinyl decanoate, is:
Haloperidol decanoate is almost insoluble in water (0.01 mg/mL), but is soluble in
most organic solvents.
Reference ID: 2999248
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Each mL of HALDOL Decanoate 50 for IM injection contains 50 mg haloperidol
(present as haloperidol decanoate 70.52 mg) in a sesame oil vehicle, with 1.2% (w/v)
benzyl alcohol as a preservative.
Each mL of HALDOL Decanoate 100 for IM injection contains 100 mg haloperidol
(present as haloperidol decanoate 141.04 mg) in a sesame oil vehicle, with 1.2%
(w/v) benzyl alcohol as a preservative.
CLINICAL PHARMACOLOGY
HALDOL Decanoate 50 and HALDOL Decanoate 100 are the long-acting forms of
HALDOL (haloperidol). The basic effects of haloperidol decanoate are no different
from those of HALDOL with the exception of duration of action. Haloperidol blocks
the effects of dopamine and increases its turnover rate; however, the precise
mechanism of action is unknown.
Administration of haloperidol decanoate in sesame oil results in slow and sustained
release of haloperidol. The plasma concentrations of haloperidol gradually rise,
reaching a peak at about 6 days after the injection, and falling thereafter, with an
apparent half-life of about 3 weeks. Steady state plasma concentrations are achieved
after the third or fourth dose. The relationship between dose of haloperidol decanoate
and plasma haloperidol concentration is roughly linear for doses below 450 mg. It
should be noted, however, that the pharmacokinetics of haloperidol decanoate
following intramuscular injections can be quite variable between subjects.
INDICATIONS AND USAGE
HALDOL Decanoate 50 and HALDOL Decanoate 100 are indicated for the treatment
of schizophrenic patients who require prolonged parenteral antipsychotic therapy.
CONTRAINDICATIONS
Since the pharmacologic and clinical actions of HALDOL Decanoate 50 and
HALDOL Decanoate 100 are attributed to HALDOL (haloperidol) as the active
medication, Contraindications, Warnings, and additional information are those of
HALDOL, modified only to reflect the prolonged action.
HALDOL is contraindicated in severe toxic central nervous system depression or
comatose states from any cause and in individuals who are hypersensitive to this drug
or have Parkinson’s disease.
Reference ID: 2999248
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WARNINGS
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic
drugs are at an increased risk of death. HALDOL Decanoate is not approved for
the treatment of patients with dementia-related psychosis (see BOXED
WARNING).
Cardiovascular Effects
Cases of sudden death, QT-prolongation, and Torsades de Pointes have been reported
in patients receiving haloperidol. Higher than recommended doses of any formulation
and intravenous administration of haloperidol appear to be associated with a higher
risk of QT-prolongation and Torsades de Pointes. Although cases have been reported
even in the absence of predisposing factors, particular caution is advised in treating
patients with other QT-prolonging conditions (including electrolyte imbalance
[particularly hypokalemia and hypomagnesemia], drugs known to prolong QT,
underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome).
HALDOL DECANOATE MUST NOT BE ADMINISTERED INTRAVENOUSLY.
Tardive Dyskinesia
A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements
may develop in patients treated with antipsychotic drugs. Although the prevalence of
the syndrome appears to be highest among the elderly, especially elderly women, it is
impossible to rely upon prevalence estimates to predict, at the inception of
antipsychotic treatment, which patients are likely to develop the syndrome. Whether
antipsychotic drug products differ in their potential to cause tardive dyskinesia is
unknown.
Both the risk of developing tardive dyskinesia and the likelihood that it will become
irreversible are believed to increase as the duration of treatment and the total
cumulative dose of antipsychotic drugs administered to the patient increase. However,
the syndrome can develop, although much less commonly, after relatively brief
treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the
syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.
Antipsychotic treatment, itself, however, may suppress (or partially suppress) the
signs and symptoms of the syndrome and thereby may possibly mask the underlying
process. The effect that symptomatic suppression has upon the long-term course of
the syndrome is unknown.
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Given these considerations, antipsychotic drugs should be prescribed in a manner that
is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic
treatment should generally be reserved for patients who suffer from a chronic illness
that 1) is known to respond to antipsychotic drugs, and 2) for whom alternative,
equally effective, but potentially less harmful treatments are not available or
appropriate. In patients who do require chronic treatment, the smallest dose and the
shortest duration of treatment producing a satisfactory clinical response should be
sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics,
drug discontinuation should be considered. However, some patients may require
treatment despite the presence of the syndrome. (For further information about the
description of tardive dyskinesia and its clinical detection, please refer to ADVERSE
REACTIONS.)
Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant
Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical
manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status
(including catatonic signs) and evidence of autonomic instability (irregular pulse or
blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs
may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and
acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at
a diagnosis, it is important to identify cases where the clinical presentation includes
both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated
or inadequately treated extrapyramidal signs and symptoms (EPS). Other important
considerations in the differential diagnosis include central anticholinergic toxicity,
heat stroke, drug fever and primary central nervous system (CNS) pathology.
The management of NMS should include 1) immediate discontinuation of
antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive
symptomatic treatment and medical monitoring, and 3) treatment of any concomitant
serious medical problems for which specific treatments are available. There is no
general agreement about specific pharmacological treatment regimens for
uncomplicated NMS.
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If a patient requires antipsychotic drug treatment after recovery from NMS, the
potential reintroduction of drug therapy should be carefully considered. The patient
should be carefully monitored, since recurrences of NMS have been reported.
Hyperpyrexia and heat stroke, not associated with the above symptom complex, have
also been reported with HALDOL.
Combined Use of HALDOL and Lithium
An encephalopathic syndrome (characterized by weakness, lethargy, fever,
tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated
serum enzymes, BUN, and fasting blood sugar) followed by irreversible brain
damage has occurred in a few patients treated with lithium plus HALDOL. A causal
relationship between these events and the concomitant administration of lithium and
HALDOL has not been established; however, patients receiving such combined
therapy should be monitored closely for early evidence of neurological toxicity and
treatment discontinued promptly if such signs appear.
General
A number of cases of bronchopneumonia, some fatal, have followed the use of
antipsychotic drugs, including HALDOL (haloperidol). It has been postulated that
lethargy and decreased sensation of thirst due to central inhibition may lead to
dehydration, hemoconcentration and reduced pulmonary ventilation. Therefore, if the
above signs and symptoms appear, especially in the elderly, the physician should
institute remedial therapy promptly.
Although not reported with HALDOL, decreased serum cholesterol and/or cutaneous
and ocular changes have been reported in patients receiving chemically-related drugs.
PRECAUTIONS
Leukopenia, Neutropenia, and Agranulocytosis
Class Effect: In clinical trial and/or postmarketing experience, events of
leukopenia/neutropenia have been reported temporally related to antipsychotic agents,
including HALDOL Decanoate. Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood
cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with
a
history
of
a
clinically
significant
low
WBC
or
a
drug-induced
leukopenia/neutropenia should have their complete blood count (CBC) monitored
frequently during the first few months of therapy and discontinuation of HALDOL
Decanoate should be considered at the first sign of a clinically significant decline in
WBC in the absence of other causative factors.
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Patients with clinically significant neutropenia should be carefully monitored for
fever or other symptoms or signs of infection and treated promptly if such symptoms
or signs occur. Patients with severe neutropenia (absolute neutrophil count
<1000/mm3) should discontinue HALDOL Decanoate and have their WBC followed
until recovery.
Other
HALDOL Decanoate 50 and HALDOL Decanoate 100 should be administered
cautiously to patients:
• with severe cardiovascular disorders, because of the possibility of transient
hypotension and/or precipitation of anginal pain. Should hypotension occur and a
vasopressor be required, epinephrine should not be used since HALDOL
(haloperidol) may block its vasopressor activity, and paradoxical further lowering
of the blood pressure may occur. Instead, metaraminol, phenylephrine or
norepinephrine should be used.
• receiving anticonvulsant medications, with a history of seizures, or with EEG
abnormalities, because HALDOL may lower the convulsive threshold. If
indicated, adequate anticonvulsant therapy should be concomitantly maintained.
• with known allergies, or with a history of allergic reactions to drugs.
• receiving anticoagulants, since an isolated instance of interference occurred with
the effects of one anticoagulant (phenindione).
If concomitant antiparkinson medication is required, it may have to be continued after
HALDOL Decanoate 50 or HALDOL Decanoate 100 is discontinued because of the
prolonged action of haloperidol decanoate. If both drugs are discontinued
simultaneously, extrapyramidal symptoms may occur. The physician should keep in
mind the possible increase in intraocular pressure when anticholinergic drugs,
including antiparkinson agents, are administered concomitantly with haloperidol
decanoate.
When HALDOL Decanoate is used to control mania in cyclic disorders, there may be
a rapid mood swing to depression.
Severe neurotoxicity (rigidity, inability to walk or talk) may occur in patients with
thyrotoxicosis who are also receiving antipsychotic medication, including HALDOL.
Information for Patients
Haloperidol decanoate may impair the mental and/or physical abilities required for
the performance of hazardous tasks such as operating machinery or driving a motor
vehicle. The ambulatory patient should be warned accordingly.
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The use of alcohol with this drug should be avoided due to possible additive effects
and hypotension.
Drug Interactions
Drug-drug interactions can be pharmacodynamic (combined pharmacologic effects)
or pharmacokinetic (alteration of plasma levels). The risks of using haloperidol in
combination with other drugs have been evaluated as described below.
Pharmacodynamic Interactions
Since QT-prolongation has been observed during Haldol treatment, caution is advised
when prescribing to patient with QT-prolongation conditions (long QT-syndrome,
hypokalemia, electrolyte imbalance) or to patients receiving medications known to
prolong the QT-interval or known to cause electrolyte imbalance.
As with other antipsychotic agents, it should be noted that HALDOL may be capable
of potentiating CNS depressants such as anesthetics, opiates and alcohol.
Ketoconazole is a potent inhibitor of CYP3A4. Increases in QTc have been observed
when haloperidol was given in combination with the metabolic inhibitors
ketoconazole (400 mg/day) and paroxetine (20 mg/day). It may be necessary to
reduce the haloperidol dosage.
Pharmacokinetic Interactions
The Effect of Other Drugs on Haldol® Decanoate
Haloperidol is metabolized by several routes, including the glucuronidation and the
cytochrome P450 enzyme system. Inhibition of these routes of metabolism by another
drug may result in increased haloperidol concentrations and potentially increase the
risk of certain adverse events, including QT-prolongation.
Drugs Characterized as Substrates, Inhibitors or Inducers of CYP3A4,
CYP2D6 or Glucuronidation
In pharmacokinetic studies, mild to moderately increased haloperidol concentrations
have been reported when haloperidol was given concomitantly with drugs
characterized as substrates or inhibitors of CYP3A4 or CYP2D6 isoenzymes, such as,
itraconazole,
nefazodone,
buspirone,
venlafaxine,
alprazolam,
fluvoxamine,
quinidine, fluoxetine, sertraline, chlorpromazine, and promethazine.
When prolonged treatment (1-2 weeks) with enzyme-inducing drugs such as rifampin
or carbamazepine is added to Haldol therapy, this results in a significant reduction of
haloperidol plasma levels.
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Rifampin
In a study of 12 schizophrenic patients coadministered oral haloperidol and rifampin,
plasma haloperidol levels were decreased by a mean of 70% and mean scores on the
Brief Psychiatric Rating Scale were increased from baseline. In 5 other schizophrenic
patients treated with haloperidol and rifampin, discontinuation of rifampin produced a
mean 3.3-fold increase in haloperidol concentrations.
Carbamazepine
In a study in 11 schizophrenic patients co-administered haloperidol and increasing
doses of carbamazepine, haloperidol plasma concentrations decreased linearly with
increasing carbamazepine concentrations.
Thus, careful monitoring of clinical status is warranted when enzyme inducing drugs
such as rifampin or carbamazepine are administered or discontinued in
haloperidol-treated patients. During combination treatment, the Haldol dose should be
adjusted, when necessary. After discontinuation of such drugs, it may be necessary to
reduce the dosage of Haldol.
Valproate
Sodium valproate, a drug know to inhibit glucuronidation, does not affect haloperidol
plasma concentrations.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
No mutagenic potential of haloperidol decanoate was found in the Ames Salmonella
microsomal activation assay. Negative or inconsistent positive findings have been
obtained in in vitro and in vivo studies of effects of short-acting haloperidol on
chromosome structure and number. The available cytogenetic evidence is considered
too inconsistent to be conclusive at this time.
Carcinogenicity studies using oral haloperidol were conducted in Wistar rats (dosed
at up to 5 mg/kg daily for 24 months) and in Albino Swiss mice (dosed at up to
5 mg/kg daily for 18 months). In the rat study survival was less than optimal in all
dose groups, reducing the number of rats at risk for developing tumors. However,
although a relatively greater number of rats survived to the end of the study in
high-dose male and female groups, these animals did not have a greater incidence of
tumors than control animals. Therefore, although not optimal, this study does suggest
the absence of a haloperidol related increase in the incidence of neoplasia in rats at
doses up to 20 times the usual daily human dose for chronic or resistant patients.
In female mice at 5 and 20 times the highest initial daily dose for chronic or resistant
patients, there was a statistically significant increase in mammary gland neoplasia and
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total tumor incidence; at 20 times the same daily dose there was a statistically
significant increase in pituitary gland neoplasia. In male mice, no statistically
significant differences in incidences of total tumors or specific tumor types were
noted.
Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic
administration. Tissue culture experiments indicate that approximately one-third of
human breast cancers are prolactin dependent in vitro, a factor of potential
importance if the prescription of these drugs is contemplated in a patient with a
previously detected breast cancer. Although disturbances such as galactorrhea,
amenorrhea, gynecomastia, and impotence have been reported, the clinical
significance of elevated serum prolactin levels is unknown for most patients.
An increase in mammary neoplasms has been found in rodents after chronic
administration of antipsychotic drugs. Neither clinical studies nor epidemiologic
studies conducted to date, however, have shown an association between chronic
administration of these drugs and mammary tumorigenesis; the available evidence is
considered too limited to be conclusive at this time.
Usage in Pregnancy
Pregnancy Category C. Rodents given up to 3 times the usual maximum human dose
of haloperidol decanoate showed an increase in incidence of resorption, fetal
mortality, and pup mortality. No fetal abnormalities were observed.
Cleft palate has been observed in mice given oral haloperidol at 15 times the usual
maximum human dose. Cleft palate in mice appears to be a nonspecific response to
stress or nutritional imbalance as well as to a variety of drugs, and there is no
evidence to relate this phenomenon to predictable human risk for most of these
agents.
There are no adequate and well-controlled studies in pregnant women. There are
reports, however, of cases of limb malformations observed following maternal use of
HALDOL along with other drugs which have suspected teratogenic potential during
the first trimester of pregnancy. Causal relationships were not established with these
cases. Since such experience does not exclude the possibility of fetal damage due to
HALDOL, haloperidol decanoate should be used during pregnancy or in women
likely to become pregnant only if the benefit clearly justifies a potential risk to the
fetus.
Non-teratogenic Effects
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Neonates exposed to antipsychotic drugs (including haloperidol) during the third
trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms
following delivery. There have been reports of agitation, hypertonia, hypotonia,
tremor, somnolence, respiratory distress, and feeding disorder in these neonates.
These complications have varied in severity; while in some cases symptoms have
been self-limited, in other cases neonates have required intensive care unit support
and prolonged hospitalization.
HALDOL Decanoate should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
Nursing Mothers
Since haloperidol is excreted in human breast milk, infants should not be nursed
during drug treatment with haloperidol decanoate.
Pediatric Use
Safety and effectiveness of haloperidol decanoate in children have not been
established.
Geriatric Use
Clinical studies of haloperidol did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience has not consistently identified differences
in responses between the elderly and younger patients. However, the prevalence of
tardive dyskinesia appears to be highest among the elderly, especially elderly women
(see WARNINGS, Tardive dyskinesia). Also, the pharmacokinetics of haloperidol in
geriatric patients generally warrants the use of lower doses (see DOSAGE AND
ADMINISTRATION).
ADVERSE REACTIONS
Adverse reactions following the administration of HALDOL Decanoate 50 or
HALDOL Decanoate 100 are those of HALDOL (haloperidol). Since vast experience
has accumulated with HALDOL, the adverse reactions are reported for that
compound as well as for haloperidol decanoate. As with all injectable medications,
local tissue reactions have been reported with haloperidol decanoate.
Cardiovascular Effects
Tachycardia, hypotension, and hypertension have been reported. QT prolongation
and/or ventricular arrhythmias have also been reported, in addition to ECG pattern
changes compatible with the polymorphous configuration of torsade de pointes, and
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may occur more frequently with high doses and in predisposed patients (see
WARNINGS and PRECAUTIONS).
Cases of sudden and unexpected death have been reported in association with the
administration of HALDOL. The nature of the evidence makes it impossible to
determine definitively what role, if any, HALDOL played in the outcome of the
reported cases. The possibility that HALDOL caused death cannot, of course, be
excluded, but it is to be kept in mind that sudden and unexpected death may occur in
psychotic patients when they go untreated or when they are treated with other
antipsychotic drugs.
CNS Effects
Extrapyramidal Symptoms (EPS)
EPS during the administration of HALDOL (haloperidol) have been reported
frequently, often during the first few days of treatment. EPS can be categorized
generally as Parkinson-like symptoms, akathisia, or dystonia (including opisthotonos
and oculogyric crisis). While all can occur at relatively low doses, they occur more
frequently and with greater severity at higher doses. The symptoms may be controlled
with dose reductions or administration of antiparkinson drugs such as benztropine
mesylate USP or trihexyphenidyl hydrochloride USP. It should be noted that
persistent EPS have been reported; the drug may have to be discontinued in such
cases.
Dystonia
Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle
groups, may occur in susceptible individuals during the first few days of treatment.
Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to
tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion
of the tongue. While these symptoms can occur at low doses, they occur more
frequently and with greater severity with high potency and at higher doses of first
generation antipsychotic drugs. An elevated risk of acute dystonia is observed in
males and younger age groups.
Withdrawal Emergent Neurological Signs
Generally, patients receiving short-term therapy experience no problems with abrupt
discontinuation of antipsychotic drugs. However, some patients on maintenance
treatment experience transient dyskinetic signs after abrupt withdrawal. In certain of
these cases the dyskinetic movements are indistinguishable from the syndrome
described below under “Tardive Dyskinesia” except for duration. Although the
long-acting properties of haloperidol decanoate provide gradual withdrawal, it is not
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For current labeling information, please visit https://www.fda.gov/drugsatfda
known whether gradual withdrawal of antipsychotic drugs will reduce the rate of
occurrence of withdrawal emergent neurological signs.
Tardive Dyskinesia
As with all antipsychotic agents HALDOL has been associated with persistent
dyskinesias. Tardive dyskinesia, a syndrome consisting of potentially irreversible,
involuntary, dyskinetic movements, may appear in some patients on long-term
therapy with haloperidol decanoate or may occur after drug therapy has been
discontinued. The risk appears to be greater in elderly patients on high-dose therapy,
especially females. The symptoms are persistent and in some patients appear
irreversible. The syndrome is characterized by rhythmical involuntary movements of
tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of
mouth, chewing movements). Sometimes these may be accompanied by involuntary
movements of extremities and the trunk.
There is no known effective treatment for tardive dyskinesia; antiparkinson agents
usually do not alleviate the symptoms of this syndrome. It is suggested that all
antipsychotic agents be discontinued if these symptoms appear. Should it be
necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a
different antipsychotic agent, this syndrome may be masked.
It has been reported that fine vermicular movement of the tongue may be an early
sign of tardive dyskinesia and if the medication is stopped at that time the full
syndrome may not develop.
Tardive Dystonia
Tardive dystonia, not associated with the above syndrome, has also been reported.
Tardive dystonia is characterized by delayed onset of choreic or dystonic movements,
is often persistent, and has the potential of becoming irreversible.
Other CNS Effects
Insomnia, restlessness, anxiety, euphoria, agitation, drowsiness, depression, lethargy,
headache, confusion, vertigo, grand mal seizures, exacerbation of psychotic
symptoms including hallucinations, and catatonic-like behavioral states which may be
responsive to drug withdrawal and/or treatment with anticholinergic drugs.
Body as a Whole
Neuroleptic malignant syndrome (NMS), hyperpyrexia and heat stroke have been
reported with HALDOL. (See WARNINGS for further information concerning
NMS.)
Reference ID: 2999248
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Hematologic Effects
Reports have appeared citing the occurrence of mild and usually transient leukopenia
and leukocytosis, minimal decreases in red blood cell counts, anemia, or a tendency
toward lymphomonocytosis. Agranulocytosis has rarely been reported to have
occurred with the use of HALDOL, and then only in association with other
medication. (See PRECAUTIONS: Leukopenia, Neutropenia, and Agranulocytosis.)
Liver Effects
Impaired liver function and/or jaundice have been reported.
Dermatologic Reactions
Maculopapular and acneiform skin reactions and isolated cases of photosensitivity
and loss of hair.
Endocrine Disorders
Lactation, breast engorgement, mastalgia, menstrual irregularities, gynecomastia,
impotence, increased libido, hyperglycemia, hypoglycemia and hyponatremia.
Gastrointestinal Effects
Anorexia, constipation, diarrhea, hypersalivation, dyspepsia, nausea and vomiting.
Autonomic Reactions
Dry mouth, blurred vision, urinary retention, diaphoresis and priapism.
Respiratory Effects
Laryngospasm, bronchospasm and increased depth of respiration.
Special Senses
Cataracts, retinopathy and visual disturbances.
Postmarketing Events
Hyperammonemia has been reported in a 5 1 /2 year old child with citrullinemia, an
inherited disorder of ammonia excretion, following treatment with HALDOL.
OVERDOSAGE
While overdosage is less likely to occur with a parenteral than with an oral
medication, information pertaining to HALDOL (haloperidol) is presented, modified
only to reflect the extended duration of action of haloperidol decanoate.
Manifestations
In general, the symptoms of overdosage would be an exaggeration of known
pharmacologic effects and adverse reactions, the most prominent of which would be:
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1) severe extrapyramidal reactions, 2) hypotension, or 3) sedation. The patient would
appear comatose with respiratory depression and hypotension which could be severe
enough to produce a shock-like state. The extrapyramidal reactions would be
manifested by muscular weakness or rigidity and a generalized or localized tremor, as
demonstrated by the akinetic or agitans types, respectively. With accidental
overdosage, hypertension rather than hypotension occurred in a two-year old child.
The risk of ECG changes associated with torsade de pointes should be considered.
(For further information regarding torsade de pointes, please refer to ADVERSE
REACTIONS.)
Treatment
Since there is no specific antidote, treatment is primarily supportive. A patent airway
must be established by use of an oropharyngeal airway or endotracheal tube or, in
prolonged cases of coma, by tracheostomy. Respiratory depression may be
counteracted by artificial respiration and mechanical respirators. Hypotension and
circulatory collapse may be counteracted by use of intravenous fluids, plasma, or
concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine
and norepinephrine. Epinephrine should not be used. In case of severe extrapyramidal
reactions, antiparkinson medication should be administered, and should be continued
for several weeks, and then withdrawn gradually as extrapyramidal symptoms may
emerge. ECG and vital signs should be monitored especially for signs of Q-T
prolongation or dysrhythmias and monitoring should continue until the ECG is
normal. Severe arrhythmias should be treated with appropriate anti-arrhythmic
measures.
DOSAGE AND ADMINISTRATION
HALDOL Decanoate 50 and HALDOL Decanoate 100 should be administered by
deep intramuscular injection. A 21 gauge needle is recommended. The maximum
volume per injection site should not exceed 3 mL. DO NOT ADMINISTER
INTRAVENOUSLY.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
HALDOL Decanoate 50 and HALDOL Decanoate 100 are intended for use in
schizophrenic patients who require prolonged parenteral antipsychotic therapy. These
patients should be previously stabilized on antipsychotic medication before
considering a conversion to haloperidol decanoate. Furthermore, it is recommended
that patients being considered for haloperidol decanoate therapy have been treated
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with, and tolerate well, short-acting HALDOL (haloperidol) in order to reduce the
possibility of an unexpected adverse sensitivity to haloperidol. Close clinical
supervision is required during the initial period of dose adjustment in order to
minimize the risk of overdosage or reappearance of psychotic symptoms before the
next injection. During dose adjustment or episodes of exacerbation of symptoms of
schizophrenia, haloperidol decanoate therapy can be supplemented with short-acting
forms of haloperidol.
The dose of HALDOL Decanoate 50 or HALDOL Decanoate 100 should be
expressed in terms of its haloperidol content. The starting dose of haloperidol
decanoate should be based on the patient’s age, clinical history, physical condition,
and response to previous antipsychotic therapy. The preferred approach to
determining the minimum effective dose is to begin with lower initial doses and to
adjust the dose upward as needed. For patients previously maintained on low doses of
antipsychotics (e.g. up to the equivalent of 10 mg/day oral haloperidol), it is
recommended that the initial dose of haloperidol decanoate be 10-15 times the
previous daily dose in oral haloperidol equivalents; limited clinical experience
suggests that lower initial doses may be adequate.
Initial Therapy
Conversion from oral haloperidol to haloperidol decanoate can be achieved by using
an initial dose of haloperidol decanoate that is 10 to 20 times the previous daily dose
in oral haloperidol equivalents.
In patients who are elderly, debilitated, or stable on low doses of oral haloperidol
(e.g. up to the equivalent of 10 mg/day oral haloperidol), a range of 10 to 15 times the
previous daily dose in oral haloperidol equivalents is appropriate for initial
conversion.
In patients previously maintained on higher doses of antipsychotics for whom a low
dose approach risks recurrence of psychiatric decompensation and in patients whose
long-term use of haloperidol has resulted in a tolerance to the drug, 20 times the
previous daily dose in oral haloperidol equivalents should be considered for initial
conversion, with downward titration on succeeding injections.
The initial dose of haloperidol decanoate should not exceed 100 mg regardless of
previous antipsychotic dose requirements. If, therefore, conversion requires more than
100 mg of haloperidol decanoate as an initial dose, that dose should be administered
in two injections, i.e. a maximum of 100 mg initially followed by the balance in
3 to 7 days.
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Maintenance Therapy
The maintenance dosage of haloperidol decanoate must be individualized with
titration upward or downward based on therapeutic response. The usual maintenance
range is 10 to 15 times the previous daily dose in oral haloperidol equivalents
dependent on the clinical response of the patient.
HALDOL DECANOATE DOSING RECOMMENDATIONS
Monthly
Patients
1st Month
Maintenance
Stabilized on low daily oral doses
10-15 x Daily Oral Dose
10-15 x Previous Daily Oral Dose
(up to 10 mg/day)
Elderly or Debilitated
High dose
20 x Daily Oral Dose
10-15 x Previous Daily Oral Dose
Risk of relapse
Tolerant to oral haloperidol
Close clinical supervision is required during initiation and stabilization of haloperidol
decanoate therapy. Haloperidol decanoate is usually administered monthly or every
4 weeks. However, variation in patient response may dictate a need for adjustment of
the dosing interval as well as the dose (See CLINICAL PHARMACOLOGY).
Clinical experience with haloperidol decanoate at doses greater than 450 mg per
month has been limited.
INSTRUCTIONS FOR OPENING AMPULE
Step 1
1. Medication often rests in the top
part of the ampule. Before breaking
the ampoule, lightly tap the top of
the ampule with your finger until all
fluid moves to the bottom portion
of the ampule. The ampoule has a
colored ring(s) and colored point
which aids in the placement of
fingers while breaking the ampule.
Step
2
usage illustration
Reference ID: 2999248
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
u
s
a
ge illustration
2. Hold the ampule between thumb and
index finger with the colored point
facing you. usage illustration
Step 3usage illustration
3. Position the index finger of the
other hand to support the neck of
the ampule. Position the thumb so
that it covers the colored point and
is parallel to colored ring(s).
4. Keeping the thumb on the colored Step 4
point, and with the index fingers
close together, apply firm pressure
on the colored point in the direction
of the arrow to snap the ampule
open.
HOW SUPPLIED
HALDOL® (haloperidol) Decanoate 50 for IM injection, 50 mg haloperidol as
70.52 mg per mL haloperidol decanoate:
Reference ID: 2999248
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDC 50458-253-03 3 x 1 mL ampules.
HALDOL® (haloperidol) Decanoate 100 for IM injection, 100 mg haloperidol as
141.04 mg per mL haloperidol decanoate:
NDC 50458-254-14, 5 x 1 mL ampules.
Store at controlled room temperature (15°-30° C, 59°-86° F). Do not refrigerate or
freeze.
Protect from light.
Manufactured by:
Janssen Pharmaceutica N.V.
Beerse, Belgium
Manufactured for:
Ortho-McNeil Neurologics, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.
Titusville, NJ 08560
Revised June 2011
© Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2005
Reference ID: 2999248
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:44:51.880685
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018701s054lbl.pdf', 'application_number': 18701, 'submission_type': 'SUPPL ', 'submission_number': 54}
|
11,280
|
HALDOL®
brand of
haloperidol injection
(For Immediate Release)
WARNING
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic
drugs are at an increased risk of death. Analyses of seventeen placebo-controlled
trials (modal duration of 10 weeks), largely in patients taking atypical
antipsychotic drugs, revealed a risk of death in drug-treated patients of between
1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a
typical 10-week controlled trial, the rate of death in drug-treated patients was
about 4.5%, compared to a rate of about 2.6% in the placebo group. Although
the causes of death were varied, most of the deaths appeared to be either
cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia)
in nature. Observational studies suggest that, similar to atypical antipsychotic
drugs, treatment with conventional antipsychotic drugs may increase mortality.
The extent to which the findings of increased mortality in observational studies
may be attributed to the antipsychotic drug as opposed to some characteristic(s)
of the patients is not clear. HALDOL Injection is not approved for the treatment
of patients with dementia-related psychosis (see WARNINGS).
DESCRIPTION
Haloperidol is the first of the butyrophenone series of major antipsychotics. The
chemical
designation
is
4-[4-(p-chlorophenyl)-4-hydroxypiperidino]
4’-fluorobutyrophenone and it has the following structural formula: structural formula
HALDOL (haloperidol) is available as a sterile parenteral form for intramuscular
injection. The injection provides 5 mg haloperidol (as the lactate) and lactic acid for
pH adjustment between 3.0 – 3.6.
ACTIONS
The precise mechanism of action has not been clearly established.
INDICATIONS
HALDOL (haloperidol) is indicated for use in the treatment of schizophrenia.
1
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HALDOL is indicated for the control of tics and vocal utterances of Tourette’s
Disorder.
CONTRAINDICATIONS
HALDOL (haloperidol) is contraindicated in severe toxic central nervous system
depression or comatose states from any cause and in individuals who are
hypersensitive to this drug or have Parkinson’s disease.
WARNINGS
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic
drugs are at an increased risk of death. HALDOL Injection is not approved for
the treatment of patients with dementia-related psychosis (see BOXED
WARNING).
Cardiovascular Effects
Cases of sudden death, QT-prolongation, and Torsades de Pointes have been reported
in patients receiving HALDOL. Higher than recommended doses of any formulation
and intravenous administration of HALDOL appear to be associated with a higher
risk of QT-prolongation and Torsades de Pointes. Although cases have been reported
even in the absence of predisposing factors, particular caution is advised in treating
patients with other QT-prolonging conditions (including electrolyte imbalance
[particularly hypokalemia and hypomagnesemia], drugs known to prolong QT,
underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome).
HALDOL
INJECTION
IS
NOT
APPROVED
FOR
INTRAVENOUS
ADMINISTRATION. If HALDOL is administered intravenously, the ECG should be
monitored for QT prolongation and arrhythmias.
Tardive Dyskinesia
A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements
may develop in patients treated with antipsychotic drugs. Although the prevalence of
the syndrome appears to be highest among the elderly, especially elderly women, it is
impossible to rely upon prevalence estimates to predict, at the inception of
antipsychotic treatment, which patients are likely to develop the syndrome. Whether
antipsychotic drug products differ in their potential to cause tardive dyskinesia is
unknown.
Both the risk of developing tardive dyskinesia and the likelihood that it will become
irreversible are believed to increase as the duration of treatment and the total
cumulative dose of antipsychotic drugs administered to the patient increase.
However, the syndrome can develop, although much less commonly, after relatively
brief treatment periods at low doses.
2
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There is no known treatment for established cases of tardive dyskinesia, although the
syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.
Antipsychotic treatment, itself, however, may suppress (or partially suppress) the
signs and symptoms of the syndrome and thereby may possibly mask the underlying
process. The effect that symptomatic suppression has upon the long-term course of
the syndrome is unknown.
Given these considerations, antipsychotic drugs should be prescribed in a manner that
is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic
treatment should generally be reserved for patients who suffer from a chronic illness
that, 1) is known to respond to antipsychotic drugs, and, 2) for whom alternative,
equally effective, but potentially less harmful treatments are not available or
appropriate. In patients who do require chronic treatment, the smallest dose and the
shortest duration of treatment producing a satisfactory clinical response should be
sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics,
drug discontinuation should be considered. However, some patients may require
treatment despite the presence of the syndrome.
(For further information about the description of tardive dyskinesia and its clinical
detection, please refer to ADVERSE REACTIONS.)
Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant
Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical
manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status
(including catatonic signs) and evidence of autonomic instability (irregular pulse or
blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs
may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and
acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at
a diagnosis, it is important to identify cases where the clinical presentation includes
both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated
or inadequately treated extrapyramidal signs and symptoms (EPS). Other important
considerations in the differential diagnosis include central anticholinergic toxicity,
heat stroke, drug fever and primary central nervous system (CNS) pathology.
The management of NMS should include 1) immediate discontinuation of
antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive
3
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symptomatic treatment and medical monitoring, and 3) treatment of any concomitant
serious medical problems for which specific treatments are available. There is no
general agreement about specific pharmacological treatment regimens for
uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the
potential reintroduction of drug therapy should be carefully considered. The patient
should be carefully monitored, since recurrences of NMS have been reported.
Hyperpyrexia and heat stroke, not associated with the above symptom complex, have
also been reported with HALDOL.
Usage in Pregnancy
Rodents given 2 to 20 times the usual maximum human dose of haloperidol by oral or
parenteral routes showed an increase in incidence of resorption, reduced fertility,
delayed delivery and pup mortality. No teratogenic effect has been reported in rats,
rabbits or dogs at dosages within this range, but cleft palate has been observed in
mice given 15 times the usual maximum human dose. Cleft palate in mice appears to
be a nonspecific response to stress or nutritional imbalance as well as to a variety of
drugs, and there is no evidence to relate this phenomenon to predictable human risk
for most of these agents.
There are no well controlled studies with HALDOL (haloperidol) in pregnant women.
There are reports, however, of cases of limb malformations observed following
maternal use of HALDOL along with other drugs which have suspected teratogenic
potential during the first trimester of pregnancy. Causal relationships were not
established in these cases. Since such experience does not exclude the possibility of
fetal damage due to HALDOL, this drug should be used during pregnancy or in
women likely to become pregnant only if the benefit clearly justifies a potential risk
to the fetus. Infants should not be nursed during drug treatment.
Combined Use of HALDOL and Lithium
An encephalopathic syndrome (characterized by weakness, lethargy, fever,
tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated
serum enzymes, BUN, and FBS) followed by irreversible brain damage has occurred
in a few patients treated with lithium plus HALDOL. A causal relationship between
these events and the concomitant administration of lithium and HALDOL has not
been established; however, patients receiving such combined therapy should be
monitored closely for early evidence of neurological toxicity and treatment
discontinued promptly if such signs appear.
4
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For current labeling information, please visit https://www.fda.gov/drugsatfda
General
A number of cases of bronchopneumonia, some fatal, have followed the use of
antipsychotic drugs, including HALDOL. It has been postulated that lethargy and
decreased sensation of thirst due to central inhibition may lead to dehydration,
hemoconcentration and reduced pulmonary ventilation. Therefore, if the above signs
and symptoms appear, especially in the elderly, the physician should institute
remedial therapy promptly.
Although not reported with HALDOL, decreased serum cholesterol and/or cutaneous
and ocular changes have been reported in patients receiving chemically-related drugs.
HALDOL may impair the mental and/or physical abilities required for the
performance of hazardous tasks such as operating machinery or driving a motor
vehicle. The ambulatory patient should be warned accordingly.
The use of alcohol with this drug should be avoided due to possible additive effects
and hypotension.
PRECAUTIONS
Leukopenia, Neutropenia, and Agranulocytosis
Class Effect: In clinical trial and/or postmarketing experience, events of
leukopenia/neutropenia have been reported temporally related to antipsychotic agents,
including HALDOL. Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood
cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with
a
history
of
a
clinically
significant
low
WBC
or
a
drug-induced
leukopenia/neutropenia should have their complete blood count (CBC) monitored
frequently during the first few months of therapy and discontinuation of HALDOL
should be considered at the first sign of a clinically significant decline in WBC in the
absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for
fever or other symptoms or signs of infection and treated promptly if such symptoms
or signs occur. Patients with severe neutropenia (absolute neutrophil count
<1000/mm3) should discontinue HALDOL and have their WBC followed until
recovery.
Other
HALDOL (haloperidol) should be administered cautiously to patients:
5
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For current labeling information, please visit https://www.fda.gov/drugsatfda
− with severe cardiovascular disorders, because of the possibility of transient
hypotension and/or precipitation of anginal pain. Should hypotension occur and
a vasopressor be required, epinephrine should not be used since HALDOL may
block its vasopressor activity and paradoxical further lowering of the blood
pressure may occur. Instead, metaraminol, phenylephrine or norepinephrine
should be used.
− receiving anticonvulsant medications, with a history of seizures, or with EEG
abnormalities, because HALDOL may lower the convulsive threshold. If
indicated, adequate anticonvulsant therapy should be concomitantly maintained.
− with known allergies, or with a history of allergic reactions to drugs.
− receiving anticoagulants, since an isolated instance of interference occurred
with the effects of one anticoagulant (phenindione).
If concomitant antiparkinson medication is required, it may have to be continued after
HALDOL is discontinued because of the difference in excretion rates. If both are
discontinued simultaneously, extrapyramidal symptoms may occur. The physician
should keep in mind the possible increase in intraocular pressure when
anticholinergic drugs, including antiparkinson agents, are administered concomitantly
with HALDOL.
As with other antipsychotic agents, it should be noted that HALDOL may be capable
of potentiating CNS depressants such as anesthetics, opiates, and alcohol.
In a study of 12 schizophrenic patients coadministered haloperidol and rifampin,
plasma haloperidol levels were decreased by a mean of 70% and mean scores on the
Brief Psychiatric Rating Scale were increased from baseline. In 5 other schizophrenic
patients treated with haloperidol and rifampin, discontinuation of rifampin produced a
mean 3.3-fold increase in haloperidol concentrations. Thus, careful monitoring of
clinical status is warranted when rifampin is administered or discontinued in
haloperidol-treated patients.
When HALDOL is used to control mania in cyclic disorders, there may be a rapid
mood swing to depression.
Severe neurotoxicity (rigidity, inability to walk or talk) may occur in patients with
thyrotoxicosis who are also receiving antipsychotic medication, including HALDOL.
No mutagenic potential of haloperidol was found in the Ames Salmonella microsomal
activation assay. Negative or inconsistent positive findings have been obtained in
in vitro and in vivo studies of effects of haloperidol on chromosome structure and
6
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For current labeling information, please visit https://www.fda.gov/drugsatfda
number. The available cytogenetic evidence is considered too inconsistent to be
conclusive at this time.
Carcinogenicity studies using oral haloperidol were conducted in Wistar rats (dosed
at up to 5 mg/kg daily for 24 months) and in Albino Swiss mice (dosed at up to
5 mg/kg daily for 18 months). In the rat study survival was less than optimal in all
dose groups, reducing the number of rats at risk for developing tumors. However,
although a relatively greater number of rats survived to the end of the study in high-
dose male and female groups, these animals did not have a greater incidence of
tumors than control animals. Therefore, although not optimal, this study does suggest
the absence of a haloperidol related increase in the incidence of neoplasia in rats at
doses up to 20 times the usual daily human dose for chronic or resistant patients.
In female mice at 5 and 20 times the highest initial daily dose for chronic or resistant
patients, there was a statistically significant increase in mammary gland neoplasia and
total tumor incidence; at 20 times the same daily dose there was a statistically
significant increase in pituitary gland neoplasia. In male mice, no statistically
significant differences in incidences of total tumors or specific tumor types were
noted.
Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic
administration. Tissue culture experiments indicate that approximately one-third of
human breast cancers are prolactin dependent in vitro, a factor of potential
importance if the prescription of these drugs is contemplated in a patient with a
previously detected breast cancer. Although disturbances such as galactorrhea,
amenorrhea, gynecomastia, and impotence have been reported, the clinical
significance of elevated serum prolactin levels is unknown for most patients. An
increase in mammary neoplasms has been found in rodents after chronic
administration of antipsychotic drugs. Neither clinical studies nor epidemiologic
studies conducted to date, however, have shown an association between chronic
administration of these drugs and mammary tumorigenesis; the available evidence is
considered too limited to be conclusive at this time.
There are no well controlled studies with HALDOL (haloperidol) in pregnant women.
There are reports, however, of cases of limb malformations observed following
maternal use of HALDOL along with other drugs which have suspected teratogenic
potential during the first trimester of pregnancy. Causal relationships were not
established in these cases. Since such experience does not exclude the possibility of
fetal damage due to HALDOL, this drug should be used during pregnancy or in
women likely to become pregnant only if the benefit clearly justifies a potential risk
to the fetus. Infants should not be nursed during drug treatment.
7
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of haloperidol did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience has not consistently identified differences
in responses between the elderly and younger patients. However, the prevalence of
tardive dyskinesia appears to be highest among the elderly, especially elderly women
(see WARNINGS, Tardive Dyskinesia). Also, the pharmacokinetics of haloperidol in
geriatric patients generally warrants the use of lower doses (see DOSAGE AND
ADMINISTRATION).
ADVERSE REACTIONS
Cardiovascular Effects
Tachycardia, hypotension, and hypertension have been reported. QT prolongation
and/or ventricular arrhythmias have also been reported, in addition to ECG pattern
changes compatible with the polymorphous configuration of torsade de pointes, and
may occur more frequently with high doses and in predisposed patients
(see WARNINGS and PRECAUTIONS).
Cases of sudden and unexpected death have been reported in association with the
administration of HALDOL. The nature of the evidence makes it impossible to
determine definitively what role, if any, HALDOL played in the outcome of the
reported cases. The possibility that HALDOL caused death cannot, of course, be
excluded, but it is to be kept in mind that sudden and unexpected death may occur in
psychotic patients when they go untreated or when they are treated with other
antipsychotic drugs.
CNS Effects
Extrapyramidal Symptoms (EPS)
EPS during the administration of HALDOL (haloperidol) have been reported
frequently, often during the first few days of treatment. EPS can be categorized
generally as Parkinson-like symptoms, akathisia, or dystonia (including opisthotonos
and oculogyric crisis). While all can occur at relatively low doses, they occur more
frequently and with greater severity at higher doses. The symptoms may be controlled
with dose reductions or administration of antiparkinson drugs such as benztropine
mesylate USP or trihexyphenidyl hydrochloride USP. It should be noted that
persistent EPS have been reported; the drug may have to be discontinued in such
cases.
8
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Dystonia
Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle
groups, may occur in susceptible individuals during the first few days of treatment.
Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to
tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion
of the tongue. While these symptoms can occur at low doses, they occur more
frequently and with greater severity with high potency and at higher doses of first
generation antipsychotic drugs. An elevated risk of acute dystonia is observed in
males and younger age groups.
Withdrawal Emergent Neurological Signs
Generally, patients receiving short-term therapy experience no problems with abrupt
discontinuation of antipsychotic drugs. However, some patients on maintenance
treatment experience transient dyskinetic signs after abrupt withdrawal. In certain of
these cases the dyskinetic movements are indistinguishable from the syndrome
described below under “Tardive Dyskinesia” except for duration. It is not known
whether gradual withdrawal of antipsychotic drugs will reduce the rate of occurrence
of withdrawal emergent neurological signs but until further evidence becomes
available, it seems reasonable to gradually withdraw use of HALDOL.
Tardive Dyskinesia
As with all antipsychotic agents HALDOL has been associated with persistent
dyskinesias. Tardive dyskinesia, a syndrome consisting of potentially irreversible,
involuntary, dyskinetic movements, may appear in some patients on long-term
therapy or may occur after drug therapy has been discontinued. The risk appears to be
greater in elderly patients on high-dose therapy, especially females. The symptoms
are persistent and in some patients appear irreversible. The syndrome is characterized
by rhythmical involuntary movements of tongue, face, mouth or jaw (e.g., protrusion
of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes
these may be accompanied by involuntary movements of extremities and the trunk.
There is no known effective treatment for tardive dyskinesia; antiparkinson agents
usually do not alleviate the symptoms of this syndrome. It is suggested that all
antipsychotic agents be discontinued if these symptoms appear. Should it be
necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a
different antipsychotic agent, this syndrome may be masked.
It has been reported that fine vermicular movement of the tongue may be an early
sign of tardive dyskinesia and if the medication is stopped at that time the full
syndrome may not develop.
9
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Tardive Dystonia
Tardive dystonia, not associated with the above syndrome, has also been reported.
Tardive dystonia is characterized by delayed onset of choreic or dystonic movements,
is often persistent, and has the potential of becoming irreversible.
Other CNS Effects
Insomnia, restlessness, anxiety, euphoria, agitation, drowsiness, depression, lethargy,
headache, confusion, vertigo, grand mal seizures, exacerbation of psychotic
symptoms including hallucinations, and catatonic-like behavioral states which may be
responsive to drug withdrawal and/or treatment with anticholinergic drugs.
Body as a Whole
Neuroleptic malignant syndrome (NMS), hyperpyrexia and heat stroke have been
reported with HALDOL. (See WARNINGS for further information concerning
NMS.)
Hematologic Effects
Reports have appeared citing the occurrence of mild and usually transient leukopenia
and leukocytosis, minimal decreases in red blood cell counts, anemia, or a tendency
toward lymphomonocytosis. Agranulocytosis has rarely been reported to have
occurred with the use of HALDOL, and then only in association with other
medication.
Liver Effects
Impaired liver function and/or jaundice have been reported.
Dermatologic Reactions
Maculopapular and acneiform skin reactions and isolated cases of photosensitivity
and loss of hair.
Endocrine Disorders
Lactation, breast engorgement, mastalgia, menstrual irregularities, gynecomastia,
impotence, increased libido, hyperglycemia, hypoglycemia and hyponatremia.
Gastrointestinal Effects
Anorexia, constipation, diarrhea, hypersalivation, dyspepsia, nausea and vomiting.
Autonomic Reactions
Dry mouth, blurred vision, urinary retention, diaphoresis and priapism.
Respiratory Effects
Laryngospasm, bronchospasm and increased depth of respiration.
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Special Senses
Cataracts, retinopathy and visual disturbances.
Postmarketing Events
Hyperammonemia has been reported in a 5½ year old child with citrullinemia, an
inherited disorder of ammonia excretion, following treatment with HALDOL.
OVERDOSAGE
Manifestations
In general, the symptoms of overdosage would be an exaggeration of known
pharmacologic effects and adverse reactions, the most prominent of which would
be: 1) severe extrapyramidal reactions, 2) hypotension, or 3) sedation. The patient
would appear comatose with respiratory depression and hypotension which could be
severe enough to produce a shock-like state. The extrapyramidal reaction would be
manifest by muscular weakness or rigidity and a generalized or localized tremor as
demonstrated by the akinetic or agitans types respectively. With accidental
overdosage, hypertension rather than hypotension occurred in a two-year old child.
The risk of ECG changes associated with torsade de pointes should be considered.
(For further information regarding torsade de pointes, please refer to
ADVERSE REACTIONS.)
Treatment
Since there is no specific antidote, treatment is primarily supportive. A patent airway
must be established by use of an oropharyngeal airway or endotracheal tube or, in
prolonged cases of coma, by tracheostomy. Respiratory depression may be
counteracted by artificial respiration and mechanical respirators. Hypotension and
circulatory collapse may be counteracted by use of intravenous fluids, plasma, or
concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine
and norepinephrine. Epinephrine should not be used. In case of severe extrapyramidal
reactions, antiparkinson medication should be administered. ECG and vital signs
should be monitored especially for signs of Q-T prolongation or dysrhythmias and
monitoring should continue until the ECG is normal. Severe arrhythmias should be
treated with appropriate anti-arrhythmic measures.
DOSAGE AND ADMINISTRATION
There is considerable variation from patient to patient in the amount of medication
required for treatment. As with all drugs used to treat schizophrenia, dosage should be
individualized according to the needs and response of each patient. Dosage
adjustments, either upward or downward, should be carried out as rapidly as
practicable to achieve optimum therapeutic control.
11
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For current labeling information, please visit https://www.fda.gov/drugsatfda
To determine the initial dosage, consideration should be given to the patient’s age,
severity of illness, previous response to other antipsychotic drugs, and any
concomitant medication or disease state. Debilitated or geriatric patients, as well as
those with a history of adverse reactions to antipsychotic drugs, may require less
HALDOL (haloperidol). The optimal response in such patients is usually obtained
with more gradual dosage adjustments and at lower dosage levels.
Parenteral medication, administered intramuscularly in doses of 2 to 5 mg, is utilized
for prompt control of the acutely agitated schizophrenic patient with moderately
severe to very severe symptoms. Depending on the response of the patient,
subsequent doses may be given, administered as often as every hour, although 4 to 8
hour intervals may be satisfactory.
Controlled trials to establish the safety and effectiveness of intramuscular
administration in children have not been conducted.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
Switchover Procedure
An oral form should supplant the injectable as soon as practicable. In the absence of
bioavailability studies establishing bioequivalence between these two dosage forms
the following guidelines for dosage are suggested. For an initial approximation of the
total daily dose required, the parenteral dose administered in the preceding 24 hours
may be used. Since this dose is only an initial estimate, it is recommended that careful
monitoring of clinical signs and symptoms, including clinical efficacy, sedation, and
adverse effects, be carried out periodically for the first several days following the
initiation of switchover. In this way, dosage adjustments, either upward or downward,
can be quickly accomplished. Depending on the patient’s clinical status, the first oral
dose should be given within 12-24 hours following the last parenteral dose.
HOW SUPPLIED
HALDOL® brand of haloperidol Injection (For Immediate Release) 5 mg per mL (as
the lactate) – NDC 0045-0255-01, units of 10 x 1 mL ampuls.
Store HALDOL® haloperidol Injection at controlled room temperature (15°-30°C,
59°-86°F). Protect from light. Do not freeze.
Manufactured by:
Janssen Pharmaceutica N.V.
Beerse, Belgium
12
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Distributed by:
Ortho-McNeil Pharmaceutical, Inc.
Raritan, NJ 08869
Revised June 2009
©OMP 2005
US-XXXXXX
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HALDOL® Decanoate 50 (haloperidol)
HALDOL® Decanoate 100 (haloperidol)
For IM Injection Only
WARNING
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic
drugs are at an increased risk of death. Analyses of seventeen placebo-controlled
trials (modal duration of 10 weeks), largely in patients taking atypical
antipsychotic drugs, revealed a risk of death in drug-treated patients of between
1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a
typical 10-week controlled trial, the rate of death in drug-treated patients was
about 4.5%, compared to a rate of about 2.6% in the placebo group. Although
the causes of death were varied, most of the deaths appeared to be either
cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia)
in nature. Observational studies suggest that, similar to atypical antipsychotic
drugs, treatment with conventional antipsychotic drugs may increase mortality.
The extent to which the findings of increased mortality in observational studies
may be attributed to the antipsychotic drug as opposed to some characteristic(s)
of the patients is not clear. HALDOL Decanoate is not approved for the
treatment of patients with dementia-related psychosis (see WARNINGS).
DESCRIPTION
Haloperidol decanoate is the decanoate ester of the butyrophenone, HALDOL
(haloperidol). It has a markedly extended duration of effect. It is available in sesame
oil in sterile form for intramuscular (IM) injection. The structural formula of
haloperidol
decanoate,
4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-4
piperidinyl decanoate, is: structural formula
Haloperidol decanoate is almost insoluble in water (0.01 mg/mL), but is soluble in
most organic solvents.
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Each mL of HALDOL Decanoate 50 for IM injection contains 50 mg haloperidol
(present as haloperidol decanoate 70.52 mg) in a sesame oil vehicle, with 1.2% (w/v)
benzyl alcohol as a preservative.
Each mL of HALDOL Decanoate 100 for IM injection contains 100 mg haloperidol
(present as haloperidol decanoate 141.04 mg) in a sesame oil vehicle, with 1.2%
(w/v) benzyl alcohol as a preservative.
CLINICAL PHARMACOLOGY
HALDOL Decanoate 50 and HALDOL Decanoate 100 are the long-acting forms of
HALDOL (haloperidol). The basic effects of haloperidol decanoate are no different
from those of HALDOL with the exception of duration of action. Haloperidol blocks
the effects of dopamine and increases its turnover rate; however, the precise
mechanism of action is unknown.
Administration of haloperidol decanoate in sesame oil results in slow and sustained
release of haloperidol. The plasma concentrations of haloperidol gradually rise,
reaching a peak at about 6 days after the injection, and falling thereafter, with an
apparent half-life of about 3 weeks. Steady state plasma concentrations are achieved
after the third or fourth dose. The relationship between dose of haloperidol decanoate
and plasma haloperidol concentration is roughly linear for doses below 450 mg. It
should be noted, however, that the pharmacokinetics of haloperidol decanoate
following intramuscular injections can be quite variable between subjects.
INDICATIONS AND USAGE
HALDOL Decanoate 50 and HALDOL Decanoate 100 are indicated for the treatment
of schizophrenic patients who require prolonged parenteral antipsychotic therapy.
CONTRAINDICATIONS
Since the pharmacologic and clinical actions of HALDOL Decanoate 50 and
HALDOL Decanoate 100 are attributed to HALDOL (haloperidol) as the active
medication, Contraindications, Warnings, and additional information are those of
HALDOL, modified only to reflect the prolonged action.
HALDOL is contraindicated in severe toxic central nervous system depression or
comatose states from any cause and in individuals who are hypersensitive to this drug
or have Parkinson’s disease.
2
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For current labeling information, please visit https://www.fda.gov/drugsatfda
WARNINGS
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic
drugs are at an increased risk of death. HALDOL Decanoate is not approved for
the treatment of patients with dementia-related psychosis (see BOXED
WARNING).
Cardiovascular Effects
Cases of sudden death, QT-prolongation, and Torsades de Pointes have been reported
in patients receiving haloperidol. Higher than recommended doses of any formulation
and intravenous administration of haloperidol appear to be associated with a higher
risk of QT-prolongation and Torsades de Pointes. Although cases have been reported
even in the absence of predisposing factors, particular caution is advised in treating
patients with other QT-prolonging conditions (including electrolyte imbalance
[particularly hypokalemia and hypomagnesemia], drugs known to prolong QT,
underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome).
HALDOL DECANOATE MUST NOT BE ADMINISTERED INTRAVENOUSLY.
Tardive Dyskinesia
A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements
may develop in patients treated with antipsychotic drugs. Although the prevalence of
the syndrome appears to be highest among the elderly, especially elderly women, it is
impossible to rely upon prevalence estimates to predict, at the inception of
antipsychotic treatment, which patients are likely to develop the syndrome. Whether
antipsychotic drug products differ in their potential to cause tardive dyskinesia is
unknown.
Both the risk of developing tardive dyskinesia and the likelihood that it will become
irreversible are believed to increase as the duration of treatment and the total
cumulative dose of antipsychotic drugs administered to the patient increase. However,
the syndrome can develop, although much less commonly, after relatively brief
treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the
syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.
Antipsychotic treatment, itself, however, may suppress (or partially suppress) the
signs and symptoms of the syndrome and thereby may possibly mask the underlying
process. The effect that symptomatic suppression has upon the long-term course of
the syndrome is unknown.
3
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Given these considerations, antipsychotic drugs should be prescribed in a manner that
is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic
treatment should generally be reserved for patients who suffer from a chronic illness
that 1) is known to respond to antipsychotic drugs, and 2) for whom alternative,
equally effective, but potentially less harmful treatments are not available or
appropriate. In patients who do require chronic treatment, the smallest dose and the
shortest duration of treatment producing a satisfactory clinical response should be
sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics,
drug discontinuation should be considered. However, some patients may require
treatment despite the presence of the syndrome. (For further information about the
description of tardive dyskinesia and its clinical detection, please refer to ADVERSE
REACTIONS.)
Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant
Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical
manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status
(including catatonic signs) and evidence of autonomic instability (irregular pulse or
blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs
may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and
acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at
a diagnosis, it is important to identify cases where the clinical presentation includes
both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated
or inadequately treated extrapyramidal signs and symptoms (EPS). Other important
considerations in the differential diagnosis include central anticholinergic toxicity,
heat stroke, drug fever and primary central nervous system (CNS) pathology.
The management of NMS should include 1) immediate discontinuation of
antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive
symptomatic treatment and medical monitoring, and 3) treatment of any concomitant
serious medical problems for which specific treatments are available. There is no
general agreement about specific pharmacological treatment regimens for
uncomplicated NMS.
4
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For current labeling information, please visit https://www.fda.gov/drugsatfda
If a patient requires antipsychotic drug treatment after recovery from NMS, the
potential reintroduction of drug therapy should be carefully considered. The patient
should be carefully monitored, since recurrences of NMS have been reported.
Hyperpyrexia and heat stroke, not associated with the above symptom complex, have
also been reported with HALDOL.
General
A number of cases of bronchopneumonia, some fatal, have followed the use of
antipsychotic drugs, including HALDOL (haloperidol). It has been postulated that
lethargy and decreased sensation of thirst due to central inhibition may lead to
dehydration, hemoconcentration and reduced pulmonary ventilation. Therefore, if the
above signs and symptoms appear, especially in the elderly, the physician should
institute remedial therapy promptly.
Although not reported with HALDOL, decreased serum cholesterol and/or cutaneous
and ocular changes have been reported in patients receiving chemically-related drugs.
PRECAUTIONS
Leukopenia, Neutropenia, and Agranulocytosis
Class Effect: In clinical trial and/or postmarketing experience, events of
leukopenia/neutropenia have been reported temporally related to antipsychotic agents,
including HALDOL Decanoate. Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood
cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with
a
history
of
a
clinically
significant
low
WBC
or
a
drug-induced
leukopenia/neutropenia should have their complete blood count (CBC) monitored
frequently during the first few months of therapy and discontinuation of HALDOL
Decanoate should be considered at the first sign of a clinically significant decline in
WBC in the absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for
fever or other symptoms or signs of infection and treated promptly if such symptoms
or signs occur. Patients with severe neutropenia (absolute neutrophil count
<1000/mm3) should discontinue HALDOL Decanoate and have their WBC followed
until recovery.
Other
HALDOL Decanoate 50 and HALDOL Decanoate 100 should be administered
cautiously to patients:
5
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For current labeling information, please visit https://www.fda.gov/drugsatfda
− with severe cardiovascular disorders, because of the possibility of transient
hypotension and/or precipitation of anginal pain. Should hypotension occur and
a vasopressor be required, epinephrine should not be used since HALDOL
(haloperidol) may block its vasopressor activity, and paradoxical further
lowering of the blood pressure may occur. Instead, metaraminol, phenylephrine
or norepinephrine should be used.
− receiving anticonvulsant medications, with a history of seizures, or with EEG
abnormalities, because HALDOL may lower the convulsive threshold. If
indicated, adequate anticonvulsant therapy should be concomitantly maintained.
− with known allergies, or with a history of allergic reactions to drugs.
− receiving anticoagulants, since an isolated instance of interference occurred
with the effects of one anticoagulant (phenindione).
If concomitant antiparkinson medication is required, it may have to be continued after
HALDOL Decanoate 50 or HALDOL Decanoate 100 is discontinued because of the
prolonged action of haloperidol decanoate. If both drugs are discontinued
simultaneously, extrapyramidal symptoms may occur. The physician should keep in
mind the possible increase in intraocular pressure when anticholinergic drugs,
including antiparkinson agents, are administered concomitantly with haloperidol
decanoate.
In patients with thyrotoxicosis who are also receiving antipsychotic medication,
including haloperidol decanoate, severe neurotoxicity (rigidity, inability to walk or
talk) may occur.
When HALDOL is used to control mania in bipolar disorders, there may be a rapid
mood swing to depression.
Information for Patients
Haloperidol decanoate may impair the mental and/or physical abilities required for
the performance of hazardous tasks such as operating machinery or driving a motor
vehicle. The ambulatory patient should be warned accordingly.
The use of alcohol with this drug should be avoided due to possible additive effects
and hypotension.
Drug Interactions
An encephalopathic syndrome (characterized by weakness, lethargy, fever,
tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated
serum enzymes, BUN, and FBS) followed by irreversible brain damage has occurred
in a few patients treated with lithium plus HALDOL. A causal relationship between
these events and the concomitant administration of lithium and HALDOL has not
6
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For current labeling information, please visit https://www.fda.gov/drugsatfda
been established; however, patients receiving such combined therapy should be
monitored closely for early evidence of neurological toxicity and treatment
discontinued promptly if such signs appear.
As with other antipsychotic agents, it should be noted that HALDOL may be capable
of potentiating CNS depressants such as anesthetics, opiates, and alcohol.
In a study of 12 schizophrenic patients coadministered oral haloperidol and rifampin,
plasma haloperidol levels were decreased by a mean of 70% and mean scores on the
Brief Psychiatric Rating Scale were increased from baseline. In 5 other schizophrenic
patients treated with oral haloperidol and rifampin, discontinuation of rifampin
produced a mean 3.3-fold increase in haloperidol concentrations. Thus, careful
monitoring of clinical status is warranted when rifampin is administered or
discontinued in haloperidol-treated patients.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
No mutagenic potential of haloperidol decanoate was found in the Ames Salmonella
microsomal activation assay. Negative or inconsistent positive findings have been
obtained in in vitro and in vivo studies of effects of short-acting haloperidol on
chromosome structure and number. The available cytogenetic evidence is considered
too inconsistent to be conclusive at this time.
Carcinogenicity studies using oral haloperidol were conducted in Wistar rats (dosed
at up to 5 mg/kg daily for 24 months) and in Albino Swiss mice (dosed at up to
5 mg/kg daily for 18 months). In the rat study survival was less than optimal in all
dose groups, reducing the number of rats at risk for developing tumors. However,
although a relatively greater number of rats survived to the end of the study in
high-dose male and female groups, these animals did not have a greater incidence of
tumors than control animals. Therefore, although not optimal, this study does suggest
the absence of a haloperidol related increase in the incidence of neoplasia in rats at
doses up to 20 times the usual daily human dose for chronic or resistant patients.
In female mice at 5 and 20 times the highest initial daily dose for chronic or resistant
patients, there was a statistically significant increase in mammary gland neoplasia and
total tumor incidence; at 20 times the same daily dose there was a statistically
significant increase in pituitary gland neoplasia. In male mice, no statistically
significant differences in incidences of total tumors or specific tumor types were
noted.
Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic
administration. Tissue culture experiments indicate that approximately one-third of
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
human breast cancers are prolactin dependent in vitro, a factor of potential
importance if the prescription of these drugs is contemplated in a patient with a
previously detected breast cancer. Although disturbances such as galactorrhea,
amenorrhea, gynecomastia, and impotence have been reported, the clinical
significance of elevated serum prolactin levels is unknown for most patients.
An increase in mammary neoplasms has been found in rodents after chronic
administration of antipsychotic drugs. Neither clinical studies nor epidemiologic
studies conducted to date, however, have shown an association between chronic
administration of these drugs and mammary tumorigenesis; the available evidence is
considered too limited to be conclusive at this time.
Usage in Pregnancy
Pregnancy Category C. Rodents given up to 3 times the usual maximum human dose
of haloperidol decanoate showed an increase in incidence of resorption, fetal
mortality, and pup mortality. No fetal abnormalities were observed.
Cleft palate has been observed in mice given oral haloperidol at 15 times the usual
maximum human dose. Cleft palate in mice appears to be a nonspecific response to
stress or nutritional imbalance as well as to a variety of drugs, and there is no
evidence to relate this phenomenon to predictable human risk for most of these
agents.
There are no adequate and well-controlled studies in pregnant women. There are
reports, however, of cases of limb malformations observed following maternal use of
HALDOL along with other drugs which have suspected teratogenic potential during
the first trimester of pregnancy. Causal relationships were not established with these
cases. Since such experience does not exclude the possibility of fetal damage due to
HALDOL, haloperidol decanoate should be used during pregnancy or in women
likely to become pregnant only if the benefit clearly justifies a potential risk to the
fetus.
Nursing Mothers
Since haloperidol is excreted in human breast milk, infants should not be nursed
during drug treatment with haloperidol decanoate.
Pediatric Use
Safety and effectiveness of haloperidol decanoate in children have not been
established.
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Geriatric Use
Clinical studies of haloperidol did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience has not consistently identified differences
in responses between the elderly and younger patients. However, the prevalence of
tardive dyskinesia appears to be highest among the elderly, especially elderly women
(see WARNINGS, Tardive dyskinesia). Also, the pharmacokinetics of haloperidol in
geriatric patients generally warrants the use of lower doses (see DOSAGE AND
ADMINISTRATION).
ADVERSE REACTIONS
Adverse reactions following the administration of HALDOL Decanoate 50 or
HALDOL Decanoate 100 are those of HALDOL (haloperidol). Since vast experience
has accumulated with HALDOL, the adverse reactions are reported for that
compound as well as for haloperidol decanoate. As with all injectable medications,
local tissue reactions have been reported with haloperidol decanoate.
Cardiovascular Effects
Tachycardia, hypotension, and hypertension have been reported. QT prolongation
and/or ventricular arrhythmias have also been reported, in addition to ECG pattern
changes compatible with the polymorphous configuration of torsade de pointes, and
may occur more frequently with high doses and in predisposed patients (see
WARNINGS and PRECAUTIONS).
Cases of sudden and unexpected death have been reported in association with the
administration of HALDOL. The nature of the evidence makes it impossible to
determine definitively what role, if any, HALDOL played in the outcome of the
reported cases. The possibility that HALDOL caused death cannot, of course, be
excluded, but it is to be kept in mind that sudden and unexpected death may occur in
psychotic patients when they go untreated or when they are treated with other
antipsychotic drugs.
CNS Effects
Extrapyramidal Symptoms (EPS)
EPS during the administration of HALDOL (haloperidol) have been reported
frequently, often during the first few days of treatment. EPS can be categorized
generally as Parkinson-like symptoms, akathisia, or dystonia (including opisthotonos
and oculogyric crisis). While all can occur at relatively low doses, they occur more
frequently and with greater severity at higher doses. The symptoms may be controlled
with dose reductions or administration of antiparkinson drugs such as benztropine
9
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For current labeling information, please visit https://www.fda.gov/drugsatfda
mesylate USP or trihexyphenidyl hydrochloride USP. It should be noted that
persistent EPS have been reported; the drug may have to be discontinued in such
cases.
Dystonia
Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle
groups, may occur in susceptible individuals during the first few days of treatment.
Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to
tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion
of the tongue. While these symptoms can occur at low doses, they occur more
frequently and with greater severity with high potency and at higher doses of first
generation antipsychotic drugs. An elevated risk of acute dystonia is observed in
males and younger age groups.
Withdrawal Emergent Neurological Signs
Generally, patients receiving short-term therapy experience no problems with abrupt
discontinuation of antipsychotic drugs. However, some patients on maintenance
treatment experience transient dyskinetic signs after abrupt withdrawal. In certain of
these cases the dyskinetic movements are indistinguishable from the syndrome
described below under “Tardive Dyskinesia” except for duration. Although the long-
acting properties of haloperidol decanoate provide gradual withdrawal, it is not
known whether gradual withdrawal of antipsychotic drugs will reduce the rate of
occurrence of withdrawal emergent neurological signs.
Tardive Dyskinesia
As with all antipsychotic agents HALDOL has been associated with persistent
dyskinesias. Tardive dyskinesia, a syndrome consisting of potentially irreversible,
involuntary, dyskinetic movements, may appear in some patients on long-term
therapy with haloperidol decanoate or may occur after drug therapy has been
discontinued. The risk appears to be greater in elderly patients on high-dose therapy,
especially females. The symptoms are persistent and in some patients appear
irreversible. The syndrome is characterized by rhythmical involuntary movements of
tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of
mouth, chewing movements). Sometimes these may be accompanied by involuntary
movements of extremities and the trunk.
There is no known effective treatment for tardive dyskinesia; antiparkinson agents
usually do not alleviate the symptoms of this syndrome. It is suggested that all
antipsychotic agents be discontinued if these symptoms appear. Should it be
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a
different antipsychotic agent, this syndrome may be masked.
It has been reported that fine vermicular movement of the tongue may be an early
sign of tardive dyskinesia and if the medication is stopped at that time the full
syndrome may not develop.
Tardive Dystonia
Tardive dystonia, not associated with the above syndrome, has also been reported.
Tardive dystonia is characterized by delayed onset of choreic or dystonic movements,
is often persistent, and has the potential of becoming irreversible.
Other CNS Effects
Insomnia, restlessness, anxiety, euphoria, agitation, drowsiness, depression, lethargy,
headache, confusion, vertigo, grand mal seizures, exacerbation of psychotic
symptoms including hallucinations, and catatonic-like behavioral states which may be
responsive to drug withdrawal and/or treatment with anticholinergic drugs.
Body as a Whole
Neuroleptic malignant syndrome (NMS), hyperpyrexia and heat stroke have been
reported with HALDOL. (See WARNINGS for further information concerning
NMS.)
Hematologic Effects
Reports have appeared citing the occurrence of mild and usually transient leukopenia
and leukocytosis, minimal decreases in red blood cell counts, anemia, or a tendency
toward lymphomonocytosis. Agranulocytosis has rarely been reported to have
occurred with the use of HALDOL, and then only in association with other
medication.
Liver Effects
Impaired liver function and/or jaundice have been reported.
Dermatologic Reactions
Maculopapular and acneiform skin reactions and isolated cases of photosensitivity
and loss of hair.
Endocrine Disorders
Lactation, breast engorgement, mastalgia, menstrual irregularities, gynecomastia,
impotence, increased libido, hyperglycemia, hypoglycemia and hyponatremia.
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Gastrointestinal Effects
Anorexia, constipation, diarrhea, hypersalivation, dyspepsia, nausea and vomiting.
Autonomic Reactions
Dry mouth, blurred vision, urinary retention, diaphoresis and priapism.
Respiratory Effects
Laryngospasm, bronchospasm and increased depth of respiration.
Special Senses
Cataracts, retinopathy and visual disturbances.
Postmarketing Events
Hyperammonemia has been reported in a 5 1 /2 year old child with citrullinemia, an
inherited disorder of ammonia excretion, following treatment with HALDOL.
OVERDOSAGE
While overdosage is less likely to occur with a parenteral than with an oral
medication, information pertaining to HALDOL (haloperidol) is presented, modified
only to reflect the extended duration of action of haloperidol decanoate.
Manifestations
In general, the symptoms of overdosage would be an exaggeration of known
pharmacologic effects and adverse reactions, the most prominent of which would be:
1) severe extrapyramidal reactions, 2) hypotension, or 3) sedation. The patient would
appear comatose with respiratory depression and hypotension which could be severe
enough to produce a shock-like state. The extrapyramidal reactions would be
manifested by muscular weakness or rigidity and a generalized or localized tremor, as
demonstrated by the akinetic or agitans types, respectively. With accidental
overdosage, hypertension rather than hypotension occurred in a two-year old child.
The risk of ECG changes associated with torsade de pointes should be considered.
(For further information regarding torsade de pointes, please refer to ADVERSE
REACTIONS.)
Treatment
Since there is no specific antidote, treatment is primarily supportive. A patent airway
must be established by use of an oropharyngeal airway or endotracheal tube or, in
prolonged cases of coma, by tracheostomy. Respiratory depression may be
counteracted by artificial respiration and mechanical respirators. Hypotension and
circulatory collapse may be counteracted by use of intravenous fluids, plasma, or
concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine
12
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For current labeling information, please visit https://www.fda.gov/drugsatfda
and norepinephrine. Epinephrine should not be used. In case of severe extrapyramidal
reactions, antiparkinson medication should be administered, and should be continued
for several weeks, and then withdrawn gradually as extrapyramidal symptoms may
emerge. ECG and vital signs should be monitored especially for signs of Q-T
prolongation or dysrhythmias and monitoring should continue until the ECG is
normal. Severe arrhythmias should be treated with appropriate anti-arrhythmic
measures.
DOSAGE AND ADMINISTRATION
HALDOL Decanoate 50 and HALDOL Decanoate 100 should be administered by
deep intramuscular injection. A 21 gauge needle is recommended. The maximum
volume per injection site should not exceed 3 mL. DO NOT ADMINISTER
INTRAVENOUSLY.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
HALDOL Decanoate 50 and HALDOL Decanoate 100 are intended for use in
schizophrenic patients who require prolonged parenteral antipsychotic therapy. These
patients should be previously stabilized on antipsychotic medication before
considering a conversion to haloperidol decanoate. Furthermore, it is recommended
that patients being considered for haloperidol decanoate therapy have been treated
with, and tolerate well, short-acting HALDOL (haloperidol) in order to reduce the
possibility of an unexpected adverse sensitivity to haloperidol. Close clinical
supervision is required during the initial period of dose adjustment in order to
minimize the risk of overdosage or reappearance of psychotic symptoms before the
next injection. During dose adjustment or episodes of exacerbation of symptoms of
schizophrenia, haloperidol decanoate therapy can be supplemented with short-acting
forms of haloperidol.
The dose of HALDOL Decanoate 50 or HALDOL Decanoate 100 should be
expressed in terms of its haloperidol content. The starting dose of haloperidol
decanoate should be based on the patient’s age, clinical history, physical condition,
and response to previous antipsychotic therapy. The preferred approach to
determining the minimum effective dose is to begin with lower initial doses and to
adjust the dose upward as needed. For patients previously maintained on low doses of
antipsychotics (e.g. up to the equivalent of 10 mg/day oral haloperidol), it is
recommended that the initial dose of haloperidol decanoate be 10-15 times the
previous daily dose in oral haloperidol equivalents; limited clinical experience
suggests that lower initial doses may be adequate.
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Initial Therapy
Conversion from oral haloperidol to haloperidol decanoate can be achieved by using
an initial dose of haloperidol decanoate that is 10 to 20 times the previous daily dose
in oral haloperidol equivalents.
In patients who are elderly, debilitated, or stable on low doses of oral haloperidol
(e.g. up to the equivalent of 10 mg/day oral haloperidol), a range of 10 to 15 times the
previous daily dose in oral haloperidol equivalents is appropriate for initial
conversion.
In patients previously maintained on higher doses of antipsychotics for whom a low
dose approach risks recurrence of psychiatric decompensation and in patients whose
long-term use of haloperidol has resulted in a tolerance to the drug, 20 times the
previous daily dose in oral haloperidol equivalents should be considered for initial
conversion, with downward titration on succeeding injections.
The initial dose of haloperidol decanoate should not exceed 100 mg regardless of
previous antipsychotic dose requirements. If, therefore, conversion requires more than
100 mg of haloperidol decanoate as an initial dose, that dose should be administered
in two injections, i.e. a maximum of 100 mg initially followed by the balance in
3 to 7 days.
Maintenance Therapy
The maintenance dosage of haloperidol decanoate must be individualized with
titration upward or downward based on therapeutic response. The usual maintenance
range is 10 to 15 times the previous daily dose in oral haloperidol equivalents
dependent on the clinical response of the patient.
HALDOL DECANOATE DOSING RECOMMENDATIONS
Monthly
Patients
1st Month
Maintenance
Stabilized on low daily oral doses
10-15 x Daily Oral Dose
10-15 x Previous Daily Oral Dose
(up to 10 mg/day)
Elderly or Debilitated
High dose
20 x Daily Oral Dose
10-15 x Previous Daily Oral Dose
Risk of relapse
Tolerant to oral haloperidol
Close clinical supervision is required during initiation and stabilization of haloperidol
decanoate therapy. Haloperidol decanoate is usually administered monthly or every
4 weeks. However, variation in patient response may dictate a need for adjustment of
the dosing interval as well as the dose (See CLINICAL PHARMACOLOGY).
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Clinical experience with haloperidol decanoate at doses greater than 450 mg per
month has been limited.
HOW SUPPLIED
HALDOL® (haloperidol) Decanoate 50 for IM injection, 50 mg haloperidol as
70.52 mg per mL haloperidol decanoate—NDC 0045-0253, 10 x 1 mL ampuls and
3 x 1 mL ampuls.
HALDOL® (haloperidol) Decanoate 100 for IM injection, 100 mg haloperidol as
141.04 mg per mL haloperidol decanoate—NDC 0045-0254, 5 x 1 mL ampuls.
Store at controlled room temperature (15°-30° C, 59°-86° F). Do not refrigerate or
freeze.
Protect from light.
Manufactured by:
Janssen Pharmaceutica N.V.
Beerse, Belgium
Distributed by:
Ortho-McNeil Pharmaceutical, Inc.
Raritan, NJ 08869
(ORTHO-McNEIL LOGO)
Revised June 2009
©OMP 2005
US-XXXXXX
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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custom-source
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2025-02-12T13:44:51.883257
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018701s059lbl.pdf', 'application_number': 18701, 'submission_type': 'SUPPL ', 'submission_number': 59}
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HALDOL
brand of
haloperidol injection
(For Immediate Release)
WARNING
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic
drugs are at an increased risk of death. Analyses of seventeen placebo-controlled
trials (modal duration of 10 weeks), largely in patients taking atypical
antipsychotic drugs, revealed a risk of death in drug-treated patients of between
1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a
typical 10-week controlled trial, the rate of death in drug-treated patients was
about 4.5%, compared to a rate of about 2.6% in the placebo group. Although
the causes of death were varied, most of the deaths appeared to be either
cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia)
in nature. Observational studies suggest that, similar to atypical antipsychotic
drugs, treatment with conventional antipsychotic drugs may increase mortality.
The extent to which the findings of increased mortality in observational studies
may be attributed to the antipsychotic drug as opposed to some characteristic(s)
of the patients is not clear. HALDOL Injection is not approved for the treatment
of patients with dementia-related psychosis (see WARNINGS).
DESCRIPTION
Haloperidol is the first of the butyrophenone series of major antipsychotics. The
chemical
designation
is
4-[4-(p-chlorophenyl)-4-hydroxypiperidino]
4’-fluorobutyrophenone and it has the following structural formula: structural formula
HALDOL (haloperidol) is available as a sterile parenteral form for intramuscular
injection. The injection provides 5 mg haloperidol (as the lactate) and lactic acid for
pH adjustment between 3.0 – 3.6.
ACTIONS
The precise mechanism of action has not been clearly established.
INDICATIONS
HALDOL (haloperidol) is indicated for use in the treatment of schizophrenia.
Reference ID: 3933083
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HALDOL is indicated for the control of tics and vocal utterances of Tourette’s
Disorder.
CONTRAINDICATIONS
HALDOL (haloperidol) is contraindicated in severe toxic central nervous system
depression or comatose states from any cause and in individuals who are
hypersensitive to this drug or have Parkinson’s disease.
WARNINGS
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic
drugs are at an increased risk of death. HALDOL Injection is not approved for
the treatment of patients with dementia-related psychosis (see BOXED
WARNING).
Cardiovascular Effects
Cases of sudden death, QT-prolongation, and Torsades de Pointes have been reported
in patients receiving HALDOL. Higher than recommended doses of any formulation
and intravenous administration of HALDOL appear to be associated with a higher
risk of QT-prolongation and Torsades de Pointes. Although cases have been reported
even in the absence of predisposing factors, particular caution is advised in treating
patients with other QT-prolonging conditions (including electrolyte imbalance
[particularly hypokalemia and hypomagnesemia], drugs known to prolong QT,
underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome).
HALDOL
INJECTION
IS
NOT
APPROVED
FOR
INTRAVENOUS
ADMINISTRATION. If HALDOL is administered intravenously, the ECG should be
monitored for QT prolongation and arrhythmias.
Tardive Dyskinesia
A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements
may develop in patients treated with antipsychotic drugs. Although the prevalence of
the syndrome appears to be highest among the elderly, especially elderly women, it is
impossible to rely upon prevalence estimates to predict, at the inception of
antipsychotic treatment, which patients are likely to develop the syndrome. Whether
antipsychotic drug products differ in their potential to cause tardive dyskinesia is
unknown.
Both the risk of developing tardive dyskinesia and the likelihood that it will become
irreversible are believed to increase as the duration of treatment and the total
cumulative dose of antipsychotic drugs administered to the patient increase.
Reference ID: 3933083
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However, the syndrome can develop, although much less commonly, after relatively
brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the
syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.
Antipsychotic treatment, itself, however, may suppress (or partially suppress) the
signs and symptoms of the syndrome and thereby may possibly mask the underlying
process. The effect that symptomatic suppression has upon the long-term course of
the syndrome is unknown.
Given these considerations, antipsychotic drugs should be prescribed in a manner that
is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic
treatment should generally be reserved for patients who suffer from a chronic illness
that, 1) is known to respond to antipsychotic drugs, and, 2) for whom alternative,
equally effective, but potentially less harmful treatments are not available or
appropriate. In patients who do require chronic treatment, the smallest dose and the
shortest duration of treatment producing a satisfactory clinical response should be
sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics,
drug discontinuation should be considered. However, some patients may require
treatment despite the presence of the syndrome.
(For further information about the description of tardive dyskinesia and its clinical
detection, please refer to ADVERSE REACTIONS.)
Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant
Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical
manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status
(including catatonic signs) and evidence of autonomic instability (irregular pulse or
blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs
may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and
acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at
a diagnosis, it is important to identify cases where the clinical presentation includes
both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated
or inadequately treated extrapyramidal signs and symptoms (EPS). Other important
considerations in the differential diagnosis include central anticholinergic toxicity,
heat stroke, drug fever and primary central nervous system (CNS) pathology.
Reference ID: 3933083
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The management of NMS should include 1) immediate discontinuation of
antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive
symptomatic treatment and medical monitoring, and 3) treatment of any concomitant
serious medical problems for which specific treatments are available. There is no
general agreement about specific pharmacological treatment regimens for
uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the
potential reintroduction of drug therapy should be carefully considered. The patient
should be carefully monitored, since recurrences of NMS have been reported.
Hyperpyrexia and heat stroke, not associated with the above symptom complex, have
also been reported with HALDOL.
Usage in Pregnancy
Rodents given 2 to 20 times the usual maximum human dose of haloperidol by oral or
parenteral routes showed an increase in incidence of resorption, reduced fertility,
delayed delivery and pup mortality. No teratogenic effect has been reported in rats,
rabbits or dogs at dosages within this range, but cleft palate has been observed in
mice given 15 times the usual maximum human dose. Cleft palate in mice appears to
be a nonspecific response to stress or nutritional imbalance as well as to a variety of
drugs, and there is no evidence to relate this phenomenon to predictable human risk
for most of these agents.
There are no well controlled studies with HALDOL (haloperidol) in pregnant women.
There are reports, however, of cases of limb malformations observed following
maternal use of HALDOL along with other drugs which have suspected teratogenic
potential during the first trimester of pregnancy. Causal relationships were not
established in these cases. Since such experience does not exclude the possibility of
fetal damage due to HALDOL, this drug should be used during pregnancy or in
women likely to become pregnant only if the benefit clearly justifies a potential risk
to the fetus. Infants should not be nursed during drug treatment.
Non-teratogenic Effects
Neonates exposed to antipsychotic drugs (including haloperidol) during the third
trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms
following delivery. There have been reports of agitation, hypertonia, hypotonia,
tremor, somnolence, respiratory distress, and feeding disorder in these neonates.
These complications have varied in severity; while in some cases symptoms have
Reference ID: 3933083
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For current labeling information, please visit https://www.fda.gov/drugsatfda
been self-limited, in other cases neonates have required intensive care unit support
and prolonged hospitalization.
HALDOL should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
Combined Use of HALDOL and Lithium
An encephalopathic syndrome (characterized by weakness, lethargy, fever,
tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated
serum enzymes, BUN, and fasting blood sugar) followed by irreversible brain
damage has occurred in a few patients treated with lithium plus HALDOL. A causal
relationship between these events and the concomitant administration of lithium and
HALDOL has not been established; however, patients receiving such combined
therapy should be monitored closely for early evidence of neurological toxicity and
treatment discontinued promptly if such signs appear.
General
A number of cases of bronchopneumonia, some fatal, have followed the use of
antipsychotic drugs, including HALDOL. It has been postulated that lethargy and
decreased sensation of thirst due to central inhibition may lead to dehydration,
hemoconcentration and reduced pulmonary ventilation. Therefore, if the above signs
and symptoms appear, especially in the elderly, the physician should institute
remedial therapy promptly.
Although not reported with HALDOL, decreased serum cholesterol and/or cutaneous
and ocular changes have been reported in patients receiving chemically-related drugs.
PRECAUTIONS
Leukopenia, Neutropenia, and Agranulocytosis
Class Effect: In clinical trial and/or postmarketing experience, events of
leukopenia/neutropenia have been reported temporally related to antipsychotic agents,
including HALDOL. Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood
cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with
a
history
of
a
clinically
significant
low
WBC
or
a
drug-induced
leukopenia/neutropenia should have their complete blood count (CBC) monitored
frequently during the first few months of therapy and discontinuation of HALDOL
should be considered at the first sign of a clinically significant decline in WBC in the
absence of other causative factors.
Reference ID: 3933083
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Patients with clinically significant neutropenia should be carefully monitored for
fever or other symptoms or signs of infection and treated promptly if such symptoms
or signs occur. Patients with severe neutropenia (absolute neutrophil count
<1000/mm3) should discontinue HALDOL and have their WBC followed until
recovery.
Other
HALDOL (haloperidol) should be administered cautiously to patients:
• with severe cardiovascular disorders, because of the possibility of transient
hypotension and/or precipitation of anginal pain. Should hypotension occur and a
vasopressor be required, epinephrine should not be used since HALDOL may
block its vasopressor activity and paradoxical further lowering of the blood
pressure may occur. Instead, metaraminol, phenylephrine or norepinephrine should
be used.
• receiving anticonvulsant medications, with a history of seizures, or with EEG
abnormalities, because HALDOL may lower the convulsive threshold. If
indicated, adequate anticonvulsant therapy should be concomitantly maintained.
• with known allergies, or with a history of allergic reactions to drugs.
• receiving anticoagulants, since an isolated instance of interference occurred with
the effects of one anticoagulant (phenindione).
When HALDOL is used to control mania in cyclic disorders, there may be a rapid
mood swing to depression.
Severe neurotoxicity (rigidity, inability to walk or talk) may occur in patients with
thyrotoxicosis who are also receiving antipsychotic medication, including HALDOL.
Drug Interactions
Drug-drug interactions can be pharmacodynamic (combined pharmacologic effects)
or pharmacokinetic (alteration of plasma levels). The risks of using haloperidol in
combination with other drugs have been evaluated as described below.
Pharmacodynamic Interactions
Since QT-prolongation has been observed during Haldol treatment, caution is advised
when prescribing to a patient with QT-prolongation conditions (long QT-syndrome,
hypokalemia, electrolyte imbalance) or to patients receiving medications known to
prolong the QT-interval or known to cause electrolyte imbalance.
If concomitant antiparkinson medication is required, it may have to be continued after
HALDOL is discontinued because of the difference in excretion rates. If both are
discontinued simultaneously, extrapyramidal symptoms may occur. The physician
should keep in mind the possible increase in intraocular pressure when
Reference ID: 3933083
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anticholinergic drugs, including antiparkinson agents, are administered concomitantly
with HALDOL.
As with other antipsychotic agents, it should be noted that HALDOL may be capable
of potentiating CNS depressants such as anesthetics, opiates and alcohol.
Ketoconazole is a potent inhibitor of CYP3A4. Increases in QTc have been observed
when haloperidol was given in combination with the metabolic inhibitors
ketoconazole (400 mg/day) and paroxetine (20 mg/day). It may be necessary to
reduce the haloperidol dosage.
Pharmacokinetic Interactions
The Effect of Other Drugs on Haldol®
Haloperidol is metabolized by several routes, including the glucuronidation and the
cytochrome P450 enzyme system. Inhibition of these routes of metabolism by another
drug may result in increased haloperidol concentrations and potentially increase the
risk of certain adverse events, including QT-prolongation.
Drugs Characterized as Substrates, Inhibitors or Inducers of CYP3A4,
CYP2D6 or Glucuronidation
In pharmacokinetic studies, mild to moderately increased haloperidol concentrations
have been reported when haloperidol was given concomitantly with drugs
characterized as substrates or inhibitors of CYP3A4 or CYP2D6 isoenzymes, such as
itraconazole,
nefazodone,
buspirone,
venlafaxine,
alprazolam,
fluvoxamine,
quinidine, fluoxetine, sertraline, chlorpromazine, and promethazine.
When prolonged treatment (1-2 weeks) with enzyme-inducing drugs such as rifampin
or carbamazepine is added to Haldol therapy, this results in a significant reduction of
haloperidol plasma levels.
Rifampin
In a study of 12 schizophrenic patients coadministered oral haloperidol and rifampin,
plasma haloperidol levels were decreased by a mean of 70% and mean scores on the
Brief Psychiatric Rating Scale were increased from baseline. In 5 other schizophrenic
patients treated with haloperidol and rifampin, discontinuation of rifampin produced a
mean 3.3-fold increase in haloperidol concentrations.
Carbamazepine
In a study in 11 schizophrenic patients co-administered haloperidol and increasing
doses of carbamazepine, haloperidol plasma concentrations decreased linearly with
increasing carbamazepine concentrations.
Reference ID: 3933083
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Thus, careful monitoring of clinical status is warranted when enzyme inducing drugs
such as rifampin or carbamazepine are administered or discontinued in haloperidol
treated patients. During combination treatment, the Haldol dose should be adjusted,
when necessary. After discontinuation of such drugs, it may be necessary to reduce
the dosage of Haldol.
Valproate
Sodium valproate, a drug know to inhibit glucuronidation, does not affect haloperidol
plasma concentrations.
Information for Patients
HALDOL may impair the mental and/or physical abilities required for the
performance of hazardous tasks such as operating machinery or driving a motor
vehicle. The ambulatory patient should be warned accordingly.
The use of alcohol with this drug should be avoided due to possible additive effects
and hypotension.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
No mutagenic potential of haloperidol was found in the Ames Salmonella microsomal
activation assay. Negative or inconsistent positive findings have been obtained in
in vitro and in vivo studies of effects of haloperidol on chromosome structure and
number. The available cytogenetic evidence is considered too inconsistent to be
conclusive at this time.
Carcinogenicity studies using oral haloperidol were conducted in Wistar rats (dosed
at up to 5 mg/kg daily for 24 months) and in Albino Swiss mice (dosed at up to
5 mg/kg daily for 18 months). In the rat study survival was less than optimal in all
dose groups, reducing the number of rats at risk for developing tumors. However,
although a relatively greater number of rats survived to the end of the study in high-
dose male and female groups, these animals did not have a greater incidence of
tumors than control animals. Therefore, although not optimal, this study does suggest
the absence of a haloperidol related increase in the incidence of neoplasia in rats at
doses up to 20 times the usual daily human dose for chronic or resistant patients.
In female mice at 5 and 20 times the highest initial daily dose for chronic or resistant
patients, there was a statistically significant increase in mammary gland neoplasia and
total tumor incidence; at 20 times the same daily dose there was a statistically
significant increase in pituitary gland neoplasia. In male mice, no statistically
Reference ID: 3933083
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For current labeling information, please visit https://www.fda.gov/drugsatfda
significant differences in incidences of total tumors or specific tumor types were
noted.
Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic
administration. Tissue culture experiments indicate that approximately one-third of
human breast cancers are prolactin dependent in vitro, a factor of potential
importance if the prescription of these drugs is contemplated in a patient with a
previously detected breast cancer. Although disturbances such as galactorrhea,
amenorrhea, gynecomastia, and impotence have been reported, the clinical
significance of elevated serum prolactin levels is unknown for most patients. An
increase in mammary neoplasms has been found in rodents after chronic
administration of antipsychotic drugs. Neither clinical studies nor epidemiologic
studies conducted to date, however, have shown an association between chronic
administration of these drugs and mammary tumorigenesis; the available evidence is
considered too limited to be conclusive at this time.
There are no well controlled studies with HALDOL (haloperidol) in pregnant women.
There are reports, however, of cases of limb malformations observed following
maternal use of HALDOL along with other drugs which have suspected teratogenic
potential during the first trimester of pregnancy. Causal relationships were not
established in these cases. Since such experience does not exclude the possibility of
fetal damage due to HALDOL, this drug should be used during pregnancy or in
women likely to become pregnant only if the benefit clearly justifies a potential risk
to the fetus.
Nursing Mothers
Since haloperidol is excreted in human breast milk, infants should not be nursed
during drug treatment with haloperidol.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of haloperidol did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience has not consistently identified differences
in responses between the elderly and younger patients. However, the prevalence of
tardive dyskinesia appears to be highest among the elderly, especially elderly women
(see WARNINGS, Tardive Dyskinesia). Also, the pharmacokinetics of haloperidol in
geriatric patients generally warrants the use of lower doses (see DOSAGE AND
ADMINISTRATION).
Reference ID: 3933083
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ADVERSE REACTIONS
Cardiovascular Effects
Tachycardia, hypotension, and hypertension have been reported. QT prolongation
and/or ventricular arrhythmias have also been reported, in addition to ECG pattern
changes compatible with the polymorphous configuration of torsade de pointes, and
may occur more frequently with high doses and in predisposed patients
(see WARNINGS and PRECAUTIONS).
Cases of sudden and unexpected death have been reported in association with the
administration of HALDOL. The nature of the evidence makes it impossible to
determine definitively what role, if any, HALDOL played in the outcome of the
reported cases. The possibility that HALDOL caused death cannot, of course, be
excluded, but it is to be kept in mind that sudden and unexpected death may occur in
psychotic patients when they go untreated or when they are treated with other
antipsychotic drugs.
CNS Effects
Extrapyramidal Symptoms (EPS)
EPS during the administration of HALDOL (haloperidol) have been reported
frequently, often during the first few days of treatment. EPS can be categorized
generally as Parkinson-like symptoms, akathisia, or dystonia (including opisthotonos
and oculogyric crisis). While all can occur at relatively low doses, they occur more
frequently and with greater severity at higher doses. The symptoms may be controlled
with dose reductions or administration of antiparkinson drugs such as benztropine
mesylate USP or trihexyphenidyl hydrochloride USP. It should be noted that
persistent EPS have been reported; the drug may have to be discontinued in such
cases.
Dystonia
Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle
groups, may occur in susceptible individuals during the first few days of treatment.
Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to
tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion
of the tongue. While these symptoms can occur at low doses, they occur more
frequently and with greater severity with high potency and at higher doses of first
generation antipsychotic drugs. An elevated risk of acute dystonia is observed in
males and younger age groups.
Withdrawal Emergent Neurological Signs
Generally, patients receiving short-term therapy experience no problems with abrupt
discontinuation of antipsychotic drugs. However, some patients on maintenance
Reference ID: 3933083
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For current labeling information, please visit https://www.fda.gov/drugsatfda
treatment experience transient dyskinetic signs after abrupt withdrawal. In certain of
these cases the dyskinetic movements are indistinguishable from the syndrome
described below under “Tardive Dyskinesia” except for duration. It is not known
whether gradual withdrawal of antipsychotic drugs will reduce the rate of occurrence
of withdrawal emergent neurological signs but until further evidence becomes
available, it seems reasonable to gradually withdraw use of HALDOL.
Tardive Dyskinesia
As with all antipsychotic agents HALDOL has been associated with persistent
dyskinesias. Tardive dyskinesia, a syndrome consisting of potentially irreversible,
involuntary, dyskinetic movements, may appear in some patients on long-term
therapy or may occur after drug therapy has been discontinued. The risk appears to be
greater in elderly patients on high-dose therapy, especially females. The symptoms
are persistent and in some patients appear irreversible. The syndrome is characterized
by rhythmical involuntary movements of tongue, face, mouth or jaw (e.g., protrusion
of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes
these may be accompanied by involuntary movements of extremities and the trunk.
There is no known effective treatment for tardive dyskinesia; antiparkinson agents
usually do not alleviate the symptoms of this syndrome. It is suggested that all
antipsychotic agents be discontinued if these symptoms appear. Should it be
necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a
different antipsychotic agent, this syndrome may be masked.
It has been reported that fine vermicular movement of the tongue may be an early
sign of tardive dyskinesia and if the medication is stopped at that time the full
syndrome may not develop.
Tardive Dystonia
Tardive dystonia, not associated with the above syndrome, has also been reported.
Tardive dystonia is characterized by delayed onset of choreic or dystonic movements,
is often persistent, and has the potential of becoming irreversible.
Other CNS Effects
Insomnia, restlessness, anxiety, euphoria, agitation, drowsiness, depression, lethargy,
headache, confusion, vertigo, grand mal seizures, exacerbation of psychotic
symptoms including hallucinations, and catatonic-like behavioral states which may be
responsive to drug withdrawal and/or treatment with anticholinergic drugs.
Reference ID: 3933083
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Body as a Whole
Neuroleptic malignant syndrome (NMS), hyperpyrexia and heat stroke have been
reported with HALDOL. (See WARNINGS for further information concerning
NMS.)
Hematologic Effects
Reports have appeared citing the occurrence of mild and usually transient leukopenia
and leukocytosis, minimal decreases in red blood cell counts, anemia, or a tendency
toward lymphomonocytosis. Agranulocytosis has rarely been reported to have
occurred with the use of HALDOL, and then only in association with other
medication. (See PRECAUTIONS: Leukopenia, Neutropenia, and Agranulocytosis.)
Liver Effects
Impaired liver function and/or jaundice have been reported.
Dermatologic Reactions
Maculopapular and acneiform skin reactions and isolated cases of photosensitivity
and loss of hair.
Endocrine Disorders
Lactation, breast engorgement, mastalgia, menstrual irregularities, gynecomastia,
impotence, increased libido, hyperglycemia, hypoglycemia and hyponatremia.
Gastrointestinal Effects
Anorexia, constipation, diarrhea, hypersalivation, dyspepsia, nausea and vomiting.
Autonomic Reactions
Dry mouth, blurred vision, urinary retention, diaphoresis and priapism.
Respiratory Effects
Laryngospasm, bronchospasm and increased depth of respiration.
Special Senses
Cataracts, retinopathy and visual disturbances.
Postmarketing Events
Hyperammonemia has been reported in a 5½ year old child with citrullinemia, an
inherited disorder of ammonia excretion, following treatment with HALDOL.
Rhabdomyolysis has been reported.
Reference ID: 3933083
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OVERDOSAGE
Manifestations
In general, the symptoms of overdosage would be an exaggeration of known
pharmacologic effects and adverse reactions, the most prominent of which would
be: 1) severe extrapyramidal reactions, 2) hypotension, or 3) sedation. The patient
would appear comatose with respiratory depression and hypotension which could be
severe enough to produce a shock-like state. The extrapyramidal reactions would be
manifested by muscular weakness or rigidity and a generalized or localized tremor as
demonstrated by the akinetic or agitans types respectively. With accidental
overdosage, hypertension rather than hypotension occurred in a two-year old child.
The risk of ECG changes associated with torsade de pointes should be considered.
(For further information regarding torsade de pointes, please refer to
ADVERSE REACTIONS.)
Treatment
Since there is no specific antidote, treatment is primarily supportive. A patent airway
must be established by use of an oropharyngeal airway or endotracheal tube or, in
prolonged cases of coma, by tracheostomy. Respiratory depression may be
counteracted by artificial respiration and mechanical respirators. Hypotension and
circulatory collapse may be counteracted by use of intravenous fluids, plasma, or
concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine
and norepinephrine. Epinephrine should not be used. In case of severe extrapyramidal
reactions, antiparkinson medication should be administered. ECG and vital signs
should be monitored especially for signs of Q-T prolongation or dysrhythmias and
monitoring should continue until the ECG is normal. Severe arrhythmias should be
treated with appropriate anti-arrhythmic measures.
DOSAGE AND ADMINISTRATION
There is considerable variation from patient to patient in the amount of medication
required for treatment. As with all drugs used to treat schizophrenia, dosage should be
individualized according to the needs and response of each patient. Dosage
adjustments, either upward or downward, should be carried out as rapidly as
practicable to achieve optimum therapeutic control.
To determine the initial dosage, consideration should be given to the patient’s age,
severity of illness, previous response to other antipsychotic drugs, and any
concomitant medication or disease state. Debilitated or geriatric patients, as well as
those with a history of adverse reactions to antipsychotic drugs, may require less
HALDOL (haloperidol). The optimal response in such patients is usually obtained
with more gradual dosage adjustments and at lower dosage levels.
Reference ID: 3933083
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Parenteral medication, administered intramuscularly in doses of 2 to 5 mg, is utilized
for prompt control of the acutely agitated schizophrenic patient with moderately
severe to very severe symptoms. Depending on the response of the patient,
subsequent doses may be given, administered as often as every hour, although 4 to
8 hour intervals may be satisfactory. The maximum dose is 20 mg/day.
Controlled trials to establish the safety and effectiveness of intramuscular
administration in children have not been conducted.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
Switchover Procedure
An oral form should supplant the injectable as soon as practicable. In the absence of
bioavailability studies establishing bioequivalence between these two dosage forms
the following guidelines for dosage are suggested. For an initial approximation of the
total daily dose required, the parenteral dose administered in the preceding 24 hours
may be used. Since this dose is only an initial estimate, it is recommended that careful
monitoring of clinical signs and symptoms, including clinical efficacy, sedation, and
adverse effects, be carried out periodically for the first several days following the
initiation of switchover. In this way, dosage adjustments, either upward or downward,
can be quickly accomplished. Depending on the patient’s clinical status, the first oral
dose should be given within 12-24 hours following the last parenteral dose.
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INSTRUCTIONS FOR OPENING AMPULE
Step 1
1. Medication often rests in the top
part
of
the
ampule.
Before
breaking the ampule, lightly tap
the top of the ampule with your
finger until all fluid moves to the
bottom portion of the ampule.
The ampule has a colored ring(s)
and colored point which aids in
the placement of fingers while
breaking the ampule. usage illustration
Step 2
2. Hold the ampule between thumb
and index finger with the colored
point facing you. usage illustration
Step 3
3. Position the index finger of the
other hand to support the neck of
the ampule. Position the thumb so
that it covers the colored point
and is parallel to the colored
ring(s). usage illustration
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Step 4
4. Keeping the thumb on the colored
point and with the index fingers
close
together,
apply
firm
pressure on the colored point in
the direction of the arrow to snap
the ampule open. usage illustration
HOW SUPPLIED
HALDOL brand of haloperidol Injection (For Immediate Release) 5 mg per mL (as
the lactate) – NDC 50458-255-01, units of 10 x 1 mL ampules.
Store HALDOL haloperidol Injection at controlled room temperature (15°-30°C,
59°-86°F). Protect from light. Do not freeze.
Product of Belgium
Manufactured by:
GlaxoSmithKline Manufacturing S.p.A.
Parma, Italy
Manufactured for:
Janssen Pharmaceuticals, Inc.
Titusville, NJ 08560
Revised January 2016
Janssen Pharmaceuticals, Inc. 2005
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HALDOL® Decanoate 50 (haloperidol)
HALDOL® Decanoate 100 (haloperidol)
For IM Injection Only
WARNING
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic
drugs are at an increased risk of death. Analyses of seventeen placebo-controlled
trials (modal duration of 10 weeks), largely in patients taking atypical
antipsychotic drugs, revealed a risk of death in drug-treated patients of between
1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a
typical 10-week controlled trial, the rate of death in drug-treated patients was
about 4.5%, compared to a rate of about 2.6% in the placebo group. Although
the causes of death were varied, most of the deaths appeared to be either
cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia)
in nature. Observational studies suggest that, similar to atypical antipsychotic
drugs, treatment with conventional antipsychotic drugs may increase mortality.
The extent to which the findings of increased mortality in observational studies
may be attributed to the antipsychotic drug as opposed to some characteristic(s)
of the patients is not clear. HALDOL Decanoate is not approved for the
treatment of patients with dementia-related psychosis (see WARNINGS).
DESCRIPTION
Haloperidol decanoate is the decanoate ester of the butyrophenone, HALDOL
(haloperidol). It has a markedly extended duration of effect. It is available in sesame
oil in sterile form for intramuscular (IM) injection. The structural formula of
haloperidol
decanoate,
4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-4
piperidinyl decanoate, is: structural formula
Haloperidol decanoate is almost insoluble in water (0.01 mg/mL), but is soluble in
most organic solvents.
Each mL of HALDOL Decanoate 50 for IM injection contains 50 mg haloperidol
(present as haloperidol decanoate 70.52 mg) in a sesame oil vehicle, with 1.2% (w/v)
benzyl alcohol as a preservative.
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Each mL of HALDOL Decanoate 100 for IM injection contains 100 mg haloperidol
(present as haloperidol decanoate 141.04 mg) in a sesame oil vehicle, with 1.2%
(w/v) benzyl alcohol as a preservative.
CLINICAL PHARMACOLOGY
HALDOL Decanoate 50 and HALDOL Decanoate 100 are the long-acting forms of
HALDOL (haloperidol). The basic effects of haloperidol decanoate are no different
from those of HALDOL with the exception of duration of action. Haloperidol blocks
the effects of dopamine and increases its turnover rate; however, the precise
mechanism of action is unknown.
Administration of haloperidol decanoate in sesame oil results in slow and sustained
release of haloperidol. The plasma concentrations of haloperidol gradually rise,
reaching a peak at about 6 days after the injection, and falling thereafter, with an
apparent half-life of about 3 weeks. Steady state plasma concentrations are achieved
after the third or fourth dose. The relationship between dose of haloperidol decanoate
and plasma haloperidol concentration is roughly linear for doses below 450 mg. It
should be noted, however, that the pharmacokinetics of haloperidol decanoate
following intramuscular injections can be quite variable between subjects.
INDICATIONS AND USAGE
HALDOL Decanoate 50 and HALDOL Decanoate 100 are indicated for the treatment
of schizophrenic patients who require prolonged parenteral antipsychotic therapy.
CONTRAINDICATIONS
Since the pharmacologic and clinical actions of HALDOL Decanoate 50 and
HALDOL Decanoate 100 are attributed to HALDOL (haloperidol) as the active
medication, Contraindications, Warnings, and additional information are those of
HALDOL, modified only to reflect the prolonged action.
HALDOL is contraindicated in severe toxic central nervous system depression or
comatose states from any cause and in individuals who are hypersensitive to this drug
or have Parkinson’s disease.
WARNINGS
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic
drugs are at an increased risk of death. HALDOL Decanoate is not approved for
the treatment of patients with dementia-related psychosis (see BOXED
WARNING).
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Cardiovascular Effects
Cases of sudden death, QT-prolongation, and Torsades de Pointes have been reported
in patients receiving haloperidol. Higher than recommended doses of any formulation
and intravenous administration of haloperidol appear to be associated with a higher
risk of QT-prolongation and Torsades de Pointes. Although cases have been reported
even in the absence of predisposing factors, particular caution is advised in treating
patients with other QT-prolonging conditions (including electrolyte imbalance
[particularly hypokalemia and hypomagnesemia], drugs known to prolong QT,
underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome).
HALDOL DECANOATE MUST NOT BE ADMINISTERED INTRAVENOUSLY.
Tardive Dyskinesia
A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements
may develop in patients treated with antipsychotic drugs. Although the prevalence of
the syndrome appears to be highest among the elderly, especially elderly women, it is
impossible to rely upon prevalence estimates to predict, at the inception of
antipsychotic treatment, which patients are likely to develop the syndrome. Whether
antipsychotic drug products differ in their potential to cause tardive dyskinesia is
unknown.
Both the risk of developing tardive dyskinesia and the likelihood that it will become
irreversible are believed to increase as the duration of treatment and the total
cumulative dose of antipsychotic drugs administered to the patient increase. However,
the syndrome can develop, although much less commonly, after relatively brief
treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the
syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.
Antipsychotic treatment, itself, however, may suppress (or partially suppress) the
signs and symptoms of the syndrome and thereby may possibly mask the underlying
process. The effect that symptomatic suppression has upon the long-term course of
the syndrome is unknown.
Given these considerations, antipsychotic drugs should be prescribed in a manner that
is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic
treatment should generally be reserved for patients who suffer from a chronic illness
that 1) is known to respond to antipsychotic drugs, and 2) for whom alternative,
equally effective, but potentially less harmful treatments are not available or
appropriate. In patients who do require chronic treatment, the smallest dose and the
shortest duration of treatment producing a satisfactory clinical response should be
sought. The need for continued treatment should be reassessed periodically.
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If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics,
drug discontinuation should be considered. However, some patients may require
treatment despite the presence of the syndrome. (For further information about the
description of tardive dyskinesia and its clinical detection, please refer to ADVERSE
REACTIONS.)
Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant
Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical
manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status
(including catatonic signs) and evidence of autonomic instability (irregular pulse or
blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs
may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and
acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at
a diagnosis, it is important to identify cases where the clinical presentation includes
both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated
or inadequately treated extrapyramidal signs and symptoms (EPS). Other important
considerations in the differential diagnosis include central anticholinergic toxicity,
heat stroke, drug fever and primary central nervous system (CNS) pathology.
The management of NMS should include 1) immediate discontinuation of
antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive
symptomatic treatment and medical monitoring, and 3) treatment of any concomitant
serious medical problems for which specific treatments are available. There is no
general agreement about specific pharmacological treatment regimens for
uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the
potential reintroduction of drug therapy should be carefully considered. The patient
should be carefully monitored, since recurrences of NMS have been reported.
Hyperpyrexia and heat stroke, not associated with the above symptom complex, have
also been reported with HALDOL.
Combined Use of HALDOL and Lithium
An encephalopathic syndrome (characterized by weakness, lethargy, fever,
tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated
serum enzymes, BUN, and fasting blood sugar) followed by irreversible brain
damage has occurred in a few patients treated with lithium plus HALDOL. A causal
relationship between these events and the concomitant administration of lithium and
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HALDOL has not been established; however, patients receiving such combined
therapy should be monitored closely for early evidence of neurological toxicity and
treatment discontinued promptly if such signs appear.
General
A number of cases of bronchopneumonia, some fatal, have followed the use of
antipsychotic drugs, including HALDOL (haloperidol). It has been postulated that
lethargy and decreased sensation of thirst due to central inhibition may lead to
dehydration, hemoconcentration and reduced pulmonary ventilation. Therefore, if the
above signs and symptoms appear, especially in the elderly, the physician should
institute remedial therapy promptly.
Although not reported with HALDOL, decreased serum cholesterol and/or cutaneous
and ocular changes have been reported in patients receiving chemically-related drugs.
PRECAUTIONS
Leukopenia, Neutropenia, and Agranulocytosis
Class Effect: In clinical trial and/or postmarketing experience, events of
leukopenia/neutropenia have been reported temporally related to antipsychotic agents,
including HALDOL Decanoate. Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood
cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with
a
history
of
a
clinically
significant
low
WBC
or
a
drug-induced
leukopenia/neutropenia should have their complete blood count (CBC) monitored
frequently during the first few months of therapy and discontinuation of HALDOL
Decanoate should be considered at the first sign of a clinically significant decline in
WBC in the absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for
fever or other symptoms or signs of infection and treated promptly if such symptoms
or signs occur. Patients with severe neutropenia (absolute neutrophil count
<1000/mm3) should discontinue HALDOL Decanoate and have their WBC followed
until recovery.
Other
HALDOL Decanoate 50 and HALDOL Decanoate 100 should be administered
cautiously to patients:
• with severe cardiovascular disorders, because of the possibility of transient
hypotension and/or precipitation of anginal pain. Should hypotension occur and a
vasopressor be required, epinephrine should not be used since HALDOL
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(haloperidol) may block its vasopressor activity, and paradoxical further lowering
of the blood pressure may occur. Instead, metaraminol, phenylephrine or
norepinephrine should be used.
• receiving anticonvulsant medications, with a history of seizures, or with EEG
abnormalities, because HALDOL may lower the convulsive threshold. If
indicated, adequate anticonvulsant therapy should be concomitantly maintained.
• with known allergies, or with a history of allergic reactions to drugs.
• receiving anticoagulants, since an isolated instance of interference occurred with
the effects of one anticoagulant (phenindione).
If concomitant antiparkinson medication is required, it may have to be continued after
HALDOL Decanoate 50 or HALDOL Decanoate 100 is discontinued because of the
prolonged action of haloperidol decanoate. If both drugs are discontinued
simultaneously, extrapyramidal symptoms may occur. The physician should keep in
mind the possible increase in intraocular pressure when anticholinergic drugs,
including antiparkinson agents, are administered concomitantly with haloperidol
decanoate.
When HALDOL Decanoate is used to control mania in cyclic disorders, there may be
a rapid mood swing to depression.
Severe neurotoxicity (rigidity, inability to walk or talk) may occur in patients with
thyrotoxicosis who are also receiving antipsychotic medication, including HALDOL.
Information for Patients
Haloperidol decanoate may impair the mental and/or physical abilities required for
the performance of hazardous tasks such as operating machinery or driving a motor
vehicle. The ambulatory patient should be warned accordingly.
The use of alcohol with this drug should be avoided due to possible additive effects
and hypotension.
Drug Interactions
Drug-drug interactions can be pharmacodynamic (combined pharmacologic effects)
or pharmacokinetic (alteration of plasma levels). The risks of using haloperidol in
combination with other drugs have been evaluated as described below.
Pharmacodynamic Interactions
Since QT-prolongation has been observed during Haldol treatment, caution is advised
when prescribing to a patient with QT-prolongation conditions (long QT-syndrome,
hypokalemia, electrolyte imbalance) or to patients receiving medications known to
prolong the QT-interval or known to cause electrolyte imbalance.
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As with other antipsychotic agents, it should be noted that HALDOL may be capable
of potentiating CNS depressants such as anesthetics, opiates, and alcohol.
Ketoconazole is a potent inhibitor of CYP3A4. Increases in QTc have been observed
when haloperidol was given in combination with the metabolic inhibitors
ketoconazole (400 mg/day) and paroxetine (20 mg/day). It may be necessary to
reduce the haloperidol dosage.
Pharmacokinetic Interactions
The Effect of Other Drugs on Haldol® Decanoate
Haloperidol is metabolized by several routes, including the glucuronidation and the
cytochrome P450 enzyme system. Inhibition of these routes of metabolism by another
drug may result in increased haloperidol concentrations and potentially increase the
risk of certain adverse events, including QT-prolongation.
Drugs Characterized as Substrates, Inhibitors or Inducers of CYP3A4,
CYP2D6 or Glucuronidation
In pharmacokinetic studies, mild to moderately increased haloperidol concentrations
have been reported when haloperidol was given concomitantly with drugs
characterized as substrates or inhibitors of CYP3A4 or CYP2D6 isoenzymes, such as
itraconazole,
nefazodone,
buspirone,
venlafaxine,
alprazolam,
fluvoxamine,
quinidine, fluoxetine, sertraline, chlorpromazine, and promethazine.
When prolonged treatment (1-2 weeks) with enzyme-inducing drugs such as rifampin
or carbamazepine is added to Haldol therapy, this results in a significant reduction of
haloperidol plasma levels.
Rifampin
In a study of 12 schizophrenic patients coadministered oral haloperidol and rifampin,
plasma haloperidol levels were decreased by a mean of 70% and mean scores on the
Brief Psychiatric Rating Scale were increased from baseline. In 5 other schizophrenic
patients treated with oral haloperidol and rifampin, discontinuation of rifampin
produced a mean 3.3-fold increase in haloperidol concentrations.
Carbamazepine
In a study in 11 schizophrenic patients co-administered haloperidol and increasing
doses of carbamazepine, haloperidol plasma concentrations decreased linearly with
increasing carbamazepine concentrations.
Thus, careful monitoring of clinical status is warranted when enzyme inducing drugs
such as rifampin or carbamazepine are administered or discontinued in
haloperidol-treated patients. During combination treatment, the Haldol dose should be
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adjusted, when necessary. After discontinuation of such drugs, it may be necessary to
reduce the dosage of Haldol.
Valproate
Sodium valproate, a drug know to inhibit glucuronidation, does not affect haloperidol
plasma concentrations.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
No mutagenic potential of haloperidol decanoate was found in the Ames Salmonella
microsomal activation assay. Negative or inconsistent positive findings have been
obtained in in vitro and in vivo studies of effects of short-acting haloperidol on
chromosome structure and number. The available cytogenetic evidence is considered
too inconsistent to be conclusive at this time.
Carcinogenicity studies using oral haloperidol were conducted in Wistar rats (dosed
at up to 5 mg/kg daily for 24 months) and in Albino Swiss mice (dosed at up to
5 mg/kg daily for 18 months). In the rat study survival was less than optimal in all
dose groups, reducing the number of rats at risk for developing tumors. However,
although a relatively greater number of rats survived to the end of the study in
high-dose male and female groups, these animals did not have a greater incidence of
tumors than control animals. Therefore, although not optimal, this study does suggest
the absence of a haloperidol related increase in the incidence of neoplasia in rats at
doses up to 20 times the usual daily human dose for chronic or resistant patients.
In female mice at 5 and 20 times the highest initial daily dose for chronic or resistant
patients, there was a statistically significant increase in mammary gland neoplasia and
total tumor incidence; at 20 times the same daily dose there was a statistically
significant increase in pituitary gland neoplasia. In male mice, no statistically
significant differences in incidences of total tumors or specific tumor types were
noted.
Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic
administration. Tissue culture experiments indicate that approximately one-third of
human breast cancers are prolactin dependent in vitro, a factor of potential
importance if the prescription of these drugs is contemplated in a patient with a
previously detected breast cancer. Although disturbances such as galactorrhea,
amenorrhea, gynecomastia, and impotence have been reported, the clinical
significance of elevated serum prolactin levels is unknown for most patients.
An increase in mammary neoplasms has been found in rodents after chronic
administration of antipsychotic drugs. Neither clinical studies nor epidemiologic
studies conducted to date, however, have shown an association between chronic
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administration of these drugs and mammary tumorigenesis; the available evidence is
considered too limited to be conclusive at this time.
Usage in Pregnancy
Pregnancy Category C.
Rodents given up to 3 times the usual maximum human dose of haloperidol
decanoate showed an increase in incidence of resorption, fetal mortality, and pup
mortality. No fetal abnormalities were observed.
Cleft palate has been observed in mice given oral haloperidol at 15 times the usual
maximum human dose. Cleft palate in mice appears to be a nonspecific response to
stress or nutritional imbalance as well as to a variety of drugs, and there is no
evidence to relate this phenomenon to predictable human risk for most of these
agents.
There are no adequate and well-controlled studies in pregnant women. There are
reports, however, of cases of limb malformations observed following maternal use of
HALDOL along with other drugs which have suspected teratogenic potential during
the first trimester of pregnancy. Causal relationships were not established with these
cases. Since such experience does not exclude the possibility of fetal damage due to
HALDOL, haloperidol decanoate should be used during pregnancy or in women
likely to become pregnant only if the benefit clearly justifies a potential risk to the
fetus.
Non-teratogenic Effects
Neonates exposed to antipsychotic drugs (including haloperidol) during the third
trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms
following delivery. There have been reports of agitation, hypertonia, hypotonia,
tremor, somnolence, respiratory distress, and feeding disorder in these neonates.
These complications have varied in severity; while in some cases symptoms have
been self-limited, in other cases neonates have required intensive care unit support
and prolonged hospitalization.
HALDOL Decanoate should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
Nursing Mothers
Since haloperidol is excreted in human breast milk, infants should not be nursed
during drug treatment with haloperidol decanoate.
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Pediatric Use
Safety and effectiveness of haloperidol decanoate in children have not been
established.
Geriatric Use
Clinical studies of haloperidol did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience has not consistently identified differences
in responses between the elderly and younger patients. However, the prevalence of
tardive dyskinesia appears to be highest among the elderly, especially elderly women
(see WARNINGS, Tardive dyskinesia). Also, the pharmacokinetics of haloperidol in
geriatric patients generally warrants the use of lower doses (see DOSAGE AND
ADMINISTRATION).
ADVERSE REACTIONS
Adverse reactions following the administration of HALDOL Decanoate 50 or
HALDOL Decanoate 100 are those of HALDOL (haloperidol). Since vast experience
has accumulated with HALDOL, the adverse reactions are reported for that
compound as well as for haloperidol decanoate. As with all injectable medications,
local tissue reactions have been reported with haloperidol decanoate.
Cardiovascular Effects
Tachycardia, hypotension, and hypertension have been reported. QT prolongation
and/or ventricular arrhythmias have also been reported, in addition to ECG pattern
changes compatible with the polymorphous configuration of torsade de pointes, and
may occur more frequently with high doses and in predisposed patients (see
WARNINGS and PRECAUTIONS).
Cases of sudden and unexpected death have been reported in association with the
administration of HALDOL. The nature of the evidence makes it impossible to
determine definitively what role, if any, HALDOL played in the outcome of the
reported cases. The possibility that HALDOL caused death cannot, of course, be
excluded, but it is to be kept in mind that sudden and unexpected death may occur in
psychotic patients when they go untreated or when they are treated with other
antipsychotic drugs.
CNS Effects
Extrapyramidal Symptoms (EPS)
EPS during the administration of HALDOL (haloperidol) have been reported
frequently, often during the first few days of treatment. EPS can be categorized
generally as Parkinson-like symptoms, akathisia, or dystonia (including opisthotonos
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and oculogyric crisis). While all can occur at relatively low doses, they occur more
frequently and with greater severity at higher doses. The symptoms may be controlled
with dose reductions or administration of antiparkinson drugs such as benztropine
mesylate USP or trihexyphenidyl hydrochloride USP. It should be noted that
persistent EPS have been reported; the drug may have to be discontinued in such
cases.
Dystonia
Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle
groups, may occur in susceptible individuals during the first few days of treatment.
Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to
tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion
of the tongue. While these symptoms can occur at low doses, they occur more
frequently and with greater severity with high potency and at higher doses of first
generation antipsychotic drugs. An elevated risk of acute dystonia is observed in
males and younger age groups.
Withdrawal Emergent Neurological Signs
Generally, patients receiving short-term therapy experience no problems with abrupt
discontinuation of antipsychotic drugs. However, some patients on maintenance
treatment experience transient dyskinetic signs after abrupt withdrawal. In certain of
these cases the dyskinetic movements are indistinguishable from the syndrome
described below under “Tardive Dyskinesia” except for duration. Although the
long-acting properties of haloperidol decanoate provide gradual withdrawal, it is not
known whether gradual withdrawal of antipsychotic drugs will reduce the rate of
occurrence of withdrawal emergent neurological signs.
Tardive Dyskinesia
As with all antipsychotic agents HALDOL has been associated with persistent
dyskinesias. Tardive dyskinesia, a syndrome consisting of potentially irreversible,
involuntary, dyskinetic movements, may appear in some patients on long-term
therapy with haloperidol decanoate or may occur after drug therapy has been
discontinued. The risk appears to be greater in elderly patients on high-dose therapy,
especially females. The symptoms are persistent and in some patients appear
irreversible. The syndrome is characterized by rhythmical involuntary movements of
tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of
mouth, chewing movements). Sometimes these may be accompanied by involuntary
movements of extremities and the trunk.
There is no known effective treatment for tardive dyskinesia; antiparkinson agents
usually do not alleviate the symptoms of this syndrome. It is suggested that all
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antipsychotic agents be discontinued if these symptoms appear. Should it be
necessary to reinstitute treatment, or increase the dosage of the agent, or switch to a
different antipsychotic agent, this syndrome may be masked.
It has been reported that fine vermicular movement of the tongue may be an early
sign of tardive dyskinesia and if the medication is stopped at that time the full
syndrome may not develop.
Tardive Dystonia
Tardive dystonia, not associated with the above syndrome, has also been reported.
Tardive dystonia is characterized by delayed onset of choreic or dystonic movements,
is often persistent, and has the potential of becoming irreversible.
Other CNS Effects
Insomnia, restlessness, anxiety, euphoria, agitation, drowsiness, depression, lethargy,
headache, confusion, vertigo, grand mal seizures, exacerbation of psychotic
symptoms including hallucinations, and catatonic-like behavioral states which may be
responsive to drug withdrawal and/or treatment with anticholinergic drugs.
Body as a Whole
Neuroleptic malignant syndrome (NMS), hyperpyrexia and heat stroke have been
reported with HALDOL. (See WARNINGS for further information concerning
NMS.)
Hematologic Effects
Reports have appeared citing the occurrence of mild and usually transient leukopenia
and leukocytosis, minimal decreases in red blood cell counts, anemia, or a tendency
toward lymphomonocytosis. Agranulocytosis has rarely been reported to have
occurred with the use of HALDOL, and then only in association with other
medication. (See PRECAUTIONS: Leukopenia, Neutropenia, and Agranulocytosis.)
Liver Effects
Impaired liver function and/or jaundice have been reported.
Dermatologic Reactions
Maculopapular and acneiform skin reactions and isolated cases of photosensitivity
and loss of hair.
Endocrine Disorders
Lactation, breast engorgement, mastalgia, menstrual irregularities, gynecomastia,
impotence, increased libido, hyperglycemia, hypoglycemia and hyponatremia.
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Gastrointestinal Effects
Anorexia, constipation, diarrhea, hypersalivation, dyspepsia, nausea and vomiting.
Autonomic Reactions
Dry mouth, blurred vision, urinary retention, diaphoresis and priapism.
Respiratory Effects
Laryngospasm, bronchospasm and increased depth of respiration.
Special Senses
Cataracts, retinopathy and visual disturbances.
Postmarketing Events
Hyperammonemia has been reported in a 5 1 /2 year old child with citrullinemia, an
inherited disorder of ammonia excretion, following treatment with HALDOL.
Rhabdomyolysis has been reported.
OVERDOSAGE
While overdosage is less likely to occur with a parenteral than with an oral
medication, information pertaining to HALDOL (haloperidol) is presented, modified
only to reflect the extended duration of action of haloperidol decanoate.
Manifestations
In general, the symptoms of overdosage would be an exaggeration of known
pharmacologic effects and adverse reactions, the most prominent of which would be:
1) severe extrapyramidal reactions, 2) hypotension, or 3) sedation. The patient would
appear comatose with respiratory depression and hypotension which could be severe
enough to produce a shock-like state. The extrapyramidal reactions would be
manifested by muscular weakness or rigidity and a generalized or localized tremor, as
demonstrated by the akinetic or agitans types, respectively. With accidental
overdosage, hypertension rather than hypotension occurred in a two-year old child.
The risk of ECG changes associated with torsade de pointes should be considered.
(For further information regarding torsade de pointes, please refer to ADVERSE
REACTIONS.)
Treatment
Since there is no specific antidote, treatment is primarily supportive. A patent airway
must be established by use of an oropharyngeal airway or endotracheal tube or, in
prolonged cases of coma, by tracheostomy. Respiratory depression may be
counteracted by artificial respiration and mechanical respirators. Hypotension and
circulatory collapse may be counteracted by use of intravenous fluids, plasma, or
Reference ID: 3933083
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine
and norepinephrine. Epinephrine should not be used. In case of severe extrapyramidal
reactions, antiparkinson medication should be administered, and should be continued
for several weeks, and then withdrawn gradually as extrapyramidal symptoms may
emerge. ECG and vital signs should be monitored especially for signs of Q-T
prolongation or dysrhythmias and monitoring should continue until the ECG is
normal. Severe arrhythmias should be treated with appropriate anti-arrhythmic
measures.
DOSAGE AND ADMINISTRATION
HALDOL Decanoate 50 and HALDOL Decanoate 100 should be administered by
deep intramuscular injection. A 21 gauge needle is recommended. The maximum
volume per injection site should not exceed 3 mL. DO NOT ADMINISTER
INTRAVENOUSLY.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
HALDOL Decanoate 50 and HALDOL Decanoate 100 are intended for use in
schizophrenic patients who require prolonged parenteral antipsychotic therapy. These
patients should be previously stabilized on antipsychotic medication before
considering a conversion to haloperidol decanoate. Furthermore, it is recommended
that patients being considered for haloperidol decanoate therapy have been treated
with, and tolerate well, short-acting HALDOL (haloperidol) in order to reduce the
possibility of an unexpected adverse sensitivity to haloperidol. Close clinical
supervision is required during the initial period of dose adjustment in order to
minimize the risk of overdosage or reappearance of psychotic symptoms before the
next injection. During dose adjustment or episodes of exacerbation of symptoms of
schizophrenia, haloperidol decanoate therapy can be supplemented with short-acting
forms of haloperidol.
The dose of HALDOL Decanoate 50 or HALDOL Decanoate 100 should be
expressed in terms of its haloperidol content. The starting dose of haloperidol
decanoate should be based on the patient’s age, clinical history, physical condition,
and response to previous antipsychotic therapy. The preferred approach to
determining the minimum effective dose is to begin with lower initial doses and to
adjust the dose upward as needed. For patients previously maintained on low doses of
antipsychotics (e.g. up to the equivalent of 10 mg/day oral haloperidol), it is
recommended that the initial dose of haloperidol decanoate be 10-15 times the
previous daily dose in oral haloperidol equivalents; limited clinical experience
suggests that lower initial doses may be adequate.
Reference ID: 3933083
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Initial Therapy
Conversion from oral haloperidol to haloperidol decanoate can be achieved by using
an initial dose of haloperidol decanoate that is 10 to 20 times the previous daily dose
in oral haloperidol equivalents.
In patients who are elderly, debilitated, or stable on low doses of oral haloperidol
(e.g. up to the equivalent of 10 mg/day oral haloperidol), a range of 10 to 15 times the
previous daily dose in oral haloperidol equivalents is appropriate for initial
conversion.
In patients previously maintained on higher doses of antipsychotics for whom a low
dose approach risks recurrence of psychiatric decompensation and in patients whose
long-term use of haloperidol has resulted in a tolerance to the drug, 20 times the
previous daily dose in oral haloperidol equivalents should be considered for initial
conversion, with downward titration on succeeding injections.
The initial dose of haloperidol decanoate should not exceed 100 mg regardless of
previous antipsychotic dose requirements. If, therefore, conversion requires more than
100 mg of haloperidol decanoate as an initial dose, that dose should be administered
in two injections, i.e. a maximum of 100 mg initially followed by the balance in
3 to 7 days.
Maintenance Therapy
The maintenance dosage of haloperidol decanoate must be individualized with
titration upward or downward based on therapeutic response. The usual maintenance
range is 10 to 15 times the previous daily dose in oral haloperidol equivalents
dependent on the clinical response of the patient.
HALDOL DECANOATE DOSING RECOMMENDATIONS
Monthly
Patients
1st Month
Maintenance
Stabilized on low daily oral doses
10-15 x Daily Oral Dose
10-15 x Previous Daily Oral Dose
(up to 10 mg/day)
Elderly or Debilitated
High dose
20 x Daily Oral Dose
10-15 x Previous Daily Oral Dose
Risk of relapse
Tolerant to oral haloperidol
Close clinical supervision is required during initiation and stabilization of haloperidol
decanoate therapy. Haloperidol decanoate is usually administered monthly or every
4 weeks. However, variation in patient response may dictate a need for adjustment of
the dosing interval as well as the dose (See CLINICAL PHARMACOLOGY).
Reference ID: 3933083
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Clinical experience with haloperidol decanoate at doses greater than 450 mg per
month has been limited.
INSTRUCTIONS FOR OPENING AMPULE
Step 1
1. Medication often rests in the top
part
of
the
ampule.
Before
breaking the ampule, lightly tap
the top of the ampule with your
finger until all fluid moves to the
bottom portion of the ampule.
The ampule has a colored ring(s)
and colored point which aids in
the placement of fingers while
breaking the ampule. usage illustration
Step 2
2. Hold the ampule between thumb
and index finger with the colored
point facing you. usage illustration
Step 3
3. Position the index finger of the
other hand to support the neck of
the ampule. Position the thumb so
that it covers the colored point
and is parallel to the colored
ring(s). usage illustration
Step 4
Reference ID: 3933083
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4. Keeping the thumb on the colored
point, and with the index fingers
close
together,
apply
firm
pressure on the colored point in
the direction of the arrow to snap
the ampule open. usage illustration
HOW SUPPLIED
HALDOL® (haloperidol) Decanoate 50 for IM injection, 50 mg haloperidol as
70.52 mg per mL haloperidol decanoate:
NDC 50458-253-03 3 x 1 mL ampules.
HALDOL® (haloperidol) Decanoate 100 for IM injection, 100 mg haloperidol as
141.04 mg per mL haloperidol decanoate:
NDC 50458-254-14, 5 x 1 mL ampules.
Store at controlled room temperature (15°-30° C, 59°-86° F). Do not refrigerate or
freeze.
Protect from light.
Product of Belgium
Manufactured by:
GlaxoSmithKline Manufacturing S.p.A.
Parma, Italy
Manufactured for:
Janssen Pharmaceuticals, Inc.
Titusville, NJ 08560
Revised January 2016
Janssen Pharmaceuticals, Inc. 2005
Reference ID: 3933083
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This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/015923s094,018701s072lbl.pdf', 'application_number': 18701, 'submission_type': 'SUPPL ', 'submission_number': 72}
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/018707s008lbl.pdf', 'application_number': 18702, 'submission_type': 'SUPPL ', 'submission_number': 7}
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ACLOVATE® (alclometasone dipropionate cream) Cream, 0.05%
ACLOVATE® (alclometasone dipropionate ointment) Ointment, 0.05%
Rx only
For Dermatologic Use Only–
Not for Ophthalmic Use.
DESCRIPTION
ACLOVATE® (alclometasone dipropionate cream) Cream, 0.05% and ACLOVATE®
(alclometasone dipropionate ointment) Ointment, 0.05% contain alclometasone
dipropionate (7α-chloro-11β,17,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione
17,21-dipropionate), a synthetic corticosteroid for topical dermatologic use. The
corticosteroids constitute a class of primarily synthetic steroids used topically as anti
inflammatory and antipruritic agents.
Chemically, alclometasone dipropionate is C28H37CIO7. It has the following structural
formula: chemical structure
Alclometasone dipropionate has the molecular weight of 521. It is a white powder
insoluble in water, slightly soluble in propylene glycol, and moderately soluble in
hexylene glycol.
Reference ID: 2928129
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Each gram of ACLOVATE® Cream contains 0.5 mg of alclometasone dipropionate in a
hydrophilic, emollient cream base of propylene glycol, white petrolatum, cetearyl
alcohol, glyceryl stearate, PEG 100 stearate, Ceteth-20, monobasic sodium phosphate,
chlorocresol, phosphoric acid, and purified water.
Each gram of ACLOVATE® Ointment contains 0.5 mg of alclometasone dipropionate in
an ointment base of hexylene glycol, white wax, propylene glycol stearate, and white
petrolatum.
CLINICAL PHARMACOLOGY
Like other topical corticosteroids, alclometasone dipropionate has anti-inflammatory,
antipruritic, and vasoconstrictive properties. The mechanism of the anti-inflammatory
activity of the topical steroids, in general, is unclear. However, corticosteroids are
thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called
lipocortins. It is postulated that these proteins control the biosynthesis of potent
mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the
release of their common precursor, arachidonic acid. Arachidonic acid is released from
membrane phospholipids by phospholipase A2.
Pharmacokinetics: The extent of percutaneous absorption of topical corticosteroids is
determined by many factors, including the vehicle and the integrity of the epidermal
barrier. Occlusive dressings with hydrocortisone for up to 24 hours have not been
demonstrated to increase penetration; however, occlusion of hydrocortisone for 96
hours markedly enhances penetration. Topical corticosteroids can be absorbed from
normal intact skin. Inflammation and/or other disease processes in the skin may
increase percutaneous absorption. A study utilizing a radio labeled alclometasone
dipropionate ointment formulation was performed to measure systemic absorption and
excretion. Results indicated that approximately 3% of the steroid was absorbed during 8
hours of contact with intact skin of normal volunteers.
Reference ID: 2928129
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Studies performed with ACLOVATE® Cream and Ointment indicate that these products
are in the low to medium range of potency as compared with other topical
corticosteroids.
INDICATIONS AND USAGE
ACLOVATE® Cream and Ointment are low to medium potency corticosteroids indicated
for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive
dermatoses. ACLOVATE® Cream and Ointment may be used in pediatric patients 1
year of age or older, although the safety and efficacy of drug use for longer than 3
weeks have not been established (see PRECAUTIONS: Pediatric Use). Since the
safety and efficacy of ACLOVATE® Cream and Ointment have not been established in
pediatric patients below 1 year of age, their use in this age-group is not recommended.
CONTRAINDICATIONS
ACLOVATE® Cream and Ointment are contraindicated in those patients with a history of
hypersensitivity to any of the components in these preparations.
PRECAUTIONS
General: Systemic absorption of topical corticosteroids can produce reversible
hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for
glucocorticosteroid insufficiency after withdrawal of treatment. Manifestations of
Cushing syndrome, hyperglycemia, and glucosuria can also be produced in some
patients by systemic absorption of topical corticosteroids while on treatment. Patients
applying a topical steroid to a large surface area or to areas under occlusion should be
evaluated periodically for evidence of HPA axis suppression. This may be done by
using the ACTH stimulation, A.M. plasma cortisol, and urinary free cortisol tests.
The effects of ACLOVATE® Cream and Ointment on the HPA axis have been
evaluated. In one study, ACLOVATE® Cream and Ointment were applied to 30% of the
Reference ID: 2928129
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
body twice daily for 7 days, and occlusive dressings were used in selected patients
either 12 hours or 24 hours daily. In another study, ACLOVATE® Cream was applied to
80% of the body surface of normal subjects twice daily for 21 days with daily 12-hour
periods of whole body occlusion. Average plasma and urinary free cortisol levels and
urinary levels of 17-hydroxysteroids were decreased (about 10%), suggesting
suppression of the HPA axis under these conditions. Plasma cortisol levels have also
been demonstrated to decrease in pediatric patients treated twice daily for 3 weeks
without occlusion.
If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to
reduce the frequency of application, or to substitute a less potent corticosteroid.
Recovery of HPA axis function is generally prompt upon discontinuation of topical
corticosteroids. Infrequently, signs and symptoms of glucocorticosteroid insufficiency
may occur, requiring supplemental systemic corticosteroids. For information on
systemic supplementation, see prescribing information for those products.
Pediatric patients may be more susceptible to systemic toxicity from equivalent doses
due to their larger skin surface area to body mass ratios (see PRECAUTIONS: Pediatric
Use).
If irritation develops, ACLOVATE® Cream or Ointment should be discontinued and
appropriate therapy instituted. Allergic contact dermatitis with corticosteroids is usually
diagnosed by observing a failure to heal rather than noting a clinical exacerbation, as
with most topical products not containing corticosteroids. Such an observation should
be corroborated with appropriate diagnostic patch testing. If concomitant skin infections
are present or develop, an appropriate antifungal or antibacterial agent should be used.
If a favorable response does not occur promptly, use of ACLOVATE® Cream or
Ointment should be discontinued until the infection has been adequately controlled.
In a transgenic mouse study, chronic use of Aclovate cream led to an increased number
of animals with benign neoplasms of the skin at the treatment site (see PRECAUTIONS:
Reference ID: 2928129
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Carcinogenesis, Mutagenesis, and Impairment of Fertility). The clinical relevance of the
findings in animal studies to humans is not clear.
Information for Patients: Patients using topical corticosteroids should receive the
following information and instructions:
1. This medication is to be used as directed by the physician. It is for external use
only. Avoid contact with the eyes.
2. This medication should not be used for any disorder other than that for which it
was prescribed.
3. The treated skin area should not be bandaged, otherwise covered or wrapped so
as to be occlusive, unless directed by the physician.
4. Patients should report to their physician any signs of local adverse reactions.
5. Parents of pediatric patients should be advised not to use ACLOVATE® Cream or
Ointment in the treatment of diaper dermatitis. ACLOVATE® Cream or Ointment
should not be applied in the diaper area as diapers or plastic pants may constitute
occlusive dressing (see DOSAGE AND ADMINISTRATION).
6. This medication should not be used on the face, underarms, or groin areas unless
directed by the physician.
7. As with other corticosteroids, therapy should be discontinued when control is
achieved. If no improvement is seen within 2 weeks, contact the physician.
Laboratory Tests: The following tests may be helpful in evaluating patients for HPA axis
suppression:
ACTH stimulation test
A.M. plasma cortisol test
Urinary free cortisol test
Reference ID: 2928129
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Systemic long-term animal studies have not been performed to evaluate the
carcinogenic potential of alclometasone dipropionate. The effects of alclometasone
dipropionate on mutagenesis or fertility have not been evaluated.
In a 26-week dermal carcinogenicity study conducted in transgenic (Tg.AC) mice,
topical application once daily of both the vehicle cream and the 0.05% alclometasone
dipropionate cream significantly increased the incidence of benign neoplasms of the
skin in both sexes at the treatment site when compared to untreated controls. This
suggests that the positive effect may be associated with the vehicle application. The
clinical relevance of the findings in animals to humans is not clear.
Pregnancy: Teratogenic Effects: Pregnancy Category C. Corticosteroids have been
shown to be teratogenic in laboratory animals when administered systemically at
relatively low dosage levels. Some corticosteroids have been shown to be teratogenic
after dermal application in laboratory animals. There are no adequate and well-
controlled studies in pregnant women. ACLOVATE® Cream or Ointment should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: Systemically administered corticosteroids appear in human milk and
could suppress growth, interfere with endogenous corticosteroid production, or cause
other untoward effects. It is not known whether topical administration of topical
corticosteroids could result in sufficient systemic absorption to produce detectable
quantities in human milk. Because many drugs are excreted in human milk, caution
should be exercised when ACLOVATE® Cream or Ointment is administered to a nursing
woman.
Pediatric Use: ACLOVATE® Cream and Ointment may be used with caution in pediatric
patients 1 year of age or older, although the safety and efficacy of drug use for longer
Reference ID: 2928129
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
than 3 weeks have not been established. Use of ACLOVATE® Cream and Ointment is
supported by results from adequate and well-controlled studies in pediatric patients with
corticosteroid-responsive dermatoses. Since the safety and efficacy of ACLOVATE®
Cream and Ointment have not been established in pediatric patients below 1 year of
age, its use in this age-group is not recommended. Because of a higher ratio of skin
surface area to body mass, pediatric patients are at a greater risk than adults of HPA
axis suppression and Cushing syndrome when they are treated with topical
corticosteroids. They are therefore also at greater risk of adrenal insufficiency during
and/or after withdrawal of treatment. Adverse effects, including striae, have been
reported with inappropriate use of topical corticosteroids in infants and children.
Pediatric patients applying ACLOVATE® Cream or Ointment to >20% of the body
surface area are at higher risk for HPA axis suppression.
HPA axis suppression, Cushing syndrome, linear growth retardation, delayed weight
gain, and intracranial hypertension have been reported in pediatric patients receiving
topical corticosteroids. Manifestations of adrenal suppression in pediatric patients
include low plasma cortisol levels and absence of response to ACTH stimulation.
Manifestations of intracranial hypertension include bulging fontanelles, headaches, and
bilateral papilledema.
ACLOVATE® Cream or Ointment should not be used in the treatment of diaper
dermatitis.
Geriatric Use: A limited number of patients at or above 65 years of age have been
treated with ACLOVATE® Cream and Ointment in US clinical trials. The number of
patients is too small to permit separate analysis of efficacy and safety. No adverse
events were reported with ACLOVATE® Ointment in geriatric patients, and the single
adverse reaction reported with ACLOVATE® Cream in this population was similar to
those reactions reported by younger patients. Based on available data, no adjustment of
dosage of ACLOVATE® Cream and Ointment in geriatric patients is warranted.
Reference ID: 2928129
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ADVERSE REACTIONS
The following local adverse reactions have been reported with ACLOVATE® Cream in
approximately 2% of patients: itching and burning, erythema, dryness, irritation, and
papular rashes.
The following local adverse reactions have been reported with ACLOVATE® Ointment in
approximately 1% of patients: itching, burning, and erythema. The following additional
local adverse reactions have been reported infrequently with topical corticosteroids, but
may occur more frequently with the use of occlusive dressings. These reactions are
listed in approximate decreasing order of occurrence: folliculitis, acneiform eruptions,
hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection,
skin atrophy, striae, and miliaria.
OVERDOSAGE
Topically applied ACLOVATE® Cream and Ointment can be absorbed in sufficient
amounts to produce systemic effects (see PRECAUTIONS).
DOSAGE AND ADMINISTRATION
Apply a thin film of ACLOVATE® Cream or Ointment to the affected skin areas 2 or 3
times daily; massage gently until the medication disappears.
ACLOVATE® Cream and Ointment may be used in pediatric patients 1 year of age or
older. Safety and effectiveness of ACLOVATE® Cream or Ointment in pediatric patients
for more than 3 weeks of use have not been established. Use in pediatric patients under
1 year of age is not recommended.
As with other corticosteroids, therapy should be discontinued when control is achieved.
If no improvement is seen within 2 weeks, reassessment of diagnosis may be
necessary.
Reference ID: 2928129
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ACLOVATE® Cream or Ointment should not be used with occlusive dressings unless
directed by a physician. ACLOVATE® Cream or Ointment should not be applied in the
diaper area if the child still requires diapers or plastic pants as these garments may
constitute occlusive dressing.
Geriatric Use: In studies where geriatric patients (65 years of age or older, see
PRECAUTIONS) have been treated with ACLOVATE® Cream or Ointment, safety did
not differ from that in younger patients; therefore, no dosage adjustment is
recommended.
HOW SUPPLIED
ACLOVATE® (alclometasone dipropionate cream) Cream, 0.05% is supplied in:
15-g tubes (NDC 0462-0263-15), and
60-g tubes (NDC 0462-0263-60).
ACLOVATE® (alclometasone dipropionate ointment) Ointment, 0.05% is supplied in:
15-g tubes (NDC 0462-0264-15), and
60-g tubes (NDC 0462-0264-60).
Store between 2° and 30°C (36° and 86°F).
PharmaDerm®
A division of Nycomed US Inc.
Melville, NY 11747 USA
www.pharmaderm.com
Revised 11/2010
Reference ID: 2928129
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018702s011lbl.pdf', 'application_number': 18702, 'submission_type': 'SUPPL ', 'submission_number': 11}
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1
PRESCRIBING INFORMATION
1
ZANTAC® 150
2
(ranitidine hydrochloride)
3
Tablets, USP
4
5
ZANTAC® 300
6
(ranitidine hydrochloride)
7
Tablets, USP
8
9
ZANTAC® 25
10
(ranitidine hydrochloride effervescent)
11
EFFERdose® Tablets
12
13
ZANTAC® 150
14
(ranitidine hydrochloride effervescent)
15
EFFERdose® Tablets
16
17
ZANTAC®
18
(ranitidine hydrochloride)
19
Syrup, USP
20
DESCRIPTION
21
The active ingredient in ZANTAC 150 Tablets, ZANTAC 300 Tablets, ZANTAC 25
22
EFFERdose Tablets, ZANTAC 150 EFFERdose Tablets, and ZANTAC Syrup is ranitidine
23
hydrochloride (HCl), USP, a histamine H2-receptor antagonist. Chemically it is N[2-[[[5-
24
[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]-N′-methyl-2-nitro-1,1-ethenediamine,
25
HCl. It has the following structure:
26
27
28
29
The empirical formula is C13H22N4O3S•HCl, representing a molecular weight of 350.87.
30
Ranitidine HCl is a white to pale yellow, granular substance that is soluble in water. It has a
31
slightly bitter taste and sulfurlike odor.
32
Each ZANTAC 150 Tablet for oral administration contains 168 mg of ranitidine HCl
33
equivalent to 150 mg of ranitidine. Each tablet also contains the inactive ingredients FD&C
34
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
Yellow No. 6 Aluminum Lake, hypromellose, magnesium stearate, microcrystalline cellulose,
35
titanium dioxide, triacetin, and yellow iron oxide.
36
Each ZANTAC 300 Tablet for oral administration contains 336 mg of ranitidine HCl
37
equivalent to 300 mg of ranitidine. Each tablet also contains the inactive ingredients
38
croscarmellose sodium, D&C Yellow No. 10 Aluminum Lake, hypromellose, magnesium
39
stearate, microcrystalline cellulose, titanium dioxide, and triacetin.
40
ZANTAC 25 EFFERdose Tablets for oral administration is an effervescent formulation of
41
ranitidine that must be dissolved in water before use. Each individual tablet contains 28 mg of
42
ranitidine HCl equivalent to 25 mg of ranitidine and the following inactive ingredients:
43
aspartame, monosodium citrate anhydrous, povidone, and sodium bicarbonate. Each tablet also
44
contains sodium benzoate. The total sodium content of each tablet is 30.52 mg (1.33 mEq) per
45
25 mg of ranitidine.
46
ZANTAC 150 EFFERdose Tablets for oral administration is an effervescent formulation of
47
ranitidine that must be dissolved in water before use. Each individual tablet contains 168 mg of
48
ranitidine HCl equivalent to 150 mg of ranitidine and the following inactive ingredients:
49
aspartame, monosodium citrate anhydrous, povidone, and sodium bicarbonate. Each tablet also
50
contains sodium benzoate. The total sodium content of each tablet is 183.12 mg (7.96 mEq) per
51
150 mg of ranitidine.
52
Each 1 mL of ZANTAC Syrup contains 16.8 mg of ranitidine HCl equivalent to 15 mg of
53
ranitidine. ZANTAC Syrup also contains the inactive ingredients alcohol (7.5%), butylparaben,
54
dibasic sodium phosphate, hypromellose, peppermint flavor, monobasic potassium phosphate,
55
propylparaben, purified water, saccharin sodium, sodium chloride, and sorbitol.
56
CLINICAL PHARMACOLOGY
57
ZANTAC is a competitive, reversible inhibitor of the action of histamine at the histamine
58
H2-receptors, including receptors on the gastric cells. ZANTAC does not lower serum Ca++ in
59
hypercalcemic states. ZANTAC is not an anticholinergic agent.
60
Pharmacokinetics:
61
Absorption: ZANTAC is 50% absorbed after oral administration, compared to an
62
intravenous (IV) injection with mean peak levels of 440 to 545 ng/mL occurring 2 to 3 hours
63
after a 150-mg dose. The syrup and EFFERdose formulations are bioequivalent to the tablets.
64
Absorption is not significantly impaired by the administration of food or antacids. Propantheline
65
slightly delays and increases peak blood levels of ZANTAC, probably by delaying gastric
66
emptying and transit time. In one study, simultaneous administration of high-potency antacid
67
(150 mmol) in fasting subjects has been reported to decrease the absorption of ZANTAC.
68
Distribution: The volume of distribution is about 1.4 L/kg. Serum protein binding averages
69
15%.
70
Metabolism: In humans, the N-oxide is the principal metabolite in the urine; however, this
71
amounts to <4% of the dose. Other metabolites are the S-oxide (1%) and the desmethyl ranitidine
72
(1%). The remainder of the administered dose is found in the stool. Studies in patients with
73
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For current labeling information, please visit https://www.fda.gov/drugsatfda
3
hepatic dysfunction (compensated cirrhosis) indicate that there are minor, but clinically
74
insignificant, alterations in ranitidine half-life, distribution, clearance, and bioavailability.
75
Excretion: The principal route of excretion is the urine, with approximately 30% of the
76
orally administered dose collected in the urine as unchanged drug in 24 hours. Renal clearance is
77
about 410 mL/min, indicating active tubular excretion. The elimination half-life is 2.5 to 3 hours.
78
Four patients with clinically significant renal function impairment (creatinine clearance 25 to
79
35 mL/min) administered 50 mg of ranitidine intravenously had an average plasma half-life of
80
4.8 hours, a ranitidine clearance of 29 mL/min, and a volume of distribution of 1.76 L/kg. In
81
general, these parameters appear to be altered in proportion to creatinine clearance (see
82
DOSAGE AND ADMINISTRATION).
83
Geriatrics: The plasma half-life is prolonged and total clearance is reduced in the elderly
84
population due to a decrease in renal function. The elimination half-life is 3 to 4 hours. Peak
85
levels average 526 ng/mL following a 150-mg twice daily dose and occur in about 3 hours (see
86
PRECAUTIONS: Geriatric Use and DOSAGE AND ADMINISTRATION: Dosage Adjustment
87
for Patients With Impaired Renal Function).
88
Pediatrics: There are no significant differences in the pharmacokinetic parameter values for
89
ranitidine in pediatric patients (from 1 month up to 16 years of age) and healthy adults when
90
correction is made for body weight. The average bioavailability of ranitidine given orally to
91
pediatric patients is 48% which is comparable to the bioavailability of ranitidine in the adult
92
population. All other pharmacokinetic parameter values (t1/2, Vd, and CL) are similar to those
93
observed with intravenous ranitidine use in pediatric patients. Estimates of Cmax and Tmax are
94
displayed in Table 1.
95
96
Table 1. Ranitidine Pharmacokinetics in Pediatric Patients Following Oral Dosing
97
Population
(age)
n
Dosage Form
(dose)
Cmax
(ng/mL)
Tmax
(hours)
Gastric or duodenal ulcer
(3.5 to 16 years)
12
Tablets
(1 to 2 mg/kg)
54 to 492
2.0
Otherwise healthy requiring ZANTAC
(0.7 to 14 years, Single dose)
10
Syrup
(2 mg/kg)
244
1.61
Otherwise healthy requiring ZANTAC
(0.7 to 14 years, Multiple dose)
10
Syrup
(2 mg/kg)
320
1.66
98
Plasma clearance measured in 2 neonatal patients (less than 1 month of age) was considerably
99
lower (3 mL/min/kg) than children or adults and is likely due to reduced renal function observed
100
in this population (see PRECAUTIONS: Pediatric Use and DOSAGE AND
101
ADMINISTRATION: Pediatric Use).
102
Pharmacodynamics: Serum concentrations necessary to inhibit 50% of stimulated gastric
103
acid secretion are estimated to be 36 to 94 ng/mL. Following a single oral dose of 150 mg, serum
104
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4
concentrations of ZANTAC are in this range up to 12 hours. However, blood levels bear no
105
consistent relationship to dose or degree of acid inhibition.
106
In a pharmacodynamic comparison of the EFFERdose with the ZANTAC Tablets, during the
107
first hour after administration, the EFFERdose tablet formulation gave a significantly higher
108
intragastric pH, by approximately 1 pH unit, compared to the ZANTAC tablets.
109
Antisecretory Activity: 1. Effects on Acid Secretion: ZANTAC inhibits both daytime
110
and nocturnal basal gastric acid secretions as well as gastric acid secretion stimulated by food,
111
betazole, and pentagastrin, as shown in Table 2.
112
113
Table 2. Effect of Oral ZANTAC on Gastric Acid Secretion
114
Time After
% Inhibition of Gastric Acid Output by Dose, mg
Dose, h
75-80
100
150
200
Basal
Up to 4
99
95
Nocturnal
Up to 13
95
96
92
Betazole
Up to 3
97
99
Pentagastrin
Up to 5
58
72
72
80
Meal
Up to 3
73
79
95
115
It appears that basal-, nocturnal-, and betazole-stimulated secretions are most sensitive to
116
inhibition by ZANTAC, responding almost completely to doses of 100 mg or less, while
117
pentagastrin- and food-stimulated secretions are more difficult to suppress.
118
2. Effects on Other Gastrointestinal Secretions:
119
Pepsin: Oral ZANTAC does not affect pepsin secretion. Total pepsin output is reduced in
120
proportion to the decrease in volume of gastric juice.
121
Intrinsic Factor: Oral ZANTAC has no significant effect on pentagastrin-stimulated
122
intrinsic factor secretion.
123
Serum Gastrin: ZANTAC has little or no effect on fasting or postprandial serum gastrin.
124
Other Pharmacologic Actions:
125
a. Gastric bacterial flora—increase in nitrate-reducing organisms, significance not known.
126
b. Prolactin levels—no effect in recommended oral or intravenous (IV) dosage, but small,
127
transient, dose-related increases in serum prolactin have been reported after IV bolus injections
128
of 100 mg or more.
129
c. Other pituitary hormones—no effect on serum gonadotropins, TSH, or GH. Possible
130
impairment of vasopressin release.
131
d. No change in cortisol, aldosterone, androgen, or estrogen levels.
132
e. No antiandrogenic action.
133
f. No effect on count, motility, or morphology of sperm.
134
Pediatrics: Oral doses of 6 to 10 mg/kg per day in 2 or 3 divided doses maintain gastric
135
pH>4 throughout most of the dosing interval.
136
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5
Clinical Trials: Active Duodenal Ulcer: In a multicenter, double-blind, controlled, US
137
study of endoscopically diagnosed duodenal ulcers, earlier healing was seen in the patients
138
treated with ZANTAC as shown in Table 3.
139
140
Table 3. Duodenal Ulcer Patient Healing Rates
141
ZANTAC*
Placebo*
Number
Entered
Healed/
Evaluable
Number
Entered
Healed/
Evaluable
Outpatients
Week 2
69/182
(38%)†
31/164
(19%)
Week 4
195
137/187
(73%)†
188
76/168
(45%)
*All patients were permitted p.r.n. antacids for relief of pain.
142
†P<0.0001.
143
144
In these studies, patients treated with ZANTAC reported a reduction in both daytime and
145
nocturnal pain, and they also consumed less antacid than the placebo-treated patients.
146
147
Table 4. Mean Daily Doses of Antacid
148
Ulcer Healed
Ulcer Not Healed
ZANTAC
0.06
0.71
Placebo
0.71
1.43
149
Foreign studies have shown that patients heal equally well with 150 mg b.i.d. and 300 mg h.s.
150
(85% versus 84%, respectively) during a usual 4-week course of therapy. If patients require
151
extended therapy of 8 weeks, the healing rate may be higher for 150 mg b.i.d. as compared to
152
300 mg h.s. (92% versus 87%, respectively).
153
Studies have been limited to short-term treatment of acute duodenal ulcer. Patients whose
154
ulcers healed during therapy had recurrences of ulcers at the usual rates.
155
Maintenance Therapy in Duodenal Ulcer: Ranitidine has been found to be effective as
156
maintenance therapy for patients following healing of acute duodenal ulcers. In 2 independent,
157
double-blind, multicenter, controlled trials, the number of duodenal ulcers observed was
158
significantly less in patients treated with ZANTAC (150 mg h.s.) than in patients treated with
159
placebo over a 12-month period.
160
161
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6
Table 5. Duodenal Ulcer Prevalence
162
Double-Blind, Multicenter, Placebo-Controlled Trials
Multicenter
Trial
Drug
Duodenal Ulcer Prevalence
No. of
Patients
0-4
Months
0-8
Months
0-12
Months
USA
RAN
20%*
24%*
35%*
138
PLC
44%
54%
59%
139
Foreign
RAN
12%*
21%*
28%*
174
PLC
56%
64%
68%
165
% = Life table estimate.
163
* = P<0.05 (ZANTAC versus comparator).
164
RAN = ranitidine (ZANTAC).
165
PLC = placebo.
166
167
As with other H2-antagonists, the factors responsible for the significant reduction in the
168
prevalence of duodenal ulcers include prevention of recurrence of ulcers, more rapid healing of
169
ulcers that may occur during maintenance therapy, or both.
170
Gastric Ulcer: In a multicenter, double-blind, controlled, US study of endoscopically
171
diagnosed gastric ulcers, earlier healing was seen in the patients treated with ZANTAC as shown
172
in Table 6.
173
174
Table 6. Gastric Ulcer Patient Healing Rates
175
ZANTAC*
Placebo*
Number
Entered
Healed/
Evaluable
Number
Entered
Healed/
Evaluable
Outpatients
Week 2
16/83
(19%)
10/83
(12%)
Week 6
92
50/73
(68%)†
94
35/69
(51%)
*All patients were permitted p.r.n. antacids for relief of pain.
176
†P = 0.009.
177
178
In this multicenter trial, significantly more patients treated with ZANTAC became pain free
179
during therapy.
180
Maintenance of Healing of Gastric Ulcers: In 2 multicenter, double-blind, randomized,
181
placebo-controlled, 12-month trials conducted in patients whose gastric ulcers had been
182
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7
previously healed, ZANTAC 150 mg h.s. was significantly more effective than placebo in
183
maintaining healing of gastric ulcers.
184
Pathological Hypersecretory Conditions (such as Zollinger-Ellison syndrome):
185
ZANTAC inhibits gastric acid secretion and reduces occurrence of diarrhea, anorexia, and pain
186
in patients with pathological hypersecretion associated with Zollinger-Ellison syndrome,
187
systemic mastocytosis, and other pathological hypersecretory conditions (e.g., postoperative,
188
"short-gut" syndrome, idiopathic). Use of ZANTAC was followed by healing of ulcers in 8 of 19
189
(42%) patients who were intractable to previous therapy.
190
Gastroesophageal Reflux Disease (GERD): In 2 multicenter, double-blind,
191
placebo-controlled, 6-week trials performed in the United States and Europe, ZANTAC 150 mg
192
b.i.d. was more effective than placebo for the relief of heartburn and other symptoms associated
193
with GERD. Ranitidine-treated patients consumed significantly less antacid than did
194
placebo-treated patients.
195
The US trial indicated that ZANTAC 150 mg b.i.d. significantly reduced the frequency of
196
heartburn attacks and severity of heartburn pain within 1 to 2 weeks after starting therapy. The
197
improvement was maintained throughout the 6-week trial period. Moreover, patient response
198
rates demonstrated that the effect on heartburn extends through both the day and night time
199
periods.
200
In 2 additional US multicenter, double-blind, placebo-controlled, 2-week trials, ZANTAC
201
150 mg b.i.d. was shown to provide relief of heartburn pain within 24 hours of initiating therapy
202
and a reduction in the frequency of severity of heartburn. In these trials, ZANTAC EFFERdose
203
Tablets were shown to provide heartburn relief within 45 minutes of dosing.
204
Erosive Esophagitis: In 2 multicenter, double-blind, randomized, placebo-controlled,
205
12-week trials performed in the United States, ZANTAC 150 mg q.i.d. was significantly more
206
effective than placebo in healing endoscopically diagnosed erosive esophagitis and in relieving
207
associated heartburn. The erosive esophagitis healing rates were as follows:
208
209
Table 7. Erosive Esophagitis Patient Healing Rates
210
Healed/Evaluable
Placebo*
n = 229
ZANTAC
150 mg q.i.d.*
n = 215
Week 4
43/198 (22%)
96/206 (47%)†
Week 8
63/176 (36%)
142/200 (71%)†
Week 12
92/159 (58%)
162/192 (84%)†
*All patients were permitted p.r.n. antacids for relief of pain.
211
†P<0.001 versus placebo.
212
213
No additional benefit in healing of esophagitis or in relief of heartburn was seen with a
214
ranitidine dose of 300 mg q.i.d.
215
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8
Maintenance of Healing of Erosive Esophagitis: In 2 multicenter, double-blind,
216
randomized, placebo-controlled, 48-week trials conducted in patients whose erosive esophagitis
217
had been previously healed, ZANTAC 150 mg b.i.d. was significantly more effective than
218
placebo in maintaining healing of erosive esophagitis.
219
INDICATIONS AND USAGE
220
ZANTAC is indicated in:
221
1. Short-term treatment of active duodenal ulcer. Most patients heal within 4 weeks. Studies
222
available to date have not assessed the safety of ranitidine in uncomplicated duodenal ulcer
223
for periods of more than 8 weeks.
224
2. Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of acute
225
ulcers. No placebo-controlled comparative studies have been carried out for periods of longer
226
than 1 year.
227
3. The treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome
228
and systemic mastocytosis).
229
4. Short-term treatment of active, benign gastric ulcer. Most patients heal within 6 weeks and
230
the usefulness of further treatment has not been demonstrated. Studies available to date have
231
not assessed the safety of ranitidine in uncomplicated, benign gastric ulcer for periods of
232
more than 6 weeks.
233
5. Maintenance therapy for gastric ulcer patients at reduced dosage after healing of acute ulcers.
234
Placebo-controlled studies have been carried out for 1 year.
235
6. Treatment of GERD. Symptomatic relief commonly occurs within 24 hours after starting
236
therapy with ZANTAC 150 mg b.i.d.
237
7. Treatment of endoscopically diagnosed erosive esophagitis. Symptomatic relief of heartburn
238
commonly occurs within 24 hours of therapy initiation with ZANTAC 150 mg q.i.d.
239
8. Maintenance of healing of erosive esophagitis. Placebo-controlled trials have been carried
240
out for 48 weeks.
241
Concomitant antacids should be given as needed for pain relief to patients with active
242
duodenal ulcer; active, benign gastric ulcer; hypersecretory states; GERD; and erosive
243
esophagitis.
244
CONTRAINDICATIONS
245
ZANTAC is contraindicated for patients known to have hypersensitivity to the drug or any of
246
the ingredients (see PRECAUTIONS).
247
PRECAUTIONS
248
General: 1. Symptomatic response to therapy with ZANTAC does not preclude the presence of
249
gastric malignancy.
250
2. Since ZANTAC is excreted primarily by the kidney, dosage should be adjusted in patients
251
with impaired renal function (see DOSAGE AND ADMINISTRATION). Caution should be
252
observed in patients with hepatic dysfunction since ZANTAC is metabolized in the liver.
253
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9
3. Rare reports suggest that ZANTAC may precipitate acute porphyric attacks in patients with
254
acute porphyria. ZANTAC should therefore be avoided in patients with a history of acute
255
porphyria.
256
Information for Patients: Phenylketonurics: ZANTAC 25 EFFERdose Tablets contain
257
phenylalanine 2.81 mg per 25 mg of ranitidine. ZANTAC 150 EFFERdose Tablets contain
258
phenylalanine 16.84 mg per 150 mg of ranitidine. ZANTAC EFFERdose Tablets should not be
259
chewed, swallowed whole, or dissolved on the tongue.
260
Laboratory Tests: False-positive tests for urine protein with MULTISTIX
® may occur during
261
ZANTAC therapy, and therefore testing with sulfosalicylic acid is recommended.
262
Drug Interactions: Although ZANTAC has been reported to bind weakly to cytochrome
263
P-450 in vitro, recommended doses of the drug do not inhibit the action of the cytochrome
264
P-450–linked oxygenase enzymes in the liver. However, there have been isolated reports of drug
265
interactions that suggest that ZANTAC may affect the bioavailability of certain drugs by some
266
mechanism as yet unidentified (e.g., a pH-dependent effect on absorption or a change in volume
267
of distribution).
268
Increased or decreased prothrombin times have been reported during concurrent use of
269
ranitidine and warfarin. However, in human pharmacokinetic studies with dosages of ranitidine
270
up to 400 mg/day, no interaction occurred; ranitidine had no effect on warfarin clearance or
271
prothrombin time. The possibility of an interaction with warfarin at dosages of ranitidine higher
272
than 400 mg/day has not been investigated.
273
In a ranitidine-triazolam drug-drug interaction study, triazolam plasma concentrations were
274
higher during b.i.d. dosing of ranitidine than triazolam given alone. The mean area under the
275
triazolam concentration-time curve (AUC) values in 18- to 60-year-old subjects were 10% and
276
28% higher following administration of 75-mg and 150-mg ranitidine tablets, respectively, than
277
triazolam given alone. In subjects older than 60 years of age, the mean AUC values were
278
approximately 30% higher following administration of 75-mg and 150-mg ranitidine tablets. It
279
appears that there were no changes in pharmacokinetics of triazolam and α-hydroxytriazolam, a
280
major metabolite, and in their elimination. Reduced gastric acidity due to ranitidine may have
281
resulted in an increase in the availability of triazolam. The clinical significance of this triazolam
282
and ranitidine pharmacokinetic interaction is unknown.
283
Carcinogenesis, Mutagenesis, Impairment of Fertility: There was no indication of
284
tumorigenic or carcinogenic effects in life-span studies in mice and rats at dosages up to
285
2,000 mg/kg per day.
286
Ranitidine was not mutagenic in standard bacterial tests (Salmonella, Escherichia coli) for
287
mutagenicity at concentrations up to the maximum recommended for these assays.
288
In a dominant lethal assay, a single oral dose of 1,000 mg/kg to male rats was without effect
289
on the outcome of 2 matings per week for the next 9 weeks.
290
Pregnancy: Teratogenic Effects: Pregnancy Category B. Reproduction studies have been
291
performed in rats and rabbits at doses up to 160 times the human dose and have revealed no
292
evidence of impaired fertility or harm to the fetus due to ZANTAC. There are, however, no
293
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10
adequate and well-controlled studies in pregnant women. Because animal reproduction studies
294
are not always predictive of human response, this drug should be used during pregnancy only if
295
clearly needed.
296
Nursing Mothers: ZANTAC is secreted in human milk. Caution should be exercised when
297
ZANTAC is administered to a nursing mother.
298
Pediatric Use: The safety and effectiveness of ZANTAC have been established in the
299
age-group of 1 month to 16 years for the treatment of duodenal and gastric ulcers,
300
gastroesophageal reflux disease and erosive esophagitis, and the maintenance of healed duodenal
301
and gastric ulcer. Use of ZANTAC in this age-group is supported by adequate and
302
well-controlled studies in adults, as well as additional pharmacokinetic data in pediatric patients
303
and an analysis of the published literature (see CLINICAL PHARMACOLOGY: Pediatrics and
304
DOSAGE AND ADMINISTRATION: Pediatric Use).
305
Safety and effectiveness in pediatric patients for the treatment of pathological hypersecretory
306
conditions or the maintenance of healing of erosive esophagitis have not been established.
307
Safety and effectiveness in neonates (less than 1 month of age) have not been established (see
308
CLINICAL PHARMACOLOGY: Pediatrics).
309
Geriatric Use: Of the total number of subjects enrolled in US and foreign controlled clinical
310
trials of oral formulations of ZANTAC, for which there were subgroup analyses, 4,197 were 65
311
and over, while 899 were 75 and over. No overall differences in safety or effectiveness were
312
observed between these subjects and younger subjects, and other reported clinical experience has
313
not identified differences in responses between the elderly and younger patients, but greater
314
sensitivity of some older individuals cannot be ruled out.
315
This drug is known to be substantially excreted by the kidney and the risk of toxic reactions to
316
this drug may be greater in patients with impaired renal function. Because elderly patients are
317
more likely to have decreased renal function, caution should be exercised in dose selection, and
318
it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY:
319
Pharmacokinetics: Geriatrics and DOSAGE AND ADMINISTRATION: Dosage Adjustment for
320
Patients With Impaired Renal Function).
321
ADVERSE REACTIONS
322
The following have been reported as events in clinical trials or in the routine management of
323
patients treated with ZANTAC. The relationship to therapy with ZANTAC has been unclear in
324
many cases. Headache, sometimes severe, seems to be related to administration of ZANTAC.
325
Central Nervous System: Rarely, malaise, dizziness, somnolence, insomnia, and vertigo.
326
Rare cases of reversible mental confusion, agitation, depression, and hallucinations have been
327
reported, predominantly in severely ill elderly patients. Rare cases of reversible blurred vision
328
suggestive of a change in accommodation have been reported. Rare reports of reversible
329
involuntary motor disturbances have been received.
330
Cardiovascular: As with other H2-blockers, rare reports of arrhythmias such as tachycardia,
331
bradycardia, atrioventricular block, and premature ventricular beats.
332
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11
Gastrointestinal: Constipation, diarrhea, nausea/vomiting, abdominal discomfort/pain, and
333
rare reports of pancreatitis.
334
Hepatic: There have been occasional reports of hepatocellular, cholestatic, or mixed hepatitis,
335
with or without jaundice. In such circumstances, ranitidine should be immediately discontinued.
336
These events are usually reversible, but in rare circumstances death has occurred. Rare cases of
337
hepatic failure have also been reported. In normal volunteers, SGPT values were increased to at
338
least twice the pretreatment levels in 6 of 12 subjects receiving 100 mg q.i.d. intravenously for
339
7 days, and in 4 of 24 subjects receiving 50 mg q.i.d. intravenously for 5 days.
340
Musculoskeletal: Rare reports of arthralgias and myalgias.
341
Hematologic: Blood count changes (leukopenia, granulocytopenia, and thrombocytopenia)
342
have occurred in a few patients. These were usually reversible. Rare cases of agranulocytosis,
343
pancytopenia, sometimes with marrow hypoplasia, and aplastic anemia and exceedingly rare
344
cases of acquired immune hemolytic anemia have been reported.
345
Endocrine: Controlled studies in animals and man have shown no stimulation of any pituitary
346
hormone by ZANTAC and no antiandrogenic activity, and cimetidine-induced gynecomastia and
347
impotence in hypersecretory patients have resolved when ZANTAC has been substituted.
348
However, occasional cases of gynecomastia, impotence, and loss of libido have been reported in
349
male patients receiving ZANTAC, but the incidence did not differ from that in the general
350
population.
351
Integumentary: Rash, including rare cases of erythema multiforme. Rare cases of alopecia and
352
vasculitis.
353
Other: Rare cases of hypersensitivity reactions (e.g., bronchospasm, fever, rash, eosinophilia),
354
anaphylaxis, angioneurotic edema, and small increases in serum creatinine.
355
OVERDOSAGE
356
There has been limited experience with overdosage. Reported acute ingestions of up to 18 g
357
orally have been associated with transient adverse effects similar to those encountered in normal
358
clinical experience (see ADVERSE REACTIONS). In addition, abnormalities of gait and
359
hypotension have been reported.
360
When overdosage occurs, the usual measures to remove unabsorbed material from the
361
gastrointestinal tract, clinical monitoring, and supportive therapy should be employed.
362
Studies in dogs receiving dosages of ZANTAC in excess of 225 mg/kg per day have shown
363
muscular tremors, vomiting, and rapid respiration. Single oral doses of 1,000 mg/kg in mice and
364
rats were not lethal. Intravenous LD50 values in mice and rats were 77 and 83 mg/kg,
365
respectively.
366
DOSAGE AND ADMINISTRATION
367
Active Duodenal Ulcer: The current recommended adult oral dosage of ZANTAC for
368
duodenal ulcer is 150 mg or 10 mL of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of
369
ranitidine) twice daily. An alternative dosage of 300 mg or 20 mL of syrup (4 teaspoonfuls of
370
syrup equivalent to 300 mg of ranitidine) once daily after the evening meal or at bedtime can be
371
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12
used for patients in whom dosing convenience is important. The advantages of one treatment
372
regimen compared to the other in a particular patient population have yet to be demonstrated (see
373
Clinical Trials: Active Duodenal Ulcer). Smaller doses have been shown to be equally effective
374
in inhibiting gastric acid secretion in US studies, and several foreign trials have shown that
375
100 mg twice daily is as effective as the 150-mg dose.
376
Antacid should be given as needed for relief of pain (see CLINICAL PHARMACOLOGY:
377
Pharmacokinetics).
378
Maintenance of Healing of Duodenal Ulcers: The current recommended adult oral dosage
379
is 150 mg or 10 mL of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) at
380
bedtime.
381
Pathological Hypersecretory Conditions (such as Zollinger-Ellison syndrome):
382
The current recommended adult oral dosage is 150 mg or 10 mL of syrup (2 teaspoonfuls of
383
syrup equivalent to 150 mg of ranitidine) twice a day. In some patients it may be necessary to
384
administer ZANTAC 150-mg doses more frequently. Dosages should be adjusted to individual
385
patient needs, and should continue as long as clinically indicated. Dosages up to 6 g/day have
386
been employed in patients with severe disease.
387
Benign Gastric Ulcer: The current recommended adult oral dosage is 150 mg or 10 mL of
388
syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) twice a day.
389
Maintenance of Healing of Gastric Ulcers: The current recommended adult oral dosage is
390
150 mg or 10 mL of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) at
391
bedtime.
392
GERD: The current recommended adult oral dosage is 150 mg or 10 mL of syrup
393
(2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) twice a day.
394
Erosive Esophagitis: The current recommended adult oral dosage is 150 mg or 10 mL of
395
syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) 4 times a day.
396
Maintenance of Healing of Erosive Esophagitis: The current recommended adult oral
397
dosage is 150 mg or 10 mL of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine)
398
twice a day.
399
Pediatric Use: The safety and effectiveness of ZANTAC have been established in the
400
age-group of 1 month to 16 years. There is insufficient information about the pharmacokinetics
401
of ZANTAC in neonatal patients (less than 1 month of age) to make dosing recommendations.
402
The following 3 subsections provide dosing information for each of the pediatric indications.
403
Also, see the subsection on Preparation of ZANTAC 25 EFFERdose Tablets, below.
404
Treatment of Duodenal and Gastric Ulcers: The recommended oral dose for the
405
treatment of active duodenal and gastric ulcers is 2 to 4 mg/kg twice daily to a maximum of
406
300 mg/day. This recommendation is derived from adult clinical studies and pharmacokinetic
407
data in pediatric patients.
408
Maintenance of Healing of Duodenal and Gastric Ulcers: The recommended oral
409
dose for the maintenance of healing of duodenal and gastric ulcers is 2 to 4 mg/kg once daily to a
410
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
maximum of 150 mg/day. This recommendation is derived from adult clinical studies and
411
pharmacokinetic data in pediatric patients.
412
Treatment of GERD and Erosive Esophagitis: Although limited data exist for these
413
conditions in pediatric patients, published literature supports a dosage of 5 to 10 mg/kg per day,
414
usually given as 2 divided doses.
415
Dosage Adjustment for Patients With Impaired Renal Function: On the basis of
416
experience with a group of subjects with severely impaired renal function treated with ZANTAC,
417
the recommended dosage in patients with a creatinine clearance <50 mL/min is 150 mg or 10 mL
418
of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) every 24 hours. Should the
419
patient's condition require, the frequency of dosing may be increased to every 12 hours or even
420
further with caution. Hemodialysis reduces the level of circulating ranitidine. Ideally, the dosing
421
schedule should be adjusted so that the timing of a scheduled dose coincides with the end of
422
hemodialysis.
423
Elderly patients are more likely to have decreased renal function, therefore caution should be
424
exercised in dose selection, and it may be useful to monitor renal function (see CLINICAL
425
PHARMACOLOGY: Pharmacokinetics: Geriatrics and PRECAUTIONS: Geriatric Use).
426
Preparation of ZANTAC 25 EFFERdose Tablets: Tablets should not be chewed,
427
swallowed whole, or dissolved on the tongue. Dissolve 1 tablet in no less than 5 mL (1
428
teaspoonful) of water in an appropriate measuring cup. Wait until the tablet is completely
429
dissolved before administering the solution to the infant/child. The solution may be administered
430
by medicine dropper or oral syringe for infants.
431
Preparation of ZANTAC 150 EFFERdose Tablets: Tablets should not be chewed,
432
swallowed whole, or dissolved on the tongue. Dissolve each dose in approximately 6 to 8 oz of
433
water before drinking.
434
HOW SUPPLIED
435
ZANTAC 150 Tablets (ranitidine HCl equivalent to 150 mg of ranitidine) are peach,
436
film-coated, 5-sided tablets embossed with "ZANTAC 150" on one side and "Glaxo" on the
437
other. They are available in bottles of 60 (NDC 0173-0344-42), 180 (NDC 0173-0344-17), 500
438
(NDC 0173-0344-14), and 1,000 (NDC 0173-0344-12) tablets and unit dose packs of 100 (NDC
439
0173-0344-47) tablets.
440
ZANTAC 300 Tablets (ranitidine HCl equivalent to 300 mg of ranitidine) are yellow,
441
film-coated, capsule-shaped tablets embossed with "ZANTAC 300" on one side and "Glaxo" on
442
the other. They are available in bottles of 30 (NDC 0173-0393-40) and 250 (NDC 0173-0393-
443
06) tablets and unit dose packs of 100 (NDC 0173-0393-47) tablets.
444
Store between 15° and 30°C (59° and 86°F) in a dry place. Protect from light. Replace
445
cap securely after each opening.
446
ZANTAC 25 EFFERdose Tablets (ranitidine HCl equivalent to 25 mg of ranitidine) are white
447
to pale yellow, round, flat-faced, bevel-edged tablets embossed with “GS” on one side and
448
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
“25C” on the other side. They are packaged in foil strips and are available in a carton of 60
449
(NDC 0173-0734-00) tablets.
450
ZANTAC 150 EFFERdose Tablets (ranitidine HCl equivalent to 150 mg of ranitidine) are
451
white to pale yellow, round, flat-faced, bevel-edged tablets embossed with "ZANTAC 150" on
452
one side and "427" on the other. They are packaged individually in foil and are available in a
453
carton of 60 (NDC 0173-0427-02) tablets.
454
Store between 2° and 30°C (36° and 86°F).
455
ZANTAC Syrup, a clear, peppermint-flavored liquid, contains 16.8 mg of ranitidine HCl
456
equivalent to 15 mg of ranitidine per 1 mL (75 mg/5 mL) in bottles of 16 fluid ounces (one pint)
457
(NDC 0173-0383-54).
458
Store between 4° and 25°C (39° and 77°F). Dispense in tight, light-resistant containers as
459
defined in the USP/NF.
460
461
462
463
GlaxoSmithKline
464
Research Triangle Park, NC 27709
465
466
ZANTAC and EFFERdose are registered trademarks of Warner-Lambert Company, used under
467
license.
468
469
©2004, GlaxoSmithKline. All rights reserved.
470
471
October 2004
RL-2131
472
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
t
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ZntMntFM
®
®
|
custom-source
|
2025-02-12T13:44:52.319658
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/018703s065,019675s031,020251s016lbl.pdf', 'application_number': 18703, 'submission_type': 'SUPPL ', 'submission_number': 65}
|
11,286
|
PRESCRIBING INFORMATION
ZANTAC® 150
(ranitidine hydrochloride)
Tablets, USP
ZANTAC® 300
(ranitidine hydrochloride)
Tablets, USP
ZANTAC® 25
(ranitidine hydrochloride effervescent)
EFFERdose® Tablets
ZANTAC®
(ranitidine hydrochloride)
Syrup, USP
DESCRIPTION
The active ingredient in ZANTAC 150 Tablets, ZANTAC 300 Tablets, ZANTAC 25
EFFERdose Tablets, and ZANTAC Syrup is ranitidine hydrochloride (HCl), USP, a histamine
H2-receptor antagonist. Chemically it is N[2-[[[5-[(dimethylamino)methyl]-2
furanyl]methyl]thio]ethyl]-N′-methyl-2-nitro-1,1-ethenediamine, HCl. It has the following
structure: Structural Formula
The empirical formula is C13H22N4O3S•HCl, representing a molecular weight of 350.87.
Ranitidine HCl is a white to pale yellow, granular substance that is soluble in water. It has a
slightly bitter taste and sulfurlike odor.
Each ZANTAC 150 Tablet for oral administration contains 168 mg of ranitidine HCl
equivalent to 150 mg of ranitidine. Each tablet also contains the inactive ingredients FD&C
Yellow No. 6 Aluminum Lake, hypromellose, magnesium stearate, microcrystalline cellulose,
titanium dioxide, triacetin, and yellow iron oxide.
Each ZANTAC 300 Tablet for oral administration contains 336 mg of ranitidine HCl
equivalent to 300 mg of ranitidine. Each tablet also contains the inactive ingredients
croscarmellose sodium, D&C Yellow No. 10 Aluminum Lake, hypromellose, magnesium
stearate, microcrystalline cellulose, titanium dioxide, and triacetin.
1
ZANTAC 25 EFFERdose Tablets for oral administration is an effervescent formulation of
ranitidine that must be dissolved in water before use. Each individual tablet contains 28 mg of
ranitidine HCl equivalent to 25 mg of ranitidine and the following inactive ingredients:
aspartame, monosodium citrate anhydrous, povidone, and sodium bicarbonate. Each tablet also
contains sodium benzoate. The total sodium content of each tablet is 30.52 mg (1.33 mEq) per
25 mg of ranitidine.
Each 1 mL of ZANTAC Syrup contains 16.8 mg of ranitidine HCl equivalent to 15 mg of
ranitidine. ZANTAC Syrup also contains the inactive ingredients alcohol (7.5%), butylparaben,
dibasic sodium phosphate, hypromellose, peppermint flavor, monobasic potassium phosphate,
propylparaben, purified water, saccharin sodium, sodium chloride, and sorbitol.
CLINICAL PHARMACOLOGY
ZANTAC is a competitive, reversible inhibitor of the action of histamine at the histamine
H2-receptors, including receptors on the gastric cells. ZANTAC does not lower serum Ca++ in
hypercalcemic states. ZANTAC is not an anticholinergic agent.
Pharmacokinetics:
Absorption: ZANTAC is 50% absorbed after oral administration, compared to an
intravenous (IV) injection with mean peak levels of 440 to 545 ng/mL occurring 2 to 3 hours
after a 150-mg dose. The syrup and EFFERdose formulations are bioequivalent to the tablets.
Absorption is not significantly impaired by the administration of food or antacids. Propantheline
slightly delays and increases peak blood levels of ranitidine, probably by delaying gastric
emptying and transit time. In one study, simultaneous administration of high-potency antacid
(150 mmol) in fasting subjects has been reported to decrease the absorption of ZANTAC.
Distribution: The volume of distribution is about 1.4 L/kg. Serum protein binding averages
15%.
Metabolism: In humans, the N-oxide is the principal metabolite in the urine; however, this
amounts to <4% of the dose. Other metabolites are the S-oxide (1%) and the desmethyl ranitidine
(1%). The remainder of the administered dose is found in the stool. Studies in patients with
hepatic dysfunction (compensated cirrhosis) indicate that there are minor, but clinically
insignificant, alterations in ranitidine half-life, distribution, clearance, and bioavailability.
Excretion: The principal route of excretion is the urine, with approximately 30% of the
orally administered dose collected in the urine as unchanged drug in 24 hours. Renal clearance is
about 410 mL/min, indicating active tubular excretion. The elimination half-life is 2.5 to 3 hours.
Four patients with clinically significant renal function impairment (creatinine clearance 25 to
35 mL/min) administered 50 mg of ranitidine intravenously had an average plasma half-life of
4.8 hours, a ranitidine clearance of 29 mL/min, and a volume of distribution of 1.76 L/kg. In
general, these parameters appear to be altered in proportion to creatinine clearance (see
DOSAGE AND ADMINISTRATION).
Geriatrics: The plasma half-life is prolonged and total clearance is reduced in the elderly
population due to a decrease in renal function. The elimination half-life is 3 to 4 hours. Peak
2
levels average 526 ng/mL following a 150-mg twice-daily dose and occur in about 3 hours (see
PRECAUTIONS: Geriatric Use and DOSAGE AND ADMINISTRATION: Dosage Adjustment
for Patients With Impaired Renal Function).
Pediatrics: There are no significant differences in the pharmacokinetic parameter values for
ranitidine in pediatric patients (from 1 month up to 16 years of age) and healthy adults when
correction is made for body weight. The average bioavailability of ranitidine given orally to
pediatric patients is 48% which is comparable to the bioavailability of ranitidine in the adult
population. All other pharmacokinetic parameter values (t1/2, Vd, and CL) are similar to those
observed with intravenous ranitidine use in pediatric patients. Estimates of Cmax and Tmax are
displayed in Table 1.
Table 1. Ranitidine Pharmacokinetics in Pediatric Patients Following Oral Dosing
Population
(age)
n
Dosage Form
(dose)
Cmax
(ng/mL)
Tmax
(hours)
Gastric or duodenal ulcer
(3.5 to 16 years)
12
Tablets
(1 to 2 mg/kg)
54 to 492
2.0
Otherwise healthy requiring ZANTAC
(0.7 to 14 years, Single dose)
10
Syrup
(2 mg/kg)
244
1.61
Otherwise healthy requiring ZANTAC
(0.7 to 14 years, Multiple dose)
10
Syrup
(2 mg/kg)
320
1.66
Plasma clearance measured in 2 neonatal patients (less than 1 month of age) was considerably
lower (3 mL/min/kg) than children or adults and is likely due to reduced renal function observed
in this population (see PRECAUTIONS: Pediatric Use and DOSAGE AND
ADMINISTRATION: Pediatric Use).
Pharmacodynamics: Serum concentrations necessary to inhibit 50% of stimulated gastric
acid secretion are estimated to be 36 to 94 ng/mL. Following a single oral dose of 150 mg, serum
concentrations of ranitidine are in this range up to 12 hours. However, blood levels bear no
consistent relationship to dose or degree of acid inhibition.
In a pharmacodynamic comparison of the EFFERdose with the ZANTAC Tablets, during the
first hour after administration, the EFFERdose tablet formulation gave a significantly higher
intragastric pH, by approximately 1 pH unit, compared to the ZANTAC Tablets.
Antisecretory Activity: 1. Effects on Acid Secretion: ZANTAC inhibits both daytime
and nocturnal basal gastric acid secretions as well as gastric acid secretion stimulated by food,
betazole, and pentagastrin, as shown in Table 2.
3
Table 2. Effect of Oral ZANTAC on Gastric Acid Secretion
Time After
Dose, hours
% Inhibition of Gastric Acid Output by Dose, mg
75-80
100
150
200
Basal
Up to 4
99
95
Nocturnal
Up to 13
95
96
92
Betazole
Up to 3
97
99
Pentagastrin
Up to 5
58
72
72
80
Meal
Up to 3
73
79
95
It appears that basal-, nocturnal-, and betazole-stimulated secretions are most sensitive to
inhibition by ZANTAC, responding almost completely to doses of 100 mg or less, while
pentagastrin- and food-stimulated secretions are more difficult to suppress.
2. Effects on Other Gastrointestinal Secretions:
Pepsin: Oral ZANTAC does not affect pepsin secretion. Total pepsin output is reduced
in proportion to the decrease in volume of gastric juice.
Intrinsic Factor: Oral ZANTAC has no significant effect on pentagastrin-stimulated
intrinsic factor secretion.
Serum Gastrin: ZANTAC has little or no effect on fasting or postprandial serum
gastrin.
Other Pharmacologic Actions:
1. Gastric bacterial flora—increase in nitrate-reducing organisms, significance not known.
2. Prolactin levels—no effect in recommended oral or IV dosage, but small, transient,
dose-related increases in serum prolactin have been reported after IV bolus injections of
100 mg or more.
3. Other pituitary hormones—no effect on serum gonadotropins, TSH, or GH. Possible
impairment of vasopressin release.
4. No change in cortisol, aldosterone, androgen, or estrogen levels.
5. No antiandrogenic action.
6. No effect on count, motility, or morphology of sperm.
Pediatrics: Oral doses of 6 to 10 mg/kg/day in 2 or 3 divided doses maintain gastric pH >4
throughout most of the dosing interval.
Clinical Trials: Active Duodenal Ulcer: In a multicenter, double-blind, controlled, US
study of endoscopically diagnosed duodenal ulcers, earlier healing was seen in the patients
treated with ZANTAC as shown in Table 3.
4
Table 3. Duodenal Ulcer Patient Healing Rates
ZANTAC*
Placebo*
Number
Entered
Healed/
Evaluable
Number
Entered
Healed/
Evaluable
Outpatients
Week 2
195
69/182
(38%)†
188
31/164
(19%)
Week 4
137/187
(73%)†
76/168
(45%)
*All patients were permitted antacids as needed for relief of pain.
†P<0.0001.
In these studies, patients treated with ZANTAC reported a reduction in both daytime and
nocturnal pain, and they also consumed less antacid than the placebo-treated patients.
Table 4. Mean Daily Doses of Antacid
Ulcer Healed
Ulcer Not Healed
ZANTAC
0.06
0.71
Placebo
0.71
1.43
Foreign studies have shown that patients heal equally well with 150 mg twice daily and
300 mg at bedtime (85% versus 84%, respectively) during a usual 4-week course of therapy. If
patients require extended therapy of 8 weeks, the healing rate may be higher for 150 mg twice
daily as compared to 300 mg at bedtime (92% versus 87%, respectively).
Studies have been limited to short-term treatment of acute duodenal ulcer. Patients whose
ulcers healed during therapy had recurrences of ulcers at the usual rates.
Maintenance Therapy in Duodenal Ulcer: Ranitidine has been found to be effective as
maintenance therapy for patients following healing of acute duodenal ulcers. In 2 independent,
double-blind, multicenter, controlled trials, the number of duodenal ulcers observed was
significantly less in patients treated with ZANTAC (150 mg at bedtime) than in patients treated
with placebo over a 12-month period.
5
Table 5. Duodenal Ulcer Prevalence
Double-Blind, Multicenter, Placebo-Controlled Trials
Multicenter
Trial
Drug
Duodenal Ulcer Prevalence
No. of
Patients
0-4
Months
0-8
Months
0-12
Months
USA
RAN
20%*
24%*
35%*
138
PLC
44%
54%
59%
139
Foreign
RAN
12%*
21%*
28%*
174
PLC
56%
64%
68%
165
% = Life table estimate.
* = P<0.05 (ZANTAC versus comparator).
RAN = ranitidine (ZANTAC).
PLC = placebo.
As with other H2-antagonists, the factors responsible for the significant reduction in the
prevalence of duodenal ulcers include prevention of recurrence of ulcers, more rapid healing of
ulcers that may occur during maintenance therapy, or both.
Gastric Ulcer: In a multicenter, double-blind, controlled, US study of endoscopically
diagnosed gastric ulcers, earlier healing was seen in the patients treated with ZANTAC as shown
in Table 6.
Table 6. Gastric Ulcer Patient Healing Rates
ZANTAC*
Placebo*
Number
Entered
Healed/
Evaluable
Number
Entered
Healed/
Evaluable
Outpatients
Week 2
92
16/83
(19%)
94
10/83
(12%)
Week 6
50/73
(68%)†
35/69
(51%)
*All patients were permitted antacids as needed for relief of pain.
†P = 0.009.
In this multicenter trial, significantly more patients treated with ZANTAC became pain free
during therapy.
Maintenance of Healing of Gastric Ulcers: In 2 multicenter, double-blind, randomized,
placebo-controlled, 12-month trials conducted in patients whose gastric ulcers had been
6
previously healed, ZANTAC 150 mg at bedtime was significantly more effective than placebo in
maintaining healing of gastric ulcers.
Pathological Hypersecretory Conditions (such as Zollinger-Ellison syndrome):
ZANTAC inhibits gastric acid secretion and reduces occurrence of diarrhea, anorexia, and pain
in patients with pathological hypersecretion associated with Zollinger-Ellison syndrome,
systemic mastocytosis, and other pathological hypersecretory conditions (e.g., postoperative,
"short-gut" syndrome, idiopathic). Use of ZANTAC was followed by healing of ulcers in 8 of 19
(42%) patients who were intractable to previous therapy.
Gastroesophageal Reflux Disease (GERD): In 2 multicenter, double-blind,
placebo-controlled, 6-week trials performed in the United States and Europe, ZANTAC 150 mg
twice daily was more effective than placebo for the relief of heartburn and other symptoms
associated with GERD. Ranitidine-treated patients consumed significantly less antacid than did
placebo-treated patients.
The US trial indicated that ZANTAC 150 mg twice daily significantly reduced the frequency
of heartburn attacks and severity of heartburn pain within 1 to 2 weeks after starting therapy. The
improvement was maintained throughout the 6-week trial period. Moreover, patient response
rates demonstrated that the effect on heartburn extends through both the day and night time
periods.
In 2 additional US multicenter, double-blind, placebo-controlled, 2-week trials, ZANTAC
150 mg twice daily was shown to provide relief of heartburn pain within 24 hours of initiating
therapy and a reduction in the frequency of severity of heartburn. In these trials, ZANTAC
EFFERdose Tablets were shown to provide heartburn relief within 45 minutes of dosing.
Erosive Esophagitis: In 2 multicenter, double-blind, randomized, placebo-controlled,
12-week trials performed in the United States, ZANTAC 150 mg 4 times daily was significantly
more effective than placebo in healing endoscopically diagnosed erosive esophagitis and in
relieving associated heartburn. The erosive esophagitis healing rates were as follows:
Table 7. Erosive Esophagitis Patient Healing Rates
Healed/Evaluable
Placebo*
n = 229
ZANTAC
150 mg 4 times daily*
n = 215
Week 4
43/198 (22%)
96/206 (47%)†
Week 8
63/176 (36%)
142/200 (71%)†
Week 12
92/159 (58%)
162/192 (84%)†
*All patients were permitted antacids as needed for relief of pain.
†P<0.001 versus placebo.
No additional benefit in healing of esophagitis or in relief of heartburn was seen with a
ranitidine dose of 300 mg 4 times daily.
7
Maintenance of Healing of Erosive Esophagitis: In 2 multicenter, double-blind,
randomized, placebo-controlled, 48-week trials conducted in patients whose erosive esophagitis
had been previously healed, ZANTAC 150 mg twice daily was significantly more effective than
placebo in maintaining healing of erosive esophagitis.
INDICATIONS AND USAGE
ZANTAC is indicated in:
1. Short-term treatment of active duodenal ulcer. Most patients heal within 4 weeks. Studies
available to date have not assessed the safety of ranitidine in uncomplicated duodenal ulcer
for periods of more than 8 weeks.
2. Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of acute
ulcers. No placebo-controlled comparative studies have been carried out for periods of longer
than 1 year.
3. The treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome
and systemic mastocytosis).
4. Short-term treatment of active, benign gastric ulcer. Most patients heal within 6 weeks and
the usefulness of further treatment has not been demonstrated. Studies available to date have
not assessed the safety of ranitidine in uncomplicated, benign gastric ulcer for periods of
more than 6 weeks.
5. Maintenance therapy for gastric ulcer patients at reduced dosage after healing of acute ulcers.
Placebo-controlled studies have been carried out for 1 year.
6. Treatment of GERD. Symptomatic relief commonly occurs within 24 hours after starting
therapy with ZANTAC 150 mg twice daily.
7. Treatment of endoscopically diagnosed erosive esophagitis. Symptomatic relief of heartburn
commonly occurs within 24 hours of therapy initiation with ZANTAC 150 mg 4 times daily.
8. Maintenance of healing of erosive esophagitis. Placebo-controlled trials have been carried
out for 48 weeks.
Concomitant antacids should be given as needed for pain relief to patients with active
duodenal ulcer; active, benign gastric ulcer; hypersecretory states; GERD; and erosive
esophagitis.
CONTRAINDICATIONS
ZANTAC is contraindicated for patients known to have hypersensitivity to the drug or any of
the ingredients (see PRECAUTIONS).
PRECAUTIONS
General:
1. Symptomatic response to therapy with ZANTAC does not preclude the presence of gastric
malignancy.
8
2. Since ZANTAC is excreted primarily by the kidney, dosage should be adjusted in patients
with impaired renal function (see DOSAGE AND ADMINISTRATION). Caution should be
observed in patients with hepatic dysfunction since ZANTAC is metabolized in the liver.
3. Rare reports suggest that ZANTAC may precipitate acute porphyric attacks in patients with
acute porphyria. ZANTAC should therefore be avoided in patients with a history of acute
porphyria.
Information for Patients: Phenylketonurics: ZANTAC 25 EFFERdose Tablets contain
phenylalanine 2.81 mg per 25 mg of ranitidine. ZANTAC EFFERdose Tablets should not be
chewed, swallowed whole, or dissolved on the tongue.
Laboratory Tests: False-positive tests for urine protein with MULTISTIX® may occur during
therapy with ZANTAC, and therefore testing with sulfosalicylic acid is recommended.
Drug Interactions: Ranitidine has been reported to affect the bioavailability of other drugs
through several different mechanisms such as competition for renal tubular secretion, alteration
of gastric pH, and inhibition of cytochrome P450 enzymes.
Procainamide: Ranitidine, a substrate of the renal organic cation transport system, may
affect the clearance of other drugs eliminated by this route. High doses of ranitidine (e.g., such as
those used in the treatment of Zollinger-Ellison syndrome) have been shown to reduce the renal
excretion of procainamide and N-acetylprocainamide resulting in increased plasma levels of
these drugs. Although this interaction is unlikely to be clinically relevant at usual ranitidine
doses, it may be prudent to monitor for procainamide toxicity when administered with oral
ranitidine at a dose exceeding 300 mg per day.
Warfarin: There have been reports of altered prothrombin time among patients on
concomitant warfarin and ranitidine therapy. Due to the narrow therapeutic index, close
monitoring of increased or decreased prothrombin time is recommended during concurrent
treatment with ranitidine.
Ranitidine may alter the absorption of drugs in which gastric pH is an important determinant
of bioavailability. This can result in either an increase in absorption (e.g., triazolam, midazolam,
glipizide) or a decrease in absorption (e.g., ketoconazole, atazanavir, delavirdine, gefitinib).
Appropriate clinical monitoring is recommended.
Atazanavir: Atazanavir absorption may be impaired based on known interactions with other
agents that increase gastric pH. Use with caution. See atazanavir label for specific
recommendations.
Delavirdine: Delavirdine absorption may be impaired based on known interactions with
other agents that increase gastric pH. Chronic use of H2-receptor antagonists with delavirdine is
not recommended.
Gefitinib: Gefitinib exposure was reduced by 44% with the coadministration of ranitidine and
sodium bicarbonate (dosed to maintain gastric pH above 5.0). Use with caution.
Glipizide: In diabetic patients, glipizide exposure was increased by 34% following a single
150-mg dose of oral ranitidine. Use appropriate clinical monitoring when initiating or
discontinuing ranitidine.
9
Ketoconazole: Oral ketoconazole exposure was reduced by up to 95% when oral ranitidine
was coadministered in a regimen to maintain a gastric pH of 6 or above. The degree of
interaction with usual dose of ranitidine (150 mg twice daily) is unknown.
Midazolam: Oral midazolam exposure in 5 healthy volunteers was increased by up to 65%
when administered with oral ranitidine at a dose of 150 mg twice daily. However, in another
interaction study in 8 volunteers receiving IV midazolam, a 300 mg oral dose of ranitidine
increased midazolam exposure by about 9%. Monitor patients for excessive or prolonged
sedation when ranitidine is coadministered with oral midazolam.
Triazolam: Triazolam exposure in healthy volunteers was increased by approximately 30%
when administered with oral ranitidine at a dose of 150 mg twice daily. Monitor patients for
excessive or prolonged sedation.
Carcinogenesis, Mutagenesis, Impairment of Fertility: There was no indication of
tumorigenic or carcinogenic effects in life-span studies in mice and rats at dosages up to
2,000 mg/kg/day.
Ranitidine was not mutagenic in standard bacterial tests (Salmonella, Escherichia coli) for
mutagenicity at concentrations up to the maximum recommended for these assays.
In a dominant lethal assay, a single oral dose of 1,000 mg/kg to male rats was without effect
on the outcome of 2 matings per week for the next 9 weeks.
Pregnancy: Teratogenic Effects: Pregnancy Category B. Reproduction studies have been
performed in rats and rabbits at doses up to 160 times the human dose and have revealed no
evidence of impaired fertility or harm to the fetus due to ZANTAC. There are, however, no
adequate and well-controlled studies in pregnant women. Because animal reproduction studies
are not always predictive of human response, this drug should be used during pregnancy only if
clearly needed.
Nursing Mothers: Ranitidine is secreted in human milk. Caution should be exercised when
ZANTAC is administered to a nursing mother.
Pediatric Use: The safety and effectiveness of ZANTAC have been established in the
age-group of 1 month to 16 years for the treatment of duodenal and gastric ulcers,
gastroesophageal reflux disease and erosive esophagitis, and the maintenance of healed duodenal
and gastric ulcer. Use of ZANTAC in this age-group is supported by adequate and
well-controlled studies in adults, as well as additional pharmacokinetic data in pediatric patients
and an analysis of the published literature (see CLINICAL PHARMACOLOGY: Pediatrics and
DOSAGE AND ADMINISTRATION: Pediatric Use).
Safety and effectiveness in pediatric patients for the treatment of pathological hypersecretory
conditions or the maintenance of healing of erosive esophagitis have not been established.
Safety and effectiveness in neonates (less than 1 month of age) have not been established (see
CLINICAL PHARMACOLOGY: Pediatrics).
Geriatric Use: Of the total number of subjects enrolled in US and foreign controlled clinical
trials of oral formulations of ZANTAC, for which there were subgroup analyses, 4,197 were 65
and over, while 899 were 75 and over. No overall differences in safety or effectiveness were
10
observed between these subjects and younger subjects, and other reported clinical experience has
not identified differences in responses between the elderly and younger patients, but greater
sensitivity of some older individuals cannot be ruled out.
This drug is known to be substantially excreted by the kidney and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, caution should be exercised in dose selection, and
it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY:
Pharmacokinetics: Geriatrics and DOSAGE AND ADMINISTRATION: Dosage Adjustment for
Patients With Impaired Renal Function).
ADVERSE REACTIONS
The following have been reported as events in clinical trials or in the routine management of
patients treated with ZANTAC. The relationship to therapy with ZANTAC has been unclear in
many cases. Headache, sometimes severe, seems to be related to administration of ZANTAC.
Central Nervous System: Rarely, malaise, dizziness, somnolence, insomnia, and vertigo.
Rare cases of reversible mental confusion, agitation, depression, and hallucinations have been
reported, predominantly in severely ill elderly patients. Rare cases of reversible blurred vision
suggestive of a change in accommodation have been reported. Rare reports of reversible
involuntary motor disturbances have been received.
Cardiovascular: As with other H2-blockers, rare reports of arrhythmias such as tachycardia,
bradycardia, atrioventricular block, and premature ventricular beats.
Gastrointestinal: Constipation, diarrhea, nausea/vomiting, abdominal discomfort/pain, and
rare reports of pancreatitis.
Hepatic: There have been occasional reports of hepatocellular, cholestatic, or mixed hepatitis,
with or without jaundice. In such circumstances, ranitidine should be immediately discontinued.
These events are usually reversible, but in rare circumstances death has occurred. Rare cases of
hepatic failure have also been reported. In normal volunteers, SGPT values were increased to at
least twice the pretreatment levels in 6 of 12 subjects receiving 100 mg intravenously 4 times
daily for 7 days, and in 4 of 24 subjects receiving 50 mg intravenously 4 times daily for 5 days.
Musculoskeletal: Rare reports of arthralgias and myalgias.
Hematologic: Blood count changes (leukopenia, granulocytopenia, and thrombocytopenia)
have occurred in a few patients. These were usually reversible. Rare cases of agranulocytosis,
pancytopenia, sometimes with marrow hypoplasia, and aplastic anemia and exceedingly rare
cases of acquired immune hemolytic anemia have been reported.
Endocrine: Controlled studies in animals and man have shown no stimulation of any pituitary
hormone by ZANTAC and no antiandrogenic activity, and cimetidine-induced gynecomastia and
impotence in hypersecretory patients have resolved when ZANTAC has been substituted.
However, occasional cases of impotence and loss of libido have been reported in male patients
receiving ZANTAC, but the incidence did not differ from that in the general population. Rare
11
cases of breast symptoms and conditions, including galactorrhea and gynecomastia, have been
reported in both males and females.
Integumentary: Rash, including rare cases of erythema multiforme. Rare cases of alopecia and
vasculitis.
Respiratory: A large epidemiological study suggested an increased risk of developing
pneumonia in current users of histamine-2-receptor antagonists (H2RAs) compared to patients
who had stopped H2RA treatment, with an observed adjusted relative risk of 1.63 (95% CI, 1.07
2.48). However, a causal relationship between use of H2RAs and pneumonia has not been
established.
Other: Rare cases of hypersensitivity reactions (e.g., bronchospasm, fever, rash, eosinophilia),
anaphylaxis, angioneurotic edema, acute interstitial nephritis, and small increases in serum
creatinine.
OVERDOSAGE
There has been limited experience with overdosage. Reported acute ingestions of up to 18 g
orally have been associated with transient adverse effects similar to those encountered in normal
clinical experience (see ADVERSE REACTIONS). In addition, abnormalities of gait and
hypotension have been reported.
When overdosage occurs, the usual measures to remove unabsorbed material from the
gastrointestinal tract, clinical monitoring, and supportive therapy should be employed.
Studies in dogs receiving dosages of ZANTAC in excess of 225 mg/kg/day have shown
muscular tremors, vomiting, and rapid respiration. Single oral doses of 1,000 mg/kg in mice and
rats were not lethal. Intravenous LD50 values in mice and rats were 77 and 83 mg/kg,
respectively.
DOSAGE AND ADMINISTRATION
Active Duodenal Ulcer: The current recommended adult oral dosage of ZANTAC for
duodenal ulcer is 150 mg or 10 mL of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of
ranitidine) twice daily. An alternative dosage of 300 mg or 20 mL of syrup (4 teaspoonfuls of
syrup equivalent to 300 mg of ranitidine) once daily after the evening meal or at bedtime can be
used for patients in whom dosing convenience is important. The advantages of one treatment
regimen compared to the other in a particular patient population have yet to be demonstrated (see
Clinical Trials: Active Duodenal Ulcer). Smaller doses have been shown to be equally effective
in inhibiting gastric acid secretion in US studies, and several foreign trials have shown that
100 mg twice daily is as effective as the 150-mg dose.
Antacid should be given as needed for relief of pain (see CLINICAL PHARMACOLOGY:
Pharmacokinetics).
Maintenance of Healing of Duodenal Ulcers: The current recommended adult oral dosage
is 150 mg or 10 mL of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) at
bedtime.
12
Pathological Hypersecretory Conditions (such as Zollinger-Ellison syndrome):
The current recommended adult oral dosage is 150 mg or 10 mL of syrup (2 teaspoonfuls of
syrup equivalent to 150 mg of ranitidine) twice daily. In some patients it may be necessary to
administer ZANTAC 150-mg doses more frequently. Dosages should be adjusted to individual
patient needs, and should continue as long as clinically indicated. Dosages up to 6 g/day have
been employed in patients with severe disease.
Benign Gastric Ulcer: The current recommended adult oral dosage is 150 mg or 10 mL of
syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) twice daily.
Maintenance of Healing of Gastric Ulcers: The current recommended adult oral dosage is
150 mg or 10 mL of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) at
bedtime.
GERD: The current recommended adult oral dosage is 150 mg or 10 mL of syrup
(2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) twice daily.
Erosive Esophagitis: The current recommended adult oral dosage is 150 mg or 10 mL of
syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) 4 times daily.
Maintenance of Healing of Erosive Esophagitis: The current recommended adult oral
dosage is 150 mg or 10 mL of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine)
twice daily.
Pediatric Use: The safety and effectiveness of ZANTAC have been established in the
age-group of 1 month to 16 years. There is insufficient information about the pharmacokinetics
of ZANTAC in neonatal patients (less than 1 month of age) to make dosing recommendations.
The following 3 subsections provide dosing information for each of the pediatric indications.
Also, see the subsection on Preparation of ZANTAC 25 EFFERdose Tablets, below.
Treatment of Duodenal and Gastric Ulcers: The recommended oral dose for the
treatment of active duodenal and gastric ulcers is 2 to 4 mg/kg twice daily to a maximum of
300 mg/day. This recommendation is derived from adult clinical studies and pharmacokinetic
data in pediatric patients.
Maintenance of Healing of Duodenal and Gastric Ulcers: The recommended oral
dose for the maintenance of healing of duodenal and gastric ulcers is 2 to 4 mg/kg once daily to a
maximum of 150 mg/day. This recommendation is derived from adult clinical studies and
pharmacokinetic data in pediatric patients.
Treatment of GERD and Erosive Esophagitis: Although limited data exist for these
conditions in pediatric patients, published literature supports a dosage of 5 to 10 mg/kg/day,
usually given as 2 divided doses.
Dosage Adjustment for Patients With Impaired Renal Function: On the basis of
experience with a group of subjects with severely impaired renal function treated with ZANTAC,
the recommended dosage in patients with a creatinine clearance <50 mL/min is 150 mg or 10 mL
of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) every 24 hours. Should the
patient's condition require, the frequency of dosing may be increased to every 12 hours or even
further with caution. Hemodialysis reduces the level of circulating ranitidine. Ideally, the dosing
13
C
ompany logo
schedule should be adjusted so that the timing of a scheduled dose coincides with the end of
hemodialysis.
Elderly patients are more likely to have decreased renal function, therefore caution should be
exercised in dose selection, and it may be useful to monitor renal function (see CLINICAL
PHARMACOLOGY: Pharmacokinetics: Geriatrics and PRECAUTIONS: Geriatric Use).
Preparation of ZANTAC 25 EFFERdose Tablets: Tablets should not be chewed,
swallowed whole, or dissolved on the tongue. Dissolve 1 tablet in no less than 5 mL
(1 teaspoonful) of water in an appropriate measuring cup. Wait until the tablet is completely
dissolved before administering the solution to the infant/child. The solution may be administered
to infants by medicine dropper or oral syringe.
HOW SUPPLIED
ZANTAC 150 Tablets (ranitidine HCl equivalent to 150 mg of ranitidine) are peach,
film-coated, 5-sided tablets embossed with "ZANTAC 150" on one side and "Glaxo" on the
other. They are available in bottles of 60 (NDC 0173-0344-42), 180 (NDC 0173-0344-17), and
500 (NDC 0173-0344-14) tablets.
ZANTAC 300 Tablets (ranitidine HCl equivalent to 300 mg of ranitidine) are yellow,
film-coated, capsule-shaped tablets embossed with "ZANTAC 300" on one side and "Glaxo" on
the other. They are available in bottles of 30 (NDC 0173-0393-40) tablets.
Store between 15° and 30°C (59°and 86°F) in a dry place. Protect from light. Replace
cap securely after each opening.
ZANTAC 25 EFFERdose Tablets (ranitidine HCl equivalent to 25 mg of ranitidine) are white
to pale yellow, round, flat-faced, bevel-edged tablets embossed with “GS” on one side and
“25C” on the other side. They are packaged in foil strips and are available in a carton of 60
(NDC 0173-0734-00) tablets.
Store between 2° and 30°C (36° and 86°F).
ZANTAC Syrup, a clear, pale yellow, peppermint-flavored liquid, contains 16.8 mg of
ranitidine HCl equivalent to 15 mg of ranitidine per 1 mL (75 mg/5 mL) in bottles of 16 fluid
ounces (one pint) (NDC 0173-0383-54).
Store between 4° and 25°C (39° and 77°F). Dispense in tight, light-resistant containers as
defined in the USP/NF.
Research Triangle Park, NC 27709
ZANTAC and EFFERdose are registered trademarks of Warner-Lambert Company, used under
license.
14
MULTISTIX is a registered trademark of Bayer Healthcare LLC.
©2009, GlaxoSmithKline. All rights reserved.
April 2009
ZNT:5PI
15
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{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018703s068,019675s035,020251s019lbl.pdf', 'application_number': 18703, 'submission_type': 'SUPPL ', 'submission_number': 68}
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PRESCRIBING INFORMATION
ZANTAC® 150
(ranitidine hydrochloride)
Tablets, USP
ZANTAC® 300
(ranitidine hydrochloride)
Tablets, USP
ZANTAC® 25
(ranitidine hydrochloride effervescent)
EFFERdose® Tablets
ZANTAC®
(ranitidine hydrochloride)
Syrup, USP
DESCRIPTION
The active ingredient in ZANTAC 150 Tablets, ZANTAC 300 Tablets, ZANTAC 25
EFFERdose Tablets, and ZANTAC Syrup is ranitidine hydrochloride (HCl), USP, a histamine
H2-receptor antagonist. Chemically it is N[2-[[[5-[(dimethylamino)methyl]-2
furanyl]methyl]thio]ethyl]-N′-methyl-2-nitro-1,1-ethenediamine, HCl. It has the following
structure: Chemical Structure
The empirical formula is C13H22N4O3S•HCl, representing a molecular weight of 350.87.
Ranitidine HCl is a white to pale yellow, granular substance that is soluble in water. It has a
slightly bitter taste and sulfurlike odor.
Each ZANTAC 150 Tablet for oral administration contains 168 mg of ranitidine HCl
equivalent to 150 mg of ranitidine. Each tablet also contains the inactive ingredients FD&C
Yellow No. 6 Aluminum Lake, hypromellose, magnesium stearate, microcrystalline cellulose,
titanium dioxide, triacetin, and yellow iron oxide.
Each ZANTAC 300 Tablet for oral administration contains 336 mg of ranitidine HCl
equivalent to 300 mg of ranitidine. Each tablet also contains the inactive ingredients
croscarmellose sodium, D&C Yellow No. 10 Aluminum Lake, hypromellose, magnesium
stearate, microcrystalline cellulose, titanium dioxide, and triacetin.
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ZANTAC 25 EFFERdose Tablets for oral administration is an effervescent formulation of
ranitidine that must be dissolved in water before use. Each individual tablet contains 28 mg of
ranitidine HCl equivalent to 25 mg of ranitidine and the following inactive ingredients:
aspartame, monosodium citrate anhydrous, povidone, and sodium bicarbonate. Each tablet also
contains sodium benzoate. The total sodium content of each tablet is 30.52 mg (1.33 mEq) per
25 mg of ranitidine.
Each 1 mL of ZANTAC Syrup contains 16.8 mg of ranitidine HCl equivalent to 15 mg of
ranitidine. ZANTAC Syrup also contains the inactive ingredients alcohol (7.5%), butylparaben,
dibasic sodium phosphate, hypromellose, peppermint flavor, monobasic potassium phosphate,
propylparaben, purified water, saccharin sodium, sodium chloride, and sorbitol.
CLINICAL PHARMACOLOGY
ZANTAC is a competitive, reversible inhibitor of the action of histamine at the histamine
H2-receptors, including receptors on the gastric cells. ZANTAC does not lower serum Ca++ in
hypercalcemic states. ZANTAC is not an anticholinergic agent.
Pharmacokinetics:
Absorption: ZANTAC is 50% absorbed after oral administration, compared to an
intravenous (IV) injection with mean peak levels of 440 to 545 ng/mL occurring 2 to 3 hours
after a 150-mg dose. The syrup and EFFERdose formulations are bioequivalent to the tablets.
Absorption is not significantly impaired by the administration of food or antacids. Propantheline
slightly delays and increases peak blood levels of ranitidine, probably by delaying gastric
emptying and transit time. In one study, simultaneous administration of high-potency antacid
(150 mmol) in fasting subjects has been reported to decrease the absorption of ZANTAC.
Distribution: The volume of distribution is about 1.4 L/kg. Serum protein binding averages
15%.
Metabolism: In humans, the N-oxide is the principal metabolite in the urine; however, this
amounts to <4% of the dose. Other metabolites are the S-oxide (1%) and the desmethyl ranitidine
(1%). The remainder of the administered dose is found in the stool. Studies in patients with
hepatic dysfunction (compensated cirrhosis) indicate that there are minor, but clinically
insignificant, alterations in ranitidine half-life, distribution, clearance, and bioavailability.
Excretion: The principal route of excretion is the urine, with approximately 30% of the
orally administered dose collected in the urine as unchanged drug in 24 hours. Renal clearance is
about 410 mL/min, indicating active tubular excretion. The elimination half-life is 2.5 to 3 hours.
Four patients with clinically significant renal function impairment (creatinine clearance 25 to
35 mL/min) administered 50 mg of ranitidine intravenously had an average plasma half-life of
4.8 hours, a ranitidine clearance of 29 mL/min, and a volume of distribution of 1.76 L/kg. In
general, these parameters appear to be altered in proportion to creatinine clearance (see
DOSAGE AND ADMINISTRATION).
Geriatrics: The plasma half-life is prolonged and total clearance is reduced in the elderly
population due to a decrease in renal function. The elimination half-life is 3 to 4 hours. Peak
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
levels average 526 ng/mL following a 150-mg twice-daily dose and occur in about 3 hours (see
PRECAUTIONS: Geriatric Use and DOSAGE AND ADMINISTRATION: Dosage Adjustment
for Patients With Impaired Renal Function).
Pediatrics: There are no significant differences in the pharmacokinetic parameter values for
ranitidine in pediatric patients (from 1 month up to 16 years of age) and healthy adults when
correction is made for body weight. The average bioavailability of ranitidine given orally to
pediatric patients is 48% which is comparable to the bioavailability of ranitidine in the adult
population. All other pharmacokinetic parameter values (t1/2, Vd, and CL) are similar to those
observed with intravenous ranitidine use in pediatric patients. Estimates of Cmax and Tmax are
displayed in Table 1.
Table 1. Ranitidine Pharmacokinetics in Pediatric Patients Following Oral Dosing
Population
(age)
n
Dosage Form
(dose)
Cmax
(ng/mL)
Tmax
(hours)
Gastric or duodenal ulcer
(3.5 to 16 years)
12
Tablets
(1 to 2 mg/kg)
54 to 492
2.0
Otherwise healthy requiring ZANTAC
(0.7 to 14 years, Single dose)
10
Syrup
(2 mg/kg)
244
1.61
Otherwise healthy requiring ZANTAC
(0.7 to 14 years, Multiple dose)
10
Syrup
(2 mg/kg)
320
1.66
Plasma clearance measured in 2 neonatal patients (less than 1 month of age) was considerably
lower (3 mL/min/kg) than children or adults and is likely due to reduced renal function observed
in this population (see PRECAUTIONS: Pediatric Use and DOSAGE AND
ADMINISTRATION: Pediatric Use).
Pharmacodynamics: Serum concentrations necessary to inhibit 50% of stimulated gastric
acid secretion are estimated to be 36 to 94 ng/mL. Following a single oral dose of 150 mg, serum
concentrations of ranitidine are in this range up to 12 hours. However, blood levels bear no
consistent relationship to dose or degree of acid inhibition.
In a pharmacodynamic comparison of the EFFERdose with the ZANTAC Tablets, during the
first hour after administration, the EFFERdose tablet formulation gave a significantly higher
intragastric pH, by approximately 1 pH unit, compared to the ZANTAC Tablets.
Antisecretory Activity: 1. Effects on Acid Secretion: ZANTAC inhibits both daytime
and nocturnal basal gastric acid secretions as well as gastric acid secretion stimulated by food,
betazole, and pentagastrin, as shown in Table 2.
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 2. Effect of Oral ZANTAC on Gastric Acid Secretion
Time After
Dose, hours
% Inhibition of Gastric Acid Output by Dose, mg
75-80
100
150
200
Basal
Up to 4
99
95
Nocturnal
Up to 13
95
96
92
Betazole
Up to 3
97
99
Pentagastrin
Up to 5
58
72
72
80
Meal
Up to 3
73
79
95
It appears that basal-, nocturnal-, and betazole-stimulated secretions are most sensitive to
inhibition by ZANTAC, responding almost completely to doses of 100 mg or less, while
pentagastrin- and food-stimulated secretions are more difficult to suppress.
2. Effects on Other Gastrointestinal Secretions:
Pepsin: Oral ZANTAC does not affect pepsin secretion. Total pepsin output is reduced
in proportion to the decrease in volume of gastric juice.
Intrinsic Factor: Oral ZANTAC has no significant effect on pentagastrin-stimulated
intrinsic factor secretion.
Serum Gastrin: ZANTAC has little or no effect on fasting or postprandial serum
gastrin.
Other Pharmacologic Actions:
1. Gastric bacterial flora—increase in nitrate-reducing organisms, significance not known.
2. Prolactin levels—no effect in recommended oral or IV dosage, but small, transient,
dose-related increases in serum prolactin have been reported after IV bolus injections of
100 mg or more.
3. Other pituitary hormones—no effect on serum gonadotropins, TSH, or GH. Possible
impairment of vasopressin release.
4. No change in cortisol, aldosterone, androgen, or estrogen levels.
5. No antiandrogenic action.
6. No effect on count, motility, or morphology of sperm.
Pediatrics: Oral doses of 6 to 10 mg/kg/day in 2 or 3 divided doses maintain gastric pH >4
throughout most of the dosing interval.
Clinical Trials: Active Duodenal Ulcer: In a multicenter, double-blind, controlled, US
study of endoscopically diagnosed duodenal ulcers, earlier healing was seen in the patients
treated with ZANTAC as shown in Table 3.
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3. Duodenal Ulcer Patient Healing Rates
ZANTAC*
Placebo*
Number
Entered
Healed/
Evaluable
Number
Entered
Healed/
Evaluable
Outpatients
Week 2
195
69/182
(38%)†
188
31/164
(19%)
Week 4
137/187
(73%)†
76/168
(45%)
*All patients were permitted antacids as needed for relief of pain.
†P<0.0001.
In these studies, patients treated with ZANTAC reported a reduction in both daytime and
nocturnal pain, and they also consumed less antacid than the placebo-treated patients.
Table 4. Mean Daily Doses of Antacid
Ulcer Healed
Ulcer Not Healed
ZANTAC
0.06
0.71
Placebo
0.71
1.43
Foreign studies have shown that patients heal equally well with 150 mg twice daily and
300 mg at bedtime (85% versus 84%, respectively) during a usual 4-week course of therapy. If
patients require extended therapy of 8 weeks, the healing rate may be higher for 150 mg twice
daily as compared to 300 mg at bedtime (92% versus 87%, respectively).
Studies have been limited to short-term treatment of acute duodenal ulcer. Patients whose
ulcers healed during therapy had recurrences of ulcers at the usual rates.
Maintenance Therapy in Duodenal Ulcer: Ranitidine has been found to be effective as
maintenance therapy for patients following healing of acute duodenal ulcers. In 2 independent,
double-blind, multicenter, controlled trials, the number of duodenal ulcers observed was
significantly less in patients treated with ZANTAC (150 mg at bedtime) than in patients treated
with placebo over a 12-month period.
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 5. Duodenal Ulcer Prevalence
Double-Blind, Multicenter, Placebo-Controlled Trials
Multicenter
Trial
Drug
Duodenal Ulcer Prevalence
No. of
Patients
0-4
Months
0-8
Months
0-12
Months
USA
RAN
20%*
24%*
35%*
138
PLC
44%
54%
59%
139
Foreign
RAN
12%*
21%*
28%*
174
PLC
56%
64%
68%
165
% = Life table estimate.
* = P<0.05 (ZANTAC versus comparator).
RAN = ranitidine (ZANTAC).
PLC = placebo.
As with other H2-antagonists, the factors responsible for the significant reduction in the
prevalence of duodenal ulcers include prevention of recurrence of ulcers, more rapid healing of
ulcers that may occur during maintenance therapy, or both.
Gastric Ulcer: In a multicenter, double-blind, controlled, US study of endoscopically
diagnosed gastric ulcers, earlier healing was seen in the patients treated with ZANTAC as shown
in Table 6.
Table 6. Gastric Ulcer Patient Healing Rates
ZANTAC*
Placebo*
Number
Entered
Healed/
Evaluable
Number
Entered
Healed/
Evaluable
Outpatients
Week 2
92
16/83
(19%)
94
10/83
(12%)
Week 6
50/73
(68%)†
35/69
(51%)
*All patients were permitted antacids as needed for relief of pain.
†P = 0.009.
In this multicenter trial, significantly more patients treated with ZANTAC became pain free
during therapy.
Maintenance of Healing of Gastric Ulcers: In 2 multicenter, double-blind, randomized,
placebo-controlled, 12-month trials conducted in patients whose gastric ulcers had been
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
previously healed, ZANTAC 150 mg at bedtime was significantly more effective than placebo in
maintaining healing of gastric ulcers.
Pathological Hypersecretory Conditions (such as Zollinger-Ellison syndrome):
ZANTAC inhibits gastric acid secretion and reduces occurrence of diarrhea, anorexia, and pain
in patients with pathological hypersecretion associated with Zollinger-Ellison syndrome,
systemic mastocytosis, and other pathological hypersecretory conditions (e.g., postoperative,
"short-gut" syndrome, idiopathic). Use of ZANTAC was followed by healing of ulcers in 8 of 19
(42%) patients who were intractable to previous therapy.
Gastroesophageal Reflux Disease (GERD): In 2 multicenter, double-blind,
placebo-controlled, 6-week trials performed in the United States and Europe, ZANTAC 150 mg
twice daily was more effective than placebo for the relief of heartburn and other symptoms
associated with GERD. Ranitidine-treated patients consumed significantly less antacid than did
placebo-treated patients.
The US trial indicated that ZANTAC 150 mg twice daily significantly reduced the frequency
of heartburn attacks and severity of heartburn pain within 1 to 2 weeks after starting therapy. The
improvement was maintained throughout the 6-week trial period. Moreover, patient response
rates demonstrated that the effect on heartburn extends through both the day and night time
periods.
In 2 additional US multicenter, double-blind, placebo-controlled, 2-week trials, ZANTAC
150 mg twice daily was shown to provide relief of heartburn pain within 24 hours of initiating
therapy and a reduction in the frequency of severity of heartburn. In these trials, ZANTAC
EFFERdose Tablets were shown to provide heartburn relief within 45 minutes of dosing.
Erosive Esophagitis: In 2 multicenter, double-blind, randomized, placebo-controlled,
12-week trials performed in the United States, ZANTAC 150 mg 4 times daily was significantly
more effective than placebo in healing endoscopically diagnosed erosive esophagitis and in
relieving associated heartburn. The erosive esophagitis healing rates were as follows:
Table 7. Erosive Esophagitis Patient Healing Rates
Healed/Evaluable
Placebo*
n = 229
ZANTAC
150 mg 4 times daily*
n = 215
Week 4
43/198 (22%)
96/206 (47%)†
Week 8
63/176 (36%)
142/200 (71%)†
Week 12
92/159 (58%)
162/192 (84%)†
*All patients were permitted antacids as needed for relief of pain.
†P<0.001 versus placebo.
No additional benefit in healing of esophagitis or in relief of heartburn was seen with a
ranitidine dose of 300 mg 4 times daily.
7
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For current labeling information, please visit https://www.fda.gov/drugsatfda
Maintenance of Healing of Erosive Esophagitis: In 2 multicenter, double-blind,
randomized, placebo-controlled, 48-week trials conducted in patients whose erosive esophagitis
had been previously healed, ZANTAC 150 mg twice daily was significantly more effective than
placebo in maintaining healing of erosive esophagitis.
INDICATIONS AND USAGE
ZANTAC is indicated in:
1. Short-term treatment of active duodenal ulcer. Most patients heal within 4 weeks. Studies
available to date have not assessed the safety of ranitidine in uncomplicated duodenal ulcer
for periods of more than 8 weeks.
2. Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of acute
ulcers. No placebo-controlled comparative studies have been carried out for periods of longer
than 1 year.
3. The treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome
and systemic mastocytosis).
4. Short-term treatment of active, benign gastric ulcer. Most patients heal within 6 weeks and
the usefulness of further treatment has not been demonstrated. Studies available to date have
not assessed the safety of ranitidine in uncomplicated, benign gastric ulcer for periods of
more than 6 weeks.
5. Maintenance therapy for gastric ulcer patients at reduced dosage after healing of acute ulcers.
Placebo-controlled studies have been carried out for 1 year.
6. Treatment of GERD. Symptomatic relief commonly occurs within 24 hours after starting
therapy with ZANTAC 150 mg twice daily.
7. Treatment of endoscopically diagnosed erosive esophagitis. Symptomatic relief of heartburn
commonly occurs within 24 hours of therapy initiation with ZANTAC 150 mg 4 times daily.
8. Maintenance of healing of erosive esophagitis. Placebo-controlled trials have been carried
out for 48 weeks.
Concomitant antacids should be given as needed for pain relief to patients with active
duodenal ulcer; active, benign gastric ulcer; hypersecretory states; GERD; and erosive
esophagitis.
CONTRAINDICATIONS
ZANTAC is contraindicated for patients known to have hypersensitivity to the drug or any of
the ingredients (see PRECAUTIONS).
PRECAUTIONS
General:
1. Symptomatic response to therapy with ZANTAC does not preclude the presence of gastric
malignancy.
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2. Since ZANTAC is excreted primarily by the kidney, dosage should be adjusted in patients
with impaired renal function (see DOSAGE AND ADMINISTRATION). Caution should be
observed in patients with hepatic dysfunction since ZANTAC is metabolized in the liver.
3. Rare reports suggest that ZANTAC may precipitate acute porphyric attacks in patients with
acute porphyria. ZANTAC should therefore be avoided in patients with a history of acute
porphyria.
Information for Patients: Phenylketonurics: ZANTAC 25 EFFERdose Tablets contain
phenylalanine 2.81 mg per 25 mg of ranitidine. ZANTAC EFFERdose Tablets should not be
chewed, swallowed whole, or dissolved on the tongue.
Laboratory Tests: False-positive tests for urine protein with MULTISTIX
® may occur during
therapy with ZANTAC, and therefore testing with sulfosalicylic acid is recommended.
Drug Interactions: Ranitidine has been reported to affect the bioavailability of other drugs
through several different mechanisms such as competition for renal tubular secretion, alteration
of gastric pH, and inhibition of cytochrome P450 enzymes.
Procainamide: Ranitidine, a substrate of the renal organic cation transport system, may
affect the clearance of other drugs eliminated by this route. High doses of ranitidine (e.g., such as
those used in the treatment of Zollinger-Ellison syndrome) have been shown to reduce the renal
excretion of procainamide and N-acetylprocainamide resulting in increased plasma levels of
these drugs. Although this interaction is unlikely to be clinically relevant at usual ranitidine
doses, it may be prudent to monitor for procainamide toxicity when administered with oral
ranitidine at a dose exceeding 300 mg per day.
Warfarin: There have been reports of altered prothrombin time among patients on
concomitant warfarin and ranitidine therapy. Due to the narrow therapeutic index, close
monitoring of increased or decreased prothrombin time is recommended during concurrent
treatment with ranitidine.
Ranitidine may alter the absorption of drugs in which gastric pH is an important determinant
of bioavailability. This can result in either an increase in absorption (e.g., triazolam, midazolam,
glipizide) or a decrease in absorption (e.g., ketoconazole, atazanavir, delavirdine, gefitinib).
Appropriate clinical monitoring is recommended.
Atazanavir: Atazanavir absorption may be impaired based on known interactions with other
agents that increase gastric pH. Use with caution. See atazanavir label for specific
recommendations.
Delavirdine: Delavirdine absorption may be impaired based on known interactions with
other agents that increase gastric pH. Chronic use of H2-receptor antagonists with delavirdine is
not recommended.
Gefitinib: Gefitinib exposure was reduced by 44% with the coadministration of ranitidine and
sodium bicarbonate (dosed to maintain gastric pH above 5.0). Use with caution.
Glipizide: In diabetic patients, glipizide exposure was increased by 34% following a single
150-mg dose of oral ranitidine. Use appropriate clinical monitoring when initiating or
discontinuing ranitidine.
9
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Ketoconazole: Oral ketoconazole exposure was reduced by up to 95% when oral ranitidine
was coadministered in a regimen to maintain a gastric pH of 6 or above. The degree of
interaction with usual dose of ranitidine (150 mg twice daily) is unknown.
Midazolam: Oral midazolam exposure in 5 healthy volunteers was increased by up to 65%
when administered with oral ranitidine at a dose of 150 mg twice daily. However, in another
interaction study in 8 volunteers receiving IV midazolam, a 300 mg oral dose of ranitidine
increased midazolam exposure by about 9%. Monitor patients for excessive or prolonged
sedation when ranitidine is coadministered with oral midazolam.
Triazolam: Triazolam exposure in healthy volunteers was increased by approximately 30%
when administered with oral ranitidine at a dose of 150 mg twice daily. Monitor patients for
excessive or prolonged sedation.
Carcinogenesis, Mutagenesis, Impairment of Fertility: There was no indication of
tumorigenic or carcinogenic effects in life-span studies in mice and rats at dosages up to
2,000 mg/kg/day.
Ranitidine was not mutagenic in standard bacterial tests (Salmonella, Escherichia coli) for
mutagenicity at concentrations up to the maximum recommended for these assays.
In a dominant lethal assay, a single oral dose of 1,000 mg/kg to male rats was without effect
on the outcome of 2 matings per week for the next 9 weeks.
Pregnancy: Teratogenic Effects: Pregnancy Category B. Reproduction studies have been
performed in rats and rabbits at doses up to 160 times the human dose and have revealed no
evidence of impaired fertility or harm to the fetus due to ZANTAC. There are, however, no
adequate and well-controlled studies in pregnant women. Because animal reproduction studies
are not always predictive of human response, this drug should be used during pregnancy only if
clearly needed.
Nursing Mothers: Ranitidine is secreted in human milk. Caution should be exercised when
ZANTAC is administered to a nursing mother.
Pediatric Use: The safety and effectiveness of ZANTAC have been established in the
age-group of 1 month to 16 years for the treatment of duodenal and gastric ulcers,
gastroesophageal reflux disease and erosive esophagitis, and the maintenance of healed duodenal
and gastric ulcer. Use of ZANTAC in this age-group is supported by adequate and
well-controlled studies in adults, as well as additional pharmacokinetic data in pediatric patients
and an analysis of the published literature (see CLINICAL PHARMACOLOGY: Pediatrics and
DOSAGE AND ADMINISTRATION: Pediatric Use).
Safety and effectiveness in pediatric patients for the treatment of pathological hypersecretory
conditions or the maintenance of healing of erosive esophagitis have not been established.
Safety and effectiveness in neonates (less than 1 month of age) have not been established (see
CLINICAL PHARMACOLOGY: Pediatrics).
Geriatric Use: Of the total number of subjects enrolled in US and foreign controlled clinical
trials of oral formulations of ZANTAC, for which there were subgroup analyses, 4,197 were 65
and over, while 899 were 75 and over. No overall differences in safety or effectiveness were
10
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observed between these subjects and younger subjects, and other reported clinical experience has
not identified differences in responses between the elderly and younger patients, but greater
sensitivity of some older individuals cannot be ruled out.
This drug is known to be substantially excreted by the kidney and the risk of toxic reactions to
this drug may be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, caution should be exercised in dose selection, and
it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY:
Pharmacokinetics: Geriatrics and DOSAGE AND ADMINISTRATION: Dosage Adjustment for
Patients With Impaired Renal Function).
ADVERSE REACTIONS
The following have been reported as events in clinical trials or in the routine management of
patients treated with ZANTAC. The relationship to therapy with ZANTAC has been unclear in
many cases. Headache, sometimes severe, seems to be related to administration of ZANTAC.
Central Nervous System: Rarely, malaise, dizziness, somnolence, insomnia, and vertigo.
Rare cases of reversible mental confusion, agitation, depression, and hallucinations have been
reported, predominantly in severely ill elderly patients. Rare cases of reversible blurred vision
suggestive of a change in accommodation have been reported. Rare reports of reversible
involuntary motor disturbances have been received.
Cardiovascular: As with other H2-blockers, rare reports of arrhythmias such as tachycardia,
bradycardia, atrioventricular block, and premature ventricular beats.
Gastrointestinal: Constipation, diarrhea, nausea/vomiting, abdominal discomfort/pain, and
rare reports of pancreatitis.
Hepatic: There have been occasional reports of hepatocellular, cholestatic, or mixed hepatitis,
with or without jaundice. In such circumstances, ranitidine should be immediately discontinued.
These events are usually reversible, but in rare circumstances death has occurred. Rare cases of
hepatic failure have also been reported. In normal volunteers, SGPT values were increased to at
least twice the pretreatment levels in 6 of 12 subjects receiving 100 mg intravenously 4 times
daily for 7 days, and in 4 of 24 subjects receiving 50 mg intravenously 4 times daily for 5 days.
Musculoskeletal: Rare reports of arthralgias and myalgias.
Hematologic: Blood count changes (leukopenia, granulocytopenia, and thrombocytopenia)
have occurred in a few patients. These were usually reversible. Rare cases of agranulocytosis,
pancytopenia, sometimes with marrow hypoplasia, and aplastic anemia and exceedingly rare
cases of acquired immune hemolytic anemia have been reported.
Endocrine: Controlled studies in animals and man have shown no stimulation of any pituitary
hormone by ZANTAC and no antiandrogenic activity, and cimetidine-induced gynecomastia and
impotence in hypersecretory patients have resolved when ZANTAC has been substituted.
However, occasional cases of gynecomastia, impotence, and loss of libido have been reported in
male patients receiving ZANTAC, but the incidence did not differ from that in the general
population.
11
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Integumentary: Rash, including rare cases of erythema multiforme. Rare cases of alopecia and
vasculitis.
Respiratory: A large epidemiological study suggested an increased risk of developing
pneumonia in current users of histamine-2-receptor antagonists (H2RAs) compared to patients
who had stopped H2RA treatment, with an observed adjusted relative risk of 1.63 (95% CI, 1.07
2.48). However, a causal relationship between use of H2RAs and pneumonia has not been
established.
Other: Rare cases of hypersensitivity reactions (e.g., bronchospasm, fever, rash, eosinophilia),
anaphylaxis, angioneurotic edema, acute interstitial nephritis, and small increases in serum
creatinine.
OVERDOSAGE
There has been limited experience with overdosage. Reported acute ingestions of up to 18 g
orally have been associated with transient adverse effects similar to those encountered in normal
clinical experience (see ADVERSE REACTIONS). In addition, abnormalities of gait and
hypotension have been reported.
When overdosage occurs, the usual measures to remove unabsorbed material from the
gastrointestinal tract, clinical monitoring, and supportive therapy should be employed.
Studies in dogs receiving dosages of ZANTAC in excess of 225 mg/kg/day have shown
muscular tremors, vomiting, and rapid respiration. Single oral doses of 1,000 mg/kg in mice and
rats were not lethal. Intravenous LD50 values in mice and rats were 77 and 83 mg/kg,
respectively.
DOSAGE AND ADMINISTRATION
Active Duodenal Ulcer: The current recommended adult oral dosage of ZANTAC for
duodenal ulcer is 150 mg or 10 mL of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of
ranitidine) twice daily. An alternative dosage of 300 mg or 20 mL of syrup (4 teaspoonfuls of
syrup equivalent to 300 mg of ranitidine) once daily after the evening meal or at bedtime can be
used for patients in whom dosing convenience is important. The advantages of one treatment
regimen compared to the other in a particular patient population have yet to be demonstrated (see
Clinical Trials: Active Duodenal Ulcer). Smaller doses have been shown to be equally effective
in inhibiting gastric acid secretion in US studies, and several foreign trials have shown that
100 mg twice daily is as effective as the 150-mg dose.
Antacid should be given as needed for relief of pain (see CLINICAL PHARMACOLOGY:
Pharmacokinetics).
Maintenance of Healing of Duodenal Ulcers: The current recommended adult oral dosage
is 150 mg or 10 mL of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) at
bedtime.
Pathological Hypersecretory Conditions (such as Zollinger-Ellison syndrome):
The current recommended adult oral dosage is 150 mg or 10 mL of syrup (2 teaspoonfuls of
syrup equivalent to 150 mg of ranitidine) twice daily. In some patients it may be necessary to
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
administer ZANTAC 150-mg doses more frequently. Dosages should be adjusted to individual
patient needs, and should continue as long as clinically indicated. Dosages up to 6 g/day have
been employed in patients with severe disease.
Benign Gastric Ulcer: The current recommended adult oral dosage is 150 mg or 10 mL of
syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) twice daily.
Maintenance of Healing of Gastric Ulcers: The current recommended adult oral dosage is
150 mg or 10 mL of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) at
bedtime.
GERD: The current recommended adult oral dosage is 150 mg or 10 mL of syrup
(2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) twice daily.
Erosive Esophagitis: The current recommended adult oral dosage is 150 mg or 10 mL of
syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) 4 times daily.
Maintenance of Healing of Erosive Esophagitis: The current recommended adult oral
dosage is 150 mg or 10 mL of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine)
twice daily.
Pediatric Use: The safety and effectiveness of ZANTAC have been established in the
age-group of 1 month to 16 years. There is insufficient information about the pharmacokinetics
of ZANTAC in neonatal patients (less than 1 month of age) to make dosing recommendations.
The following 3 subsections provide dosing information for each of the pediatric indications.
Also, see the subsection on Preparation of ZANTAC 25 EFFERdose Tablets, below.
Treatment of Duodenal and Gastric Ulcers: The recommended oral dose for the
treatment of active duodenal and gastric ulcers is 2 to 4 mg/kg twice daily to a maximum of
300 mg/day. This recommendation is derived from adult clinical studies and pharmacokinetic
data in pediatric patients.
Maintenance of Healing of Duodenal and Gastric Ulcers: The recommended oral
dose for the maintenance of healing of duodenal and gastric ulcers is 2 to 4 mg/kg once daily to a
maximum of 150 mg/day. This recommendation is derived from adult clinical studies and
pharmacokinetic data in pediatric patients.
Treatment of GERD and Erosive Esophagitis: Although limited data exist for these
conditions in pediatric patients, published literature supports a dosage of 5 to 10 mg/kg/day,
usually given as 2 divided doses.
Dosage Adjustment for Patients With Impaired Renal Function: On the basis of
experience with a group of subjects with severely impaired renal function treated with ZANTAC,
the recommended dosage in patients with a creatinine clearance <50 mL/min is 150 mg or 10 mL
of syrup (2 teaspoonfuls of syrup equivalent to 150 mg of ranitidine) every 24 hours. Should the
patient's condition require, the frequency of dosing may be increased to every 12 hours or even
further with caution. Hemodialysis reduces the level of circulating ranitidine. Ideally, the dosing
schedule should be adjusted so that the timing of a scheduled dose coincides with the end of
hemodialysis.
13
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Elderly patients are more likely to have decreased renal function, therefore caution should be
exercised in dose selection, and it may be useful to monitor renal function (see CLINICAL
PHARMACOLOGY: Pharmacokinetics: Geriatrics and PRECAUTIONS: Geriatric Use).
Preparation of ZANTAC 25 EFFERdose Tablets: Tablets should not be chewed,
swallowed whole, or dissolved on the tongue. Dissolve 1 tablet in no less than 5 mL
(1 teaspoonful) of water in an appropriate measuring cup. Wait until the tablet is completely
dissolved before administering the solution to the infant/child. The solution may be administered
to infants by medicine dropper or oral syringe.
HOW SUPPLIED
ZANTAC 150 Tablets (ranitidine HCl equivalent to 150 mg of ranitidine) are peach,
film-coated, 5-sided tablets embossed with "ZANTAC 150" on one side and "Glaxo" on the
other. They are available in bottles of 60 (NDC 0173-0344-42), 180 (NDC 0173-0344-17), and
500 (NDC 0173-0344-14) tablets.
ZANTAC 300 Tablets (ranitidine HCl equivalent to 300 mg of ranitidine) are yellow,
film-coated, capsule-shaped tablets embossed with "ZANTAC 300" on one side and "Glaxo" on
the other. They are available in bottles of 30 (NDC 0173-0393-40) tablets.
Store between 15° and 30°C (59°and 86°F) in a dry place. Protect from light. Replace
cap securely after each opening.
ZANTAC 25 EFFERdose Tablets (ranitidine HCl equivalent to 25 mg of ranitidine) are white
to pale yellow, round, flat-faced, bevel-edged tablets embossed with “GS” on one side and
“25C” on the other side. They are packaged in foil strips and are available in a carton of 60
(NDC 0173-0734-00) tablets.
Store between 2° and 30°C (36° and 86°F).
ZANTAC Syrup, a clear, pale yellow, peppermint-flavored liquid, contains 16.8 mg of
ranitidine HCl equivalent to 15 mg of ranitidine per 1 mL (75 mg/5 mL) in bottles of 16 fluid
ounces (one pint) (NDC 0173-0383-54).
Store between 4° and 25°C (39° and 77°F). Dispense in tight, light-resistant containers as
defined in the USP/NF. Company Logo
GlaxoSmithKline
Research Triangle Park, NC 27709
ZANTAC and EFFERdose are registered trademarks of Warner-Lambert Company, used under
license.
MULTISTIX is a registered trademark of Bayer Healthcare LLC.
14
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For current labeling information, please visit https://www.fda.gov/drugsatfda
©2009, GlaxoSmithKline. All rights reserved.
(Date of issue)
ZNT:4PI
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|
custom-source
|
2025-02-12T13:44:52.418743
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018703s067,019675s034,020251s018lbl.pdf', 'application_number': 18703, 'submission_type': 'SUPPL ', 'submission_number': 67}
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Lopressor®
metoprolol tartrate tablets, USP
metoprolol tartrate injection, USP
Rx only
Prescribing Information
DESCRIPTION
Lopressor, metoprolol tartrate USP, is a selective beta1-adrenoreceptor blocking agent, available
as 50- and 100-mg tablets for oral administration and in 5-mL ampuls for intravenous
administration. Each ampul contains a sterile solution of metoprolol tartrate USP, 5 mg, and
sodium chloride USP, 45 mg, and water for injection USP. Metoprolol tartrate USP is (±)-1
(Isopropylamino)-3-[p-(2-methoxyethyl)phenoxy]-2-propanol L-(+)-tartrate (2:1) salt, and its
structural formula is Structural Formula
Metoprolol tartrate USP is a white, practically odorless, crystalline powder with a molecular
weight of 684.82. It is very soluble in water; freely soluble in methylene chloride, in chloroform,
and in alcohol; slightly soluble in acetone; and insoluble in ether.
Inactive Ingredients: Tablets contain cellulose compounds, colloidal silicon dioxide, D&C Red
No. 30 aluminum lake (50-mg tablets), FD&C Blue No. 2 aluminum lake (100-mg tablets),
lactose, magnesium stearate, polyethylene glycol, propylene glycol, povidone, sodium starch
glycolate, talc, and titanium dioxide.
CLINICAL PHARMACOLOGY
Lopressor is a beta-adrenergic receptor blocking agent. In vitro and in vivo animal studies have
shown that it has a preferential effect on beta1 adrenoreceptors, chiefly located in cardiac muscle.
This preferential effect is not absolute, however, and at higher doses, Lopressor also inhibits
beta2 adrenoreceptors, chiefly located in the bronchial and vascular musculature.
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Clinical pharmacology studies have confirmed the beta-blocking activity of metoprolol in man,
as shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction
of systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and
(4) reduction of reflex orthostatic tachycardia.
Relative beta1 selectivity has been confirmed by the following: (1) In normal subjects, Lopressor
is unable to reverse the beta2-mediated vasodilating effects of epinephrine. This contrasts with
the effect of nonselective (beta1 plus beta2) beta blockers, which completely reverse the
vasodilating effects of epinephrine. (2) In asthmatic patients, Lopressor reduces FEV1 and FVC
significantly less than a nonselective beta blocker, propranolol, at equivalent beta1-receptor
blocking doses.
Lopressor has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is
detectable only at doses much greater than required for beta blockade. Lopressor crosses the
blood-brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous
plasma concentration. Animal and human experiments indicate that Lopressor slows the sinus
rate and decreases AV nodal conduction.
In controlled clinical studies, Lopressor has been shown to be an effective antihypertensive agent
when used alone or as concomitant therapy with thiazide-type diuretics, at dosages of 100
450 mg daily. In controlled, comparative, clinical studies, Lopressor has been shown to be as
effective an antihypertensive agent as propranolol, methyldopa, and thiazide-type diuretics, and
to be equally effective in supine and standing positions.
The mechanism of the antihypertensive effects of beta-blocking agents has not been elucidated.
However, several possible mechanisms have been proposed: (1) competitive antagonism of
catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased
cardiac output; (2) a central effect leading to reduced sympathetic outflow to the periphery; and
(3) suppression of renin activity.
By blocking catecholamine-induced increases in heart rate, in velocity and extent of myocardial
contraction, and in blood pressure, Lopressor reduces the oxygen requirements of the heart at any
given level of effort, thus making it useful in the long-term management of angina pectoris.
However, in patients with heart failure, beta-adrenergic blockade may increase oxygen
requirements by increasing left ventricular fiber length and end-diastolic pressure.
Although beta-adrenergic receptor blockade is useful in the treatment of angina and
hypertension, there are situations in which sympathetic stimulation is vital. In patients with
severely damaged hearts, adequate ventricular function may depend on sympathetic drive. In the
presence of AV block, beta blockade may prevent the necessary facilitating effect of sympathetic
activity on conduction. Beta2-adrenergic blockade results in passive bronchial constriction by
interfering with endogenous adrenergic bronchodilator activity in patients subject to
bronchospasm and may also interfere with exogenous bronchodilators in such patients.
In controlled clinical trials, Lopressor, administered two or four times daily, has been shown to
be an effective antianginal agent, reducing the number of angina attacks and increasing exercise
tolerance. The dosage used in these studies ranged from 100-400 mg daily. A controlled,
comparative, clinical trial showed that Lopressor was indistinguishable from propranolol in the
treatment of angina pectoris.
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In a large (1,395 patients randomized), double-blind, placebo-controlled clinical study, Lopressor
was shown to reduce 3-month mortality by 36% in patients with suspected or definite myocardial
infarction.
Patients were randomized and treated as soon as possible after their arrival in the hospital, once
their clinical condition had stabilized and their hemodynamic status had been carefully
evaluated. Subjects were ineligible if they had hypotension, bradycardia, peripheral signs of
shock, and/or more than minimal basal rales as signs of congestive heart failure. Initial treatment
consisted of intravenous followed by oral administration of Lopressor or placebo, given in a
coronary care or comparable unit. Oral maintenance therapy with Lopressor or placebo was then
continued for 3 months. After this double-blind period, all patients were given Lopressor and
followed up to 1 year.
The median delay from the onset of symptoms to the initiation of therapy was 8 hours in both the
Lopressor- and placebo-treatment groups. Among patients treated with Lopressor, there were
comparable reductions in 3-month mortality for those treated early (≤8 hours) and those in whom
treatment was started later. Significant reductions in the incidence of ventricular fibrillation and
in chest pain following initial intravenous therapy were also observed with Lopressor and were
independent of the interval between onset of symptoms and initiation of therapy.
The precise mechanism of action of Lopressor in patients with suspected or definite myocardial
infarction is not known.
In this study, patients treated with metoprolol received the drug both very early (intra-venously)
and during a subsequent 3-month period, while placebo patients received no beta-blocker
treatment for this period. The study thus was able to show a benefit from the overall metoprolol
regimen but cannot separate the benefit of very early intravenous treatment from the benefit of
later beta-blocker therapy. Nonetheless, because the overall regimen showed a clear beneficial
effect on survival without evidence of an early adverse effect on survival, one acceptable dosage
regimen is the precise regimen used in the trial. Because the specific benefit of very early
treatment remains to be defined however, it is also reasonable to administer the drug orally to
patients at a later time as is recommended for certain other beta blockers.
Pharmacokinetics
In man, absorption of Lopressor is rapid and complete. Plasma levels following oral
administration, however, approximate 50% of levels following intravenous administration,
indicating about 50% first-pass metabolism.
Plasma levels achieved are highly variable after oral administration. Only a small fraction of the
drug (about 12%) is bound to human serum albumin. Metoprolol is a racemic mixture of R- and
S-enantiomers. Less than 5% of an oral dose of Lopressor is recovered unchanged in the urine;
the rest is excreted by the kidneys as metabolites that appear to have no clinical significance. The
systemic availability and half-life of Lopressor in patients with renal failure do not differ to a
clinically significant degree from those in normal subjects. Consequently, no reduction in dosage
is usually needed in patients with chronic renal failure.
Lopressor is extensively metabolized by the cytochrome P450 enzyme system in the liver. The
oxidative metabolism of Lopressor is under genetic control with a major contribution of the
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For current labeling information, please visit https://www.fda.gov/drugsatfda
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Page 7
polymorphic cytochrome P450 isoform 2D6 (CYP2D6). There are marked ethnic differences in
the prevalence of the poor metabolizers (PM) phenotype. Approximately 7% of Caucasians and
less than 1% Asian are poor metabolizers.
Poor CYP2D6 metabolizers exhibit several-fold higher plasma concentrations of Lopressor than
extensive metabolizers with normal CYP2D6 activity. The elimination half-life of metoprolol is
about 7.5 hours in poor metabolizers and 2.8 hours in extensive metabolizers. However, the
CYP2D6 dependent metabolism of Lopressor seems to have little or no effect on safety or
tolerability of the drug. None of the metabolites of Lopressor contribute significantly to its beta-
blocking effect.
Significant beta-blocking effect (as measured by reduction of exercise heart rate) occurs within 1
hour after oral administration, and its duration is dose-related. For example, a 50% reduction of
the maximum registered effect after single oral doses of 20, 50, and 100 mg occurred at 3.3, 5.0,
and 6.4 hours, respectively, in normal subjects. After repeated oral dosages of 100 mg twice
daily, a significant reduction in exercise systolic blood pressure was evident at 12 hours.
Following intravenous administration of Lopressor, the urinary recovery of unchanged drug is
approximately 10%. When the drug was infused over a 10-minute period, in normal volunteers,
maximum beta blockade was achieved at approximately 20 minutes. Doses of 5 mg and 15 mg
yielded a maximal reduction in exercise-induced heart rate of approximately 10% and 15%,
respectively. The effect on exercise heart rate decreased linearly with time at the same rate for
both doses, and disappeared at approximately 5 hours and 8 hours for the 5-mg and 15-mg doses,
respectively.
Equivalent maximal beta-blocking effect is achieved with oral and intravenous doses in the ratio
of approximately 2.5:1.
There is a linear relationship between the log of plasma levels and reduction of exercise heart
rate. However, antihypertensive activity does not appear to be related to plasma levels. Because
of variable plasma levels attained with a given dose and lack of a consistent relationship of
antihypertensive activity to dose, selection of proper dosage requires individual titration.
In several studies of patients with acute myocardial infarction, intravenous followed by oral
administration of Lopressor caused a reduction in heart rate, systolic blood pressure, and cardiac
output. Stroke volume, diastolic blood pressure, and pulmonary artery end diastolic pressure
remained unchanged.
In patients with angina pectoris, plasma concentration measured at 1 hour is linearly related to
the oral dose within the range of 50-400 mg. Exercise heart rate and systolic blood pressure are
reduced in relation to the logarithm of the oral dose of metoprolol. The increase in exercise
capacity and the reduction in left ventricular ischemia are also significantly related to the
logarithm of the oral dose.
In elderly subjects with clinically normal renal and hepatic function, there are no significant
differences in Lopressor pharmacokinetics compared to young subjects.
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For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 017963/S-063
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Page 8
INDICATIONS AND USAGE
Hypertension
Lopressor tablets are indicated for the treatment of hypertension. They may be used alone or in
combination with other antihypertensive agents.
Angina Pectoris
Lopressor is indicated in the long-term treatment of angina pectoris.
Myocardial Infarction
Lopressor ampuls and tablets are indicated in the treatment of hemodynamically stable patients
with definite or suspected acute myocardial infarction to reduce cardiovascular mortality.
Treatment with intravenous Lopressor can be initiated as soon as the patient’s clinical condition
allows (see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and
WARNINGS). Alternatively, treatment can begin within 3 to 10 days of the acute event (see
DOSAGE AND ADMINISTRATION).
CONTRAINDICATIONS
Hypertension and Angina
Lopressor is contraindicated in sinus bradycardia, heart block greater than first degree,
cardiogenic shock, and overt cardiac failure (see WARNINGS).
Hypersensitivity to Lopressor and related derivatives, or to any of the excipients;
hypersensitivity to other beta blockers (cross sensitivity between beta blockers can occur).
Sick-sinus syndrome.
Severe peripheral arterial circulatory disorders.
Myocardial Infarction
Lopressor is contraindicated in patients with a heart rate <45 beats/min; second- and third-degree
heart block; significant first-degree heart block (P-R interval ≥0.24 sec); systolic blood pressure
<100 mmHg; or moderate-to-severe cardiac failure (see WARNINGS).
WARNINGS
Hypertension and Angina
Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function
in congestive heart failure, and beta blockade carries the potential hazard of further depressing
myocardial contractility and precipitating more severe failure. In hypertensive and angina
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patients who have congestive heart failure controlled by digitalis and diuretics, Lopressor should
be administered cautiously.
In Patients Without a History of Cardiac Failure: Continued depression of the myocardium
with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the
first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or
given a diuretic. The response should be observed closely. If cardiac failure continues, despite
adequate digitalization and diuretic therapy, Lopressor should be withdrawn.
Ischemic Heart Disease: Following abrupt cessation of therapy with certain beta-blocking
agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred.
When discontinuing chronically administered Lopressor, particularly in patients with ischemic
heart disease, the dosage should be gradually reduced over a period of 1-2 weeks and the patient
should be carefully monitored. If angina markedly worsens or acute coronary insufficiency
develops, Lopressor administration should be reinstated promptly, at least temporarily, and other
measures appropriate for the management of unstable angina should be taken. Patients should be
warned against interruption or discontinuation of therapy without the physician’s advice.
Because coronary artery disease is common and may be unrecognized, it may be prudent not to
discontinue Lopressor therapy abruptly even in patients treated only for hypertension.
Bronchospastic Diseases: PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD,
IN GENERAL, NOT RECEIVE BETA BLOCKERS, including Lopressor. Because of its
relative beta1 selectivity, however, Lopressor may be used with caution in patients with
bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive
treatment. Since beta1 selectivity is not absolute, a beta2-stimulating agent should be
administered concomitantly, and the lowest possible dose of Lopressor should be used. In
these circumstances it would be prudent initially to administer Lopressor in smaller doses
three times daily, instead of larger doses two times daily, to avoid the higher plasma levels
associated with the longer dosing interval (see DOSAGE AND ADMINISTRATION).
Major Surgery: The necessity or desirability of withdrawing beta-blocking therapy, including
Lopressor, prior to major surgery is controversial; the impaired ability of the heart to respond to
reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
Lopressor, like other beta blockers, is a competitive inhibitor of beta-receptor agonists, and its
effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol.
However, such patients may be subject to protracted severe hypotension. Difficulty in restarting
and maintaining the heart beat has also been reported with beta blockers.
Diabetes and Hypoglycemia: Lopressor should be used with caution in diabetic patients if a
beta-blocking agent is required. Beta blockers may mask tachycardia occurring with
hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly
affected.
Pheochromocytoma: If Lopressor is used in the setting of pheochromocytoma, it should be
given in combination with an alpha blocker, and only after the alpha blocker has been initiated.
Administration of beta blockers alone in the setting of pheochromocytoma has been associated
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with a paradoxical increase in blood pressure due to the attenuation of beta-mediated
vasodilatation in skeletal muscle.
Thyrotoxicosis: Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of
hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to
avoid abrupt withdrawal of beta blockade, which might precipitate a thyroid storm.
Myocardial Infarction
Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function,
and beta blockade carries the potential hazard of depressing myocardial contractility and
precipitating or exacerbating minimal cardiac failure.
During treatment with Lopressor, the hemodynamic status of the patient should be carefully
monitored. If heart failure occurs or persists despite appropriate treatment, Lopressor should be
discontinued.
Bradycardia: Lopressor produces a decrease in sinus heart rate in most patients; this decrease is
greatest among patients with high initial heart rates and least among patients with low initial
heart rates. Acute myocardial infarction (particularly inferior infarction) may in itself produce
significant lowering of the sinus rate. If the sinus rate decreases to <40 beats/min, particularly if
associated with evidence of lowered cardiac output, atropine (0.25-0.5 mg) should be
administered intravenously. If treatment with atropine is not successful, Lopressor should be
discontinued, and cautious administration of isoproterenol or installation of a cardiac pacemaker
should be considered.
AV Block: Lopressor slows AV conduction and may produce significant first- (P-R interval
≥0.26 sec), second-, or third-degree heart block. Acute myocardial infarction also produces heart
block.
If heart block occurs, Lopressor should be discontinued and atropine (0.25-0.5 mg) should be
administered intravenously. If treatment with atropine is not successful, cautious administration
of isoproterenol or installation of a cardiac pacemaker should be considered.
Hypotension: If hypotension (systolic blood pressure ≤90 mmHg) occurs, Lopressor should be
discontinued, and the hemodynamic status of the patient and the extent of myocardial damage
carefully assessed. Invasive monitoring of central venous, pulmonary capillary wedge, and
arterial pressures may be required. Appropriate therapy with fluids, positive inotropic agents,
balloon counterpulsation, or other treatment modalities should be instituted. If hypotension is
associated with sinus bradycardia or AV block, treatment should be directed at reversing these
(see above).
Bronchospastic Diseases: PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD,
IN GENERAL, NOT RECEIVE BETA BLOCKERS, including Lopressor. Because of its
relative beta1 selectivity, Lopressor may be used with extreme caution in patients with
bronchospastic disease. Because it is unknown to what extent beta2-stimulating agents may
exacerbate myocardial ischemia and the extent of infarction, these agents should not be
used prophylactically. If bronchospasm not related to congestive heart failure occurs,
Lopressor should be discontinued. A theophylline derivative or a beta2 agonist may be
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administered cautiously, depending on the clinical condition of the patient. Both
theophylline derivatives and beta2 agonists may produce serious cardiac arrhythmias.
PRECAUTIONS
General
Lopressor should be used with caution in patients with impaired hepatic function.
Information for Patients
Patients should be advised to take Lopressor regularly and continuously, as directed, with or
immediately following meals. If a dose should be missed, the patient should take only the next
scheduled dose (without doubling it). Patients should not discontinue Lopressor without
consulting the physician.
Patients should be advised (1) to avoid operating automobiles and machinery or engaging in
other tasks requiring alertness until the patient’s response to therapy with Lopressor has been
determined; (2) to contact the physician if any difficulty in breathing occurs; (3) to inform the
physician or dentist before any type of surgery that he or she is taking Lopressor.
Drug Interactions
Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with
beta-blocking agents. Patients treated with Lopressor plus a catecholamine depletor should
therefore be closely observed for evidence of hypotension or marked bradycardia, which may
produce vertigo, syncope, or postural hypotension.
Both digitalis glycosides and beta blockers slow atrioventricular conduction and decrease heart
rate. Concomitant use can increase the risk of bradycardia.
Risk of Anaphylactic Reaction: While taking beta blockers, patients with a history of severe
anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either
accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of
epinephrine used to treat allergic reaction.
General Anesthetics
Some inhalation anesthetics may enhance the cardiodepressant effect of beta blockers (see
WARNINGS, Major Surgery).
CYP2D6 Inhibitors
Potent inhibitors of the CYP2D6 enzyme may increase the plasma concentration of Lopressor.
Strong inhibition of CYP2D6 would mimic the pharmacokinetics of CYP2D6 poor metabolizer
(see Pharmacokinetics section). Caution should therefore be exercised when coadministering
potent CYP2D6 inhibitors with Lopressor. Known clinically significant potent inhibitors of
CYP2D6 are antidepressants such as fluoxetine, paroxetine or bupropion, antipsychotics such as
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NDA 017963/S-063
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thioridazine, antiarrhythmics such as quinidine or propafenone, antiretrovirals such as ritonavir,
antihistamines such as diphenhydramine, antimalarials such as hydroxychloroquine or quinidine,
antifungals such as terbinafine and medications for stomach ulcers such as cimetidine.
Clonidine
If a patient is treated with clonidine and Lopressor concurrently, and clonidine treatment is to be
discontinued, Lopressor should be stopped several days before clonidine is withdrawn. Rebound
hypertension that can follow withdrawal of clonidine may be increased in patients receiving
concurrent beta-blocker treatment.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have been conducted to evaluate carcinogenic potential. In a 2-year
study in rats at three oral dosage levels of up to 800 mg/kg per day, there was no increase in the
development of spontaneously occurring benign or malignant neoplasms of any type. The only
histologic changes that appeared to be drug related were an increased incidence of generally mild
focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary
hyperplasia. In a 21-month study in Swiss albino mice at three oral dosage levels of up to
750 mg/kg per day, benign lung tumors (small adenomas) occurred more frequently in female
mice receiving the highest dose than in untreated control animals. There was no increase in
malignant or total (benign plus malignant) lung tumors, or in the overall incidence of tumors or
malignant tumors. This 21-month study was repeated in CD-1 mice, and no statistically or
biologically significant differences were observed between treated and control mice of either sex
for any type of tumor.
All mutagenicity tests performed (a dominant lethal study in mice, chromosome studies in
somatic cells, a Salmonella/mammalian-microsome mutagenicity test, and a nucleus anomaly
test in somatic interphase nuclei) were negative.
No evidence of impaired fertility due to Lopressor was observed in a study performed in rats at
doses up to 55.5 times the maximum daily human dose of 450 mg.
Pregnancy Category C
Lopressor has been shown to increase postimplantation loss and decrease neonatal survival in
rats at doses up to 55.5 times the maximum daily human dose of 450 mg. Distribution studies in
mice confirm exposure of the fetus when Lopressor is administered to the pregnant animal.
These studies have revealed no evidence of impaired fertility or teratogenicity. There are no
adequate and well-controlled studies in pregnant women. Because animal reproduction studies
are not always predictive of human response, this drug should be used during pregnancy only if
clearly needed.
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NDA 017963/S-063
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Nursing Mothers
Lopressor is excreted in breast milk in a very small quantity. An infant consuming 1 liter of
breast milk daily would receive a dose of less than 1 mg of the drug. Caution should be exercised
when Lopressor is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical trials of Lopressor in hypertension did not include sufficient numbers of elderly patients
to determine whether patients over 65 years of age differ from younger subjects in their response
to Lopressor. Other reported clinical experience in elderly hypertensive patients has not
identified any difference in response from younger patients.
In worldwide clinical trials of Lopressor in myocardial infarction, where approximately 478
patients were over 65 years of age (0 over 75 years of age), no age-related differences in safety
and effectiveness were found. Other reported clinical experience in myocardial infarction has not
identified differences in response between the elderly and younger patients. However, greater
sensitivity of some elderly individuals taking Lopressor cannot be categorically ruled out.
Therefore, in general, it is recommended that dosing proceed with caution in this population.
ADVERSE REACTIONS
Hypertension and Angina
Most adverse effects have been mild and transient.
Central Nervous System: Tiredness and dizziness have occurred in about 10 of 100 patients.
Depression has been reported in about 5 of 100 patients. Mental confusion and short-term
memory loss have been reported. Headache, nightmares, and insomnia have also been reported.
Cardiovascular: Shortness of breath and bradycardia have occurred in approximately 3 of 100
patients. Cold extremities; arterial insufficiency, usually of the Raynaud type; palpitations;
congestive heart failure; peripheral edema; and hypotension have been reported in about 1 of 100
patients. Gangrene in patients with pre-existing severe peripheral circulatory disorders has also
been reported very rarely. (See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS.)
Respiratory: Wheezing (bronchospasm) and dyspnea have been reported in about 1 of 100
patients (see WARNINGS). Rhinitis has also been reported.
Gastrointestinal: Diarrhea has occurred in about 5 of 100 patients. Nausea, dry mouth, gastric
pain, constipation, flatulence, and heartburn have been reported in about 1 of 100 patients.
Vomiting was a common occurrence. Postmarketing experience reveals very rare reports of
hepatitis, jaundice and non-specific hepatic dysfunction. Isolated cases of transaminase, alkaline
phosphatase, and lactic dehydrogenase elevations have also been reported.
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Hypersensitive Reactions: Pruritus or rash have occurred in about 5 of 100 patients. Very rarely,
photosensitivity and worsening of psoriasis has been reported.
Miscellaneous: Peyronie’s disease has been reported in fewer than 1 of 100,000 patients.
Musculoskeletal pain, blurred vision, and tinnitus have also been reported.
There have been rare reports of reversible alopecia, agranulocytosis, and dry eyes.
Discontinuation of the drug should be considered if any such reaction is not otherwise
explicable. There have been very rare reports of weight gain, arthritis, and retroperitoneal
fibrosis (relationship to Lopressor has not been definitely established).
The oculomucocutaneous syndrome associated with the beta blocker practolol has not been
reported with Lopressor.
Myocardial Infarction
Central Nervous System: Tiredness has been reported in about 1 of 100 patients. Vertigo, sleep
disturbances, hallucinations, headache, dizziness, visual disturbances, confusion, and reduced
libido have also been reported, but a drug relationship is not clear.
Cardiovascular: In the randomized comparison of Lopressor and placebo described in the
CLINICAL PHARMACOLOGY section, the following adverse reactions were reported:
Lopressor®
Placebo
Hypotension (systolic BP <90 mmHg)
27.4%
23.2%
Bradycardia (heart rate <40 beats/min)
15.9%
6.7%
Second- or third-degree heart block
4.7%
4.7%
First-degree heart block (P-R ≥0.26 sec)
5.3%
1.9%
Heart failure
27.5%
29.6%
Respiratory: Dyspnea of pulmonary origin has been reported in fewer than 1 of 100 patients.
Gastrointestinal: Nausea and abdominal pain have been reported in fewer than 1 of 100 patients.
Dermatologic: Rash and worsened psoriasis have been reported, but a drug relationship is not
clear.
Miscellaneous: Unstable diabetes and claudication have been reported, but a drug relationship is
not clear.
Potential Adverse Reactions
A variety of adverse reactions not listed above have been reported with other beta-adrenergic
blocking agents and should be considered potential adverse reactions to Lopressor.
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Central Nervous System: Reversible mental depression progressing to catatonia; an acute
reversible syndrome characterized by disorientation for time and place, short-term memory loss,
emotional lability, slightly clouded sensorium, and decreased performance on
neuropsychometrics.
Cardiovascular: Intensification of AV block (see CONTRAINDICATIONS).
Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.
Hypersensitive Reactions: Fever combined with aching and sore throat, laryngospasm, and
respiratory distress.
Postmarketing Experience
The following adverse reactions have been reported during postapproval use of Lopressor:
confusional state, an increase in blood triglycerides and a decrease in High Density Lipoprotein
(HDL). Because these reports are from a population of uncertain size and are subject to
confounding factors, it is not possible to reliably estimate their frequency.
OVERDOSAGE
Acute Toxicity
Several cases of overdosage have been reported, some leading to death.
Oral LD 50’s (mg/kg): mice, 1158-2460; rats, 3090-4670.
Signs and Symptoms
Potential signs and symptoms associated with overdosage with Lopressor are bradycardia,
hypotension, bronchospasm, and cardiac failure.
Treatment
There is no specific antidote.
In general, patients with acute or recent myocardial infarction may be more hemodynamically
unstable than other patients and should be treated accordingly (see WARNINGS, Myocardial
Infarction).
On the basis of the pharmacologic actions of Lopressor, the following general measures should
be employed:
Elimination of the Drug: Gastric lavage should be performed.
Bradycardia: Atropine should be administered. If there is no response to vagal blockade,
isoproterenol should be administered cautiously.
Hypotension: A vasopressor should be administered, e.g., levarterenol or dopamine.
Bronchospasm: A beta2-stimulating agent and/or a theophylline derivative should be
administered.
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Cardiac Failure: A digitalis glycoside and diuretic should be administered. In shock resulting
from inadequate cardiac contractility, administration of dobutamine, isoproterenol, or glucagon
may be considered.
DOSAGE AND ADMINISTRATION
Hypertension
The dosage of Lopressor tablets should be individualized. Lopressor tablets should be taken with
or immediately following meals.
The usual initial dosage of Lopressor tablets is 100 mg daily in single or divided doses, whether
used alone or added to a diuretic. The dosage may be increased at weekly (or longer) intervals
until optimum blood pressure reduction is achieved. In general, the maximum effect of any given
dosage level will be apparent after 1 week of therapy. The effective dosage range of Lopressor
tablets is 100-450 mg per day. Dosages above 450 mg per day have not been studied. While
once-daily dosing is effective and can maintain a reduction in blood pressure throughout the day,
lower doses (especially 100 mg) may not maintain a full effect at the end of the 24-hour period,
and larger or more frequent daily doses may be required. This can be evaluated by measuring
blood pressure near the end of the dosing interval to determine whether satisfactory control is
being maintained throughout the day. Beta1 selectivity diminishes as the dose of Lopressor is
increased.
Angina Pectoris
The dosage of Lopressor tablets should be individualized. Lopressor tablets should be taken with
or immediately following meals.
The usual initial dosage of Lopressor tablets is 100 mg daily, given in two divided doses. The
dosage may be gradually increased at weekly intervals until optimum clinical response has been
obtained or there is pronounced slowing of the heart rate. The effective dosage range of
Lopressor tablets is 100-400 mg per day. Dosages above 400 mg per day have not been studied.
If treatment is to be discontinued, the dosage should be reduced gradually over a period of 1-2
weeks (see WARNINGS).
Myocardial Infarction
Early Treatment: During the early phase of definite or suspected acute myocardial infarction,
treatment with Lopressor can be initiated as soon as possible after the patient’s arrival in the
hospital. Such treatment should be initiated in a coronary care or similar unit immediately after
the patient’s hemodynamic condition has stabilized.
Treatment in this early phase should begin with the intravenous administration of three bolus
injections of 5 mg of Lopressor each; the injections should be given at approximately 2-minute
intervals. During the intravenous administration of Lopressor, blood pressure, heart rate, and
electrocardiogram should be carefully monitored.
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In patients who tolerate the full intravenous dose (15 mg), Lopressor tablets, 50 mg every
6 hours, should be initiated 15 minutes after the last intravenous dose and continued for 48 hours.
Thereafter, patients should receive a maintenance dosage of 100 mg twice daily (see Late
Treatment below).
Patients who appear not to tolerate the full intravenous dose should be started on Lopressor
tablets either 25 mg or 50 mg every 6 hours (depending on the degree of intolerance) 15 minutes
after the last intravenous dose or as soon as their clinical condition allows. In patients with
severe intolerance, treatment with Lopressor should be discontinued (see WARNINGS).
Late Treatment: Patients with contraindications to treatment during the early phase of suspected
or definite myocardial infarction, patients who appear not to tolerate the full early treatment, and
patients in whom the physician wishes to delay therapy for any other reason should be started on
Lopressor tablets, 100 mg twice daily, as soon as their clinical condition allows. Therapy should
be continued for at least 3 months. Although the efficacy of Lopressor beyond 3 months has not
been conclusively established, data from studies with other beta blockers suggest that treatment
should be continued for 1-3 years.
Note: Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
HOW SUPPLIED
Lopressor® Tablets
metoprolol tartrate tablets, USP
Tablets 50 mg – capsule-shaped, biconvex, pink, scored (imprinted GEIGY on one side and 51
twice on the scored side)
Bottles of 100.................................................................................................NDC 0078-0458-05
Tablets 100 mg – capsule-shaped, biconvex, light blue, scored (imprinted GEIGY on one side
and 71 twice on the scored side)
Bottles of 100.................................................................................................NDC 0078-0459-05
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
Temperature]. Protect from moisture.
Dispense in tight, light-resistant container (USP).
Lopressor® Injection
metoprolol tartrate injection, USP
Ampuls 5 mL – each containing 5 mg of metoprolol tartrate
Carton of 10 ampuls.......................................................................................NDC 0078-0400-01
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
Temperature]. Protect from light.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 017963/S-063
NDA 018704/S-023
Page 18
To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals
Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
Tablets manufactured by:
Novartis Pharmaceuticals Corporation
Suffern, New York 10901
Ampuls manufactured by:
Novartis Pharma Stein AG
Stein, Switzerland
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
REV: MARCH 2009
T2009-41
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
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2025-02-12T13:44:52.546346
|
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