id
int64 737
80.8k
| text
stringlengths 1
1.03M
⌀ | source
stringclasses 1
value | added
stringlengths 26
26
| metadata
stringlengths 156
263
|
|---|---|---|---|---|
11,509
|
NDA 19-462/S-030
NDA 19-527/S-024
NDA 20-752/S-005
Page 3
PEPCID®
(FAMOTIDINE) TABLETS
PEPCID®
(FAMOTIDINE) FOR ORAL SUSPENSION
PEPCID RPD®
(FAMOTIDINE) ORALLY DISINTEGRATING TABLETS
DESCRIPTION
The active ingredient in PEPCID* (famotidine) is a histamine H2-receptor antagonist. Famotidine is N′-
(aminosulfonyl)-3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propanimidamide. The empirical formula
of famotidine is C8H15N7O2S3 and its molecular weight is 337.43. Its structural formula is:
Famotidine is a white to pale yellow crystalline compound that is freely soluble in glacial acetic acid, slightly
soluble in methanol, very slightly soluble in water, and practically insoluble in ethanol.
Each tablet for oral administration contains either 20 mg or 40 mg of famotidine and the following inactive
ingredients: hydroxypropyl cellulose, hydroxypropyl methylcellulose, iron oxides, magnesium stearate,
microcrystalline cellulose, corn starch, talc, and titanium dioxide.
Each Orally Disintegrating Tablet for oral administration contains either 20 mg or 40 mg of famotidine and the
following inactive ingredients: aspartame, mint flavor, gelatin, mannitol, red ferric oxide, and xanthan gum.
Each 5 mL of the oral suspension when prepared as directed contains 40 mg of famotidine and the following
inactive ingredients: citric acid, flavors, microcrystalline cellulose and carboxymethylcellulose sodium, sucrose and
xanthan gum. Added as preservatives are sodium benzoate 0.1%, sodium methylparaben 0.1%, and sodium
propylparaben 0.02%.
CLINICAL PHARMACOLOGY IN ADULTS
GI Effects
PEPCID is a competitive inhibitor of histamine H2-receptors. The primary clinically important pharmacologic
activity of PEPCID is inhibition of gastric secretion. Both the acid concentration and volume of gastric secretion are
suppressed by PEPCID, while changes in pepsin secretion are proportional to volume output.
In normal volunteers and hypersecretors, PEPCID inhibited basal and nocturnal gastric secretion, as well as
secretion stimulated by food and pentagastrin. After oral administration, the onset of the antisecretory effect occurred
within one hour; the maximum effect was dose-dependent, occurring within one to three hours. Duration of inhibition
of secretion by doses of 20 and 40 mg was 10 to 12 hours.
Single evening oral doses of 20 and 40 mg inhibited basal and nocturnal acid secretion in all subjects; mean
nocturnal gastric acid secretion was inhibited by 86% and 94%, respectively, for a period of at least 10 hours. The
same doses given in the morning suppressed food-stimulated acid secretion in all subjects. The mean suppression
was 76% and 84%, respectively, 3 to 5 hours after administration, and 25% and 30%, respectively, 8 to 10 hours
after administration. In some subjects who received the 20 mg dose, however, the antisecretory effect was dissipated
within 6-8 hours. There was no cumulative effect with repeated doses. The nocturnal intragastric pH was raised by
evening doses of 20 and 40 mg of PEPCID to mean values of 5.0 and 6.4, respectively. When PEPCID was given
after breakfast, the basal daytime interdigestive pH at 3 and 8 hours after 20 or 40 mg of PEPCID was raised to
about 5.
PEPCID had little or no effect on fasting or postprandial serum gastrin levels. Gastric emptying and exocrine
pancreatic function were not affected by PEPCID.
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT © MERCK & CO., Inc., 1986, 1988, 1991, 1995, 1996
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 19-462/S-030
NDA 19-527/S-024
NDA 20-752/S-005
Page 4
Other Effects
Systemic effects of PEPCID in the CNS, cardiovascular, respiratory or endocrine systems were not noted in
clinical pharmacology studies. Also, no antiandrogenic effects were noted. (See ADVERSE REACTIONS.) Serum
hormone levels, including prolactin, cortisol, thyroxine (T4), and testosterone, were not altered after treatment with
PEPCID.
Pharmacokinetics
PEPCID is incompletely absorbed. The bioavailability of oral doses is 40-45%. PEPCID Tablets, PEPCID for Oral
Suspension and PEPCID RPD Orally Disintegrating Tablets are bioequivalent. Bioavailability may be slightly
increased by food, or slightly decreased by antacids; however, these effects are of no clinical consequence. PEPCID
undergoes minimal first-pass metabolism. After oral doses, peak plasma levels occur in 1-3 hours. Plasma levels
after multiple doses are similar to those after single doses. Fifteen to 20% of PEPCID in plasma is protein bound.
PEPCID has an elimination half-life of 2.5-3.5 hours. PEPCID is eliminated by renal (65-70%) and metabolic
(30-35%) routes. Renal clearance is 250-450 mL/min, indicating some tubular excretion. Twenty-five to 30% of an
oral dose and 65-70% of an intravenous dose are recovered in the urine as unchanged compound. The only
metabolite identified in man is the S-oxide.
There is a close relationship between creatinine clearance values and the elimination half-life of PEPCID. In
patients with severe renal insufficiency, i.e., creatinine clearance less than 10 mL/min, the elimination half-life of
PEPCID may exceed 20 hours and adjustment of dose or dosing intervals in moderate and severe renal insufficiency
may be necessary (see PRECAUTIONS, DOSAGE AND ADMINISTRATION).
In elderly patients, there are no clinically significant age-related changes in the pharmacokinetics of PEPCID.
However, in elderly patients with decreased renal function, the clearance of the drug may be decreased (see
PRECAUTIONS, Geriatric Use).
Clinical Studies
Duodenal Ulcer
In a U.S. multicenter, double-blind study in outpatients with endoscopically confirmed duodenal ulcer, orally
administered PEPCID was compared to placebo. As shown in Table 1, 70% of patients treated with PEPCID 40 mg
h.s. were healed by week 4.
Table 1
Outpatients with Endoscopically
Confirmed Healed Duodenal Ulcers
PEPCID
40 mg h.s.
(N = 89)
PEPCID
20 mg b.i.d.
(N = 84)
Placebo
h.s.
(N = 97)
Week 2
Week 4
**32%
**70%
**38%
**67%
17%
31%
**Statistically significantly different than placebo (p<0.001)
Patients not healed by week 4 were continued in the study. By week 8, 83% of patients treated with PEPCID had
healed versus 45% of patients treated with placebo. The incidence of ulcer healing with PEPCID was significantly
higher than with placebo at each time point based on proportion of endoscopically confirmed healed ulcers.
In this study, time to relief of daytime and nocturnal pain was significantly shorter for patients receiving PEPCID
than for patients receiving placebo; patients receiving PEPCID also took less antacid than the patients receiving
placebo.
Long-Term Maintenance
Treatment of Duodenal Ulcers
PEPCID, 20 mg p.o. h.s. was compared to placebo h.s. as maintenance therapy in two double-blind, multicenter
studies of patients with endoscopically confirmed healed duodenal ulcers. In the U.S. study the observed ulcer
incidence within 12 months in patients treated with placebo was 2.4 times greater than in the patients treated with
PEPCID. The 89 patients treated with PEPCID had a cumulative observed ulcer incidence of 23.4% compared to an
observed ulcer incidence of 56.6% in the 89 patients receiving placebo (p<0.01). These results were confirmed in an
international study where the cumulative observed ulcer incidence within 12 months in the 307 patients treated with
PEPCID was 35.7%, compared to an incidence of 75.5% in the 325 patients treated with placebo (p<0.01).
Gastric Ulcer
In both a U.S. and an international multicenter, double-blind study in patients with endoscopically confirmed active
benign gastric ulcer, orally administered PEPCID, 40 mg h.s., was compared to placebo h.s. Antacids were permitted
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-030
NDA 19-527/S-024
NDA 20-752/S-005
Page 5
during the studies, but consumption was not significantly different between the PEPCID and placebo groups. As
shown in Table 2, the incidence of ulcer healing (dropouts counted as unhealed) with PEPCID was statistically
significantly better than placebo at weeks 6 and 8 in the U.S. study, and at weeks 4, 6 and 8 in the international study,
based on the number of ulcers that healed, confirmed by endoscopy.
Table 2
Patients with Endoscopically
Confirmed Healed Gastric Ulcers
U.S. Study
International Study
PEPCID
40 mg h.s.
(N=74)
Placebo
h.s.
(N=75)
PEPCID
40 mg h.s.
(N=149)
Placebo
h.s.
(N=145)
Week 4
Week 6
Week 8
45%
†66%
***78%
39%
44%
64%
†47%
†65%
†80%
31%
46%
54%
***,† Statistically significantly better than placebo (p≤0.05, p≤0.01 respectively)
Time to complete relief of daytime and nighttime pain was statistically significantly shorter for patients receiving
PEPCID than for patients receiving placebo; however, in neither study was there a statistically significant difference in
the proportion of patients whose pain was relieved by the end of the study (week 8).
Gastroesophageal Reflux Disease (GERD)
Orally administered PEPCID was compared to placebo in a U.S. study that enrolled patients with symptoms of
GERD and without endoscopic evidence of erosion or ulceration of the esophagus. PEPCID 20 mg b.i.d. was
statistically significantly superior to 40 mg h.s. and to placebo in providing a successful symptomatic outcome,
defined as moderate or excellent improvement of symptoms (Table 3).
Table 3
% Successful Symptomatic Outcome
PEPCID
20 mg b.i.d.
(N=154)
PEPCID
40 mg h.s.
(N=149)
Placebo
(N=73)
Week 6
82††
69
62
†† p≤0.01 vs Placebo
By two weeks of treatment symptomatic success was observed in a greater percentage of patients taking
PEPCID 20 mg b.i.d. compared to placebo (p≤0.01).
Symptomatic improvement and healing of endoscopically verified erosion and ulceration were studied in two
additional trials. Healing was defined as complete resolution of all erosions or ulcerations visible with endoscopy. The
U.S. study comparing PEPCID 40 mg p.o. b.i.d. to placebo and PEPCID 20 mg p.o. b.i.d. showed a significantly
greater percentage of healing for PEPCID 40 mg b.i.d. at weeks 6 and 12 (Table 4).
Table 4
% Endoscopic Healing - U.S. Study
PEPCID
40 mg b.i.d.
(N=127)
PEPCID
20 mg b.i.d.
(N=125)
Placebo
(N=66)
Week 6
Week 12
48†††,‡‡
69†††,‡
32
54†††
18
29
††† p≤0.01 vs Placebo
‡ p≤0.05 vs PEPCID 20 mg b.i.d.
‡‡ p≤0.01 vs PEPCID 20 mg b.i.d.
As compared to placebo, patients who received PEPCID had faster relief of daytime and nighttime heartburn and
a greater percentage of patients experienced complete relief of nighttime heartburn. These differences were
statistically significant.
In the international study, when PEPCID 40 mg p.o. b.i.d., was compared to ranitidine 150 mg p.o. b.i.d., a
statistically significantly greater percentage of healing was observed with PEPCID 40 mg b.i.d. at week 12 (Table 5).
There was, however, no significant difference among treatments in symptom relief.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-030
NDA 19-527/S-024
NDA 20-752/S-005
Page 6
Table 5
% Endoscopic Healing - International Study
PEPCID
40 mg b.i.d.
(N=175)
PEPCID
20 mg b.i.d.
(N=93)
Ranitidine
150 mg b.i.d.
(N=172)
Week 6
Week 12
48
71‡‡‡
52
68
42
60
‡‡‡ p≤0.05 vs Ranitidine 150 mg b.i.d.
Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas)
In studies of patients with pathological hypersecretory conditions such as Zollinger-Ellison Syndrome with or
without multiple endocrine adenomas, PEPCID significantly inhibited gastric acid secretion and controlled associated
symptoms. Orally administered doses from 20 to 160 mg q 6 h maintained basal acid secretion below 10 mEq/hr;
initial doses were titrated to the individual patient need and subsequent adjustments were necessary with time in
some patients. PEPCID was well tolerated at these high dose levels for prolonged periods (greater than 12 months)
in eight patients, and there were no cases reported of gynecomastia, increased prolactin levels, or impotence which
were considered to be due to the drug.
CLINICAL PHARMACOLOGY IN PEDIATRIC PATIENTS
Pharmacokinetics
Table 6 presents pharmacokinetic data from clinical trials and a published study in pediatric patients (<1 year of
age; N=27) given famotidine I.V. 0.5 mg/kg and from published studies of small numbers of pediatric patients (1-15
years of age) given famotidine intravenously. Areas under the curve (AUCs) are normalized to a dose of 0.5 mg/kg
I.V. for pediatric patients 1-15 years of age and compared with an extrapolated 40 mg intravenous dose in adults
(extrapolation based on results obtained with a 20 mg I.V. adult dose).
Table 6
Pharmacokinetic Parametersa of Intravenous Famotidine
Age
(N=number of
patients)
Area Under
the Curve (AUC)
(ng-hr/mL)
Total
Clearance (Cl)
(L/hr/kg)
Volume of
Distribution (Vd)
(L/kg)
Elimination
Half-life (T1/2)
(hours)
0-1 monthc
(N=10)
NA
0.13 ± 0.06
1.4 ± 0.4
10.5 ± 5.4
0-3 monthsd
(N=6)
2688 ± 847
0.21 ± 0.06
1.8 ± 0.3
8.1 ± 3.5
>3–12 monthsd
(N=11)
1160 ± 474
0.49 ± 0.17
2.3 ± 0.7
4.5 ± 1.1
1-11 yrs (N=20)
1089 ± 834
0.54 ± 0.34
2.07 ± 1.49
3.38 ± 2.60
11-15 yrs (N=6)
1140 ± 320
0.48 ± 0.14
1.5 ± 0.4
2.3 ± 0.4
Adult (N=16)
1726b
0.39 ± 0.14
1.3 ± 0.2
2.83 ± 0.99
aValues are presented as means ± SD unless indicated otherwise.
bMean value only.
cSingle center study.
dMulticenter study.
Plasma clearance is reduced and elimination half-life is prolonged in pediatric patients 0-3 months of age
compared to older pediatric patients. The pharmacokinetic parameters for pediatric patients, ages >3 months-15
years, are comparable to those obtained for adults.
Bioavailability studies of 8 pediatric patients (11-15 years of age) showed a mean oral bioavailability of 0.5
compared to adult values of 0.42 to 0.49. Oral doses of 0.5 mg/kg achieved AUCs of 645 ± 249 ng-hr/mL and
580 ± 60 ng-hr/mL in pediatric patients <1 year of age (N=5) and in pediatric patients 11-15 years of age,
respectively, compared to 482 ± 181 ng-hr/mL in adults treated with 40 mg orally.
Pharmacodynamics
Pharmacodynamics of famotidine were evaluated in 5 pediatric patients 2-13 years of age using the sigmoid Emax
model. These data suggest that the relationship between serum concentration of famotidine and gastric acid
suppression is similar to that observed in one study of adults (Table 7).
Table 7
Pharmacodynamics of famotidine using the sigmoid Emax model
EC50 (ng/mL)*
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-030
NDA 19-527/S-024
NDA 20-752/S-005
Page 7
Pediatric Patients
26 ± 13
Data from one study
a) healthy adult subjects
26.5 ± 10.3
b) adult patients with upper GI bleeding
18.7 ± 10.8
*Serum concentration of famotidine associated with 50% maximum gastric acid reduction. Values are presented as means ± SD.
Five published studies (Table 8) examined the effect of famotidine on gastric pH and duration of acid suppression
in pediatric patients. While each study had a different design, acid suppression data over time are summarized as
follows:
Table 8
Dosage
Route
Effect
a
Number of Patients
(age range)
0.5 mg/kg, single dose
I.V.
gastric pH >4 for 19.5 hours (17.3,
21.8)c
11 (5-19 days)
0.3 mg/kg, single dose
I.V.
gastric pH >3.5 for 8.7 ± 4.7
b hours
6 (2-7 years)
0.4-0.8 mg/kg
I.V.
gastric pH >4 for 6-9 hours
18 (2-69 months)
0.5 mg/kg, single dose
I.V.
a >2 pH unit increase above baseline
in gastric pH for >8 hours
9 (2-13 years)
0.5 mg/kg b.i.d.
I.V.
gastric pH >5 for 13.5 ± 1.8
b hours
4 (6-15 years)
0.5 mg/kg b.i.d.
oral
gastric pH >5 for 5.0 ± 1.1
b hours
4 (11-15 years)
aValues reported in published literature.
bMeans ± SD.
cMean (95% confidence interval).
The duration of effect of famotidine I.V. 0.5 mg/kg on gastric pH and acid suppression was shown in one study to
be longer in pediatric patients <1 month of age than in older pediatric patients. This longer duration of gastric acid
suppression is consistent with the decreased clearance in pediatric patients <3 months of age (see Table 6).
INDICATIONS AND USAGE
PEPCID is indicated in:
1. Short term treatment of active duodenal ulcer. Most adult patients heal within 4 weeks; there is rarely reason to
use PEPCID at full dosage for longer than 6 to 8 weeks. Studies have not assessed the safety of famotidine in
uncomplicated active duodenal ulcer for periods of more than eight weeks.
2. Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of an active ulcer. Controlled
studies in adults have not extended beyond one year.
3. Short term treatment of active benign gastric ulcer. Most adult patients heal within 6 weeks. Studies have not
assessed the safety or efficacy of famotidine in uncomplicated active benign gastric ulcer for periods of more than 8
weeks.
4. Short term treatment of gastroesophageal reflux disease (GERD). PEPCID is indicated for short term treatment
of patients with symptoms of GERD (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies).
PEPCID is also indicated for the short term treatment of esophagitis due to GERD including erosive or ulcerative
disease diagnosed by endoscopy (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies).
5. Treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison Syndrome, multiple endocrine
adenomas) (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies).
CONTRAINDICATIONS
Hypersensitivity to any component of these products. Cross sensitivity in this class of compounds has been
observed. Therefore, PEPCID should not be administered to patients with a history of hypersensitivity to other
H2-receptor antagonists.
PRECAUTIONS
General
Symptomatic response to therapy with PEPCID does not preclude the presence of gastric malignancy.
Patients with Moderate or Severe Renal Insufficiency
Since CNS adverse effects have been reported in patients with moderate and severe renal insufficiency, longer
intervals between doses or lower doses may need to be used in patients with moderate (creatinine clearance
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-030
NDA 19-527/S-024
NDA 20-752/S-005
Page 8
<50 mL/min) or severe (creatinine clearance <10 mL/min) renal insufficiency to adjust for the longer elimination half-
life of famotidine (see CLINICAL PHARMACOLOGY IN ADULTS and DOSAGE AND ADMINISTRATION).
Information for Patients
The patient should be instructed to shake the oral suspension vigorously for 5-10 seconds prior to each use.
Unused constituted oral suspension should be discarded after 30 days.
Patients should be instructed to leave the PEPCID RPD Orally Disintegrating Tablet in the unopened package
until the time of use. Patients should then open the tablet blister pack with dry hands, place the tablet on the tongue
to dissolve and be swallowed with saliva. No water is needed for taking the tablet.
Phenylketonurics: Phenylketonuric patients should be informed that PEPCID RPD contains phenylalanine
1.05 mg per 20 mg orally disintegrating tablet and 2.10 mg per 40 mg orally disintegrating tablet.
Drug Interactions
No drug interactions have been identified. Studies with famotidine in man, in animal models, and in vitro have
shown no significant interference with the disposition of compounds metabolized by the hepatic microsomal
enzymes, e.g., cytochrome P450 system. Compounds tested in man include warfarin, theophylline, phenytoin,
diazepam, aminopyrine and antipyrine. Indocyanine green as an index of hepatic drug extraction has been tested and
no significant effects have been found.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 106 week study in rats and a 92 week study in mice given oral doses of up to 2000 mg/kg/day (approximately
2500 times the recommended human dose for active duodenal ulcer), there was no evidence of carcinogenic
potential for PEPCID.
Famotidine was negative in the microbial mutagen test (Ames test) using Salmonella typhimurium and
Escherichia coli with or without rat liver enzyme activation at concentrations up to 10,000 mcg/plate. In in vivo studies
in mice, with a micronucleus test and a chromosomal aberration test, no evidence of a mutagenic effect was
observed.
In studies with rats given oral doses of up to 2000 mg/kg/day or intravenous doses of up to 200 mg/kg/day, fertility
and reproductive performance were not affected.
Pregnancy
Pregnancy Category B
Reproductive studies have been performed in rats and rabbits at oral doses of up to 2000 and 500 mg/kg/day,
respectively, and in both species at I.V. doses of up to 200 mg/kg/day, and have revealed no significant evidence of
impaired fertility or harm to the fetus due to PEPCID. While no direct fetotoxic effects have been observed, sporadic
abortions occurring only in mothers displaying marked decreased food intake were seen in some rabbits at oral
doses of 200 mg/kg/day (250 times the usual human dose) or higher. There are, however, no adequate or well-
controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human
response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers
Studies performed in lactating rats have shown that famotidine is secreted into breast milk. Transient growth
depression was observed in young rats suckling from mothers treated with maternotoxic doses of at least 600 times
the usual human dose. Famotidine is detectable in human milk. Because of the potential for serious adverse
reactions in nursing infants from PEPCID, 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 Patients <1 year of age
Use of PEPCID in pediatric patients <1 year of age is supported by evidence from adequate and well-controlled
studies of PEPCID in adults, and by the following studies in pediatric patients <1 year of age.
Two pharmacokinetic studies in pediatric patients <1 year of age (N=48) demonstrated that clearance of
famotidine in patients >3 months to 1 year of age is similar to that seen in older pediatric patients (1-15 years of age)
and adults. In contrast, pediatric patients 0-3 months of age had famotidine clearance values that were 2- to 4-fold
less than those in older pediatric patients and adults. These studies also show that the mean bioavailability in
pediatric patients <1 year of age after oral dosing is similar to older pediatric patients and adults. Pharmacodynamic
data in pediatric patients 0-3 months of age suggest that the duration of acid suppression is longer compared with
older pediatric patients, consistent with the longer famotidine half-life in pediatric patients 0-3 months of age. (See
CLINICAL PHARMACOLOGY IN PEDIATRIC PATIENTS, Pharmacokinetics and Pharmacodynamics.)
In a double-blinded, randomized, treatment-withdrawal study, 35 pediatric patients <1 year of age who were
diagnosed as having gastroesophageal reflux disease were treated for up to 4 weeks with famotidine oral suspension
(0.5 mg/kg/dose or 1 mg/kg/dose). Although an intravenous famotidine formulation was available, no patients were
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-030
NDA 19-527/S-024
NDA 20-752/S-005
Page 9
treated with intravenous famotidine in this study. Also, caregivers were instructed to provide conservative treatment
including thickened feedings. Enrolled patients were diagnosed primarily by history of vomiting (spitting up) and
irritability (fussiness). The famotidine dosing regimen was once daily for patients <3 months of age and twice daily for
patients ≥3 months of age. After 4 weeks of treatment, patients were randomly withdrawn from the treatment and
followed an additional 4 weeks for adverse events and symptomatology. Patients were evaluated for vomiting
(spitting up), irritability (fussiness) and global assessments of improvement. The study patients ranged in age at entry
from 1.3 to 10.5 months (mean 5.6 ± 2.9 months), 57% were female, 91% were white and 6% were black. Most
patients (27/35) continued into the treatment-withdrawal phase of the study. Two patients discontinued famotidine
due to adverse events. Most patients improved during the initial treatment phase of the study. Results of the
treatment-withdrawal phase were difficult to interpret because of small numbers of patients. Of the 35 patients
enrolled in the study, agitation was observed in 5 patients on famotidine that resolved when the medication was
discontinued; agitation was not observed in patients on placebo (see ADVERSE REACTIONS, Pediatric Patients).
These studies suggest that a starting dose of 0.5 mg/kg/dose of famotidine oral suspension may be of benefit for
the treatment of GERD for up to 4 weeks once daily in patients <3 months of age and twice daily in patients 3 months
to <1 year of age; the safety and benefit of famotidine treatment beyond 4 weeks have not been established.
Famotidine should be considered for the treatment of GERD only if conservative measures (e.g., thickened feedings)
are used concurrently and if the potential benefit outweighs the risk.
Pediatric Patients 1-16 years of age
Use of PEPCID in pediatric patients 1-16 years of age is supported by evidence from adequate and well-
controlled studies of PEPCID in adults, and by the following studies in pediatric patients: In published studies in small
numbers of pediatric patients 1-15 years of age, clearance of famotidine was similar to that seen in adults. In
pediatric patients 11-15 years of age, oral doses of 0.5 mg/kg were associated with a mean area under the curve
(AUC) similar to that seen in adults treated orally with 40 mg. Similarly, in pediatric patients 1-15 years of age,
intravenous doses of 0.5 mg/kg were associated with a mean AUC similar to that seen in adults treated intravenously
with 40 mg. Limited published studies also suggest that the relationship between serum concentration and acid
suppression is similar in pediatric patients 1-15 years of age as compared with adults. These studies suggest a
starting dose for pediatric patients 1-16 years of age as follows:
Peptic ulcer - 0.5 mg/kg/day p.o. at bedtime or divided b.i.d. up to 40 mg/day.
Gastroesophageal Reflux Disease with or without esophagitis including erosions and ulcerations - 1.0 mg/kg/day
p.o. divided b.i.d. up to 40 mg b.i.d.
While published uncontrolled studies suggest effectiveness of famotidine in the treatment of gastroesophageal
reflux disease and peptic ulcer, data in pediatric patients are insufficient to establish percent response with dose and
duration of therapy. Therefore, treatment duration (initially based on adult duration recommendations) and dose
should be individualized based on clinical response and/or pH determination (gastric or esophageal) and endoscopy.
Published uncontrolled clinical studies in pediatric patients have employed doses up to 1 mg/kg/day for peptic ulcer
and 2 mg/kg/day for GERD with or without esophagitis including erosions and ulcerations.
Geriatric Use
Of the 4,966 subjects in clinical studies who were treated with famotidine, 488 subjects (9.8%) were 65 and older,
and 88 subjects (1.7%) were greater than 75 years of age. No overall differences in safety or effectiveness were
observed between these subjects and younger subjects. However, greater sensitivity of some older individuals
cannot be ruled out.
No dosage adjustment is required based on age (see CLINICAL PHARMACOLOGY IN ADULTS,
Pharmacokinetics). 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.
Dosage adjustment in the case of moderate or severe renal impairment is necessary (see PRECAUTIONS, Patients
with Moderate or Severe Renal Insufficiency and DOSAGE AND ADMINISTRATION, Dosage Adjustment for
Patients with Moderate or Severe Renal Insufficiency).
ADVERSE REACTIONS
The adverse reactions listed below have been reported during domestic and international clinical trials in
approximately 2500 patients. In those controlled clinical trials in which PEPCID Tablets were compared to placebo,
the incidence of adverse experiences in the group which received PEPCID Tablets, 40 mg at bedtime, was similar to
that in the placebo group.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-030
NDA 19-527/S-024
NDA 20-752/S-005
Page 10
The following adverse reactions have been reported to occur in more than 1% of patients on therapy with PEPCID
in controlled clinical trials, and may be causally related to the drug: headache (4.7%), dizziness (1.3%), constipation
(1.2%) and diarrhea (1.7%).
The following other adverse reactions have been reported infrequently in clinical trials or since the drug was
marketed. The relationship to therapy with PEPCID has been unclear in many cases. Within each category the
adverse reactions are listed in order of decreasing severity:
Body as a Whole: fever, asthenia, fatigue
Cardiovascular: arrhythmia, AV block, palpitation
Gastrointestinal: cholestatic jaundice, liver enzyme abnormalities, vomiting, nausea, abdominal discomfort,
anorexia, dry mouth
Hematologic: rare cases of agranulocytosis, pancytopenia, leukopenia, thrombocytopenia
Hypersensitivity: anaphylaxis, angioedema, orbital or facial edema, urticaria, rash, conjunctival injection
Musculoskeletal: musculoskeletal pain including muscle cramps, arthralgia
Nervous System/Psychiatric: grand mal seizure; psychic disturbances, which were reversible in cases for which
follow-up was obtained, including hallucinations, confusion, agitation, depression, anxiety, decreased libido;
paresthesia; insomnia; somnolence
Respiratory: bronchospasm
Skin: toxic epidermal necrolysis (very rare), alopecia, acne, pruritus, dry skin, flushing
Special Senses: tinnitus, taste disorder
Other: rare cases of impotence and rare cases of gynecomastia have been reported; however, in controlled
clinical trials, the incidences were not greater than those seen with placebo.
The adverse reactions reported for PEPCID Tablets may also occur with PEPCID for Oral Suspension and
PEPCID RPD Orally Disintegrating Tablets.
Pediatric Patients
In a clinical study in 35 pediatric patients <1 year of age with GERD symptoms [e.g., vomiting (spitting up),
irritability (fussing)], agitation was observed in 5 patients on famotidine that resolved when the medication was
discontinued.
OVERDOSAGE
There is no experience to date with deliberate overdosage. Oral doses of up to 640 mg/day have been given to
adult patients with pathological hypersecretory conditions with no serious adverse effects. In the event of overdosage,
treatment should be symptomatic and supportive. Unabsorbed material should be removed from the gastrointestinal
tract, the patient should be monitored, and supportive therapy should be employed.
The oral LD50 of famotidine in male and female rats and mice was greater than 3000 mg/kg and the minimum
lethal acute oral dose in dogs exceeded 2000 mg/kg. Famotidine did not produce overt effects at high oral doses in
mice, rats, cats and dogs, but induced significant anorexia and growth depression in rabbits starting with
200 mg/kg/day orally. The intravenous LD50 of famotidine for mice and rats ranged from 254-563 mg/kg and the
minimum lethal single I.V. dose in dogs was approximately 300 mg/kg. Signs of acute intoxication in I.V. treated dogs
were emesis, restlessness, pallor of mucous membranes or redness of mouth and ears, hypotension, tachycardia
and collapse.
DOSAGE AND ADMINISTRATION
Duodenal Ulcer
Acute Therapy: The recommended adult oral dosage for active duodenal ulcer is 40 mg once a day at bedtime.
Most patients heal within 4 weeks; there is rarely reason to use PEPCID at full dosage for longer than 6 to 8 weeks. A
regimen of 20 mg b.i.d. is also effective.
Maintenance Therapy: The recommended adult oral dose is 20 mg once a day at bedtime.
Benign Gastric Ulcer
Acute Therapy: The recommended adult oral dosage for active benign gastric ulcer is 40 mg once a day at
bedtime.
Gastroesophageal Reflux Disease (GERD)
The recommended oral dosage for treatment of adult patients with symptoms of GERD is 20 mg b.i.d. for up to 6
weeks. The recommended oral dosage for the treatment of adult patients with esophagitis including erosions and
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-030
NDA 19-527/S-024
NDA 20-752/S-005
Page 11
ulcerations and accompanying symptoms due to GERD is 20 or 40 mg b.i.d. for up to 12 weeks (see CLINICAL
PHARMACOLOGY IN ADULTS, Clinical Studies).
Dosage for Pediatric Patients <1 year of age Gastroesophageal Reflux Disease (GERD)
See PRECAUTIONS, Pediatric Patients <1 year of age.
The studies described in PRECAUTIONS, Pediatric Patients <1 year of age suggest the following starting doses
in pediatric patients <1 year of age: Gastroesophageal Reflux Disease (GERD) - 0.5 mg/kg/dose of famotidine oral
suspension for the treatment of GERD for up to 8 weeks once daily in patients <3 months of age and 0.5 mg/kg/dose
twice daily in patients 3 months to <1 year of age. Patients should also be receiving conservative measures (e.g.,
thickened feedings). The use of intravenous famotidine in pediatric patients <1 year of age with GERD has not been
adequately studied.
Dosage for Pediatric Patients 1-16 years of age
See PRECAUTIONS, Pediatric Patients 1-16 years of age.
The studies described in PRECAUTIONS, Pediatric Patients 1-16 years of age suggest the following starting
doses in pediatric patients 1-16 years of age:
Peptic ulcer - 0.5 mg/kg/day p.o. at bedtime or divided b.i.d. up to 40 mg/day.
Gastroesophageal Reflux Disease with or without esophagitis including erosions and ulcerations - 1.0 mg/kg/day
p.o. divided b.i.d. up to 40 mg b.i.d.
While published uncontrolled studies suggest effectiveness of famotidine in the treatment of gastroesophageal
reflux disease and peptic ulcer, data in pediatric patients are insufficient to establish percent response with dose and
duration of therapy. Therefore, treatment duration (initially based on adult duration recommendations) and dose
should be individualized based on clinical response and/or pH determination (gastric or esophageal) and endoscopy.
Published uncontrolled clinical studies in pediatric patients 1-16 years of age have employed doses up to 1 mg/kg/day
for peptic ulcer and 2 mg/kg/day for GERD with or without esophagitis including erosions and ulcerations.
Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas)
The dosage of PEPCID in patients with pathological hypersecretory conditions varies with the individual patient.
The recommended adult oral starting dose for pathological hypersecretory conditions is 20 mg q 6 h. In some
patients, a higher starting dose may be required. Doses should be adjusted to individual patient needs and should
continue as long as clinically indicated. Doses up to 160 mg q 6 h have been administered to some adult patients
with severe Zollinger-Ellison Syndrome.
Oral Suspension
PEPCID for Oral Suspension may be substituted for PEPCID Tablets in any of the above indications. Each five
mL contains 40 mg of famotidine after constitution of the powder with 46 mL of Purified Water as directed.
Directions for Preparing PEPCID for Oral Suspension
Prepare suspension at time of dispensing. Slowly add 46 mL of Purified Water. Shake vigorously for 5-10
seconds immediately after adding the water and immediately before use.
Stability of PEPCID for Oral Suspension
Unused constituted oral suspension should be discarded after 30 days.
Orally Disintegrating Tablets
PEPCID RPD Orally Disintegrating Tablets may be substituted for PEPCID Tablets in any of the above indications
at the same recommended dosages.
PEPCID RPD Orally Disintegrating Tablets rapidly disintegrate on the tongue. No water is needed for taking the
tablet. Patients should be instructed to open the tablet blister pack with dry hands, place the tablet on the tongue to
disintegrate and be swallowed with saliva.
Concomitant Use of Antacids
Antacids may be given concomitantly if needed.
Dosage Adjustment for Patients with Moderate or Severe Renal Insufficiency
In adult patients with moderate (creatinine clearance <50 mL/min) or severe (creatinine clearance <10 mL/min)
renal insufficiency, the elimination half-life of PEPCID is increased. For patients with severe renal insufficiency, it may
exceed 20 hours, reaching approximately 24 hours in anuric patients. Since CNS adverse effects have been reported
in patients with moderate and severe renal insufficiency, to avoid excess accumulation of the drug in patients with
moderate or severe renal insufficiency, the dose of PEPCID may be reduced to half the dose or the dosing interval
may be prolonged to 36-48 hours as indicated by the patient's clinical response.
Based on the comparison of pharmacokinetic parameters for PEPCID in adults and pediatric patients, dosage
adjustment in pediatric patients with moderate or severe renal insufficiency should be considered.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-030
NDA 19-527/S-024
NDA 20-752/S-005
Page 12
HOW SUPPLIED
No. 3535 — PEPCID Tablets, 20 mg, are beige colored, U-shaped, film-coated tablets coded MSD 963 on one
side and PEPCID on the other. They are supplied as follows:
NDC 0006-0963-31 unit of use bottles of 30
NDC 0006-0963-94 unit of use bottles of 90
NDC 0006-0963-58 unit of use bottles of 100
NDC 0006-0963-28 unit dose package of 100
NDC 0006-0963-82 bottles of 1,000
NDC 0006-0963-87 bottles of 10,000
NDC 0006-0963-72 carton of 25 UNIBLISTER™ cards of 31 tablets each.
No. 3536 — PEPCID Tablets, 40 mg, are light brownish-orange, U-shaped, film-coated tablets coded MSD 964
on one side and PEPCID on the other. They are supplied as follows:
NDC 0006-0964-31 unit of use bottles of 30
NDC 0006-0964-94 unit of use bottles of 90
NDC 0006-0964-58 unit of use bottles of 100
NDC 0006-0964-28 unit dose package of 100
NDC 0006-0964-82 bottles of 1,000
NDC 0006-0964-87 bottles of 10,000
NDC 0006-0964-72 carton of 25 UNIBLISTER™ cards of 31 tablets each.
No. 3553 — PEPCID RPD Orally Disintegrating Tablets, 20 mg, are pale rose colored, hexagonal-shaped,
lyophilized tablets measuring 13.1 mm (side to side) and 15.2 mm (point to point), with a mint flavor. They are
supplied as follows:
NDC 0006-3553-31 unit dose package of 30
NDC 0006-3553-48 unit dose package of 100
NDC 0006-3553-28 unit dose package of 100.
No. 3554 — PEPCID RPD Orally Disintegrating Tablets, 40 mg, are pale rose colored, hexagonal-shaped,
lyophilized tablets measuring 15.9 mm (side to side) and 18.4 mm (point to point), with a mint flavor. They are
supplied as follows:
NDC 0006-3554-31 unit dose package of 30
NDC 0006-3554-48 unit dose package of 100.
No. 3538 — PEPCID for Oral Suspension is a white to off-white powder containing 400 mg of famotidine for
constitution. When constituted as directed, PEPCID for Oral Suspension is a smooth, mobile, off-white,
homogeneous suspension with a cherry-banana-mint flavor, containing 40 mg of famotidine per 5 mL.
NDC 0006-3538-92, bottles containing 400 mg famotidine.
Storage
Store PEPCID Tablets and PEPCID RPD Orally Disintegrating Tablets at 25°C (77°F); excursions permitted to
15-30°C (59-86°F) [see USP Controlled Room Temperature].
Store PEPCID for Oral Suspension dry powder and suspension at 25°C (77°F); excursions permitted to
15-30°C (59-86°F) [see USP Controlled Room Temperature]. Suspension: Protect from freezing. Discard unused
suspension after 30 days.
PEPCID (famotidine) Tablets and PEPCID (famotidine) for Oral Suspension are manufactured by:
PEPCID RPD (famotidine) Orally Disintegrating Tablets are manufactured for:
By:
Scherer DDS, Swindon, England and are
Made in England
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-030
NDA 19-527/S-024
NDA 20-752/S-005
Page 13
Issued March 2001
Printed in USA
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/
---------------------
Victor Raczkowski
6/6/02 07:01:15 PM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:25.326510
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19462s30lbl.pdf', 'application_number': 19462, 'submission_type': 'SUPPL ', 'submission_number': 30}
|
11,510
|
NDA 19-462/S-034
NDA 19-510/S-031
NDA 20-249/S-013
Page 3
PEPCID®
(FAMOTIDINE) TABLETS
PEPCID®
(FAMOTIDINE) FOR ORAL SUSPENSION
DESCRIPTION
The active ingredient in PEPCID* (famotidine) is a histamine H2-receptor antagonist. Famotidine is N′-
(aminosulfonyl)-3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propanimidamide.
The
empirical
formula of famotidine is C8H15N7O2S3 and its molecular weight is 337.43. Its structural formula is:
Famotidine is a white to pale yellow crystalline compound that is freely soluble in glacial acetic acid, slightly
soluble in methanol, very slightly soluble in water, and practically insoluble in ethanol.
Each tablet for oral administration contains either 20 mg or 40 mg of famotidine and the following inactive
ingredients: hydroxypropyl cellulose, hypromellose, iron oxides, magnesium stearate, microcrystalline cellulose,
corn starch, talc, titanium dioxide, and carnauba wax.
Each 5 mL of the oral suspension when prepared as directed contains 40 mg of famotidine and the following
inactive ingredients: citric acid, flavors, microcrystalline cellulose and carboxymethylcellulose sodium, sucrose
and xanthan gum. Added as preservatives are sodium benzoate 0.1%, sodium methylparaben 0.1%, and
sodium propylparaben 0.02%.
CLINICAL PHARMACOLOGY IN ADULTS
GI Effects
PEPCID is a competitive inhibitor of histamine H2-receptors. The primary clinically important pharmacologic
activity of PEPCID is inhibition of gastric secretion. Both the acid concentration and volume of gastric secretion
are suppressed by PEPCID, while changes in pepsin secretion are proportional to volume output.
In normal volunteers and hypersecretors, PEPCID inhibited basal and nocturnal gastric secretion, as well as
secretion stimulated by food and pentagastrin. After oral administration, the onset of the antisecretory effect
occurred within one hour; the maximum effect was dose-dependent, occurring within one to three hours.
Duration of inhibition of secretion by doses of 20 and 40 mg was 10 to 12 hours.
Single evening oral doses of 20 and 40 mg inhibited basal and nocturnal acid secretion in all subjects; mean
nocturnal gastric acid secretion was inhibited by 86% and 94%, respectively, for a period of at least 10 hours.
The same doses given in the morning suppressed food-stimulated acid secretion in all subjects. The mean
suppression was 76% and 84%, respectively, 3 to 5 hours after administration, and 25% and 30%, respectively,
8 to 10 hours after administration. In some subjects who received the 20-mg dose, however, the antisecretory
effect was dissipated within 6-8 hours. There was no cumulative effect with repeated doses. The nocturnal
intragastric pH was raised by evening doses of 20 and 40 mg of PEPCID to mean values of 5.0 and 6.4,
respectively. When PEPCID was given after breakfast, the basal daytime interdigestive pH at 3 and 8 hours
after 20 or 40 mg of PEPCID was raised to about 5.
PEPCID had little or no effect on fasting or postprandial serum gastrin levels. Gastric emptying and exocrine
pancreatic function were not affected by PEPCID.
Other Effects
Systemic effects of PEPCID in the CNS, cardiovascular, respiratory or endocrine systems were not noted in
clinical pharmacology studies. Also, no antiandrogenic effects were noted. (See ADVERSE REACTIONS.)
Serum hormone levels, including prolactin, cortisol, thyroxine (T4), and testosterone, were not altered after
treatment with PEPCID.
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT © 1986, 1988, 1991, 1995, 1996 MERCK & CO., 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 19-462/S-034
NDA 19-510/S-031
NDA 20-249/S-013
Page 4
Pharmacokinetics
PEPCID is incompletely absorbed. The bioavailability of oral doses is 40-45%. PEPCID Tablets and PEPCID
for Oral Suspension are bioequivalent. Bioavailability may be slightly increased by food, or slightly decreased by
antacids; however, these effects are of no clinical consequence. PEPCID undergoes minimal first-pass
metabolism. After oral doses, peak plasma levels occur in 1-3 hours. Plasma levels after multiple doses are
similar to those after single doses. Fifteen to 20% of PEPCID in plasma is protein bound. PEPCID has an
elimination half-life of 2.5-3.5 hours. PEPCID is eliminated by renal (65-70%) and metabolic (30-35%) routes.
Renal clearance is 250-450 mL/min, indicating some tubular excretion. Twenty-five to 30% of an oral dose and
65-70% of an intravenous dose are recovered in the urine as unchanged compound. The only metabolite
identified in man is the S-oxide.
There is a close relationship between creatinine clearance values and the elimination half-life of PEPCID. In
patients with severe renal insufficiency, i.e., creatinine clearance less than 10 mL/min, the elimination half-life of
PEPCID may exceed 20 hours and adjustment of dose or dosing intervals in moderate and severe renal
insufficiency may be necessary (see PRECAUTIONS, DOSAGE AND ADMINISTRATION).
In elderly patients, there are no clinically significant age-related changes in the pharmacokinetics of PEPCID.
However, in elderly patients with decreased renal function, the clearance of the drug may be decreased (see
PRECAUTIONS, Geriatric Use).
Clinical Studies
Duodenal Ulcer
In a U.S. multicenter, double-blind study in outpatients with endoscopically confirmed duodenal ulcer, orally
administered PEPCID was compared to placebo. As shown in Table 1, 70% of patients treated with PEPCID
40 mg h.s. were healed by week 4.
Table 1
Outpatients with Endoscopically
Confirmed Healed Duodenal Ulcers
PEPCID
40 mg h.s.
(N = 89)
PEPCID
20 mg b.i.d.
(N = 84)
Placebo
h.s.
(N = 97)
Week 2
Week 4
**32%
**70%
**38%
**67%
17%
31%
**Statistically significantly different than placebo (p<0.001)
Patients not healed by week 4 were continued in the study. By week 8, 83% of patients treated with PEPCID
had healed versus 45% of patients treated with placebo. The incidence of ulcer healing with PEPCID was
significantly higher than with placebo at each time point based on proportion of endoscopically confirmed healed
ulcers.
In this study, time to relief of daytime and nocturnal pain was significantly shorter for patients receiving
PEPCID than for patients receiving placebo; patients receiving PEPCID also took less antacid than the patients
receiving placebo.
Long-Term Maintenance
Treatment of Duodenal Ulcers
PEPCID, 20 mg p.o. h.s., was compared to placebo h.s. as maintenance therapy in two double-blind,
multicenter studies of patients with endoscopically confirmed healed duodenal ulcers. In the U.S. study the
observed ulcer incidence within 12 months in patients treated with placebo was 2.4 times greater than in the
patients treated with PEPCID. The 89 patients treated with PEPCID had a cumulative observed ulcer incidence
of 23.4% compared to an observed ulcer incidence of 56.6% in the 89 patients receiving placebo (p<0.01).
These results were confirmed in an international study where the cumulative observed ulcer incidence within 12
months in the 307 patients treated with PEPCID was 35.7%, compared to an incidence of 75.5% in the 325
patients treated with placebo (p<0.01).
Gastric Ulcer
In both a U.S. and an international multicenter, double-blind study in patients with endoscopically confirmed
active benign gastric ulcer, orally administered PEPCID, 40 mg h.s., was compared to placebo h.s. Antacids
were permitted during the studies, but consumption was not significantly different between the PEPCID and
placebo groups. As shown in Table 2, the incidence of ulcer healing (dropouts counted as unhealed) with
PEPCID was statistically significantly better than placebo at weeks 6 and 8 in the U.S. study, and at weeks 4, 6
and 8 in the international study, based on the number of ulcers that healed, confirmed by endoscopy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-034
NDA 19-510/S-031
NDA 20-249/S-013
Page 5
Table 2
Patients with Endoscopically
Confirmed Healed Gastric Ulcers
U.S. Study
International Study
PEPCID
40 mg h.s.
(N=74)
Placebo
h.s.
(N=75)
PEPCID
40 mg h.s.
(N=149)
Placebo
h.s.
(N=145)
Week 4
Week 6
Week 8
45%
†66%
***78%
39%
44%
64%
†47%
†65%
†80%
31%
46%
54%
***,† Statistically significantly better than placebo (p≤0.05, p≤0.01 respectively)
Time to complete relief of daytime and nighttime pain was statistically significantly shorter for patients
receiving PEPCID than for patients receiving placebo; however, in neither study was there a statistically
significant difference in the proportion of patients whose pain was relieved by the end of the study (week 8).
Gastroesophageal Reflux Disease (GERD)
Orally administered PEPCID was compared to placebo in a U.S. study that enrolled patients with symptoms
of GERD and without endoscopic evidence of erosion or ulceration of the esophagus. PEPCID 20 mg b.i.d. was
statistically significantly superior to 40 mg h.s. and to placebo in providing a successful symptomatic outcome,
defined as moderate or excellent improvement of symptoms (Table 3).
Table 3
% Successful Symptomatic Outcome
PEPCID
20 mg b.i.d.
(N=154)
PEPCID
40 mg h.s.
(N=149)
Placebo
(N=73)
Week 6
82††
69
62
†† p≤0.01 vs Placebo
By two weeks of treatment symptomatic success was observed in a greater percentage of patients taking
PEPCID 20 mg b.i.d. compared to placebo (p≤0.01).
Symptomatic improvement and healing of endoscopically verified erosion and ulceration were studied in two
additional trials. Healing was defined as complete resolution of all erosions or ulcerations visible with
endoscopy. The U.S. study comparing PEPCID 40 mg p.o. b.i.d. to placebo and PEPCID 20 mg p.o. b.i.d.
showed a significantly greater percentage of healing for PEPCID 40 mg b.i.d. at weeks 6 and 12 (Table 4).
Table 4
% Endoscopic Healing - U.S. Study
PEPCID
40 mg b.i.d.
(N=127)
PEPCID
20 mg b.i.d.
(N=125)
Placebo
(N=66)
Week 6
Week 12
48†††,‡‡
69†††,‡
32
54†††
18
29
††† p≤0.01 vs Placebo
‡ p≤0.05 vs PEPCID 20 mg b.i.d.
‡‡ p≤0.01 vs PEPCID 20 mg b.i.d.
As compared to placebo, patients who received PEPCID had faster relief of daytime and nighttime heartburn
and a greater percentage of patients experienced complete relief of nighttime heartburn. These differences were
statistically significant.
In the international study, when PEPCID 40 mg p.o. b.i.d. was compared to ranitidine 150 mg p.o. b.i.d., a
statistically significantly greater percentage of healing was observed with PEPCID 40 mg b.i.d. at week 12
(Table 5). There was, however, no significant difference among treatments in symptom relief.
Table 5
% Endoscopic Healing - International Study
PEPCID
40 mg b.i.d.
(N=175)
PEPCID
20 mg b.i.d.
(N=93)
Ranitidine
150 mg b.i.d.
(N=172)
Week 6
Week 12
48
71‡‡‡
52
68
42
60
‡‡‡ p≤0.05 vs Ranitidine 150 mg b.i.d.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-034
NDA 19-510/S-031
NDA 20-249/S-013
Page 6
Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas)
In studies of patients with pathological hypersecretory conditions such as Zollinger-Ellison Syndrome with or
without multiple endocrine adenomas, PEPCID significantly inhibited gastric acid secretion and controlled
associated symptoms. Orally administered doses from 20 to 160 mg q 6 h maintained basal acid secretion
below 10 mEq/hr; initial doses were titrated to the individual patient need and subsequent adjustments were
necessary with time in some patients. PEPCID was well tolerated at these high dose levels for prolonged
periods (greater than 12 months) in eight patients, and there were no cases reported of gynecomastia,
increased prolactin levels, or impotence which were considered to be due to the drug.
CLINICAL PHARMACOLOGY IN PEDIATRIC PATIENTS
Pharmacokinetics
Table 6 presents pharmacokinetic data from clinical trials and a published study in pediatric patients (<1 year
of age; N=27) given famotidine I.V. 0.5 mg/kg and from published studies of small numbers of pediatric patients
(1-15 years of age) given famotidine intravenously. Areas under the curve (AUCs) are normalized to a dose of
0.5 mg/kg I.V. for pediatric patients 1-15 years of age and compared with an extrapolated 40 mg intravenous
dose in adults (extrapolation based on results obtained with a 20 mg I.V. adult dose).
Table 6
Pharmacokinetic Parametersa of Intravenous Famotidine
Age
(N=number of
patients)
Area Under
the Curve (AUC)
(ng-hr/mL)
Total
Clearance (Cl)
(L/hr/kg)
Volume of
Distribution (Vd)
(L/kg)
Elimination
Half-life (T1/2)
(hours)
0-1 monthc
(N=10)
NA
0.13 ± 0.06
1.4 ± 0.4
10.5 ± 5.4
0-3 monthsd
(N=6)
2688 ± 847
0.21 ± 0.06
1.8 ± 0.3
8.1 ± 3.5
>3–12 monthsd
(N=11)
1160 ± 474
0.49 ± 0.17
2.3 ± 0.7
4.5 ± 1.1
1-11 yrs (N=20)
1089 ± 834
0.54 ± 0.34
2.07 ± 1.49
3.38 ± 2.60
11-15 yrs (N=6)
1140 ± 320
0.48 ± 0.14
1.5 ± 0.4
2.3 ± 0.4
Adult (N=16)
1726b
0.39 ± 0.14
1.3 ± 0.2
2.83 ± 0.99
aValues are presented as means ± SD unless indicated otherwise.
bMean value only.
cSingle center study.
dMulticenter study.
Plasma clearance is reduced and elimination half-life is prolonged in pediatric patients 0-3 months of age
compared to older pediatric patients. The pharmacokinetic parameters for pediatric patients, ages >3 months-15
years, are comparable to those obtained for adults.
Bioavailability studies of 8 pediatric patients (11-15 years of age) showed a mean oral bioavailability of 0.5
compared to adult values of 0.42 to 0.49. Oral doses of 0.5 mg/kg achieved AUCs of 645 ± 249 ng-hr/mL and
580 ± 60 ng-hr/mL in pediatric patients <1 year of age (N=5) and in pediatric patients 11-15 years of age,
respectively, compared to 482 ± 181 ng-hr/mL in adults treated with 40 mg orally.
Pharmacodynamics
Pharmacodynamics of famotidine were evaluated in 5 pediatric patients 2-13 years of age using the sigmoid
Emax model. These data suggest that the relationship between serum concentration of famotidine and gastric
acid suppression is similar to that observed in one study of adults (Table 7).
Table 7
Pharmacodynamics of famotidine using the sigmoid Emax model
EC50 (ng/mL)*
Pediatric Patients
26 ± 13
Data from one study
a) healthy adult subjects
26.5 ± 10.3
b) adult patients with upper GI bleeding
18.7 ± 10.8
*Serum concentration of famotidine associated with 50% maximum gastric acid reduction. Values are presented as means ± SD.
Five published studies (Table 8) examined the effect of famotidine on gastric pH and duration of acid
suppression in pediatric patients. While each study had a different design, acid suppression data over time are
summarized as follows:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-034
NDA 19-510/S-031
NDA 20-249/S-013
Page 7
Table 8
Dosage
Route
Effect
a
Number of Patients
(age range)
0.5 mg/kg, single dose
I.V.
gastric pH >4 for 19.5 hours (17.3,
21.8)c
11 (5-19 days)
0.3 mg/kg, single dose
I.V.
gastric pH >3.5 for 8.7 ± 4.7
b hours
6 (2-7 years)
0.4-0.8 mg/kg
I.V.
gastric pH >4 for 6-9 hours
18 (2-69 months)
0.5 mg/kg, single dose
I.V.
a >2 pH unit increase above
baseline in gastric pH for >8 hours
9 (2-13 years)
0.5 mg/kg b.i.d.
I.V.
gastric pH >5 for 13.5 ± 1.8
b hours
4 (6-15 years)
0.5 mg/kg b.i.d.
oral
gastric pH >5 for 5.0 ± 1.1
b hours
4 (11-15 years)
aValues reported in published literature.
bMeans ± SD.
cMean (95% confidence interval).
The duration of effect of famotidine I.V. 0.5 mg/kg on gastric pH and acid suppression was shown in one
study to be longer in pediatric patients <1 month of age than in older pediatric patients. This longer duration of
gastric acid suppression is consistent with the decreased clearance in pediatric patients <3 months of age (see
Table 6).
INDICATIONS AND USAGE
PEPCID is indicated in:
1. Short-term treatment of active duodenal ulcer. Most adult patients heal within 4 weeks; there is rarely
reason to use PEPCID at full dosage for longer than 6 to 8 weeks. Studies have not assessed the safety of
famotidine in uncomplicated active duodenal ulcer for periods of more than eight weeks.
2. Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of an active ulcer.
Controlled studies in adults have not extended beyond one year.
3. Short-term treatment of active benign gastric ulcer. Most adult patients heal within 6 weeks. Studies have
not assessed the safety or efficacy of famotidine in uncomplicated active benign gastric ulcer for periods of more
than 8 weeks.
4. Short-term treatment of gastroesophageal reflux disease (GERD). PEPCID is indicated for short- term
treatment of patients with symptoms of GERD (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies).
PEPCID is also indicated for the short-term treatment of esophagitis due to GERD including erosive or
ulcerative disease diagnosed by endoscopy (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies).
5. Treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison Syndrome, multiple endocrine
adenomas) (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies).
CONTRAINDICATIONS
Hypersensitivity to any component of these products. Cross sensitivity in this class of compounds has been
observed. Therefore, PEPCID should not be administered to patients with a history of hypersensitivity to other
H2-receptor antagonists.
PRECAUTIONS
General
Symptomatic response to therapy with PEPCID does not preclude the presence of gastric malignancy.
Patients with Moderate or Severe Renal Insufficiency
Since CNS adverse effects have been reported in patients with moderate and severe renal insufficiency,
longer intervals between doses or lower doses may need to be used in patients with moderate (creatinine
clearance <50 mL/min) or severe (creatinine clearance <10 mL/min) renal insufficiency to adjust for the longer
elimination half-life of famotidine (see CLINICAL PHARMACOLOGY IN ADULTS and DOSAGE AND
ADMINISTRATION).
Information for Patients
The patient should be instructed to shake the oral suspension vigorously for 5-10 seconds prior to each use.
Unused constituted oral suspension should be discarded after 30 days.
Drug Interactions
No drug interactions have been identified. Studies with famotidine in man, in animal models, and in vitro
have shown no significant interference with the disposition of compounds metabolized by the hepatic
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-034
NDA 19-510/S-031
NDA 20-249/S-013
Page 8
microsomal enzymes, e.g., cytochrome P450 system. Compounds tested in man include warfarin, theophylline,
phenytoin, diazepam, aminopyrine and antipyrine. Indocyanine green as an index of hepatic drug extraction has
been tested and no significant effects have been found.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 106 week study in rats and a 92-week study in mice given oral doses of up to 2000 mg/kg/day
(approximately 2500 times the recommended human dose for active duodenal ulcer), there was no evidence of
carcinogenic potential for PEPCID.
Famotidine was negative in the microbial mutagen test (Ames test) using Salmonella typhimurium and
Escherichia coli with or without rat liver enzyme activation at concentrations up to 10,000 mcg/plate. In in vivo
studies in mice, with a micronucleus test and a chromosomal aberration test, no evidence of a mutagenic effect
was observed.
In studies with rats given oral doses of up to 2000 mg/kg/day or intravenous doses of up to 200 mg/kg/day,
fertility and reproductive performance were not affected.
Pregnancy
Pregnancy Category B
Reproductive studies have been performed in rats and rabbits at oral doses of up to 2000 and
500 mg/kg/day, respectively, and in both species at I.V. doses of up to 200 mg/kg/day, and have revealed no
significant evidence of impaired fertility or harm to the fetus due to PEPCID. While no direct fetotoxic effects
have been observed, sporadic abortions occurring only in mothers displaying marked decreased food intake
were seen in some rabbits at oral doses of 200 mg/kg/day (250 times the usual human dose) or higher. There
are, however, no adequate or well-controlled studies in pregnant women. Because animal reproductive studies
are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers
Studies performed in lactating rats have shown that famotidine is secreted into breast milk. Transient growth
depression was observed in young rats suckling from mothers treated with maternotoxic doses of at least 600
times the usual human dose. Famotidine is detectable in human milk. Because of the potential for serious
adverse reactions in nursing infants from PEPCID, 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 Patients <1 year of age
Use of PEPCID in pediatric patients <1 year of age is supported by evidence from adequate and
well-controlled studies of PEPCID in adults, and by the following studies in pediatric patients <1 year of age.
Two pharmacokinetic studies in pediatric patients <1 year of age (N=48) demonstrated that clearance of
famotidine in patients >3 months to 1 year of age is similar to that seen in older pediatric patients (1-15 years of
age) and adults. In contrast, pediatric patients 0-3 months of age had famotidine clearance values that were 2-
to 4-fold less than those in older pediatric patients and adults. These studies also show that the mean
bioavailability in pediatric patients <1 year of age after oral dosing is similar to older pediatric patients and
adults. Pharmacodynamic data in pediatric patients 0-3 months of age suggest that the duration of acid
suppression is longer compared with older pediatric patients, consistent with the longer famotidine half-life in
pediatric patients 0-3 months of age. (See CLINICAL PHARMACOLOGY IN PEDIATRIC PATIENTS,
Pharmacokinetics and Pharmacodynamics.)
In a double-blind, randomized, treatment-withdrawal study, 35 pediatric patients <1 year of age who were
diagnosed as having gastroesophageal reflux disease were treated for up to 4 weeks with famotidine oral
suspension (0.5 mg/kg/dose or 1 mg/kg/dose). Although an intravenous famotidine formulation was available,
no patients were treated with intravenous famotidine in this study. Also, caregivers were instructed to provide
conservative treatment including thickened feedings. Enrolled patients were diagnosed primarily by history of
vomiting (spitting up) and irritability (fussiness). The famotidine dosing regimen was once daily for patients
<3 months of age and twice daily for patients ≥3 months of age. After 4 weeks of treatment, patients were
randomly withdrawn from the treatment and followed an additional 4 weeks for adverse events and
symptomatology. Patients were evaluated for vomiting (spitting up), irritability (fussiness) and global
assessments of improvement. The study patients ranged in age at entry from 1.3 to 10.5 months (mean 5.6 ±
2.9 months), 57% were female, 91% were white and 6% were black. Most patients (27/35) continued into the
treatment-withdrawal phase of the study. Two patients discontinued famotidine due to adverse events. Most
patients improved during the initial treatment phase of the study. Results of the treatment-withdrawal phase
were difficult to interpret because of small numbers of patients. Of the 35 patients enrolled in the study, agitation
was observed in 5 patients on famotidine that resolved when the medication was discontinued; agitation was not
observed in patients on placebo (see ADVERSE REACTIONS, Pediatric Patients).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-034
NDA 19-510/S-031
NDA 20-249/S-013
Page 9
These studies suggest that a starting dose of 0.5 mg/kg/dose of famotidine oral suspension may be of
benefit for the treatment of GERD for up to 4 weeks once daily in patients <3 months of age and twice daily in
patients 3 months to <1 year of age; the safety and benefit of famotidine treatment beyond 4 weeks have not
been established. Famotidine should be considered for the treatment of GERD only if conservative measures
(e.g., thickened feedings) are used concurrently and if the potential benefit outweighs the risk.
Pediatric Patients 1-16 years of age
Use of PEPCID in pediatric patients 1-16 years of age is supported by evidence from adequate and well-
controlled studies of PEPCID in adults, and by the following studies in pediatric patients: In published studies in
small numbers of pediatric patients 1-15 years of age, clearance of famotidine was similar to that seen in adults.
In pediatric patients 11-15 years of age, oral doses of 0.5 mg/kg were associated with a mean area under the
curve (AUC) similar to that seen in adults treated orally with 40 mg. Similarly, in pediatric patients 1-15 years of
age, intravenous doses of 0.5 mg/kg were associated with a mean AUC similar to that seen in adults treated
intravenously with 40 mg. Limited published studies also suggest that the relationship between serum
concentration and acid suppression is similar in pediatric patients 1-15 years of age as compared with adults.
These studies suggest a starting dose for pediatric patients 1-16 years of age as follows:
Peptic ulcer - 0.5 mg/kg/day p.o. at bedtime or divided b.i.d. up to 40 mg/day.
Gastroesophageal Reflux Disease with or without esophagitis including erosions and ulcerations -
1.0 mg/kg/day p.o. divided b.i.d. up to 40 mg b.i.d.
While published uncontrolled studies suggest effectiveness of famotidine in the treatment of
gastroesophageal reflux disease and peptic ulcer, data in pediatric patients are insufficient to establish percent
response with dose and duration of therapy. Therefore, treatment duration (initially based on adult duration
recommendations) and dose should be individualized based on clinical response and/or pH determination
(gastric or esophageal) and endoscopy. Published uncontrolled clinical studies in pediatric patients have
employed doses up to 1 mg/kg/day for peptic ulcer and 2 mg/kg/day for GERD with or without esophagitis
including erosions and ulcerations.
Geriatric Use
Of the 4,966 subjects in clinical studies who were treated with famotidine, 488 subjects (9.8%) were 65 and
older, and 88 subjects (1.7%) were greater than 75 years of age. No overall differences in safety or
effectiveness were observed between these subjects and younger subjects. However, greater sensitivity of
some older individuals cannot be ruled out.
No dosage adjustment is required based on age (see CLINICAL PHARMACOLOGY IN ADULTS,
Pharmacokinetics). 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. Dosage adjustment in the case of moderate or severe renal impairment is necessary (see
PRECAUTIONS, Patients with Moderate or Severe Renal Insufficiency and DOSAGE AND ADMINISTRATION,
Dosage Adjustment for Patients with Moderate or Severe Renal Insufficiency).
ADVERSE REACTIONS
The adverse reactions listed below have been reported during domestic and international clinical trials in
approximately 2500 patients. In those controlled clinical trials in which PEPCID Tablets were compared to
placebo, the incidence of adverse experiences in the group which received PEPCID Tablets, 40 mg at bedtime,
was similar to that in the placebo group.
The following adverse reactions have been reported to occur in more than 1% of patients on therapy with
PEPCID in controlled clinical trials, and may be causally related to the drug: headache (4.7%), dizziness (1.3%),
constipation (1.2%) and diarrhea (1.7%).
The following other adverse reactions have been reported infrequently in clinical trials or since the drug was
marketed. The relationship to therapy with PEPCID has been unclear in many cases. Within each category the
adverse reactions are listed in order of decreasing severity:
Body as a Whole: fever, asthenia, fatigue
Cardiovascular: arrhythmia, AV block, palpitation
Gastrointestinal: cholestatic jaundice, liver enzyme abnormalities, vomiting, nausea, abdominal discomfort,
anorexia, dry mouth
Hematologic: rare cases of agranulocytosis, pancytopenia, leukopenia, thrombocytopenia
Hypersensitivity: anaphylaxis, angioedema, orbital or facial edema, urticaria, rash, conjunctival injection
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-034
NDA 19-510/S-031
NDA 20-249/S-013
Page 10
Musculoskeletal: musculoskeletal pain including muscle cramps, arthralgia
Nervous System/Psychiatric: grand mal seizure; psychic disturbances, which were reversible in cases for
which follow-up was obtained, including hallucinations, confusion, agitation, depression, anxiety, decreased
libido; paresthesia; insomnia; somnolence. Convulsions, in patients with impaired renal function, have been
reported very rarely.
Respiratory: bronchospasm, interstitial pneumonia
Skin: toxic epidermal necrolysis/Stevens Johnson syndrome (very rare), alopecia, acne, pruritus, dry skin,
flushing
Special Senses: tinnitus, taste disorder
Other: rare cases of impotence and rare cases of gynecomastia have been reported; however, in controlled
clinical trials, the incidences were not greater than those seen with placebo.
The adverse reactions reported for PEPCID Tablets may also occur with PEPCID for Oral Suspension.
Pediatric Patients
In a clinical study in 35 pediatric patients <1 year of age with GERD symptoms [e.g., vomiting (spitting up),
irritability (fussing)], agitation was observed in 5 patients on famotidine that resolved when the medication was
discontinued.
OVERDOSAGE
The adverse reactions in overdose cases are similar to the adverse reactions encountered in normal clinical
experience (see ADVERSE REACTIONS). Oral doses of up to 640 mg/day have been given to adult patients
with pathological hypersecretory conditions with no serious adverse effects. In the event of overdosage,
treatment should be symptomatic and supportive. Unabsorbed material should be removed from the
gastrointestinal tract, the patient should be monitored, and supportive therapy should be employed.
The oral LD50 of famotidine in male and female rats and mice was greater than 3000 mg/kg and the minimum
lethal acute oral dose in dogs exceeded 2000 mg/kg. Famotidine did not produce overt effects at high oral
doses in mice, rats, cats and dogs, but induced significant anorexia and growth depression in rabbits starting
with 200 mg/kg/day orally. The intravenous LD50 of famotidine for mice and rats ranged from 254-563 mg/kg and
the minimum lethal single I.V. dose in dogs was approximately 300 mg/kg. Signs of acute intoxication in I.V.
treated dogs were emesis, restlessness, pallor of mucous membranes or redness of mouth and ears,
hypotension, tachycardia and collapse.
DOSAGE AND ADMINISTRATION
Duodenal Ulcer
Acute Therapy: The recommended adult oral dosage for active duodenal ulcer is 40 mg once a day at
bedtime. Most patients heal within 4 weeks; there is rarely reason to use PEPCID at full dosage for longer than
6 to 8 weeks. A regimen of 20 mg b.i.d. is also effective.
Maintenance Therapy: The recommended adult oral dose is 20 mg once a day at bedtime.
Benign Gastric Ulcer
Acute Therapy: The recommended adult oral dosage for active benign gastric ulcer is 40 mg once a day at
bedtime.
Gastroesophageal Reflux Disease (GERD)
The recommended oral dosage for treatment of adult patients with symptoms of GERD is 20 mg b.i.d. for up
to 6 weeks. The recommended oral dosage for the treatment of adult patients with esophagitis including
erosions and ulcerations and accompanying symptoms due to GERD is 20 or 40 mg b.i.d. for up to 12 weeks
(see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies).
Dosage for Pediatric Patients <1 year of age Gastroesophageal Reflux Disease (GERD)
See PRECAUTIONS, Pediatric Patients <1 year of age.
The studies described in PRECAUTIONS, Pediatric Patients <1 year of age suggest the following starting
doses in pediatric patients <1 year of age: Gastroesophageal Reflux Disease (GERD) - 0.5 mg/kg/dose of
famotidine oral suspension for the treatment of GERD for up to 8 weeks once daily in patients <3 months of age
and 0.5 mg/kg/dose twice daily in patients 3 months to <1 year of age. Patients should also be receiving
conservative measures (e.g., thickened feedings). The use of intravenous famotidine in pediatric patients
<1 year of age with GERD has not been adequately studied.
Dosage for Pediatric Patients 1-16 years of age
See PRECAUTIONS, Pediatric Patients 1-16 years of age.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-034
NDA 19-510/S-031
NDA 20-249/S-013
Page 11
The studies described in PRECAUTIONS, Pediatric Patients 1-16 years of age suggest the following starting
doses in pediatric patients 1-16 years of age:
Peptic ulcer - 0.5 mg/kg/day p.o. at bedtime or divided b.i.d. up to 40 mg/day.
Gastroesophageal Reflux Disease with or without esophagitis including erosions and ulcerations -
1.0 mg/kg/day p.o. divided b.i.d. up to 40 mg b.i.d.
While published uncontrolled studies suggest effectiveness of famotidine in the treatment of
gastroesophageal reflux disease and peptic ulcer, data in pediatric patients are insufficient to establish percent
response with dose and duration of therapy. Therefore, treatment duration (initially based on adult duration
recommendations) and dose should be individualized based on clinical response and/or pH determination
(gastric or esophageal) and endoscopy. Published uncontrolled clinical studies in pediatric patients 1-16 years
of age have employed doses up to 1 mg/kg/day for peptic ulcer and 2 mg/kg/day for GERD with or without
esophagitis including erosions and ulcerations.
Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas)
The dosage of PEPCID in patients with pathological hypersecretory conditions varies with the individual
patient. The recommended adult oral starting dose for pathological hypersecretory conditions is 20 mg q 6 h. In
some patients, a higher starting dose may be required. Doses should be adjusted to individual patient needs
and should continue as long as clinically indicated. Doses up to 160 mg q 6 h have been administered to some
adult patients with severe Zollinger-Ellison Syndrome.
Oral Suspension
PEPCID for Oral Suspension may be substituted for PEPCID Tablets in any of the above indications. Each
five mL contains 40 mg of famotidine after constitution of the powder with 46 mL of Purified Water as directed.
Directions for Preparing PEPCID for Oral Suspension
Prepare suspension at time of dispensing. Slowly add 46 mL of Purified Water. Shake vigorously for 5-10
seconds immediately after adding the water and immediately before use.
Stability of PEPCID for Oral Suspension
Unused constituted oral suspension should be discarded after 30 days.
Concomitant Use of Antacids
Antacids may be given concomitantly if needed.
Dosage Adjustment for Patients with Moderate or Severe Renal Insufficiency
In adult patients with moderate (creatinine clearance <50 mL/min) or severe (creatinine clearance
<10 mL/min) renal insufficiency, the elimination half-life of PEPCID is increased. For patients with severe renal
insufficiency, it may exceed 20 hours, reaching approximately 24 hours in anuric patients. Since CNS adverse
effects have been reported in patients with moderate and severe renal insufficiency, to avoid excess
accumulation of the drug in patients with moderate or severe renal insufficiency, the dose of PEPCID may be
reduced to half the dose or the dosing interval may be prolonged to 36-48 hours as indicated by the patient's
clinical response.
Based on the comparison of pharmacokinetic parameters for PEPCID in adults and pediatric patients,
dosage adjustment in pediatric patients with moderate or severe renal insufficiency should be considered.
HOW SUPPLIED
No. 9786 — PEPCID Tablets, 20 mg, are beige colored, rounded square shaped, film-coated tablets coded
MSD 963 on one side and plain on the other. They are supplied as follows:
NDC 0006-0963-31 unit of use bottles of 30
NDC 0006-0963-58 unit of use bottles of 100.
No. 9788 — PEPCID Tablets, 40 mg, are tan, rounded square shaped, film-coated tablets coded MSD 964
on one side and plain on the other. They are supplied as follows:
NDC 0006-0964-31 unit of use bottles of 30
NDC 0006-0964-58 unit of use bottles of 100.
No. 3538 — PEPCID for Oral Suspension is a white to off-white powder containing 400 mg of famotidine for
constitution. When constituted as directed, PEPCID for Oral Suspension is a smooth, mobile, off-white,
homogeneous suspension with a cherry-banana-mint flavor, containing 40 mg of famotidine per 5 mL.
NDC 0006-3538-92, bottles containing 400 mg famotidine.
Storage
Preserve in well-closed, light-resistant containers. Store at controlled room temperature.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-034
NDA 19-510/S-031
NDA 20-249/S-013
Page 12
Store PEPCID for Oral Suspension dry powder and suspension at 25°C (77°F); excursions permitted to
15-30°C (59-86°F) [see USP Controlled Room Temperature]. Suspension: Protect from freezing. Discard
unused suspension after 30 days.
PEPCID (famotidine) for Oral Suspension is manufactured by:
PEPCID (famotidine) Tablets 20 mg and Tablets 40 mg are manufactured for:
By:
MERCK SHARP & DOHME Pty., Ltd.
South Granville, NSW, Australia 2142.
Issued October 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
NDA 19-462/S-034
NDA 19-510/S-031
NDA 20-249/S-013
Page 13
PEPCID®
(FAMOTIDINE) INJECTION PREMIXED
PEPCID®
(FAMOTIDINE) INJECTION
DESCRIPTION
The active ingredient in PEPCID* (famotidine) Injection Premixed and PEPCID (famotidine) Injection is a
histamine
H2-receptor
antagonist.
Famotidine
is
N'-(aminosulfonyl)-3-[[[2-[(diaminomethylene)amino]-4-
thiazolyl]methyl]thio]propanimidamide. The empirical formula of famotidine is C8H15N7O2S3 and its molecular
weight is 337.43. Its structural formula is:
Famotidine is a white to pale yellow crystalline compound that is freely soluble in glacial acetic acid, slightly
soluble in methanol, very slightly soluble in water, and practically insoluble in ethanol.
PEPCID Injection Premixed is supplied as a sterile solution, for intravenous use only, in plastic single dose
containers. Each 50 mL of the premixed, iso-osmotic intravenous injection contains 20 mg famotidine, USP, and
the following inactive ingredients: L-aspartic acid 6.8 mg, sodium chloride, USP, 450 mg, and Water for
Injection. The pH ranges from 5.7 to 6.4 and may have been adjusted with additional L-aspartic acid or with
sodium hydroxide.
The plastic container is fabricated from a specially designed multilayer plastic (PL 2501). Solutions are in
contact with the polyethylene layer of the container and can leach out certain chemical components of the
plastic in very small amounts within the expiration period. The suitability and safety of the plastic have been
confirmed in tests in animals according to the USP biological tests for plastic containers, as well as by tissue
culture toxicity studies.
PEPCID (famotidine) Injection is supplied as a sterile concentrated solution for intravenous injection. Each
mL of the solution contains 10 mg of famotidine and the following inactive ingredients: L-aspartic acid 4 mg,
mannitol 20 mg, and Water for Injection q.s. 1 mL. The multidose injection also contains benzyl alcohol 0.9%
added as preservative.
CLINICAL PHARMACOLOGY IN ADULTS
GI Effects
PEPCID is a competitive inhibitor of histamine H2-receptors. The primary clinically important pharmacologic
activity of PEPCID is inhibition of gastric secretion. Both the acid concentration and volume of gastric secretion
are suppressed by PEPCID, while changes in pepsin secretion are proportional to volume output.
In normal volunteers and hypersecretors, PEPCID inhibited basal and nocturnal gastric secretion, as well as
secretion stimulated by food and pentagastrin. After oral administration, the onset of the antisecretory effect
occurred within one hour; the maximum effect was dose-dependent, occurring within one to three hours.
Duration of inhibition of secretion by doses of 20 and 40 mg was 10 to 12 hours.
After intravenous administration, the maximum effect was achieved within 30 minutes. Single intravenous
doses of 10 and 20 mg inhibited nocturnal secretion for a period of 10 to 12 hours. The 20 mg dose was
associated with the longest duration of action in most subjects.
Single evening oral doses of 20 and 40 mg inhibited basal and nocturnal acid secretion in all subjects; mean
nocturnal gastric acid secretion was inhibited by 86% and 94%, respectively, for a period of at least 10 hours.
The same doses given in the morning suppressed food-stimulated acid secretion in all subjects. The mean
suppression was 76% and 84%, respectively, 3 to 5 hours after administration, and 25% and 30%, respectively,
8 to 10 hours after administration. In some subjects who received the 20 mg dose, however, the antisecretory
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT © 1993, 1995, 1996 MERCK & CO., 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 19-462/S-034
NDA 19-510/S-031
NDA 20-249/S-013
Page 14
effect was dissipated within 6-8 hours. There was no cumulative effect with repeated doses. The nocturnal
intragastric pH was raised by evening doses of 20 and 40 mg of PEPCID to mean values of 5.0 and 6.4,
respectively. When PEPCID was given after breakfast, the basal daytime interdigestive pH at 3 and 8 hours
after 20 or 40 mg of PEPCID was raised to about 5.
PEPCID had little or no effect on fasting or postprandial serum gastrin levels. Gastric emptying and exocrine
pancreatic function were not affected by PEPCID.
Other Effects
Systemic effects of PEPCID in the CNS, cardiovascular, respiratory or endocrine systems were not noted in
clinical pharmacology studies. Also, no antiandrogenic effects were noted. (See ADVERSE REACTIONS.)
Serum hormone levels, including prolactin, cortisol, thyroxine (T4), and testosterone, were not altered after
treatment with PEPCID.
Pharmacokinetics
Orally administered PEPCID is incompletely absorbed and its bioavailability is 40-45%. PEPCID undergoes
minimal first-pass metabolism. After oral doses, peak plasma levels occur in 1-3 hours. Plasma levels after
multiple doses are similar to those after single doses. Fifteen to 20% of PEPCID in plasma is protein bound.
PEPCID has an elimination half-life of 2.5-3.5 hours. PEPCID is eliminated by renal (65-70%) and metabolic
(30-35%) routes. Renal clearance is 250-450 mL/min, indicating some tubular excretion. Twenty-five to 30% of
an oral dose and 65-70% of an intravenous dose are recovered in the urine as unchanged compound. The only
metabolite identified in man is the S-oxide.
There is a close relationship between creatinine clearance values and the elimination half-life of PEPCID. In
patients with severe renal insufficiency, i.e., creatinine clearance less than 10 mL/min, the elimination half-life of
PEPCID may exceed 20 hours and adjustment of dose or dosing intervals in moderate and severe renal
insufficiency may be necessary (see PRECAUTIONS, DOSAGE AND ADMINISTRATION).
In elderly patients, there are no clinically significant age-related changes in the pharmacokinetics of PEPCID.
However, in elderly patients with decreased renal function, the clearance of the drug may be decreased (see
PRECAUTIONS, Geriatric Use).
Clinical Studies
The majority of clinical study experience involved oral administration of PEPCID Tablets, and is provided
herein for reference.
Duodenal Ulcer
In a U.S. multicenter, double-blind study in outpatients with endoscopically confirmed duodenal ulcer, orally
administered PEPCID was compared to placebo. As shown in Table 1, 70% of patients treated with PEPCID
40 mg h.s. were healed by week 4.
Table 1
Outpatients with Endoscopically
Confirmed Healed Duodenal Ulcers
PEPCID
40 mg h.s.
(N=89)
PEPCID
20 mg b.i.d.
(N=84)
Placebo
h.s.
(N=97)
Week 2
Week 4
**32%
**70%
**38%
**67%
17%
31%
** Statistically significantly different than placebo (p<0.001)
Patients not healed by week 4 were continued in the study. By week 8, 83% of patients treated with PEPCID
had healed versus 45% of patients treated with placebo. The incidence of ulcer healing with PEPCID was
significantly higher than with placebo at each time point based on proportion of endoscopically confirmed healed
ulcers.
In this study, time to relief of daytime and nocturnal pain was significantly shorter for patients receiving
PEPCID than for patients receiving placebo; patients receiving PEPCID also took less antacid than the patients
receiving placebo.
Long-Term Maintenance
Treatment of Duodenal Ulcers
PEPCID, 20 mg p.o. h.s. was compared to placebo h.s. as maintenance therapy in two double-blind,
multicenter studies of patients with endoscopically confirmed healed duodenal ulcers. In the U.S. study the
observed ulcer incidence within 12 months in patients treated with placebo was 2.4 times greater than in the
patients treated with PEPCID. The 89 patients treated with PEPCID had a cumulative observed ulcer incidence
of 23.4% compared to an observed ulcer incidence of 56.6% in the 89 patients receiving placebo (p<0.01).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-034
NDA 19-510/S-031
NDA 20-249/S-013
Page 15
These results were confirmed in an international study where the cumulative observed ulcer incidence within 12
months in the 307 patients treated with PEPCID was 35.7%, compared to an incidence of 75.5% in the 325
patients treated with placebo (p<0.01).
Gastric Ulcer
In both a U.S. and an international multicenter, double-blind study in patients with endoscopically confirmed
active benign gastric ulcer, orally administered PEPCID, 40 mg h.s., was compared to placebo h.s. Antacids
were permitted during the studies, but consumption was not significantly different between the PEPCID and
placebo groups. As shown in Table 2, the incidence of ulcer healing (dropouts counted as unhealed) with
PEPCID was statistically significantly better than placebo at weeks 6 and 8 in the U.S. study, and at weeks 4, 6
and 8 in the international study, based on the number of ulcers that healed, confirmed by endoscopy.
Table 2
Patients with Endoscopically
Confirmed Healed Gastric Ulcers
U.S. Study
International Study
PEPCID
40 mg h.s.
(N=74)
Placebo
h.s.
(N=75)
PEPCID
40 mg h.s.
(N=149)
Placebo
h.s.
(N=145)
Week 4
Week 6
Week 8
45%
†66%
***78%
39%
44%
64%
†47%
†65%
†80%
31%
46%
54%
***,† Statistically significantly better than placebo (p≤0.05, p≤0.01 respectively)
Time to complete relief of daytime and nighttime pain was statistically significantly shorter for patients
receiving PEPCID than for patients receiving placebo; however, in neither study was there a statistically
significant difference in the proportion of patients whose pain was relieved by the end of the study (week 8).
Gastroesophageal Reflux Disease (GERD)
Orally administered PEPCID was compared to placebo in a U.S. study that enrolled patients with symptoms
of GERD and without endoscopic evidence of erosion or ulceration of the esophagus. PEPCID 20 mg b.i.d. was
statistically significantly superior to 40 mg h.s. and to placebo in providing a successful symptomatic outcome,
defined as moderate or excellent improvement of symptoms (Table 3).
Table 3
% Successful Symptomatic Outcome
PEPCID
20 mg b.i.d.
(N=154)
PEPCID
40 mg h.s.
(N=149)
Placebo
(N=73)
Week 6
82††
69
62
†† p≤0.01 vs Placebo
By two weeks of treatment, symptomatic success was observed in a greater percentage of patients taking
PEPCID 20 mg b.i.d. compared to placebo (p≤0.01).
Symptomatic improvement and healing of endoscopically verified erosion and ulceration were studied in two
additional trials. Healing was defined as complete resolution of all erosions or ulcerations visible with
endoscopy. The U.S. study comparing PEPCID 40 mg p.o. b.i.d. to placebo and PEPCID 20 mg p.o. b.i.d.,
showed a significantly greater percentage of healing for PEPCID 40 mg b.i.d. at weeks 6 and 12 (Table 4).
Table 4
% Endoscopic Healing - U.S. Study
PEPCID
40 mg b.i.d.
(N=127)
PEPCID
20 mg b.i.d.
(N=125)
Placebo
(N=66)
Week 6
Week 12
48†††,‡‡
69†††,‡
32
54†††
18
29
††† p≤0.01 vs Placebo
‡ p≤0.05 vs PEPCID 20 mg b.i.d.
‡‡ p≤0.01 vs PEPCID 20 mg b.i.d.
As compared to placebo, patients who received PEPCID had faster relief of daytime and nighttime heartburn
and a greater percentage of patients experienced complete relief of nighttime heartburn. These differences were
statistically significant.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-034
NDA 19-510/S-031
NDA 20-249/S-013
Page 16
In the international study, when PEPCID 40 mg p.o. b.i.d. was compared to ranitidine 150 mg p.o. b.i.d., a
statistically significantly greater percentage of healing was observed with PEPCID 40 mg b.i.d. at week 12
(Table 5). There was, however, no significant difference among treatments in symptom relief.
Table 5
% Endoscopic Healing - International Study
PEPCID
40 mg b.i.d.
(N=175)
PEPCID
20 mg b.i.d.
(N=93)
Ranitidine
150 mg b.i.d.
(N=172)
Week 6
Week 12
48
71‡‡‡
52
68
42
60
‡‡‡ p≤0.05 vs Ranitidine 150 mg b.i.d.
Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas)
In studies of patients with pathological hypersecretory conditions such as Zollinger-Ellison Syndrome with or
without multiple endocrine adenomas, PEPCID significantly inhibited gastric acid secretion and controlled
associated symptoms. Orally administered doses from 20 to 160 mg q 6 h maintained basal acid secretion
below 10 mEq/hr; initial doses were titrated to the individual patient need and subsequent adjustments were
necessary with time in some patients. PEPCID was well tolerated at these high dose levels for prolonged
periods (greater than 12 months) in eight patients, and there were no cases reported of gynecomastia,
increased prolactin levels, or impotence which were considered to be due to the drug.
CLINICAL PHARMACOLOGY IN PEDIATRIC PATIENTS
Pharmacokinetics
Table 6 presents pharmacokinetic data from clinical trials and a published study in pediatric patients (<1 year
of age; N=27) given famotidine I.V. 0.5 mg/kg and from published studies of small numbers of pediatric patients
(1-15 years of age) given famotidine intravenously. Areas under the curve (AUCs) are normalized to a dose of
0.5 mg/kg I.V. for pediatric patients 1-15 years of age and compared with an extrapolated 40 mg intravenous
dose in adults (extrapolation based on results obtained with a 20 mg I.V. adult dose).
Table 6
Pharmacokinetic Parametersa of Intravenous Famotidine
Age
(N=number of
patients)
Area Under
the Curve (AUC)
(ng-hr/mL)
Total
Clearance (Cl)
(L/hr/kg)
Volume of
Distribution (Vd)
(L/kg)
Elimination
Half-life (T1/2)
(hours)
0-1 monthc
(N=10)
NA
0.13 ± 0.06
1.4 ± 0.4
10.5 ± 5.4
0-3 monthsd
(N=6)
2688 ± 847
0.21 ± 0.06
1.8 ± 0.3
8.1 ± 3.5
>3-12 monthsd
(N=11)
1160 ± 474
0.49 ± 0.17
2.3 ± 0.7
4.5 ± 1.1
1-11 yrs (N=20)
1089 ± 834
0.54 ± 0.34
2.07 ± 1.49
3.38 ± 2.60
11-15 yrs (N=6)
1140 ± 320
0.48 ± 0.14
1.5 ± 0.4
2.3 ± 0.4
Adult (N=16)
1726b
0.39 ± 0.14
1.3 ± 0.2
2.83 ± 0.99
aValues are presented as means ± SD unless indicated otherwise.
bMean value only.
cSingle center study.
dMulticenter study.
Plasma clearance is reduced and elimination half-life is prolonged in pediatric patients 0-3 months of age
compared to older pediatric patients. The pharmacokinetic parameters for pediatric patients, ages
>3 months-15 years, are comparable to those obtained for adults.
Bioavailability studies of 8 pediatric patients (11-15 years of age) showed a mean oral bioavailability of 0.5
compared to adult values of 0.42 to 0.49. Oral doses of 0.5 mg/kg achieved AUCs of 645 ± 249 ng-hr/mL and
580 ± 60 ng-hr/mL in pediatric patients <1 year of age (N=5) and in pediatric patients 11-15 years of age,
respectively, compared to 482 ± 181 ng-hr/mL in adults treated with 40 mg orally.
Pharmacodynamics
Pharmacodynamics of famotidine were evaluated in 5 pediatric patients 2-13 years of age using the sigmoid
Emax model. These data suggest that the relationship between serum concentration of famotidine and gastric
acid suppression is similar to that observed in one study of adults (Table 7).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-034
NDA 19-510/S-031
NDA 20-249/S-013
Page 17
Table 7
Pharmacodynamics of famotidine using the sigmoid Emax model
EC50 (ng/mL)*
Pediatric Patients
26 ± 13
Data from one study
a) healthy adult subjects
26.5 ± 10.3
b) adult patients with upper GI bleeding
18.7 ± 10.8
*Serum concentration of famotidine associated with 50% maximum gastric acid reduction. Values are presented as means ± SD.
Five published studies (Table 8) examined the effect of famotidine on gastric pH and duration of acid
suppression in pediatric patients. While each study had a different design, acid suppression data over time are
summarized as follows:
Table 8
Dosage
Route
Effecta
Number of Patients
(age range)
0.5 mg/kg, single dose
I.V.
gastric pH >4 for 19.5 hours (17.3,
21.8)c
11 (5-19 days)
0.3 mg/kg, single dose
I.V.
gastric pH >3.5 for 8.7 ± 4.7b hours
6 (2-7 years)
0.4-0.8 mg/kg
I.V.
gastric pH >4 for 6-9 hours
18 (2-69 months)
0.5 mg/kg, single dose
I.V.
a >2 pH unit increase above
baseline in gastric pH for >8 hours
9 (2-13 years)
0.5 mg/kg b.i.d.
I.V.
gastric pH >5 for 13.5 ± 1.8b hours
4 (6-15 years)
0.5 mg/kg b.i.d.
oral
gastric pH >5 for 5.0 ± 1.1b hours
4 (11-15 years)
aValues reported in published literature.
bMeans ± SD.
cMean (95% confidence interval).
The duration of effect of famotidine I.V. 0.5 mg/kg on gastric pH and acid suppression was shown in one
study to be longer in pediatric patients <1 month of age than in older pediatric patients. This longer duration of
gastric acid suppression is consistent with the decreased clearance in pediatric patients <3 months of age (see
Table 6).
INDICATIONS AND USAGE
PEPCID Injection Premixed, supplied as a premixed solution in plastic containers (PL 2501 Plastic), and
PEPCID Injection, supplied as a concentrated solution for intravenous injection, are intended for intravenous
use only. PEPCID Injection Premixed and PEPCID Injection are indicated in some hospitalized patients with
pathological hypersecretory conditions or intractable ulcers, or as an alternative to the oral dosage forms for
short term use in patients who are unable to take oral medication for the following conditions:
1. Short term treatment of active duodenal ulcer. Most adult patients heal within 4 weeks; there is rarely
reason to use PEPCID at full dosage for longer than 6 to 8 weeks. Studies have not assessed the safety of
famotidine in uncomplicated active duodenal ulcer for periods of more than eight weeks.
2. Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of an active ulcer.
Controlled studies in adults have not extended beyond one year.
3. Short term treatment of active benign gastric ulcer. Most adult patients heal within 6 weeks. Studies have
not assessed the safety or efficacy of famotidine in uncomplicated active benign gastric ulcer for periods of more
than 8 weeks.
4. Short term treatment of gastroesophageal reflux disease (GERD). PEPCID is indicated for short term
treatment of patients with symptoms of GERD (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies).
PEPCID is also indicated for the short term treatment of esophagitis due to GERD including erosive or
ulcerative disease diagnosed by endoscopy (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies).
5. Treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison Syndrome, multiple endocrine
adenomas) (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies).
CONTRAINDICATIONS
Hypersensitivity to any component of these products. Cross sensitivity in this class of compounds has been
observed. Therefore, PEPCID should not be administered to patients with a history of hypersensitivity to other
H2-receptor antagonists.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-034
NDA 19-510/S-031
NDA 20-249/S-013
Page 18
PRECAUTIONS
General
Symptomatic response to therapy with PEPCID does not preclude the presence of gastric malignancy.
Patients with Moderate or Severe Renal Insufficiency
Since CNS adverse effects have been reported in patients with moderate and severe renal insufficiency,
longer intervals between doses or lower doses may need to be used in patients with moderate (creatinine
clearance <50 mL/min) or severe (creatinine clearance <10 mL/min) renal insufficiency to adjust for the longer
elimination half-life of famotidine (see CLINICAL PHARMACOLOGY IN ADULTS, DOSAGE AND
ADMINISTRATION).
Drug Interactions
No drug interactions have been identified. Studies with famotidine in man, in animal models, and in vitro
have shown no significant interference with the disposition of compounds metabolized by the hepatic
microsomal enzymes, e.g., cytochrome P450 system. Compounds tested in man include warfarin, theophylline,
phenytoin, diazepam, aminopyrine and antipyrine. Indocyanine green as an index of hepatic drug extraction has
been tested and no significant effects have been found.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 106 week study in rats and a 92 week study in mice given oral doses of up to 2000 mg/kg/day
(approximately 2500 times the recommended human dose for active duodenal ulcer), there was no evidence of
carcinogenic potential for PEPCID.
Famotidine was negative in the microbial mutagen test (Ames test) using Salmonella typhimurium and
Escherichia coli with or without rat liver enzyme activation at concentrations up to 10,000 mcg/plate. In in vivo
studies in mice, with a micronucleus test and a chromosomal aberration test, no evidence of a mutagenic effect
was observed.
In studies with rats given oral doses of up to 2000 mg/kg/day or intravenous doses of up to 200 mg/kg/day,
fertility and reproductive performance were not affected.
Pregnancy
Pregnancy Category B
Reproductive studies have been performed in rats and rabbits at oral doses of up to 2000 and
500 mg/kg/day, respectively, and in both species at I.V. doses of up to 200 mg/kg/day, and have revealed no
significant evidence of impaired fertility or harm to the fetus due to PEPCID. While no direct fetotoxic effects
have been observed, sporadic abortions occurring only in mothers displaying marked decreased food intake
were seen in some rabbits at oral doses of 200 mg/kg/day (250 times the usual human dose) or higher. There
are, however, no adequate or well-controlled studies in pregnant women. Because animal reproductive studies
are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers
Studies performed in lactating rats have shown that famotidine is secreted into breast milk. Transient growth
depression was observed in young rats suckling from mothers treated with maternotoxic doses of at least 600
times the usual human dose. Famotidine is detectable in human milk. Because of the potential for serious
adverse reactions in nursing infants from PEPCID, 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 Patients <1 year of age
Use of PEPCID in pediatric patients <1 year of age is supported by evidence from adequate and
well-controlled studies of PEPCID in adults, and by the following studies in pediatric patients <1 year of age.
Two pharmacokinetic studies in pediatric patients <1 year of age (N=48) demonstrated that clearance of
famotidine in patients >3 months to 1 year of age is similar to that seen in older pediatric patients (1-15 years of
age) and adults. In contrast, pediatric patients 0-3 months of age had famotidine clearance values that were 2-
to 4-fold less than those in older pediatric patients and adults. These studies also show that the mean
bioavailability in pediatric patients <1 year of age after oral dosing is similar to older pediatric patients and
adults. Pharmacodynamic data in pediatric patients 0-3 months of age suggest that the duration of acid
suppression is longer compared with older pediatric patients, consistent with the longer famotidine half-life in
pediatric patients 0-3 months of age. (See CLINICAL PHARMACOLOGY IN PEDIATRIC PATIENTS,
Pharmacokinetics and Pharmacodynamics.)
In a double-blind, randomized, treatment-withdrawal study, 35 pediatric patients <1 year of age who were
diagnosed as having gastroesophageal reflux disease were treated for up to 4 weeks with famotidine oral
suspension (0.5 mg/kg/dose or 1 mg/kg/dose). Although an intravenous famotidine formulation was available,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-034
NDA 19-510/S-031
NDA 20-249/S-013
Page 19
no patients were treated with intravenous famotidine in this study. Also, caregivers were instructed to provide
conservative treatment including thickened feedings. Enrolled patients were diagnosed primarily by history of
vomiting (spitting up) and irritability (fussiness). The famotidine dosing regimen was once daily for patients
<3 months of age and twice daily for patients ≥3 months of age. After 4 weeks of treatment, patients were
randomly withdrawn from the treatment and followed an additional 4 weeks for adverse events and
symptomatology. Patients were evaluated for vomiting (spitting up), irritability (fussiness) and global
assessments of improvement. The study patients ranged in age at entry from 1.3 to 10.5 months (mean 5.6 ±
2.9 months), 57% were female, 91% were white and 6% were black. Most patients (27/35) continued into the
treatment withdrawal phase of the study. Two patients discontinued famotidine due to adverse events. Most
patients improved during the initial treatment phase of the study. Results of the treatment withdrawal phase
were difficult to interpret because of small numbers of patients. Of the 35 patients enrolled in the study, agitation
was observed in 5 patients on famotidine that resolved when the medication was discontinued; agitation was not
observed in patients on placebo (see ADVERSE REACTIONS, Pediatric Patients).
These studies suggest that a starting dose of 0.5 mg/kg/dose of famotidine oral suspension may be of benefit
for the treatment of GERD for up to 4 weeks once daily in patients <3 months of age and twice daily in patients
3 months to <1 year of age; the safety and benefit of famotidine treatment beyond 4 weeks have not been
established. Famotidine should be considered for the treatment of GERD only if conservative measures (e.g.,
thickened feedings) are used concurrently and if the potential benefit outweighs the risk.
Pediatric Patients 1-16 years of age
Use of PEPCID in pediatric patients 1-16 years of age is supported by evidence from adequate and well-
controlled studies of PEPCID in adults, and by the following studies in pediatric patients: In published studies in
small numbers of pediatric patients 1-15 years of age, clearance of famotidine was similar to that seen in adults.
In pediatric patients 11-15 years of age, oral doses of 0.5 mg/kg were associated with a mean area under the
curve (AUC) similar to that seen in adults treated orally with 40 mg. Similarly, in pediatric patients 1-15 years of
age, intravenous doses of 0.5 mg/kg were associated with a mean AUC similar to that seen in adults treated
intravenously with 40 mg. Limited published studies also suggest that the relationship between serum
concentration and acid suppression is similar in pediatric patients 1-15 years of age as compared with adults.
These studies suggest that the starting dose for pediatric patients 1-16 years of age is 0.25 mg/kg intravenously
(injected over a period of not less than two minutes or as a 15-minute infusion) q 12 h up to 40 mg/day.
While published uncontrolled clinical studies suggest effectiveness of famotidine in the treatment of peptic
ulcer, data in pediatric patients are insufficient to establish percent response with dose and duration of therapy.
Therefore, treatment duration (initially based on adult duration recommendations) and dose should be
individualized based on clinical response and/or gastric pH determination and endoscopy. Published
uncontrolled studies in pediatric patients have demonstrated gastric acid suppression with doses up to
0.5 mg/kg intravenously q 12 h.
Geriatric Use
Of the 4,966 subjects in clinical studies who were treated with famotidine, 488 subjects (9.8%) were 65 and
older, and 88 subjects (1.7%) were greater than 75 years of age. No overall differences in safety or
effectiveness were observed between these subjects and younger subjects. However, greater sensitivity of
some older patients cannot be ruled out.
No dosage adjustment is required based on age (see CLINICAL PHARMACOLOGY IN ADULTS,
Pharmacokinetics). 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. Dosage adjustment in the case of moderate or severe renal impairment is necessary (see
PRECAUTIONS, Patients with Moderate or Severe Renal Insufficiency and DOSAGE AND ADMINISTRATION,
Dosage Adjustment for Patients with Moderate or Severe Renal Insufficiency).
ADVERSE REACTIONS
The adverse reactions listed below have been reported during domestic and international clinical trials in
approximately 2500 patients. In those controlled clinical trials in which PEPCID Tablets were compared to
placebo, the incidence of adverse experiences in the group which received PEPCID Tablets, 40 mg at bedtime,
was similar to that in the placebo group.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-034
NDA 19-510/S-031
NDA 20-249/S-013
Page 20
The following adverse reactions have been reported to occur in more than 1% of patients on therapy with
PEPCID in controlled clinical trials, and may be causally related to the drug: headache (4.7%), dizziness (1.3%),
constipation (1.2%) and diarrhea (1.7%).
The following other adverse reactions have been reported infrequently in clinical trials or since the drug was
marketed. The relationship to therapy with PEPCID has been unclear in many cases. Within each category the
adverse reactions are listed in order of decreasing severity:
Body as a Whole: fever, asthenia, fatigue
Cardiovascular: arrhythmia, AV block, palpitation
Gastrointestinal: cholestatic jaundice, liver enzyme abnormalities, vomiting, nausea, abdominal discomfort,
anorexia, dry mouth
Hematologic: rare cases of agranulocytosis, pancytopenia, leukopenia, thrombocytopenia
Hypersensitivity: anaphylaxis, angioedema, orbital or facial edema, urticaria, rash, conjunctival injection
Musculoskeletal: musculoskeletal pain including muscle cramps, arthralgia
Nervous System/Psychiatric: grand mal seizure; psychic disturbances, which were reversible in cases for
which follow-up was obtained, including hallucinations, confusion, agitation, depression, anxiety, decreased
libido; paresthesia; insomnia; somnolence. Convulsions, in patients with impaired renal function, have been
reported very rarely.
Respiratory: bronchospasm, interstitial pneumonia
Skin: toxic epidermal necrolysis/Stevens Johnson syndrome (very rare), alopecia, acne, pruritus, dry skin,
flushing
Special Senses: tinnitus, taste disorder
Other: rare cases of impotence and rare cases of gynecomastia have been reported; however, in controlled
clinical trials, the incidences were not greater than those seen with placebo.
The adverse reactions reported for PEPCID Tablets may also occur with PEPCID for Oral Suspension,
PEPCID Injection Premixed or PEPCID Injection. In addition, transient irritation at the injection site has been
observed with PEPCID Injection.
Pediatric Patients
In a clinical study in 35 pediatric patients <1 year of age with GERD symptoms [e.g., vomiting (spitting up),
irritability (fussing)], agitation was observed in 5 patients on famotidine that resolved when the medication was
discontinued.
OVERDOSAGE
The adverse reactions in overdose cases are similar to the adverse reactions encountered in normal clinical
experience (see ADVERSE REACTIONS). Oral doses of up to 640 mg/day have been given to adult patients
with pathological hypersecretory conditions with no serious adverse effects. In the event of overdosage,
treatment should be symptomatic and supportive. Unabsorbed material should be removed from the
gastrointestinal tract, the patient should be monitored, and supportive therapy should be employed.
The intravenous LD50 of famotidine for mice and rats ranged from 254-563 mg/kg and the minimum lethal
single I.V. dose in dogs was approximately 300 mg/kg. Signs of acute intoxication in I.V. treated dogs were
emesis, restlessness, pallor of mucous membranes or redness of mouth and ears, hypotension, tachycardia and
collapse. The oral LD50 of famotidine in male and female rats and mice was greater than 3000 mg/kg and the
minimum lethal acute oral dose in dogs exceeded 2000 mg/kg. Famotidine did not produce overt effects at high
oral doses in mice, rats, cats and dogs, but induced significant anorexia and growth depression in rabbits
starting with 200 mg/kg/day orally.
DOSAGE AND ADMINISTRATION
In some hospitalized patients with pathological hypersecretory conditions or intractable ulcers, or in patients
who are unable to take oral medication, PEPCID Injection Premixed or PEPCID Injection may be administered
until oral therapy can be instituted.
The recommended dosage for PEPCID Injection Premixed and PEPCID Injection in adult patients is 20 mg
intravenously q 12 h.
The doses and regimen for parenteral administration in patients with GERD have not been established.
Dosage for Pediatric Patients <1 year of age Gastroesophageal Reflux Disease (GERD)
See PRECAUTIONS, Pediatric Patients <1 year of age.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-034
NDA 19-510/S-031
NDA 20-249/S-013
Page 21
The studies described in PRECAUTIONS, Pediatric Patients <1 year of age suggest the following starting
doses in pediatric patients <1 year of age: Gastroesophageal Reflux Disease (GERD) - 0.5 mg/kg/dose of
famotidine oral suspension for the treatment of GERD for up to 8 weeks once daily in patients <3 months of age
and 0.5 mg/kg/dose twice daily in patients 3 months to <1 year of age. Patients should also be receiving
conservative measures (e.g., thickened feedings). The use of intravenous famotidine in pediatric patients
<1 year of age with GERD has not been adequately studied.
Dosage for Pediatric Patients 1-16 years of age
See PRECAUTIONS, Pediatric Patients 1-16 years of age.
The studies described in PRECAUTIONS, Pediatric Patients 1-16 years of age suggest that the starting dose
in pediatric patients 1-16 years of age is 0.25 mg/kg intravenously (injected over a period of not less than two
minutes or as a 15-minute infusion) q 12 h up to 40 mg/day.
While published uncontrolled clinical studies suggest effectiveness of famotidine in the treatment of peptic
ulcer, data in pediatric patients are insufficient to establish percent response with dose and duration of therapy.
Therefore, treatment duration (initially based on adult duration recommendations) and dose should be
individualized based on clinical response and/or gastric pH determination and endoscopy. Published
uncontrolled studies in pediatric patients 1-16 years of age have demonstrated gastric acid suppression with
doses up to 0.5 mg/kg intravenously q 12 h.
Dosage Adjustments for Patients with Moderate or Severe Renal Insufficiency
In adult patients with moderate (creatinine clearance <50 mL/min) or severe (creatinine clearance
<10 mL/min) renal insufficiency, the elimination half-life of PEPCID is increased. For patients with severe renal
insufficiency, it may exceed 20 hours, reaching approximately 24 hours in anuric patients. Since CNS adverse
effects have been reported in patients with moderate and severe renal insufficiency, to avoid excess
accumulation of the drug in patients with moderate or severe renal insufficiency, the dose of PEPCID Injection
Premixed or PEPCID Injection may be reduced to half the dose, or the dosing interval may be prolonged to
36-48 hours as indicated by the patient's clinical response.
Based on the comparison of pharmacokinetic parameters for PEPCID in adults and pediatric patients,
dosage adjustment in pediatric patients with moderate or severe renal insufficiency should be considered.
Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas)
The dosage of PEPCID in patients with pathological hypersecretory conditions varies with the individual
patient. The recommended adult intravenous dose is 20 mg q 12 h. Doses should be adjusted to individual
patient needs and should continue as long as clinically indicated. In some patients, a higher starting dose may
be required. Oral doses up to 160 mg q 6 h have been administered to some adult patients with severe
Zollinger-Ellison Syndrome.
PEPCID Injection Premixed
PEPCID Injection Premixed, supplied in Galaxy§ containers (PL 2501 Plastic), is a 50 mL iso-osmotic
solution premixed with 0.9% sodium chloride for administration as an infusion over a 15-30 minute period. This
premixed solution is for intravenous use only using sterile equipment.
Directions for Use of Galaxy® Containers
Check the container for minute leaks prior to use by squeezing the bag firmly. If leaks are found, discard
solution as sterility may be impaired. Do not add supplementary medication. Do not use unless solution is clear
and seal is intact.
CAUTION: 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 complete.
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.
To prepare PEPCID intravenous solutions, aseptically dilute 2 mL of PEPCID Injection (solution containing
10 mg/mL) with 0.9% Sodium Chloride Injection or other compatible intravenous solution (see Stability, PEPCID
Injection) to a total volume of either 5 mL or 10 mL and inject over a period of not less than 2 minutes.
To prepare PEPCID intravenous infusion solutions, aseptically dilute 2 mL of PEPCID Injection with 100 mL
of 5% dextrose or other compatible solution (see Stability, PEPCID Injection), and infuse over a 15-30 minute
period.
§ Galaxy® is a registered trademark of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-034
NDA 19-510/S-031
NDA 20-249/S-013
Page 22
Concomitant Use of Antacids
Antacids may be given concomitantly if needed.
Stability
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit.
PEPCID Injection Premixed
PEPCID Injection Premixed, as supplied premixed in 0.9% sodium chloride in Galaxy® containers (PL 2501
Plastic), is stable through the labeled expiration date when stored under the recommended conditions. (See
HOW SUPPLIED, Storage.)
PEPCID Injection
When added to or diluted with most commonly used intravenous solutions, e.g., Water for Injection, 0.9%
Sodium Chloride Injection, 5% and 10% Dextrose Injection, or Lactated Ringer's Injection, diluted PEPCID
Injection is physically and chemically stable (i.e., maintains at least 90% of initial potency) for 7 days at room
temperature — see HOW SUPPLIED, Storage.
When added to or diluted with Sodium Bicarbonate Injection, 5%, PEPCID Injection at a concentration of
0.2 mg/mL (the recommended concentration of PEPCID intravenous infusion solutions) is physically and
chemically stable (i.e., maintains at least 90% of initial potency) for 7 days at room temperature — see HOW
SUPPLIED, Storage. However, a precipitate may form at higher concentrations of PEPCID Injection
(>0.2 mg/mL) in Sodium Bicarbonate Injection, 5%.
HOW SUPPLIED
FOR INTRAVENOUS USE ONLY
No. 3537 — PEPCID Injection Premixed 20 mg per 50 mL is a clear, non-preserved, sterile solution
premixed in a vehicle made iso-osmotic with Sodium Chloride, and is supplied as follows:
NDC 0006-3537-50, 50 mL single dose Galaxy® containers (PL 2501 Plastic).
No. 3539 — PEPCID Injection 10 mg per 1 mL, is a non-preserved, clear, colorless solution and is supplied
as follows:
NDC 0006-3539-04, 10 x 2 mL single dose vials.
No. 3541 — PEPCID Injection 10 mg per 1 mL, is a clear, colorless solution and is supplied as follows:
NDC 0006-3541-14, 4 mL vials
NDC 0006-3541-20, 20 mL vials
NDC 0006-3541-49, 10 x 20 mL vials.
Storage
Store PEPCID Injection Premixed in Galaxy® containers (PL 2501 Plastic) at room temperature (25°C, 77°F).
Exposure of the premixed product to excessive heat should be avoided. Brief exposure to temperatures up to
35°C (95°F) does not adversely affect the product.
Store PEPCID Injection at 2-8°C (36-46°F). If solution freezes, bring to room temperature; allow sufficient
time to solubilize all the components.
Although diluted PEPCID Injection has been shown to be physically and chemically stable for 7 days at room
temperature, there are no data on the maintenance of sterility after dilution. Therefore, it is recommended that if
not used immediately after preparation, diluted solutions of PEPCID Injection should be refrigerated and used
within 48 hours (see DOSAGE AND ADMINISTRATION).
PEPCID (famotidine) Injection Premixed is manufactured for:
By:
BAXTER HEALTHCARE CORPORATION
Deerfield, Illinois 60015 USA
PEPCID (famotidine) Injection is manufactured by:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-462/S-034
NDA 19-510/S-031
NDA 20-249/S-013
Page 23
Issued October 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
|
custom-source
|
2025-02-12T13:45:25.427475
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/019462s034,019510s031,020249s013lbl.pdf', 'application_number': 19462, 'submission_type': 'SUPPL ', 'submission_number': 34}
|
11,512
|
PEEL OPEN TO READ COMPLETE
DIRECTIONS AND WARNINGS
BEFORE PURCHASE
Do not use if printed inner or outer
neckband is broken or missing.
www.imodium.com
NDC 50580-134-04
4 f l oz
(120 mL)
Controls the symptoms
of diarrhea
Mint Flavor
Loperamide HCl, Anti Diarrheal
1 mg per 7.5 mL
®
A-D
Anti-Diarrheal
Oral Solu ion
Loperamide HCl, An i-Diarrheal
1 mg per 7.5 mL
®
A-D
Use cont ols symptoms of diar hea, including Travelers’ Diarrhea
Warnings
Allergy alert: Do not use if you have ever had a rash or other
alle gic reaction to loperamide HCl
Do not use if you have bloody or black stool
Ask a doctor before use if you have
I fever I mucus in the stool I a history of liver disease
Ask a doctor or pharmacist before use if you are
taking ant biotics
Drug Facts (continued)
Questions or comments?
call 1-877-895-3665 (toll-free) or 215-273-8755 (collect)
Active ingredient (in each 7.5 mL) Purpose
Loperamide HCl 1 mg...…............................................Anti-diar heal
Drug Facts
Drug Facts (continued)
When using this product tiredness, d owsiness or
dizziness may occur. Be careful when driving or
operating machinery.
Stop use and ask a doctor if
I symptoms get worse
I diarrhea lasts for more than 2 days
I you get abdominal swelling or bulging.
These may 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 medica help or contact a Poison Control Center
right away. (1-800-222-1222)
Drug Facts (continued)
Other information
I each 30 mL contains: sodium 16 mg
I store between 20-25°C (68-77°F)
I do not use if printed inner or outer neckband is
broken or missing
Inactive ingredients
anhyd ous citric acid, caramel color, D&C yellow no. 10,
FD&C blue no. 1, flavor, glycerin, mic ocrystalline cellulose
and carboxymethylcellulose sodium, p opylene glycol,
pu ified water, simethicone emulsion, sodium benzoate,
sucralose, titanium dioxide, xanthan gum
Active ingredient made in Italy
Distributed by:
JOHNSON & JOHNSON CONSUMER INC.
McNeil Consumer Healthcare Division
Fort Washington, PA 19034 USA
©J&JCI 2015
Drug Facts (continued)
children 9-11 years
(60-95 lbs)
children 6-8 years
(48-59 lbs)
15 mL after first loose stool;
7 5 mL after each subsequent
loose stool; but no more than
45 mL in 24 hours
15 mL after first loose stool;
7 5 mL after each subsequent
loose stool; but no more than
30 mL in 24 hours
children under
6 years (up to 47 lbs)
ask a doctor
Drug Facts (continued)
Directions
I drink plenty of clear fluids to help prevent
dehydration caused by diarrhea
I find right dose on chart. If possible, use weight to dose;
othe wise use age.
I shake well before using
I use only enclosed dosing cup specifically designed for use
with this p oduct. Do not use any other dosing device.
I mL = milliliter
adults and children
12 years and over
30 mL after the first loose stool;
15 mL after each subsequent
loose stool; but no more than
60 mL in 24 hours
PULL
HERE
PEEL OPEN TO READ COMPLETE
DIRECTIONS AND WARNINGS
BEFORE PURCHASE
Do not use if printed inner or outer
neckband is broken or missing.
T
XXXXXXXX
P.
3 0045-0134-04 2
PULL
HERE
NDC 50580-134-04
4 f l oz
(120 mL)
Controls the symptoms
of diarrhea
Mint Flavor
Loperamide HCl, Anti Diarrheal
1 mg per 7.5 mL
®
A-D
Anti-Diarrheal
Oral Solu ion
4 l oz
(120 mL)
4 f l oz
NN
Controls the symptoms
of diarrhea
Mint Flavor
Anti-Diarrheal
Oral Solu ion
LOT
XXXXXXXX
EXP.
3 0045-0134-04 2
PDP = 2.41 square inches
.0625”
Loperamide HCl, Anti Diarrheal
1 mg per 7.5 mL
Loperamide HCl, Anti Diarrheal
Loperamide HCl, Anti Diarrheal
Loperamide HCl, Anti Diarrheal
Loperamide HCl, Anti Diarrheal
®
A-D
Reference ID: 3912606
(b) (4)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PEEL OPEN TO READ COMPLETE
DIRECTIONS AND WARNINGS
BEFORE PURCHASE
www.imodium.com
Do not use if printed inner or outer
neckband is broken or missing.
NDC 50580-134-04
4 f l oz
(120 mL)
Controls the symptoms
of diarrhea
Mint Flavor
Loperamide HCl, Anti Diarrheal
1 mg per 7.5 mL
®
A-D
Anti-Diarrheal
Oral Solu ion
Loperamide HCl, An i-Diarrheal
1 mg per 7.5 mL
®
A-D
Use controls symptoms of diarrhea, including Travelers’ Diar hea
Warnings
Allergy alert: Do not use if you have ever had a rash or other
allergic reaction to loperamide HCl
Do not use if you have bloody or black stool
Ask a doctor before use if you have
I fever I mucus in the stool I a history of liver disease
Ask a doctor or pharmacist before use if you are
taking antibiotics
Drug Facts (continued)
Questions or comments?
call 1-877-895-3665 (toll-free) or 215-273-8755 (collect)
Active ingredient (in each 7.5 mL) Purpose
Loperamide HCl 1 mg...…........................................... Anti-diar heal
Drug Facts
Active ingredient made in Italy
Distributed by:
JOHNSON & JOHNSON CONSUMER INC.
McNeil Consumer Healthcare Division
Fort Washington, PA 19034 USA
©J&JCI 2015
Drug Facts (continued)
When using this product tiredness, d owsiness or
dizziness may occur. Be careful when driving or
operating machinery.
Stop use and ask a doctor if
I symptoms get worse
I diarrhea lasts for more than 2 days
I you get abdominal swelling or bulging.
These may be signs of a serious condition.
If pregnant or breast-feeding, ask a hea th
p ofessional before use.
Keep out of reach of children. In case of overdose,
get medica help or contact a Poison Control Center
right away. (1-800-222-1222)
Drug Facts (continued)
Other information
I each 30 mL contains: sodium 16 mg
I store between 20-25°C (68-77°F)
I do not use if printed inner or outer neckband
is broken or missing
Inactive ingredients
anhydrous citric acid, caramel color, D&C yellow no. 10,
FD&C blue no. 1, flavor, glycerin, mic ocrystalline cellulose
and ca boxymethylcellulose sodium, propylene glycol,
purified water, simethicone emulsion, sodium benzoate,
sucralose, titanium dioxide, xanthan gum
Drug Facts (continued)
children 9-11 years
(60-95 lbs)
children 6-8 years
(48-59 lbs)
15 mL after first loose stool;
7 5 mL after each subsequent
loose stool; but no more than
45 mL in 24 hours
15 mL after first loose stool;
7 5 mL after each subsequent
loose stool; but no more than
30 mL in 24 hours
children under
6 years (up to 47 lbs)
ask a doctor
Drug Facts (continued)
Directions
I drink plenty of clear fluids to help prevent
dehydration caused by diarrhea
I find ight dose on chart. If possible, use weight to dose;
otherwise use age.
I shake well before using
I use only enclosed dosing cup specifically designed for use
with this product. Do not use any other dosing device.
I mL = milliliter
adults and children
12 years and over
30 mL after the first loose stool;
15 mL after each subsequent
loose stool; but no more than
60 mL in 24 hours
PULL
HERE
PEEL OPEN TO READ COMPLETE
DIRECTIONS AND WARNINGS
BEFORE PURCHASE
Do not use if printed inner or outer
neckband is broken or missing.
NDC 50580-134-04
4 f l oz
(120 mL)
Controls the symptoms
of diarrhea
Mint Flavor
Loperamide HCl, Anti Diarrheal
1 mg per 7.5 mL
®
A-D
Anti-Diarrheal
Oral Solu ion
3
0 0 4 5 - 0 1 3 4 - 0 4 2
000
0000
PULL
HERE
T:
EXP
3
0 0 4 5 - 0 1 3 4 - 0 4 2
00000000
LOT:
EXP:
4 l oz
(120 mL)
4 f l oz
NN
Controls the symptoms
of diarrhea
Mint Flavor
Anti-Diarrheal
Oral Solu ion
PDP = 2.41 square inches
.0625”
Loperamide HCl, Anti Diarrheal
1 mg per 7.5 mL
Loperamide HCl, Anti Diarrheal
Loperamide HCl, Anti Diarrheal
Loperamide HCl, Anti Diarrheal
Loperamide HCl, Anti Diarrheal
®
A-D
Reference ID: 3912606
(b) (4)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PEEL OPEN TO READ COMPLETE
DIRECTIONS AND WARNINGS
BEFORE PURCHASE
www.imodium.com
Do not use if printed inner or outer
neckband is broken or missing.
NDC 50580-134-44
4 f l oz
(120 mL)
Controls the symptoms
of diarrhea
Mint Flavor
Loperamide HCl, Anti Diarrheal
1 mg per 7.5 mL
®
A-D
Anti-Diarrheal
Oral Solu ion
Loperamide HCl, An i-Diarrheal
1 mg per 7.5 mL
®
A-D
For ages
6 years & up
4 f l oz
(120 mL)
4
Controls the symptoms
of diarrhea
Mint Flavor
Anti-Diarrheal
Oral Solu ion
Use cont ols symptoms of diar hea, including Travelers’ Diarrhea
Warnings
Allergy alert: Do not use if you have ever had a rash or other
alle gic reaction to loperamide HCl
Do not use if you have bloody or black stool
Ask a doctor before use if you have
I fever I mucus in the stool I a history of liver disease
Ask a doctor or pharmacist before use if you are
taking ant biotics
Drug Facts (continued)
Questions or comments?
call 1-877-895-3665 (toll-free) or 215-273-8755 (collect)
Active ingredient (in each 7.5 mL) Purpose
Loperamide HCl 1 mg...…............................................Anti-diar heal
Drug Facts
Drug Facts (continued)
When using this product tiredness, d owsiness or
dizziness may occur. Be careful when driving or
operating machinery.
Stop use and ask a doctor if
I symptoms get worse
I diarrhea lasts for more than 2 days
I you get abdominal swelling or bulging.
These may 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 medica help or contact a Poison Control Center
right away. (1-800-222-1222)
Drug Facts (continued)
Other information
I each 30 mL contains: sodium 16 mg
I store between 20-25°C (68-77°F)
I do not use if printed inner or outer neckband is
broken or missing
Inactive ingredients
anhyd ous citric acid, caramel color, D&C yellow no. 10,
FD&C blue no. 1, flavor, glycerin, mic ocrystalline cellulose
and carboxymethylcellulose sodium, p opylene glycol,
pu ified water, simethicone emulsion, sodium benzoate,
sucralose, titanium dioxide, xanthan gum
Drug Facts (continued)
children 9-11 years
(60-95 lbs)
children 6-8 years
(48-59 lbs)
15 mL after first loose stool;
7 5 mL after each subsequent
loose stool; but no more than
45 mL in 24 hours
15 mL after first loose stool;
7 5 mL after each subsequent
loose stool; but no more than
30 mL in 24 hours
children under
6 years (up to 47 lbs)
ask a doctor
Drug Facts (continued)
Directions
I drink plenty of clear fluids to help prevent
dehydration caused by diarrhea
I find right dose on chart. If possible, use weight to dose;
othe wise use age.
I shake well before using
I use only enclosed dosing cup specifically designed for use
with this p oduct. Do not use any other dosing device.
I mL = milliliter
adults and children
12 years and over
30 mL after the first loose stool;
15 mL after each subsequent
loose stool; but no more than
60 mL in 24 hours
PULL
HERE
PEEL OPEN TO READ COMPLETE
DIRECTIONS AND WARNINGS
BEFORE PURCHASE
T
XXXXXXXX
P.
PULL
HERE
NDC 50580-134-44
4 f l oz
(120 mL)
Controls the symptoms
of diarrhea
Mint Flavor
Loperamide HCl, Anti Diarrheal
1 mg per 7.5 mL
®
A-D
Anti-Diarrheal
Oral Solu ion
For ages
6 years & up
Do not use if printed inner or outer
neckband is broken or missing.
LOT
XXXXXXXX
EXP.
PDP = 2.41 square inches
.0625”
Loperamide HCl, Anti Diarrheal
1 mg per 7.5 mL
Loperamide HCl, Anti Diarrheal
Loperamide HCl, Anti Diarrheal
Loperamide HCl, Anti Diarrheal
Loperamide HCl, Anti Diarrheal
®
A-D
NN
Active ingredient made in Italy
Distributed by:
JOHNSON & JOHNSON CONSUMER INC.
McNeil Consumer Healthcare Division
Fort Washington, PA 19034 USA
©J&JCI 2015
Reference ID: 3912606
(b) (4)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
www.imodium.com
PEEL OPEN TO READ COMPLETE
DIRECTIONS AND WARNINGS
BEFORE PURCHASE
Do not use if printed inner or outer
neckband is broken or missing.
Loperamide HCl, An i-Diarrheal
1 mg per 7.5 mL
®
A-D
NDC 50580-134-44
4 f l oz
(120 mL)
Controls the symptoms
of diarrhea
Mint Flavor
Loperamide HCl, Anti Diarrheal
1 mg per 7.5 mL
®
A-D
Anti-Diarrheal
Oral Solu ion
For ages
6 years & up
Use controls symptoms of diarrhea, including Travelers’ Diar hea
Warnings
Allergy alert: Do not use if you have ever had a rash or other
allergic reaction to loperamide HCl
Do not use if you have bloody or black stool
Ask a doctor before use if you have
I fever I mucus in the stool I a history of liver disease
Ask a doctor or pharmacist before use if you are
taking antibiotics
Drug Facts (continued)
Questions or comments?
call 1-877-895-3665 (toll-free) or 215-273-8755 (collect)
Active ingredient (in each 7.5 mL) Purpose
Loperamide HCl 1 mg...…........................................... Anti-diar heal
Drug Facts
Active ingredient made in Italy
Distributed by:
JOHNSON & JOHNSON CONSUMER INC.
McNeil Consumer Healthcare Division
Fort Washington, PA 19034 USA
©J&JCI 2015
Drug Facts (continued)
When using this product tiredness, d owsiness or
dizziness may occur. Be careful when driving or
operating machinery.
Stop use and ask a doctor if
I symptoms get worse
I diarrhea lasts for more than 2 days
I you get abdominal swelling or bulging.
These may be signs of a serious condition.
If pregnant or breast-feeding, ask a hea th
p ofessional before use.
Keep out of reach of children. In case of overdose,
get medica help or contact a Poison Control Center
right away. (1-800-222-1222)
Drug Facts (continued)
Other information
I each 30 mL contains: sodium 16 mg
I store between 20-25°C (68-77°F)
I do not use if printed inner or outer neckband
is broken or missing
Inactive ingredients
anhydrous citric acid, caramel color, D&C yellow no. 10,
FD&C blue no. 1, flavor, glycerin, mic ocrystalline cellulose
and ca boxymethylcellulose sodium, propylene glycol,
purified water, simethicone emulsion, sodium benzoate,
sucralose, titanium dioxide, xanthan gum
Drug Facts (continued)
children 9-11 years
(60-95 lbs)
children 6-8 years
(48-59 lbs)
15 mL after first loose stool;
7 5 mL after each subsequent
loose stool; but no more than
45 mL in 24 hours
15 mL after first loose stool;
7 5 mL after each subsequent
loose stool; but no more than
30 mL in 24 hours
children under
6 years (up to 47 lbs)
ask a doctor
Drug Facts (continued)
Directions
I drink plenty of clear fluids to help prevent
dehydration caused by diarrhea
I find ight dose on chart. If possible, use weight to dose;
otherwise use age.
I shake well before using
I use only enclosed dosing cup specifically designed for use
with this product. Do not use any other dosing device.
I mL = milliliter
adults and children
12 years and over
30 mL after the first loose stool;
15 mL after each subsequent
loose stool; but no more than
60 mL in 24 hours
PULL
HERE
3
004 5-0 134 -44 8
00000000
3
0 0
5 -
1 3
-
2
00000000
PULL
HERE
PULL
HERE
3
004 5-0 134 -44 8
00000000
PEEL OPEN TO READ COMPLETE
DIRECTIONS AND WARNINGS
BEFORE PURCHASE
NDC 50580-134-44
4 f l oz
(120 mL)
Controls the symptoms
of diarrhea
Mint Flavor
Loperamide HCl, Anti Diarrheal
1 mg per 7.5 mL
®
A-D
Anti-Diarrheal
Oral Solu ion
For ages
6 years & up
Do not use if printed inner or outer
neckband is broken or missing.
T:
LOT:
EXP:
4 f l oz
(120 mL)
4
Controls the symptoms
of diarrhea
Mint Flavor
Anti-Diarrheal
Oral Solu ion
NN
PDP = 2.41 square inches
.0625”
Loperamide HCl, Anti Diarrheal
1 mg per 7.5 mL
Loperamide HCl, Anti Diarrheal
Loperamide HCl, Anti Diarrheal
Loperamide HCl, Anti Diarrheal
Loperamide HCl, Anti Diarrheal
®
A-D
Reference ID: 3912606
(b) (4)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
www.imodium.com
PEEL OPEN TO READ COMPLETE
DIRECTIONS AND WARNINGS
BEFORE PURCHASE
Loperamide HCl Anti Diarrheal
mg per 75 mL
®
A-D
Loperamide HCl, Anti Diarrheal
1 mg per 7.5 mL
NDC 50580-134-08
Controls the symptoms
of diarrhea
Mint Flavor
Anti-Diarrheal
®
A-D
Oral Solution
8 f l oz
(240 mL)
PULL
HERE
Active ingredient made in taly
Distributed by: JOHNSON & JOHNSON CONSUMER INC.
McNeil Consumer Healthcare Division
Fort Washington, PA 19034 USA
©J&JCI 2015
Do not use if printed inner or outer
neckband is broken or missing.
I store between 20 25°C (68-77°F)
I do not use if printed inner or outer neckband is
broken or missing
Inactive ingredients anhydr us citric acid, caramel
color, D&C ye low no. 10, FD&C blue no. 1, flavor, glycerin,
microcrysta line cellulose and carboxyme hylce lulose sodium,
propylene glycol, purified water, simethicone emulsion,
sodium benzoate, sucralose, titanium diox de, xan han gum
Questions or comments?
call 1-877-895-3665 (toll-free) or 215-273-8755 (collect)
If pregnant or breast-feeding, ask a health professional
before use.
Keep out of reach of children. In case of ove dose, get medical
help or c ntact a Pois n Control Center right away. (1 800 222-1222)
Directions
I drink plenty of clear fluids to help prevent
dehydration caused by diarrhea
I find right dose on chart. If poss ble, use weight to dose;
otherwise use age.
I shake well before using
I only use enclosed dosing up specifically designed for use
wi h his product. Do not use any o her dosing device.
Warnings
Allergy alert Do not use if you have ever had a rash or
other allergic reaction to loperamide HCl
Do not use if you have bloody or black stool
Ask a doctor before use if you have
I fever I mucus in the stool I a history of liver disease
Active ingredient (in each 7.5 mL) Purpose
Loperamide HCl 1 mg........................ ................Anti-diarrheal
Drug Facts
Use controls symptoms of diarrhea, including Travelers’
Diarrhea
Ask a doctor or pharmacist before use if you are
taking ant biotics
Drug Facts (continued)
When using this product tiredness, drowsiness or dizziness
may occur. Be careful when driving or operating machinery.
Other information
I each 30 mL contains: sodium 16 mg
Drug Facts (continued)
Drug Facts (continued)
adults and
children 12
years and over
children
9-11 years
(60-95 lbs)
chi dren
6-8 years
(48-59 lbs)
30 mL after the first loose stool; 15 mL
after each subsequent loose stool; but
no more than 60 mL in 24 hours
15 mL after first loose stool; 7.5 mL
after each subsequent loose stool;
but no more than 45 mL in 24 hours
5 mL after first loose stool; 7 5 mL after
each subsequent loose stool; but no
more han 30 mL in 24 hours
children
under 6 years
(up to 47 bs)
ask a doctor
Stop use and ask a doctor if I symptoms get worse
I diarrhea lasts for more than 2 days
I you get abdominal swelling or bulging. These may be
signs of a serious condition.
I mL = mil iliter
PULL
HERE
T
XXXXXXXX
.
Active ingredient made in taly
Distr buted by: JOHNSON & JOHNSON CONSUMER INC.
McNeil Consumer Healthcare Division
Fort Washington, PA 19034 USA
©J&JCI 2015
Loperamide HCl, Anti Diarrheal
1 mg per 7.5 mL
NDC 50580 134-08
Controls the symptoms
of diarrhea
Mint Flavor
Anti-Diarrheal
®
A-D
Oral Solution
8 f l oz
(240 mL)
PEEL OPEN TO READ COMPLETE
DIRECTIONS AND WARNINGS
BEFORE PURCHASE
Do not use if printed inner or outer
neckband is broken or missing.
LOT
XXXXXXXX
EXP.
Controls the symptoms
of diarrhea
Mint Flavor
Anti-Diarrheal
Oral Solution
8 f l oz
(240 mL)NN
8 f l oz
PDP = 3.88 square inches
.073”
Loperamide HCl, Anti Diarrhea
Loperamide HCl, Anti Diarrhea
Loperamide HCl, Anti Diarrhea
Loperamide HCl, Anti Diarrhea
®
A-D
Reference ID: 3912606
(b) (4)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PEEL OPEN TO READ COMPLETE
DIRECTIONS AND WARNINGS
BEFORE PURCHASE
www.imodium.com
Loperamide HCl, Anti Diarrheal
1 mg per 7.5 mL
NDC 50580-134-08
Controls the symptoms
of diarrhea
Mint Flavor
Anti-Diarrheal
®
A-D
Oral Solution
8 f l oz
(240 mL)
Loperamide HCl Anti Diarrheal
mg per 75 mL
®
A-D
0000000
Active ingredient made in taly
Distributed by: JOHNSON & JOHNSON CONSUMER INC.
McNeil Consumer Healthcare Division
Fort Washington, PA 19034 USA
©J&JCI 2015
PULL
HERE
Loperamide HCl, Anti Diarrheal
1 mg per 7.5 mL
NDC 50580 134-08
Controls the symptoms
of diarrhea
Mint Flavor
Anti-Diarrheal
®
A-D
Oral Solution
8 f l oz
(240 mL)
PEEL OPEN TO READ COMPLETE
DIRECTIONS AND WARNINGS
BEFORE PURCHASE
Do not use if printed inner or outer
neckband is broken or missing.
3
0 0 4 5 - 0 1 3 4 - 0 8 0
PULL
HERE
I store between 20 25°C (68-77°F)
I do not use if printed inner or outer neckband is
broken or missing
Inactive ingredients anhydrous citric acid, caramel
color, D&C yellow no. 0, FD&C blue no. 1, flavor, glycerin,
microcrystal ine cellulose and carboxyme hylcellulose sodium,
propylene glycol, purified water, sime hicone emulsion,
sodium benzoate, sucralose, itanium dioxide, xanthan gum
Questions or comments?
call 1-877-895-3665 (toll-free) or 215-273-8755 (co lect)
If pregnant or breast-feeding, ask a health professional
before use.
Keep out of reach of children. In case of ove dose, get medical
help or contact a Poison Control Center right away. ( 800 222-1222)
Directions
I drink plenty of clear fluids to help prevent
dehydration caused by diarrhea
I find right dose on chart. If possible, use weight to dose;
otherwise use age.
I shake well before using
I only use enclosed dosing cup specifically designed for use
wi h his product. Do not use any o her dosing device.
Warnings
Allergy alert Do not use if you have ever had a rash or
other a lergic reaction to loperamide HCl
Do not use if you have bloody or black stool
Ask a doctor before use if you have
I fever I mucus in the stool I a history of iver disease
Active ingredient (in each 7.5 mL) Purpose
Loperamide HCl 1 mg....... ......................... .......Anti-diarrheal
Drug Facts
Use controls symptoms of diarrhea, including Travelers’
Diarrhea
Ask a doctor or pharmacist before use if you are
taking antibiotics
Drug Facts (continued)
When using this product tiredness, drowsiness or dizziness
may occur. Be careful when driving or operating machinery.
Other information
I each 30 mL contains: sodium 16 mg
Drug Facts (continued)
Drug Facts (continued)
adults and
children 12
years and over
children
9-11 years
(60-95 lbs)
children
6-8 years
(48-59 lbs)
30 mL after the first loose stool; 15 mL
after each subsequent loose stool; but
no more than 60 mL in 24 hours
15 mL after first loose stool; 7.5 mL
after each subsequent loose stool;
but no more than 45 mL in 24 hours
15 mL after first loose stool; 7 5 mL after
each subsequent loose stool; but no
more han 30 mL in 24 hours
children
under 6 years
(up to 47 lbs)
ask a doctor
Stop use and ask a doctor if I symptoms get worse
I diarrhea lasts for more than 2 days
I you get abdominal swelling or bulging. These may be
signs of a serious condition.
I mL = milli iter
Active ingredient made in taly
Distributed by: JOHNSON & JOHNSON CONSUMER INC.
McNeil Consumer Healthcare Division
Fort Washington, PA 19034 USA
©J&JCI 2015
Do not use if printed inner or outer
neckband is broken or missing.
3
0 0 4 5 - 0 1 3 4 - 0 8 0
00000000
LOT:
EXP:
LOT:
EXP:
Controls the symptoms
of diarrhea
Mint Flavor
Anti-Diarrheal
Oral Solution
8 f l oz
(240 mL)NN
8 f l oz
PDP = 3.88 square inches
.073”
Loperamide HCl, Anti Diarrhea
Loperamide HCl, Anti Diarrhea
Loperamide HCl, Anti Diarrhea
Loperamide HCl, Anti Diarrhea
®
A-D
Reference ID: 3912606
(b) (4)
1 Page(s) of Draft Labeling have been Withheld in Full as B4 (CCI/TS) immediately following this page
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:26.024084
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019487Orig1s028lbl.pdf', 'application_number': 19487, 'submission_type': 'SUPPL ', 'submission_number': 28}
|
11,513
|
NDA 19-500/S-010
Page 3
C98-38 (Rev. 7/2002)
667753
Lamprene®
clofazimine
Soft Gelatin Capsules
Prescribing Information
Rx only
DESCRIPTION
Lamprene, clofazimine, is an antileprosy agent available as soft gelatin capsules for oral
administration. Each capsule contains 50 mg of micronized clofazimine suspended in an oil-wax base.
Clofazimine
is
a
substituted
iminophenazine
bright-red
dye.
Its
chemical
name
is
3-(p-chloroanilino)-10-(p-chlorophenyl)-2, 10-dihydro-2-isopropyliminophenazine, and its structural
formula is
Clofazimine is a reddish-brown powder. It is readily soluble in benzene; soluble in chloroform; poorly
soluble in acetone and in ethyl acetate; sparingly soluble in methanol and in ethanol; and virtually
insoluble in water. Its molecular weight is 473.4.
Inactive Ingredients. Beeswax, butylated hydroxytoluene, citric acid, ethyl vanillin, gelatin, glycerin,
iron oxide, lecithin, p-methoxy acetophenone, parabens, plant oils, propylene glycol.
CLINICAL PHARMACOLOGY
Lamprene exerts a slow bactericidal effect on Mycobacterium leprae (Hansen’s bacillus). Lamprene
inhibits mycobacterial growth and binds preferentially to mycobacterial DNA. Lamprene also exerts
anti-inflammatory properties in controlling erythema nodosum leprosum reactions. However, its
precise mechanisms of action are unknown.
Pharmacokinetics
Lamprene has a variable absorption rate in leprosy patients, ranging from 45%-62% after oral
administration. The average serum concentrations in leprosy patients treated with 100 mg and 300 mg
daily were 0.7 µg/mL and 1.0 µg/mL, respectively. After ingestion of a single dose of 300 mg,
elimination of unchanged Lamprene and its metabolites in a 24-hour urine collection was negligible.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-500/S-010
Page 4
Lamprene is retained in the human body for a long time. The half-life of Lamprene following repeated
oral doses is estimated to be at least 70 days. Part of the ingested drug recovered from the feces may
represent excretion via the bile. A small amount is also eliminated in the sputum, sebum, and sweat.
Lamprene is highly lipophilic and tends to be deposited predominantly in fatty tissue and in cells of the
reticuloendothelial system. It is taken up by macrophages throughout the body. In autopsies performed
on leprosy patients, clofazimine crystals were found predominantly in the mesenteric lymph nodes,
adrenals, subcutaneous fat, liver, bile, gall bladder, spleen, small intestine, muscles, bones, and skin.
Microbiology
Measurement of the minimum inhibitory concentration (MIC) of Lamprene against leprosy bacilli in
vitro is not yet feasible. In the mouse footpad system, the multiplication of M. leprae is inhibited by
introducing 0.0001%- 0.001% Lamprene in the diet. Although bacterial killing may begin shortly after
starting the drug, it cannot be measured in biopsy tissues taken from patients for mouse footpad studies
until approximately 50 days after the start of therapy.
Lamprene does not show cross-resistance with dapsone or rifampin.
The following in vitro data are available, but their clinical significance is unknown. Lamprene has
been shown in vitro to inhibit M. avium and M. bovis at concentrations of approximately 0.1-1.0
µg/mL. The MIC for M. avium-intracellulare isolated from patients with acquired immunodeficiency
syndrome (AIDS) ranged from 1.0 to 5.0 µg/mL. With a few exceptions, microorganisms other than
mycobacteria are not inhibited by Lamprene.
INDICATIONS AND USAGE
Lamprene is indicated in the treatment of lepromatous leprosy, including dapsone-resistant
lepromatous leprosy and lepromatous leprosy complicated by erythema nodosum leprosum. Lamprene
has not been demonstrated to be effective in the treatment of other leprosy-associated inflammatory
reactions.
Combination drug therapy has been recommended for initial treatment of multibacillary leprosy to
prevent the development of drug resistance.
CONTRAINDICATIONS
There are no known contraindications.
WARNINGS
Severe abdominal symptoms (see below) have necessitated exploratory laparotomies in some
patients receiving Lamprene. Rare reports have included splenic infarction, bowel obstruction,
and gastrointestinal bleeding. There have also been reports of death following severe abdominal
symptoms. Autopsies have revealed crystalline deposits of clofazimine in various tissues
including the intestinal mucosa, liver, spleen, and mesenteric lymph nodes.
Lamprene should be used with caution in patients who have gastrointestinal problems such as
abdominal pain and diarrhea. Dosages of Lamprene of more than 100 mg daily should be given for as
short a period as possible and only under close medical supervision. If a patient complains of colicky
or burning pain in the abdomen, nausea, vomiting, or diarrhea, the dose should be reduced, and if
necessary, the interval between doses should be increased, or the drug should be discontinued.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-500/S-010
Page 5
PRECAUTIONS
General
Physicians should be aware that skin discoloration due to Lamprene may result in depression. Two
suicides have been reported in patients receiving Lamprene.
For skin dryness and ichthyosis, oil can be applied to the skin.
Information for Patients
Patients should be warned that Lamprene may cause a discoloration of the skin from red to
brownish-black, as well as discoloration of the conjunctivae, lacrimal fluid, sweat, sputum, urine, and
feces. Patients should be advised that skin discoloration, although reversible, may take several months
or years to disappear after the conclusion of therapy with Lamprene.
Patients should be told to take Lamprene with meals.
Drug Interactions
Preliminary data which suggest that dapsone may inhibit the anti-inflammatory activity of Lamprene
have not been confirmed. If leprosy-associated inflammatory reactions develop in patients being
treated with dapsone and clofazimine, it is still advisable to continue treatment with both drugs.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term carcinogenicity studies in animals have not been conducted with Lamprene. Results of
mutagenicity studies (Ames test) were negative. There was some evidence of impaired fertility in one
study in rats treated at a dose 25 times the usual human dose; the number of offspring was reduced and
there was a lower proportion of implantations.
Pregnancy Category C
Lamprene was not teratogenic in laboratory animals at dose levels equivalent to 8 times (rabbit) and 25
times (rat) the usual human daily dose. However, there was evidence of fetotoxicity in the mouse at
12-25 times the human dose, i.e., retardation of fetal skull ossification, increased incidence of
abortions and stillbirths, and impaired neonatal survival. The skin and fatty tissue of offspring became
discolored approximately 3 days after birth, which was attributed to the presence of Lamprene in the
maternal milk.
It has been found that Lamprene crosses the human placenta. The skin of infants born to women who
had received the drug during pregnancy was found to be deeply pigmented at birth. No evidence of
teratogenicity was found in these infants. There are no adequate and well-controlled studies in
pregnant women. Lamprene should be used during pregnancy only if the potential benefit justifies the
risk to the fetus.
Nursing Mothers
Lamprene is excreted in the milk of nursing mothers. Lamprene should not be administered to a
nursing woman unless clearly indicated.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-500/S-010
Page 6
Pediatric Use
Safety and effectiveness in pediatric patients have not been established. Several cases of pediatric
patients treated with Lamprene have been reported in the literature.
Geriatric Use
Clinical studies of Lamprene 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
In general, Lamprene is well tolerated when administered in dosages no greater than 100 mg daily. The
most consistent adverse reactions are usually dose related and are usually reversible when Lamprene is
discontinued.
Adverse Reactions Occurring In More Than 1% of Patients
Skin: Pigmentation from pink to brownish-black in 75%-100% of the patients within a few weeks of
treatment; ichthyosis and dryness (8%-28%); rash and pruritus (1%-5%).
Gastrointestinal: Abdominal and epigastric pain, diarrhea, nausea, vomiting, gastrointestinal
intolerance (40%-50%).
Ocular: Conjunctival and corneal pigmentation due to clofazimine crystal deposits; dryness; burning;
itching; irritation.
Other: Discoloration of urine, feces, sputum, sweat; elevated blood sugar; elevated ESR.
Adverse Reactions Occurring In Less Than 1% of Patients
Skin: Phototoxicity, erythroderma, acneiform eruptions, monilial cheilosis.
Gastrointestinal: Bowel obstruction (see WARNINGS), gastrointestinal bleeding (see WARNINGS),
anorexia, constipation, weight loss, hepatitis, jaundice, eosinophilic enteritis, enlarged liver.
Ocular: Diminished vision.
Nervous: Dizziness, drowsiness, fatigue, headache, giddiness, neuralgia, taste disorder.
Psychiatric: Depression secondary to skin discoloration; two suicides have been reported.
Laboratory: Elevated levels of albumin, serum bilirubin, and AST (SGOT); eosinophilia;
hypokalemia.
Other: Splenic infarction (see WARNINGS), thromboembolism, anemia, cystitis, bone pain, edema,
fever, lymphadenopathy, vascular pain.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-500/S-010
Page 7
OVERDOSAGE
No specific data are available on the treatment of overdosage with Lamprene. However, in case of
overdose, the stomach should be emptied by inducing vomiting or by gastric lavage, and supportive
symptomatic treatment should be employed.
DOSAGE AND ADMINISTRATION
Lamprene should be taken with meals.
Lamprene should be used preferably in combination with one or more other antileprosy agents to
prevent the emergence of drug resistance.
For the treatment of proven dapsone-resistant leprosy, Lamprene should be given at a dosage of 100
mg daily in combination with one or more other antileprosy drugs for 3 years, followed by
monotherapy with 100 mg of Lamprene daily. Clinical improvement usually can be detected between
the first and third months of treatment and is usually clearly evident by the sixth month.
For dapsone-sensitive multibacillary leprosy, a combination therapy with two other antileprosy drugs
is recommended. The triple-drug regimen should be given for at least 2 years and continued, if
possible, until negative skin smears are obtained. At this time, monotherapy with an appropriate
antileprosy drug can be instituted.
The treatment of erythema nodosum leprosum reactions depends on the severity of symptoms. In
general, the basic antileprosy treatment should be continued, and if nerve injury or skin ulceration is
threatened, corticosteroids should be given. Where prolonged corticosteroid therapy becomes
necessary, Lamprene administered at dosages of 100 to 200 mg daily for up to 3 months may be useful
in eliminating or reducing corticosteroid requirements. Dosages above 200 mg daily are not
recommended, and the dosage should be tapered to 100 mg daily as quickly as possible after the
reactive episode is controlled. The patient must remain under medical surveillance.
For advice about combination drug regimens, contact the USPHS Gillis W. Long Hansen’s Disease
Center, Carville, LA (504-642-7771).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-500/S-010
Page 8
HOW SUPPLIED
Soft Gelatin Capsules 50 mg–brown, spherical
Bottles of 100.................………………………………………...............NDC 0028-0108-01
Store below 30ºC (86ºF). Protect from moisture.
Dispense in tight container (USP).
667753
Printed in U.S.A.
C98-38 (Rev. 7/2002)
Distributed by
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
©1998 Novartis
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:26.289261
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19500slr010_lamprene_lbl.pdf', 'application_number': 19500, 'submission_type': 'SUPPL ', 'submission_number': 10}
|
11,514
|
LOT/EXP
Women’s Rogaine
® is for women who have a general
thinning of hair on the top of the scalp as shown.
Women’s Rogaine
® has been shown to regrow
hair in women with the following degrees of
thinning hair or hair loss.
Do not use if you have patchy
hair loss as shown above.
Dist: Johnson & Johnson Healthcare Products
Division of McNEIL-PPC, Inc. Skillman, NJ 08558 USA
Active Made in Italy
©McNEIL-PPC, Inc. 2014 30028743
NEW
LOOK
REACTIVATES
HAIR FOLLICLES
TO STIMULATE
REGROWTH
CLINICALLY PROVEN
TO HELP REGROW HAIR
One Month Supply
One 60 mL (2 fl oz) Bottle
UNSCENTED
2% Minoxidil Topical Solution
HAIR REGROWTH
TREATMENT
THIS PACKAGE CONTAINS
UÊÊ"iÊÈäÊ ÊÓÊvÊâ®Ê ÌÌiÊvÊWomen’s
Rogaine
® iÊÌ
ÊÃÕ««Þ®
UÊÊ"iÊV
`ÀiÃÃÌ>ÌÊ`À««iÀÊ>««V>ÌÀ
UÊÊvÀ>ÌÊLiÌÊÜÌ
ÊV«iÌiÊÊ
Ê `ÀiVÌÃÊÊ
ÜÊÌÊÕÃiÊ>`ÊLÌ>ÊÊ
Ê LiÃÌÊÀiÃÕÌÃ
If women have more hair loss than shown
above, Women’s Rogaine
® may not work.
Topical Solution
Drug Facts
Active ingredient
Purpose
Minoxidil 2% w/v........................................................................................... Hair regrowth treatment
Use to regrow hair on the scalp
Warnings
For external use only
Flammable: Keep away from fire or flame
Do not use if
■ your degree of hair loss is different than that shown on the side of this carton, because this
product may not work for you
■ you have no family history of hair loss
■ your hair loss is sudden and/or patchy
■ your hair loss is associated with childbirth
■ you do not know the reason for your hair loss
■ you are under 18 years of age. Do not use on babies and children.
■ your scalp is red, inflamed, infected, irritated, or painful
■ you use other medicines on the scalp
Ask a doctor before use if you have heart disease
When using this product
■ do not apply on other parts of the body
■ avoid contact with the eyes. In case of accidental contact, rinse eyes with large amounts
of cool tap water.
■ some people have experienced changes in hair color and/or texture
■ it takes time to regrow hair. You may need to use this product 2 times a day for at least 4 months
before you see results.
■ the amount of hair regrowth is different for each person. This product will not work for everyone.
Stop use and ask a doctor if
■ chest pain, rapid heartbeat, faintness, or dizziness occurs
■ sudden, unexplained weight gain occurs
■ your hands or feet swell
■ scalp irritation or redness occurs
■ unwanted facial hair growth occurs
■ you do not see hair regrowth in 4 months
May be harmful if used when pregnant or breast-feeding.
Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center
right away.
Directions
■ apply one mL with dropper 2 times a day directly onto the scalp in the hair loss area
■ using more or more often will not improve results
■ continued use is necessary to increase and keep your hair regrowth, or hair loss will begin again
Other information
■ see hair loss pictures on side of this carton
■ before use, read all information on carton and enclosed booklet
■ keep the carton. It contains important information.
■ In clinical studies of mostly white women aged 18-45 years with mild to moderate degrees
of hair loss, the following response to 2% minoxidil topical solution was reported: 19%
of women reported moderate hair regrowth after using 2% minoxidil topical solution for 8 months
(19% had moderate regrowth; 40% had minimal regrowth). This compares with 7% of women
reporting moderate hair regrowth after using the placebo, the liquid without minoxidil in it, for
8 months (7% had moderate regrowth; 33% had minimal regrowth).
■ store at controlled room temperature 20° to 25°C (68° to 77°F)
Inactive ingredients
alcohol, propylene glycol, purified water
Questions?
■ call toll-free 800-764-2463 or 215-273-8755 (collect)
■ visit www.rogaine.com
2% Minoxidil
Topical Solution
Hair Regrowth
Treatment
3
12547 78020
9
Reference ID: 3736657
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LOT/EXP
NEW
LOOK
REACTIVATES
HAIR FOLLICLES
TO STIMULATE
REGROWTH
CLINICALLY PROVEN
TO HELP REGROW HAIR
UNSCENTED
2% Minoxidil Topical Solution
HAIR REGROWTH TREATMENT
UNSCENTED
Women’s Rogaine
® is for women who have a general
thinning of hair on the top of the scalp as shown.
Women’s Rogaine
® has been shown to regrow
hair in women with the following degrees of
thinning hair or hair loss.
Do not use if you have patchy
hair loss as shown above.
2% Minoxidil Topical Solution
HAIR REGROWTH
TREATMENT
THIS PACKAGE CONTAINS
UÊÊ/
ÀiiÊÈäÊ ÊÓÊvÊâ®Ê ÌÌiÃÊvÊWomen’s
Rogaine
® Ì
ÀiiÊÌ
ÊÃÕ««Þ®
UÊÊ"iÊV
`ÀiÃÃÌ>ÌÊ`À««iÀÊ>««V>ÌÀ
UÊÊvÀ>ÌÊLiÌÊÜÌ
ÊV«iÌiÊÊ
Ê `ÀiVÌÃÊÊ
ÜÊÌÊÕÃiÊ>`ÊLÌ>ÊÊ
Ê LiÃÌÊÀiÃÕÌÃ
If women have more hair loss than shown
above, Women’s Rogaine
® may not work.
Dist: Johnson & Johnson Healthcare Products
Division of McNEIL-PPC, Inc. Skillman, NJ 08558 USA
Active Made in Italy
©McNEIL-PPC, Inc. 2014 30028744
Drug Facts
Active ingredient Purpose
Minoxidil 2% w/v...................................................Hair regrowth treatment
Use to regrow hair on the scalp
Warnings
For external use only
Flammable: Keep away from fire or flame
Do not use if
■ your degree of hair loss is different than that shown on the side
of this carton, because this product may not work for you
■ you have no family history of hair loss
■ your hair loss is sudden and/or patchy
■ your hair loss is associated with childbirth
■ you do not know the reason for your hair loss
■ you are under 18 years of age. Do not use on babies and children.
■ your scalp is red, inflamed, infected, irritated, or painful
■ you use other medicines on the scalp
Ask a doctor before use if you have heart disease
When using this product
■ do not apply on other parts of the body
■ avoid contact with the eyes. In case of accidental contact, rinse eyes
with large amounts of cool tap water.
■ some people have experienced changes in hair color and/or texture
■ it takes time to regrow hair. You may need to use this product
2 times a day for at least 4 months before you see results.
■ the amount of hair regrowth is different for each person.
This product will not work for everyone.
Stop use and ask a doctor if
■ chest pain, rapid heartbeat, faintness, or dizziness occurs
■ sudden, unexplained weight gain occurs
■ your hands or feet swell
■ scalp irritation or redness occurs
■ unwanted facial hair growth occurs
■ you do not see hair regrowth in 4 months
Drug Facts (continued)
May be harmful if used when pregnant or breast-feeding.
Keep out of reach of children. If swallowed, get medical help or contact
a Poison Control Center right away.
Directions
■ apply one mL with dropper 2 times a day directly onto the scalp
in the hair loss area
■ using more or more often will not improve results
■ continued use is necessary to increase and keep your hair regrowth,
or hair loss will begin again
Other information
■ see hair loss pictures on side of this carton
■ before use, read all information on carton and enclosed booklet
■ keep the carton. It contains important information.
■ In clinical studies of mostly white women aged 18-45 years with
mild to moderate degrees of hair loss, the following response to
2% minoxidil topical solution was reported: 19% of women reported
moderate hair regrowth after using 2% minoxidil topical solution for
8 months (19% had moderate regrowth; 40% had minimal regrowth).
This compares with 7% of women reporting moderate hair regrowth
after using the placebo, the liquid without minoxidil in it, for 8 months
(7% had moderate regrowth; 33% had minimal regrowth).
■ store at controlled room temperature 20° to 25°C (68° to 77°F)
Inactive ingredients
alcohol, propylene glycol, purified water
Questions?
■ call toll-free 800-764-2463 or 215-273-8755 (collect)
■ visit www.rogaine.com
Topical Solution
Three Month Supply
Three 60 mL (2 fl oz) Bottles
2% Minoxidil
Topical Solution
Hair Regrowth
Treatment
3
12547 78060
5
Reference ID: 3736657
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Topical Solution
T
One Month Supply One 60 mL (2 fl oz) Bottle
LOT
EXP
Read and keep carton and booklet for full
product information
Active ingredient Minoxidil 2% w/v
Warnings
For external use only
Flammable: Keep away from fire or flame
Do not use if
¬you have no family history of hair loss
¬your hair loss is sudden and/or patchy
¬your hair loss is associated with childbirth
¬you do not know the reason for your hair loss
¬you are under 18 years of age. Do not use on
babies and children.
¬your scalp is red, inflamed, infected, irritated,
or painful
you use other medicines on the scalp
Ask a doctor before use if you have heart disease
When using this product
do not apply on other parts of the body
avoid contact with the eyes. In case of accidental
contact, rinse eyes with large amounts of cool tap
water.
some people have experienced changes in hair
color and/or texture
Stop use and ask a doctor if
chest pain, rapid heartbeat, faintness, or dizziness
occurs
sudden, unexplained weight gain occurs
your hands or feet swell
scalp irritation or redness occurs
unwanted facial hair growth occurs
May be harmful if used when pregnant or
breast-feeding.
Keep out of reach of children. If swallowed, get
medical help or contact a Poison Control Center
right away.
Directions
¬apply one mL 2 times a day directly onto the scalp
in the hair loss area
¬VHHLQQHUFDUWRQDQGHQFORVHGERRNOHWIRU
complete directions
¬using more or more often will not improve results
¬continued use is necessary or hair loss will
begin again
Inactive ingredients
alcohol, propylene glycol, purified water
Questions? call toll-free 800-764-2463 or
215-273-8755 (collect) visit www.rogaine.com
Store at Controlled Room Temperature
20° to 25°C (68° to 77°F)
Dist: Johnson & Johnson Healthcare Products
Division of McNEIL-PPC, Inc., Skillman, NJ 08558 USA
Active Made in Italy
©McNEIL-PPC, Inc. 2014
Dist: Johnson & Johnson Healthcare Products
Division of McNEIL-PPC, Inc., Skillman, NJ 08558 USA
Active Made in Italy
©McNEIL-PPC, Inc. 2014
30028741
2% Minoxidil Topical Solution
Hair Regrowth Treatment
REACTIVATES HAIR FOLLICLES
TO STIMULATE REGROWTH
UNSCENTED
FOR BEST RESULTS
APPLY DIRECTLY TO SCALP
TWICE DAILY
Reference ID: 3736657
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
REACTIVATES
HAIR FOLLICLES
TO STIMULATE
REGROWTH
CLINICALLY PROVEN
TO HELP REGROW HAIR
2% Minoxidil
Topical Solution
Hair Regrowth
Treatment
UNSCENTED
Topical Solution
Dist: Johnson & Johnson Healthcare Products Company
Division of McNEIL-PPC, Inc.
Skillman, NJ 08558 USA
©McNEIL-PPC, Inc. 2014
30028742
Reference ID: 3736657
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
2% MINOXIDIL TOPICAL SOLUTION
HAIR REGROWTH TREATMENT
UNSCENTED
Save this booklet for future reference.
/HPYYLNYV^[O[YLH[TLU[
7YL]PV\ZS`H]HPSHISLVUS`I`WYLZJYPW[PVU
6]LYTPSSPVU(TLYPJHU^VTLUL_WLYPLUJL
OHPY[OPUUPUNVYOHPYSVZZZV`V\»YLUV[HSVUL
>VTLU»Z96.(05,®JVU[HPUZ[OLVUS`PUNYLKPLU[
[OH[PZTLKPJHSS`WYV]LULMMLJ[P]L[VOLSWYLNYV^
OHPYPU^VTLU
7SLHZLYLHK[OPZIVVRSL[JHYLM\SS`0[^PSSOLSW
`V\\UKLYZ[HUKOV^[V\ZL96.(05,®HUK^OH[
[VL_WLJ[MYVTP[Z\ZL0M`V\OH]LHU`X\LZ[PVUZ
HM[LYYLHKPUN[OPZIVVRSL[VYHU`[PTL^OPSL\ZPUN
>VTLU»Z96.(05,®`V\ZOV\SKHZR`V\YOLHS[O
JHYLWYVMLZZPVUHSVYJHSS[VSSMYLL800-764-2463VY
215-273-8755JVSSLJ[]PZP[^^^YVNHPULJVT
Reference ID: 3736657
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
What is Women’s ROGAINE®?
ROGAINE® is a colorless liquid medication for use
only on the top of the scalp to help regrow hair.
Who may use Women’s ROGAINE®?
Women’s ROGAINE® may be appropriate for you
if you are an adult who is at least 18 years
old and experiencing gradually thinning hair
or gradual hair loss on the top of the head.
The common hereditary thinning or hair loss
process begins slowly and may become
noticeable only after years of gradual loss.
Women’s ROGAINE® is for general thinning of
hair on the top of the scalp as shown on the next
page. ROGAINE® has been shown to regrow hair
in women with the degrees of hair loss shown.
If women have more hair loss than shown,
ROGAINE® may not work.
Many of those experiencing hair loss have other
family members with gradual thinning hair or hair
loss. If there is no family history of gradual
thinning or gradual hair loss, or hair loss is
patchy, talk to your doctor.
Reference ID: 3736657
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Reference ID: 3736657
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Who should NOT use Women’s ROGAINE®?
ROGAINE® will not prevent or improve
hair loss related to pregnancy, the use of some
prescription and non-prescription medications,
certain severe nutritional problems (very low body
iron; excessive vitamin A intake), the recently
discontinued use of birth control pills, low thyroid
states (hypothyroidism), chemotherapy,
or diseases which cause scarring of the scalp.
Also, ROGAINE® will not improve hair loss due to:
°KHTHNLMYVT[OL\ZLVMOHPYJHYL
products which cause scarring or deep burns
of the scalp.
°OHPYNYVVTPUNTL[OVKZZ\JOHZJVYUYV^PUN
or ponytails which require pulling the hair tightly
back from the scalp.
Do not use ROGAINE® if hair loss is patchy as
shown below.
You should ask your doctor if you are unsure
of the cause of your hair loss.
Reference ID: 3736657
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Female Response to ROGAINE®
Percent reporting hair regrowth
Minimal regrowth
Placebo after
8 months
ROGAINE® after
8 months
Percent of females
80%
60%
40%
20%
100%
0%
19%
40%
Moderate regrowth
7%
33%
Will Women’s ROGAINE® work for me?
The amount of hair regrowth is different for each
person. Not everyone will respond to ROGAINE®.
The response to ROGAINE® cannot be predicted.
No one will be able to grow back all their hair.
In clinical studies of mostly white women aged
18-45 years with mild to moderate degrees
of hair loss, the following response to ROGAINE®
was reported:
19% of women reported moderate hair regrowth
after using ROGAINE® for 8 months (19% had
moderate regrowth; 40% had minimal regrowth).
This compares with 7% of women reporting
moderate hair regrowth after using the placebo,
the liquid without minoxidil in it, for 8 months
(7% had moderate regrowth; 33% had
minimal regrowth).
Reference ID: 3736657
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
Some new hairs
are seen, but not
enough to cover
thinning areas.
New hairs cover
some or all of
thinning areas.
New hairs cover,
or almost
completely cover,
thinning areas.
Hairs in thinning areas
do not grow as closely
together as hairs on
the rest of the head.
Hairs in the thinning
areas grow more
closely together, but
are not as close
together as hairs on
the rest of the head.
Hairs in thinning
areas grow as closely
together as hairs on
the rest of head.
Dense
Moderate
Minimal
Number of Hairs
Hair Density
What Minimal, Moderate and Dense Hair
Regrowth Will Mean For You
Can Women’s ROGAINE® be used
to prevent hair loss?
We do not know if ROGAINE® will prevent hair loss.
How soon can I expect results from using
Women’s ROGAINE®?
Since normal hair usually grows only 1/2
to 1 inch per month, hair regrowth with
ROGAINE® also takes time. Generally new hair
growth is slow for a ROGAINE® user. Continued
use of 2 times a day for at least 4 months is
usually needed before you notice hair regrowth.
Reference ID: 3736657
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
If you do not see hair regrowth in 4 months,
stop using ROGAINE® and see your doctor.
When you first begin to use ROGAINE®,
your hair loss may continue for up to 2 weeks.
This hair loss is temporary. If you continue to lose
hair after two weeks, see your doctor.
If Women’s ROGAINE® is working, what will
the hair look like?
At first, hair growth may be soft, downy, colorless
hairs. After further use, the new hairs should be
the same color and thickness as the other hairs
on your scalp.
How long do I need to use
Women’s ROGAINE®?
If you respond to ROGAINE®, you need to use it
2 times a day to keep and continue the hair
regrowth. Up to 8 months of usage may be
needed to see your best results from ROGAINE®.
What happens if I completely stop using
Women’s ROGAINE®? Will I keep the new hair?
Continuous use of ROGAINE® is needed
to maintain hair regrowth. If you stop using
ROGAINE®, the normal hair loss process will start
again. You will probably lose your newly regrown
hair in three to four months.
Reference ID: 3736657
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
What is the dosage of Women’s ROGAINE®?
You should apply a dose (1 mL) of ROGAINE®
directly onto the scalp in the hair loss area
TWO TIMES A DAY; for example, once in the
morning and once at night. Each bottle should
last about one month, if used as directed.
Please refer to the “Directions for Use” section
of this booklet.
What if I miss a dose or forget
to use Women’s ROGAINE®?
If you miss one or two daily doses of ROGAINE®,
just continue with your next dose. You should not
make up for missed doses.
Can I use Women’s ROGAINE® more than
two times a day? Will it work faster, better?
No. ROGAINE® will not work faster or better if
used more than two times a day. Studies have
been carefully conducted to determine the
correct amount of ROGAINE® needed to get the
best results. More frequent use or larger doses
have not been shown to speed up hair growth
and may increase your chances of side effects.
Reference ID: 3736657
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
What are the most common side effects
with Women’s ROGAINE®?
The most common side effects are itching and
other skin irritations of the treated area of the
scalp. ROGAINE® contains alcohol, which would
cause burning or irritation of the eyes or sensitive
skin areas. If ROGAINE® accidentally gets into
these areas, rinse with large amounts of cool tap
water. Contact your doctor if irritation persists.
What kind of shampoo should
I use with Women’s ROGAINE®?
If you wash your scalp before applying
ROGAINE®, use a mild shampoo.
Can I use hair sprays, mousses,
conditioners, gels, etc.?
Yes. There is no reason to change your usual hair
care routine when using ROGAINE®. However,
you should apply ROGAINE® first and wait for it
to dry before applying your styling aids.
Can I have my hair colored or permed or use
hair relaxers while using Women’s ROGAINE®?
Yes. We have no information that these
treatments change the effect of ROGAINE®.
However, to avoid possible scalp irritation,
you should make sure all of the ROGAINE®
has been washed off the hair and scalp before
using these chemicals.
Reference ID: 3736657
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
Can I apply Women’s ROGAINE®
and wash my hair an hour later?
No. For ROGAINE® to work best, you should
allow ROGAINE® to remain on the scalp for about
4 hours before washing.
Can I go swimming or out in the rain?
Yes. Avoid washing off the ROGAINE®. If
possible, apply ROGAINE® to a dry scalp after
swimming, or wait about 4 hours after application
before going swimming. Do not let your scalp get
wet from the rain after applying ROGAINE®.
Can Women’s ROGAINE® produce
unwanted hair?
Although unwanted hair growth has been
reported on the face and on other parts
of the body, such reports have been infrequent.
The unwanted hair growth may be caused
by the transfer of ROGAINE® to areas other than
the scalp, or by absorption into the circulatory
system of low levels of the active ingredient,
or by a medical condition not related to the use
of ROGAINE®.
Reference ID: 3736657
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
If you experience unwanted hair,
discontinue using ROGAINE® and see your
doctor for recommendations about appropriate
treatment. After stopping use of ROGAINE®,
the unwanted hair, if caused by the use
of ROGAINE®, should go away over time.
You can take steps to decrease the chances for
unwanted hair growth:
1.°SPTP[[OLHWWSPJH[PVUVMROGAINE® only
to the scalp,
°if you use your hands to apply ROGAINE®,
wash your hands thoroughly afterwards, and
3.°HSSV^Z\MMPJPLU[KY`PUN[PTL\Z\HSS`[VOV\YZ
before going to bed) after your nighttime
application of ROGAINE®.
Can I use Women’s ROGAINE® for baldness
or hair loss in babies and children?
No. ROGAINE® must not be used to treat
baldness or hair loss in babies or children.
Are there any special warnings about the
use of Women’s ROGAINE®?
For external use only
Flammable: Keep away from fire
or flame
Reference ID: 3736657
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
Do not use if
°`V\YKLNYLLVMOHPYSVZZPZTVYL[OHU[OH[
ZOV^UVUWHNLVM[OPZIVVRSL[ILJH\ZL[OPZ
WYVK\J[TH`UV[^VYRMVY`V\
°`V\OH]LUVMHTPS`OPZ[VY`VMOHPYSVZZ
°`V\YOHPYSVZZPZZ\KKLUHUKVYWH[JO`
°`V\YOHPYSVZZPZHZZVJPH[LK^P[OJOPSKIPY[O
°`V\KVUV[RUV^[OLYLHZVUMVY`V\YOHPYSVZZ
°`V\HYL\UKLY `LHYZVMHNL+VUV[\ZL
VUIHIPLZHUKJOPSKYLU
°`V\YZJHSWPZYLKPUMSHTLKPUMLJ[LKPYYP[H[LK
VYWHPUM\S
°`V\\ZLV[OLYTLKPJPULZVU[OLZJHSW
Ask a doctor before use if you have
heart disease.
When using this product
°KVUV[HWWS`VUV[OLYWHY[ZVM[OLIVK`
°H]VPKJVU[HJ[^P[O[OLL`LZ0UJHZLVM
HJJPKLU[HSJVU[HJ[YPUZLL`LZ^P[OSHYNL
HTV\U[ZVMJVVS[HW^H[LY
°ZVTLWLVWSLOH]LL_WLYPLUJLKJOHUNLZ
PUOHPYJVSVYHUKVY[L_[\YL
Reference ID: 3736657
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
°P[[HRLZ[PTL[VYLNYV^OHPY@V\TH`ULLK
[V\ZL[OPZWYVK\J[[PTLZHKH`MVYH[SLHZ[
TVU[OZILMVYL`V\ZLLYLZ\S[Z
°[OLHTV\U[VMOHPYYLNYV^[OPZKPMMLYLU[MVYLHJO
WLYZVU;OPZWYVK\J[^PSSUV[^VYRMVYL]LY`VUL
Stop use and ask a doctor if
°JOLZ[WHPUYHWPKOLHY[ILH[MHPU[ULZZ
VYKPaaPULZZVJJ\YZ
°Z\KKLU\UL_WSHPULK^LPNO[NHPUVJJ\YZ
°`V\YOHUKZVYMLL[Z^LSS
°ZJHSWPYYP[H[PVUVYYLKULZZVJJ\YZ
°\U^HU[LKMHJPHSOHPYNYV^[OVJJ\YZ
°`V\KVUV[ZLLOHPYYLNYV^[OPUTVU[OZ
May be harmful if used when pregnant or
breast-feeding. Keep out of reach of
children. 0MZ^HSSV^LKNL[TLKPJHSOLSWVY
JVU[HJ[H7VPZVU*VU[YVSJLU[LYYPNO[H^H`
What factors may increase the risk of
serious side effects with Women’s
ROGAINE®?
ROGAINE®ZOV\SKILHWWSPLKVUS`[V[OLZJHSW
;OLYPZRVMZPKLLMMLJ[ZTH`ILNYLH[LY^OLU
ROGAINE®PZHWWSPLK[VV[OLYWHY[ZVM[OLIVK`
Reference ID: 3736657
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
Directions for Use
1. Remove the overcap.
2. Remove the inner cap. To remove, push down
and turn in direction of the arrows on the cap.
3. Part your hair in the area of hair thinning/loss.
Follow the instructions below for using the dropper
applicator and apply one mL 2 times a day directly
onto the scalp in the hair loss area. Do not use
more. Spread the liquid evenly over the hair loss
area. If you use your fingers, wash hands with soap
and water immediately. Each bottle should last
about one month, if used as directed.
Use a mild shampoo if you wash your scalp
before applying ROGAINE®.
Using the Dropper Applicator
1. Squeeze the rubber bulb and insert the
dropper into the bottle. Release the bulb,
allowing the dropper to fill to the 1 mL
line. If the level of the solution is above
the 1 mL line, squeeze the extra amount
back into the bottle.
2. Next, place the tip of the dropper near
the part of the scalp you want to treat
and gently squeeze the bulb to gradually
release the solution. To prevent the
solution from running off the scalp, apply
a small amount at a time.
3. After each use attach the dropper
to the bottle to make it child-resistant
by turning it clockwise until tightly closed.
Reference ID: 3736657
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
If you have any other questions, ask your health
care professional or call toll-free 800-764-2463 or
215-273-8755 (collect) visit www.rogaine.com
Store at Controlled Room Temperature
20° to 25° C (68° to 77° F).
Save this booklet for future reference.
Reference ID: 3736657
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:26.433755
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019501Orig1s029lbl.pdf', 'application_number': 19501, 'submission_type': 'SUPPL ', 'submission_number': 29}
|
11,515
|
NDC 65726-144-15
AXID
®
(nizatidine)
Capsules, USP
1514M400
Rx only
60 PULVULES
®
Usual Adult Dose:
See accompanying literature
for dosage.
Keep tightly closed.
Store at controlled room
temperature 20° to 25°C
(68° to 77°F) [see USP].
Manufactured for:
Reliant Pharmaceuticals, Inc.
Liberty Corner, NJ 07938
by:
Patheon Pharmaceuticals Inc.
Cincinnati, OH 45237
Black
PMS 1245
Non-varnish area inside
Label Size: 1 3/4” x 3 3/4”
LOT
EXP.
150 mg
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
®
DESCRIPTION
Axid® (Nizatidine, USP) is a histamine H2-receptor antagonist.
Chemically, it is N-[2-[[[2-[(dimethylamino)methyl]-4-thia-
zolyl]methyl]thio]ethyl]-Nı-methyl-2-nitro-1,1-ethenediamine.
The structural formula is as follows:
Nizatidine has the empirical formula C12H21N5O2S2 representing a
molecular weight of 331.47. It is an off-white to buff crystalline solid
that is soluble in water. Nizatidine has a bitter taste and mild sulfur-
like odor. Each Pulvule® (capsule) contains for oral administration
gelatin, pregelatinized starch, dimethicone, starch, titanium dioxide,
yellow iron oxide, 150 mg (0.45 mmol) or 300 mg (0.91 mmol) of
nizatidine, and other inactive ingredients. The 150-mg Pulvule also
contains magnesium stearate, and the 300-mg Pulvule also contains
croscarmellose sodium, povidone, red iron oxide, and talc.
CLINICAL PHARMACOLOGY
Axid is a competitive, reversible inhibitor of histamine at the his-
tamine H2-receptors, particularly those in the gastric parietal cells.
Antisecretory Activity —1. Effects on Acid Secretion: Axid signifi-
cantly inhibited nocturnal gastric acid secretion for up to 12 hours.
Axid also significantly inhibited gastric acid secretion stimulated by
food, caffeine, betazole, and pentagastrin (Table 1).
Table 1
Effect of Oral Axid on Gastric Acid Secretion
2. Effects on Other Gastrointestinal Secretions—Pepsin: Oral
administration of 75 to 300 mg of Axid did not affect pepsin activity in
gastric secretions. Total pepsin output was reduced in proportion to
the reduced volume of gastric secretions.
Intrinsic Factor: Oral administration of 75 to 300 mg of Axid
increased betazole-stimulated secretion of intrinsic factor.
Serum Gastrin: Axid had no effect on basal serum gastrin. No
rebound of gastrin secretion was observed when food was ingested
12 hours after administration of Axid.
3. Other Pharmacologic Actions—
a. Hormones: Axid was not shown to affect the serum concen-
trations of gonadotropins, prolactin, growth hormone, antidi-
uretic hormone, cortisol, triiodothyronine, thyroxin, testos-
terone, 5α-dihydrotestosterone, androstenedione, or
estradiol.
b. Axid had no demonstrable antiandrogenic action.
4. Pharmacokinetics—The absolute oral bioavailability of nizati-
dine exceeds 70%. Peak plasma concentrations (700 to 1,800 µg/L
for a 150-mg dose and 1,400 to 3,600 µg/L for a 300-mg dose) occur
from 0.5 to 3 hours following the dose. A concentration of 1,000 µg/L
is equivalent to 3 µmol/L; a dose of 300 mg is equivalent to
905 µmoles. Plasma concentrations 12 hours after administration
are less than 10 µg/L. The elimination half-life is 1 to 2 hours,
plasma clearance is 40 to 60 L/h, and the volume of distribution is
0.8 to 1.5 L/kg. Because of the short half-life and rapid clearance of
nizatidine, accumulation of the drug would not be expected in indi-
viduals with normal renal function who take either 300 mg once daily
at bedtime or 150 mg twice daily. Axid exhibits dose proportionality
over the recommended dose range.
The oral bioavailability of nizatidine is unaffected by concomitant
ingestion of propantheline. Antacids consisting of aluminum and
magnesium hydroxides with simethicone decrease the absorption of
nizatidine by about 10%. With food, the AUC and Cmax increase by
approximately 10%.
In humans, less than 7% of an oral dose is metabolized as N2-
monodes-methylnizatidine, an H2-receptor antagonist, which is the
principal metabolite excreted in the urine. Other likely metabolites
are the N2-oxide (less than 5% of the dose) and the S-oxide (less
than 6% of the dose).
More than 90% of an oral dose of nizatidine is excreted in the
urine within 12 hours. About 60% of an oral dose is excreted as
unchanged drug. Renal clearance is about 500 mL/min, which indi-
cates excretion by active tubular secretion. Less than 6% of an
administered dose is eliminated in the feces.
Moderate to severe renal impairment significantly prolongs the
half-life and decreases the clearance of nizatidine. In individuals who
are functionally anephric, the half-life is 3.5 to 11 hours, and the
plasma clearance is 7 to 14 L/h. To avoid accumulation of the drug
in individuals with clinically significant renal impairment, the amount
and/or frequency of doses of Axid should be reduced in proportion to
the severity of dysfunction (see Dosage and Administration).
Approximately 35% of nizatidine is bound to plasma protein, mainly
to α1-acid glycoprotein. Warfarin, diazepam, acetaminophen,
propantheline, phenobarbital, and propranolol did not affect plasma
protein binding of nizatidine in vitro.
Clinical Trials —1. Active Duodenal Ulcer: In multicenter, double-
blind, placebo-controlled studies in the United States, endoscopically
diagnosed duodenal ulcers healed more rapidly following administra-
tion of Axid, 300 mg h.s. or 150 mg b.i.d., than with placebo (Table 2).
Lower doses, such as 100 mg h.s., had slightly lower effectiveness.
*P <0.01 as compared with placebo.
†P <0.05 as compared with placebo.
2. Maintenance of Healed Duodenal Ulcer:
Treatment with a reduced dose of Axid has been shown to be
effective as maintenance therapy following healing of active duode-
nal ulcers. In multicenter, double-blind, placebo-controlled studies
conducted in the United States, 150 mg of Axid taken at bedtime
resulted in a significantly lower incidence of duodenal ulcer recur-
rence in patients treated for up to 1 year (Table 3).
Table 3
Percentage of Ulcers Recurring by 3, 6, and 12 Months in
Double-Blind Studies Conducted in the United States
3. Gastroesophageal Reflux Disease (GERD):
In 2 multicenter, double-blind, placebo-controlled clinical trials per-
formed in the United States and Canada, Axid was more effective
than placebo in improving endoscopically diagnosed esophagitis and
in healing erosive and ulcerative esophagitis.
In patients with erosive or ulcerative esophagitis, 150 mg b.i.d. of
Axid given to 88 patients compared with placebo in 98 patients in
Study 1 yielded a higher healing rate at 3 weeks (16% vs 7%) and at
6 weeks (32% vs 16%, P<0.05). Of 99 patients on Axid and 94
patients on placebo, Study 2 at the same dosage yielded similar
results at 6 weeks (21% vs 11%, P< 0.05) and at 12 weeks (29% vs
13%, P<0.01).
In addition, relief of associated heartburn was greater in patients
treated with Axid. Patients treated with Axid consumed fewer
antacids than did patients treated with placebo.
4. Active Benign Gastric Ulcer:
In a multicenter, double-blind, placebo-controlled study conducted
in the United States and Canada, endoscopically diagnosed benign
gastric ulcers healed significantly more rapidly following administra-
tion of nizatidine than of placebo (Table 4).
In a multicenter, double-blind, comparator-controlled study in
Europe, healing rates for patients receiving nizatidine (300 mg h.s.
or 150 mg b.i.d.) were equivalent to rates for patients receiving a
comparator drug, and statistically superior to historical placebo con-
trol rates.
INDICATIONS AND USAGE
Axid is indicated for up to 8 weeks for the treatment of active duo-
denal ulcer. In most patients, the ulcer will heal within 4 weeks.
Axid is indicated for maintenance therapy for duodenal ulcer
patients, at a reduced dosage of 150 mg h.s. after healing of an
active duodenal ulcer. The consequences of continuous therapy with
Axid for longer than 1 year are not known.
Axid is indicated for up to 12 weeks for the treatment of endoscop-
ically diagnosed esophagitis, including erosive and ulcerative
esophagitis, and associated heartburn due to GERD.
Axid is indicated for up to 8 weeks for the treatment of active
benign gastric ulcer. Before initiating therapy, care should be taken
to exclude the possibility of malignant gastric ulceration.
CONTRAINDICATION
Axid is contraindicated in patients with known hypersensitivity to
the drug. Because cross sensitivity in this class of compounds has
been observed, H2-receptor antagonists, including Axid, should not
be administered to patients with a history of hypersensitivity to other
H2-receptor antagonists.
PRECAUTIONS
General —1. Symptomatic response to nizatidine therapy does not
preclude the presence of gastric malignancy.
2. Because nizatidine is excreted primarily by the kidney, dosage
should be reduced in patients with moderate to severe renal insuffi-
ciency (see Dosage and Administration).
3. Pharmacokinetic studies in patients with hepatorenal syndrome
have not been done. Part of the dose of nizatidine is metabolized in
the liver. In patients with normal renal function and uncomplicated
hepatic dysfunction, the disposition of nizatidine is similar to that in
normal subjects.
Laboratory Tests — False-positive tests for urobilinogen with
Multistix® may occur during therapy with nizatidine.
Drug Interactions— No interactions have been observed between
Axid and theophylline, chlordiazepoxide, lorazepam, lidocaine,
phenytoin, and warfarin. Axid does not inhibit the cytochrome P-450-
linked drug-metabolizing enzyme system; therefore, drug interac-
tions mediated by inhibition of hepatic metabolism are not expected
to occur. In patients given very high doses (3,900 mg) of aspirin daily,
increases in serum salicylate levels were seen when nizatidine,
150 mg b.i.d., was administered concurrently.
Carcinogenesis, Mutagenesis, Impairment of Fertility—A 2-year
oral carcinogenicity study in rats with doses as high as
500 mg/kg/day (about 80 times the recommended daily
therapeutic dose) showed no evidence of a carcinogenic effect.
There was a dose-related increase in the density of enterochromaf-
fin-like (ECL) cells in the gastric oxyntic mucosa. In a 2-year study in
mice, there was no evidence of a carcinogenic effect in male mice;
although hyperplastic nodules of the liver were increased in the high-
dose males as compared with placebo. Female mice given the high
dose of Axid (2,000 mg/kg/day, about 330 times the human dose)
showed marginally statistically significant increases in hepatic carci-
noma and hepatic nodular hyperplasia with no numerical increase
seen in any of the other dose groups. The rate of hepatic carcinoma
in the high-dose animals was within the historical control limits seen
for the strain of mice used. The female mice were given a dose larger
than the maximum tolerated dose, as indicated by excessive (30%)
weight decrement as compared with concurrent controls and evi-
dence of mild liver injury (transaminase elevations). The occurrence
of a marginal finding at high dose only in animals given an excessive
and somewhat hepatotoxic dose, with no evidence of a carcinogenic
effect in rats, male mice, and female mice (given up to
360 mg/kg/day, about 60 times the human dose), and a negative
mutagenicity battery are not considered evidence of a carcinogenic
potential for Axid.
Axid was not mutagenic in a battery of tests performed to evaluate
its potential genetic toxicity, including bacterial mutation tests,
unscheduled DNA synthesis, sister chromatid exchange, mouse lym-
phoma assay, chromosome aberration tests, and a micronucleus
test.
In a 2-generation, perinatal and postnatal fertility study in rats,
doses of nizatidine up to 650 mg/kg/day produced no adverse
effects on the reproductive performance of parental animals or their
progeny.
Pregnancy —Teratogenic Effects—Pregnancy Category B—Oral
reproduction studies in pregnant rats at doses up to 1500 mg/kg/day
(9000 mg/m2/day, 40.5 times the recommended human dose based
on body surface area) and in pregnant rabbits at doses up to
275 mg/kg/day (3245 mg/m2/day, 14.6 times the recommended
human dose based on body surface area) have revealed no evi-
dence of impaired fertility or harm to the fetus due to nizatidine.
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 dur-
ing pregnancy only if clearly needed.
Nursing Mothers —Studies conducted in lactating women have
shown that 0.1% of the administered oral dose of nizatidine is
secreted in human milk in proportion to plasma concentrations.
Because of the growth depression in pups reared by lactating rats
treated with nizatidine, a decision should be made whether to dis-
continue 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.
Time After
% Inhibition of Gastric Acid
Dose (h)
Output by Dose (mg)
20-50
75
100
150
300
Nocturnal
Up to 10
57
73
90
Betazole
Up to 3
93
100
99
Pentagastrin
Up to 6
25
64
67
Meal
Up to 4
41
64
98
97
Caffeine
Up to 3
73
85
96
Table 2
Healing Response of Ulcers to Axid
AXID
300 mg h.s.
150 mg b.i.d.
Placebo
Number
Healed/
Number
Healed/
Number
Healed/
Entered
Evaluable
Entered
Evaluable
Entered
Evaluable
STUDY 1
Week 2
276
93/265 (35%)*
279
55/260 (21%)
Week 4
198/259 (76%)*
95/243 (39%)
STUDY 2
Week 2
108
24/103 (23%)*
106
27/101 (27%)*
101
9/93 (10%)
Week 4
65/97 (67%)*
66/97 (68%)*
24/84 (29%)
STUDY 3
Week 2
92
22/90 (24%)†
98
13/92 (14%)
Week 4
52/85 (61%)*
29/88 (33%)
Week 8
68/83 (82%)*
39/79 (49%)
Month
Axid, 150 mg h.s.
Placebo
3
13% (28/208)*
40% (82/204)
6
24% (45/188)*
57% (106/187)
12
34% (57/166)*
64% (112/175)
*P <0.001 as compared with placebo.
Table 4
Week
Treatment
Healing Rate
vs. Placebo
p-value*
4
Niz 300 mg h.s.
52/153 (34%)
0.342
Niz 150 mg b.i.d.
65/151 (43%)
0.022
Placebo
48/151 (32%)
8
Niz 300 mg h.s.
99/153 (65%)
0.011
Niz 150 mg b.i.d.
105/151 (70%)
<0.001
Placebo
78/151 (52%)
*P-values are one-sided, obtained by Chi-square test, and not adjusted for
multiple comparisons.
AXID®
(nizatidine) Capsules, USP
214F400
2143400
Nizatidine
Axid Trade P.I_2.qxd 4/26/05 12:03 PM Page 1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Geriatric Use — Of the 955 patients in clinical studies who were
treated with nizatidine, 337 (35.3%) were 65 and older. No overall
differences in safety or effectiveness were observed between these
and younger subjects. 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, care should be taken in dose selec-
tion, and it may be useful to monitor renal function (see Dosage and
Administration).
ADVERSE REACTIONS
Worldwide, controlled clinical trials of nizatidine included over
6,000 patients given nizatidine in studies of varying durations. Placebo-
controlled trials in the United States and Canada included over 2,600
patients given nizatidine and over 1,700 given placebo. Among the
adverse events in these placebo-controlled trials, anemia (0.2% vs
0%) and urticaria (0.5% vs 0.1%) were significantly more common in
the nizatidine group.
Incidence in Placebo-Controlled Clinical Trials in the United
States and Canada —Table 5 lists adverse events that occurred at a
frequency of 1% or more among nizatidine-treated patients who par-
ticipated in placebo-controlled trials. The cited figures provide some
basis for estimating the relative contribution of drug and nondrug fac-
tors to the side effect incidence rate in the population studied.
A variety of less common events were also reported; it was not
possible to determine whether these were caused by nizatidine.
Hepatic — Hepatocellular injury, evidenced by elevated liver
enzyme tests (SGOT [AST], SGPT [ALT], or alkaline phosphatase),
occurred in some patients and was possibly or probably related to
nizatidine. In some cases there was marked elevation of SGOT,
SGPT enzymes (greater than 500 IU/L) and, in a single instance,
SGPT was greater than 2,000 IU/L. The overall rate of occurrences
of elevated liver enzymes and elevations to 3 times the upper limit of
normal, however, did not significantly differ from the rate of liver
enzyme abnormalities in placebo-treated patients. All abnormalities
were reversible after discontinuation of Axid. Since market introduc-
tion, hepatitis and jaundice have been reported. Rare cases of
cholestatic or mixed hepatocellular and cholestatic injury with jaun-
dice have been reported with reversal of the abnormalities after dis-
continuation of Axid.
Cardiovascular—In clinical pharmacology studies, short episodes
of asymptomatic ventricular tachycardia occurred in 2 individuals
administered Axid and in 3 untreated subjects.
CNS—Rare cases of reversible mental confusion have been
reported.
Endocrine — Clinical pharmacology studies and controlled clinical
trials showed no evidence of antiandrogenic activity due to Axid.
Impotence and decreased libido were reported with similar frequency
by patients who received Axid and by those given placebo. Rare
reports of gynecomastia occurred.
Hematologic — Anemia was reported significantly more frequently
in nizatidine- than in placebo-treated patients. Fatal thrombocytope-
nia was reported in a patient who was treated with Axid and another
H2-receptor antagonist. On previous occasions, this patient had
experienced thrombocytopenia while taking other drugs. Rare cases
of thrombocytopenic purpura have been reported.
Integumental — Sweating and urticaria were reported significantly
more frequently in nizatidine- than in placebo-treated patients. Rash
and exfoliative dermatitis were also reported. Vasculitis has been
reported rarely.
Hypersensitivity —As with other H2-receptor antagonists, rare cases
of anaphylaxis following administration of nizatidine have been
reported. Rare episodes of hypersensitivity reactions (eg, bron-
chospasm, laryngeal edema, rash, and eosinophilia) have been
reported.
Body as a Whole —Serum sickness-like reactions have occurred
rarely in conjunction with nizatidine use.
Genitourinary — Reports of impotence have occurred.
Other — Hyperuricemia unassociated with gout or nephrolithiasis
was reported. Eosinophilia, fever, and nausea related to nizatidine
administration have been reported.
OVERDOSAGE
Overdoses of Axid have been reported rarely. The following is pro-
vided to serve as a guide should such an overdose be encountered.
Signs and Symptoms —There is little clinical experience with over-
dosage of Axid in humans. Test animals that received large doses of
nizatidine have exhibited cholinergic-type effects, including lacrima-
tion, salivation, emesis, miosis, and diarrhea. Single oral doses of
800 mg/kg in dogs and of 1,200 mg/kg in monkeys were not lethal.
Intravenous median lethal doses in the rat and mouse were
301 mg/kg and 232 mg/kg respectively.
Treatment —To obtain up-to-date information about the treatment
of overdose, a good resource is your certified Regional Poison Con-
trol Center. Telephone numbers of certified poison control centers
are listed in the Physicians’ Desk Reference (PDR). In managing
overdosage, consider the possibility of multiple drug overdoses,
interaction among drugs, and unusual drug kinetics in your patient.
If overdosage occurs, use of activated charcoal, emesis, or lavage
should be considered along with clinical monitoring and supportive
therapy. The ability of hemodialysis to remove nizatidine from the
body has not been conclusively demonstrated; however, due to its
large volume of distribution, nizatidine is not expected to be efficiently
removed from the body by this method.
DOSAGE AND ADMINISTRATION
Active Duodenal Ulcer —The recommended oral dosage for adults
is 300 mg once daily at bedtime. An alternative dosage regimen is
150 mg twice daily.
Maintenance of Healed Duodenal Ulcer —The recommended oral
dosage for adults is 150 mg once daily at bedtime.
Gastroesophageal Reflux Disease —The recommended oral
dosage in adults for the treatment of erosions, ulcerations, and asso-
ciated heartburn is 150 mg twice daily.
Active Benign Gastric Ulcer —The recommended oral dosage is
300 mg given either as 150 mg twice daily or 300 mg once daily at
bedtime. Prior to treatment, care should be taken to exclude the pos-
sibility of malignant gastric ulceration.
Dosage Adjustment for Patients With Moderate to Severe Renal
Insufficiency —The dose for patients with renal dysfunction should
be reduced as follows:
Active Duodenal Ulcer, GERD and Benign Gastric Ulcer
Ccr
Dose
20-50 mL/min
150 mg daily
<20 mL/min
150 mg every other day
Maintenance Therapy
Ccr
Dose
20-50 mL/min
150 mg every other day
<20 mL/min
150 mg every 3 days
Some elderly patients may have creatinine clearances of less than
50 mL/min, and, based on pharmacokinetic data in patients with
renal impairment, the dose for such patients should be reduced
accordingly. The clinical effects of this dosage reduction in patients
with renal failure have not been evaluated.
HOW SUPPLIED
Axid® Pulvules®* are available in:
The 150-mg Pulvules are imprinted with “150” on the opaque dark
yellow cap and “AXID” and “Reliant” on the opaque pale yellow
body, using black ink. They are available as follows:
Bottles of 60
NDC 65726-144-15
The 300-mg Pulvules are imprinted with “300” on the opaque brown
cap and “AXID” and “Reliant” on the opaque pale yellow body, using
black ink. They are available as follows:
Bottles of 30
NDC 65726-145-10
*Pulvules® (filled gelatin capsules, Lilly)
Store at controlled room temperature 20° to 25°C (68° to 77°F) in
a tightly closed container [see USP].
The USP defines controlled room temperature as: A temperature
maintained thermostatically that encompasses the usual and cus-
tomary working environment of 20° to 25°C (68° to 77°F); that
results in a mean kinetic temperature calculated to be not more
than 25°C; and that allows for excursions between 15° and 30°C
(59° and 86°F) that are experienced in pharmacies, hospitals, and
warehouses.
Rx Only
March 2005
Distributed by:
Reliant Pharmaceuticals, Inc.
Liberty Corner, NJ 07938, USA
Address Medical Inquiries to:
Reliant Pharmaceuticals, Inc.
Medical Affairs
110 Allen Road
Liberty Corner, NJ 07938, USA
© 2005 Reliant Pharmaceuticals, Inc.
214F400
PRINTED IN U.S.A.
Table 5
INCIDENCE OF TREATMENT-EMERGENT
ADVERSE EVENTS IN PLACEBO-CONTROLLED
CLINICAL TRIALS
IN THE UNITED STATES AND CANADA
Percentage of Patients Reporting Event
Body System/Adverse Event*
Nizatidine(N=2,694)
Placebo(N=1,729)
Body as a Whole
Headache
16.6
15.6
Abdominal pain
7.5
12.5
Pain
4.2
3.8
Asthenia
3.1
2.9
Back pain
2.4
2.6
Chest pain
2.3
2.1
Infection
1.7
1.1
Fever
1.6
2.3
Surgical procedure
1.4
1.5
Injury, accident
1.2
0.9
Digestive
Diarrhea
7.2
6.9
Nausea
5.4
7.4
Flatulence
4.9
5.4
Vomiting
3.6
5.6
Dyspepsia
3.6
4.4
Constipation
2.5
3.8
Dry mouth
1.4
1.3
Nausea and vomiting
1.2
1.9
Anorexia
1.2
1.6
Gastrointestinal disorder
1.1
1.2
Tooth disorder
1.0
0.8
Musculoskeletal
Myalgia
1.7
1.5
Nervous
Dizziness
4.6
3.8
Insomnia
2.7
3.4
Abnormal dreams
1.9
1.9
Somnolence
1.9
1.6
Anxiety
1.6
1.4
Nervousness
1.1
0.8
Respiratory
Rhinitis
9.8
9.6
Pharyngitis
3.3
3.1
Sinusitis
2.4
2.1
Cough, increased
2.0
2.0
Skin and Appendages
Rash
1.9
2.1
Pruritus
1.7
1.3
Special Senses
Amblyopia
1.0
0.9
*Events reported by at least 1% of nizatidine-treated patients are included.
AXID®
(nizatidine) Capsules, USP
Axid Trade P.I_2.qxd 4/26/05 12:03 PM Page 2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
AXID®
(nizatidine) Capsules, USP
Description: Axid® (Nizatidine, USP) is a histamine H2-
receptor antagonist. Chemically, it is N-[2-[[[2-
[(dimethylamino)methyl]-4-thiazolyl]methyl]thio]ethyl]-N'-
methyl-2-nitro-1,1-ethenediamine.
The structural formula is as follows:
Nizatidine has the empirical formula C12H21N5O2S2
representing a molecular weight of 331.47. It is an off-white
to buff crystalline solid that is soluble in water. Nizatidine
has a bitter taste and mild sulfur-like odor. Each Pulvule®
(capsule) contains for oral administration gelatin, pregelat-
inized starch, dimethicone, starch, titanium dioxide, yellow
iron oxide, 150 mg (0.45 mmol) or 300 mg (0.91 mmol) of
nizatidine, and other inactive ingredients. The 150-mg
Pulvule also contains magnesium stearate, and the 300-mg
Pulvule also contains croscarmellose sodium, povidone,
red iron oxide, and talc.
Clinical Pharmacology: Axid is a competitive, reversible
inhibitor of histamine at the histamine H2-receptors,
particularly those in the gastric parietal cells.
Antisecretory Activity—1. Effects on Acid Secretion: Axid
significantly inhibited nocturnal gastric acid secretion for
up to 12 hours. Axid also significantly inhibited gastric acid
secretion stimulated by food, caffeine, betazole, and penta-
gastrin (Table 1).
Table 1.—Effect of Oral Axid on Gastric Acid Secretion
2. Effects on Other Gastrointestinal Secretions—Pepsin:
Oral administration of 75 to 300 mg of Axid did not affect
pepsin activity in gastric secretions.Total pepsin output was
reduced in proportion to the reduced volume of gastric
secretions.
Intrinsic Factor: Oral administration of 75 to 300 mg of Axid
increased betazole-stimulated secretion of intrinsic factor.
Serum Gastrin: Axid had no effect on basal serum gastrin.
No rebound of gastrin secretion was observed when food
was ingested 12 hours after administration of Axid.
3. Other Pharmacologic Actions—
a. Hormones: Axid was not shown to affect the serum
concentrations of gonadotropins, prolactin, growth
hormone, antidiuretic hormone, cortisol, triiodo-
thyronine, thyroxin, testosterone, 5α-dihydrotestos-
terone, androstenedione, or estradiol.
b. Axid had no demonstrable antiandrogenic action.
4. Pharmacokinetics—The absolute oral bioavailability of
nizatidine exceeds 70%. Peak plasma concentrations (700
to 1,800 µg/L for a 150-mg dose and 1,400 to 3,600 µg/L for
a 300-mg dose) occur from 0.5 to 3 hours following the
dose. A concentration of 1,000 µg/L is equivalent to 3 µmol/L;
a dose of 300 mg is equivalent to 905 µmoles. Plasma
concentrations 12 hours after administration are less than
10 µg/L. The elimination half-life is 1 to 2 hours, plasma
clearance is 40 to 60 L/h, and the volume of distribution is
0.8 to 1.5 L/kg. Because of the short half-life and rapid
clearance of nizatidine, accumulation of the drug would not
be expected in individuals with normal renal function who
take either 300 mg once daily at bedtime or 150 mg twice
daily. Axid exhibits dose proportionality over the recom-
mended dose range.
The oral bioavailability of nizatidine is unaffected by
concomitant ingestion of propantheline. Antacids consisting
of aluminum and magnesium hydroxides with simethicone
decrease the absorption of nizatidine by about 10%. With
food, the AUC and Cmax increase by approximately 10%.
In humans, less than 7% of an oral dose is metabolized
as N2-monodesmethylnizatidine, an H2-receptor
antagonist, which is the principal metabolite excreted in the
urine. Other likely metabolites are the N2-oxide (less than
5% of the dose) and the S-oxide (less than 6% of the dose).
More than 90% of an oral dose of nizatidine is excreted in
the urine within 12 hours. About 60% of an oral dose is
excreted as unchanged drug. Renal clearance is about 500
mL/min, which indicates excretion by active tubular secre-
tion. Less than 6% of an administered dose is eliminated in
the feces.
Moderate to severe renal impairment significantly pro-
longs the half-life and decreases the clearance of nizatidine.
In individuals who are functionally anephric, the half-life is
3.5 to 11 hours, and the plasma clearance is 7 to 14 L/h. To
avoid accumulation of the drug in individuals with clinically
significant renal impairment, the amount and/or frequency of
doses of Axid should be reduced in proportion to the severity
of dysfunction (see Dosage and Administration).
Approximately 35% of nizatidine is bound to plasma
protein, mainly to α1-acid glycoprotein. Warfarin, diazepam,
acetaminophen, propantheline, phenobarbital, and propran-
olol did not affect plasma protein binding of nizatidine in vitro.
Clinical Trials—1. Active Duodenal Ulcer: In multicenter,
double-blind, placebo-controlled studies in the United
States, endoscopically diagnosed duodenal ulcers healed
more rapidly following administration of Axid, 300 mg h.s. or
150 mg b.i.d., than with placebo (Table 2). Lower doses,
such as 100 mg h.s., had slightly lower effectiveness.
Table 2.—Healing Response of Ulcers to Axid
Axid
Placebo
300 mg h.s.
150 mg b.i.d.
Number
Healed/
Number
Healed/
Number
Healed/
Entered
Evaluable
Entered
Evaluable
Entered
Evaluable
STUDY 1
Week 2
276
93/265 (35%)*
279
55/260 (21%)
Week 4
198/259 (76%)*
95/243 (39%)
STUDY 2
Week 2 108
24/103 (23%)*
106
27/101 (27%)*
101
9/93 (10%)
Week 4
65/97 (67%)*
66/97 (68%)*
24/84 (29%)
STUDY 3
Week 2
92
22/90 (24%)†
98
13/92 (14%)
Week 4
52/85 (61%)*
29/88 (33%)
Week 8
68/83 (82%)*
39/79 (49%)
*P<0.01 as compared with placebo.
†P<0.05 as compared with placebo.
2. Maintenance of Healed Duodenal Ulcer: Treatment
with a reduced dose of Axid has been shown to be effective
as maintenance therapy following healing of active
duodenal ulcers. In multicenter, double-blind, placebo-
controlled studies conducted in the United States, 150 mg
of Axid taken at bedtime resulted in a significantly lower
incidence of duodenal ulcer recurrence in patients treated
for up to 1 year (Table 3).
Table 3.
Percentage of Ulcers Recurring by 3, 6, and 12 Months
in Double-Blind Studies Conducted in the United States
Month
Axid, 150 mg h.s.
Placebo
3
13% (28/208)*
40% (82/204)
6
24% (45/188)*
57% (106/187)
12
34% (57/166)*
64% (112/175)
*P<0.001 as compared with placebo.
3. Gastroesophageal Reflux Disease (GERD): In 2 multi-
center, double-blind, placebo-controlled clinical trials
performed in the United States and Canada, Axid was more
effective than placebo in improving endoscopically
diagnosed esophagitis and in healing erosive and
ulcerative esophagitis.
In patients with erosive or ulcerative esophagitis, 150 mg
b.i.d. of Axid given to 88 patients compared with placebo in
98 patients in Study 1 yielded a higher healing rate at 3
weeks (16% vs 7%) and at 6 weeks (32% vs 16%, P<0.05).
Of 99 patients on Axid and 94 patients on placebo, Study 2
at the same dosage yielded similar results at 6 weeks (21%
vs 11%, P<0.05) and at 12 weeks (29% vs 13%, P<0.01).
In addition, relief of associated heartburn was greater in
patients treated with Axid. Patients treated with Axid con-
sumed fewer antacids than did patients treated with placebo.
4. Active Benign Gastric Ulcer: In a multicenter, double-
blind, placebo-controlled study conducted in the United
States and Canada, endoscopically diagnosed benign
gastric ulcers healed significantly more rapidly following
administration of nizatidine than of placebo (Table 4).
Table 4.
Week
Treatment
Healing Rate
vs. Placebo
p-value*
4
Niz 300 mg h.s.
52/153 (34%)
0.342
Niz 150 mg b.i.d.
65/151 (43%)
0.022
Placebo
48/151 (32%)
8
Niz 300 mg h.s.
99/153 (65%)
0.011
Niz 150 mg b.i.d.
105/151 (70%)
<0.001
Placebo
78/151 (52%)
*P-values are one-sided, obtained by Chi-square test, and not adjusted for
multiple comparisons.
In a multicenter, double-blind, comparator-controlled study
in Europe, healing rates for patients receiving nizatidine (300
mg h.s. or 150 mg b.i.d.) were equivalent to rates for patients
receiving a comparator drug, and statistically superior to
historical placebo control rates.
Indications and Usage: Axid is indicated for up to 8 weeks
for the treatment of active duodenal ulcer. In most patients,
the ulcer will heal within 4 weeks.
Axid is indicated for maintenance therapy for duodenal
ulcer patients at a reduced dosage of 150 mg h.s. after
healing of an active duodenal ulcer. The consequences of
continuous therapy with Axid for longer than 1 year are
not known.
Axid is indicated for up to 12 weeks for the treatment of
endoscopically diagnosed esophagitis, including erosive
and ulcerative esophagitis, and associated heartburn due
to GERD.
Axid is indicated for up to 8 weeks for the treatment of
active benign gastric ulcer. Before initiating therapy, care
should be taken to exclude the possibility of malignant
gastric ulceration.
Contraindication: Axid is contraindicated in patients with
known hypersensitivity to the drug. Because cross sen-
sitivity in this class of compounds has been observed, H2-
receptor antagonists, including Axid, should not be
administered to patients with a history of hypersensitivity to
other H2-receptor antagonists.
Precautions: General—1. Symptomatic response to
nizatidine therapy does not preclude the presence of
gastric malignancy.
2. Because nizatidine is excreted primarily by the kidney,
dosage should be reduced in patients with moderate to
severe renal insufficiency (see Dosage and Administration).
3. Pharmacokinetic studies in patients with hepatorenal
syndrome have not been done. Part of the dose of
nizatidine is metabolized in the liver. In patients with normal
renal function and uncomplicated hepatic dysfunction, the
disposition of nizatidine is similar to that in normal subjects.
Laboratory Tests—False-positive tests for urobilinogen
with Multistix® may occur during therapy with nizatidine.
Drug Interactions—No interactions have been observed
between Axid and theophylline, chlordiazepoxide,
lorazepam, lidocaine, phenytoin, and warfarin. Axid does
not inhibit the cytochrome P-450-linked drug-metabolizing
enzyme system; therefore, drug interactions mediated by
inhibition of hepatic metabolism are not expected to occur.
In patients given very high doses (3,900 mg) of aspirin
daily, increases in serum salicylate levels were seen when
nizatidine, 150 mg b.i.d., was administered concurrently.
Carcinogenesis, Mutagenesis, Impairment of Fertility—A
2-year oral carcinogenicity study in rats with doses as high
as 500 mg/kg/day (about 80 times the recommended daily
therapeutic dose) showed no evidence of a carcinogenic
effect. There was a dose-related increase in the density of
enterochromaffin-like (ECL) cells in the gastric oxyntic
mucosa. In a 2-year study in mice, there was no evidence
of a carcinogenic effect in male mice; although hyperplastic
nodules of the liver were increased in the high-dose males
as compared with placebo. Female mice given the high
dose of Axid (2,000 mg/kg/day, about 330 times the human
dose) showed marginally statistically significant increases
in hepatic carcinoma and hepatic nodular hyperplasia with
no numerical increase seen in any of the other dose
groups. The rate of hepatic carcinoma in the high-dose
animals was within the historical control limits seen for the
strain of mice used. The female mice were given a dose
larger than the maximum tolerated dose, as indicated by
excessive (30%) weight decrement as compared with
concurrent controls and evidence of mild liver injury
(transaminase elevations). The occurrence of a marginal
finding at high dose only in animals given an excessive and
somewhat hepatotoxic dose, with no evidence of a
carcinogenic effect in rats, male mice, and female mice
(given up to 360 mg/kg/day, about 60 times the human
dose), and a negative mutagenicity battery are not
considered evidence of a carcinogenic potential for Axid.
Axid was not mutagenic in a battery of tests performed to
evaluate its potential genetic toxicity, including bacterial
mutation tests, unscheduled DNA synthesis, sister
chromatid exchange, mouse lymphoma assay, chromo-
some aberration tests, and a micronucleus test.
In a 2-generation, perinatal and postnatal fertility study in
rats, doses of nizatidine up to 650 mg/kg/day produced no
adverse effects on the reproductive performance of
parental animals or their progeny.
Pregnancy—Teratogenic Effects—Pregnancy Category
B—Oral reproduction studies in pregnant rats at doses up
Time After
% Inhibition of Gastric Acid
Dose (h)
Output by Dose (mg)
20-50
75
100
150
300
Nocturnal
Up to 10
57
73
90
Betazole
Up to 3
93
100
99
Pentagastrin
Up to 6
25
64
67
Meal
Up to 4
41
64
98
97
Caffeine
Up to 3
73
85
96
AXID®
(nizatidine) Capsules, USP
AXID®
(nizatidine) Capsules, USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
to 1500 mg/kg/day (9000 mg/m2/day, 40.5 times the
recommended human dose based on body surface area)
and in pregnant rabbits at doses up to 275 mg/kg/day (3245
mg/m2/day, 14.6 times the recommended human dose
based on body surface area) have revealed no evidence of
impaired fertility or harm to the fetus due to nizatidine.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 —Studies conducted in lactating
women have shown that 0.1% of the administered oral
dose of nizatidine is secreted in human milk in proportion to
plasma concentrations. Because of the growth depression
in pups reared by lactating rats treated with nizatidine, 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— Of the 955 patients in clinical studies who
were treated with nizatidine, 337 (35.3%) were 65 and
older. No overall differences in safety or effectiveness were
observed between these and younger subjects. 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, care should be taken in dose selection, and it may
be useful to monitor renal function (see Dosage and
Administration).
Adverse Reactions: Worldwide, controlled clinical trials of
nizatidine included over 6,000 patients given nizatidine in
studies of varying durations. Placebo-controlled trials in the
United States and Canada included over 2,600 patients
given nizatidine and over 1,700 given placebo. Among the
adverse events in these placebo-controlled trials, anemia
(0.2% vs 0%) and urticaria (0.5% vs 0.1%) were
significantly more common in the nizatidine group.
Incidence in Placebo-Controlled Clinical Trials in the
United States and Canada—Table 5 lists adverse events
that occurred at a frequency of 1% or more among
nizatidine-treated patients who participated in placebo-
controlled trials. The cited figures provide some basis for
estimating the relative contribution of drug and nondrug
factors to the side-effect incidence rate in the population
studied.
Table 5.
Incidence of Treatment-Emergent Adverse Events
in Placebo-Controlled Clinical Trials in
the United States and Canada
Percentage of
Percentage of
Patients Reporting
Patients Reporting
Event
Event
Body System/
Nizatidine
Placebo
Body System/
Nizatidine
Placebo
Adverse Event*
(N=2,694) (N=1,729)
Adverse Event* (N=2,694) (N=1,729)
Body as a Whole
Headache
16.6
15.6
Abdominal pain
7.5
12.5
Pain
4.2
3.8
Asthenia
3.1
2.9
Back pain
2.4
2.6
Chest pain
2.3
2.1
Infection
1.7
1.1
Fever
1.6
2.3
Surgical
procedure
1.4
1.5
Injury, accident
1.2
0.9
Digestive
Diarrhea
7.2
6.9
Nausea
5.4
7.4
Flatulence
4.9
5.4
Vomiting
3.6
5.6
Dyspepsia
3.6
4.4
Constipation
2.5
3.8
Dry mouth
1.4
1.3
Nausea and
vomiting
1.2
1.9
Anorexia
1.2
1.6
Gastrointestinal
disorder
1.1
1.2
Tooth disorder
1.0
0.8
*Events reported by at least 1% of nizatidine-treated patients are included.
A variety of less common events were also reported; it
was not possible to determine whether these were caused
by nizatidine.
Hepatic—Hepatocellular injury, evidenced by elevated
liver enzyme tests (SGOT [AST], SGPT [ALT], or alkaline
phosphatase), occurred in some patients and was possibly
or probably related to nizatidine. In some cases, there was
marked elevation of SGOT, SGPT enzymes (greater than
500 IU/L) and, in a single instance, SGPT was greater than
2,000 IU/L. The overall rate of occurrences of elevated liver
enzymes and elevations to 3 times the upper limit of
normal, however, did not significantly differ from the rate of
liver enzyme abnormalities in placebo-treated patients. All
abnormalities were reversible after discontinuation of Axid.
Since market introduction, hepatitis and jaundice have
been reported. Rare cases of cholestatic or mixed
hepatocellular and cholestatic injury with jaundice have
been reported with reversal of the abnormalities after
discontinuation of Axid.
Cardiovascular—In clinical pharmacology studies, short
episodes of asymptomatic ventricular tachycardia occurred
in 2 individuals administered Axid and in 3 untreated subjects.
CNS—Rare cases of reversible mental confusion have
been reported.
Endocrine —Clinical pharmacology studies and
controlled clinical trials showed no evidence of
antiandrogenic activity due to Axid. Impotence and
decreased libido were reported with similar frequency by
patients who received Axid and by those given placebo.
Rare reports of gynecomastia occurred.
Hematologic—Anemia was reported significantly more
frequently in nizatidine- than in placebo-treated patients.
Fatal thrombocytopenia was reported in a patient who was
treated with Axid and another H2-receptor antagonist. On
previous occasions, this patient had experienced thrombo-
cytopenia while taking other drugs. Rare cases of throm-
bocytopenic purpura have been reported.
Integumental — Sweating and urticaria were reported
significantly more frequently in nizatidine- than in placebo-
treated patients. Rash and exfoliative dermatitis were also
reported.Vasculitis has been reported rarely.
Hypersensitivity —As with other H2-receptor antagonists,
rare cases of anaphylaxis following administration of
nizatidine have been reported. Rare episodes of
hypersensitivity reactions (eg, bronchospasm, laryngeal
edema, rash, and eosinophilia) have been reported.
Body as a Whole—Serum sickness-like reactions have
occurred rarely in conjunction with nizatidine use.
Genitourinary—Reports of impotence have occurred.
Other—Hyperuricemia unassociated with gout or neph-
rolithiasis was reported. Eosinophilia, fever, and nausea
related to nizatidine administration have been reported.
Overdosage: Overdoses of Axid have been reported
rarely. The following is provided to serve as a guide should
such an overdose be encountered.
Signs and Symptoms—There is little clinical experience
with overdosage of Axid in humans. Test animals that
received large doses of nizatidine have exhibited
cholinergic-type effects, including lacrimation, salivation,
emesis, miosis, and diarrhea. Single oral doses of 800
mg/kg in dogs and of 1,200 mg/kg in monkeys were not
lethal. Intravenous median lethal doses in the rat and
mouse were 301 mg/kg and 232 mg/kg respectively.
Treatment—To obtain up-to-date information about the
treatment of overdose, a good resource is your certified
Regional Poison Control Center. Telephone numbers of
certified poison control centers are listed in the Physicians’
Desk Reference (PDR). In managing overdosage, consider
the possibility of multiple drug overdoses, interaction
among drugs, and unusual drug kinetics in your patient.
If overdosage occurs, use of activated charcoal, emesis,
or lavage should be considered along with clinical
monitoring and supportive therapy. The ability of
hemodialysis to remove nizatidine from the body has not
been conclusively demonstrated; however, due to its large
volume of distribution, nizatidine is not expected to be
efficiently removed from the body by this method.
Dosage and Administration:
Active Duodenal Ulcer —The recommended oral dosage
for adults is 300 mg once daily at bedtime. An alternative
dosage regimen is 150 mg twice daily.
Maintenance of Healed Duodenal Ulcer —The recom-
mended oral dosage for adults is 150 mg once daily at
bedtime.
Gastroesophageal Reflux Disease —The recommended
oral dosage in adults for the treatment of erosions, ulcera-
tions, and associated heartburn is 150 mg twice daily.
Active Benign Gastric Ulcer—The recommended oral
dosage is 300 mg given either as 150 mg twice daily or 300
mg once daily at bedtime. Prior to treatment, care should be
taken to exclude the possibility of malignant gastric
ulceration.
Dosage Adjustment for Patients With Moderate to
Severe Renal Insufficiency —The dose for patients with
renal dysfunction should be reduced as follows:
Active Duodenal Ulcer, GERD, and Benign Gastric Ulcer
Ccr
Dose
20-50 mL/min
150 mg daily
<20 mL/min
150 mg every other day
Maintenance Therapy
Ccr
Dose
20-50 mL/min
150 mg every other day
<20 mL/min
150 mg every 3 days
Some elderly patients may have creatinine clearances of
less than 50 mL/min, and, based on pharmacokinetic data
in patients with renal impairment, the dose for such patients
should be reduced accordingly. The clinical effects of this
dosage reduction in patients with renal failure have not
been evaluated.
How Supplied:
Axid®Pulvules®* are available in:
The 150-mg Pulvules are imprinted with “150” on the
opaque dark yellow cap and “AXID” and “Reliant” on the
opaque pale yellow body, using black ink. They are
available as follows:
Bottles of 60
NDC 65726-144-15
The 300-mg Pulvules are imprinted with “300” on the
opaque brown cap and “AXID” and “Reliant” on the opaque
pale yellow body, using black ink. They are available as
follows:
Bottles of 30
NDC 65726-145-10
*Pulvules® (filled gelatin capsules, Lilly)
Store at controlled room temperature 20° to 25°C (68° to
77°F) in a tightly closed container [see USP].
The USP defines controlled room temperature as: A
temperature maintained thermostatically that encompasses
the usual and customary working environment of 20° to
25°C (68° to 77°F); that results in a mean kinetic
temperature calculated to be not more than 25°C; and that
allows for excursions between 15° and 30°C (59° and 86°F)
that are experienced in pharmacies, hospitals, and
warehouses.
Rx Only
March 2005
Distributed by:
Reliant Pharmaceuticals, Inc.
Liberty Corner, NJ 07938, USA
Address Medical Inquiries to:
Reliant Pharmaceuticals, Inc.
Medical Affairs
110 Allen Road
Liberty Corner, NJ 07938, USA
© 2005 Reliant Pharmaceuticals, Inc.
214R400
PRINTED IN U.S.A.
Musculoskeletal
Myalgia
1.7
1.5
Nervous
Dizziness
4.6
3.8
Insomnia
2.7
3.4
Abnormal dreams 1.9
1.9
Somnolence
1.9
1.6
Anxiety
1.6
1.4
Nervousness
1.1
0.8
Respiratory
Rhinitis
9.8
9.6
Pharyngitis
3.3
3.1
Sinusitis
2.4
2.1
Cough, increased 2.0
2.0
Skin and
Appendages
Rash
1.9
2.1
Pruritus
1.7
1.3
Special Senses
Amblyopia
1.0
0.9
AXID®
(nizatidine) Capsules, USP
AXID®
(nizatidine) Capsules, USP
AXID®
(nizatidine) Capsules, USP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:26.655818
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/019508s033lbl.pdf', 'application_number': 19508, 'submission_type': 'SUPPL ', 'submission_number': 33}
|
11,516
|
NDA 19510/S-028
NDA 20249/S-011
Page 3
PEPCID®
(FAMOTIDINE) INJECTION PREMIXED
PEPCID®
(FAMOTIDINE) INJECTION
DESCRIPTION
The active ingredient in PEPCID* (famotidine) Injection Premixed and PEPCID (famotidine) Injection is a
histamine
H2-receptor
antagonist.
Famotidine
is
N'-(aminosulfonyl)-3-[[[2-[(diaminomethylene)amino]-4-
thiazolyl]methyl]thio]propanimidamide. The empirical formula of famotidine is C8H15N7O2S3 and its molecular weight
is 337.43. Its structural formula is:
Famotidine is a white to pale yellow crystalline compound that is freely soluble in glacial acetic acid, slightly
soluble in methanol, very slightly soluble in water, and practically insoluble in ethanol.
PEPCID Injection Premixed is supplied as a sterile solution, for intravenous use only, in plastic single dose
containers. Each 50 mL of the premixed, iso-osmotic intravenous injection contains 20 mg famotidine, USP, and the
following inactive ingredients: L-aspartic acid 6.8 mg, sodium chloride, USP, 450 mg, and Water for Injection. The pH
ranges from 5.7 to 6.4 and may have been adjusted with additional L-aspartic acid or with sodium hydroxide.
The plastic container is fabricated from a specially designed multilayer plastic (PL 2501). Solutions are in contact
with the polyethylene layer of the container and can leach out certain chemical components of the plastic in very
small amounts within the expiration period. The suitability and safety of the plastic have been confirmed in tests in
animals according to the USP biological tests for plastic containers, as well as by tissue culture toxicity studies.
PEPCID (famotidine) Injection is supplied as a sterile concentrated solution for intravenous injection. Each mL of
the solution contains 10 mg of famotidine and the following inactive ingredients: L-aspartic acid 4 mg, mannitol
20 mg, and Water for Injection q.s. 1 mL. The multidose injection also contains benzyl alcohol 0.9% added as
preservative.
CLINICAL PHARMACOLOGY IN ADULTS
GI Effects
PEPCID is a competitive inhibitor of histamine H2-receptors. The primary clinically important pharmacologic
activity of PEPCID is inhibition of gastric secretion. Both the acid concentration and volume of gastric secretion are
suppressed by PEPCID, while changes in pepsin secretion are proportional to volume output.
In normal volunteers and hypersecretors, PEPCID inhibited basal and nocturnal gastric secretion, as well as
secretion stimulated by food and pentagastrin. After oral administration, the onset of the antisecretory effect occurred
within one hour; the maximum effect was dose-dependent, occurring within one to three hours. Duration of inhibition
of secretion by doses of 20 and 40 mg was 10 to 12 hours.
After intravenous administration, the maximum effect was achieved within 30 minutes. Single intravenous doses
of 10 and 20 mg inhibited nocturnal secretion for a period of 10 to 12 hours. The 20 mg dose was associated with the
longest duration of action in most subjects.
Single evening oral doses of 20 and 40 mg inhibited basal and nocturnal acid secretion in all subjects; mean
nocturnal gastric acid secretion was inhibited by 86% and 94%, respectively, for a period of at least 10 hours. The
same doses given in the morning suppressed food-stimulated acid secretion in all subjects. The mean suppression
was 76% and 84%, respectively, 3 to 5 hours after administration, and 25% and 30%, respectively, 8 to 10 hours
after administration. In some subjects who received the 20 mg dose, however, the antisecretory effect was dissipated
within 6-8 hours. There was no cumulative effect with repeated doses. The nocturnal intragastric pH was raised by
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT © MERCK & CO., Inc., 1993, 1995, 1996
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 19510/S-028
NDA 20249/S-011
Page 4
evening doses of 20 and 40 mg of PEPCID to mean values of 5.0 and 6.4, respectively. When PEPCID was given
after breakfast, the basal daytime interdigestive pH at 3 and 8 hours after 20 or 40 mg of PEPCID was raised to
about 5.
PEPCID had little or no effect on fasting or postprandial serum gastrin levels. Gastric emptying and exocrine
pancreatic function were not affected by PEPCID.
Other Effects
Systemic effects of PEPCID in the CNS, cardiovascular, respiratory or endocrine systems were not noted in
clinical pharmacology studies. Also, no antiandrogenic effects were noted. (See ADVERSE REACTIONS.) Serum
hormone levels, including prolactin, cortisol, thyroxine (T4), and testosterone, were not altered after treatment with
PEPCID.
Pharmacokinetics
Orally administered PEPCID is incompletely absorbed and its bioavailability is 40-45%. PEPCID undergoes
minimal first-pass metabolism. After oral doses, peak plasma levels occur in 1-3 hours. Plasma levels after multiple
doses are similar to those after single doses. Fifteen to 20% of PEPCID in plasma is protein bound. PEPCID has an
elimination half-life of 2.5-3.5 hours. PEPCID is eliminated by renal (65-70%) and metabolic (30-35%) routes. Renal
clearance is 250-450 mL/min, indicating some tubular excretion. Twenty-five to 30% of an oral dose and 65-70% of
an intravenous dose are recovered in the urine as unchanged compound. The only metabolite identified in man is the
S-oxide.
There is a close relationship between creatinine clearance values and the elimination half-life of PEPCID. In
patients with severe renal insufficiency, i.e., creatinine clearance less than 10 mL/min, the elimination half-life of
PEPCID may exceed 20 hours and adjustment of dose or dosing intervals in moderate and severe renal insufficiency
may be necessary (see PRECAUTIONS, DOSAGE AND ADMINISTRATION).
In elderly patients, there are no clinically significant age-related changes in the pharmacokinetics of PEPCID.
However, in elderly patients with decreased renal function, the clearance of the drug may be decreased (see
PRECAUTIONS, Geriatric Use).
Clinical Studies
The majority of clinical study experience involved oral administration of PEPCID Tablets, and is provided herein
for reference.
Duodenal Ulcer
In a U.S. multicenter, double-blind study in outpatients with endoscopically confirmed duodenal ulcer, orally
administered PEPCID was compared to placebo. As shown in Table 1, 70% of patients treated with PEPCID 40 mg
h.s. were healed by week 4.
Table 1
Outpatients with Endoscopically
Confirmed Healed Duodenal Ulcers
PEPCID
40 mg h.s.
(N=89)
PEPCID
20 mg b.i.d.
(N=84)
Placebo
h.s.
(N=97)
Week 2
Week 4
**32%
**70%
**38%
**67%
17%
31%
** Statistically significantly different than placebo (p<0.001)
Patients not healed by week 4 were continued in the study. By week 8, 83% of patients treated with PEPCID had
healed versus 45% of patients treated with placebo. The incidence of ulcer healing with PEPCID was significantly
higher than with placebo at each time point based on proportion of endoscopically confirmed healed ulcers.
In this study, time to relief of daytime and nocturnal pain was significantly shorter for patients receiving PEPCID
than for patients receiving placebo; patients receiving PEPCID also took less antacid than the patients receiving
placebo.
Long-Term Maintenance
Treatment of Duodenal Ulcers
PEPCID, 20 mg p.o. h.s. was compared to placebo h.s. as maintenance therapy in two double-blind, multicenter
studies of patients with endoscopically confirmed healed duodenal ulcers. In the U.S. study the observed ulcer
incidence within 12 months in patients treated with placebo was 2.4 times greater than in the patients treated with
PEPCID. The 89 patients treated with PEPCID had a cumulative observed ulcer incidence of 23.4% compared to an
observed ulcer incidence of 56.6% in the 89 patients receiving placebo (p<0.01). These results were confirmed in an
international study where the cumulative observed ulcer incidence within 12 months in the 307 patients treated with
PEPCID was 35.7%, compared to an incidence of 75.5% in the 325 patients treated with placebo (p<0.01).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19510/S-028
NDA 20249/S-011
Page 5
Gastric Ulcer
In both a U.S. and an international multicenter, double-blind study in patients with endoscopically confirmed active
benign gastric ulcer, orally administered PEPCID, 40 mg h.s., was compared to placebo h.s. Antacids were permitted
during the studies, but consumption was not significantly different between the PEPCID and placebo groups. As
shown in Table 2, the incidence of ulcer healing (dropouts counted as unhealed) with PEPCID was statistically
significantly better than placebo at weeks 6 and 8 in the U.S. study, and at weeks 4, 6 and 8 in the international study,
based on the number of ulcers that healed, confirmed by endoscopy.
Table 2
Patients with Endoscopically
Confirmed Healed Gastric Ulcers
U.S. Study
International Study
PEPCID
40 mg h.s.
(N=74)
Placebo
h.s.
(N=75)
PEPCID
40 mg h.s.
(N=149)
Placebo
h.s.
(N=145)
Week 4
Week 6
Week 8
45%
†66%
***78%
39%
44%
64%
†47%
†65%
†80%
31%
46%
54%
***,† Statistically significantly better than placebo (p≤0.05, p≤0.01 respectively)
Time to complete relief of daytime and nighttime pain was statistically significantly shorter for patients receiving
PEPCID than for patients receiving placebo; however, in neither study was there a statistically significant difference in
the proportion of patients whose pain was relieved by the end of the study (week 8).
Gastroesophageal Reflux Disease (GERD)
Orally administered PEPCID was compared to placebo in a U.S. study that enrolled patients with symptoms of
GERD and without endoscopic evidence of erosion or ulceration of the esophagus. PEPCID 20 mg b.i.d. was
statistically significantly superior to 40 mg h.s. and to placebo in providing a successful symptomatic outcome,
defined as moderate or excellent improvement of symptoms (Table 3).
Table 3
% Successful Symptomatic Outcome
PEPCID
20 mg b.i.d.
(N=154)
PEPCID
40 mg h.s.
(N=149)
Placebo
(N=73)
Week 6
82††
69
62
†† p≤0.01 vs Placebo
By two weeks of treatment, symptomatic success was observed in a greater percentage of patients taking
PEPCID 20 mg b.i.d. compared to placebo (p≤0.01).
Symptomatic improvement and healing of endoscopically verified erosion and ulceration were studied in two
additional trials. Healing was defined as complete resolution of all erosions or ulcerations visible with endoscopy. The
U.S. study comparing PEPCID 40 mg p.o. b.i.d. to placebo and PEPCID 20 mg p.o. b.i.d., showed a significantly
greater percentage of healing for PEPCID 40 mg b.i.d. at weeks 6 and 12 (Table 4).
Table 4
% Endoscopic Healing - U.S. Study
PEPCID
40 mg b.i.d.
(N=127)
PEPCID
20 mg b.i.d.
(N=125)
Placebo
(N=66)
Week 6
Week 12
48†††,‡‡
69†††,‡
32
54†††
18
29
††† p≤0.01 vs Placebo
‡ p≤0.05 vs PEPCID 20 mg b.i.d.
‡‡ p≤0.01 vs PEPCID 20 mg b.i.d.
As compared to placebo, patients who received PEPCID had faster relief of daytime and nighttime heartburn and
a greater percentage of patients experienced complete relief of nighttime heartburn. These differences were
statistically significant.
In the international study, when PEPCID 40 mg p.o. b.i.d. was compared to ranitidine 150 mg p.o. b.i.d., a
statistically significantly greater percentage of healing was observed with PEPCID 40 mg b.i.d. at week 12 (Table 5).
There was, however, no significant difference among treatments in symptom relief.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19510/S-028
NDA 20249/S-011
Page 6
Table 5
% Endoscopic Healing - International Study
PEPCID
40 mg b.i.d.
(N=175)
PEPCID
20 mg b.i.d.
(N=93)
Ranitidine
150 mg b.i.d.
(N=172)
Week 6
Week 12
48
71‡‡‡
52
68
42
60
‡‡‡ p≤0.05 vs Ranitidine 150 mg b.i.d.
Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas)
In studies of patients with pathological hypersecretory conditions such as Zollinger-Ellison Syndrome with or
without multiple endocrine adenomas, PEPCID significantly inhibited gastric acid secretion and controlled associated
symptoms. Orally administered doses from 20 to 160 mg q 6 h maintained basal acid secretion below 10 mEq/hr;
initial doses were titrated to the individual patient need and subsequent adjustments were necessary with time in
some patients. PEPCID was well tolerated at these high dose levels for prolonged periods (greater than 12 months)
in eight patients, and there were no cases reported of gynecomastia, increased prolactin levels, or impotence which
were considered to be due to the drug.
CLINICAL PHARMACOLOGY IN PEDIATRIC PATIENTS
Pharmacokinetics
Table 6 presents pharmacokinetic data from clinical trials and a published study in pediatric patients (<1 year of
age; N=27) given famotidine I.V. 0.5 mg/kg and from published studies of small numbers of pediatric patients (1-15
years of age) given famotidine intravenously. Areas under the curve (AUCs) are normalized to a dose of 0.5 mg/kg
I.V. for pediatric patients 1-15 years of age and compared with an extrapolated 40 mg intravenous dose in adults
(extrapolation based on results obtained with a 20 mg I.V. adult dose).
Table 6
Pharmacokinetic Parametersa of Intravenous Famotidine
Age
(N=number of
patients)
Area Under
the Curve (AUC)
(ng-hr/mL)
Total
Clearance (Cl)
(L/hr/kg)
Volume of
Distribution (Vd)
(L/kg)
Elimination
Half-life (T1/2)
(hours)
0-1 monthc
(N=10)
NA
0.13 ± 0.06
1.4 ± 0.4
10.5 ± 5.4
0-3 monthsd
(N=6)
2688 ± 847
0.21 ± 0.06
1.8 ± 0.3
8.1 ± 3.5
>3-12 monthsd
(N=11)
1160 ± 474
0.49 ± 0.17
2.3 ± 0.7
4.5 ± 1.1
1-11 yrs (N=20)
1089 ± 834
0.54 ± 0.34
2.07 ± 1.49
3.38 ± 2.60
11-15 yrs (N=6)
1140 ± 320
0.48 ± 0.14
1.5 ± 0.4
2.3 ± 0.4
Adult (N=16)
1726b
0.39 ± 0.14
1.3 ± 0.2
2.83 ± 0.99
aValues are presented as means ± SD unless indicated otherwise.
bMean value only.
cSingle center study.
dMulticenter study.
Plasma clearance is reduced and elimination half-life is prolonged in pediatric patients 0-3 months of age
compared to older pediatric patients. The pharmacokinetic parameters for pediatric patients, ages >3 months-15
years, are comparable to those obtained for adults.
Bioavailability studies of 8 pediatric patients (11-15 years of age) showed a mean oral bioavailability of 0.5
compared to adult values of 0.42 to 0.49. Oral doses of 0.5 mg/kg achieved AUCs of 645 ± 249 ng-hr/mL and
580 ± 60 ng-hr/mL in pediatric patients <1 year of age (N=5) and in pediatric patients 11-15 years of age,
respectively, compared to 482 ± 181 ng-hr/mL in adults treated with 40 mg orally.
Pharmacodynamics
Pharmacodynamics of famotidine were evaluated in 5 pediatric patients 2-13 years of age using the sigmoid Emax
model. These data suggest that the relationship between serum concentration of famotidine and gastric acid
suppression is similar to that observed in one study of adults (Table 7).
Table 7
Pharmacodynamics of famotidine using the sigmoid Emax model
EC50 (ng/mL)*
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19510/S-028
NDA 20249/S-011
Page 7
Pediatric Patients
26 ± 13
Data from one study
a) healthy adult subjects
26.5 ± 10.3
b) adult patients with upper GI bleeding
18.7 ± 10.8
*Serum concentration of famotidine associated with 50% maximum gastric acid reduction. Values are presented as means ± SD.
Five published studies (Table 8) examined the effect of famotidine on gastric pH and duration of acid suppression
in pediatric patients. While each study had a different design, acid suppression data over time are summarized as
follows:
Table 8
Dosage
Route
Effect
a
Number of Patients
(age range)
0.5 mg/kg, single dose
I.V.
gastric pH >4 for 19.5 hours (17.3,
21.8)c
11 (5-19 days)
0.3 mg/kg, single dose
I.V.
gastric pH >3.5 for 8.7 ± 4.7
b hours
6 (2-7 years)
0.4-0.8 mg/kg
I.V.
gastric pH >4 for 6-9 hours
18 (2-69 months)
0.5 mg/kg, single dose
I.V.
a >2 pH unit increase above baseline
in gastric pH for >8 hours
9 (2-13 years)
0.5 mg/kg b.i.d.
I.V.
gastric pH >5 for 13.5 ± 1.8
b hours
4 (6-15 years)
0.5 mg/kg b.i.d.
oral
gastric pH >5 for 5.0 ± 1.1
b hours
4 (11-15 years)
aValues reported in published literature.
bMeans ± SD.
cMean (95% confidence interval).
The duration of effect of famotidine I.V. 0.5 mg/kg on gastric pH and acid suppression was shown in one study to
be longer in pediatric patients <1 month of age than in older pediatric patients. This longer duration of gastric acid
suppression is consistent with the decreased clearance in pediatric patients <3 months of age (see Table 6).
INDICATIONS AND USAGE
PEPCID Injection Premixed, supplied as a premixed solution in plastic containers (PL 2501 Plastic), and PEPCID
Injection, supplied as a concentrated solution for intravenous injection, are intended for intravenous use only.
PEPCID Injection Premixed and PEPCID Injection are indicated in some hospitalized patients with pathological
hypersecretory conditions or intractable ulcers, or as an alternative to the oral dosage forms for short term use in
patients who are unable to take oral medication for the following conditions:
1. Short term treatment of active duodenal ulcer. Most adult patients heal within 4 weeks; there is rarely reason to
use PEPCID at full dosage for longer than 6 to 8 weeks. Studies have not assessed the safety of famotidine in
uncomplicated active duodenal ulcer for periods of more than eight weeks.
2. Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of an active ulcer. Controlled
studies in adults have not extended beyond one year.
3. Short term treatment of active benign gastric ulcer. Most adult patients heal within 6 weeks. Studies have not
assessed the safety or efficacy of famotidine in uncomplicated active benign gastric ulcer for periods of more than 8
weeks.
4. Short term treatment of gastroesophageal reflux disease (GERD). PEPCID is indicated for short term treatment
of patients with symptoms of GERD (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies).
PEPCID is also indicated for the short term treatment of esophagitis due to GERD including erosive or ulcerative
disease diagnosed by endoscopy (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies).
5. Treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison Syndrome, multiple endocrine
adenomas) (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies).
CONTRAINDICATIONS
Hypersensitivity to any component of these products. Cross sensitivity in this class of compounds has been
observed. Therefore, PEPCID should not be administered to patients with a history of hypersensitivity to other
H2-receptor antagonists.
PRECAUTIONS
General
Symptomatic response to therapy with PEPCID does not preclude the presence of gastric malignancy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19510/S-028
NDA 20249/S-011
Page 8
Patients with Moderate or Severe Renal Insufficiency
Since CNS adverse effects have been reported in patients with moderate and severe renal insufficiency, longer
intervals between doses or lower doses may need to be used in patients with moderate (creatinine clearance
<50 mL/min) or severe (creatinine clearance <10 mL/min) renal insufficiency to adjust for the longer elimination half-
life of famotidine (see CLINICAL PHARMACOLOGY IN ADULTS, DOSAGE AND ADMINISTRATION).
Drug Interactions
No drug interactions have been identified. Studies with famotidine in man, in animal models, and in vitro have
shown no significant interference with the disposition of compounds metabolized by the hepatic microsomal
enzymes, e.g., cytochrome P450 system. Compounds tested in man include warfarin, theophylline, phenytoin,
diazepam, aminopyrine and antipyrine. Indocyanine green as an index of hepatic drug extraction has been tested and
no significant effects have been found.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 106 week study in rats and a 92 week study in mice given oral doses of up to 2000 mg/kg/day (approximately
2500 times the recommended human dose for active duodenal ulcer), there was no evidence of carcinogenic
potential for PEPCID.
Famotidine was negative in the microbial mutagen test (Ames test) using Salmonella typhimurium and
Escherichia coli with or without rat liver enzyme activation at concentrations up to 10,000 mcg/plate. In in vivo studies
in mice, with a micronucleus test and a chromosomal aberration test, no evidence of a mutagenic effect was
observed.
In studies with rats given oral doses of up to 2000 mg/kg/day or intravenous doses of up to 200 mg/kg/day, fertility
and reproductive performance were not affected.
Pregnancy
Pregnancy Category B
Reproductive studies have been performed in rats and rabbits at oral doses of up to 2000 and 500 mg/kg/day,
respectively, and in both species at I.V. doses of up to 200 mg/kg/day, and have revealed no significant evidence of
impaired fertility or harm to the fetus due to PEPCID. While no direct fetotoxic effects have been observed, sporadic
abortions occurring only in mothers displaying marked decreased food intake were seen in some rabbits at oral
doses of 200 mg/kg/day (250 times the usual human dose) or higher. There are, however, no adequate or well-
controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human
response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers
Studies performed in lactating rats have shown that famotidine is secreted into breast milk. Transient growth
depression was observed in young rats suckling from mothers treated with maternotoxic doses of at least 600 times
the usual human dose. Famotidine is detectable in human milk. Because of the potential for serious adverse
reactions in nursing infants from PEPCID, 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 Patients <1 year of age
Use of PEPCID in pediatric patients <1 year of age is supported by evidence from adequate and well-controlled
studies of PEPCID in adults, and by the following studies in pediatric patients <1 year of age.
Two pharmacokinetic studies in pediatric patients <1 year of age (N=48) demonstrated that clearance of
famotidine in patients >3 months to 1 year of age is similar to that seen in older pediatric patients (1-15 years of age)
and adults. In contrast, pediatric patients 0-3 months of age had famotidine clearance values that were 2- to 4-fold
less than those in older pediatric patients and adults. These studies also show that the mean bioavailability in
pediatric patients <1 year of age after oral dosing is similar to older pediatric patients and adults. Pharmacodynamic
data in pediatric patients 0-3 months of age suggest that the duration of acid suppression is longer compared with
older pediatric patients, consistent with the longer famotidine half-life in pediatric patients 0-3 months of age. (See
CLINICAL PHARMACOLOGY IN PEDIATRIC PATIENTS, Pharmacokinetics and Pharmacodynamics.)
In a double-blinded, randomized, treatment-withdrawal study, 35 pediatric patients <1 year of age who were
diagnosed as having gastroesophageal reflux disease were treated for up to 4 weeks with famotidine oral suspension
(0.5 mg/kg/dose or 1 mg/kg/dose). Although an intravenous famotidine formulation was available, no patients were
treated with intravenous famotidine in this study. Also, caregivers were instructed to provide conservative treatment
including thickened feedings. Enrolled patients were diagnosed primarily by history of vomiting (spitting up) and
irritability (fussiness). The famotidine dosing regimen was once daily for patients <3 months of age and twice daily for
patients ≥≥≥≥3 months of age. After 4 weeks of treatment, patients were randomly withdrawn from the treatment and
followed an additional 4 weeks for adverse events and symptomatology. Patients were evaluated for vomiting
(spitting up), irritability (fussiness) and global assessments of improvement. The study patients ranged in age at entry
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19510/S-028
NDA 20249/S-011
Page 9
from 1.3 to 10.5 months (mean 5.6 ± 2.9 months), 57% were female, 91% were white and 6% were black. Most
patients (27/35) continued into the treatment withdrawal phase of the study. Two patients discontinued famotidine
due to adverse events. Most patients improved during the initial treatment phase of the study. Results of the
treatment withdrawal phase were difficult to interpret because of small numbers of patients. Of the 35 patients
enrolled in the study, agitation was observed in 5 patients on famotidine that resolved when the medication was
discontinued; agitation was not observed in patients on placebo (see ADVERSE REACTIONS, Pediatric Patients).
These studies suggest that a starting dose of 0.5 mg/kg/dose of famotidine oral suspension may be of benefit for
the treatment of GERD for up to 4 weeks once daily in patients <3 months of age and twice daily in patients 3 months
to <1 year of age; the safety and benefit of famotidine treatment beyond 4 weeks have not been established.
Famotidine should be considered for the treatment of GERD only if conservative measures (e.g., thickened feedings)
are used concurrently and if the potential benefit outweighs the risk.
Pediatric Patients 1-16 years of age
Use of PEPCID in pediatric patients 1-16 years of age is supported by evidence from adequate and well-
controlled studies of PEPCID in adults, and by the following studies in pediatric patients: In published studies in small
numbers of pediatric patients 1-15 years of age, clearance of famotidine was similar to that seen in adults. In
pediatric patients 11-15 years of age, oral doses of 0.5 mg/kg were associated with a mean area under the curve
(AUC) similar to that seen in adults treated orally with 40 mg. Similarly, in pediatric patients 1-15 years of age,
intravenous doses of 0.5 mg/kg were associated with a mean AUC similar to that seen in adults treated intravenously
with 40 mg. Limited published studies also suggest that the relationship between serum concentration and acid
suppression is similar in pediatric patients 1-15 years of age as compared with adults. These studies suggest that the
starting dose for pediatric patients 1-16 years of age is 0.25 mg/kg intravenously (injected over a period of not less
than two minutes or as a 15 minute infusion) q 12 h up to 40 mg/day.
While published uncontrolled clinical studies suggest effectiveness of famotidine in the treatment of peptic ulcer,
data in pediatric patients are insufficient to establish percent response with dose and duration of therapy. Therefore,
treatment duration (initially based on adult duration recommendations) and dose should be individualized based on
clinical response and/or gastric pH determination and endoscopy. Published uncontrolled studies in pediatric patients
have demonstrated gastric acid suppression with doses up to 0.5 mg/kg intravenously q 12 h.
Geriatric Use
Of the 4,966 subjects in clinical studies who were treated with famotidine, 488 subjects (9.8%) were 65 and older,
and 88 subjects (1.7%) were greater than 75 years of age. No overall differences in safety or effectiveness were
observed between these subjects and younger subjects. However, greater sensitivity of some older patients cannot
be ruled out.
No dosage adjustment is required based on age (see CLINICAL PHARMACOLOGY IN ADULTS,
Pharmacokinetics). 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.
Dosage adjustment in the case of moderate or severe renal impairment is necessary (see PRECAUTIONS, Patients
with Moderate or Severe Renal Insufficiency and DOSAGE AND ADMINISTRATION, Dosage Adjustment for
Patients with Moderate or Severe Renal Insufficiency).
ADVERSE REACTIONS
The adverse reactions listed below have been reported during domestic and international clinical trials in
approximately 2500 patients. In those controlled clinical trials in which PEPCID Tablets were compared to placebo,
the incidence of adverse experiences in the group which received PEPCID Tablets, 40 mg at bedtime, was similar to
that in the placebo group.
The following adverse reactions have been reported to occur in more than 1% of patients on therapy with PEPCID
in controlled clinical trials, and may be causally related to the drug: headache (4.7%), dizziness (1.3%), constipation
(1.2%) and diarrhea (1.7%).
The following other adverse reactions have been reported infrequently in clinical trials or since the drug was
marketed. The relationship to therapy with PEPCID has been unclear in many cases. Within each category the
adverse reactions are listed in order of decreasing severity:
Body as a Whole: fever, asthenia, fatigue
Cardiovascular: arrhythmia, AV block, palpitation
Gastrointestinal: cholestatic jaundice, liver enzyme abnormalities, vomiting, nausea, abdominal discomfort,
anorexia, dry mouth
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19510/S-028
NDA 20249/S-011
Page 10
Hematologic: rare cases of agranulocytosis, pancytopenia, leukopenia, thrombocytopenia
Hypersensitivity: anaphylaxis, angioedema, orbital or facial edema, urticaria, rash, conjunctival injection
Musculoskeletal: musculoskeletal pain including muscle cramps, arthralgia
Nervous System/Psychiatric: grand mal seizure; psychic disturbances, which were reversible in cases for which
follow-up was obtained, including hallucinations, confusion, agitation, depression, anxiety, decreased libido;
paresthesia; insomnia; somnolence
Respiratory: bronchospasm
Skin: toxic epidermal necrolysis (very rare), alopecia, acne, pruritus, dry skin, flushing
Special Senses: tinnitus, taste disorder
Other: rare cases of impotence and rare cases of gynecomastia have been reported; however, in controlled
clinical trials, the incidences were not greater than those seen with placebo.
The adverse reactions reported for PEPCID Tablets may also occur with PEPCID for Oral Suspension, PEPCID
RPD Orally Disintegrating Tablets, PEPCID Injection Premixed or PEPCID Injection. In addition, transient irritation at
the injection site has been observed with PEPCID Injection.
Pediatric Patients
In a clinical study in 35 pediatric patients <1 year of age with GERD symptoms [e.g., vomiting (spitting up),
irritability (fussing)], agitation was observed in 5 patients on famotidine that resolved when the medication was
discontinued.
OVERDOSAGE
There is no experience to date with deliberate overdosage. Oral doses of up to 640 mg/day have been given to
adult patients with pathological hypersecretory conditions with no serious adverse effects. In the event of overdosage,
treatment should be symptomatic and supportive. Unabsorbed material should be removed from the gastrointestinal
tract, the patient should be monitored, and supportive therapy should be employed.
The intravenous LD50 of famotidine for mice and rats ranged from 254-563 mg/kg and the minimum lethal single
I.V. dose in dogs was approximately 300 mg/kg. Signs of acute intoxication in I.V. treated dogs were emesis,
restlessness, pallor of mucous membranes or redness of mouth and ears, hypotension, tachycardia and collapse.
The oral LD50 of famotidine in male and female rats and mice was greater than 3000 mg/kg and the minimum lethal
acute oral dose in dogs exceeded 2000 mg/kg. Famotidine did not produce overt effects at high oral doses in mice,
rats, cats and dogs, but induced significant anorexia and growth depression in rabbits starting with 200 mg/kg/day
orally.
DOSAGE AND ADMINISTRATION
In some hospitalized patients with pathological hypersecretory conditions or intractable ulcers, or in patients who
are unable to take oral medication, PEPCID Injection Premixed or PEPCID Injection may be administered until oral
therapy can be instituted.
The recommended dosage for PEPCID Injection Premixed and PEPCID Injection in adult patients is 20 mg
intravenously q 12 h.
The doses and regimen for parenteral administration in patients with GERD have not been established.
Dosage for Pediatric Patients <1 year of age Gastroesophageal Reflux Disease (GERD)
See PRECAUTIONS, Pediatric Patients <1 year of age.
The studies described in PRECAUTIONS, Pediatric Patients <1 year of age suggest the following starting doses
in pediatric patients <1 year of age: Gastroesophageal Reflux Disease (GERD) - 0.5 mg/kg/dose of famotidine oral
suspension for the treatment of GERD for up to 8 weeks once daily in patients <3 months of age and 0.5 mg/kg/dose
twice daily in patients 3 months to <1 year of age. Patients should also be receiving conservative measures (e.g.,
thickened feedings). The use of intravenous famotidine in pediatric patients <1 year of age with GERD has not been
adequately studied.
Dosage for Pediatric Patients 1-16 years of age
See PRECAUTIONS, Pediatric Patients 1-16 years of age.
The studies described in PRECAUTIONS, Pediatric Patients 1-16 years of age suggest that the starting dose in
pediatric patients 1-16 years of age is 0.25 mg/kg intravenously (injected over a period of not less than two minutes
or as a 15 minute infusion) q 12 h up to 40 mg/day.
While published uncontrolled clinical studies suggest effectiveness of famotidine in the treatment of peptic ulcer,
data in pediatric patients are insufficient to establish percent response with dose and duration of therapy. Therefore,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19510/S-028
NDA 20249/S-011
Page 11
treatment duration (initially based on adult duration recommendations) and dose should be individualized based on
clinical response and/or gastric pH determination and endoscopy. Published uncontrolled studies in pediatric patients
1–16 years of age have demonstrated gastric acid suppression with doses up to 0.5 mg/kg intravenously q 12 h.
Dosage Adjustments for Patients with Moderate or Severe Renal Insufficiency
In adult patients with moderate (creatinine clearance <50 mL/min) or severe (creatinine clearance <10 mL/min)
renal insufficiency, the elimination half-life of PEPCID is increased. For patients with severe renal insufficiency, it may
exceed 20 hours, reaching approximately 24 hours in anuric patients. Since CNS adverse effects have been reported
in patients with moderate and severe renal insufficiency, to avoid excess accumulation of the drug in patients with
moderate or severe renal insufficiency, the dose of PEPCID Injection Premixed or PEPCID Injection may be reduced
to half the dose, or the dosing interval may be prolonged to 36-48 hours as indicated by the patient's clinical
response.
Based on the comparison of pharmacokinetic parameters for PEPCID in adults and pediatric patients, dosage
adjustment in pediatric patients with moderate or severe renal insufficiency should be considered.
Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas)
The dosage of PEPCID in patients with pathological hypersecretory conditions varies with the individual patient.
The recommended adult intravenous dose is 20 mg q 12 h. Doses should be adjusted to individual patient needs and
should continue as long as clinically indicated. In some patients, a higher starting dose may be required. Oral doses
up to 160 mg q 6 h have been administered to some adult patients with severe Zollinger-Ellison Syndrome.
PEPCID Injection Premixed
PEPCID Injection Premixed, supplied in Galaxy§ containers (PL 2501 Plastic), is a 50 mL iso-osmotic solution
premixed with 0.9% sodium chloride for administration as an infusion over a 15-30 minute period. This premixed
solution is for intravenous use only using sterile equipment.
Directions for Use of Galaxy® Containers
Check the container for minute leaks prior to use by squeezing the bag firmly. If leaks are found, discard solution
as sterility may be impaired. Do not add supplementary medication. Do not use unless solution is clear and seal is
intact.
CAUTION: 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
complete.
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.
To prepare PEPCID intravenous solutions, aseptically dilute 2 mL of PEPCID Injection (solution containing
10 mg/mL) with 0.9% Sodium Chloride Injection or other compatible intravenous solution (see Stability, PEPCID
Injection) to a total volume of either 5 mL or 10 mL and inject over a period of not less than 2 minutes.
To prepare PEPCID intravenous infusion solutions, aseptically dilute 2 mL of PEPCID Injection with 100 mL of 5%
dextrose or other compatible solution (see Stability, PEPCID Injection), and infuse over a 15-30 minute period.
Concomitant Use of Antacids
Antacids may be given concomitantly if needed.
Stability
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit.
PEPCID Injection Premixed
PEPCID Injection Premixed, as supplied premixed in 0.9% sodium chloride in Galaxy® containers (PL 2501
Plastic), is stable through the labeled expiration date when stored under the recommended conditions. (See HOW
SUPPLIED, Storage.)
PEPCID Injection
When added to or diluted with most commonly used intravenous solutions, e.g., Water for Injection, 0.9% Sodium
Chloride Injection, 5% and 10% Dextrose Injection, or Lactated Ringer's Injection, diluted PEPCID Injection is
physically and chemically stable (i.e., maintains at least 90% of initial potency) for 7 days at room temperature — see
HOW SUPPLIED, Storage.
When added to or diluted with Sodium Bicarbonate Injection, 5%, PEPCID Injection at a concentration of
0.2 mg/mL (the recommended concentration of PEPCID intravenous infusion solutions) is physically and chemically
§ Galaxy® is a registered trademark of Baxter International Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19510/S-028
NDA 20249/S-011
Page 12
stable (i.e., maintains at least 90% of initial potency) for 7 days at room temperature — see HOW SUPPLIED,
Storage. However, a precipitate may form at higher concentrations of PEPCID Injection (>0.2 mg/mL) in Sodium
Bicarbonate Injection, 5%.
HOW SUPPLIED
FOR INTRAVENOUS USE ONLY
No. 3537 — PEPCID Injection Premixed 20 mg per 50 mL is a clear, non-preserved, sterile solution premixed in a
vehicle made iso-osmotic with Sodium Chloride, and is supplied as follows:
NDC 0006-3537-50, 50 mL single dose Galaxy® containers (PL 2501 Plastic).
No. 3539 — PEPCID Injection 10 mg per 1 mL, is a non-preserved, clear, colorless solution and is supplied as
follows:
NDC 0006-3539-04, 10 x 2 mL single dose vials
No. 3541 — PEPCID Injection 10 mg per 1 mL, is a clear, colorless solution and is supplied as follows:
NDC 0006-3541-14, 4 mL vials
NDC 0006-3541-20, 20 mL vials
NDC 0006-3541-49, 10 x 20 mL vials.
Storage
Store PEPCID Injection Premixed in Galaxy® containers (PL 2501 Plastic) at room temperature (25°C, 77°F).
Exposure of the premixed product to excessive heat should be avoided. Brief exposure to temperatures up to 35°C
(95°F) does not adversely affect the product.
Store PEPCID Injection at 2-8°C (36-46°F). If solution freezes, bring to room temperature; allow sufficient time to
solubilize all the components.
Although diluted PEPCID Injection has been shown to be physically and chemically stable for 7 days at room
temperature, there are no data on the maintenance of sterility after dilution. Therefore, it is recommended that if not
used immediately after preparation, diluted solutions of PEPCID Injection should be refrigerated and used within 48
hours (see DOSAGE AND ADMINISTRATION).
PEPCID (famotidine) Injection Premixed is manufactured for:
By:
BAXTER HEALTHCARE CORPORATION
Deerfield, Illinois 60015 USA
PEPCID (famotidine) Injection is manufactured by:
Issued MarchXXXXX 2001
Printed in USA
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/
---------------------
Victor Raczkowski
6/6/02 06:57:31 PM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:26.809743
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19510s28lbl20249s11lbl.pdf', 'application_number': 19510, 'submission_type': 'SUPPL ', 'submission_number': 28}
|
11,517
|
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
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
|
custom-source
|
2025-02-12T13:45:26.834213
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/19532s12lbl.pdf', 'application_number': 19532, 'submission_type': 'SUPPL ', 'submission_number': 12}
|
11,511
|
PEEL OPEN TO READ COMPLETE
DIRECTIONS AND WARNINGS
BEFORE PURCHASE
Tamper evident s atement
www.imodium.com
NDC 50580 134 04
4 f l oz
( 20 ml)
Controls the symptoms
of diarrhea
Mint Flavor
Lop
d HC Ant D
h
1
g p
5
L
®
A-D
the symptoms
ea
Mint F
Anti-Diarrheal
nt Flavor
Liquid
Loperamide HCl Anti Diarrheal
mg per 75 mL
®
A-D
Use controls symptoms of diarrhea, including Travelers’ Diarrhea
Warnings
Allergy alert: Do not use if you have ever had a rash or other
allergic reaction to loperamide HCl
Do not use if you have bloody or black stool
Ask a doctor before use if you have
■ fever ■ mucus in he stool ■ a history of liver disease
Ask a doctor or pharmacist before use if you are
taking antibiotics
Drug Facts (continued)
Questions or comments?
ca l 1 877 895 3665 (toll free) or 215 273 8755 (co lect)
Active ingredient (in each 7.5 mL) Purpose
Loperamide HCl 1 mg
Anti diarrheal
Drug Facts
Drug Facts (continued)
When using this product iredness, drowsiness or
dizziness may occur Be careful when driving or
operating machinery
Stop use and ask a doctor if
■ symptoms get worse
■ diarrhea lasts for more than 2 days
■ you get abdominal swel ing or bulging
These may be signs of a serious condition
If pregnant or breast feeding, ask a heal h
professional before use
Keep out of reach of children. In case of overdose,
get medical help or contact a Poison Control Center
right away (1 800 222 1222)
Drug Facts (continued)
Other information
■ each 30 mL (6 tsp) contains: sodium 16 mg
■ store between 20 25°C (68 77°F)
■ tamper evident statement
Inactive ingredients
anhydrous cit ic acid, caramel color, D&C yellow no 10,
FD&C blue no 1, flavor, glycerin, microcrysta line ce lulose
and carboxymethylce lulose sodium, propylene glycol,
purified water, simethicone emulsion, sodium benzoate,
sucralose, titanium dioxide, xanthan gum
Ac ive ingred ent made in Italy
Distribu ed by: McNeil Consumer Hea thcare
Division of McNE L PPC nc
Fo t Wash ngton PA 19034 USA
©McNE L PPC NC 2014
Drug Facts (continued)
children 9 11 years
(60 95 bs)
children 6 8 years
(48 59 bs)
15 mL (3 tsp) a ter first loose stool;
7 5 mL (1 1/2 tsp) after each
subsequent loose stool; but no mo e
than 45 mL (9 tsp) in 24 hours
15 mL (3 tsp) a ter first loose stool;
7 5 mL (1 1/2 tsp) after each
subsequent loose stool; but no mo e
than 30 mL (6 tsp) in 24 hours
children under
6 years (up to 47 lbs)
ask a doctor
Drug Facts (continued)
Directions
■ drink plenty of clear fluids to help prevent
dehydration caused by diarrhea
■ ind right dose on chart If possible, use weight to dose;
otherwise use age
■ shake well before using
■ use only enclosed dosing cup spec fically designed for use
w th this product Do not use any other dosing device
■ mL = mil il ter; tsp = teaspoonful
adults and children
12 years and over
30 mL (6 tsp) after the first loose stool;
15 mL (3 tsp) after each subsequent
loose stool; but no more than
60 mL (12 tsp) in 24 hours
PULL
HERE
PEEL OPEN TO READ COMPLETE
DIRECTIONS AND WARNINGS
BEFORE PURCHASE
Tamper evident s atement
O
XX
X
3 0045-0134-04 2
PULL
HERE
NDC 50580 134 04
4 f l oz
( 20 ml)
Controls the symptoms
of diarrhea
Mint Flavor
Lop
d HC Ant D
h
1
g p
5
L
®
A-D
the symptoms
ea
Mint F
Anti-Diarrheal
nt Flavor
Liquid
4 f l oz
( 20 ml)
4 f l oz
NN
Controls the s mptoms
of diarrhea
Mint Flavor
NN
the symptoms
ea
Mint F
Anti-Diarrheal
nt Flavor
Liquid
LOT
XXXXXXXX
EXP.
3 0045-0134-04 2
PDP = 2.41 square inches
.0625”
Lop
d HC Ant D
h
1
g p
5
L
L p
d HC Ant D
h
L p
d HC Ant D
h
L p
d HC Ant D
h
L p
d HC Ant D
h
®
A-D
Reference ID: 3708537
Reference ID: 3718169
(b) (4)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PEEL OPEN TO READ COMPLETE
DIRECTIONS AND WARNINGS
BEFORE PURCHASE
www.imodium.com
Tamper evident s atement
NDC 50580 134 44
z
( 2 ml)
Controls the symptoms
of diarrhea
Mint Flavor
Lop
d HC Ant D
h
1
g p
5
L
®
A-D
4 f z
l o
( 2
the symptoms
ea
Mint Flavor
Anti-Diarrheal
z
0 ml)
vor
Liquid
Loperamide HCl Anti Diarrheal
mg per 75 mL
®
A-D
For ages
6 years & up
z
( 2
4
Controls the symptoms
of diarrhea
Mint Flavor
4 f z
l o
( 2
4
ntrols the symptoms
diarrhea
Mint Flavo
Anti-Diarrheal
z
0 ml)
vor
Liquid
Use controls symptoms of diarrhea, including Travelers’ Diarrhea
Warnings
Allergy alert: Do not use if you have ever had a rash or other
allergic reaction to loperamide HCl
Do not use if you have bloody or black stool
Ask a doctor before use if you have
■ fever ■ mucus in he stool ■ a history of liver disease
Ask a doctor or pharmacist before use if you are
taking antibiotics
Drug Facts (continued)
Questions or comments?
ca l 1 877 895 3665 (to l free) or 215 273 8755 (co lect)
Active ingredient (in each 7.5 mL) Purpose
Loperamide HCl 1 mg
Anti diarrheal
Drug Facts
Drug Facts (continued)
When using this product iredness, drowsiness or
dizziness may occur Be careful when driving or
operating machinery
Stop use and ask a doctor if
■ symptoms get worse
■ diarrhea lasts for more than 2 days
■ you get abdominal swel ing or bulging
These may be signs of a serious condition
If pregnant or breast feeding, ask a heal h
professional before use
Keep out of reach of children. In case of overdose,
get medical help or contact a Poison Control Center
right away (1 800 222 1222)
Drug Facts (continued)
Other information
■ each 30 mL (6 tsp) contains: sodium 16 mg
■ store between 20 25°C (68 77°F)
■ tamper evident statement
Inactive ingredients
anhydrous cit ic acid, caramel color, D&C yellow no 10,
FD&C blue no 1, flavor, glycerin, microcrysta line ce lulose
and carboxymethylce lulose sodium, propylene glycol,
purified water, simethicone emulsion, sodium benzoate,
sucralose, titanium dioxide, xanthan gum
Ac ive ingred ent made in Italy
Distribu ed by: McNeil Consumer Hea thca e
Division of McNE L PPC nc
Fort Wash ngton PA 19034 USA
©McNE L PPC NC 2014
Drug Facts (continued)
children 9 11 years
(60 95 bs)
children 6 8 years
(48 59 bs)
15 mL (3 tsp) a ter first loose stool;
7 5 mL (1 1/2 tsp) after each
subsequent loose stool; but no more
than 45 mL (9 tsp) in 24 hours
15 mL (3 tsp) a ter first loose stool;
7 5 mL (1 1/2 tsp) after each
subsequent loose stool; but no more
than 30 mL (6 tsp) in 24 hours
children under
6 years (up to 47 lbs)
ask a doctor
Drug Facts (continued)
Directions
■ drink plenty of clear fluids to help prevent
dehydration caused by diarrhea
■ ind right dose on chart If possible, use weight to dose;
otherwise use age
■ shake well before using
■ use only enclosed dosing cup spec fically designed for use
w th this product Do not use any other dosing device
■ mL = mil il ter; tsp = teaspoonful
adults and children
12 years and over
30 mL (6 tsp) after the first loose stool;
15 mL (3 tsp) after each subsequent
loose stool; but no more than
60 mL (12 tsp) in 24 hours
PULL
HERE
PEEL OPEN TO READ COMPLETE
DIRECTIONS AND WARNINGS
BEFORE PURCHASE
O
XX
X
PULL
HERE
NDC 50580 134 44
z
( 2
Controls the symptoms
of diarrhea
Mint Flavor
Lop
d HC Ant D
h
1
g p
5
L
®
A-D
4 f z
l o
( 2
the symptoms
ea
Mint Flavo
Anti-Diarrheal
z
0 ml)
vor
Liquid
For ages
6 years & up
Tamper evident s atement
LOT
XXXXXXXX
EXP.
PDP = 2.41 square inches
.0625”
Lop
d HC Ant D
h
1
g p
5
L
L p
d HC Ant D
h
L p
d HC Ant D
h
L p
d HC Ant D
h
L p
d HC Ant D
h
®
A-D
NN
Reference ID: 3708537
Reference ID: 3718169
(b) (4)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PEEL OPEN TO READ COMPLETE
DIRECTIONS AND WARNINGS
BEFORE PURCHASE
Tamper evident s atement
www imodium com
Loperamide HCl, Anti Diarrheal
1 mg per 7.5 mL
NDC 50580 134 08
Controls the symptoms
o diarrhea
Mint Flavor
Anti-Diarrheal
t Flavor
®
A-D
Liquid
8 l oz
(240 ml)
Lop
d HC Ant D
h
1
g p
5
L
®
A-D
PULL
HERE
If pregnant or breast feeding, ask a heath professional befo e
use
Keep out of reach of children. In case of overdose, get medical
help or contact a Poison Control Center ight away (1 800 222 1222)
Di ections
■ drink plenty of clear fluids to help prevent dehydration
caused by diarrhea
■ find right dose on chart f possble, use weight to dose;
otherwise use age
■ shake wel before using
■ only use enclosed dosing cup specficaly designed for use
wi h this product Do not use any o her dosing device
Warnings
Allergy alert: Do not use f you have ever had a rash or o her
allergic reac ion to loperamde HCl
Do not use f you have bloody or black stool
Ask a doctor before use if you have
■ fever ■ mucus in he stool ■ a history of iver disease
Active ing edient (in each 7.5 mL) Purpose
Lope amde HCl 1 mg
Anti diarrheal
Drug Facts
Use
controls symptoms of diar hea, including Travelers’ Diarrhea
Ask a doctor or pharmacist before use if you are taking
antbiotics
Drug Facts (continued)
When using his p oduct tiredness, drowsiness or dizziness
may occur Be careful when driving or operating machinery
■ store between 20 25$C (68 77$F)
■ tamper evident statement
Other info mation
■ each 30 mL (6 tsp) contains: sodium 16 mg
Inacti e ing edients
anhydrous ctric acd, caramel color, D&C yellow no 10, FD&C
blue no 1, flavor, glycerin, microcrystaline cellulose and
ca boxyme hylcellulose sodium, propylene glycol, puri ied
water, sime hicone emulsion, sodium benzoate, sucralose,
ttanium dioxide, xanthan gum
Drug Facts (continued)
Drug Facts ( ontinued)
Q estions or c mments?
cal 1 877 895 3665 (tol free) or 215 273 8755 (colec )
adults and
chldren 12
years and over
chldren
9 11 yea s
(60 95 lbs)
chldren
6 8 years
(48 59 lbs)
30 mL (6 tsp) after the first loose stool; 15 mL
(3 tsp) after each subsequent loose stool; but
no mo e than 60 mL (12 tsp) in 24 hours
15 mL (3 tsp) after i st loose stool; 75 mL
(1 1/2 tsp) after each subsequent loose stool;
but no more than 45 mL (9 tsp) in 24 hours
15 mL (3 tsp) after first loose stool; 75 mL
(1 1/2 tsp) after each subsequent loose stool;
but no more han 30 mL (6 tsp) in 24 hou s
chldren
under 6 years
(up to 47 lbs)
ask a doctor
Act ve ingred ent made in taly
D s ributed by: McNeil Consumer Heal hcare
D v sion of McNEIL PPC Inc
Fort Washington PA 19034 USA
©McNEIL PPC INC 2014
Stop use a d ask a doctor if ■ symptoms get o se
■ da hea asts fo more than 2 days
■ you get abdomna swel ng or bugng. These may be
sgns of a se ous ondton.
■ mL mli ter; tsp teaspoonful
PULL
HERE
XXXXX
XX
Act ve ing edient made in taly
Dis ributed by: McNeil Consumer Heal hcare
Div s on of McNE L PPC nc
Fort Washing on PA 19034 USA
©McNE L PPC NC 2014
Loperamide HCl, Anti Diarrheal
1 mg per 7.5 mL
NDC 50580 134 08
Controls the symptoms
o diarrhea
Mint Flavor
Anti-Diarrheal
t Flavor
®
A-D
Liquid
8 l oz
(240 ml)
PEEL OPEN TO READ COMPLETE
DIRECTIONS AND WARNINGS
BEFORE PURCHASE
Tamper evident statement
Controls the symptoms
o diarrhea
Mint Flavo
Anti-Diarrheal
t Flavor
Liquid
8 l oz
(240 ml) NN
8 l oz
LOT
XXXXXXXX
EXP.
PDP = 3.88 square inches
.073”
Loperamide hydrochloride oral solution
Loperamide hydrochloride oral solution
Loperamide hydrochloride oral solution
Loperamide hydrochloride oral solution
®
A-D
Reference ID: 3708537
Reference ID: 3718169
(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
|
2025-02-12T13:45:27.547805
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019487Orig1s027lbl.pdf', 'application_number': 19487, 'submission_type': 'SUPPL ', 'submission_number': 27}
|
11,528
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
DIPROLENE AF Cream safely and effectively. See full prescribing
information for DIPROLENE AF Cream.
DIPROLENE®
AF
(augmented
betamethasone
dipropionate)
Cream, 0.05% for topical use
Initial U.S. Approval: 1983
----------------------------INDICATIONS AND USAGE ---------------------------
DIPROLENE AF Cream is a corticosteroid indicated for the relief of the
inflammatory and pruritic manifestations of corticosteroid-responsive
dermatoses in patients 13 years of age and older. (1)
----------------------- DOSAGE AND ADMINISTRATION ----------------------
x
Apply a thin film to the affected skin areas once or twice daily. (2)
x
Discontinue therapy when control is achieved. (2)
x
Use no more than 50 g per week. (2)
x
Do not use with occlusive dressings unless directed by a
physician. (2)
x
Avoid use on the face, groin, or axillae, or if skin atrophy is
present at the treatment site. (2)
x
Not for oral, ophthalmic, or intravaginal use. (2)
--------------------- DOSAGE FORMS AND STRENGTHS --------------------
x
Cream, 0.05% (3)
-------------------------------CONTRAINDICATIONS ------------------------------
x
Hypersensitivity to any component of this medicine. (4)
----------------------- WARNINGS AND PRECAUTIONS ----------------------
x
Effects on endocrine system: DIPROLENE AF Cream can cause
reversible
HPA
axis
suppression
with
the
potential
for
glucocorticosteroid insufficiency during and after withdrawal of
treatment. Risk factor(s) include the use of high-potency topical
corticosteroids, use over a large surface area or to areas under
occlusion, prolonged use, altered skin barrier, liver failure, and use
in pediatric patients. Modify use should HPA axis suppression
develop. (5.1, 8.4)
------------------------------ ADVERSE REACTIONS -----------------------------
x
The most common adverse reaction reported in 0.4% of adult
patients is stinging. (6.1)
x
The most common adverse reactions reported in 10% of pediatric
patients are signs of skin atrophy, telangiectasia, bruising,
shininess. (6.1, 8.4)
To report SUSPECTED ADVERSE REACTIONS, contact Merck
Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877
888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 078/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Effects on Endocrine System
5.2
Allergic Contact Dermatitis
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
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.
Reference ID: 3644528
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
DIPROLENE® AF Cream is a corticosteroid indicated for the relief of the inflammatory and pruritic
manifestations of corticosteroid-responsive dermatoses in patients 13 years of age or older.
2
DOSAGE AND ADMINISTRATION
Apply a thin film of DIPROLENE AF Cream to the affected skin areas once or twice daily.
Therapy should be discontinued when control is achieved. DIPROLENE AF Cream is a high-
potency corticosteroid. Treatment with DIPROLENE AF Cream should not exceed 50 g per week
because of the potential for the drug to suppress the hypothalamic-pituitary-adrenal (HPA) axis.
DIPROLENE AF Cream should not be used with occlusive dressings unless directed by a
physician.
DIPROLENE AF Cream is for topical use only. It is not for oral, ophthalmic, or intravaginal use.
Avoid use on the face, groin, or axillae, or if skin atrophy is present at the treatment site.
3
DOSAGE FORMS AND STRENGTHS
Cream, 0.05%. Each gram of DIPROLENE AF Cream, 0.05% contains 0.643 mg betamethasone
dipropionate (equivalent to 0.5 mg betamethasone) in a white cream base.
4
CONTRAINDICATIONS
DIPROLENE AF Cream 0.05% is contraindicated in patients who are hypersensitive to
betamethasone dipropionate, to other corticosteroids, or to any ingredient in this preparation.
5
WARNINGS AND PRECAUTIONS
5.1
Effects on Endocrine System
DIPROLENE AF Cream can produce reversible hypothalamic-pituitary-adrenal (HPA) axis
suppression with the potential for glucocorticosteroid insufficiency. This may occur during treatment or
after withdrawal of treatment. Factors that predispose to HPA axis suppression include the use of high-
potency steroids, large treatment surface areas, prolonged use, use of occlusive dressings, altered skin
barrier, liver failure, and young age. Evaluation for HPA axis suppression may be done by using the
adrenocorticotropic hormone (ACTH) stimulation test.
DIPROLENE AF Cream 0.05% was applied once daily at 7 grams per day for 1 week to diseased
skin, in adult subjects with psoriasis or atopic dermatitis, to study its effects on the HPA axis. The results
suggested that the drug lowered adrenal corticosteroid secretion, although plasma cortisol levels did not
go below the lower limit of the normal range.
In an open-label pediatric trial of 60 evaluable subjects (3 months to 12 years of age), 19 subjects
showed evidence of HPA axis suppression. Four (4) subjects were tested 2 weeks after discontinuation of
DIPROLENE AF Cream 0.05%, and 3 of the 4 (75%) had complete recovery of HPA axis function. The
proportion of subjects with adrenal suppression in this trial was progressively greater, the younger the
age group.
If HPA axis suppression is documented, gradually withdraw the drug, reduce the frequency of
application, or substitute with a less potent corticosteroid. Infrequently, signs and symptoms of steroid
withdrawal may occur, requiring supplemental systemic corticosteroids.
Cushing’s syndrome and hyperglycemia may also occur with topical corticosteroids. These events
are rare and generally occur after prolonged exposure to excessively large doses, especially of high-
potency topical corticosteroids.
Pediatric patients may be more susceptible to systemic toxicity due to their larger skin surface to
body mass ratios [see Use in Specific Populations (8.4)].
5.2
Allergic Contact Dermatitis
Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to heal
rather than noting a clinical exacerbation. Such an observation should be corroborated with appropriate
diagnostic patch testing. If irritation develops, topical corticosteroids should be discontinued and
appropriate therapy instituted.
2
Reference ID: 3644528
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
ADVERSE REACTIONS
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 to rates in the clinical trials of another
drug and may not reflect the rates observed in clinical practice.
In controlled clinical trials, involving 242 adult subjects, the adverse reaction associated with the
use of DIPROLENE AF Cream reported at a frequency of 0.4% was stinging. It occurred in 1 subject.
In a controlled clinical trial involving 67 pediatric subjects from 3 months to 12 years of age, the
adverse reactions associated with the use of DIPROLENE AF Cream occurred in 7 of 67 (10%) subjects.
Reported reactions included signs of skin atrophy (telangiectasia, bruising, shininess).
6.2
Postmarketing Experience
Because adverse 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.
Postmarketing reports for local adverse reactions to topical corticosteroids may also include:
burning, itching, irritation, dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis,
allergic contact dermatitis, secondary infection, hypertrichosis, skin atrophy, striae, and miliaria.
Hypersensitivity reactions, consisting of predominantly skin signs and symptoms, e.g., contact
dermatitis, pruritus, bullous dermatitis, and erythematous rash have been reported.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Teratogenic Effects: Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. DIPROLENE AF Cream
should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Betamethasone dipropionate has been shown to be teratogenic in rabbits when given by the
intramuscular route at doses of 0.05 mg/kg. The abnormalities observed included umbilical hernias,
cephalocele, and cleft palate.
8.3
Nursing Mothers
Systemically administered corticosteroids appear in human milk and can suppress growth, interfere
with endogenous corticosteroid production, or cause other untoward effects. It is not known whether
topical administration of corticosteroids can 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 DIPROLENE AF Cream is administered to a nursing woman.
8.4
Pediatric Use
Use of DIPROLENE AF Cream in pediatric patients younger than 13 years of age is not
recommended due to the potential for HPA axis suppression [see Warnings and Precautions (5.1)].
In an open-label HPA axis safety trial in subjects 3 months to 12 years of age with atopic dermatitis,
DIPROLENE AF Cream 0.05% was applied twice daily for 2 to 3 weeks over a mean body surface area of
58% (range 35% to 95%). In 19 of 60 (32%) evaluable subjects, adrenal suppression was indicated by
either a d5 mcg/dL pre-stimulation cortisol, or a cosyntropin post-stimulation cortisol d18 mcg/dL and/or
an increase of <7 mcg/dL from the baseline cortisol. Out of the 19 subjects with HPA axis suppression, 4
subjects were tested 2 weeks after discontinuation of DIPROLENE AF Cream, and 3 of the 4 (75%) had
complete recovery of HPA axis function. The proportion of subjects with adrenal suppression in this trial
was progressively greater, the younger the age group [see Warnings and Precautions (5.1)].
Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk
than adults of systemic toxicity when treated with topical drugs. They are, therefore, also at greater risk of
HPA axis suppression and adrenal insufficiency upon the use of topical corticosteroids.
Rare systemic effects such as Cushing's syndrome, linear growth retardation, delayed weight gain,
and intracranial hypertension have been reported in pediatric patients, especially those with prolonged
exposure to large doses of high potency topical corticosteroids.
Local adverse reactions including skin atrophy have also been reported with use of topical
corticosteroids in pediatric patients.
3
Reference ID: 3644528
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Avoid use of DIPROLENE AF Cream in the treatment of diaper dermatitis.
8.5
Geriatric Use
Clinical trials of DIPROLENE AF Cream included 104 subjects who were 65 years of age and over
and 8 subjects who were 75 years of age and over. 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. However, greater sensitivity
of some older individuals cannot be ruled out.
11
DESCRIPTION
DIPROLENE AF (augmented betamethasone dipropionate) Cream 0.05% contains betamethasone
dipropionate USP, a synthetic adrenocorticosteroid, for topical use in a cream base. Betamethasone, an
analog of prednisolone, has a high degree of corticosteroid activity and a slight degree of
mineralocorticoid activity. Betamethasone dipropionate is the 17,21-dipropionate ester of betamethasone.
Chemically, betamethasone dipropionate is 9-fluoro-11E,17,21-trihydroxy-16E-methylpregna-1,4
diene-3,20-dione 17,21-dipropionate, with the empirical formula C 28H37FO7, a molecular weight of 504.6,
and the following structural formula: structural formula
Betamethasone dipropionate is a white to creamy white, odorless crystalline powder, insoluble in
water.
Each gram of DIPROLENE AF Cream 0.05% contains: 0.643 mg betamethasone dipropionate
USP (equivalent to 0.5 mg betamethasone) in a white cream base of carbomer 940; ceteareth-30;
chlorocresol; cyclomethicone; glyceryl oleate/propylene glycol; propylene glycol; purified water; sodium
hydroxide; sorbitol solution; white petrolatum; and white wax.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Corticosteroids play a role in cellular signaling, immune function, inflammation, and protein
regulation; however, the precise mechanism of action of DIPROLENE AF Cream in corticosteroid
responsive dermatoses is unknown.
12.2 Pharmacodynamics
Vasoconstrictor Assay
Trials performed with DIPROLENE AF Cream, 0.05% indicate that it is in the high range of potency
as demonstrated in vasoconstrictor trials in healthy subjects when compared with other topical
corticosteroids. However, similar blanching scores do not necessarily imply therapeutic equivalence.
12.3 Pharmacokinetics
No pharmacokinetics trials have been conducted with DIPROLENE AF Cream 0.05%. 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 [see Dosage and Administration
(2)].
Topical corticosteroids can be absorbed through normal intact skin. Inflammation and/or other
disease processes in the skin may increase percutaneous absorption. Occlusive dressings substantially
increase the percutaneous absorption of topical corticosteroids [see Dosage and Administration (2)].
Once absorbed through the skin, topical corticosteroids enter pharmacokinetic pathways similar
to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying
4
Reference ID: 3644528
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
degrees, are metabolized primarily in the liver, and excreted by the kidneys. Some of the topical
corticosteroids and their metabolites are also excreted into the bile.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies have not been performed to evaluate the carcinogenic potential of
betamethasone dipropionate.
Betamethasone was negative in the bacterial mutagenicity assay (Salmonella typhimurium and
Escherichia coli), and in the mammalian cell mutagenicity assay (CHO/HGPRT). It was positive in the in
vitro human lymphocyte chromosome aberration assay, and equivocal in the in vivo mouse bone marrow
micronucleus assay.
Studies in rabbits, mice, and rats using intramuscular doses up to 1, 33, and 2 mg/kg, respectively,
resulted in dose-related increases in fetal resorptions in rabbits and mice.
14
CLINICAL STUDIES
The safety and efficacy of DIPROLENE AF Cream for the treatment of corticosteroid-responsive
dermatoses have been established in two randomized and active controlled trials in subjects with chronic
plaque psoriasis. A total of 81 subjects who received DIPROLENE AF Cream were included in these
trials. These trials evaluated DIPROLENE AF Cream applied once or twice daily for 14 and 21 days,
respectively, on bilateral paired psoriatic lesions. DIPROLENE AF Cream was shown to be effective in
relieving the signs and symptoms of chronic plaque psoriasis.
16
HOW SUPPLIED/STORAGE AND HANDLING
DIPROLENE AF Cream 0.05% is a white cream supplied in 15-g (NDC 0085-0517-01) and 50-g
(NDC 0085-0517-04) tubes.
Store at 25qC (77qF); excursions permitted to 15-30qC (59-86qF) [see USP Controlled Room
Temperature].
17
PATIENT COUNSELING INFORMATION
Inform patients of the following:
x
Discontinue therapy when control is achieved, unless directed otherwise by the physician.
x
Use no more than 50 grams per week.
x
Avoid contact with the eyes.
x
Avoid use of DIPROLENE AF Cream on the face, underarms, or groin areas unless directed by
the physician.
x
Do not occlude the treatment area with bandage or other covering, unless directed by the
physician.
x
Note that local reactions and skin atrophy are more likely to occur with occlusive use, prolonged
use or use of higher potency corticosteroids. company logo
Manufactured by: Schering Plough Canada, Inc.
Pointe Claire, Quebec H9R 1B4, Canada
For patent information: www.merck.com/product/patent/home.html
Copyright © 1987, 2001, 2014 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.
uspi-mk1460-cr-1407r003
5
Reference ID: 3644528
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:27.648668
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019555s033lbl.pdf', 'application_number': 19555, 'submission_type': 'SUPPL ', 'submission_number': 33}
|
11,529
|
Rx only
VePesid
®
(etoposide)
For Injection and Capsules
DESCRIPTION
VePesid® (etoposide) (also commonly known as VP-16) is a semisynthetic derivative of
podophyllotoxin used in the treatment of certain neoplastic diseases. It is
4'-demethylepipodophyllotoxin 9-[4,6-O-(R)-ethylidene-β-D-glucopyranoside]. It is very
soluble in methanol and chloroform, slightly soluble in ethanol, and sparingly soluble in
water and ether. It is made more miscible with water by means of organic solvents. It has a
molecular weight of 588.58 and a molecular formula of C29H32O13.
VePesid may be administered either intravenously or orally. VePesid For Injection is available
in 100 mg (5 mL), 150 mg (7.5 mL), 500 mg (25 mL), or 1 gram (50 mL) sterile, multiple dose
vials. The pH of the clear, nearly colorless to yellow liquid is 3 to 4. Each mL contains 20 mg
etoposide, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg modified polysorbate 80/tween 80,
650 mg polyethylene glycol 300, and 30.5 percent (v/v) alcohol.Vial headspace contains nitrogen.
VePesid is also available as 50 mg pink capsules. Each liquid filled, soft gelatin capsule
contains 50 mg of etoposide in a vehicle consisting of citric acid, glycerin, purified water,
and polyethylene glycol 400. The soft gelatin capsules contain gelatin, glycerin, sorbitol,
purified water, and parabens (ethyl and propyl) with the following dye system: iron oxide
(red) and titanium dioxide; the capsules are printed with edible ink.
The structural formula is:
CLINICAL PHARMACOLOGY
VePesid has been shown to cause metaphase arrest in chick fibroblasts. Its main effect, how-
ever, appears to be at the G2 portion of the cell cycle in mammalian cells. Two different dose-
dependent responses are seen. At high concentrations (10 µg/mL or more), lysis of cells
entering mitosis is observed. At low concentrations (0.3 to 10 µg/mL), cells are inhibited
from entering prophase. It does not interfere with microtubular assembly. The predominant
macromolecular effect of etoposide appears to be the induction of DNA strand breaks by an
interaction with DNA topoisomerase II or the formation of free radicals.
Pharmacokinetics
On intravenous administration, the disposition of etoposide is best described as a biphasic
process with a distribution half-life of about 1.5 hours and terminal elimination half-life rang-
ing from 4 to 11 hours. Total body clearance values range from 33 to 48 mL/min or 16 to
36 mL/min/m2 and, like the terminal elimination half-life, are independent of dose over a
range 100-600 mg/m2. Over the same dose range, the areas under the plasma concentration
vs time curves (AUC) and the maximum plasma concentration (Cmax) values increase linearly
with dose. Etoposide does not accumulate in the plasma following daily administration of
100 mg/m2 for 4 to 5 days.
The mean volumes of distribution at steady state fall in the range of 18 to
29 liters or 7 to 17 L/m2. Etoposide enters the CSF poorly. Although it is detectable in CSF
and intracerebral tumors, the concentrations are lower than in extracerebral tumors and in
plasma. Etoposide concentrations are higher in normal lung than in lung metastases and
are similar in primary tumors and normal tissues of the myometrium. In vitro, etoposide is
highly protein bound (97%) to human plasma proteins. An inverse relationship between
plasma albumin levels and etoposide renal clearance is found in children. In a study deter-
mining the effect of other therapeutic agents on the in vitro binding of carbon-14 labeled
etoposide to human serum proteins, only phenylbutazone, sodium salicylate, and aspirin
displaced protein-bound etoposide at concentrations achieved in vivo.
Etoposide binding ratio correlates directly with serum albumin in patients with cancer
and in normal volunteers. The unbound fraction of etoposide significantly correlated with
bilirubin in a population of cancer patients. Data have suggested a significant inverse cor-
relation between serum albumin concentration and free fraction of etoposide. (See PRE-
CAUTIONS section.)
After intravenous administration of 14C-etoposide (100-124 mg/m2), mean recovery of
radioactivity in the urine was 56% of the dose at 120 hours, 45% of which was excreted as
etoposide; fecal recovery of radioactivity was 44% of the dose at 120 hours.
In children, approximately 55% of the dose is excreted in the urine as etoposide in 24 hours.
The mean renal clearance of etoposide is 7 to 10 mL/min/m2 or about 35% of the total body
clearance over a dose range of 80 to 600 mg/m2. Etoposide, therefore, is cleared by both
renal and nonrenal processes, i.e., metabolism and biliary excretion. The effect of renal dis-
ease on plasma etoposide clearance is not known.
Biliary excretion of unchanged drug and/or metabolites is an important route of etoposide
elimination as fecal recovery of radioactivity is 44% of the intravenous dose. The hydroxy
acid metabolite [4'-demethylepipodophyllic acid-9-(4,6-O-(R)-ethylidene-β-D-glucopyra-
noside)], formed by opening of the lactone ring, is found in the urine of adults and children. It
is also present in human plasma, presumably as the trans isomer. Glucuronide and/or sulfate
conjugates of etoposide are also excreted in human urine. Only 8% or less of an intravenous
dose is excreted in the urine as radiolabeled metabolites of 14C-etoposide. In addition,
O-demethylation of the dimethoxyphenol ring occurs through the CYP450 3A4 isoenzyme
pathway to produce the corresponding catechol.
After either intravenous infusion or oral capsule administration, the Cmax and AUC values
exhibit marked intra- and inter-subject variability. This results in variability in the estimates
of the absolute oral bioavailability of etoposide oral capsules.
Cmax and AUC values for orally administered etoposide capsules consistently fall in the
same range as the Cmax and AUC values for an intravenous dose of one-half the size of the
oral dose. The overall mean value of oral capsule bioavailability is approximately 50%
(range 25–75%). The bioavailability of etoposide capsules appears to be linear up to a dose
of at least 250 mg/m2.
There is no evidence of a first-pass effect for etoposide. For example, no correlation
exists between the absolute oral bioavailability of etoposide capsules and nonrenal clear-
ance. No evidence exists for any other differences in etoposide metabolism and excretion
after administration of oral capsules as compared to intravenous infusion.
In adults, the total body clearance of etoposide is correlated with creatinine clearance,
serum albumin concentration, and nonrenal clearance. Patients with impaired renal func-
tion receiving etoposide have exhibited reduced total body clearance, increased AUC and a
lower volume of distribution at steady state. (See PRECAUTIONS section.) Use of cisplatin ther-
apy is associated with reduced total body clearance. In children, elevated serum SGPT lev-
els are associated with reduced drug total body clearance. Prior use of cisplatin may also
result in a decrease of etoposide total body clearance in children.
Although some minor differences in pharmacokinetic parameters between age and gender
have been observed, these differences were not considered clinically significant.
INDICATION AND USAGE
VePesid (etoposide) is indicated in the management of the following neoplasms:
Refractory Testicular Tumors—VePesid For Injection in combination therapy with other
approved chemotherapeutic agents in patients with refractory testicular tumors who have
already received appropriate surgical, chemotherapeutic, and radiotherapeutic therapy.
Adequate data on the use of VePesid Capsules in the treatment of testicular cancer are not
available.
Small Cell Lung Cancer—VePesid For Injection and/or Capsules in combination with
other approved chemotherapeutic agents as first line treatment in patients with small cell
lung cancer.
CONTRAINDICATIONS
VePesid is contraindicated in patients who have demonstrated a previous hypersensitivity to
etoposide or any component of the formulation.
WARNINGS
Patients being treated with VePesid must be frequently observed for myelosuppression both
during and after therapy. Myelosuppression resulting in death has been reported. Dose-
limiting bone marrow suppression is the most significant toxicity associated with VePesid
therapy. Therefore, the following studies should be obtained at the start of therapy and prior
to each subsequent cycle of VePesid: platelet count, hemoglobin, white blood cell count, and
differential. The occurrence of a platelet count below 50,000/mm3 or an absolute neutrophil
count below 500/mm3 is an indication to withhold further therapy until the blood counts
have sufficiently recovered.
Physicians should be aware of the possible occurrence of an anaphylactic
reaction manifested by chills, fever, tachycardia, bronchospasm, dyspnea, and hypotension.
Higher rates of anaphylactic-like reactions have been reported in children who received
infusions at concentrations higher than those recommended. The role that concentration of
infusion (or rate of infusion) plays in the development of anaphylactic-like reactions is
uncertain. (See ADVERSE REACTIONS section.) Treatment is symptomatic. The infusion
should be terminated immediately, followed by the administration of pressor agents, corti-
costeroids, antihistamines, or volume expanders at the discretion of the physician.
For parenteral administration, VePesid should be given only by slow intravenous infusion
(usually over a 30- to 60-minute period) since hypotension has been reported as a possible
side effect of rapid intravenous injection.
Pregnancy
VePesid can cause fetal harm when administered to a pregnant woman. Etoposide has been
shown to be teratogenic in mice and rats.
In rats, an intravenous etoposide dose of 0.4 mg/kg/day (about 1/20th of the human dose
on a mg/m2 basis) during organogenesis caused maternal toxicity, embryotoxicity, and ter-
atogenicity (skeletal abnormalities, exencephaly, encephalocele, and anophthalmia); higher
doses of 1.2 and 3.6 mg/kg/day (about 1/7th and 1/2 of human dose on a mg/m2 basis)
resulted in 90 and 100% embryonic resorptions. In mice, a single 1.0 mg/kg (1/16th of
human dose on a mg/m2 basis) dose of etoposide administered intraperitoneally on days 6,
7, or 8 of gestation caused embryotoxicity, cranial abnormalities, and major skeletal mal-
formations. An I.P. dose of 1.5 mg/kg (about 1/10th of human dose on a mg/m2 basis) on
day 7 of gestation caused an increase in the incidence of intrauterine death and fetal mal-
formations and a significant decrease in the average fetal body weight.
Women of childbearing potential should be advised to avoid becoming pregnant. If this
drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug,
the patient should be warned of the potential hazard to the fetus.
VePesid should be considered a potential carcinogen in humans. The occurrence of acute
leukemia with or without a preleukemic phase has been reported in rare instances in patients
treated with etoposide alone or in association with other neoplastic agents. The risk of devel-
opment of a preleukemic or leukemic syndrome is unclear. Carcinogenicity tests with VePesid
have not been conducted in laboratory animals.
PRECAUTIONS
General
In all instances where the use of VePesid is considered for chemotherapy, the physician must
evaluate the need and usefulness of the drug against the risk of adverse reactions. Most such
adverse reactions are reversible if detected early. If severe reactions occur, the drug should
be reduced in dosage or discontinued and appropriate corrective measures should be taken
according to the clinical judgment of the physician. Reinstitution of VePesid therapy should
be carried out with caution, and with adequate consideration of the further need for the drug
and alertness as to possible recurrence of toxicity.
Patients with low serum albumin may be at an increased risk for etoposide associated
toxicities.
Drug Interactions
High-dose cyclosporin A resulting in concentrations above 2000 ng/mL administered with
oral etoposide has led to an 80% increase in etoposide exposure with a 38% decrease in
total body clearance of etoposide compared to etoposide alone.
Laboratory Tests
Periodic complete blood counts should be done during the course of VePesid treatment.
They should be performed prior to each cycle of therapy and at appropriate intervals during
and after therapy. At least one determination should be done prior to each dose of VePesid.
Renal Impairment
In patients with impaired renal function, the following initial dose modification should be
considered based on measured creatinine clearance:
Subsequent VePesid dosing should be based on patient tolerance and clinical effect.
Data are not available in patients with creatinine clearances <15 mL/min and further
dose reduction should be considered in these patients.
Carcinogenesis (see WARNINGS section), Mutagenesis, Impairment of Fertility
Etoposide has been shown to be mutagenic in Ames assay.
Treatment of Swiss-Albino mice with 1.5 mg/kg I.P. of VePesid on day 7 of gestation
increased the incidence of intrauterine death and fetal malformations as well as signifi-
cantly decreased the average fetal body weight. Maternal weight gain was not affected.
Irreversible testicular atrophy was present in rats treated with etoposide intravenously for
30 days at 0.5 mg/kg/day (about 1/16th of the human dose on a mg/m2 basis).
Pregnancy
Pregnancy “Category D.” (See WARNINGS section.)
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excret-
ed in human milk and because of the potential for serious adverse reactions in nursing infants
from VePesid, 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 pediatric patients have not been established.
VePesid (etoposide) For Injection contains polysorbate 80. In premature infants, a life-
threatening syndrome consisting of liver and renal failure, pulmonary deterioration, thrombocy-
topenia, and ascites has been associated with an injectable vitamin E product containing
polysorbate 80. Anaphylactic reactions have been reported in pediatric patients. (See
WARNINGS section.)
Geriatric Use
Clinical studies of VePesid (etoposide) for the treatment of refractory testicular tumors did
not include sufficient numbers of patients aged 65 years and over to determine whether
they respond differently from younger patients. Of more than 600 patients in four clinical
studies in the NDA databases who received VePesid or etoposide phosphate in combination
with other chemotherapeutic agents for the treatment of small cell lung cancer (SCLC),
about one third were older than 65 years. When advanced age was determined to be a prog-
nostic factor for response or survival in these studies, comparisons between treatment
groups were performed for the elderly subset. In the one study (etoposide in combination
Measured Creatinine Clearance
>50 mL/min
15-50 mL/min
etoposide
100% of dose
75% of dose
WARNINGS
VePesid (etoposide) should be administered under the supervision of a qualified
physician experienced in the use of cancer chemotherapeutic agents. Severe
myelosuppression with resulting infection or bleeding may occur.
F.P.O.
with cyclophosphamide and vincristine compared with cyclophosphamide and vincristine or
cyclophosphamide, vincristine, and doxorubicin) where age was a significant prognostic fac-
tor for survival, a survival benefit for elderly patients was observed for the etoposide regimen
compared with the control regimens. No differences in myelosuppression were seen between
elderly and younger patients in these studies except for an increased frequency of WHO Grade III
or IV leukopenia among elderly patients in a study of etoposide phosphate or etoposide in com-
bination with cisplatin. Elderly patients in this study also had more anorexia, mucositis, dehy-
dration, somnolence, and elevated BUN levels than younger patients.
In five single-agent studies of etoposide phosphate in patients with a variety of tumor types,
34% of patients were age 65 years or more. WHO Grade III or IV leukopenia, granulocytope-
nia, and asthenia were more frequent among elderly patients.
Postmarketing experience also suggests that elderly patients may be more sensitive to some
of the known adverse effects of etoposide, including myelosuppression, gastrointestinal
effects, infectious complications, and alopecia.
Although some minor differences in pharmacokinetic parameters between elderly and
nonelderly patients have been observed, these differences were not considered clinically sig-
nificant.
Etoposide and its metabolites are known to be substantially excreted by the kidney, and the
risk of adverse 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:
Renal Impairment for recommended dosing adjustments in patients with renal impairment).
ADVERSE REACTIONS
The following data on adverse reactions are based on both oral and intravenous administra-
tion of VePesid (etoposide) as a single agent, using several different dose schedules for treat-
ment of a wide variety of malignancies.
Hematologic Toxicity
Myelosuppression is dose related and dose limiting, with granulocyte nadirs occurring 7 to
14 days after drug administration and platelet nadirs occurring 9 to 16 days after drug admin-
istration. Bone marrow recovery is usually complete by day 20, and no cumulative toxicity has
been reported. Fever and infection have also been reported in patients with neutropenia. Death
associated with myelosuppression has been reported.
The occurrence of acute leukemia with or without a preleukemic phase has been reported
rarely in patients treated with VePesid in association with other antineoplastic agents. (See
WARNINGS section.)
Gastrointestinal Toxicity
Nausea and vomiting are the major gastrointestinal toxicities. The severity of such nausea and
vomiting is generally mild to moderate with treatment discontinuation required in 1% of
patients. Nausea and vomiting can usually be controlled with standard antiemetic therapy.
Mild to severe mucositis/esophagitis may occur. Gastrointestinal toxicities are slightly more
frequent after oral administration than after intravenous infusion.
Hypotension
Transient hypotension following rapid intravenous administration has been reported in 1% to
2% of patients. It has not been associated with cardiac toxicity or electrocardiographic
changes. No delayed hypotension has been noted. To prevent this rare occurrence, it is recom-
mended that VePesid be administered by slow intravenous infusion over a 30- to 60-minute
period. If hypotension occurs, it usually responds to cessation of the infusion and administra-
tion of fluids or other supportive therapy as appropriate. When restarting the infusion, a slower
administration rate should be used.
Allergic Reactions
Anaphylactic-like reactions characterized by chills, fever, tachycardia, bronchospasm, dysp-
nea, and/or hypotension have been reported to occur in 0.7% to 2% of patients receiving
intravenous VePesid and in less than 1% of the patients treated with the oral capsules. These
reactions have usually responded promptly to the cessation of the infusion and administration
of pressor agents, corticosteroids, antihistamines, or volume expanders as appropriate; how-
ever, the reactions can be fatal. Hypertension and/or flushing have also been reported. Blood
pressure usually normalizes within a few hours after cessation of the infusion. Anaphylactic-
like reactions have occurred during the initial infusion of VePesid.
Facial/tongue swelling, coughing, diaphoresis, cyanosis, tightness in throat, laryngospasm,
back pain, and/or loss of consciousness have sometimes occurred in association with the above
reactions. In addition, an apparent hypersensitivity-associated apnea has been reported rarely.
Rash, urticaria, and/or pruritus have infrequently been reported at recommended doses. At
investigational doses, a generalized pruritic erythematous maculopapular rash, consistent
with perivasculitis, has been reported.
Alopecia
Reversible alopecia, sometimes progressing to total baldness, was observed in up to 66%
of patients.
Other Toxicities
The following adverse reactions have been infrequently reported: abdominal pain, aftertaste,
constipation, dysphagia, asthenia, fatigue, malaise, somnolence, transient cortical blindness,
optic neuritis, interstitial pneumonitis/pulmonary fibrosis, fever, seizure (occasionally associ-
ated with allergic reactions), Stevens-Johnson syndrome, and toxic epidermal necrolysis, pig-
mentation, and a single report of radiation recall dermatitis.
Hepatic toxicity, generally in patients receiving higher doses of the drug than those recom-
mended, has been reported with VePesid. Metabolic acidosis has also been reported in
patients receiving higher doses.
Reports of extravasation with swelling have been received postmarketing. Rarely extrava-
sation has been associated with necrosis and venous induration.
The incidences of adverse reactions in the table that follows are derived from multiple data
bases from studies in 2,081 patients when VePesid was used either orally or by injection as a
single agent.
OVERDOSAGE
No proven antidotes have been established for VePesid overdosage.
DOSAGE AND ADMINISTRATION
Note: Plastic devices made of acrylic or ABS (a polymer composed of acrylonitrile, buta-
diene, and styrene) have been reported to crack and leak when used with undiluted
VePesid For Injection.
VePesid For Injection
The usual dose of VePesid For Injection in testicular cancer in combination with other approved
chemotherapeutic agents ranges from 50 to 100 mg/m2/day on days 1 through 5 to 100 mg/m2/day
on days 1, 3, and 5.
In small cell lung cancer, the VePesid For Injection dose in combination with other approved
chemotherapeutic drugs ranges from 35 mg/m2/day for 4 days to 50 mg/m2/day for 5 days.
For recommended dosing adjustments in patients with renal impairment see PRECAU-
TIONS section.
Chemotherapy courses are repeated at 3- to 4-week intervals after adequate recovery from
any toxicity.
PERCENT RANGE OF
ADVERSE DRUG EFFECT
REPORTED INCIDENCE
Hematologic toxicity
Leukopenia (less than 1,000 WBC/mm3)
3–17
Leukopenia (less than 4,000 WBC/mm3)
60–91
Thrombocytopenia (less than 50,000 platelets/mm3)
1–20
Thrombocytopenia (less than 100,000 platelets/mm3)
22–41
Anemia
0–33
Gastrointestinal toxicity
Nausea and vomiting
31–43
Abdominal pain
0–20
Anorexia
10–13
Diarrhea
1–13
Stomatitis
1–60
Hepatic
0–30
Alopecia
8–66
Peripheral neurotoxicity
1–20
Hypotension
1–20
Allergic reaction
1–20
VePesid Capsules
In small cell lung cancer, the recommended dose of VePesid Capsules is two times the IV
dose rounded to the nearest 50 mg.
The dosage, by either route, should be modified to take into account the myelosuppres-
sive effects of other drugs in the combination or the effects of prior x-ray therapy or
chemotherapy which may have compromised bone marrow reserve.
Administration Precautions
As with other potentially toxic compounds, caution should be exercised in handling and
preparing the solution of VePesid. Skin reactions associated with accidental exposure to
VePesid may occur. The use of gloves is recommended. If VePesid solution contacts the skin
or mucosa, immediately and thoroughly wash the skin with soap and water and flush the
mucosa with water.
Preparation for Intravenous Administration
VePesid For Injection must be diluted prior to use with either 5% Dextrose Injection, USP, or
0.9% Sodium Chloride Injection, USP, to give a final concentration of 0.2 to 0.4 mg/mL. If
solutions are prepared at concentrations above 0.4 mg/mL, precipitation may occur.
Hypotension following rapid intravenous administration has been reported, hence, it is rec-
ommended that the VePesid solution be administered over a 30- to 60-minute period. A
longer duration of administration may be used if the volume of fluid to be infused is a con-
cern. VePesid should not be given by rapid intravenous injection.
Parenteral drug products should be inspected visually for particulate matter and discoloration
(see DESCRIPTION section) prior to administration whenever solution and container permit.
Stability
Unopened vials of VePesid For Injection are stable for 24 months at room temperature (25° C).
Vials diluted as recommended to a concentration of 0.2 to 0.4 mg/mL are stable for 96 and
24 hours, respectively, at room temperature (25° C) under normal room fluorescent light in
both glass and plastic containers.
VePesid Capsules must be stored under refrigeration 2°–8° C (36°–46° F). The capsules
are stable for 24 months under such refrigeration conditions.
Procedures for proper handling and disposal of anticancer drugs should be considered.
Several guidelines on this subject have been published.1–8 There is no general agreement that
all of the procedures recommended in the guidelines are necessary or appropriate.
HOW SUPPLIED
VePesid® (etoposide) For Injection
NDC 0015-3095-20—100 mg/5 mL Sterile, Multiple Dose Vial, 10’s
NDC 0015-3084-20—150 mg/7.5 mL Sterile, Multiple Dose Vial
NDC 0015-3061-20—500 mg/25 mL Sterile, Multiple Dose Vial
NDC 0015-3062-20—1 gram/50 mL Sterile, Multiple Dose Vial
VePesid® (etoposide) Capsules
NDC 0015-3091-45—50 mg pink capsules with “BRISTOL 3091” printed in black in blis-
terpacks of 20 individually labeled blisters, each containing one capsule.
Capsules are to be stored under refrigeration 2°–8° C (36°–46° F).
DO NOT FREEZE.
Dispense in child-resistant containers.
For information on package sizes available, refer to the current price schedule.
References
1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommen-
dations for Practice Pittsburgh, PA: Oncology Nursing Society; 1999:32-41.
2. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington,
DC: Division of Safety, National Institutes of Health; 1983. US Dept of Health and Human
Services, Public Health Service publication NIH 83-2621.
3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics.
JAMA. 1985;253:1590-1591.
4. National Study Commission on Cytotoxic Exposure. Recommendations for handling cyto-
toxic agents. 1987.Available from Louis P. Jeffrey, Chairman, National Study Commission
on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences,
179 Longwood Avenue, Boston, MA 02115.
5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe
handling of antineoplastic agents. Med J Australia. 1983;1:426-428.
6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from the
Mount Sinai Medical Center. CA–A Cancer J for Clin. 1983;33:258-263.
7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on han-
dling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049.
8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice
Guidelines.). Am J Health-SystPharm. 1996;53:1669-1685.
Capsules:
Injection:
Manufactured by:
R.P. Scherer GmbH
Eberback/Baden, Germany
Bristol-Myers Squibb Co.
Princeton, New Jersey 08543 USA
Distributed by:
Bristol-Myers Squibb Co.
Princeton, New Jersey 08543 USA
51-001106-05
Revised November 2004
Item 2 Vol 1 Page 018
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:27.651870
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/019557s028lbl.pdf', 'application_number': 19557, 'submission_type': 'SUPPL ', 'submission_number': 28}
|
11,530
|
7825248
1
TABLETS
PRINIVIL®
(LISINOPRIL)
USE IN PREGNANCY
When used in pregnancy during the second and third trimesters, ACE inhibitors can cause
injury and even death to the developing fetus. When pregnancy is detected, PRINIVIL should
be discontinued as soon as possible. See WARNINGS, Fetal/Neonatal Morbidity and Mortality.
DESCRIPTION
PRINIVIL* (Lisinopril), a synthetic peptide derivative, is an oral long-acting angiotensin
converting enzyme inhibitor. Lisinopril is chemically described as (S)-1-[N2-(1-carboxy-3-
phenylpropyl)-L-lysyl]-L-proline dihydrate. Its empirical formula is C21H31N3O5•2H2O and its
structural formula is:
Lisinopril is a white to off-white, crystalline powder, with a molecular weight of 441.52. It is
soluble in water and sparingly soluble in methanol and practically insoluble in ethanol.
PRINIVIL is supplied as 2.5 mg, 5 mg, 10 mg, 20 mg and 40 mg tablets for oral administration.
In addition to the active ingredient lisinopril, each tablet contains the following inactive
ingredients: calcium phosphate, mannitol, magnesium stearate, and starch. The 10 mg, 20 mg
and 40 mg tablets also contain iron oxide.
CLINICAL PHARMACOLOGY
Mechanism of Action
Lisinopril inhibits angiotensin converting enzyme (ACE) in human subjects and animals. ACE
is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor
substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal
cortex. The beneficial effects of lisinopril in hypertension and heart failure appear to result
primarily from suppression of the renin-angiotensin-aldosterone system. Inhibition of ACE results
in decreased plasma angiotensin II which leads to decreased vasopressor activity and to
decreased aldosterone secretion. The latter decrease may result in a small increase of serum
potassium. In hypertensive patients with normal renal function treated with PRINIVIL alone for up
to 24 weeks, the mean increase in serum potassium was approximately 0.1 mEq/L; however,
approximately 15 percent of patients had increases greater than 0.5 mEq/L and approximately six
percent had a decrease greater than 0.5 mEq/L. In the same study, patients treated with
PRINIVIL and hydrochlorothiazide for up to 24 weeks had a mean decrease in serum potassium
of 0.1 mEq/L; approximately 4 percent of patients had increases greater than 0.5 mEq/L and
approximately 12 percent had a decrease greater than 0.5 mEq/L. (See PRECAUTIONS.)
Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin
activity.
ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of
bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of PRINIVIL
remains to be elucidated.
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT © MERCK & CO., Inc., 1988, 1989, 1992, 1993, 1995
All rights reserved
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
2
While the mechanism through which PRINIVIL lowers blood pressure is believed to be
primarily suppression of the renin-angiotensin-aldosterone system, PRINIVIL is antihypertensive
even in patients with low-renin hypertension. Although PRINIVIL was antihypertensive in all races
studied, Black hypertensive patients (usually a low-renin hypertensive population) had a smaller
average response to monotherapy than non-Black patients.
Concomitant administration of PRINIVIL and hydrochlorothiazide further reduced blood
pressure in Black and non-Black patients and any racial difference in blood pressure response
was no longer evident.
Pharmacokinetics and Metabolism
Adult Patients: Following oral administration of PRINIVIL, peak serum concentrations of
lisinopril occur within about 7 hours, although there was a trend to a small delay in time taken to
reach peak serum concentrations in acute myocardial infarction patients. Declining serum
concentrations exhibit a prolonged terminal phase which does not contribute to drug
accumulation. This terminal phase probably represents saturable binding to ACE and is not
proportional to dose. Lisinopril does not appear to be bound to other serum proteins.
Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine.
Based on urinary recovery, the mean extent of absorption of lisinopril is approximately 25
percent, with large inter-subject variability (6-60 percent) at all doses tested (5-80 mg). Lisinopril
absorption is not influenced by the presence of food in the gastrointestinal tract. The absolute
bioavailability of lisinopril is reduced to about 16 percent in patients with stable NYHA Class II-IV
congestive heart failure, and the volume of distribution appears to be slightly smaller than that in
normal subjects.
The oral bioavailability of lisinopril in patients with acute myocardial infarction is similar to that
in healthy volunteers.
Upon multiple dosing, lisinopril exhibits an effective half-life of accumulation of 12 hours.
Impaired renal function decreases elimination of lisinopril, which is excreted principally through
the kidneys, but this decrease becomes clinically important only when the glomerular filtration
rate is below 30 mL/min. Above this glomerular filtration rate, the elimination half-life is little
changed. With greater impairment, however, peak and trough lisinopril levels increase, time to
peak concentration increases and time to attain steady state is prolonged. Older patients, on
average, have (approximately doubled) higher blood levels and area under the plasma
concentration time curve (AUC) than younger patients. (See DOSAGE AND ADMINISTRATION.)
Lisinopril can be removed by hemodialysis.
Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly. Multiple doses of
lisinopril in rats do not result in accumulation in any tissues. Milk of lactating rats contains
radioactivity following administration of 14C lisinopril. By whole body autoradiography, radioactivity
was found in the placenta following administration of labeled drug to pregnant rats, but none was
found in the fetuses.
Pediatric Patients: The pharmacokinetics of lisinopril were studied in 29 pediatric hypertensive
patients between 6 years and 16 years with glomerular filtration rate >30 mL/min/1.73 m2. After
doses of 0.1 to 0.2 mg/kg, steady state peak plasma concentrations of lisinopril occurred within 6
hours and the extent of absorption based on urinary recovery was about 28%. These values are
similar to those obtained previously in adults. The typical value of lisinopril oral clearance
(systemic clearance/absolute bioavailability) in a child weighing 30 kg is 10 L/h, which increases
in proportion to renal function.
Pharmacodynamics and Clinical Effects
Hypertension:
Adult Patients: Administration of PRINIVIL to patients with hypertension results in a reduction
of supine and standing blood pressure to about the same extent with no compensatory
tachycardia. Symptomatic postural hypotension is usually not observed although it can occur and
should be anticipated in volume and/or salt-depleted patients. (See WARNINGS.) When given
together with thiazide-type diuretics, the blood pressure lowering effects of the two drugs are
approximately additive.
In most patients studied, onset of antihypertensive activity was seen at one hour after oral
administration of an individual dose of PRINIVIL, with peak reduction of blood pressure achieved
by six hours. Although an antihypertensive effect was observed 24 hours after dosing with
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
3
recommended single daily doses, the effect was more consistent and the mean effect was
considerably larger in some studies with doses of 20 mg or more than with lower doses.
However, at all doses studied, the mean antihypertensive effect was substantially smaller 24
hours after dosing than it was six hours after dosing.
In some patients achievement of optimal blood pressure reduction may require two to four
weeks of therapy.
The antihypertensive effects of PRINIVIL are maintained during long-term therapy. Abrupt
withdrawal of PRINIVIL has not been associated with a rapid increase in blood pressure or a
significant increase in blood pressure compared to pretreatment levels.
Two dose-response studies utilizing a once daily regimen were conducted in 438 mild to
moderate hypertensive patients not on a diuretic. Blood pressure was measured 24 hours after
dosing. An antihypertensive effect of PRINIVIL was seen with 5 mg in some patients. However, in
both studies blood pressure reduction occurred sooner and was greater in patients treated with
10, 20, or 80 mg of PRINIVIL. In controlled clinical studies, PRINIVIL 20-80 mg has been
compared in patients with mild to moderate hypertension to hydrochlorothiazide 12.5-50 mg and
with atenolol 50-500 mg; and in patients with moderate to severe hypertension to metoprolol
100-200 mg. It was superior to hydrochlorothiazide in effects on systolic and diastolic blood
pressure in a population that was ¾ caucasian. PRINIVIL was approximately equivalent to
atenolol and metoprolol in effects on diastolic blood pressure and had somewhat greater effects
on systolic blood pressure.
PRINIVIL had similar effectiveness and adverse effects in younger and older (>65 years)
patients. It was less effective in Blacks than in caucasians.
In hemodynamic studies in patients with essential hypertension, blood pressure reduction was
accompanied by a reduction in peripheral arterial resistance with little or no change in cardiac
output and in heart rate. In a study in nine hypertensive patients, following administration of
PRINIVIL, there was an increase in mean renal blood flow that was not significant. Data from
several small studies are inconsistent with respect to the effect of PRINIVIL on glomerular
filtration rate in hypertensive patients with normal renal function, but suggest that changes, if any,
are not large.
In patients with renovascular hypertension PRINIVIL has been shown to be well tolerated and
effective in controlling blood pressure (see PRECAUTIONS).
Pediatric Patients: In a clinical study involving 115 hypertensive pediatric patients 6 to 16
years of age, patients who weighed <50 kg received either 0.625, 2.5, or 20 mg of lisinopril daily
and patients who weighed ≥50 kg received either 1.25, 5, or 40 mg of lisinopril daily. At the end
of 2 weeks, lisinopril administered once daily lowered trough blood pressure in a dose-dependent
manner with consistent antihypertensive efficacy demonstrated at doses >1.25 mg (0.02 mg/kg).
This effect was confirmed in a withdrawal phase, where the diastolic pressure rose by about 9
mmHg more in patients randomized to placebo than it did in patients who were randomized to
remain on the middle and high doses of lisinopril. The dose-dependent antihypertensive effect of
lisinopril was consistent across several demographic subgroups: age, Tanner stage, gender,
race. In this study, lisinopril was generally well-tolerated.
In the above pediatric studies, lisinopril was given either as tablets or in a suspension for
those children and infants who were unable to swallow tablets or who required a lower dose than
is available in tablet form (see DOSAGE AND ADMINISTRATION, Preparation of Suspension).
Heart Failure: During baseline-controlled clinical trials, in patients receiving digitalis and
diuretics, single doses of PRINIVIL resulted in decreases in pulmonary capillary wedge pressure,
systemic vascular resistance and blood pressure accompanied by an increase in cardiac output
and no change in heart rate.
In two placebo-controlled, 12-week clinical studies using doses of PRINIVIL up to 20 mg,
PRINIVIL as adjunctive therapy to digitalis and diuretics improved the following signs and
symptoms due to congestive heart failure: edema, rales, paroxysmal nocturnal dyspnea and
jugular venous distention. In one of the studies beneficial response was also noted for:
orthopnea, presence of third heart sound and the number of patients classified as NYHA Class III
and IV. Exercise tolerance was also improved in this study. The effect of lisinopril on mortality in
patients with heart failure has not been evaluated.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
4
The once daily dosing for the treatment of congestive heart failure was the only dosage
regimen used during clinical trial development and was determined by the measurement of
hemodynamic responses.
Acute Myocardial Infarction: The Gruppo Italiano per lo Studio della Sopravvienza nell'Infarto
Miocardico (GISSI - 3) study was a multicenter, controlled, randomized, unblinded clinical trial
conducted in 19,394 patients with acute myocardial infarction admitted to a coronary care unit. It
was designed to examine the effects of short-term (6 week) treatment with lisinopril, nitrates, their
combination, or no therapy on short-term (6 week) mortality and on long-term death and markedly
impaired cardiac function. Patients presenting within 24 hours of the onset of symptoms who
were hemodynamically stable were randomized, in a 2 x 2 factorial design, to six weeks of either
1) PRINIVIL alone (n = 4841),
2) nitrates alone (n = 4869),
3) PRINIVIL plus nitrates (n = 4841), or
4) open control (n = 4843).
All patients received routine therapies, including thrombolytics (72%), aspirin (84%), and a
beta-blocker (31%), as appropriate, normally utilized in acute myocardial infarction (MI) patients.
The protocol excluded patients with hypotension (systolic blood pressure ≤100 mmHg), severe
heart failure, cardiogenic shock and renal dysfunction (serum creatinine >2 mg/dL and/or
proteinuria >500 mg/24 h). Doses of PRINIVIL were adjusted as necessary according to protocol.
(See DOSAGE AND ADMINISTRATION.)
Study treatment was withdrawn at six weeks except where clinical conditions indicated
continuation of treatment.
The primary outcomes of the trial were the overall mortality at six weeks and a combined
endpoint at six months after the myocardial infarction, consisting of the number of patients who
died, had late (day 4) clinical congestive heart failure, or had extensive left ventricular damage
defined as ejection fraction ≤35%, or an akinetic-dyskinetic [A-D] score ≥45%. Patients receiving
PRINIVIL (n = 9646) alone or with nitrates, had an 11 percent lower risk of death (2p [two-
tailed] = 0.04) compared to patients receiving no PRINIVIL (n = 9672) (6.4 percent versus 7.2
percent, respectively) at six weeks. Although patients randomized to receive PRINIVIL for up to
six weeks also fared numerically better on the combined end-point at 6 months, the open nature
of the assessment of heart failure, substantial loss to follow-up echocardiography, and substantial
excess use of lisinopril between 6 weeks and 6 months in the group randomized to 6 weeks of
lisinopril, preclude any conclusion about this endpoint.
Patients with acute myocardial infarction, treated with PRINIVIL had a higher (9.0 percent
versus 3.7 percent, respectively) incidence of persistent hypotension (systolic blood pressure
<90 mmHg for more than 1 hour) and renal dysfunction (2.4 percent versus 1.1 percent) in-
hospital and at six weeks (increasing creatinine concentration to over 3 mg/dL or a doubling or
more of the baseline serum creatinine concentration). See ADVERSE REACTIONS, ACUTE
MYOCARDIAL INFARCTION.
INDICATIONS AND USAGE
Hypertension
PRINIVIL is indicated for the treatment of hypertension. It may be used alone as initial therapy
or concomitantly with other classes of antihypertensive agents.
Heart Failure
PRINIVIL is indicated as adjunctive therapy in the management of heart failure in patients who
are not responding adequately to diuretics and digitalis.
Acute Myocardial Infarction
PRINIVIL is indicated for the treatment of hemodynamically stable patients within 24 hours of
acute myocardial infarction, to improve survival. Patients should receive, as appropriate, the
standard recommended treatments such as thrombolytics, aspirin and beta-blockers.
In using PRINIVIL, consideration should be given to the fact that another angiotensin
converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with
renal impairment or collagen vascular disease, and that available data are insufficient to show
that PRINIVIL does not have a similar risk. (See WARNINGS.)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
5
In considering use of PRINIVIL, it should be noted that in controlled clinical trials ACE
inhibitors have an effect on blood pressure that is less in Black patients than in non-Blacks. In
addition, it should be noted that Black patients receiving ACE inhibitors have been reported to
have a higher incidence of angioedema compared to non-Blacks (see WARNINGS,
Anaphylactoid and Possibly Related Reactions, Angioedema).
CONTRAINDICATIONS
PRINIVIL is contraindicated in patients who are hypersensitive to this product and in patients
with a history of angioedema related to previous treatment with an angiotensin converting
enzyme inhibitor and in patients with hereditary or idiopathic angioedema.
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 PRINIVIL) may be subject to a variety of adverse reactions, some of them serious.
Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has
been reported in patients treated with angiotensin converting enzyme inhibitors, including
PRINIVIL. This may occur at any time during treatment. ACE inhibitors have been associated with
a higher rate of angioedema in Black than in non-Black patients. In such cases PRINIVIL should
be promptly discontinued and appropriate therapy and monitoring should be provided until
complete and sustained resolution of signs and symptoms has occurred. In instances where
swelling has been confined to the face and lips the condition has generally resolved without
treatment, although antihistamines have been useful in relieving symptoms. Angioedema
associated with laryngeal edema may be fatal. Where there is involvement of the tongue,
glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g.,
subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary
to ensure a patent airway, should be promptly provided. (See ADVERSE REACTIONS.)
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased
risk of angioedema while receiving an ACE inhibitor (see also INDICATIONS AND USAGE and
CONTRAINDICATIONS).
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: Sudden and potentially life-threatening
anaphylactoid reactions have been reported in some patients dialyzed with high-flux membranes
(e.g., AN69®) and treated concomitantly with an ACE inhibitor. In such patients, dialysis must be
stopped immediately, and aggressive therapy for anaphylactoid reactions be initiated. Symptoms
have not been relieved by antihistamines in these situations. In these patients, consideration
should be given to using a different type of dialysis membrane or a different class of
antihypertensive agent. Anaphylactoid reactions have also been reported in patients undergoing
low-density lipoprotein apheresis with dextran sulfate absorption.
Hypotension
Excessive hypotension is rare in patients with uncomplicated hypertension treated with
PRINIVIL alone.
Patients with heart failure given PRINIVIL commonly have some reduction in blood pressure
with peak blood pressure reduction occurring 6 to 8 hours post dose, but discontinuation of
therapy because of continuing symptomatic hypotension usually is not necessary when dosing
instructions are followed; caution should be observed when initiating therapy. (See DOSAGE
AND ADMINISTRATION.)
Patients at risk of excessive hypotension, sometimes associated with oliguria and/or
progressive azotemia, and rarely with acute renal failure and/or death, include those with the
following conditions or characteristics: heart failure with systolic blood pressure below 100 mmHg,
hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
6
renal dialysis, or severe volume and/or salt depletion of any etiology. It may be advisable to
eliminate the diuretic (except in patients with heart failure), reduce the diuretic dose or increase
salt intake cautiously before initiating therapy with PRINIVIL in patients at risk for excessive
hypotension who are able to tolerate such adjustments. (See PRECAUTIONS, Drug Interactions,
and ADVERSE REACTIONS.)
Patients with acute myocardial infarction in the GISSI - 3 study had a higher (9.0 percent
versus 3.7 percent) incidence of persistent hypotension (systolic blood pressure <90 mmHg for
more than 1 hour) when treated with PRINIVIL. Treatment with PRINIVIL must not be initiated in
acute myocardial infarction patients at risk of further serious hemodynamic deterioration after
treatment with a vasodilator (e.g., systolic blood pressure of 100 mmHg or lower) or cardiogenic
shock.
In patients at risk of excessive hypotension, therapy should be started under very close
medical supervision and such patients should be followed closely for the first two weeks of
treatment and whenever the dose of PRINIVIL and/or diuretic is increased. Similar considerations
may apply to patients with ischemic heart or cerebrovascular disease, or in patients with acute
myocardial infarction, in whom an excessive fall in blood pressure could result in a myocardial
infarction or cerebrovascular accident.
If excessive hypotension occurs, the patient should be placed in the supine position and, if
necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is
not a contraindication to further doses of PRINIVIL which usually can be given without difficulty
once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or
discontinuation of PRINIVIL or concomitant diuretic may be necessary.
Leukopenia/Neutropenia/Agranulocytosis
Another angiotensin converting enzyme inhibitor, captopril, has been shown to cause
agranulocytosis and bone marrow depression, rarely in uncomplicated patients but more
frequently in patients with renal impairment especially if they also have a collagen vascular
disease. Available data from clinical trials of PRINIVIL are insufficient to show that PRINIVIL does
not cause agranulocytosis at similar rates. Marketing experience has revealed rare cases of
leukopenia/neutropenia and bone marrow depression in which a causal relationship to lisinopril
cannot be excluded. Periodic monitoring of white blood cell counts in patients with collagen
vascular disease and renal disease should be considered.
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.
Fetal/Neonatal Morbidity and Mortality
ACE inhibitors can cause fetal and neonatal morbidity and death when administered to
pregnant women. Several dozen cases have been reported in the world literature. When
pregnancy is detected, ACE inhibitors should be discontinued as soon as possible.
The use of ACE inhibitors during the second and third trimesters of pregnancy has been
associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia,
anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been
reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting
has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung
development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also
been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor
exposure.
These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor
exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are
exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless,
when patients become pregnant, physicians should make every effort to discontinue the use of
PRINIVIL as soon as possible.
Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE
inhibitors will be found. In these rare cases, the mothers should be apprised of the potential
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
7
hazards to their fetuses, and serial ultrasound examinations should be performed to assess the
intraamniotic environment.
If oligohydramnios is observed, PRINIVIL should be discontinued unless it is considered
lifesaving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical
profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and
physicians should be aware, however, that oligohydramnios may not appear until after the fetus
has sustained irreversible injury.
Infants with histories of in utero exposure to ACE inhibitors should be closely observed for
hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward
support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required
as means of reversing hypotension and/or substituting for disordered renal function. Lisinopril,
which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis
with some clinical benefit, and theoretically may be removed by exchange transfusion, although
there is no experience with the latter procedure.
No teratogenic effects of lisinopril were seen in studies of pregnant mice, rats and rabbits. On
a body surface area basis, the doses used were 55 times, 33 times, and 0.15 times, respectively,
the maximum recommended human daily dose (MRHDD).
PRECAUTIONS
General
Aortic Stenosis/Hypertrophic Cardiomyopathy: As with all vasodilators, lisinopril should be
given with caution to patients with obstruction in the outflow tract of the left ventricle.
Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone
system, changes in renal function may be anticipated in susceptible individuals. In patients with
severe congestive heart failure whose renal function may depend on the activity of the renin-
angiotensin-aldosterone system, treatment with angiotensin converting enzyme inhibitors,
including PRINIVIL, may be associated with oliguria and/or progressive azotemia and rarely with
acute renal failure and/or death.
In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood
urea nitrogen and serum creatinine may occur. Experience with another angiotensin converting
enzyme inhibitor suggests that these increases are usually reversible upon discontinuation of
PRINIVIL and/or diuretic therapy. In such patients renal function should be monitored during the
first few weeks of therapy.
Some patients with hypertension or heart failure with no apparent pre-existing renal vascular
disease have developed increases in blood urea nitrogen and serum creatinine, usually minor
and transient, especially when PRINIVIL has been given concomitantly with a diuretic. This is
more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or
discontinuation of the diuretic and/or PRINIVIL may be required.
Patients with acute myocardial infarction in the GISSI - 3 study, treated with PRINIVIL, had a
higher (2.4 percent versus 1.1 percent) incidence of renal dysfunction in-hospital and at six weeks
(increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum
creatinine concentration). In acute myocardial infarction, treatment with PRINIVIL should be
initiated with caution in patients with evidence of renal dysfunction, defined as serum creatinine
concentration exceeding 2 mg/dL. If renal dysfunction develops during treatment with PRINIVIL
(serum creatinine concentration exceeding 3 mg/dL or a doubling from the pre-treatment value)
then the physician should consider withdrawal of PRINIVIL.
Evaluation of patients with hypertension, heart failure, or myocardial infarction should
always include assessment of renal function. (See DOSAGE AND ADMINISTRATION.)
Hyperkalemia: In clinical trials hyperkalemia (serum potassium greater than 5.7 mEq/L)
occurred in approximately 2.2 percent of hypertensive patients and 4.8 percent of patients with
heart failure. In most cases these were isolated values which resolved despite continued therapy.
Hyperkalemia was a cause of discontinuation of therapy in approximately 0.1 percent of
hypertensive patients, 0.6 percent of patients with heart failure and 0.1 percent of patients with
myocardial infarction. Risk factors for the development of hyperkalemia include renal
insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
8
potassium supplements and/or potassium-containing salt substitutes, which should be used
cautiously, if at all, with PRINIVIL. (See Drug Interactions.)
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.
Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents
that produce hypotension, PRINIVIL may 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.
Information for Patients
Angioedema: Angioedema, including laryngeal edema, may occur at any time during
treatment with angiotensin converting enzyme inhibitors, including lisinopril. Patients should be so
advised and told to report immediately any signs or symptoms suggesting angioedema (swelling
of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more
drug until they have consulted with the prescribing physician.
Symptomatic Hypotension: Patients should be cautioned to report lightheadedness especially
during the first few days of therapy. If actual syncope occurs, the patients should be told to
discontinue the drug until they have consulted with the prescribing physician.
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 their physician.
Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without
consulting their physician.
Leukopenia/Neutropenia: Patients should be told to report promptly any indication of infection
(e.g., sore throat, fever) which may be a sign of leukopenia/neutropenia.
Pregnancy: Female patients of childbearing age should be told about the consequences of
second- and third-trimester exposure to ACE inhibitors, and they should also be told that these
consequences do not appear to have resulted from intrauterine ACE-inhibitor exposure that has
been limited to the first trimester. These patients should be asked to report pregnancies to their
physicians as soon as possible.
NOTE: As with many other drugs, certain advice to patients being treated with PRINIVIL is
warranted. This information is intended to aid in the safe and effective use of this medication. It is
not a disclosure of all possible adverse or intended effects.
Drug Interactions
Hypotension - Patients on Diuretic Therapy: Patients on diuretics, and especially those in
whom diuretic therapy was recently instituted, may occasionally experience an excessive
reduction of blood pressure after initiation of therapy with PRINIVIL. The possibility of hypotensive
effects with PRINIVIL can be minimized by either discontinuing the diuretic or increasing the salt
intake prior to initiation of treatment with PRINIVIL. If it is necessary to continue the diuretic,
initiate therapy with PRINIVIL at a dose of 5 mg daily, and provide close medical supervision after
the initial dose until blood pressure has stabilized. (See WARNINGS and DOSAGE AND
ADMINISTRATION.) When a diuretic is added to the therapy of a patient receiving PRINIVIL, an
additional antihypertensive effect is usually observed. Studies with ACE inhibitors in combination
with diuretics indicate that the dose of the ACE inhibitor can be reduced when it is given with a
diuretic. (See DOSAGE AND ADMINISTRATION.)
Non-steroidal Anti-inflammatory Agents: In some patients with compromised renal function
who are being treated with non-steroidal anti-inflammatory drugs, the co-administration of
lisinopril may result in a further deterioration of renal function. These effects are usually
reversible.
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors,
including lisinopril. This interaction should be given consideration in patients taking NSAIDs
concomitantly with ACE inhibitors.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
9
In a study in 36 patients with mild to moderate hypertension where the antihypertensive
effects of PRINIVIL alone were compared to PRINIVIL given concomitantly with indomethacin,
the use of indomethacin was associated with a reduced antihypertensive effect, although the
difference between the two regimens was not significant.
Other Agents: PRINIVIL has been used concomitantly with nitrates and/or digoxin without
evidence of clinically significant adverse interactions. This included post myocardial infarction
patients who were receiving intravenous or transdermal nitroglycerin. No clinically important
pharmacokinetic interactions occurred when PRINIVIL was used concomitantly with propranolol
or hydrochlorothiazide. The presence of food in the stomach does not alter the bioavailability of
PRINIVIL.
Agents Increasing Serum Potassium: PRINIVIL attenuates potassium loss caused by thiazide-
type diuretics. Use of PRINIVIL with potassium-sparing diuretics (e.g., spironolactone,
triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may
lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is
indicated because of demonstrated hypokalemia, they should be used with caution and with
frequent monitoring of serum potassium. Potassium sparing agents should generally not be used
in patients with heart failure who are receiving PRINIVIL.
Lithium: Lithium toxicity has been reported in patients receiving lithium concomitantly with
drugs which cause elimination of sodium, including ACE inhibitors. Lithium toxicity was usually
reversible upon discontinuation of lithium and the ACE inhibitor. It is recommended that serum
lithium levels be monitored frequently if PRINIVIL is administered concomitantly with lithium.
Carcinogenesis, Mutagenesis, Impairment of Fertility
There was no evidence of a tumorigenic effect when lisinopril was administered orally for 105
weeks to male and female rats at doses up to 90 mg/kg/day or for 92 weeks to male and female
mice at doses up to 135 mg/kg/day. These doses are 10 times and 7 times, respectively, the
maximum recommended human daily dose (MRHDD) when compared on a body surface area
basis.
Lisinopril was not mutagenic in the Ames microbial mutagen test with or without metabolic
activation. It was also negative in a forward mutation assay using Chinese hamster lung cells.
Lisinopril did not produce single strand DNA breaks in an in vitro alkaline elution rat hepatocyte
assay. In addition, lisinopril did not produce increases in chromosomal aberrations in an in vitro
test in Chinese hamster ovary cells or in an in vivo study in mouse bone marrow.
There were no adverse effects on reproductive performance in male and female rats treated
with up to 300 mg/kg/day of lisinopril (33 times the MRHDD when compared on a body surface
area basis).
Pregnancy
Pregnancy Categories C (first trimester) and D (second and third trimesters). See
WARNINGS, Fetal/Neonatal Morbidity and Mortality.
Nursing Mothers
Milk of lactating rats contains radioactivity following administration of 14C lisinopril. It is not
known whether this drug is secreted in human milk. Because many drugs are secreted in human
milk, and because of the potential for serious adverse reactions in nursing infants from ACE
inhibitors, a decision should be made whether to discontinue nursing or discontinue PRINIVIL,
taking into account the importance of the drug to the mother.
Pediatric Use
Antihypertensive effects of PRINIVIL have been established in hypertensive pediatric patients
aged 6 to 16 years.
There are no data on the effect of PRINIVIL on blood pressure in pediatric patients under the
age of 6 or in pediatric patients with glomerular filtration rate <30mL/min/1.73 m2 (see CLINICAL
PHARMACOLOGY, Pharmacokinetics and Metabolism and Pharmacodynamics and Clinical
Effects, 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
PRINIVIL® (Lisinopril)
7825248
10
ADVERSE REACTIONS
PRINIVIL has been found to be generally well tolerated in controlled clinical trials involving
1969 patients with hypertension or heart failure. For the most part, adverse experiences were
mild and transient.
HYPERTENSION
In clinical trials in patients with hypertension treated with PRINIVIL, discontinuation of therapy
due to clinical adverse experiences occurred in 5.7 percent of patients. The overall frequency of
adverse experiences could not be related to total daily dosage within the recommended
therapeutic dosage range.
For adverse experiences occurring in greater than one percent of patients with hypertension
treated with PRINIVIL or PRINIVIL plus hydrochlorothiazide in controlled clinical trials and more
frequently with PRINIVIL and/or PRINIVIL plus hydrochlorothiazide than placebo, comparative
incidence data are listed in the table below:
Percent of Patients
in Controlled Studies
PRINIVIL
(n = 1349)
Incidence
(discontinuation)
PRINIVIL/
Hydrochlorothiazide
(n = 629)
Incidence
(discontinuation)
Placebo
(n = 207)
Incidence
(discontinuation)
Body As A Whole
Fatigue
Asthenia
Orthostatic Effects
2.5 (0.3)
1.3 (0.5)
1.2 (0.0)
4.0 (0.5)
2.1 (0.2)
3.5 (0.2)
1.0 (0.0)
1.0 (0.0)
1.0 (0.0)
Cardiovascular
Hypotension
1.2 (0.5)
1.6 (0.5)
0.5 (0.5)
Digestive
Diarrhea
Nausea
Vomiting
Dyspepsia
2.7 (0.2)
2.0 (0.4)
1.1 (0.2)
0.9 (0.0)
2.7 (0.3)
2.5 (0.2)
1.4 (0.1)
1.9 (0.0)
2.4 (0.0)
2.4 (0.0)
0.5 (0.0)
0.0 (0.0)
Musculoskeletal
Muscle Cramps
0.5 (0.0)
2.9 (0.8)
0.5 (0.0)
Nervous/Psychiatric
Headache
Dizziness
Paresthesia
Decreased Libido
Vertigo
5.7 (0.2)
5.4 (0.4)
0.8 (0.1)
0.4 (0.1)
0.2 (0.1)
4.5 (0.5)
9.2 (1.0)
2.1 (0.2)
1.3 (0.1)
1.1 (0.2)
1.9 (0.0)
1.9 (0.0)
0.0 (0.0)
0.0 (0.0)
0.0 (0.0)
Respiratory
Cough
Upper Respiratory
Infection
Common Cold
Nasal Congestion
Influenza
3.5 (0.7)
2.1 (0.1)
1.1 (0.1)
0.4 (0.1)
0.3 (0.1)
4.6 (0.8)
2.7 (0.1)
1.3 (0.1)
1.3 (0.1)
1.1 (0.1)
1.0 (0.0)
0.0 (0.0)
0.0 (0.0)
0.0 (0.0)
0.0 (0.0)
Skin
Rash
1.3 (0.4)
1.6 (0.2)
0.5 (0.5)
Urogenital
Impotence
1.0 (0.4)
1.6 (0.5)
0.0 (0.0)
Chest pain and back pain were also seen but were more common on placebo than PRINIVIL.
HEART FAILURE
In patients with heart failure treated with PRINIVIL for up to four years, discontinuation of
therapy due to clinical adverse experiences occurred in 11.0 percent of patients. In controlled
studies in patients with heart failure, therapy was discontinued in 8.1 percent of patients treated
with PRINIVIL for up to 12 weeks, compared to 7.7 percent of patients treated with placebo for 12
weeks.
The following table lists those adverse experiences which occurred in greater than one
percent of patients with heart failure treated with PRINIVIL or placebo for up to 12 weeks in
controlled clinical trials and more frequently on PRINIVIL than placebo.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
11
Controlled Trials
PRINIVIL
(n=407)
Incidence
(discontinuation)
Placebo
(n=155)
Incidence
(discontinuation)
12 weeks
12 weeks
Body As A Whole
Chest Pain
Abdominal Pain
3.4 (0.2)
2.2 (0.7)
1.3 (0.0)
1.9 (0.0)
Cardiovascular
Hypotension
4.4 (1.7)
0.6 (0.6)
Digestive
Diarrhea
3.7 (0.5)
1.9 (0.0)
Nervous/Psychiatric
Dizziness
Headache
11.8 (1.2)
4.4 (0.2)
4.5 (1.3)
3.9 (0.0)
Respiratory
Upper Respiratory
Infection
1.5 (0.0)
1.3 (0.0)
Skin
Rash
1.7 (0.5)
0.6 (0.6)
Also observed at >1% with PRINIVIL but more frequent or as frequent on placebo than
PRINIVIL in controlled trials were asthenia, angina pectoris, nausea, dyspnea, cough and
pruritus.
Worsening of heart failure, anorexia, increased salivation, muscle cramps, back pain, myalgia,
depression, chest sound abnormalities and pulmonary edema were also seen in controlled
clinical trials, but were more common on placebo than PRINIVIL.
ACUTE MYOCARDIAL INFARCTION
In the GISSI - 3 trial, in patients treated with PRINIVIL for six weeks following acute
myocardial infarction, discontinuation of therapy occurred in 17.6 percent of patients.
Patients treated with PRINIVIL had a significantly higher incidence of hypotension and renal
dysfunction compared with patients not taking PRINIVIL.
In the GISSI - 3 trial, hypotension (9.7 percent), renal dysfunction (2.0 percent), cough (0.5
percent), post-infarction angina (0.3 percent), skin rash and generalized edema (0.01 percent),
and angioedema (0.01 percent) resulted in withdrawal of treatment. In elderly patients treated
with PRINIVIL, discontinuation due to renal dysfunction was 4.2 percent.
Other clinical adverse experiences occurring in 0.3 to 1.0 percent of patients with hypertension
or heart failure treated with PRINIVIL in controlled trials and rarer, serious, possibly drug-related
events reported in uncontrolled studies or marketing experience are listed below, and within each
category, are in order of decreasing severity:
Body as a Whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid and Possibly
Related Reactions), syncope, orthostatic effects, chest discomfort, pain, pelvic pain, flank pain,
edema, facial edema, virus infection, fever, chills, malaise.
Cardiovascular: Cardiac arrest; myocardial infarction or cerebrovascular accident, possibly
secondary to excessive hypotension in high risk patients (see WARNINGS, Hypotension);
pulmonary embolism and infarction, arrhythmias (including ventricular tachycardia, atrial
tachycardia, atrial fibrillation, bradycardia and premature ventricular contractions), palpitations,
transient ischemic attacks, paroxysmal nocturnal dyspnea, orthostatic hypotension, decreased
blood pressure, peripheral edema, vasculitis.
Digestive: Pancreatitis, hepatitis (hepatocellular or cholestatic jaundice) (see WARNINGS,
Hepatic Failure), vomiting, gastritis, dyspepsia, heartburn, gastrointestinal cramps, constipation,
flatulence, dry mouth.
Hematologic:
Rare
cases
of
bone
marrow
depression,
hemolytic
anemia,
leukopenia/neutropenia, and thrombocytopenia.
Endocrine: Diabetes mellitus.
Metabolic: Weight loss, dehydration, fluid overload, gout, weight gain.
Musculoskeletal: Arthritis, arthralgia, neck pain, hip pain, low back pain, joint pain, leg pain,
knee pain, shoulder pain, arm pain, lumbago.
Nervous System/Psychiatric: Stroke, ataxia, memory impairment, tremor, peripheral
neuropathy (e.g., dysesthesia), spasm, paresthesia, confusion, insomnia, somnolence,
hypersomnia, irritability, and nervousness.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
12
Respiratory
System:
Malignant
lung
neoplasms,
hemoptysis,
pulmonary
infiltrates,
eosinophilic pneumonitis, bronchospasm, asthma, pleural effusion, pneumonia, bronchitis,
wheezing, orthopnea, painful respiration, epistaxis, laryngitis, sinusitis, pharyngeal pain,
pharyngitis, rhinitis, rhinorrhea.
Skin: Urticaria, alopecia, herpes zoster, photosensitivity, skin lesions, skin infections,
pemphigus, erythema, flushing, diaphoresis. Other severe skin reactions (including toxic
epidermal necrolysis and Stevens-Johnson syndrome) have been reported rarely; causal
relationship has not been established.
Special Senses: Visual loss, diplopia, blurred vision, tinnitus, photophobia, taste disturbances.
Urogenital System: Acute renal failure, oliguria, anuria, uremia, progressive azotemia, renal
dysfunction (see PRECAUTIONS and DOSAGE AND ADMINISTRATION), pyelonephritis,
dysuria, urinary tract infection, breast pain.
Miscellaneous: A symptom complex has been reported which may include a positive ANA, an
elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia
and leukocytosis. Rash, photosensitivity or other dermatological manifestations may occur alone
or in combination with these symptoms.
Angioedema: Angioedema has been reported in patients receiving PRINIVIL (0.1%) with an
incidence higher in Black than in non-Black patients. Angioedema associated with laryngeal
edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx
occurs, treatment with PRINIVIL should be discontinued and appropriate therapy instituted
immediately. (See WARNINGS.)
Hypotension: In hypertensive patients, hypotension occurred in 1.2 percent and syncope
occurred in 0.1 percent of patients. Hypotension or syncope was a cause for discontinuation of
therapy in 0.5 percent of hypertensive patients. In patients with heart failure, hypotension
occurred in 5.3 percent and syncope occurred in 1.8 percent of patients. These adverse
experiences were causes for discontinuation of therapy in 1.8 percent of these patients. In
patients treated with PRINIVIL for six weeks after acute myocardial infarction, hypotension
(systolic blood pressure ≤100 mmHg) resulted in discontinuation of therapy in 9.7 percent of the
patients. (See WARNINGS.)
Fetal/Neonatal Morbidity and Mortality: See WARNINGS, Fetal/Neonatal Morbidity and
Mortality.
Cough: See PRECAUTIONS, Cough.
Pediatric Patients: No relevant differences between the adverse experience profile for
pediatric patients and that previously reported for adult patients were identified.
Clinical Laboratory Test Findings
Serum Electrolytes: Hyperkalemia (see PRECAUTIONS), hyponatremia.
Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen and serum creatinine,
reversible upon discontinuation of therapy, were observed in about 2.0 percent of patients with
essential hypertension treated with PRINIVIL alone. Increases were more common in patients
receiving concomitant diuretics and in patients with renal artery stenosis. (See PRECAUTIONS.)
Reversible minor increases in blood urea nitrogen and serum creatinine were observed in
approximately 11.6 percent of patients with heart failure on concomitant diuretic therapy.
Frequently, these abnormalities resolved when the dosage of the diuretic was decreased.
Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases
of approximately 0.4 g percent and 1.3 vol percent, respectively) occurred frequently in patients
treated with PRINIVIL but were rarely of clinical importance in patients without some other cause
of anemia. In clinical trials, less than 0.1 percent of patients discontinued therapy due to anemia.
Hemolytic anemia has been reported; a causal relationship to lisinopril cannot be excluded.
Liver Function Tests: Rarely, elevations of liver enzymes and/or serum bilirubin have occurred
(see WARNINGS, Hepatic Failure).
In hypertensive patients, 2.0 percent discontinued therapy due to laboratory adverse
experiences, principally elevations in blood urea nitrogen (0.6 percent), serum creatinine (0.5
percent) and serum potassium (0.4 percent). In the heart failure trials, 3.4 percent of patients
discontinued therapy due to laboratory adverse experiences, 1.8 percent due to elevations in
blood urea nitrogen and/or creatinine and 0.6 percent due to elevations in serum potassium. In
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
13
the myocardial infarction trial, 2.0 percent of patients receiving PRINIVIL discontinued therapy
due to renal dysfunction (increasing creatinine concentration to over 3 mg/dL or a doubling or
more of the baseline serum creatinine concentration); less than 1.0 percent of patients
discontinued therapy due to other laboratory adverse experiences: 0.1 percent with hyperkalemia
and less than 0.1 percent with hepatic enzyme alterations.
OVERDOSAGE
Following a single oral dose of 20 g/kg, no lethality occurred in rats and death occurred in one
of 20 mice receiving the same dose. The most likely manifestation of overdosage would be
hypotension, for which the usual treatment would be intravenous infusion of normal saline
solution.
Lisinopril can be removed by hemodialysis. (See WARNINGS, Anaphylactoid reactions during
membrane exposure.)
DOSAGE AND ADMINISTRATION
Hypertension
Initial Therapy: In patients with uncomplicated essential hypertension not on diuretic therapy,
the recommended initial dose is 10 mg once a day. Dosage should be adjusted according to
blood pressure response. The usual dosage range is 20 to 40 mg per day administered in a
single daily dose. The antihypertensive effect may diminish toward the end of the dosing interval
regardless of the administered dose, but most commonly with a dose of 10 mg daily. This can be
evaluated by measuring blood pressure just prior to dosing to determine whether satisfactory
control is being maintained for 24 hours. If it is not, an increase in dose should be considered.
Doses up to 80 mg have been used but do not appear to give a greater effect. If blood pressure is
not controlled with PRINIVIL alone, a low dose of a diuretic may be added. Hydrochlorothiazide
12.5 mg has been shown to provide an additive effect. After the addition of a diuretic, it may be
possible to reduce the dose of PRINIVIL.
Diuretic Treated Patients: In hypertensive patients who are currently being treated with a
diuretic, symptomatic hypotension may occur occasionally following the initial dose of PRINIVIL.
The diuretic should be discontinued, if possible, for two to three days before beginning therapy
with PRINIVIL to reduce the likelihood of hypotension. (See WARNINGS.) The dosage of
PRINIVIL should be adjusted according to blood pressure response. If the patient's blood
pressure is not controlled with PRINIVIL alone, diuretic therapy may be resumed as described
above.
If the diuretic cannot be discontinued, an initial dose of 5 mg should be used under medical
supervision for at least two hours and until blood pressure has stabilized for at least an additional
hour. (See WARNINGS and PRECAUTIONS, Drug Interactions.)
Concomitant administration of PRINIVIL with potassium supplements, potassium salt
substitutes, or potassium-sparing diuretics may lead to increases of serum potassium (see
PRECAUTIONS).
Dosage Adjustment in Renal Impairment: The usual dose of PRINIVIL (10 mg) is
recommended for patients with a creatinine clearance >30 mL/min (serum creatinine of up to
approximately 3 mg/dL). For patients with creatinine clearance ≥10 mL/min ≤30 mL/min (serum
creatinine ≥3 mg/dL), the first dose is 5 mg once daily. For patients with creatinine clearance
<10 mL/min (usually on hemodialysis) the recommended initial dose is 2.5 mg. The dosage may
be titrated upward until blood pressure is controlled or to a maximum of 40 mg daily.
Renal Status
Creatinine-
Clearance
mL/min
Initial Dose
mg/day
Normal Renal Function to Mild
Impairment
>30 mL/min
10 mg
Moderate to Severe
Impairment
≥10 ≤30
mL/min
5 mg
Dialysis Patients**
<10 mL/min
2.5 mg***
** See WARNINGS, Anaphylactoid reactions during membrane exposure
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
14
*** Dosage or dosing interval should be adjusted depending on the blood pressure response.
Heart Failure
PRINIVIL is indicated as adjunctive therapy with diuretics and (usually) digitalis. The
recommended starting dose is 5 mg once a day.
When initiating treatment with lisinopril in patients with heart failure, the initial dose should be
administered under medical observation, especially in those patients with low blood pressure
(systolic blood pressure below 100 mmHg). The mean peak blood pressure lowering occurs six to
eight hours after dosing. Observation should continue until blood pressure is stable. The
concomitant diuretic dose should be reduced, if possible, to help minimize hypovolemia which
may contribute to hypotension. (See WARNINGS and PRECAUTIONS, Drug Interactions.) The
appearance of hypotension after the initial dose of PRINIVIL does not preclude subsequent
careful dose titration with the drug, following effective management of the hypotension.
The usual effective dosage range is 5 to 20 mg per day administered as a single daily dose.
Dosage Adjustment in Patients with Heart Failure and Renal Impairment or Hyponatremia: In
patients with heart failure who have hyponatremia (serum sodium <130 mEq/L) or moderate to
severe renal impairment (creatinine clearance ≤30 mL/min or serum creatinine >3 mg/dL),
therapy with PRINIVIL should be initiated at a dose of 2.5 mg once a day under close medical
supervision. (See WARNINGS and PRECAUTIONS, Drug Interactions.)
Acute Myocardial Infarction
In hemodynamically stable patients within 24 hours of the onset of symptoms of acute
myocardial infarction, the first dose of PRINIVIL is 5 mg given orally, followed by 5 mg after 24
hours, 10 mg after 48 hours and then 10 mg of PRINIVIL once daily. Dosing should continue for
six weeks. Patients should receive, as appropriate, the standard recommended treatments such
as thrombolytics, aspirin and beta-blockers. Patients with a low systolic blood pressure
(≤120 mmHg) when treatment is started or during the first 3 days after the infarct should be given
a lower 2.5 mg oral dose of PRINIVIL (see WARNINGS). If hypotension occurs (systolic blood
pressure ≤100 mmHg) a daily maintenance dose of 5 mg may be given with temporary reductions
to 2.5 mg if needed. If prolonged hypotension occurs (systolic blood pressure <90 mmHg for
more than 1 hour) PRINIVIL should be withdrawn. For patients who develop symptoms of heart
failure, see DOSAGE AND ADMINISTRATION, Heart Failure.
Dosage Adjustment in Patients with Myocardial Infarction with Renal Impairment: In acute
myocardial infarction, treatment with PRINIVIL should be initiated with caution in patients with
evidence of renal dysfunction, defined as serum creatinine concentration exceeding 2 mg/dL. No
evaluation of dosage adjustment in myocardial infarction patients with severe renal impairment
has been performed.
Use in Elderly
In general, blood pressure response and adverse experiences were similar in younger and
older patients given similar doses of PRINIVIL. Pharmacokinetic studies, however, indicate that
maximum blood levels and area under the plasma concentration time curve (AUC) are doubled in
older patients, so that dosage adjustments should be made with particular caution.
Pediatric Hypertensive Patients ≥ 6 years of age
The usual recommended starting dose is 0.07 mg/kg once daily (up to 5 mg total). Dosage
should be adjusted according to blood pressure response. Doses above 0.61 mg/kg (or in excess
of 40 mg) have not been studied in pediatric patients. See CLINICAL PHARMACOLOGY
Pharmacokinetics and Metabolism and Pharmacodynamics and Clinical Effects).
PRINIVIL is not recommended in pediatric patients <6 years or in pediatric patients with
glomerular
filtration
rate
<30 mL/min/1.73 m2
(see
CLINICAL
PHARMACOLOGY,
Pharmacokinetics
and
Metabolism,
Pharmacodynamics
and
Clinical
Effects
and
PRECAUTIONS).
Preparation of Suspension (for 200 mL of a 1.0 mg/mL suspension)
Add 10 mL of Purified Water USP to a polyethylene terephthalate (PET) bottle containing ten
20-mg tablets of PRINIVIL and shake for at least one minute. Add 30 mL of Bicitra®** diluent and
** Registered trademark of Alza Corporation
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
15
160 mL of Ora-Sweet SF™*** to the concentrate in the PET bottle and gently shake for several
seconds to disperse the ingredients. The suspension should be stored at or below 25°C (77°F)
and can be stored for up to four weeks. Shake the suspension before each use.
HOW SUPPLIED
No. 3658 — Tablets PRINIVIL, 2.5 mg, are white, round, flat-faced, beveled edge,
compressed tablets, coded MSD on one side and 15 on the other. They are supplied as follows:
NDC 0006-0015-28 unit dose packages of 100
NDC 0006-0015-31 unit of use bottles of 30
NDC 0006-0015-58 unit of use bottles of 100.
No. 3577 — Tablets PRINIVIL, 5 mg, are white, shield shaped, scored, compressed tablets,
with code MSD 19 on one side and PRINIVIL on the other. They are supplied as follows:
NDC 0006-0019-28 unit dose packages of 100
NDC 0006-0019-58 unit of use bottles of 100
NDC 0006-0019-94 unit of use bottles of 90
NDC 0006-0019-54 unit of use bottles of 90
NDC 0006-0019-82 bottles of 1,000
NDC 0006-0019-87 bottles of 10,000
NDC 0006-0019-72 carton of 25 UNIBLISTERTM cards of 31 tablets each.
No. 3578 — Tablets PRINIVIL, 10 mg, are light yellow, shield shaped, compressed tablets,
with code MSD 106 on one side and PRINIVIL on the other. They are supplied as follows:
NDC 0006-0106-28 unit dose packages of 100
NDC 0006-0106-31 unit of use bottles of 30
NDC 0006-0106-58 unit of use bottles of 100
NDC 0006-0106-94 unit of use bottles of 90
NDC 0006-0106-54 unit of use bottles of 90
NDC 0006-0106-82 bottles of 1,000
NDC 0006-0106-87 bottles of 10,000
NDC 0006-0106-72 carton of 25 UNIBLISTERTM cards of 31 tablets each.
No. 3579 — Tablets PRINIVIL, 20 mg, are peach, shield shaped, compressed tablets, with
code MSD 207 on one side and PRINIVIL on the other. They are supplied as follows:
NDC 0006-0207-28 unit dose packages of 100
NDC 0006-0207-31 unit of use bottles of 30
NDC 0006-0207-58 unit of use bottles of 100
NDC 0006-0207-94 unit of use bottles of 90
NDC 0006-0207-54 unit of use bottles of 90
NDC 0006-0207-82 bottles of 1,000
NDC 0006-0207-87 bottles of 10,000
NDC 0006-0207-72 carton of 25 UNIBLISTERTM cards of 31 tablets each.
No. 3580 — Tablets PRINIVIL, 40 mg, are rose red, shield shaped, compressed tablets, with
code MSD 237 on one side and PRINIVIL on the other. They are supplied as follows:
NDC 0006-0237-58 unit of use bottles of 100.
Storage
Store at controlled room temperature, 15-30°C (59-86°F), and protect from moisture.
Dispense in a tight container, if product package is subdivided.
Issued April 2003
*** Trademark of Paddock Laboratories, Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:27.733853
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19558se5-043_prinivil_lbl.pdf', 'application_number': 19558, 'submission_type': 'ORIG ', 'submission_number': 1}
|
11,531
|
7825248
1
TABLETS
PRINIVIL®
(LISINOPRIL)
USE IN PREGNANCY
When used in pregnancy during the second and third trimesters, ACE inhibitors can cause
injury and even death to the developing fetus. When pregnancy is detected, PRINIVIL should
be discontinued as soon as possible. See WARNINGS, Fetal/Neonatal Morbidity and Mortality.
DESCRIPTION
PRINIVIL* (Lisinopril), a synthetic peptide derivative, is an oral long-acting angiotensin
converting enzyme inhibitor. Lisinopril is chemically described as (S)-1-[N2-(1-carboxy-3-
phenylpropyl)-L-lysyl]-L-proline dihydrate. Its empirical formula is C21H31N3O5•2H2O and its
structural formula is:
Lisinopril is a white to off-white, crystalline powder, with a molecular weight of 441.52. It is
soluble in water and sparingly soluble in methanol and practically insoluble in ethanol.
PRINIVIL is supplied as 2.5 mg, 5 mg, 10 mg, 20 mg and 40 mg tablets for oral administration.
In addition to the active ingredient lisinopril, each tablet contains the following inactive
ingredients: calcium phosphate, mannitol, magnesium stearate, and starch. The 10 mg, 20 mg
and 40 mg tablets also contain iron oxide.
CLINICAL PHARMACOLOGY
Mechanism of Action
Lisinopril inhibits angiotensin converting enzyme (ACE) in human subjects and animals. ACE
is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor
substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal
cortex. The beneficial effects of lisinopril in hypertension and heart failure appear to result
primarily from suppression of the renin-angiotensin-aldosterone system. Inhibition of ACE results
in decreased plasma angiotensin II which leads to decreased vasopressor activity and to
decreased aldosterone secretion. The latter decrease may result in a small increase of serum
potassium. In hypertensive patients with normal renal function treated with PRINIVIL alone for up
to 24 weeks, the mean increase in serum potassium was approximately 0.1 mEq/L; however,
approximately 15 percent of patients had increases greater than 0.5 mEq/L and approximately six
percent had a decrease greater than 0.5 mEq/L. In the same study, patients treated with
PRINIVIL and hydrochlorothiazide for up to 24 weeks had a mean decrease in serum potassium
of 0.1 mEq/L; approximately 4 percent of patients had increases greater than 0.5 mEq/L and
approximately 12 percent had a decrease greater than 0.5 mEq/L. (See PRECAUTIONS.)
Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin
activity.
ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of
bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of PRINIVIL
remains to be elucidated.
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT © MERCK & CO., Inc., 1988, 1989, 1992, 1993, 1995
All rights reserved
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
2
While the mechanism through which PRINIVIL lowers blood pressure is believed to be
primarily suppression of the renin-angiotensin-aldosterone system, PRINIVIL is antihypertensive
even in patients with low-renin hypertension. Although PRINIVIL was antihypertensive in all races
studied, Black hypertensive patients (usually a low-renin hypertensive population) had a smaller
average response to monotherapy than non-Black patients.
Concomitant administration of PRINIVIL and hydrochlorothiazide further reduced blood
pressure in Black and non-Black patients and any racial difference in blood pressure response
was no longer evident.
Pharmacokinetics and Metabolism
Adult Patients: Following oral administration of PRINIVIL, peak serum concentrations of
lisinopril occur within about 7 hours, although there was a trend to a small delay in time taken to
reach peak serum concentrations in acute myocardial infarction patients. Declining serum
concentrations exhibit a prolonged terminal phase which does not contribute to drug
accumulation. This terminal phase probably represents saturable binding to ACE and is not
proportional to dose. Lisinopril does not appear to be bound to other serum proteins.
Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine.
Based on urinary recovery, the mean extent of absorption of lisinopril is approximately 25
percent, with large inter-subject variability (6-60 percent) at all doses tested (5-80 mg). Lisinopril
absorption is not influenced by the presence of food in the gastrointestinal tract. The absolute
bioavailability of lisinopril is reduced to about 16 percent in patients with stable NYHA Class II-IV
congestive heart failure, and the volume of distribution appears to be slightly smaller than that in
normal subjects.
The oral bioavailability of lisinopril in patients with acute myocardial infarction is similar to that
in healthy volunteers.
Upon multiple dosing, lisinopril exhibits an effective half-life of accumulation of 12 hours.
Impaired renal function decreases elimination of lisinopril, which is excreted principally through
the kidneys, but this decrease becomes clinically important only when the glomerular filtration
rate is below 30 mL/min. Above this glomerular filtration rate, the elimination half-life is little
changed. With greater impairment, however, peak and trough lisinopril levels increase, time to
peak concentration increases and time to attain steady state is prolonged. Older patients, on
average, have (approximately doubled) higher blood levels and area under the plasma
concentration time curve (AUC) than younger patients. (See DOSAGE AND ADMINISTRATION.)
Lisinopril can be removed by hemodialysis.
Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly. Multiple doses of
lisinopril in rats do not result in accumulation in any tissues. Milk of lactating rats contains
radioactivity following administration of 14C lisinopril. By whole body autoradiography, radioactivity
was found in the placenta following administration of labeled drug to pregnant rats, but none was
found in the fetuses.
Pediatric Patients: The pharmacokinetics of lisinopril were studied in 29 pediatric hypertensive
patients between 6 years and 16 years with glomerular filtration rate >30 mL/min/1.73 m2. After
doses of 0.1 to 0.2 mg/kg, steady state peak plasma concentrations of lisinopril occurred within 6
hours and the extent of absorption based on urinary recovery was about 28%. These values are
similar to those obtained previously in adults. The typical value of lisinopril oral clearance
(systemic clearance/absolute bioavailability) in a child weighing 30 kg is 10 L/h, which increases
in proportion to renal function.
Pharmacodynamics and Clinical Effects
Hypertension:
Adult Patients: Administration of PRINIVIL to patients with hypertension results in a reduction
of supine and standing blood pressure to about the same extent with no compensatory
tachycardia. Symptomatic postural hypotension is usually not observed although it can occur and
should be anticipated in volume and/or salt-depleted patients. (See WARNINGS.) When given
together with thiazide-type diuretics, the blood pressure lowering effects of the two drugs are
approximately additive.
In most patients studied, onset of antihypertensive activity was seen at one hour after oral
administration of an individual dose of PRINIVIL, with peak reduction of blood pressure achieved
by six hours. Although an antihypertensive effect was observed 24 hours after dosing with
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
3
recommended single daily doses, the effect was more consistent and the mean effect was
considerably larger in some studies with doses of 20 mg or more than with lower doses.
However, at all doses studied, the mean antihypertensive effect was substantially smaller 24
hours after dosing than it was six hours after dosing.
In some patients achievement of optimal blood pressure reduction may require two to four
weeks of therapy.
The antihypertensive effects of PRINIVIL are maintained during long-term therapy. Abrupt
withdrawal of PRINIVIL has not been associated with a rapid increase in blood pressure or a
significant increase in blood pressure compared to pretreatment levels.
Two dose-response studies utilizing a once daily regimen were conducted in 438 mild to
moderate hypertensive patients not on a diuretic. Blood pressure was measured 24 hours after
dosing. An antihypertensive effect of PRINIVIL was seen with 5 mg in some patients. However, in
both studies blood pressure reduction occurred sooner and was greater in patients treated with
10, 20, or 80 mg of PRINIVIL. In controlled clinical studies, PRINIVIL 20-80 mg has been
compared in patients with mild to moderate hypertension to hydrochlorothiazide 12.5-50 mg and
with atenolol 50-500 mg; and in patients with moderate to severe hypertension to metoprolol
100-200 mg. It was superior to hydrochlorothiazide in effects on systolic and diastolic blood
pressure in a population that was ¾ caucasian. PRINIVIL was approximately equivalent to
atenolol and metoprolol in effects on diastolic blood pressure and had somewhat greater effects
on systolic blood pressure.
PRINIVIL had similar effectiveness and adverse effects in younger and older (>65 years)
patients. It was less effective in Blacks than in caucasians.
In hemodynamic studies in patients with essential hypertension, blood pressure reduction was
accompanied by a reduction in peripheral arterial resistance with little or no change in cardiac
output and in heart rate. In a study in nine hypertensive patients, following administration of
PRINIVIL, there was an increase in mean renal blood flow that was not significant. Data from
several small studies are inconsistent with respect to the effect of PRINIVIL on glomerular
filtration rate in hypertensive patients with normal renal function, but suggest that changes, if any,
are not large.
In patients with renovascular hypertension PRINIVIL has been shown to be well tolerated and
effective in controlling blood pressure (see PRECAUTIONS).
Pediatric Patients: In a clinical study involving 115 hypertensive pediatric patients 6 to 16
years of age, patients who weighed <50 kg received either 0.625, 2.5, or 20 mg of lisinopril daily
and patients who weighed ≥50 kg received either 1.25, 5, or 40 mg of lisinopril daily. At the end
of 2 weeks, lisinopril administered once daily lowered trough blood pressure in a dose-dependent
manner with consistent antihypertensive efficacy demonstrated at doses >1.25 mg (0.02 mg/kg).
This effect was confirmed in a withdrawal phase, where the diastolic pressure rose by about 9
mmHg more in patients randomized to placebo than it did in patients who were randomized to
remain on the middle and high doses of lisinopril. The dose-dependent antihypertensive effect of
lisinopril was consistent across several demographic subgroups: age, Tanner stage, gender,
race. In this study, lisinopril was generally well-tolerated.
In the above pediatric studies, lisinopril was given either as tablets or in a suspension for
those children and infants who were unable to swallow tablets or who required a lower dose than
is available in tablet form (see DOSAGE AND ADMINISTRATION, Preparation of Suspension).
Heart Failure: During baseline-controlled clinical trials, in patients receiving digitalis and
diuretics, single doses of PRINIVIL resulted in decreases in pulmonary capillary wedge pressure,
systemic vascular resistance and blood pressure accompanied by an increase in cardiac output
and no change in heart rate.
In two placebo-controlled, 12-week clinical studies using doses of PRINIVIL up to 20 mg,
PRINIVIL as adjunctive therapy to digitalis and diuretics improved the following signs and
symptoms due to congestive heart failure: edema, rales, paroxysmal nocturnal dyspnea and
jugular venous distention. In one of the studies beneficial response was also noted for:
orthopnea, presence of third heart sound and the number of patients classified as NYHA Class III
and IV. Exercise tolerance was also improved in this study. The effect of lisinopril on mortality in
patients with heart failure has not been evaluated.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
4
The once daily dosing for the treatment of congestive heart failure was the only dosage
regimen used during clinical trial development and was determined by the measurement of
hemodynamic responses.
Acute Myocardial Infarction: The Gruppo Italiano per lo Studio della Sopravvienza nell'Infarto
Miocardico (GISSI - 3) study was a multicenter, controlled, randomized, unblinded clinical trial
conducted in 19,394 patients with acute myocardial infarction admitted to a coronary care unit. It
was designed to examine the effects of short-term (6 week) treatment with lisinopril, nitrates, their
combination, or no therapy on short-term (6 week) mortality and on long-term death and markedly
impaired cardiac function. Patients presenting within 24 hours of the onset of symptoms who
were hemodynamically stable were randomized, in a 2 x 2 factorial design, to six weeks of either
1) PRINIVIL alone (n = 4841),
2) nitrates alone (n = 4869),
3) PRINIVIL plus nitrates (n = 4841), or
4) open control (n = 4843).
All patients received routine therapies, including thrombolytics (72%), aspirin (84%), and a
beta-blocker (31%), as appropriate, normally utilized in acute myocardial infarction (MI) patients.
The protocol excluded patients with hypotension (systolic blood pressure ≤100 mmHg), severe
heart failure, cardiogenic shock and renal dysfunction (serum creatinine >2 mg/dL and/or
proteinuria >500 mg/24 h). Doses of PRINIVIL were adjusted as necessary according to protocol.
(See DOSAGE AND ADMINISTRATION.)
Study treatment was withdrawn at six weeks except where clinical conditions indicated
continuation of treatment.
The primary outcomes of the trial were the overall mortality at six weeks and a combined
endpoint at six months after the myocardial infarction, consisting of the number of patients who
died, had late (day 4) clinical congestive heart failure, or had extensive left ventricular damage
defined as ejection fraction ≤35%, or an akinetic-dyskinetic [A-D] score ≥45%. Patients receiving
PRINIVIL (n = 9646) alone or with nitrates, had an 11 percent lower risk of death (2p [two-
tailed] = 0.04) compared to patients receiving no PRINIVIL (n = 9672) (6.4 percent versus 7.2
percent, respectively) at six weeks. Although patients randomized to receive PRINIVIL for up to
six weeks also fared numerically better on the combined end-point at 6 months, the open nature
of the assessment of heart failure, substantial loss to follow-up echocardiography, and substantial
excess use of lisinopril between 6 weeks and 6 months in the group randomized to 6 weeks of
lisinopril, preclude any conclusion about this endpoint.
Patients with acute myocardial infarction, treated with PRINIVIL had a higher (9.0 percent
versus 3.7 percent, respectively) incidence of persistent hypotension (systolic blood pressure
<90 mmHg for more than 1 hour) and renal dysfunction (2.4 percent versus 1.1 percent) in-
hospital and at six weeks (increasing creatinine concentration to over 3 mg/dL or a doubling or
more of the baseline serum creatinine concentration). See ADVERSE REACTIONS, ACUTE
MYOCARDIAL INFARCTION.
INDICATIONS AND USAGE
Hypertension
PRINIVIL is indicated for the treatment of hypertension. It may be used alone as initial therapy
or concomitantly with other classes of antihypertensive agents.
Heart Failure
PRINIVIL is indicated as adjunctive therapy in the management of heart failure in patients who
are not responding adequately to diuretics and digitalis.
Acute Myocardial Infarction
PRINIVIL is indicated for the treatment of hemodynamically stable patients within 24 hours of
acute myocardial infarction, to improve survival. Patients should receive, as appropriate, the
standard recommended treatments such as thrombolytics, aspirin and beta-blockers.
In using PRINIVIL, consideration should be given to the fact that another angiotensin
converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with
renal impairment or collagen vascular disease, and that available data are insufficient to show
that PRINIVIL does not have a similar risk. (See WARNINGS.)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
5
In considering use of PRINIVIL, it should be noted that in controlled clinical trials ACE
inhibitors have an effect on blood pressure that is less in Black patients than in non-Blacks. In
addition, it should be noted that Black patients receiving ACE inhibitors have been reported to
have a higher incidence of angioedema compared to non-Blacks (see WARNINGS,
Anaphylactoid and Possibly Related Reactions, Angioedema).
CONTRAINDICATIONS
PRINIVIL is contraindicated in patients who are hypersensitive to this product and in patients
with a history of angioedema related to previous treatment with an angiotensin converting
enzyme inhibitor and in patients with hereditary or idiopathic angioedema.
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 PRINIVIL) may be subject to a variety of adverse reactions, some of them serious.
Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has
been reported in patients treated with angiotensin converting enzyme inhibitors, including
PRINIVIL. This may occur at any time during treatment. ACE inhibitors have been associated with
a higher rate of angioedema in Black than in non-Black patients. In such cases PRINIVIL should
be promptly discontinued and appropriate therapy and monitoring should be provided until
complete and sustained resolution of signs and symptoms has occurred. In instances where
swelling has been confined to the face and lips the condition has generally resolved without
treatment, although antihistamines have been useful in relieving symptoms. Angioedema
associated with laryngeal edema may be fatal. Where there is involvement of the tongue,
glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g.,
subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary
to ensure a patent airway, should be promptly provided. (See ADVERSE REACTIONS.)
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased
risk of angioedema while receiving an ACE inhibitor (see also INDICATIONS AND USAGE and
CONTRAINDICATIONS).
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: Sudden and potentially life-threatening
anaphylactoid reactions have been reported in some patients dialyzed with high-flux membranes
(e.g., AN69®) and treated concomitantly with an ACE inhibitor. In such patients, dialysis must be
stopped immediately, and aggressive therapy for anaphylactoid reactions be initiated. Symptoms
have not been relieved by antihistamines in these situations. In these patients, consideration
should be given to using a different type of dialysis membrane or a different class of
antihypertensive agent. Anaphylactoid reactions have also been reported in patients undergoing
low-density lipoprotein apheresis with dextran sulfate absorption.
Hypotension
Excessive hypotension is rare in patients with uncomplicated hypertension treated with
PRINIVIL alone.
Patients with heart failure given PRINIVIL commonly have some reduction in blood pressure
with peak blood pressure reduction occurring 6 to 8 hours post dose, but discontinuation of
therapy because of continuing symptomatic hypotension usually is not necessary when dosing
instructions are followed; caution should be observed when initiating therapy. (See DOSAGE
AND ADMINISTRATION.)
Patients at risk of excessive hypotension, sometimes associated with oliguria and/or
progressive azotemia, and rarely with acute renal failure and/or death, include those with the
following conditions or characteristics: heart failure with systolic blood pressure below 100 mmHg,
hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
6
renal dialysis, or severe volume and/or salt depletion of any etiology. It may be advisable to
eliminate the diuretic (except in patients with heart failure), reduce the diuretic dose or increase
salt intake cautiously before initiating therapy with PRINIVIL in patients at risk for excessive
hypotension who are able to tolerate such adjustments. (See PRECAUTIONS, Drug Interactions,
and ADVERSE REACTIONS.)
Patients with acute myocardial infarction in the GISSI - 3 study had a higher (9.0 percent
versus 3.7 percent) incidence of persistent hypotension (systolic blood pressure <90 mmHg for
more than 1 hour) when treated with PRINIVIL. Treatment with PRINIVIL must not be initiated in
acute myocardial infarction patients at risk of further serious hemodynamic deterioration after
treatment with a vasodilator (e.g., systolic blood pressure of 100 mmHg or lower) or cardiogenic
shock.
In patients at risk of excessive hypotension, therapy should be started under very close
medical supervision and such patients should be followed closely for the first two weeks of
treatment and whenever the dose of PRINIVIL and/or diuretic is increased. Similar considerations
may apply to patients with ischemic heart or cerebrovascular disease, or in patients with acute
myocardial infarction, in whom an excessive fall in blood pressure could result in a myocardial
infarction or cerebrovascular accident.
If excessive hypotension occurs, the patient should be placed in the supine position and, if
necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is
not a contraindication to further doses of PRINIVIL which usually can be given without difficulty
once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or
discontinuation of PRINIVIL or concomitant diuretic may be necessary.
Leukopenia/Neutropenia/Agranulocytosis
Another angiotensin converting enzyme inhibitor, captopril, has been shown to cause
agranulocytosis and bone marrow depression, rarely in uncomplicated patients but more
frequently in patients with renal impairment especially if they also have a collagen vascular
disease. Available data from clinical trials of PRINIVIL are insufficient to show that PRINIVIL does
not cause agranulocytosis at similar rates. Marketing experience has revealed rare cases of
leukopenia/neutropenia and bone marrow depression in which a causal relationship to lisinopril
cannot be excluded. Periodic monitoring of white blood cell counts in patients with collagen
vascular disease and renal disease should be considered.
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.
Fetal/Neonatal Morbidity and Mortality
ACE inhibitors can cause fetal and neonatal morbidity and death when administered to
pregnant women. Several dozen cases have been reported in the world literature. When
pregnancy is detected, ACE inhibitors should be discontinued as soon as possible.
The use of ACE inhibitors during the second and third trimesters of pregnancy has been
associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia,
anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been
reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting
has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung
development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also
been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor
exposure.
These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor
exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are
exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless,
when patients become pregnant, physicians should make every effort to discontinue the use of
PRINIVIL as soon as possible.
Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE
inhibitors will be found. In these rare cases, the mothers should be apprised of the potential
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
7
hazards to their fetuses, and serial ultrasound examinations should be performed to assess the
intraamniotic environment.
If oligohydramnios is observed, PRINIVIL should be discontinued unless it is considered
lifesaving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical
profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and
physicians should be aware, however, that oligohydramnios may not appear until after the fetus
has sustained irreversible injury.
Infants with histories of in utero exposure to ACE inhibitors should be closely observed for
hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward
support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required
as means of reversing hypotension and/or substituting for disordered renal function. Lisinopril,
which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis
with some clinical benefit, and theoretically may be removed by exchange transfusion, although
there is no experience with the latter procedure.
No teratogenic effects of lisinopril were seen in studies of pregnant mice, rats and rabbits. On
a body surface area basis, the doses used were 55 times, 33 times, and 0.15 times, respectively,
the maximum recommended human daily dose (MRHDD).
PRECAUTIONS
General
Aortic Stenosis/Hypertrophic Cardiomyopathy: As with all vasodilators, lisinopril should be
given with caution to patients with obstruction in the outflow tract of the left ventricle.
Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone
system, changes in renal function may be anticipated in susceptible individuals. In patients with
severe congestive heart failure whose renal function may depend on the activity of the renin-
angiotensin-aldosterone system, treatment with angiotensin converting enzyme inhibitors,
including PRINIVIL, may be associated with oliguria and/or progressive azotemia and rarely with
acute renal failure and/or death.
In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood
urea nitrogen and serum creatinine may occur. Experience with another angiotensin converting
enzyme inhibitor suggests that these increases are usually reversible upon discontinuation of
PRINIVIL and/or diuretic therapy. In such patients renal function should be monitored during the
first few weeks of therapy.
Some patients with hypertension or heart failure with no apparent pre-existing renal vascular
disease have developed increases in blood urea nitrogen and serum creatinine, usually minor
and transient, especially when PRINIVIL has been given concomitantly with a diuretic. This is
more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or
discontinuation of the diuretic and/or PRINIVIL may be required.
Patients with acute myocardial infarction in the GISSI - 3 study, treated with PRINIVIL, had a
higher (2.4 percent versus 1.1 percent) incidence of renal dysfunction in-hospital and at six weeks
(increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum
creatinine concentration). In acute myocardial infarction, treatment with PRINIVIL should be
initiated with caution in patients with evidence of renal dysfunction, defined as serum creatinine
concentration exceeding 2 mg/dL. If renal dysfunction develops during treatment with PRINIVIL
(serum creatinine concentration exceeding 3 mg/dL or a doubling from the pre-treatment value)
then the physician should consider withdrawal of PRINIVIL.
Evaluation of patients with hypertension, heart failure, or myocardial infarction should
always include assessment of renal function. (See DOSAGE AND ADMINISTRATION.)
Hyperkalemia: In clinical trials hyperkalemia (serum potassium greater than 5.7 mEq/L)
occurred in approximately 2.2 percent of hypertensive patients and 4.8 percent of patients with
heart failure. In most cases these were isolated values which resolved despite continued therapy.
Hyperkalemia was a cause of discontinuation of therapy in approximately 0.1 percent of
hypertensive patients, 0.6 percent of patients with heart failure and 0.1 percent of patients with
myocardial infarction. Risk factors for the development of hyperkalemia include renal
insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
8
potassium supplements and/or potassium-containing salt substitutes, which should be used
cautiously, if at all, with PRINIVIL. (See Drug Interactions.)
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.
Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents
that produce hypotension, PRINIVIL may 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.
Information for Patients
Angioedema: Angioedema, including laryngeal edema, may occur at any time during
treatment with angiotensin converting enzyme inhibitors, including lisinopril. Patients should be so
advised and told to report immediately any signs or symptoms suggesting angioedema (swelling
of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more
drug until they have consulted with the prescribing physician.
Symptomatic Hypotension: Patients should be cautioned to report lightheadedness especially
during the first few days of therapy. If actual syncope occurs, the patients should be told to
discontinue the drug until they have consulted with the prescribing physician.
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 their physician.
Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without
consulting their physician.
Leukopenia/Neutropenia: Patients should be told to report promptly any indication of infection
(e.g., sore throat, fever) which may be a sign of leukopenia/neutropenia.
Pregnancy: Female patients of childbearing age should be told about the consequences of
second- and third-trimester exposure to ACE inhibitors, and they should also be told that these
consequences do not appear to have resulted from intrauterine ACE-inhibitor exposure that has
been limited to the first trimester. These patients should be asked to report pregnancies to their
physicians as soon as possible.
NOTE: As with many other drugs, certain advice to patients being treated with PRINIVIL is
warranted. This information is intended to aid in the safe and effective use of this medication. It is
not a disclosure of all possible adverse or intended effects.
Drug Interactions
Hypotension - Patients on Diuretic Therapy: Patients on diuretics, and especially those in
whom diuretic therapy was recently instituted, may occasionally experience an excessive
reduction of blood pressure after initiation of therapy with PRINIVIL. The possibility of hypotensive
effects with PRINIVIL can be minimized by either discontinuing the diuretic or increasing the salt
intake prior to initiation of treatment with PRINIVIL. If it is necessary to continue the diuretic,
initiate therapy with PRINIVIL at a dose of 5 mg daily, and provide close medical supervision after
the initial dose until blood pressure has stabilized. (See WARNINGS and DOSAGE AND
ADMINISTRATION.) When a diuretic is added to the therapy of a patient receiving PRINIVIL, an
additional antihypertensive effect is usually observed. Studies with ACE inhibitors in combination
with diuretics indicate that the dose of the ACE inhibitor can be reduced when it is given with a
diuretic. (See DOSAGE AND ADMINISTRATION.)
Non-steroidal Anti-inflammatory Agents: In some patients with compromised renal function
who are being treated with non-steroidal anti-inflammatory drugs, the co-administration of
lisinopril may result in a further deterioration of renal function. These effects are usually
reversible.
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors,
including lisinopril. This interaction should be given consideration in patients taking NSAIDs
concomitantly with ACE inhibitors.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
9
In a study in 36 patients with mild to moderate hypertension where the antihypertensive
effects of PRINIVIL alone were compared to PRINIVIL given concomitantly with indomethacin,
the use of indomethacin was associated with a reduced antihypertensive effect, although the
difference between the two regimens was not significant.
Other Agents: PRINIVIL has been used concomitantly with nitrates and/or digoxin without
evidence of clinically significant adverse interactions. This included post myocardial infarction
patients who were receiving intravenous or transdermal nitroglycerin. No clinically important
pharmacokinetic interactions occurred when PRINIVIL was used concomitantly with propranolol
or hydrochlorothiazide. The presence of food in the stomach does not alter the bioavailability of
PRINIVIL.
Agents Increasing Serum Potassium: PRINIVIL attenuates potassium loss caused by thiazide-
type diuretics. Use of PRINIVIL with potassium-sparing diuretics (e.g., spironolactone,
triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may
lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is
indicated because of demonstrated hypokalemia, they should be used with caution and with
frequent monitoring of serum potassium. Potassium sparing agents should generally not be used
in patients with heart failure who are receiving PRINIVIL.
Lithium: Lithium toxicity has been reported in patients receiving lithium concomitantly with
drugs which cause elimination of sodium, including ACE inhibitors. Lithium toxicity was usually
reversible upon discontinuation of lithium and the ACE inhibitor. It is recommended that serum
lithium levels be monitored frequently if PRINIVIL is administered concomitantly with lithium.
Carcinogenesis, Mutagenesis, Impairment of Fertility
There was no evidence of a tumorigenic effect when lisinopril was administered orally for 105
weeks to male and female rats at doses up to 90 mg/kg/day or for 92 weeks to male and female
mice at doses up to 135 mg/kg/day. These doses are 10 times and 7 times, respectively, the
maximum recommended human daily dose (MRHDD) when compared on a body surface area
basis.
Lisinopril was not mutagenic in the Ames microbial mutagen test with or without metabolic
activation. It was also negative in a forward mutation assay using Chinese hamster lung cells.
Lisinopril did not produce single strand DNA breaks in an in vitro alkaline elution rat hepatocyte
assay. In addition, lisinopril did not produce increases in chromosomal aberrations in an in vitro
test in Chinese hamster ovary cells or in an in vivo study in mouse bone marrow.
There were no adverse effects on reproductive performance in male and female rats treated
with up to 300 mg/kg/day of lisinopril (33 times the MRHDD when compared on a body surface
area basis).
Pregnancy
Pregnancy Categories C (first trimester) and D (second and third trimesters). See
WARNINGS, Fetal/Neonatal Morbidity and Mortality.
Nursing Mothers
Milk of lactating rats contains radioactivity following administration of 14C lisinopril. It is not
known whether this drug is secreted in human milk. Because many drugs are secreted in human
milk, and because of the potential for serious adverse reactions in nursing infants from ACE
inhibitors, a decision should be made whether to discontinue nursing or discontinue PRINIVIL,
taking into account the importance of the drug to the mother.
Pediatric Use
Antihypertensive effects of PRINIVIL have been established in hypertensive pediatric patients
aged 6 to 16 years.
There are no data on the effect of PRINIVIL on blood pressure in pediatric patients under the
age of 6 or in pediatric patients with glomerular filtration rate <30mL/min/1.73 m2 (see CLINICAL
PHARMACOLOGY, Pharmacokinetics and Metabolism and Pharmacodynamics and Clinical
Effects, 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
PRINIVIL® (Lisinopril)
7825248
10
ADVERSE REACTIONS
PRINIVIL has been found to be generally well tolerated in controlled clinical trials involving
1969 patients with hypertension or heart failure. For the most part, adverse experiences were
mild and transient.
HYPERTENSION
In clinical trials in patients with hypertension treated with PRINIVIL, discontinuation of therapy
due to clinical adverse experiences occurred in 5.7 percent of patients. The overall frequency of
adverse experiences could not be related to total daily dosage within the recommended
therapeutic dosage range.
For adverse experiences occurring in greater than one percent of patients with hypertension
treated with PRINIVIL or PRINIVIL plus hydrochlorothiazide in controlled clinical trials and more
frequently with PRINIVIL and/or PRINIVIL plus hydrochlorothiazide than placebo, comparative
incidence data are listed in the table below:
Percent of Patients
in Controlled Studies
PRINIVIL
(n = 1349)
Incidence
(discontinuation)
PRINIVIL/
Hydrochlorothiazide
(n = 629)
Incidence
(discontinuation)
Placebo
(n = 207)
Incidence
(discontinuation)
Body As A Whole
Fatigue
Asthenia
Orthostatic Effects
2.5 (0.3)
1.3 (0.5)
1.2 (0.0)
4.0 (0.5)
2.1 (0.2)
3.5 (0.2)
1.0 (0.0)
1.0 (0.0)
1.0 (0.0)
Cardiovascular
Hypotension
1.2 (0.5)
1.6 (0.5)
0.5 (0.5)
Digestive
Diarrhea
Nausea
Vomiting
Dyspepsia
2.7 (0.2)
2.0 (0.4)
1.1 (0.2)
0.9 (0.0)
2.7 (0.3)
2.5 (0.2)
1.4 (0.1)
1.9 (0.0)
2.4 (0.0)
2.4 (0.0)
0.5 (0.0)
0.0 (0.0)
Musculoskeletal
Muscle Cramps
0.5 (0.0)
2.9 (0.8)
0.5 (0.0)
Nervous/Psychiatric
Headache
Dizziness
Paresthesia
Decreased Libido
Vertigo
5.7 (0.2)
5.4 (0.4)
0.8 (0.1)
0.4 (0.1)
0.2 (0.1)
4.5 (0.5)
9.2 (1.0)
2.1 (0.2)
1.3 (0.1)
1.1 (0.2)
1.9 (0.0)
1.9 (0.0)
0.0 (0.0)
0.0 (0.0)
0.0 (0.0)
Respiratory
Cough
Upper Respiratory
Infection
Common Cold
Nasal Congestion
Influenza
3.5 (0.7)
2.1 (0.1)
1.1 (0.1)
0.4 (0.1)
0.3 (0.1)
4.6 (0.8)
2.7 (0.1)
1.3 (0.1)
1.3 (0.1)
1.1 (0.1)
1.0 (0.0)
0.0 (0.0)
0.0 (0.0)
0.0 (0.0)
0.0 (0.0)
Skin
Rash
1.3 (0.4)
1.6 (0.2)
0.5 (0.5)
Urogenital
Impotence
1.0 (0.4)
1.6 (0.5)
0.0 (0.0)
Chest pain and back pain were also seen but were more common on placebo than PRINIVIL.
HEART FAILURE
In patients with heart failure treated with PRINIVIL for up to four years, discontinuation of
therapy due to clinical adverse experiences occurred in 11.0 percent of patients. In controlled
studies in patients with heart failure, therapy was discontinued in 8.1 percent of patients treated
with PRINIVIL for up to 12 weeks, compared to 7.7 percent of patients treated with placebo for 12
weeks.
The following table lists those adverse experiences which occurred in greater than one
percent of patients with heart failure treated with PRINIVIL or placebo for up to 12 weeks in
controlled clinical trials and more frequently on PRINIVIL than placebo.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
11
Controlled Trials
PRINIVIL
(n=407)
Incidence
(discontinuation)
Placebo
(n=155)
Incidence
(discontinuation)
12 weeks
12 weeks
Body As A Whole
Chest Pain
Abdominal Pain
3.4 (0.2)
2.2 (0.7)
1.3 (0.0)
1.9 (0.0)
Cardiovascular
Hypotension
4.4 (1.7)
0.6 (0.6)
Digestive
Diarrhea
3.7 (0.5)
1.9 (0.0)
Nervous/Psychiatric
Dizziness
Headache
11.8 (1.2)
4.4 (0.2)
4.5 (1.3)
3.9 (0.0)
Respiratory
Upper Respiratory
Infection
1.5 (0.0)
1.3 (0.0)
Skin
Rash
1.7 (0.5)
0.6 (0.6)
Also observed at >1% with PRINIVIL but more frequent or as frequent on placebo than
PRINIVIL in controlled trials were asthenia, angina pectoris, nausea, dyspnea, cough and
pruritus.
Worsening of heart failure, anorexia, increased salivation, muscle cramps, back pain, myalgia,
depression, chest sound abnormalities and pulmonary edema were also seen in controlled
clinical trials, but were more common on placebo than PRINIVIL.
ACUTE MYOCARDIAL INFARCTION
In the GISSI - 3 trial, in patients treated with PRINIVIL for six weeks following acute
myocardial infarction, discontinuation of therapy occurred in 17.6 percent of patients.
Patients treated with PRINIVIL had a significantly higher incidence of hypotension and renal
dysfunction compared with patients not taking PRINIVIL.
In the GISSI - 3 trial, hypotension (9.7 percent), renal dysfunction (2.0 percent), cough (0.5
percent), post-infarction angina (0.3 percent), skin rash and generalized edema (0.01 percent),
and angioedema (0.01 percent) resulted in withdrawal of treatment. In elderly patients treated
with PRINIVIL, discontinuation due to renal dysfunction was 4.2 percent.
Other clinical adverse experiences occurring in 0.3 to 1.0 percent of patients with hypertension
or heart failure treated with PRINIVIL in controlled trials and rarer, serious, possibly drug-related
events reported in uncontrolled studies or marketing experience are listed below, and within each
category, are in order of decreasing severity:
Body as a Whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid and Possibly
Related Reactions), syncope, orthostatic effects, chest discomfort, pain, pelvic pain, flank pain,
edema, facial edema, virus infection, fever, chills, malaise.
Cardiovascular: Cardiac arrest; myocardial infarction or cerebrovascular accident, possibly
secondary to excessive hypotension in high risk patients (see WARNINGS, Hypotension);
pulmonary embolism and infarction, arrhythmias (including ventricular tachycardia, atrial
tachycardia, atrial fibrillation, bradycardia and premature ventricular contractions), palpitations,
transient ischemic attacks, paroxysmal nocturnal dyspnea, orthostatic hypotension, decreased
blood pressure, peripheral edema, vasculitis.
Digestive: Pancreatitis, hepatitis (hepatocellular or cholestatic jaundice) (see WARNINGS,
Hepatic Failure), vomiting, gastritis, dyspepsia, heartburn, gastrointestinal cramps, constipation,
flatulence, dry mouth.
Hematologic:
Rare
cases
of
bone
marrow
depression,
hemolytic
anemia,
leukopenia/neutropenia, and thrombocytopenia.
Endocrine: Diabetes mellitus.
Metabolic: Weight loss, dehydration, fluid overload, gout, weight gain.
Musculoskeletal: Arthritis, arthralgia, neck pain, hip pain, low back pain, joint pain, leg pain,
knee pain, shoulder pain, arm pain, lumbago.
Nervous System/Psychiatric: Stroke, ataxia, memory impairment, tremor, peripheral
neuropathy (e.g., dysesthesia), spasm, paresthesia, confusion, insomnia, somnolence,
hypersomnia, irritability, and nervousness.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
12
Respiratory
System:
Malignant
lung
neoplasms,
hemoptysis,
pulmonary
infiltrates,
eosinophilic pneumonitis, bronchospasm, asthma, pleural effusion, pneumonia, bronchitis,
wheezing, orthopnea, painful respiration, epistaxis, laryngitis, sinusitis, pharyngeal pain,
pharyngitis, rhinitis, rhinorrhea.
Skin: Urticaria, alopecia, herpes zoster, photosensitivity, skin lesions, skin infections,
pemphigus, erythema, flushing, diaphoresis. Other severe skin reactions (including toxic
epidermal necrolysis and Stevens-Johnson syndrome) have been reported rarely; causal
relationship has not been established.
Special Senses: Visual loss, diplopia, blurred vision, tinnitus, photophobia, taste disturbances.
Urogenital System: Acute renal failure, oliguria, anuria, uremia, progressive azotemia, renal
dysfunction (see PRECAUTIONS and DOSAGE AND ADMINISTRATION), pyelonephritis,
dysuria, urinary tract infection, breast pain.
Miscellaneous: A symptom complex has been reported which may include a positive ANA, an
elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia
and leukocytosis. Rash, photosensitivity or other dermatological manifestations may occur alone
or in combination with these symptoms.
Angioedema: Angioedema has been reported in patients receiving PRINIVIL (0.1%) with an
incidence higher in Black than in non-Black patients. Angioedema associated with laryngeal
edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx
occurs, treatment with PRINIVIL should be discontinued and appropriate therapy instituted
immediately. (See WARNINGS.)
Hypotension: In hypertensive patients, hypotension occurred in 1.2 percent and syncope
occurred in 0.1 percent of patients. Hypotension or syncope was a cause for discontinuation of
therapy in 0.5 percent of hypertensive patients. In patients with heart failure, hypotension
occurred in 5.3 percent and syncope occurred in 1.8 percent of patients. These adverse
experiences were causes for discontinuation of therapy in 1.8 percent of these patients. In
patients treated with PRINIVIL for six weeks after acute myocardial infarction, hypotension
(systolic blood pressure ≤100 mmHg) resulted in discontinuation of therapy in 9.7 percent of the
patients. (See WARNINGS.)
Fetal/Neonatal Morbidity and Mortality: See WARNINGS, Fetal/Neonatal Morbidity and
Mortality.
Cough: See PRECAUTIONS, Cough.
Pediatric Patients: No relevant differences between the adverse experience profile for
pediatric patients and that previously reported for adult patients were identified.
Clinical Laboratory Test Findings
Serum Electrolytes: Hyperkalemia (see PRECAUTIONS), hyponatremia.
Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen and serum creatinine,
reversible upon discontinuation of therapy, were observed in about 2.0 percent of patients with
essential hypertension treated with PRINIVIL alone. Increases were more common in patients
receiving concomitant diuretics and in patients with renal artery stenosis. (See PRECAUTIONS.)
Reversible minor increases in blood urea nitrogen and serum creatinine were observed in
approximately 11.6 percent of patients with heart failure on concomitant diuretic therapy.
Frequently, these abnormalities resolved when the dosage of the diuretic was decreased.
Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases
of approximately 0.4 g percent and 1.3 vol percent, respectively) occurred frequently in patients
treated with PRINIVIL but were rarely of clinical importance in patients without some other cause
of anemia. In clinical trials, less than 0.1 percent of patients discontinued therapy due to anemia.
Hemolytic anemia has been reported; a causal relationship to lisinopril cannot be excluded.
Liver Function Tests: Rarely, elevations of liver enzymes and/or serum bilirubin have occurred
(see WARNINGS, Hepatic Failure).
In hypertensive patients, 2.0 percent discontinued therapy due to laboratory adverse
experiences, principally elevations in blood urea nitrogen (0.6 percent), serum creatinine (0.5
percent) and serum potassium (0.4 percent). In the heart failure trials, 3.4 percent of patients
discontinued therapy due to laboratory adverse experiences, 1.8 percent due to elevations in
blood urea nitrogen and/or creatinine and 0.6 percent due to elevations in serum potassium. In
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
13
the myocardial infarction trial, 2.0 percent of patients receiving PRINIVIL discontinued therapy
due to renal dysfunction (increasing creatinine concentration to over 3 mg/dL or a doubling or
more of the baseline serum creatinine concentration); less than 1.0 percent of patients
discontinued therapy due to other laboratory adverse experiences: 0.1 percent with hyperkalemia
and less than 0.1 percent with hepatic enzyme alterations.
OVERDOSAGE
Following a single oral dose of 20 g/kg, no lethality occurred in rats and death occurred in one
of 20 mice receiving the same dose. The most likely manifestation of overdosage would be
hypotension, for which the usual treatment would be intravenous infusion of normal saline
solution.
Lisinopril can be removed by hemodialysis. (See WARNINGS, Anaphylactoid reactions during
membrane exposure.)
DOSAGE AND ADMINISTRATION
Hypertension
Initial Therapy: In patients with uncomplicated essential hypertension not on diuretic therapy,
the recommended initial dose is 10 mg once a day. Dosage should be adjusted according to
blood pressure response. The usual dosage range is 20 to 40 mg per day administered in a
single daily dose. The antihypertensive effect may diminish toward the end of the dosing interval
regardless of the administered dose, but most commonly with a dose of 10 mg daily. This can be
evaluated by measuring blood pressure just prior to dosing to determine whether satisfactory
control is being maintained for 24 hours. If it is not, an increase in dose should be considered.
Doses up to 80 mg have been used but do not appear to give a greater effect. If blood pressure is
not controlled with PRINIVIL alone, a low dose of a diuretic may be added. Hydrochlorothiazide
12.5 mg has been shown to provide an additive effect. After the addition of a diuretic, it may be
possible to reduce the dose of PRINIVIL.
Diuretic Treated Patients: In hypertensive patients who are currently being treated with a
diuretic, symptomatic hypotension may occur occasionally following the initial dose of PRINIVIL.
The diuretic should be discontinued, if possible, for two to three days before beginning therapy
with PRINIVIL to reduce the likelihood of hypotension. (See WARNINGS.) The dosage of
PRINIVIL should be adjusted according to blood pressure response. If the patient's blood
pressure is not controlled with PRINIVIL alone, diuretic therapy may be resumed as described
above.
If the diuretic cannot be discontinued, an initial dose of 5 mg should be used under medical
supervision for at least two hours and until blood pressure has stabilized for at least an additional
hour. (See WARNINGS and PRECAUTIONS, Drug Interactions.)
Concomitant administration of PRINIVIL with potassium supplements, potassium salt
substitutes, or potassium-sparing diuretics may lead to increases of serum potassium (see
PRECAUTIONS).
Dosage Adjustment in Renal Impairment: The usual dose of PRINIVIL (10 mg) is
recommended for patients with a creatinine clearance >30 mL/min (serum creatinine of up to
approximately 3 mg/dL). For patients with creatinine clearance ≥10 mL/min ≤30 mL/min (serum
creatinine ≥3 mg/dL), the first dose is 5 mg once daily. For patients with creatinine clearance
<10 mL/min (usually on hemodialysis) the recommended initial dose is 2.5 mg. The dosage may
be titrated upward until blood pressure is controlled or to a maximum of 40 mg daily.
Renal Status
Creatinine-
Clearance
mL/min
Initial Dose
mg/day
Normal Renal Function to Mild
Impairment
>30 mL/min
10 mg
Moderate to Severe
Impairment
≥10 ≤30
mL/min
5 mg
Dialysis Patients**
<10 mL/min
2.5 mg***
** See WARNINGS, Anaphylactoid reactions during membrane exposure
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
14
*** Dosage or dosing interval should be adjusted depending on the blood pressure response.
Heart Failure
PRINIVIL is indicated as adjunctive therapy with diuretics and (usually) digitalis. The
recommended starting dose is 5 mg once a day.
When initiating treatment with lisinopril in patients with heart failure, the initial dose should be
administered under medical observation, especially in those patients with low blood pressure
(systolic blood pressure below 100 mmHg). The mean peak blood pressure lowering occurs six to
eight hours after dosing. Observation should continue until blood pressure is stable. The
concomitant diuretic dose should be reduced, if possible, to help minimize hypovolemia which
may contribute to hypotension. (See WARNINGS and PRECAUTIONS, Drug Interactions.) The
appearance of hypotension after the initial dose of PRINIVIL does not preclude subsequent
careful dose titration with the drug, following effective management of the hypotension.
The usual effective dosage range is 5 to 20 mg per day administered as a single daily dose.
Dosage Adjustment in Patients with Heart Failure and Renal Impairment or Hyponatremia: In
patients with heart failure who have hyponatremia (serum sodium <130 mEq/L) or moderate to
severe renal impairment (creatinine clearance ≤30 mL/min or serum creatinine >3 mg/dL),
therapy with PRINIVIL should be initiated at a dose of 2.5 mg once a day under close medical
supervision. (See WARNINGS and PRECAUTIONS, Drug Interactions.)
Acute Myocardial Infarction
In hemodynamically stable patients within 24 hours of the onset of symptoms of acute
myocardial infarction, the first dose of PRINIVIL is 5 mg given orally, followed by 5 mg after 24
hours, 10 mg after 48 hours and then 10 mg of PRINIVIL once daily. Dosing should continue for
six weeks. Patients should receive, as appropriate, the standard recommended treatments such
as thrombolytics, aspirin and beta-blockers. Patients with a low systolic blood pressure
(≤120 mmHg) when treatment is started or during the first 3 days after the infarct should be given
a lower 2.5 mg oral dose of PRINIVIL (see WARNINGS). If hypotension occurs (systolic blood
pressure ≤100 mmHg) a daily maintenance dose of 5 mg may be given with temporary reductions
to 2.5 mg if needed. If prolonged hypotension occurs (systolic blood pressure <90 mmHg for
more than 1 hour) PRINIVIL should be withdrawn. For patients who develop symptoms of heart
failure, see DOSAGE AND ADMINISTRATION, Heart Failure.
Dosage Adjustment in Patients with Myocardial Infarction with Renal Impairment: In acute
myocardial infarction, treatment with PRINIVIL should be initiated with caution in patients with
evidence of renal dysfunction, defined as serum creatinine concentration exceeding 2 mg/dL. No
evaluation of dosage adjustment in myocardial infarction patients with severe renal impairment
has been performed.
Use in Elderly
In general, blood pressure response and adverse experiences were similar in younger and
older patients given similar doses of PRINIVIL. Pharmacokinetic studies, however, indicate that
maximum blood levels and area under the plasma concentration time curve (AUC) are doubled in
older patients, so that dosage adjustments should be made with particular caution.
Pediatric Hypertensive Patients ≥ 6 years of age
The usual recommended starting dose is 0.07 mg/kg once daily (up to 5 mg total). Dosage
should be adjusted according to blood pressure response. Doses above 0.61 mg/kg (or in excess
of 40 mg) have not been studied in pediatric patients. See CLINICAL PHARMACOLOGY
Pharmacokinetics and Metabolism and Pharmacodynamics and Clinical Effects).
PRINIVIL is not recommended in pediatric patients <6 years or in pediatric patients with
glomerular
filtration
rate
<30 mL/min/1.73 m2
(see
CLINICAL
PHARMACOLOGY,
Pharmacokinetics
and
Metabolism,
Pharmacodynamics
and
Clinical
Effects
and
PRECAUTIONS).
Preparation of Suspension (for 200 mL of a 1.0 mg/mL suspension)
Add 10 mL of Purified Water USP to a polyethylene terephthalate (PET) bottle containing ten
20-mg tablets of PRINIVIL and shake for at least one minute. Add 30 mL of Bicitra®** diluent and
** Registered trademark of Alza Corporation
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
15
160 mL of Ora-Sweet SF™*** to the concentrate in the PET bottle and gently shake for several
seconds to disperse the ingredients. The suspension should be stored at or below 25°C (77°F)
and can be stored for up to four weeks. Shake the suspension before each use.
HOW SUPPLIED
No. 3658 — Tablets PRINIVIL, 2.5 mg, are white, round, flat-faced, beveled edge,
compressed tablets, coded MSD on one side and 15 on the other. They are supplied as follows:
NDC 0006-0015-28 unit dose packages of 100
NDC 0006-0015-31 unit of use bottles of 30
NDC 0006-0015-58 unit of use bottles of 100.
No. 3577 — Tablets PRINIVIL, 5 mg, are white, shield shaped, scored, compressed tablets,
with code MSD 19 on one side and PRINIVIL on the other. They are supplied as follows:
NDC 0006-0019-28 unit dose packages of 100
NDC 0006-0019-58 unit of use bottles of 100
NDC 0006-0019-94 unit of use bottles of 90
NDC 0006-0019-54 unit of use bottles of 90
NDC 0006-0019-82 bottles of 1,000
NDC 0006-0019-87 bottles of 10,000
NDC 0006-0019-72 carton of 25 UNIBLISTERTM cards of 31 tablets each.
No. 3578 — Tablets PRINIVIL, 10 mg, are light yellow, shield shaped, compressed tablets,
with code MSD 106 on one side and PRINIVIL on the other. They are supplied as follows:
NDC 0006-0106-28 unit dose packages of 100
NDC 0006-0106-31 unit of use bottles of 30
NDC 0006-0106-58 unit of use bottles of 100
NDC 0006-0106-94 unit of use bottles of 90
NDC 0006-0106-54 unit of use bottles of 90
NDC 0006-0106-82 bottles of 1,000
NDC 0006-0106-87 bottles of 10,000
NDC 0006-0106-72 carton of 25 UNIBLISTERTM cards of 31 tablets each.
No. 3579 — Tablets PRINIVIL, 20 mg, are peach, shield shaped, compressed tablets, with
code MSD 207 on one side and PRINIVIL on the other. They are supplied as follows:
NDC 0006-0207-28 unit dose packages of 100
NDC 0006-0207-31 unit of use bottles of 30
NDC 0006-0207-58 unit of use bottles of 100
NDC 0006-0207-94 unit of use bottles of 90
NDC 0006-0207-54 unit of use bottles of 90
NDC 0006-0207-82 bottles of 1,000
NDC 0006-0207-87 bottles of 10,000
NDC 0006-0207-72 carton of 25 UNIBLISTERTM cards of 31 tablets each.
No. 3580 — Tablets PRINIVIL, 40 mg, are rose red, shield shaped, compressed tablets, with
code MSD 237 on one side and PRINIVIL on the other. They are supplied as follows:
NDC 0006-0237-58 unit of use bottles of 100.
Storage
Store at controlled room temperature, 15-30°C (59-86°F), and protect from moisture.
Dispense in a tight container, if product package is subdivided.
Issued April 2003
*** Trademark of Paddock Laboratories, Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
7825248
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:27.980310
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19558se5-043_prinivil_lbl.pdf', 'application_number': 19558, 'submission_type': 'SUPPL ', 'submission_number': 43}
|
11,533
|
company logo
USPI-T-05211205R007
TABLETS
PRINIVIL®
(LISINOPRIL)
WARNING: Fetal Toxicity
When pregnancy is detected, discontinue PRINIVIL 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
PRINIVIL® (Lisinopril), a synthetic peptide derivative, is an oral long-acting angiotensin converting
enzyme inhibitor. Lisinopril is chemically described as (S)-1-[N2-(1-carboxy-3-phenylpropyl)-L-lysyl]-L
proline dihydrate. Its empirical formula is C21H31N3O5•2H2O and its structural formula is: structural formula
Lisinopril is a white to off-white, crystalline powder, with a molecular weight of 441.52. It is soluble in
water and sparingly soluble in methanol and practically insoluble in ethanol.
PRINIVIL is supplied as 5 mg, 10 mg, and 20 mg tablets for oral administration. In addition to the
active ingredient lisinopril, each tablet contains the following inactive ingredients: calcium phosphate,
mannitol, magnesium stearate, and starch. The 10 mg and 20 mg tablets also contain iron oxide.
CLINICAL PHARMACOLOGY
Mechanism of Action
Lisinopril inhibits angiotensin converting enzyme (ACE) in human subjects and animals. ACE is a
peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance,
angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. The beneficial
effects of lisinopril in hypertension and heart failure appear to result primarily from suppression of the
renin-angiotensin-aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II which
leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease
may result in a small increase of serum potassium. In hypertensive patients with normal renal function
treated with PRINIVIL alone for up to 24 weeks, the mean increase in serum potassium was
approximately 0.1 mEq/L; however, approximately 15 percent of patients had increases greater than
0.5 mEq/L and approximately six percent had a decrease greater than 0.5 mEq/L. In the same study,
patients treated with PRINIVIL and hydrochlorothiazide for up to 24 weeks had a mean decrease in
serum potassium of 0.1 mEq/L; approximately 4 percent of patients had increases greater than 0.5 mEq/L
and approximately 12 percent had a decrease greater than 0.5 mEq/L. (See PRECAUTIONS.) Removal
of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.
ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of
bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of PRINIVIL remains to
be elucidated.
While the mechanism through which PRINIVIL lowers blood pressure is believed to be primarily
suppression of the renin-angiotensin-aldosterone system, PRINIVIL is antihypertensive even in patients
with low-renin hypertension. Although PRINIVIL was antihypertensive in all races studied, Black
hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to
monotherapy than non-Black patients.
1
Reference ID: 3141252
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211205R007
Concomitant administration of PRINIVIL and hydrochlorothiazide further reduced blood pressure in
Black and non-Black patients and any racial difference in blood pressure response was no longer
evident.
Pharmacokinetics and Metabolism
Adult Patients: Following oral administration of PRINIVIL, peak serum concentrations of lisinopril occur
within about 7 hours, although there was a trend to a small delay in time taken to reach peak serum
concentrations in acute myocardial infarction patients. Declining serum concentrations exhibit a
prolonged terminal phase which does not contribute to drug accumulation. This terminal phase probably
represents saturable binding to ACE and is not proportional to dose. Lisinopril does not appear to be
bound to other serum proteins.
Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine. Based on
urinary recovery, the mean extent of absorption of lisinopril is approximately 25 percent, with large inter-
subject variability (6-60 percent) at all doses tested (5-80 mg). Lisinopril absorption is not influenced by
the presence of food in the gastrointestinal tract. The absolute bioavailability of lisinopril is reduced to
about 16 percent in patients with stable NYHA Class II-IV congestive heart failure, and the volume of
distribution appears to be slightly smaller than that in normal subjects.
The oral bioavailability of lisinopril in patients with acute myocardial infarction is similar to that in
healthy volunteers.
Upon multiple dosing, lisinopril exhibits an effective half-life of accumulation of 12 hours.
Impaired renal function decreases elimination of lisinopril, which is excreted principally through the
kidneys, but this decrease becomes clinically important only when the glomerular filtration rate is below
30 mL/min. Above this glomerular filtration rate, the elimination half-life is little changed. With greater
impairment, however, peak and trough lisinopril levels increase, time to peak concentration increases and
time to attain steady state is prolonged. Older patients, on average, have (approximately doubled) higher
blood levels and area under the plasma concentration time curve (AUC) than younger patients. (See
DOSAGE AND ADMINISTRATION.) Lisinopril can be removed by hemodialysis.
Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly. Multiple doses of lisinopril
in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following
administration of 14C lisinopril. By whole body autoradiography, radioactivity was found in the placenta
following administration of labeled drug to pregnant rats, but none was found in the fetuses.
Pediatric Patients: The pharmacokinetics of lisinopril were studied in 29 pediatric hypertensive
patients between 6 years and 16 years with glomerular filtration rate >30 mL/min/1.73 m2. After doses of
0.1 to 0.2 mg/kg, steady state peak plasma concentrations of lisinopril occurred within 6 hours and the
extent of absorption based on urinary recovery was about 28%. These values are similar to those
obtained previously in adults. The typical value of lisinopril oral clearance (systemic clearance/absolute
bioavailability) in a child weighing 30 kg is 10 L/h, which increases in proportion to renal function.
Pharmacodynamics and Clinical Effects
Hypertension:
Adult Patients: Administration of PRINIVIL to patients with hypertension results in a reduction of
supine and standing blood pressure to about the same extent with no compensatory tachycardia.
Symptomatic postural hypotension is usually not observed although it can occur and should be
anticipated in volume and/or salt-depleted patients. (See WARNINGS.) When given together with
thiazide-type diuretics, the blood pressure lowering effects of the two drugs are approximately additive.
In most patients studied, onset of antihypertensive activity was seen at one hour after oral
administration of an individual dose of PRINIVIL, with peak reduction of blood pressure achieved by six
hours. Although an antihypertensive effect was observed 24 hours after dosing with recommended single
daily doses, the effect was more consistent and the mean effect was considerably larger in some studies
with doses of 20 mg or more than with lower doses. However, at all doses studied, the mean
antihypertensive effect was substantially smaller 24 hours after dosing than it was six hours after dosing.
In some patients achievement of optimal blood pressure reduction may require two to four weeks of
therapy.
The antihypertensive effects of PRINIVIL are maintained during long-term therapy. Abrupt withdrawal
of PRINIVIL has not been associated with a rapid increase in blood pressure or a significant increase in
blood pressure compared to pretreatment levels.
2
Reference ID: 3141252
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211205R007
Two dose-response studies utilizing a once daily regimen were conducted in 438 mild to moderate
hypertensive patients not on a diuretic. Blood pressure was measured 24 hours after dosing. An
antihypertensive effect of PRINIVIL was seen with 5 mg in some patients. However, in both studies blood
pressure reduction occurred sooner and was greater in patients treated with 10, 20, or 80 mg of
PRINIVIL. In controlled clinical studies, PRINIVIL 20-80 mg has been compared in patients with mild to
moderate hypertension to hydrochlorothiazide 12.5-50 mg and with atenolol 50-500 mg; and in patients
with moderate to severe hypertension to metoprolol 100-200 mg. It was superior to hydrochlorothiazide in
effects on systolic and diastolic blood pressure in a population that was ¾ Caucasian. PRINIVIL was
approximately equivalent to atenolol and metoprolol in effects on diastolic blood pressure and had
somewhat greater effects on systolic blood pressure.
PRINIVIL had similar effectiveness and adverse effects in younger and older (>65 years) patients. It
was less effective in Blacks than in Caucasians.
In hemodynamic studies in patients with essential hypertension, blood pressure reduction was
accompanied by a reduction in peripheral arterial resistance with little or no change in cardiac output and
in heart rate. In a study in nine hypertensive patients, following administration of PRINIVIL, there was an
increase in mean renal blood flow that was not significant. Data from several small studies are
inconsistent with respect to the effect of PRINIVIL on glomerular filtration rate in hypertensive patients
with normal renal function, but suggest that changes, if any, are not large.
In patients with renovascular hypertension PRINIVIL has been shown to be well tolerated and
effective in controlling blood pressure (see PRECAUTIONS).
Pediatric Patients: In a clinical study involving 115 hypertensive pediatric patients 6 to 16 years of age,
patients who weighed <50 kg received either 0.625, 2.5, or 20 mg of lisinopril daily and patients who
weighed 50 kg received either 1.25, 5, or 40 mg of lisinopril daily. At the end of 2 weeks, lisinopril
administered once daily lowered trough blood pressure in a dose-dependent manner with consistent
antihypertensive efficacy demonstrated at doses >1.25 mg (0.02 mg/kg). This effect was confirmed in a
withdrawal phase, where the diastolic pressure rose by about 9 mmHg more in patients randomized to
placebo than it did in patients who were randomized to remain on the middle and high doses of lisinopril.
The dose-dependent antihypertensive effect of lisinopril was consistent across several demographic
subgroups: age, Tanner stage, gender, race. In this study, lisinopril was generally well-tolerated.
In the above pediatric studies, lisinopril was given either as tablets or in a suspension for those
children and infants who were unable to swallow tablets or who required a lower dose than is available in
tablet form (see DOSAGE AND ADMINISTRATION, Preparation of Suspension).
Heart Failure:
During baseline-controlled clinical trials, in patients receiving digitalis and diuretics, single doses of
PRINIVIL resulted in decreases in pulmonary capillary wedge pressure, systemic vascular resistance and
blood pressure accompanied by an increase in cardiac output and no change in heart rate.
In two placebo-controlled, 12-week clinical studies using doses of PRINIVIL up to 20 mg, PRINIVIL as
adjunctive therapy to digitalis and diuretics improved the following signs and symptoms due to congestive
heart failure: edema, rales, paroxysmal nocturnal dyspnea and jugular venous distention. In one of the
studies beneficial response was also noted for: orthopnea, presence of third heart sound and the number
of patients classified as NYHA Class III and IV. Exercise tolerance was also improved in this study. The
effect of lisinopril on mortality in patients with heart failure has not been evaluated.
The once daily dosing for the treatment of congestive heart failure was the only dosage regimen used
during clinical trial development and was determined by the measurement of hemodynamic responses.
Acute Myocardial Infarction:
The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI - 3) study was a
multicenter, controlled, randomized, unblinded clinical trial conducted in 19,394 patients with acute
myocardial infarction admitted to a coronary care unit. It was designed to examine the effects of short-
term (6 week) treatment with lisinopril, nitrates, their combination, or no therapy on short-term (6 week)
mortality and on long-term death and markedly impaired cardiac function. Patients presenting within 24
hours of the onset of symptoms who were hemodynamically stable were randomized, in a 2 x 2 factorial
design, to six weeks of either
1) PRINIVIL alone (n = 4841),
2) nitrates alone (n = 4869),
3
Reference ID: 3141252
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211205R007
3) PRINIVIL plus nitrates (n = 4841), or
4) open control (n = 4843).
All patients received routine therapies, including thrombolytics (72%), aspirin (84%), and a beta-
blocker (31%), as appropriate, normally utilized in acute myocardial infarction (MI) patients.
The protocol excluded patients with hypotension (systolic blood pressure 100 mmHg), severe heart
failure, cardiogenic shock and renal dysfunction (serum creatinine 2 mg/dL and/or proteinuria
>500 mg/24 h). Doses of PRINIVIL were adjusted as necessary according to protocol. (See DOSAGE
AND ADMINISTRATION.)
Study treatment was withdrawn at six weeks except where clinical conditions indicated continuation of
treatment.
The primary outcomes of the trial were the overall mortality at six weeks and a combined endpoint at
six months after the myocardial infarction, consisting of the number of patients who died, had late (day 4)
clinical congestive heart failure, or had extensive left ventricular damage defined as ejection fraction
35%, or an akinetic-dyskinetic [A-D] score 45%. Patients receiving PRINIVIL (n = 9646) alone or with
nitrates, had an 11 percent lower risk of death (2p [two-tailed] = 0.04) compared to patients receiving no
PRINIVIL (n = 9672) (6.4 percent versus 7.2 percent, respectively) at six weeks. Although patients
randomized to receive PRINIVIL for up to six weeks also fared numerically better on the combined end
point at 6 months, the open nature of the assessment of heart failure, substantial loss to follow-up
echocardiography, and substantial excess use of lisinopril between 6 weeks and 6 months in the group
randomized to 6 weeks of lisinopril, preclude any conclusion about this endpoint.
Patients with acute myocardial infarction, treated with PRINIVIL had a higher (9.0 percent versus 3.7
percent, respectively) incidence of persistent hypotension (systolic blood pressure 90 mmHg for more
than 1 hour) and renal dysfunction (2.4 percent versus 1.1 percent) in-hospital and at six weeks
(increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum
creatinine concentration). (See ADVERSE REACTIONS, ACUTE MYOCARDIAL INFARCTION.)
INDICATIONS AND USAGE
Hypertension
PRINIVIL is indicated for the treatment of hypertension. It may be used alone as initial therapy or
concomitantly with other classes of antihypertensive agents.
Heart Failure
PRINIVIL is indicated as adjunctive therapy in the management of heart failure in patients who are not
responding adequately to diuretics and digitalis.
Acute Myocardial Infarction
PRINIVIL is indicated for the treatment of hemodynamically stable patients within 24 hours of acute
myocardial infarction, to improve survival. Patients should receive, as appropriate, the standard
recommended treatments such as thrombolytics, aspirin and beta-blockers.
In using PRINIVIL, consideration should be given to the fact that another angiotensin converting
enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or
collagen vascular disease, and that available data are insufficient to show that PRINIVIL does not have a
similar risk. (See WARNINGS.)
In considering use of PRINIVIL, it should be noted that in controlled clinical trials ACE inhibitors have
an effect on blood pressure that is less in Black patients than in non-Blacks. In addition, it should be
noted that Black patients receiving ACE inhibitors have been reported to have a higher incidence of
angioedema compared to non-Blacks (see WARNINGS, Anaphylactoid and Possibly Related Reactions,
Head and Neck Angioedema).
CONTRAINDICATIONS
PRINIVIL is contraindicated in patients who are hypersensitive to this product and in patients with a
history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor and
in patients with hereditary or idiopathic angioedema.
4
Reference ID: 3141252
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211205R007
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
PRINIVIL) may be subject to a variety of adverse reactions, some of them serious.
Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx
has been reported in patients treated with angiotensin converting enzyme inhibitors, including PRINIVIL.
This may occur at any time during treatment. ACE inhibitors have been associated with a higher rate of
angioedema in Black than in non-Black patients. In such cases PRINIVIL should be promptly
discontinued and appropriate therapy and monitoring should be provided until complete and sustained
resolution of signs and symptoms has occurred. Even in those instances where swelling of only the
tongue is involved, without respiratory distress, patients may require prolonged observation since
treatment with antihistamines and corticosteroids may not be sufficient. Very rarely, fatalities have been
reported due to angioedema associated with laryngeal edema or tongue edema. Patients with
involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those
with a history of airway surgery. Where there is involvement of the tongue, glottis or larynx, likely to
cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000
(0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly
provided. (See ADVERSE REACTIONS.)
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of
angioedema while receiving an ACE inhibitor (see also INDICATIONS AND USAGE and
CONTRAINDICATIONS).
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: Sudden and potentially life-threatening
anaphylactoid reactions have been reported in some patients dialyzed with high-flux membranes (e.g.,
AN69®) and treated concomitantly with an ACE inhibitor. In such patients, dialysis must be stopped
immediately, and aggressive therapy for anaphylactoid reactions be initiated. Symptoms have not been
relieved by antihistamines in these situations. In these patients, consideration should be given to using a
different type of dialysis membrane or a different class of antihypertensive agent. Anaphylactoid reactions
have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate
absorption.
Hypotension
Excessive hypotension is rare in patients with uncomplicated hypertension treated with PRINIVIL
alone.
Patients with heart failure given PRINIVIL commonly have some reduction in blood pressure with peak
blood pressure reduction occurring 6 to 8 hours post dose, but discontinuation of therapy because of
continuing symptomatic hypotension usually is not necessary when dosing instructions are followed;
caution should be observed when initiating therapy. (See DOSAGE AND ADMINISTRATION.)
Patients at risk of excessive hypotension, sometimes associated with oliguria and/or progressive
azotemia, and rarely with acute renal failure and/or death, include those with the following conditions or
characteristics: heart failure with systolic blood pressure below 100 mmHg, hyponatremia, high-dose
diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume
and/or salt depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with
heart failure), reduce the diuretic dose or increase salt intake cautiously before initiating therapy with
5
Reference ID: 3141252
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211205R007
PRINIVIL in patients at risk for excessive hypotension who are able to tolerate such adjustments. (See
PRECAUTIONS, Drug Interactions, and ADVERSE REACTIONS.)
Patients with acute myocardial infarction in the GISSI - 3 study had a higher (9.0 percent versus 3.7
percent) incidence of persistent hypotension (systolic blood pressure 90 mmHg for more than 1 hour)
when treated with PRINIVIL. Treatment with PRINIVIL must not be initiated in acute myocardial infarction
patients at risk of further serious hemodynamic deterioration after treatment with a vasodilator (e.g.,
systolic blood pressure of 100 mmHg or lower) or cardiogenic shock.
In patients at risk of excessive hypotension, therapy should be started under very close medical
supervision and such patients should be followed closely for the first two weeks of treatment and
whenever the dose of PRINIVIL and/or diuretic is increased. Similar considerations may apply to patients
with ischemic heart or cerebrovascular disease, or in patients with acute myocardial infarction, in whom
an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary,
receive an intravenous infusion of normal saline. A transient hypotensive response is not a
contraindication to further doses of PRINIVIL which usually can be given without difficulty once the blood
pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of
PRINIVIL or concomitant diuretic may be necessary.
Leukopenia/Neutropenia/Agranulocytosis
Another angiotensin converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis
and bone marrow depression, rarely in uncomplicated patients but more frequently in patients with renal
impairment especially if they also have a collagen vascular disease. Available data from clinical trials of
PRINIVIL are insufficient to show that PRINIVIL does not cause agranulocytosis at similar rates.
Marketing experience has revealed rare cases of leukopenia/neutropenia and bone marrow depression in
which a causal relationship to lisinopril cannot be excluded. Periodic monitoring of white blood cell counts
in patients with collagen vascular disease and renal disease should be considered.
Hepatic Failure
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or
hepatitis 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.
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, discountinue PRINIVIL as soon as possible. These adverse outcomes are usually
associated with the use of these drugs in the second and third trimester of pregnancy. Most
epidemiologic studies examining fetal abnormalities after exposure 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 mother and fetus.
In the unusual case that there is no appropriate alternative therapy to 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 PRINIVIL,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 PRINIVIL for hypotension, oliguria, and hyperkalemia (see
Precautions, Pediatric Use).
No teratogenic effects of lisinopril were seen in studies of pregnant mice, rats, and rabbits. On a body
surface area basis, the doses used were 55 times, 33 times, and 0.15 times, respectively, the maximum
recommended human daily dose (MRHDD).
6
Reference ID: 3141252
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211205R007
PRECAUTIONS
General
Aortic Stenosis/Hypertrophic Cardiomyopathy: As with all vasodilators, lisinopril should be given with
caution to patients with obstruction in the outflow tract of the left ventricle.
Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system,
changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive
heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone
system, treatment with angiotensin converting enzyme inhibitors, including PRINIVIL, may be associated
with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.
In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea
nitrogen and serum creatinine may occur. Experience with another angiotensin converting enzyme
inhibitor suggests that these increases are usually reversible upon discontinuation of PRINIVIL and/or
diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy.
Some patients with hypertension or heart failure with no apparent pre-existing renal vascular disease
have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient,
especially when PRINIVIL has been given concomitantly with a diuretic. This is more likely to occur in
patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or
PRINIVIL may be required.
Patients with acute myocardial infarction in the GISSI - 3 study, treated with PRINIVIL, had a higher
(2.4 percent versus 1.1 percent) incidence of renal dysfunction in-hospital and at six weeks (increasing
creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum creatinine
concentration). In acute myocardial infarction, treatment with PRINIVIL should be initiated with caution in
patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding
2 mg/dL. If renal dysfunction develops during treatment with PRINIVIL (serum creatinine concentration
exceeding 3 mg/dL or a doubling from the pre-treatment value) then the physician should consider
withdrawal of PRINIVIL.
Evaluation of patients with hypertension, heart failure, or myocardial infarction should always
include assessment of renal function. (See DOSAGE AND ADMINISTRATION.)
Hyperkalemia: In clinical trials hyperkalemia (serum potassium greater than 5.7 mEq/L) occurred in
approximately 2.2 percent of hypertensive patients and 4.8 percent of patients with heart failure. In most
cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause
of discontinuation of therapy in approximately 0.1 percent of hypertensive patients, 0.6 percent of patients
with heart failure and 0.1 percent of patients with myocardial infarction. Risk factors for the development
of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-
sparing diuretics, potassium supplements and/or potassium-containing salt substitutes. Hyperkalemia can
cause serious, sometimes fatal, arrhythmias. PRINIVIL should be used cautiously, if at all, with these
agents and with frequent monitoring of serum potassium. (See Drug Interactions.)
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.
Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that
produce hypotension, PRINIVIL may 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.
Information for Patients
Angioedema: Angioedema, including laryngeal edema, may occur at any time during treatment with
angiotensin converting enzyme inhibitors, including lisinopril. Patients should be so advised and told to
report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes,
lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have consulted with
the prescribing physician.
Symptomatic Hypotension: Patients should be cautioned to report lightheadedness especially during
the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug
until they have consulted with the prescribing physician.
7
Reference ID: 3141252
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211205R007
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
their physician.
Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without
consulting their physician.
Hypoglycemia: Diabetic patients treated with oral antidiabetic agents or insulin starting an ACE
inhibitor should be told to closely monitor for hypoglycemia, especially during the first month of combined
use. (See Drug Interactions.)
Leukopenia/Neutropenia: Patients should be told to report promptly any indication of infection (e.g.,
sore throat, fever) which may be a sign of leukopenia/neutropenia.
Pregnancy: Female patients of childbearing age should be told about the consequences of exposure
to PRINIVIL 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
Hypotension - Patients on Diuretic Therapy: Patients on diuretics, and especially those in whom
diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood
pressure after initiation of therapy with PRINIVIL. The possibility of hypotensive effects with PRINIVIL can
be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment
with PRINIVIL. If it is necessary to continue the diuretic, initiate therapy with PRINIVIL at a dose of 5 mg
daily, and provide close medical supervision after the initial dose until blood pressure has stabilized. (See
WARNINGS and DOSAGE AND ADMINISTRATION.) When a diuretic is added to the therapy of a
patient receiving PRINIVIL, an additional antihypertensive effect is usually observed. Studies with ACE
inhibitors in combination with diuretics indicate that the dose of the ACE inhibitor can be reduced when it
is given with a diuretic. (See DOSAGE AND ADMINISTRATION.)
Antidiabetics: Epidemiological studies have suggested that concomitant administration of ACE
inhibitors and antidiabetic medicines (insulins, oral hypoglycemic agents) may cause an increased blood
glucose-lowering effect with risk of hypoglycemia. This phenomenon appeared to be more likely to occur
during the first weeks of combined treatment and in patients with renal impairment. In diabetic patients
treated with oral antidiabetic agents or insulin, glycemic control should be closely monitored for
hypoglycemia, especially during the first month of treatment with an ACE inhibitor.
Non-steroidal Anti-inflammatory Agents Including Selective Cyclooxygenase-2 (COX-2) Inhibitors:
Reports suggest that NSAIDs including selective COX-2 inhibitors may diminish the antihypertensive
effect of ACE inhibitors, including lisinopril. This interaction should be given consideration in patients
taking NSAIDs or selective COX-2 inhibitors concomitantly with ACE inhibitors.
In a study in 36 patients with mild to moderate hypertension where the antihypertensive effects of
PRINIVIL alone were compared to PRINIVIL given concomitantly with indomethacin, the use of
indomethacin was associated with a reduced antihypertensive effect, although the difference between the
two regimens was not significant.
In some patients with compromised renal function (e.g., elderly patients or patients who are volume-
depleted including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory
drugs, including selective COX-2 inhibitors, the co-administration of angiotensin II receptor antagonists or
ACE inhibitors may result in a further deterioration of renal function, including possible acute renal failure.
These effects are usually reversible.
These interactions should be considered in patients taking NSAIDS including selective COX-2
inhibitors concomitantly with diuretics and angiotensin II antagonists or ACE inhibitors. Therefore, monitor
effects on blood pressure and renal function when administering the combination, especially in the
elderly.
Dual Blockade of the Renin-angiotensin-aldosterone System: Dual blockade of the renin-angiotensin
aldosterone system is associated with increased risk of hypotension, syncope, hyperkalemia, and
changes in renal function (including acute renal failure). Closely monitor blood pressure, renal function,
and electrolytes in patients on PRINIVIL and angiotensin II receptor antagonists.
8
Reference ID: 3141252
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211205R007
Other Agents: PRINIVIL has been used concomitantly with nitrates and/or digoxin without evidence of
clinically significant adverse interactions. This included post myocardial infarction patients who were
receiving intravenous or transdermal nitroglycerin. No clinically important pharmacokinetic interactions
occurred when PRINIVIL was used concomitantly with propranolol or hydrochlorothiazide. The presence
of food in the stomach does not alter the bioavailability of PRINIVIL.
Agents Increasing Serum Potassium: PRINIVIL attenuates potassium loss caused by thiazide-type
diuretics. Use of PRINIVIL with potassium-sparing diuretics (e.g., spironolactone, eplerenone,
triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to
significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated
because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of
serum potassium. Potassium-sparing agents should generally not be used in patients with heart failure
who are receiving PRINIVIL.
Lithium: Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which
cause elimination of sodium, including ACE inhibitors. Lithium toxicity was usually reversible upon
discontinuation of lithium and the ACE inhibitor. It is recommended that serum lithium levels be monitored
frequently if PRINIVIL is administered concomitantly with lithium.
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 PRINIVIL.
Carcinogenesis, Mutagenesis, Impairment of Fertility
There was no evidence of a tumorigenic effect when lisinopril was administered orally for 105 weeks
to male and female rats at doses up to 90 mg/kg/day or for 92 weeks to male and female mice at doses
up to 135 mg/kg/day. These doses are 10 times and 7 times, respectively, the maximum recommended
human daily dose (MRHDD) when compared on a body surface area basis.
Lisinopril was not mutagenic in the Ames microbial mutagen test with or without metabolic activation.
It was also negative in a forward mutation assay using Chinese hamster lung cells. Lisinopril did not
produce single strand DNA breaks in an in vitro alkaline elution rat hepatocyte assay. In addition, lisinopril
did not produce increases in chromosomal aberrations in an in vitro test in Chinese hamster ovary cells
or in an in vivo study in mouse bone marrow.
There were no adverse effects on reproductive performance in male and female rats treated with up to
300 mg/kg/day of lisinopril (33 times the MRHDD when compared on a body surface area basis).
Nursing Mothers
Milk of lactating rats contains radioactivity following administration of 14C lisinopril. It is not known
whether this drug is secreted in human milk. Because many drugs are secreted in human milk, and
because of the potential for serious adverse reactions in nursing infants from ACE inhibitors, a decision
should be made whether to discontinue nursing or discontinue PRINIVIL, taking into account the
importance of the drug to the mother.
Pediatric Use
Neonates with a history of in utero exposure to PRINIVIL:
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. Lisinopril, which crosses the placenta, has been removed from
neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by
exchange transfusion, although there is no experience with the latter procedure.
Antihypertensive effects of PRINIVIL have been established in hypertensive pediatric patients aged 6
to 16 years.
There are no data on the effect of PRINIVIL on blood pressure in pediatric patients under the age of 6
or in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m2 (see CLINICAL
PHARMACOLOGY, Pharmacokinetics and Metabolism and Pharmacodynamics and Clinical Effects, and
DOSAGE AND ADMINISTRATION).
Geriatric Use
Clinical studies of PRINIVIL in patients with hypertension and congestive heart failure did not include
sufficient numbers of subjects aged 65 and over to determine whether they respond differently from
younger subjects. Other clinical experience in this population has not identified differences in responses
9
Reference ID: 3141252
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211205R007
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.
In a clinical study of PRINIVIL in patients with myocardial infarctions 4413 (47 percent) were 65 and
over, while 1656 (18 percent) were 75 and over. No overall differences in safety or efficacy were
observed between elderly and younger patients.
Other reported clinical experience has not identified differences in responses between elderly and
younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Pharmacokinetic studies indicate that maximum blood levels and area under plasma concentration
time curve (AUC) are doubled in elderly patients.
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. Evaluation of patients with
hypertension, congestive heart failure, or myocardial infarction should always include assessment of
renal function. (See DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
PRINIVIL has been found to be generally well tolerated in controlled clinical trials involving 1969
patients with hypertension or heart failure. For the most part, adverse experiences were mild and
transient.
HYPERTENSION
In clinical trials in patients with hypertension treated with PRINIVIL, discontinuation of therapy due to
clinical adverse experiences occurred in 5.7 percent of patients. The overall frequency of adverse
experiences could not be related to total daily dosage within the recommended therapeutic dosage range.
For adverse experiences occurring in greater than one percent of patients with hypertension treated
with PRINIVIL or PRINIVIL plus hydrochlorothiazide in controlled clinical trials and more frequently with
PRINIVIL and/or PRINIVIL plus hydrochlorothiazide than placebo, comparative incidence data are listed
in the table below:
10
Reference ID: 3141252
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211205R007
Percent of Patients
in Controlled Studies
PRINIVIL
PRINIVIL/
Hydrochlorothiazide
Placebo
(n = 1349)
Incidence
(n = 629)
Incidence
(n = 207)
Incidence
(discontinuation)
(discontinuation)
(discontinuation)
Body As A Whole
Fatigue
Asthenia
Orthostatic
Effects
2.5 (0.3)
1.3 (0.5)
1.2 (0.0)
4.0 (0.5)
2.1 (0.2)
3.5 (0.2)
1.0 (0.0)
1.0 (0.0)
1.0 (0.0)
Cardiovascular
Hypotension
1.2 (0.5)
1.6 (0.5)
0.5 (0.5)
Digestive
Diarrhea
Nausea
Vomiting
Dyspepsia
2.7 (0.2)
2.0 (0.4)
1.1 (0.2)
0.9 (0.0)
2.7 (0.3)
2.5 (0.2)
1.4 (0.1)
1.9 (0.0)
2.4 (0.0)
2.4 (0.0)
0.5 (0.0)
0.0 (0.0)
Musculoskeletal
Muscle Cramps
0.5 (0.0)
2.9 (0.8)
0.5 (0.0)
Nervous/Psychiatric
Headache
Dizziness
Paresthesia
Decreased Libido
Vertigo
5.7 (0.2)
5.4 (0.4)
0.8 (0.1)
0.4 (0.1)
0.2 (0.1)
4.5 (0.5)
9.2 (1.0)
2.1 (0.2)
1.3 (0.1)
1.1 (0.2)
1.9 (0.0)
1.9 (0.0)
0.0 (0.0)
0.0 (0.0)
0.0 (0.0)
Respiratory
Cough
3.5 (0.7)
4.6 (0.8)
1.0 (0.0)
Upper Respiratory
Infection
Common Cold
Nasal Congestion
Influenza
2.1 (0.1)
1.1 (0.1)
0.4 (0.1)
0.3 (0.1)
2.7 (0.1)
1.3 (0.1)
1.3 (0.1)
1.1 (0.1)
0.0 (0.0)
0.0 (0.0)
0.0 (0.0)
0.0 (0.0)
Skin
Rash
1.3 (0.4)
1.6 (0.2)
0.5 (0.5)
Urogenital
Impotence
1.0 (0.4)
1.6 (0.5)
0.0 (0.0)
Chest pain and back pain were also seen but were more common on placebo than PRINIVIL.
HEART FAILURE
In patients with heart failure treated with PRINIVIL for up to four years, discontinuation of therapy due
to clinical adverse experiences occurred in 11.0 percent of patients. In controlled studies in patients with
heart failure, therapy was discontinued in 8.1 percent of patients treated with PRINIVIL for up to 12
weeks, compared to 7.7 percent of patients treated with placebo for 12 weeks.
The following table lists those adverse experiences which occurred in greater than one percent of
patients with heart failure treated with PRINIVIL or placebo for up to 12 weeks in controlled clinical trials
and more frequently on PRINIVIL than placebo.
Controlled Trials
PRINIVIL
Placebo
(n=407)
(n=155)
Incidence
Incidence
(discontinuation)
(discontinuation)
12 weeks
12 weeks
Body As A Whole
Chest Pain
Abdominal Pain
3.4 (0.2)
2.2 (0.7)
1.3 (0.0)
1.9 (0.0)
Cardiovascular
Hypotension
4.4 (1.7)
0.6 (0.6)
Digestive
Diarrhea
3.7 (0.5)
1.9 (0.0)
Nervous/Psychiatric
Dizziness
11.8 (1.2)
4.5 (1.3)
Headache
4.4 (0.2)
3.9 (0.0)
Respiratory
Upper Respiratory
Infection
1.5 (0.0)
1.3 (0.0)
Skin
Rash
1.7 (0.5)
0.6 (0.6)
11
Reference ID: 3141252
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211205R007
Also observed at >1% with PRINIVIL but more frequent or as frequent on placebo than PRINIVIL in
controlled trials were asthenia, angina pectoris, nausea, dyspnea, cough and pruritus.
Worsening of heart failure, anorexia, increased salivation, muscle cramps, back pain, myalgia,
depression, chest sound abnormalities and pulmonary edema were also seen in controlled clinical trials,
but were more common on placebo than PRINIVIL.
ACUTE MYOCARDIAL INFARCTION
In the GISSI - 3 trial, in patients treated with PRINIVIL for six weeks following acute myocardial
infarction, discontinuation of therapy occurred in 17.6 percent of patients.
Patients treated with PRINIVIL had a significantly higher incidence of hypotension and renal
dysfunction compared with patients not taking PRINIVIL.
In the GISSI - 3 trial, hypotension (9.7 percent), renal dysfunction (2.0 percent), cough (0.5 percent),
post-infarction angina (0.3 percent), skin rash and generalized edema (0.01 percent), and angioedema
(0.01 percent) resulted in withdrawal of treatment. In elderly patients treated with PRINIVIL,
discontinuation due to renal dysfunction was 4.2 percent.
Other clinical adverse experiences occurring in 0.3 to 1.0 percent of patients with hypertension or
heart failure treated with PRINIVIL in controlled trials and rarer, serious, possibly drug-related events
reported in uncontrolled studies or marketing experience are listed below, and within each category, are
in order of decreasing severity:
Body as a Whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid and Possibly Related
Reactions), syncope, orthostatic effects, chest discomfort, pain, pelvic pain, flank pain, edema, facial
edema, virus infection, fever, chills, malaise.
Cardiovascular: Cardiac arrest; myocardial infarction or cerebrovascular accident, possibly secondary
to excessive hypotension in high-risk patients (see WARNINGS, Hypotension); pulmonary embolism and
infarction, arrhythmias (including ventricular tachycardia, atrial tachycardia, atrial fibrillation, bradycardia
and premature ventricular contractions), palpitations, transient ischemic attacks, paroxysmal nocturnal
dyspnea, orthostatic hypotension, decreased blood pressure, peripheral edema, vasculitis.
Digestive: Pancreatitis, hepatitis (hepatocellular or cholestatic jaundice) (see WARNINGS, Hepatic
Failure), vomiting, gastritis, dyspepsia, heartburn, gastrointestinal cramps, constipation, flatulence, dry
mouth.
Hematologic: Rare cases of bone marrow depression, hemolytic anemia, leukopenia/neutropenia, and
thrombocytopenia.
Endocrine: Diabetes mellitus, syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Metabolic: Weight loss, dehydration, fluid overload, gout, weight gain. Cases of hypoglycemia in
diabetic patients on oral antidiabetic agents or insulin have been reported (see PRECAUTIONS, Drug
Interactions).
Musculoskeletal: Arthritis, arthralgia, neck pain, hip pain, low back pain, joint pain, leg pain, knee pain,
shoulder pain, arm pain, lumbago.
Nervous System/Psychiatric: Stroke, ataxia, memory impairment, tremor, peripheral neuropathy (e.g.,
dysesthesia), spasm, paresthesia, confusion, insomnia, somnolence, hypersomnia, irritability, and
nervousness.
Respiratory System: Malignant lung neoplasms, hemoptysis, pulmonary infiltrates, eosinophilic
pneumonitis, bronchospasm, asthma, pleural effusion, pneumonia, bronchitis, wheezing, orthopnea,
painful respiration, epistaxis, laryngitis, sinusitis, pharyngeal pain, pharyngitis, rhinitis, rhinorrhea.
Skin: Urticaria, alopecia, herpes zoster, photosensitivity, skin lesions, skin infections, pemphigus,
erythema, flushing, diaphoresis. Other severe skin reactions (including toxic epidermal necrolysis,
Stevens-Johnson syndrome and cutaneous pseudolymphoma) have been reported rarely; causal
relationship has not been established.
Special Senses: Visual loss, diplopia, blurred vision, tinnitus, photophobia, taste disturbances.
Urogenital System: Acute renal failure, oliguria, anuria, uremia, progressive azotemia, renal
dysfunction (see PRECAUTIONS and DOSAGE AND ADMINISTRATION), pyelonephritis, dysuria,
urinary tract infection, breast pain.
Miscellaneous: A symptom complex has been reported which may include a positive ANA, an
elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia and
12
Reference ID: 3141252
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211205R007
leukocytosis. Rash, photosensitivity or other dermatological manifestations may occur alone or in
combination with these symptoms.
Angioedema: Angioedema has been reported in patients receiving PRINIVIL (0.1%) with an incidence
higher in Black than in non-Black patients. Angioedema associated with laryngeal edema may be fatal. If
angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with PRINIVIL
should be discontinued and appropriate therapy instituted immediately. In rare cases, intestinal
angioedema has been reported with angiotensin converting enzyme inhibitors including lisinopril. (See
WARNINGS.)
Hypotension: In hypertensive patients, hypotension occurred in 1.2 percent and syncope occurred in
0.1 percent of patients. Hypotension or syncope was a cause for discontinuation of therapy in 0.5 percent
of hypertensive patients. In patients with heart failure, hypotension occurred in 5.3 percent and syncope
occurred in 1.8 percent of patients. These adverse experiences were causes for discontinuation of
therapy in 1.8 percent of these patients. In patients treated with PRINIVIL for six weeks after acute
myocardial infarction, hypotension (systolic blood pressure 100 mmHg) resulted in discontinuation of
therapy in 9.7 percent of the patients. (See WARNINGS.)
Fetal/Neonatal Morbidity and Mortality: See WARNINGS, Fetal/Neonatal Morbidity and Mortality.
Cough: See PRECAUTIONS, Cough.
Pediatric Patients: No relevant differences between the adverse experience profile for pediatric
patients and that previously reported for adult patients were identified.
Clinical Laboratory Test Findings
Serum Electrolytes: Hyperkalemia (see PRECAUTIONS), hyponatremia.
Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen and serum creatinine,
reversible upon discontinuation of therapy, were observed in about 2.0 percent of patients with essential
hypertension treated with PRINIVIL alone. Increases were more common in patients receiving
concomitant diuretics and in patients with renal artery stenosis. (See PRECAUTIONS.) Reversible minor
increases in blood urea nitrogen and serum creatinine were observed in approximately 11.6 percent of
patients with heart failure on concomitant diuretic therapy. Frequently, these abnormalities resolved when
the dosage of the diuretic was decreased.
Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of
approximately 0.4 g percent and 1.3 vol percent, respectively) occurred frequently in patients treated with
PRINIVIL but were rarely of clinical importance in patients without some other cause of anemia. In clinical
trials, less than 0.1 percent of patients discontinued therapy due to anemia. Hemolytic anemia has been
reported; a causal relationship to lisinopril cannot be excluded.
Liver Function Tests: Rarely, elevations of liver enzymes and/or serum bilirubin have occurred (see
WARNINGS, Hepatic Failure).
In hypertensive patients, 2.0 percent discontinued therapy due to laboratory adverse experiences,
principally elevations in blood urea nitrogen (0.6 percent), serum creatinine (0.5 percent) and serum
potassium (0.4 percent). In the heart failure trials, 3.4 percent of patients discontinued therapy due to
laboratory adverse experiences, 1.8 percent due to elevations in blood urea nitrogen and/or creatinine
and 0.6 percent due to elevations in serum potassium. In the myocardial infarction trial, 2.0 percent of
patients receiving PRINIVIL discontinued therapy due to renal dysfunction (increasing creatinine
concentration to over 3 mg/dL or a doubling or more of the baseline serum creatinine concentration); less
than 1.0 percent of patients discontinued therapy due to other laboratory adverse experiences: 0.1
percent with hyperkalemia and less than 0.1 percent with hepatic enzyme alterations.
OVERDOSAGE
Following a single oral dose of 20 g/kg, no lethality occurred in rats and death occurred in one of 20
mice receiving the same dose. The most likely manifestation of overdosage would be hypotension, for
which the usual treatment would be intravenous infusion of normal saline solution.
Lisinopril can be removed by hemodialysis. (See WARNINGS, Anaphylactoid reactions during
membrane exposure.)
13
Reference ID: 3141252
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211205R007
DOSAGE AND ADMINISTRATION
Hypertension
Initial Therapy: In patients with uncomplicated essential hypertension not on diuretic therapy, the
recommended initial dose is 10 mg once a day. Dosage should be adjusted according to blood pressure
response. The usual dosage range is 20 to 40 mg per day administered in a single daily dose. The
antihypertensive effect may diminish toward the end of the dosing interval regardless of the administered
dose, but most commonly with a dose of 10 mg daily. This can be evaluated by measuring blood
pressure just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If
it is not, an increase in dose should be considered. Doses up to 80 mg have been used but do not appear
to give a greater effect. If blood pressure is not controlled with PRINIVIL alone, a low dose of a diuretic
may be added. Hydrochlorothiazide 12.5 mg has been shown to provide an additive effect. After the
addition of a diuretic, it may be possible to reduce the dose of PRINIVIL.
Diuretic Treated Patients: In hypertensive patients who are currently being treated with a diuretic,
symptomatic hypotension may occur occasionally following the initial dose of PRINIVIL. The diuretic
should be discontinued, if possible, for two to three days before beginning therapy with PRINIVIL to
reduce the likelihood of hypotension. (See WARNINGS.) The dosage of PRINIVIL should be adjusted
according to blood pressure response. If the patient's blood pressure is not controlled with PRINIVIL
alone, diuretic therapy may be resumed as described above.
If the diuretic cannot be discontinued, an initial dose of 5 mg should be used under medical
supervision for at least two hours and until blood pressure has stabilized for at least an additional hour.
(See WARNINGS and PRECAUTIONS, Drug Interactions.)
Concomitant administration of PRINIVIL with potassium supplements, potassium salt substitutes, or
potassium-sparing diuretics may lead to increases of serum potassium (see PRECAUTIONS).
Dosage Adjustment in Renal Impairment: The usual dose of PRINIVIL (10 mg) is recommended for
patients with a creatinine clearance >30 mL/min (serum creatinine of up to approximately 3 mg/dL). For
patients with creatinine clearance 10 mL/min 30 mL/min (serum creatinine 3 mg/dL), the first dose is
5 mg once daily. For patients with creatinine clearance <10 mL/min (usually on hemodialysis) the
recommended initial dose is 2.5 mg. The dosage may be titrated upward until blood pressure is controlled
or to a maximum of 40 mg daily.
Renal Status
Creatinine-
Initial Dose
Clearance
mg/day
mL/min
Normal Renal Function to Mild
>30 mL/min
10 mg
Impairment
Moderate to Severe
10 30 mL/min
5 mg
Impairment
Dialysis Patients**
<10 mL/min
2.5 mg***
** See WARNINGS, Anaphylactoid reactions during membrane exposure
*** Dosage or dosing interval should be adjusted depending on the blood pressure response.
Heart Failure
PRINIVIL is indicated as adjunctive therapy with diuretics and (usually) digitalis. The recommended
starting dose is 5 mg once a day.
When initiating treatment with lisinopril in patients with heart failure, the initial dose should be
administered under medical observation, especially in those patients with low blood pressure (systolic
blood pressure below 100 mmHg). The mean peak blood pressure lowering occurs six to eight hours
after dosing. Observation should continue until blood pressure is stable. The concomitant diuretic dose
should be reduced, if possible, to help minimize hypovolemia which may contribute to hypotension. (See
WARNINGS and PRECAUTIONS, Drug Interactions.) The appearance of hypotension after the initial
dose of PRINIVIL does not preclude subsequent careful dose titration with the drug, following effective
management of the hypotension.
The usual effective dosage range is 5 to 20 mg per day administered as a single daily dose.
Dosage Adjustment in Patients with Heart Failure and Renal Impairment or Hyponatremia: In patients
with heart failure who have hyponatremia (serum sodium <130 mEq/L) or moderate to severe renal
14
Reference ID: 3141252
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211205R007
impairment (creatinine clearance 30 mL/min or serum creatinine >3 mg/dL), therapy with PRINIVIL
should be initiated at a dose of 2.5 mg once a day under close medical supervision. (See WARNINGS
and PRECAUTIONS, Drug Interactions.)
Acute Myocardial Infarction
In hemodynamically stable patients within 24 hours of the onset of symptoms of acute myocardial
infarction, the first dose of PRINIVIL is 5 mg given orally, followed by 5 mg after 24 hours, 10 mg after 48
hours and then 10 mg of PRINIVIL once daily. Dosing should continue for six weeks. Patients should
receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin and beta-
blockers. Patients with a low systolic blood pressure (120 mmHg) when treatment is started or during
the first 3 days after the infarct should be given a lower 2.5 mg oral dose of PRINIVIL (see WARNINGS).
If hypotension occurs (systolic blood pressure 100 mmHg) a daily maintenance dose of 5 mg may be
given with temporary reductions to 2.5 mg if needed. If prolonged hypotension occurs (systolic blood
pressure <90 mmHg for more than 1 hour) PRINIVIL should be withdrawn. For patients who develop
symptoms of heart failure, see DOSAGE AND ADMINISTRATION, Heart Failure.
Dosage Adjustment in Patients with Myocardial Infarction with Renal Impairment: In acute myocardial
infarction, treatment with PRINIVIL should be initiated with caution in patients with evidence of renal
dysfunction, defined as serum creatinine concentration exceeding 2 mg/dL. No evaluation of dosage
adjustment in myocardial infarction patients with severe renal impairment has been performed.
Use in Elderly
In general, blood pressure response and adverse experiences were similar in younger and older
patients given similar doses of PRINIVIL. Pharmacokinetic studies, however, indicate that maximum
blood levels and area under the plasma concentration time curve (AUC) are doubled in older patients, so
that dosage adjustments should be made with particular caution.
Pediatric Hypertensive Patients 6 years of age
The usual recommended starting dose is 0.07 mg/kg once daily (up to 5 mg total). Dosage should be
adjusted according to blood pressure response. Doses above 0.61 mg/kg (or in excess of 40 mg) have
not been studied in pediatric patients. (See CLINICAL PHARMACOLOGY, Pharmacokinetics and
Metabolism and Pharmacodynamics and Clinical Effects.)
PRINIVIL is not recommended in pediatric patients <6 years or in pediatric patients with glomerular
filtration rate <30 mL/min/1.73 m2 (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism,
Pharmacodynamics and Clinical Effects and PRECAUTIONS).
Preparation of Suspension (for 200 mL of a 1.0 mg/mL suspension)
Add 10 mL of Purified Water USP to a polyethylene terephthalate (PET) bottle containing ten 20-mg
tablets of PRINIVIL and shake for at least one minute. Add 30 mL of Bicitra®** diluent and 160 mL of Ora-
Sweet SF™*** to the concentrate in the PET bottle and gently shake for several seconds to disperse the
ingredients. The suspension should be stored at or below 25°C (77°F) and can be stored for up to four
weeks. Shake the suspension before each use.
HOW SUPPLIED
No. 8110 — Tablets PRINIVIL, 5 mg, are white, oval shaped compressed tablets with code MSD 19
on one side and scored on the other side. They are supplied as follows:
NDC 0006-0019-54 unit of use bottles of 90.
No. 8111 — Tablets PRINIVIL, 10 mg, are light yellow, oval shaped compressed tablets with code
MSD 106 on one side and scored on the other side. They are supplied as follows:
NDC 0006-0106-54 unit of use bottles of 90.
No. 8112 — Tablets PRINIVIL, 20 mg, are peach, oval shaped compressed tablets with code
MSD 207 on one side and scored on the other side. They are supplied as follows:
NDC 0006-0207-54 unit of use bottles of 90.
Storage
Store at controlled room temperature, 15-30°C (59-86°F), and protect from moisture.
** Registered trademark of Alza Corporation
*** Trademark of Paddock Laboratories, Inc.
15
Reference ID: 3141252
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211205R007
Dispense in a tight container, if product package is subdivided. company logo
Manufactured by:
MERCK SHARP & DOHME LTD.
Cramlington, Northumberland, UK NE23 3JU
Copyright © 1988, 1989, 1992, 1993, 1995, 2005, 2006, 2011, 2012 Merck Sharp & Dohme Corp., a
subsidiary of Merck & Co., Inc.
All rights reserved.
Revised: 05/2012
USPI-T-05211205R007
16
Reference ID: 3141252
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:28.131747
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019558s055lbl.pdf', 'application_number': 19558, 'submission_type': 'SUPPL ', 'submission_number': 55}
|
11,532
|
company logo
9763206
TABLETS
PRINIVIL®
(LISINOPRIL)
USE IN PREGNANCY
When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury
and even death to the developing fetus. When pregnancy is detected, PRINIVIL should be
discontinued as soon as possible. See WARNINGS, Fetal/Neonatal Morbidity and Mortality.
DESCRIPTION
PRINIVIL® (Lisinopril), a synthetic peptide derivative, is an oral long-acting angiotensin converting
enzyme inhibitor. Lisinopril is chemically described as (S)-1-[N2-(1-carboxy-3-phenylpropyl)-L-lysyl]-L
proline dihydrate. Its empirical formula is C21H31N3O5•2H2O and its structural formula is: structural formula
Lisinopril is a white to off-white, crystalline powder, with a molecular weight of 441.52. It is soluble in
water and sparingly soluble in methanol and practically insoluble in ethanol.
PRINIVIL is supplied as 5 mg, 10 mg, and 20 mg tablets for oral administration. In addition to the
active ingredient lisinopril, each tablet contains the following inactive ingredients: calcium phosphate,
mannitol, magnesium stearate, and starch. The 10 mg and 20 mg tablets also contain iron oxide.
CLINICAL PHARMACOLOGY
Mechanism of Action
Lisinopril inhibits angiotensin converting enzyme (ACE) in human subjects and animals. ACE is a
peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance,
angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. The beneficial
effects of lisinopril in hypertension and heart failure appear to result primarily from suppression of the
renin-angiotensin-aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II which
leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease
may result in a small increase of serum potassium. In hypertensive patients with normal renal function
treated with PRINIVIL alone for up to 24 weeks, the mean increase in serum potassium was
approximately 0.1 mEq/L; however, approximately 15 percent of patients had increases greater than
0.5 mEq/L and approximately six percent had a decrease greater than 0.5 mEq/L. In the same study,
patients treated with PRINIVIL and hydrochlorothiazide for up to 24 weeks had a mean decrease in
serum potassium of 0.1 mEq/L; approximately 4 percent of patients had increases greater than 0.5 mEq/L
and approximately 12 percent had a decrease greater than 0.5 mEq/L. (See PRECAUTIONS.) Removal
of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.
ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of
bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of PRINIVIL remains to
be elucidated.
While the mechanism through which PRINIVIL lowers blood pressure is believed to be primarily
suppression of the renin-angiotensin-aldosterone system, PRINIVIL is antihypertensive even in patients
with low-renin hypertension. Although PRINIVIL was antihypertensive in all races studied, Black
1
Reference ID: 3099778
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
9763206
hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to
monotherapy than non-Black patients.
Concomitant administration of PRINIVIL and hydrochlorothiazide further reduced blood pressure in
Black and non-Black patients and any racial difference in blood pressure response was no longer
evident.
Pharmacokinetics and Metabolism
Adult Patients: Following oral administration of PRINIVIL, peak serum concentrations of lisinopril occur
within about 7 hours, although there was a trend to a small delay in time taken to reach peak serum
concentrations in acute myocardial infarction patients. Declining serum concentrations exhibit a
prolonged terminal phase which does not contribute to drug accumulation. This terminal phase probably
represents saturable binding to ACE and is not proportional to dose. Lisinopril does not appear to be
bound to other serum proteins.
Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine. Based on
urinary recovery, the mean extent of absorption of lisinopril is approximately 25 percent, with large inter-
subject variability (6-60 percent) at all doses tested (5-80 mg). Lisinopril absorption is not influenced by
the presence of food in the gastrointestinal tract. The absolute bioavailability of lisinopril is reduced to
about 16 percent in patients with stable NYHA Class II-IV congestive heart failure, and the volume of
distribution appears to be slightly smaller than that in normal subjects.
The oral bioavailability of lisinopril in patients with acute myocardial infarction is similar to that in
healthy volunteers.
Upon multiple dosing, lisinopril exhibits an effective half-life of accumulation of 12 hours.
Impaired renal function decreases elimination of lisinopril, which is excreted principally through the
kidneys, but this decrease becomes clinically important only when the glomerular filtration rate is below
30 mL/min. Above this glomerular filtration rate, the elimination half-life is little changed. With greater
impairment, however, peak and trough lisinopril levels increase, time to peak concentration increases and
time to attain steady state is prolonged. Older patients, on average, have (approximately doubled) higher
blood levels and area under the plasma concentration time curve (AUC) than younger patients. (See
DOSAGE AND ADMINISTRATION.) Lisinopril can be removed by hemodialysis.
Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly. Multiple doses of lisinopril
in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following
administration of 14C lisinopril. By whole body autoradiography, radioactivity was found in the placenta
following administration of labeled drug to pregnant rats, but none was found in the fetuses.
Pediatric Patients: The pharmacokinetics of lisinopril were studied in 29 pediatric hypertensive
patients between 6 years and 16 years with glomerular filtration rate >30 mL/min/1.73 m2. After doses of
0.1 to 0.2 mg/kg, steady state peak plasma concentrations of lisinopril occurred within 6 hours and the
extent of absorption based on urinary recovery was about 28%. These values are similar to those
obtained previously in adults. The typical value of lisinopril oral clearance (systemic clearance/absolute
bioavailability) in a child weighing 30 kg is 10 L/h, which increases in proportion to renal function.
Pharmacodynamics and Clinical Effects
Hypertension:
Adult Patients: Administration of PRINIVIL to patients with hypertension results in a reduction of
supine and standing blood pressure to about the same extent with no compensatory tachycardia.
Symptomatic postural hypotension is usually not observed although it can occur and should be
anticipated in volume and/or salt-depleted patients. (See WARNINGS.) When given together with
thiazide-type diuretics, the blood pressure lowering effects of the two drugs are approximately additive.
In most patients studied, onset of antihypertensive activity was seen at one hour after oral
administration of an individual dose of PRINIVIL, with peak reduction of blood pressure achieved by six
hours. Although an antihypertensive effect was observed 24 hours after dosing with recommended single
daily doses, the effect was more consistent and the mean effect was considerably larger in some studies
with doses of 20 mg or more than with lower doses. However, at all doses studied, the mean
antihypertensive effect was substantially smaller 24 hours after dosing than it was six hours after dosing.
In some patients achievement of optimal blood pressure reduction may require two to four weeks of
therapy.
2
Reference ID: 3099778
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
9763206
The antihypertensive effects of PRINIVIL are maintained during long-term therapy. Abrupt withdrawal
of PRINIVIL has not been associated with a rapid increase in blood pressure or a significant increase in
blood pressure compared to pretreatment levels.
Two dose-response studies utilizing a once daily regimen were conducted in 438 mild to moderate
hypertensive patients not on a diuretic. Blood pressure was measured 24 hours after dosing. An
antihypertensive effect of PRINIVIL was seen with 5 mg in some patients. However, in both studies blood
pressure reduction occurred sooner and was greater in patients treated with 10, 20, or 80 mg of
PRINIVIL. In controlled clinical studies, PRINIVIL 20-80 mg has been compared in patients with mild to
moderate hypertension to hydrochlorothiazide 12.5-50 mg and with atenolol 50-500 mg; and in patients
with moderate to severe hypertension to metoprolol 100-200 mg. It was superior to hydrochlorothiazide in
effects on systolic and diastolic blood pressure in a population that was ¾ Caucasian. PRINIVIL was
approximately equivalent to atenolol and metoprolol in effects on diastolic blood pressure and had
somewhat greater effects on systolic blood pressure.
PRINIVIL had similar effectiveness and adverse effects in younger and older (>65 years) patients. It
was less effective in Blacks than in Caucasians.
In hemodynamic studies in patients with essential hypertension, blood pressure reduction was
accompanied by a reduction in peripheral arterial resistance with little or no change in cardiac output and
in heart rate. In a study in nine hypertensive patients, following administration of PRINIVIL, there was an
increase in mean renal blood flow that was not significant. Data from several small studies are
inconsistent with respect to the effect of PRINIVIL on glomerular filtration rate in hypertensive patients
with normal renal function, but suggest that changes, if any, are not large.
In patients with renovascular hypertension PRINIVIL has been shown to be well tolerated and
effective in controlling blood pressure (see PRECAUTIONS).
Pediatric Patients: In a clinical study involving 115 hypertensive pediatric patients 6 to 16 years of age,
patients who weighed <50 kg received either 0.625, 2.5, or 20 mg of lisinopril daily and patients who
weighed 50 kg received either 1.25, 5, or 40 mg of lisinopril daily. At the end of 2 weeks, lisinopril
administered once daily lowered trough blood pressure in a dose-dependent manner with consistent
antihypertensive efficacy demonstrated at doses >1.25 mg (0.02 mg/kg). This effect was confirmed in a
withdrawal phase, where the diastolic pressure rose by about 9 mmHg more in patients randomized to
placebo than it did in patients who were randomized to remain on the middle and high doses of lisinopril.
The dose-dependent antihypertensive effect of lisinopril was consistent across several demographic
subgroups: age, Tanner stage, gender, race. In this study, lisinopril was generally well-tolerated.
In the above pediatric studies, lisinopril was given either as tablets or in a suspension for those
children and infants who were unable to swallow tablets or who required a lower dose than is available in
tablet form (see DOSAGE AND ADMINISTRATION, Preparation of Suspension).
Heart Failure:
During baseline-controlled clinical trials, in patients receiving digitalis and diuretics, single doses of
PRINIVIL resulted in decreases in pulmonary capillary wedge pressure, systemic vascular resistance and
blood pressure accompanied by an increase in cardiac output and no change in heart rate.
In two placebo-controlled, 12-week clinical studies using doses of PRINIVIL up to 20 mg, PRINIVIL as
adjunctive therapy to digitalis and diuretics improved the following signs and symptoms due to congestive
heart failure: edema, rales, paroxysmal nocturnal dyspnea and jugular venous distention. In one of the
studies beneficial response was also noted for: orthopnea, presence of third heart sound and the number
of patients classified as NYHA Class III and IV. Exercise tolerance was also improved in this study. The
effect of lisinopril on mortality in patients with heart failure has not been evaluated.
The once daily dosing for the treatment of congestive heart failure was the only dosage regimen used
during clinical trial development and was determined by the measurement of hemodynamic responses.
Acute Myocardial Infarction:
The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI - 3) study was a
multicenter, controlled, randomized, unblinded clinical trial conducted in 19,394 patients with acute
myocardial infarction admitted to a coronary care unit. It was designed to examine the effects of short-
term (6 week) treatment with lisinopril, nitrates, their combination, or no therapy on short-term (6 week)
mortality and on long-term death and markedly impaired cardiac function. Patients presenting within 24
3
Reference ID: 3099778
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
9763206
hours of the onset of symptoms who were hemodynamically stable were randomized, in a 2 x 2 factorial
design, to six weeks of either
1) PRINIVIL alone (n = 4841),
2) nitrates alone (n = 4869),
3) PRINIVIL plus nitrates (n = 4841), or
4) open control (n = 4843).
All patients received routine therapies, including thrombolytics (72%), aspirin (84%), and a beta-
blocker (31%), as appropriate, normally utilized in acute myocardial infarction (MI) patients.
The protocol excluded patients with hypotension (systolic blood pressure 100 mmHg), severe heart
failure, cardiogenic shock and renal dysfunction (serum creatinine 2 mg/dL and/or proteinuria
>500 mg/24 h). Doses of PRINIVIL were adjusted as necessary according to protocol. (See DOSAGE
AND ADMINISTRATION.)
Study treatment was withdrawn at six weeks except where clinical conditions indicated continuation of
treatment.
The primary outcomes of the trial were the overall mortality at six weeks and a combined endpoint at
six months after the myocardial infarction, consisting of the number of patients who died, had late (day 4)
clinical congestive heart failure, or had extensive left ventricular damage defined as ejection fraction
35%, or an akinetic-dyskinetic [A-D] score 45%. Patients receiving PRINIVIL (n = 9646) alone or with
nitrates, had an 11 percent lower risk of death (2p [two-tailed] = 0.04) compared to patients receiving no
PRINIVIL (n = 9672) (6.4 percent versus 7.2 percent, respectively) at six weeks. Although patients
randomized to receive PRINIVIL for up to six weeks also fared numerically better on the combined end
point at 6 months, the open nature of the assessment of heart failure, substantial loss to follow-up
echocardiography, and substantial excess use of lisinopril between 6 weeks and 6 months in the group
randomized to 6 weeks of lisinopril, preclude any conclusion about this endpoint.
Patients with acute myocardial infarction, treated with PRINIVIL had a higher (9.0 percent versus 3.7
percent, respectively) incidence of persistent hypotension (systolic blood pressure 90 mmHg for more
than 1 hour) and renal dysfunction (2.4 percent versus 1.1 percent) in-hospital and at six weeks
(increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum
creatinine concentration). (See ADVERSE REACTIONS, ACUTE MYOCARDIAL INFARCTION.)
INDICATIONS AND USAGE
Hypertension
PRINIVIL is indicated for the treatment of hypertension. It may be used alone as initial therapy or
concomitantly with other classes of antihypertensive agents.
Heart Failure
PRINIVIL is indicated as adjunctive therapy in the management of heart failure in patients who are not
responding adequately to diuretics and digitalis.
Acute Myocardial Infarction
PRINIVIL is indicated for the treatment of hemodynamically stable patients within 24 hours of acute
myocardial infarction, to improve survival. Patients should receive, as appropriate, the standard
recommended treatments such as thrombolytics, aspirin and beta-blockers.
In using PRINIVIL, consideration should be given to the fact that another angiotensin converting
enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or
collagen vascular disease, and that available data are insufficient to show that PRINIVIL does not have a
similar risk. (See WARNINGS.)
In considering use of PRINIVIL, it should be noted that in controlled clinical trials ACE inhibitors have
an effect on blood pressure that is less in Black patients than in non-Blacks. In addition, it should be
noted that Black patients receiving ACE inhibitors have been reported to have a higher incidence of
angioedema compared to non-Blacks (see WARNINGS, Anaphylactoid and Possibly Related Reactions,
Head and Neck Angioedema).
4
Reference ID: 3099778
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
9763206
CONTRAINDICATIONS
PRINIVIL is contraindicated in patients who are hypersensitive to this product and in patients with a
history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor and
in patients with hereditary or idiopathic angioedema.
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
PRINIVIL) may be subject to a variety of adverse reactions, some of them serious.
Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx
has been reported in patients treated with angiotensin converting enzyme inhibitors, including PRINIVIL.
This may occur at any time during treatment. ACE inhibitors have been associated with a higher rate of
angioedema in Black than in non-Black patients. In such cases PRINIVIL should be promptly
discontinued and appropriate therapy and monitoring should be provided until complete and sustained
resolution of signs and symptoms has occurred. Even in those instances where swelling of only the
tongue is involved, without respiratory distress, patients may require prolonged observation since
treatment with antihistamines and corticosteroids may not be sufficient. Very rarely, fatalities have been
reported due to angioedema associated with laryngeal edema or tongue edema. Patients with
involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those
with a history of airway surgery. Where there is involvement of the tongue, glottis or larynx, likely to
cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000
(0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly
provided. (See ADVERSE REACTIONS.)
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of
angioedema while receiving an ACE inhibitor (see also INDICATIONS AND USAGE and
CONTRAINDICATIONS).
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: Sudden and potentially life-threatening
anaphylactoid reactions have been reported in some patients dialyzed with high-flux membranes (e.g.,
AN69®) and treated concomitantly with an ACE inhibitor. In such patients, dialysis must be stopped
immediately, and aggressive therapy for anaphylactoid reactions be initiated. Symptoms have not been
relieved by antihistamines in these situations. In these patients, consideration should be given to using a
different type of dialysis membrane or a different class of antihypertensive agent. Anaphylactoid reactions
have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate
absorption.
Hypotension
Excessive hypotension is rare in patients with uncomplicated hypertension treated with PRINIVIL
alone.
Patients with heart failure given PRINIVIL commonly have some reduction in blood pressure with peak
blood pressure reduction occurring 6 to 8 hours post dose, but discontinuation of therapy because of
continuing symptomatic hypotension usually is not necessary when dosing instructions are followed;
caution should be observed when initiating therapy. (See DOSAGE AND ADMINISTRATION.)
5
Reference ID: 3099778
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
9763206
Patients at risk of excessive hypotension, sometimes associated with oliguria and/or progressive
azotemia, and rarely with acute renal failure and/or death, include those with the following conditions or
characteristics: heart failure with systolic blood pressure below 100 mmHg, hyponatremia, high-dose
diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume
and/or salt depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with
heart failure), reduce the diuretic dose or increase salt intake cautiously before initiating therapy with
PRINIVIL in patients at risk for excessive hypotension who are able to tolerate such adjustments. (See
PRECAUTIONS, Drug Interactions, and ADVERSE REACTIONS.)
Patients with acute myocardial infarction in the GISSI - 3 study had a higher (9.0 percent versus 3.7
percent) incidence of persistent hypotension (systolic blood pressure 90 mmHg for more than 1 hour)
when treated with PRINIVIL. Treatment with PRINIVIL must not be initiated in acute myocardial infarction
patients at risk of further serious hemodynamic deterioration after treatment with a vasodilator (e.g.,
systolic blood pressure of 100 mmHg or lower) or cardiogenic shock.
In patients at risk of excessive hypotension, therapy should be started under very close medical
supervision and such patients should be followed closely for the first two weeks of treatment and
whenever the dose of PRINIVIL and/or diuretic is increased. Similar considerations may apply to patients
with ischemic heart or cerebrovascular disease, or in patients with acute myocardial infarction, in whom
an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary,
receive an intravenous infusion of normal saline. A transient hypotensive response is not a
contraindication to further doses of PRINIVIL which usually can be given without difficulty once the blood
pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of
PRINIVIL or concomitant diuretic may be necessary.
Leukopenia/Neutropenia/Agranulocytosis
Another angiotensin converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis
and bone marrow depression, rarely in uncomplicated patients but more frequently in patients with renal
impairment especially if they also have a collagen vascular disease. Available data from clinical trials of
PRINIVIL are insufficient to show that PRINIVIL does not cause agranulocytosis at similar rates.
Marketing experience has revealed rare cases of leukopenia/neutropenia and bone marrow depression in
which a causal relationship to lisinopril cannot be excluded. Periodic monitoring of white blood cell counts
in patients with collagen vascular disease and renal disease should be considered.
Hepatic Failure
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or
hepatitis 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.
Fetal/Neonatal Morbidity and Mortality
ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant
women. Several dozen cases have been reported in the world literature. When pregnancy is detected,
ACE inhibitors should be discontinued as soon as possible.
In a published retrospective epidemiological study, infants whose mothers had taken an ACE inhibitor
drug during the first trimester of pregnancy appeared to have an increased risk of major congenital
malformations compared with infants whose mothers had not undergone first trimester exposure to ACE
inhibitor drugs. The number of cases of birth defects is small and the findings of this study have not yet
been repeated.
The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated
with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or
irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from
decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb
contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine
growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether
these occurrences were due to the ACE-inhibitor exposure.
6
Reference ID: 3099778
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
9763206
These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that
has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors
only during the first trimester should be so informed. Nonetheless, when patients become pregnant,
physicians should make every effort to discontinue the use of PRINIVIL as soon as possible.
Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors
will be found. In these rare cases, the mothers should be apprised of the potential hazards to their
fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic
environment.
If oligohydramnios is observed, PRINIVIL should be discontinued unless it is considered lifesaving for
the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may
be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware,
however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Infants with histories of in utero exposure to ACE inhibitors should be closely observed for
hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of
blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of
reversing hypotension and/or substituting for disordered renal function. Lisinopril, which crosses the
placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit,
and theoretically may be removed by exchange transfusion, although there is no experience with the
latter procedure.
No teratogenic effects of lisinopril were seen in studies of pregnant mice, rats and rabbits. On a body
surface area basis, the doses used were 55 times, 33 times, and 0.15 times, respectively, the maximum
recommended human daily dose (MRHDD).
PRECAUTIONS
General
Aortic Stenosis/Hypertrophic Cardiomyopathy: As with all vasodilators, lisinopril should be given with
caution to patients with obstruction in the outflow tract of the left ventricle.
Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system,
changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive
heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone
system, treatment with angiotensin converting enzyme inhibitors, including PRINIVIL, may be associated
with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.
In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea
nitrogen and serum creatinine may occur. Experience with another angiotensin converting enzyme
inhibitor suggests that these increases are usually reversible upon discontinuation of PRINIVIL and/or
diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy.
Some patients with hypertension or heart failure with no apparent pre-existing renal vascular disease
have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient,
especially when PRINIVIL has been given concomitantly with a diuretic. This is more likely to occur in
patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or
PRINIVIL may be required.
Patients with acute myocardial infarction in the GISSI - 3 study, treated with PRINIVIL, had a higher
(2.4 percent versus 1.1 percent) incidence of renal dysfunction in-hospital and at six weeks (increasing
creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum creatinine
concentration). In acute myocardial infarction, treatment with PRINIVIL should be initiated with caution in
patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding
2 mg/dL. If renal dysfunction develops during treatment with PRINIVIL (serum creatinine concentration
exceeding 3 mg/dL or a doubling from the pre-treatment value) then the physician should consider
withdrawal of PRINIVIL.
Evaluation of patients with hypertension, heart failure, or myocardial infarction should always
include assessment of renal function. (See DOSAGE AND ADMINISTRATION.)
Hyperkalemia: In clinical trials hyperkalemia (serum potassium greater than 5.7 mEq/L) occurred in
approximately 2.2 percent of hypertensive patients and 4.8 percent of patients with heart failure. In most
7
Reference ID: 3099778
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
9763206
cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause
of discontinuation of therapy in approximately 0.1 percent of hypertensive patients, 0.6 percent of patients
with heart failure and 0.1 percent of patients with myocardial infarction. Risk factors for the development
of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-
sparing diuretics, potassium supplements and/or potassium-containing salt substitutes. Hyperkalemia can
cause serious, sometimes fatal, arrhythmias. PRINIVIL should be used cautiously, if at all, with these
agents and with frequent monitoring of serum potassium. (See Drug Interactions.)
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.
Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that
produce hypotension, PRINIVIL may 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.
Information for Patients
Angioedema: Angioedema, including laryngeal edema, may occur at any time during treatment with
angiotensin converting enzyme inhibitors, including lisinopril. Patients should be so advised and told to
report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes,
lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have consulted with
the prescribing physician.
Symptomatic Hypotension: Patients should be cautioned to report lightheadedness especially during
the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug
until they have consulted with the prescribing physician.
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
their physician.
Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without
consulting their physician.
Hypoglycemia: Diabetic patients treated with oral antidiabetic agents or insulin starting an ACE
inhibitor should be told to closely monitor for hypoglycemia, especially during the first month of combined
use. (See Drug Interactions.)
Leukopenia/Neutropenia: Patients should be told to report promptly any indication of infection (e.g.,
sore throat, fever) which may be a sign of leukopenia/neutropenia.
Pregnancy: Female patients of childbearing age should be told about the consequences of exposure
to ACE inhibitors during pregnancy. These patients should be asked to report pregnancies to their
physicians as soon as possible.
NOTE: As with many other drugs, certain advice to patients being treated with PRINIVIL is warranted.
This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of
all possible adverse or intended effects.
Drug Interactions
Hypotension - Patients on Diuretic Therapy: Patients on diuretics, and especially those in whom
diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood
pressure after initiation of therapy with PRINIVIL. The possibility of hypotensive effects with PRINIVIL can
be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment
with PRINIVIL. If it is necessary to continue the diuretic, initiate therapy with PRINIVIL at a dose of 5 mg
daily, and provide close medical supervision after the initial dose until blood pressure has stabilized. (See
WARNINGS and DOSAGE AND ADMINISTRATION.) When a diuretic is added to the therapy of a
patient receiving PRINIVIL, an additional antihypertensive effect is usually observed. Studies with ACE
inhibitors in combination with diuretics indicate that the dose of the ACE inhibitor can be reduced when it
is given with a diuretic. (See DOSAGE AND ADMINISTRATION.)
8
Reference ID: 3099778
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
9763206
Antidiabetics: Epidemiological studies have suggested that concomitant administration of ACE
inhibitors and antidiabetic medicines (insulins, oral hypoglycemic agents) may cause an increased blood
glucose-lowering effect with risk of hypoglycemia. This phenomenon appeared to be more likely to occur
during the first weeks of combined treatment and in patients with renal impairment. In diabetic patients
treated with oral antidiabetic agents or insulin, glycemic control should be closely monitored for
hypoglycemia, especially during the first month of treatment with an ACE inhibitor.
Non-steroidal Anti-inflammatory Agents Including Selective Cyclooxygenase-2 (COX-2) Inhibitors:
Reports suggest that NSAIDs including selective COX-2 inhibitors may diminish the antihypertensive
effect of ACE inhibitors, including lisinopril. This interaction should be given consideration in patients
taking NSAIDs or selective COX-2 inhibitors concomitantly with ACE inhibitors.
In a study in 36 patients with mild to moderate hypertension where the antihypertensive effects of
PRINIVIL alone were compared to PRINIVIL given concomitantly with indomethacin, the use of
indomethacin was associated with a reduced antihypertensive effect, although the difference between the
two regimens was not significant.
In some patients with compromised renal function (e.g., elderly patients or patients who are volume-
depleted including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory
drugs, including selective COX-2 inhibitors, the co-administration of angiotensin II receptor antagonists or
ACE inhibitors may result in a further deterioration of renal function, including possible acute renal failure.
These effects are usually reversible.
These interactions should be considered in patients taking NSAIDS including selective COX-2
inhibitors concomitantly with diuretics and angiotensin II antagonists or ACE inhibitors. Therefore, monitor
effects on blood pressure and renal function when administering the combination, especially in the
elderly.
Dual Blockade of the Renin-angiotensin-aldosterone System: Dual blockade of the renin-angiotensin
aldosterone system is associated with increased risk of hypotension, syncope, hyperkalemia, and
changes in renal function (including acute renal failure). Closely monitor blood pressure, renal function,
and electrolytes in patients on PRINIVIL and angiotensin II receptor antagonists.
Other Agents: PRINIVIL has been used concomitantly with nitrates and/or digoxin without evidence of
clinically significant adverse interactions. This included post myocardial infarction patients who were
receiving intravenous or transdermal nitroglycerin. No clinically important pharmacokinetic interactions
occurred when PRINIVIL was used concomitantly with propranolol or hydrochlorothiazide. The presence
of food in the stomach does not alter the bioavailability of PRINIVIL.
Agents Increasing Serum Potassium: PRINIVIL attenuates potassium loss caused by thiazide-type
diuretics. Use of PRINIVIL with potassium-sparing diuretics (e.g., spironolactone, eplerenone,
triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to
significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated
because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of
serum potassium. Potassium-sparing agents should generally not be used in patients with heart failure
who are receiving PRINIVIL.
Lithium: Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which
cause elimination of sodium, including ACE inhibitors. Lithium toxicity was usually reversible upon
discontinuation of lithium and the ACE inhibitor. It is recommended that serum lithium levels be monitored
frequently if PRINIVIL is administered concomitantly with lithium.
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 PRINIVIL.
Carcinogenesis, Mutagenesis, Impairment of Fertility
There was no evidence of a tumorigenic effect when lisinopril was administered orally for 105 weeks
to male and female rats at doses up to 90 mg/kg/day or for 92 weeks to male and female mice at doses
up to 135 mg/kg/day. These doses are 10 times and 7 times, respectively, the maximum recommended
human daily dose (MRHDD) when compared on a body surface area basis.
Lisinopril was not mutagenic in the Ames microbial mutagen test with or without metabolic activation.
It was also negative in a forward mutation assay using Chinese hamster lung cells. Lisinopril did not
produce single strand DNA breaks in an in vitro alkaline elution rat hepatocyte assay. In addition, lisinopril
9
Reference ID: 3099778
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
9763206
did not produce increases in chromosomal aberrations in an in vitro test in Chinese hamster ovary cells
or in an in vivo study in mouse bone marrow.
There were no adverse effects on reproductive performance in male and female rats treated with up to
300 mg/kg/day of lisinopril (33 times the MRHDD when compared on a body surface area basis).
Pregnancy
Pregnancy Categories C (first trimester) and D (second and third trimesters). See WARNINGS,
Fetal/Neonatal Morbidity and Mortality.
Nursing Mothers
Milk of lactating rats contains radioactivity following administration of 14C lisinopril. It is not known
whether this drug is secreted in human milk. Because many drugs are secreted in human milk, and
because of the potential for serious adverse reactions in nursing infants from ACE inhibitors, a decision
should be made whether to discontinue nursing or discontinue PRINIVIL, taking into account the
importance of the drug to the mother.
Pediatric Use
Antihypertensive effects of PRINIVIL have been established in hypertensive pediatric patients aged 6
to 16 years.
There are no data on the effect of PRINIVIL on blood pressure in pediatric patients under the age of 6
or in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m2 (see CLINICAL
PHARMACOLOGY, Pharmacokinetics and Metabolism and Pharmacodynamics and Clinical Effects, and
DOSAGE AND ADMINISTRATION).
Geriatric Use
Clinical studies of PRINIVIL in patients with hypertension and congestive heart failure did not include
sufficient numbers of subjects aged 65 and over to determine whether they respond differently from
younger subjects. Other clinical experience in this population 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.
In a clinical study of PRINIVIL in patients with myocardial infarctions 4413 (47 percent) were 65 and
over, while 1656 (18 percent) were 75 and over. No overall differences in safety or efficacy were
observed between elderly and younger patients.
Other reported clinical experience has not identified differences in responses between elderly and
younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Pharmacokinetic studies indicate that maximum blood levels and area under plasma concentration
time curve (AUC) are doubled in elderly patients.
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. Evaluation of patients with
hypertension, congestive heart failure, or myocardial infarction should always include assessment of
renal function. (See DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
PRINIVIL has been found to be generally well tolerated in controlled clinical trials involving 1969
patients with hypertension or heart failure. For the most part, adverse experiences were mild and
transient.
HYPERTENSION
In clinical trials in patients with hypertension treated with PRINIVIL, discontinuation of therapy due to
clinical adverse experiences occurred in 5.7 percent of patients. The overall frequency of adverse
experiences could not be related to total daily dosage within the recommended therapeutic dosage range.
For adverse experiences occurring in greater than one percent of patients with hypertension treated
with PRINIVIL or PRINIVIL plus hydrochlorothiazide in controlled clinical trials and more frequently with
PRINIVIL and/or PRINIVIL plus hydrochlorothiazide than placebo, comparative incidence data are listed
in the table below:
10
Reference ID: 3099778
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
9763206
Percent of Patients
in Controlled Studies
PRINIVIL
PRINIVIL/
Hydrochlorothiazide
Placebo
(n = 1349)
Incidence
(n = 629)
Incidence
(n = 207)
Incidence
(discontinuation)
(discontinuation)
(discontinuation)
Body As A Whole
Fatigue
Asthenia
Orthostatic
Effects
2.5 (0.3)
1.3 (0.5)
1.2 (0.0)
4.0 (0.5)
2.1 (0.2)
3.5 (0.2)
1.0 (0.0)
1.0 (0.0)
1.0 (0.0)
Cardiovascular
Hypotension
1.2 (0.5)
1.6 (0.5)
0.5 (0.5)
Digestive
Diarrhea
Nausea
Vomiting
Dyspepsia
2.7 (0.2)
2.0 (0.4)
1.1 (0.2)
0.9 (0.0)
2.7 (0.3)
2.5 (0.2)
1.4 (0.1)
1.9 (0.0)
2.4 (0.0)
2.4 (0.0)
0.5 (0.0)
0.0 (0.0)
Musculoskeletal
Muscle Cramps
0.5 (0.0)
2.9 (0.8)
0.5 (0.0)
Nervous/Psychiatric
Headache
Dizziness
Paresthesia
Decreased Libido
Vertigo
5.7 (0.2)
5.4 (0.4)
0.8 (0.1)
0.4 (0.1)
0.2 (0.1)
4.5 (0.5)
9.2 (1.0)
2.1 (0.2)
1.3 (0.1)
1.1 (0.2)
1.9 (0.0)
1.9 (0.0)
0.0 (0.0)
0.0 (0.0)
0.0 (0.0)
Respiratory
Cough
3.5 (0.7)
4.6 (0.8)
1.0 (0.0)
Upper Respiratory
Infection
Common Cold
Nasal Congestion
Influenza
2.1 (0.1)
1.1 (0.1)
0.4 (0.1)
0.3 (0.1)
2.7 (0.1)
1.3 (0.1)
1.3 (0.1)
1.1 (0.1)
0.0 (0.0)
0.0 (0.0)
0.0 (0.0)
0.0 (0.0)
Skin
Rash
1.3 (0.4)
1.6 (0.2)
0.5 (0.5)
Urogenital
Impotence
1.0 (0.4)
1.6 (0.5)
0.0 (0.0)
Chest pain and back pain were also seen but were more common on placebo than PRINIVIL.
HEART FAILURE
In patients with heart failure treated with PRINIVIL for up to four years, discontinuation of therapy due
to clinical adverse experiences occurred in 11.0 percent of patients. In controlled studies in patients with
heart failure, therapy was discontinued in 8.1 percent of patients treated with PRINIVIL for up to 12
weeks, compared to 7.7 percent of patients treated with placebo for 12 weeks.
The following table lists those adverse experiences which occurred in greater than one percent of
patients with heart failure treated with PRINIVIL or placebo for up to 12 weeks in controlled clinical trials
and more frequently on PRINIVIL than placebo.
Controlled Trials
PRINIVIL
Placebo
(n=407)
(n=155)
Incidence
Incidence
(discontinuation)
(discontinuation)
12 weeks
12 weeks
Body As A Whole
Chest Pain
Abdominal Pain
3.4 (0.2)
2.2 (0.7)
1.3 (0.0)
1.9 (0.0)
Cardiovascular
Hypotension
4.4 (1.7)
0.6 (0.6)
Digestive
Diarrhea
3.7 (0.5)
1.9 (0.0)
Nervous/Psychiatric
Dizziness
11.8 (1.2)
4.5 (1.3)
Headache
4.4 (0.2)
3.9 (0.0)
Respiratory
Upper Respiratory
Infection
1.5 (0.0)
1.3 (0.0)
Skin
Rash
1.7 (0.5)
0.6 (0.6)
11
Reference ID: 3099778
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
9763206
Also observed at >1% with PRINIVIL but more frequent or as frequent on placebo than PRINIVIL in
controlled trials were asthenia, angina pectoris, nausea, dyspnea, cough and pruritus.
Worsening of heart failure, anorexia, increased salivation, muscle cramps, back pain, myalgia,
depression, chest sound abnormalities and pulmonary edema were also seen in controlled clinical trials,
but were more common on placebo than PRINIVIL.
ACUTE MYOCARDIAL INFARCTION
In the GISSI - 3 trial, in patients treated with PRINIVIL for six weeks following acute myocardial
infarction, discontinuation of therapy occurred in 17.6 percent of patients.
Patients treated with PRINIVIL had a significantly higher incidence of hypotension and renal
dysfunction compared with patients not taking PRINIVIL.
In the GISSI - 3 trial, hypotension (9.7 percent), renal dysfunction (2.0 percent), cough (0.5 percent),
post-infarction angina (0.3 percent), skin rash and generalized edema (0.01 percent), and angioedema
(0.01 percent) resulted in withdrawal of treatment. In elderly patients treated with PRINIVIL,
discontinuation due to renal dysfunction was 4.2 percent.
Other clinical adverse experiences occurring in 0.3 to 1.0 percent of patients with hypertension or
heart failure treated with PRINIVIL in controlled trials and rarer, serious, possibly drug-related events
reported in uncontrolled studies or marketing experience are listed below, and within each category, are
in order of decreasing severity:
Body as a Whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid and Possibly Related
Reactions), syncope, orthostatic effects, chest discomfort, pain, pelvic pain, flank pain, edema, facial
edema, virus infection, fever, chills, malaise.
Cardiovascular: Cardiac arrest; myocardial infarction or cerebrovascular accident, possibly secondary
to excessive hypotension in high-risk patients (see WARNINGS, Hypotension); pulmonary embolism and
infarction, arrhythmias (including ventricular tachycardia, atrial tachycardia, atrial fibrillation, bradycardia
and premature ventricular contractions), palpitations, transient ischemic attacks, paroxysmal nocturnal
dyspnea, orthostatic hypotension, decreased blood pressure, peripheral edema, vasculitis.
Digestive: Pancreatitis, hepatitis (hepatocellular or cholestatic jaundice) (see WARNINGS, Hepatic
Failure), vomiting, gastritis, dyspepsia, heartburn, gastrointestinal cramps, constipation, flatulence, dry
mouth.
Hematologic: Rare cases of bone marrow depression, hemolytic anemia, leukopenia/neutropenia, and
thrombocytopenia.
Endocrine: Diabetes mellitus, syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Metabolic: Weight loss, dehydration, fluid overload, gout, weight gain. Cases of hypoglycemia in
diabetic patients on oral antidiabetic agents or insulin have been reported (see PRECAUTIONS, Drug
Interactions).
Musculoskeletal: Arthritis, arthralgia, neck pain, hip pain, low back pain, joint pain, leg pain, knee pain,
shoulder pain, arm pain, lumbago.
Nervous System/Psychiatric: Stroke, ataxia, memory impairment, tremor, peripheral neuropathy (e.g.,
dysesthesia), spasm, paresthesia, confusion, insomnia, somnolence, hypersomnia, irritability, and
nervousness.
Respiratory System: Malignant lung neoplasms, hemoptysis, pulmonary infiltrates, eosinophilic
pneumonitis, bronchospasm, asthma, pleural effusion, pneumonia, bronchitis, wheezing, orthopnea,
painful respiration, epistaxis, laryngitis, sinusitis, pharyngeal pain, pharyngitis, rhinitis, rhinorrhea.
Skin: Urticaria, alopecia, herpes zoster, photosensitivity, skin lesions, skin infections, pemphigus,
erythema, flushing, diaphoresis. Other severe skin reactions (including toxic epidermal necrolysis,
Stevens-Johnson syndrome and cutaneous pseudolymphoma) have been reported rarely; causal
relationship has not been established.
Special Senses: Visual loss, diplopia, blurred vision, tinnitus, photophobia, taste disturbances.
Urogenital System: Acute renal failure, oliguria, anuria, uremia, progressive azotemia, renal
dysfunction (see PRECAUTIONS and DOSAGE AND ADMINISTRATION), pyelonephritis, dysuria,
urinary tract infection, breast pain.
Miscellaneous: A symptom complex has been reported which may include a positive ANA, an
elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia and
12
Reference ID: 3099778
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
9763206
leukocytosis. Rash, photosensitivity or other dermatological manifestations may occur alone or in
combination with these symptoms.
Angioedema: Angioedema has been reported in patients receiving PRINIVIL (0.1%) with an incidence
higher in Black than in non-Black patients. Angioedema associated with laryngeal edema may be fatal. If
angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with PRINIVIL
should be discontinued and appropriate therapy instituted immediately. In rare cases, intestinal
angioedema has been reported with angiotensin converting enzyme inhibitors including lisinopril. (See
WARNINGS.)
Hypotension: In hypertensive patients, hypotension occurred in 1.2 percent and syncope occurred in
0.1 percent of patients. Hypotension or syncope was a cause for discontinuation of therapy in 0.5 percent
of hypertensive patients. In patients with heart failure, hypotension occurred in 5.3 percent and syncope
occurred in 1.8 percent of patients. These adverse experiences were causes for discontinuation of
therapy in 1.8 percent of these patients. In patients treated with PRINIVIL for six weeks after acute
myocardial infarction, hypotension (systolic blood pressure 100 mmHg) resulted in discontinuation of
therapy in 9.7 percent of the patients. (See WARNINGS.)
Fetal/Neonatal Morbidity and Mortality: See WARNINGS, Fetal/Neonatal Morbidity and Mortality.
Cough: See PRECAUTIONS, Cough.
Pediatric Patients: No relevant differences between the adverse experience profile for pediatric
patients and that previously reported for adult patients were identified.
Clinical Laboratory Test Findings
Serum Electrolytes: Hyperkalemia (see PRECAUTIONS), hyponatremia.
Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen and serum creatinine,
reversible upon discontinuation of therapy, were observed in about 2.0 percent of patients with essential
hypertension treated with PRINIVIL alone. Increases were more common in patients receiving
concomitant diuretics and in patients with renal artery stenosis. (See PRECAUTIONS.) Reversible minor
increases in blood urea nitrogen and serum creatinine were observed in approximately 11.6 percent of
patients with heart failure on concomitant diuretic therapy. Frequently, these abnormalities resolved when
the dosage of the diuretic was decreased.
Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of
approximately 0.4 g percent and 1.3 vol percent, respectively) occurred frequently in patients treated with
PRINIVIL but were rarely of clinical importance in patients without some other cause of anemia. In clinical
trials, less than 0.1 percent of patients discontinued therapy due to anemia. Hemolytic anemia has been
reported; a causal relationship to lisinopril cannot be excluded.
Liver Function Tests: Rarely, elevations of liver enzymes and/or serum bilirubin have occurred (see
WARNINGS, Hepatic Failure).
In hypertensive patients, 2.0 percent discontinued therapy due to laboratory adverse experiences,
principally elevations in blood urea nitrogen (0.6 percent), serum creatinine (0.5 percent) and serum
potassium (0.4 percent). In the heart failure trials, 3.4 percent of patients discontinued therapy due to
laboratory adverse experiences, 1.8 percent due to elevations in blood urea nitrogen and/or creatinine
and 0.6 percent due to elevations in serum potassium. In the myocardial infarction trial, 2.0 percent of
patients receiving PRINIVIL discontinued therapy due to renal dysfunction (increasing creatinine
concentration to over 3 mg/dL or a doubling or more of the baseline serum creatinine concentration); less
than 1.0 percent of patients discontinued therapy due to other laboratory adverse experiences: 0.1
percent with hyperkalemia and less than 0.1 percent with hepatic enzyme alterations.
OVERDOSAGE
Following a single oral dose of 20 g/kg, no lethality occurred in rats and death occurred in one of 20
mice receiving the same dose. The most likely manifestation of overdosage would be hypotension, for
which the usual treatment would be intravenous infusion of normal saline solution.
Lisinopril can be removed by hemodialysis. (See WARNINGS, Anaphylactoid reactions during
membrane exposure.)
13
Reference ID: 3099778
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
9763206
DOSAGE AND ADMINISTRATION
Hypertension
Initial Therapy: In patients with uncomplicated essential hypertension not on diuretic therapy, the
recommended initial dose is 10 mg once a day. Dosage should be adjusted according to blood pressure
response. The usual dosage range is 20 to 40 mg per day administered in a single daily dose. The
antihypertensive effect may diminish toward the end of the dosing interval regardless of the administered
dose, but most commonly with a dose of 10 mg daily. This can be evaluated by measuring blood
pressure just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If
it is not, an increase in dose should be considered. Doses up to 80 mg have been used but do not appear
to give a greater effect. If blood pressure is not controlled with PRINIVIL alone, a low dose of a diuretic
may be added. Hydrochlorothiazide 12.5 mg has been shown to provide an additive effect. After the
addition of a diuretic, it may be possible to reduce the dose of PRINIVIL.
Diuretic Treated Patients: In hypertensive patients who are currently being treated with a diuretic,
symptomatic hypotension may occur occasionally following the initial dose of PRINIVIL. The diuretic
should be discontinued, if possible, for two to three days before beginning therapy with PRINIVIL to
reduce the likelihood of hypotension. (See WARNINGS.) The dosage of PRINIVIL should be adjusted
according to blood pressure response. If the patient's blood pressure is not controlled with PRINIVIL
alone, diuretic therapy may be resumed as described above.
If the diuretic cannot be discontinued, an initial dose of 5 mg should be used under medical
supervision for at least two hours and until blood pressure has stabilized for at least an additional hour.
(See WARNINGS and PRECAUTIONS, Drug Interactions.)
Concomitant administration of PRINIVIL with potassium supplements, potassium salt substitutes, or
potassium-sparing diuretics may lead to increases of serum potassium (see PRECAUTIONS).
Dosage Adjustment in Renal Impairment: The usual dose of PRINIVIL (10 mg) is recommended for
patients with a creatinine clearance >30 mL/min (serum creatinine of up to approximately 3 mg/dL). For
patients with creatinine clearance 10 mL/min 30 mL/min (serum creatinine 3 mg/dL), the first dose is
5 mg once daily. For patients with creatinine clearance <10 mL/min (usually on hemodialysis) the
recommended initial dose is 2.5 mg. The dosage may be titrated upward until blood pressure is controlled
or to a maximum of 40 mg daily.
Renal Status
Creatinine-
Initial Dose
Clearance
mg/day
mL/min
Normal Renal Function to Mild
>30 mL/min
10 mg
Impairment
Moderate to Severe
10 30 mL/min
5 mg
Impairment
Dialysis Patients**
<10 mL/min
2.5 mg***
** See WARNINGS, Anaphylactoid reactions during membrane exposure
*** Dosage or dosing interval should be adjusted depending on the blood pressure response.
Heart Failure
PRINIVIL is indicated as adjunctive therapy with diuretics and (usually) digitalis. The recommended
starting dose is 5 mg once a day.
When initiating treatment with lisinopril in patients with heart failure, the initial dose should be
administered under medical observation, especially in those patients with low blood pressure (systolic
blood pressure below 100 mmHg). The mean peak blood pressure lowering occurs six to eight hours
after dosing. Observation should continue until blood pressure is stable. The concomitant diuretic dose
should be reduced, if possible, to help minimize hypovolemia which may contribute to hypotension. (See
WARNINGS and PRECAUTIONS, Drug Interactions.) The appearance of hypotension after the initial
dose of PRINIVIL does not preclude subsequent careful dose titration with the drug, following effective
management of the hypotension.
The usual effective dosage range is 5 to 20 mg per day administered as a single daily dose.
Dosage Adjustment in Patients with Heart Failure and Renal Impairment or Hyponatremia: In patients
with heart failure who have hyponatremia (serum sodium <130 mEq/L) or moderate to severe renal
14
Reference ID: 3099778
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
9763206
impairment (creatinine clearance 30 mL/min or serum creatinine >3 mg/dL), therapy with PRINIVIL
should be initiated at a dose of 2.5 mg once a day under close medical supervision. (See WARNINGS
and PRECAUTIONS, Drug Interactions.)
Acute Myocardial Infarction
In hemodynamically stable patients within 24 hours of the onset of symptoms of acute myocardial
infarction, the first dose of PRINIVIL is 5 mg given orally, followed by 5 mg after 24 hours, 10 mg after 48
hours and then 10 mg of PRINIVIL once daily. Dosing should continue for six weeks. Patients should
receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin and beta-
blockers. Patients with a low systolic blood pressure (120 mmHg) when treatment is started or during
the first 3 days after the infarct should be given a lower 2.5 mg oral dose of PRINIVIL (see WARNINGS).
If hypotension occurs (systolic blood pressure 100 mmHg) a daily maintenance dose of 5 mg may be
given with temporary reductions to 2.5 mg if needed. If prolonged hypotension occurs (systolic blood
pressure <90 mmHg for more than 1 hour) PRINIVIL should be withdrawn. For patients who develop
symptoms of heart failure, see DOSAGE AND ADMINISTRATION, Heart Failure.
Dosage Adjustment in Patients with Myocardial Infarction with Renal Impairment: In acute myocardial
infarction, treatment with PRINIVIL should be initiated with caution in patients with evidence of renal
dysfunction, defined as serum creatinine concentration exceeding 2 mg/dL. No evaluation of dosage
adjustment in myocardial infarction patients with severe renal impairment has been performed.
Use in Elderly
In general, blood pressure response and adverse experiences were similar in younger and older
patients given similar doses of PRINIVIL. Pharmacokinetic studies, however, indicate that maximum
blood levels and area under the plasma concentration time curve (AUC) are doubled in older patients, so
that dosage adjustments should be made with particular caution.
Pediatric Hypertensive Patients 6 years of age
The usual recommended starting dose is 0.07 mg/kg once daily (up to 5 mg total). Dosage should be
adjusted according to blood pressure response. Doses above 0.61 mg/kg (or in excess of 40 mg) have
not been studied in pediatric patients. (See CLINICAL PHARMACOLOGY, Pharmacokinetics and
Metabolism and Pharmacodynamics and Clinical Effects.)
PRINIVIL is not recommended in pediatric patients <6 years or in pediatric patients with glomerular
filtration rate <30 mL/min/1.73 m2 (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism,
Pharmacodynamics and Clinical Effects and PRECAUTIONS).
Preparation of Suspension (for 200 mL of a 1.0 mg/mL suspension)
Add 10 mL of Purified Water USP to a polyethylene terephthalate (PET) bottle containing ten 20-mg
tablets of PRINIVIL and shake for at least one minute. Add 30 mL of Bicitra®** diluent and 160 mL of Ora-
Sweet SF™*** to the concentrate in the PET bottle and gently shake for several seconds to disperse the
ingredients. The suspension should be stored at or below 25°C (77°F) and can be stored for up to four
weeks. Shake the suspension before each use.
HOW SUPPLIED
No. 8110 — Tablets PRINIVIL, 5 mg, are white, oval shaped compressed tablets with code MSD 19
on one side and scored on the other side. They are supplied as follows:
NDC 0006-0019-54 unit of use bottles of 90.
No. 8111 — Tablets PRINIVIL, 10 mg, are light yellow, oval shaped compressed tablets with code
MSD 106 on one side and scored on the other side. They are supplied as follows:
NDC 0006-0106-54 unit of use bottles of 90.
No. 8112 — Tablets PRINIVIL, 20 mg, are peach, oval shaped compressed tablets with code
MSD 207 on one side and scored on the other side. They are supplied as follows:
NDC 0006-0207-54 unit of use bottles of 90.
Storage
Store at controlled room temperature, 15-30°C (59-86°F), and protect from moisture.
** Registered trademark of Alza Corporation
*** Trademark of Paddock Laboratories, Inc.
15
Reference ID: 3099778
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
9763206
company logo
by:
MERCK SHARP & DOHME LTD.
Cramlington, Northumberland, UK NE23 3JU
Issued November 2011
Copyright © 1988, 1989, 1992, 1993, 1995, 2005, 2006, 2011 Merck Sharp & Dohme Corp., a subsidiary
of Merck & Co., Inc.
All rights reserved
16
Reference ID: 3099778
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/
MARY R SOUTHWORTH
11/17/2011
Reference ID: 3099778
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:28.144635
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019558Orig1s054Lbl_REPLACEMENTS.pdf', 'application_number': 19558, 'submission_type': 'SUPPL ', 'submission_number': 54}
|
11,534
|
company logo
USPI-T-05211212R008
TABLETS
PRINIVIL®
(LISINOPRIL)
WARNING: FETAL TOXICITY
•
When pregnancy is detected, discontinue PRINIVIL 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
PRINIVIL® (Lisinopril), a synthetic peptide derivative, is an oral long-acting angiotensin converting
enzyme inhibitor. Lisinopril is chemically described as (S)-1-[N2-(1-carboxy-3-phenylpropyl)-L-lysyl]-L
proline dihydrate. Its empirical formula is C21H31N3O5•2H2O and its structural formula is: structural formula
Lisinopril is a white to off-white, crystalline powder, with a molecular weight of 441.52. It is soluble in
water and sparingly soluble in methanol and practically insoluble in ethanol.
PRINIVIL is supplied as 5 mg, 10 mg, and 20 mg tablets for oral administration. In addition to the
active ingredient lisinopril, each tablet contains the following inactive ingredients: calcium phosphate,
mannitol, magnesium stearate, and starch. The 10 mg and 20 mg tablets also contain iron oxide.
CLINICAL PHARMACOLOGY
Mechanism of Action
Lisinopril inhibits angiotensin converting enzyme (ACE) in human subjects and animals. ACE is a
peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance,
angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. The beneficial
effects of lisinopril in hypertension and heart failure appear to result primarily from suppression of the
renin-angiotensin-aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II which
leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease
may result in a small increase of serum potassium. In hypertensive patients with normal renal function
treated with PRINIVIL alone for up to 24 weeks, the mean increase in serum potassium was
approximately 0.1 mEq/L; however, approximately 15 percent of patients had increases greater than
0.5 mEq/L and approximately six percent had a decrease greater than 0.5 mEq/L. In the same study,
patients treated with PRINIVIL and hydrochlorothiazide for up to 24 weeks had a mean decrease in
serum potassium of 0.1 mEq/L; approximately 4 percent of patients had increases greater than 0.5 mEq/L
and approximately 12 percent had a decrease greater than 0.5 mEq/L. (See PRECAUTIONS.) Removal
of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.
ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of
bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of PRINIVIL remains to
be elucidated.
While the mechanism through which PRINIVIL lowers blood pressure is believed to be primarily
suppression of the renin-angiotensin-aldosterone system, PRINIVIL is antihypertensive even in patients
with low-renin hypertension. Although PRINIVIL was antihypertensive in all races studied, Black
hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to
monotherapy than non-Black patients.
1
Reference ID: 3267147
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211212R008
Concomitant administration of PRINIVIL and hydrochlorothiazide further reduced blood pressure in
Black and non-Black patients and any racial difference in blood pressure response was no longer
evident.
Pharmacokinetics and Metabolism
Adult Patients: Following oral administration of PRINIVIL, peak serum concentrations of lisinopril occur
within about 7 hours, although there was a trend to a small delay in time taken to reach peak serum
concentrations in acute myocardial infarction patients. Declining serum concentrations exhibit a
prolonged terminal phase which does not contribute to drug accumulation. This terminal phase probably
represents saturable binding to ACE and is not proportional to dose. Lisinopril does not appear to be
bound to other serum proteins.
Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine. Based on
urinary recovery, the mean extent of absorption of lisinopril is approximately 25 percent, with large inter-
subject variability (6-60 percent) at all doses tested (5-80 mg). Lisinopril absorption is not influenced by
the presence of food in the gastrointestinal tract. The absolute bioavailability of lisinopril is reduced to
about 16 percent in patients with stable NYHA Class II-IV congestive heart failure, and the volume of
distribution appears to be slightly smaller than that in normal subjects.
The oral bioavailability of lisinopril in patients with acute myocardial infarction is similar to that in
healthy volunteers.
Upon multiple dosing, lisinopril exhibits an effective half-life of accumulation of 12 hours.
Impaired renal function decreases elimination of lisinopril, which is excreted principally through the
kidneys, but this decrease becomes clinically important only when the glomerular filtration rate is below
30 mL/min. Above this glomerular filtration rate, the elimination half-life is little changed. With greater
impairment, however, peak and trough lisinopril levels increase, time to peak concentration increases and
time to attain steady state is prolonged. Older patients, on average, have (approximately doubled) higher
blood levels and area under the plasma concentration time curve (AUC) than younger patients. (See
DOSAGE AND ADMINISTRATION.) Lisinopril can be removed by hemodialysis.
Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly. Multiple doses of lisinopril
in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following
administration of 14C lisinopril. By whole body autoradiography, radioactivity was found in the placenta
following administration of labeled drug to pregnant rats, but none was found in the fetuses.
Pediatric Patients: The pharmacokinetics of lisinopril were studied in 29 pediatric hypertensive
patients between 6 years and 16 years with glomerular filtration rate >30 mL/min/1.73 m2. After doses of
0.1 to 0.2 mg/kg, steady state peak plasma concentrations of lisinopril occurred within 6 hours and the
extent of absorption based on urinary recovery was about 28%. These values are similar to those
obtained previously in adults. The typical value of lisinopril oral clearance (systemic clearance/absolute
bioavailability) in a child weighing 30 kg is 10 L/h, which increases in proportion to renal function.
Pharmacodynamics and Clinical Effects
Hypertension:
Adult Patients: Administration of PRINIVIL to patients with hypertension results in a reduction of
supine and standing blood pressure to about the same extent with no compensatory tachycardia.
Symptomatic postural hypotension is usually not observed although it can occur and should be
anticipated in volume and/or salt-depleted patients. (See WARNINGS.) When given together with
thiazide-type diuretics, the blood pressure lowering effects of the two drugs are approximately additive.
In most patients studied, onset of antihypertensive activity was seen at one hour after oral
administration of an individual dose of PRINIVIL, with peak reduction of blood pressure achieved by six
hours. Although an antihypertensive effect was observed 24 hours after dosing with recommended single
daily doses, the effect was more consistent and the mean effect was considerably larger in some studies
with doses of 20 mg or more than with lower doses. However, at all doses studied, the mean
antihypertensive effect was substantially smaller 24 hours after dosing than it was six hours after dosing.
In some patients achievement of optimal blood pressure reduction may require two to four weeks of
therapy.
The antihypertensive effects of PRINIVIL are maintained during long-term therapy. Abrupt withdrawal
of PRINIVIL has not been associated with a rapid increase in blood pressure or a significant increase in
blood pressure compared to pretreatment levels.
2
Reference ID: 3267147
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211212R008
Two dose-response studies utilizing a once daily regimen were conducted in 438 mild to moderate
hypertensive patients not on a diuretic. Blood pressure was measured 24 hours after dosing. An
antihypertensive effect of PRINIVIL was seen with 5 mg in some patients. However, in both studies blood
pressure reduction occurred sooner and was greater in patients treated with 10, 20, or 80 mg of
PRINIVIL. In controlled clinical studies, PRINIVIL 20-80 mg has been compared in patients with mild to
moderate hypertension to hydrochlorothiazide 12.5-50 mg and with atenolol 50-500 mg; and in patients
with moderate to severe hypertension to metoprolol 100-200 mg. It was superior to hydrochlorothiazide in
effects on systolic and diastolic blood pressure in a population that was ¾ Caucasian. PRINIVIL was
approximately equivalent to atenolol and metoprolol in effects on diastolic blood pressure and had
somewhat greater effects on systolic blood pressure.
PRINIVIL had similar effectiveness and adverse effects in younger and older (>65 years) patients. It
was less effective in Blacks than in Caucasians.
In hemodynamic studies in patients with essential hypertension, blood pressure reduction was
accompanied by a reduction in peripheral arterial resistance with little or no change in cardiac output and
in heart rate. In a study in nine hypertensive patients, following administration of PRINIVIL, there was an
increase in mean renal blood flow that was not significant. Data from several small studies are
inconsistent with respect to the effect of PRINIVIL on glomerular filtration rate in hypertensive patients
with normal renal function, but suggest that changes, if any, are not large.
In patients with renovascular hypertension PRINIVIL has been shown to be well tolerated and
effective in controlling blood pressure (see PRECAUTIONS).
Pediatric Patients: In a clinical study involving 115 hypertensive pediatric patients 6 to 16 years of age,
patients who weighed <50 kg received either 0.625, 2.5, or 20 mg of lisinopril daily and patients who
weighed ≥50 kg received either 1.25, 5, or 40 mg of lisinopril daily. At the end of 2 weeks, lisinopril
administered once daily lowered trough blood pressure in a dose-dependent manner with consistent
antihypertensive efficacy demonstrated at doses >1.25 mg (0.02 mg/kg). This effect was confirmed in a
withdrawal phase, where the diastolic pressure rose by about 9 mmHg more in patients randomized to
placebo than it did in patients who were randomized to remain on the middle and high doses of lisinopril.
The dose-dependent antihypertensive effect of lisinopril was consistent across several demographic
subgroups: age, Tanner stage, gender, race. In this study, lisinopril was generally well-tolerated.
In the above pediatric studies, lisinopril was given either as tablets or in a suspension for those
children and infants who were unable to swallow tablets or who required a lower dose than is available in
tablet form (see DOSAGE AND ADMINISTRATION, Preparation of Suspension).
Heart Failure:
During baseline-controlled clinical trials, in patients receiving digitalis and diuretics, single doses of
PRINIVIL resulted in decreases in pulmonary capillary wedge pressure, systemic vascular resistance and
blood pressure accompanied by an increase in cardiac output and no change in heart rate.
In two placebo-controlled, 12-week clinical studies using doses of PRINIVIL up to 20 mg, PRINIVIL as
adjunctive therapy to digitalis and diuretics improved the following signs and symptoms due to congestive
heart failure: edema, rales, paroxysmal nocturnal dyspnea and jugular venous distention. In one of the
studies beneficial response was also noted for: orthopnea, presence of third heart sound and the number
of patients classified as NYHA Class III and IV. Exercise tolerance was also improved in this study. The
effect of lisinopril on mortality in patients with heart failure has not been evaluated.
The once daily dosing for the treatment of congestive heart failure was the only dosage regimen used
during clinical trial development and was determined by the measurement of hemodynamic responses.
Acute Myocardial Infarction:
The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI - 3) study was a
multicenter, controlled, randomized, unblinded clinical trial conducted in 19,394 patients with acute
myocardial infarction admitted to a coronary care unit. It was designed to examine the effects of short-
term (6 week) treatment with lisinopril, nitrates, their combination, or no therapy on short-term (6 week)
mortality and on long-term death and markedly impaired cardiac function. Patients presenting within 24
hours of the onset of symptoms who were hemodynamically stable were randomized, in a 2 x 2 factorial
design, to six weeks of either
1) PRINIVIL alone (n=4841),
2) nitrates alone (n=4869),
3
Reference ID: 3267147
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211212R008
3) PRINIVIL plus nitrates (n=4841), or
4) open control (n=4843).
All patients received routine therapies, including thrombolytics (72%), aspirin (84%), and a beta-
blocker (31%), as appropriate, normally utilized in acute myocardial infarction (MI) patients.
The protocol excluded patients with hypotension (systolic blood pressure ≤100 mmHg), severe heart
failure, cardiogenic shock and renal dysfunction (serum creatinine >2 mg/dL and/or proteinuria
>500 mg/24 h). Doses of PRINIVIL were adjusted as necessary according to protocol. (See DOSAGE
AND ADMINISTRATION.)
Study treatment was withdrawn at six weeks except where clinical conditions indicated continuation of
treatment.
The primary outcomes of the trial were the overall mortality at six weeks and a combined endpoint at
six months after the myocardial infarction, consisting of the number of patients who died, had late (day 4)
clinical congestive heart failure, or had extensive left ventricular damage defined as ejection fraction
≤35%, or an akinetic-dyskinetic [A-D] score ≥45%. Patients receiving PRINIVIL (n=9646) alone or with
nitrates, had an 11 percent lower risk of death (2p [two-tailed]=0.04) compared to patients receiving no
PRINIVIL (n=9672) (6.4 percent versus 7.2 percent, respectively) at six weeks. Although patients
randomized to receive PRINIVIL for up to six weeks also fared numerically better on the combined end
point at 6 months, the open nature of the assessment of heart failure, substantial loss to follow-up
echocardiography, and substantial excess use of lisinopril between 6 weeks and 6 months in the group
randomized to 6 weeks of lisinopril, preclude any conclusion about this endpoint.
Patients with acute myocardial infarction, treated with PRINIVIL had a higher (9.0 percent versus 3.7
percent, respectively) incidence of persistent hypotension (systolic blood pressure <90 mmHg for more
than 1 hour) and renal dysfunction (2.4 percent versus 1.1 percent) in-hospital and at six weeks
(increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum
creatinine concentration). (See ADVERSE REACTIONS, ACUTE MYOCARDIAL INFARCTION.)
INDICATIONS AND USAGE
Hypertension
PRINIVIL is indicated for the treatment of hypertension. It may be used alone as initial therapy or
concomitantly with other classes of antihypertensive agents.
Heart Failure
PRINIVIL is indicated as adjunctive therapy in the management of heart failure in patients who are not
responding adequately to diuretics and digitalis.
Acute Myocardial Infarction
PRINIVIL is indicated for the treatment of hemodynamically stable patients within 24 hours of acute
myocardial infarction, to improve survival. Patients should receive, as appropriate, the standard
recommended treatments such as thrombolytics, aspirin and beta-blockers.
In using PRINIVIL, consideration should be given to the fact that another angiotensin converting
enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or
collagen vascular disease, and that available data are insufficient to show that PRINIVIL does not have a
similar risk. (See WARNINGS.)
In considering use of PRINIVIL, it should be noted that in controlled clinical trials ACE inhibitors have
an effect on blood pressure that is less in Black patients than in non-Blacks. In addition, it should be
noted that Black patients receiving ACE inhibitors have been reported to have a higher incidence of
angioedema compared to non-Blacks (see WARNINGS, Anaphylactoid and Possibly Related Reactions,
Head and Neck Angioedema).
CONTRAINDICATIONS
PRINIVIL is contraindicated in patients who are hypersensitive to this product and in patients with a
history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor and
in patients with hereditary or idiopathic angioedema.
Do not coadminister aliskiren with PRINIVIL in patients with diabetes.
4
Reference ID: 3267147
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211212R008
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
PRINIVIL) may be subject to a variety of adverse reactions, some of them serious.
Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx
has been reported in patients treated with angiotensin converting enzyme inhibitors, including PRINIVIL.
This may occur at any time during treatment. ACE inhibitors have been associated with a higher rate of
angioedema in Black than in non-Black patients. In such cases PRINIVIL should be promptly
discontinued and appropriate therapy and monitoring should be provided until complete and sustained
resolution of signs and symptoms has occurred. Even in those instances where swelling of only the
tongue is involved, without respiratory distress, patients may require prolonged observation since
treatment with antihistamines and corticosteroids may not be sufficient. Very rarely, fatalities have been
reported due to angioedema associated with laryngeal edema or tongue edema. Patients with
involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those
with a history of airway surgery. Where there is involvement of the tongue, glottis or larynx, likely to
cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000
(0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly
provided. (See ADVERSE REACTIONS.)
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of
angioedema while receiving an ACE inhibitor (see also INDICATIONS AND USAGE and
CONTRAINDICATIONS).
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: Sudden and potentially life-threatening
anaphylactoid reactions have been reported in some patients dialyzed with high-flux membranes (e.g.,
AN69®) and treated concomitantly with an ACE inhibitor. In such patients, dialysis must be stopped
immediately, and aggressive therapy for anaphylactoid reactions be initiated. Symptoms have not been
relieved by antihistamines in these situations. In these patients, consideration should be given to using a
different type of dialysis membrane or a different class of antihypertensive agent. Anaphylactoid reactions
have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate
absorption.
Hypotension
Excessive hypotension is rare in patients with uncomplicated hypertension treated with PRINIVIL
alone.
Patients with heart failure given PRINIVIL commonly have some reduction in blood pressure with peak
blood pressure reduction occurring 6 to 8 hours post dose, but discontinuation of therapy because of
continuing symptomatic hypotension usually is not necessary when dosing instructions are followed;
caution should be observed when initiating therapy. (See DOSAGE AND ADMINISTRATION.)
Patients at risk of excessive hypotension, sometimes associated with oliguria and/or progressive
azotemia, and rarely with acute renal failure and/or death, include those with the following conditions or
characteristics: heart failure with systolic blood pressure below 100 mmHg, hyponatremia, high-dose
diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume
and/or salt depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with
heart failure), reduce the diuretic dose or increase salt intake cautiously before initiating therapy with
5
Reference ID: 3267147
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211212R008
PRINIVIL in patients at risk for excessive hypotension who are able to tolerate such adjustments. (See
PRECAUTIONS, Drug Interactions, and ADVERSE REACTIONS.)
Patients with acute myocardial infarction in the GISSI - 3 study had a higher (9.0 percent versus 3.7
percent) incidence of persistent hypotension (systolic blood pressure <90 mmHg for more than 1 hour)
when treated with PRINIVIL. Treatment with PRINIVIL must not be initiated in acute myocardial infarction
patients at risk of further serious hemodynamic deterioration after treatment with a vasodilator (e.g.,
systolic blood pressure of 100 mmHg or lower) or cardiogenic shock.
In patients at risk of excessive hypotension, therapy should be started under very close medical
supervision and such patients should be followed closely for the first two weeks of treatment and
whenever the dose of PRINIVIL and/or diuretic is increased. Similar considerations may apply to patients
with ischemic heart or cerebrovascular disease, or in patients with acute myocardial infarction, in whom
an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary,
receive an intravenous infusion of normal saline. A transient hypotensive response is not a
contraindication to further doses of PRINIVIL which usually can be given without difficulty once the blood
pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of
PRINIVIL or concomitant diuretic may be necessary.
Leukopenia/Neutropenia/Agranulocytosis
Another angiotensin converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis
and bone marrow depression, rarely in uncomplicated patients but more frequently in patients with renal
impairment especially if they also have a collagen vascular disease. Available data from clinical trials of
PRINIVIL are insufficient to show that PRINIVIL does not cause agranulocytosis at similar rates.
Marketing experience has revealed rare cases of leukopenia/neutropenia and bone marrow depression in
which a causal relationship to lisinopril cannot be excluded. Periodic monitoring of white blood cell counts
in patients with collagen vascular disease and renal disease should be considered.
Hepatic Failure
Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or
hepatitis 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.
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 PRINIVIL as soon as possible. These adverse outcomes are usually
associated with the use of these drugs in the second and third trimester of pregnancy. Most
epidemiologic studies examining fetal abnormalities after exposure 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 mother and fetus.
In the unusual case that there is no appropriate alternative therapy to 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 PRINIVIL, 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 PRINIVIL for hypotension, oliguria, and hyperkalemia (see
Precautions, Pediatric Use).
No teratogenic effects of lisinopril were seen in studies of pregnant mice, rats, and rabbits. On a body
surface area basis, the doses used were 55 times, 33 times, and 0.15 times, respectively, the maximum
recommended human daily dose (MRHDD).
6
Reference ID: 3267147
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211212R008
PRECAUTIONS
General
Aortic Stenosis/Hypertrophic Cardiomyopathy: As with all vasodilators, lisinopril should be given with
caution to patients with obstruction in the outflow tract of the left ventricle.
Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system,
changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive
heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone
system, treatment with angiotensin converting enzyme inhibitors, including PRINIVIL, may be associated
with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.
In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea
nitrogen and serum creatinine may occur. Experience with another angiotensin converting enzyme
inhibitor suggests that these increases are usually reversible upon discontinuation of PRINIVIL and/or
diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy.
Some patients with hypertension or heart failure with no apparent pre-existing renal vascular disease
have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient,
especially when PRINIVIL has been given concomitantly with a diuretic. This is more likely to occur in
patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or
PRINIVIL may be required.
Patients with acute myocardial infarction in the GISSI - 3 study, treated with PRINIVIL, had a higher
(2.4 percent versus 1.1 percent) incidence of renal dysfunction in-hospital and at six weeks (increasing
creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum creatinine
concentration). In acute myocardial infarction, treatment with PRINIVIL should be initiated with caution in
patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding
2 mg/dL. If renal dysfunction develops during treatment with PRINIVIL (serum creatinine concentration
exceeding 3 mg/dL or a doubling from the pre-treatment value) then the physician should consider
withdrawal of PRINIVIL.
Evaluation of patients with hypertension, heart failure, or myocardial infarction should always
include assessment of renal function. (See DOSAGE AND ADMINISTRATION.)
Hyperkalemia: In clinical trials hyperkalemia (serum potassium greater than 5.7 mEq/L) occurred in
approximately 2.2 percent of hypertensive patients and 4.8 percent of patients with heart failure. In most
cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause
of discontinuation of therapy in approximately 0.1 percent of hypertensive patients, 0.6 percent of patients
with heart failure and 0.1 percent of patients with myocardial infarction. Risk factors for the development
of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-
sparing diuretics, potassium supplements and/or potassium-containing salt substitutes. Hyperkalemia can
cause serious, sometimes fatal, arrhythmias. PRINIVIL should be used cautiously, if at all, with these
agents and with frequent monitoring of serum potassium. (See Drug Interactions.)
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.
Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that
produce hypotension, PRINIVIL may 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.
Information for Patients
Angioedema: Angioedema, including laryngeal edema, may occur at any time during treatment with
angiotensin converting enzyme inhibitors, including lisinopril. Patients should be so advised and told to
report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes,
lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have consulted with
the prescribing physician.
Symptomatic Hypotension: Patients should be cautioned to report lightheadedness especially during
the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug
until they have consulted with the prescribing physician.
7
Reference ID: 3267147
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211212R008
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
their physician.
Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without
consulting their physician.
Hypoglycemia: Diabetic patients treated with oral antidiabetic agents or insulin starting an ACE
inhibitor should be told to closely monitor for hypoglycemia, especially during the first month of combined
use. (See Drug Interactions.)
Leukopenia/Neutropenia: Patients should be told to report promptly any indication of infection (e.g.,
sore throat, fever) which may be a sign of leukopenia/neutropenia.
Pregnancy: Female patients of childbearing age should be told about the consequences of exposure
to PRINIVIL 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
Hypotension - Patients on Diuretic Therapy: Patients on diuretics, and especially those in whom
diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood
pressure after initiation of therapy with PRINIVIL. The possibility of hypotensive effects with PRINIVIL can
be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment
with PRINIVIL. If it is necessary to continue the diuretic, initiate therapy with PRINIVIL at a dose of 5 mg
daily, and provide close medical supervision after the initial dose until blood pressure has stabilized. (See
WARNINGS and DOSAGE AND ADMINISTRATION.) When a diuretic is added to the therapy of a
patient receiving PRINIVIL, an additional antihypertensive effect is usually observed. Studies with ACE
inhibitors in combination with diuretics indicate that the dose of the ACE inhibitor can be reduced when it
is given with a diuretic. (See DOSAGE AND ADMINISTRATION.)
Antidiabetics: Epidemiological studies have suggested that concomitant administration of ACE
inhibitors and antidiabetic medicines (insulins, oral hypoglycemic agents) may cause an increased blood
glucose-lowering effect with risk of hypoglycemia. This phenomenon appeared to be more likely to occur
during the first weeks of combined treatment and in patients with renal impairment. In diabetic patients
treated with oral antidiabetic agents or insulin, glycemic control should be closely monitored for
hypoglycemia, especially during the first month of treatment with an ACE inhibitor.
Non-steroidal Anti-inflammatory Agents Including Selective Cyclooxygenase-2 (COX-2) Inhibitors:
Reports suggest that NSAIDs including selective COX-2 inhibitors may diminish the antihypertensive
effect of ACE inhibitors, including lisinopril. This interaction should be given consideration in patients
taking NSAIDs or selective COX-2 inhibitors concomitantly with ACE inhibitors.
In a study in 36 patients with mild to moderate hypertension where the antihypertensive effects of
PRINIVIL alone were compared to PRINIVIL given concomitantly with indomethacin, the use of
indomethacin was associated with a reduced antihypertensive effect, although the difference between the
two regimens was not significant.
In some patients with compromised renal function (e.g., elderly patients or patients who are volume-
depleted including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory
drugs, including selective COX-2 inhibitors, the co-administration of angiotensin II receptor antagonists or
ACE inhibitors may result in a further deterioration of renal function, including possible acute renal failure.
These effects are usually reversible.
These interactions should be considered in patients taking NSAIDS including selective COX-2
inhibitors concomitantly with diuretics and angiotensin II antagonists or ACE inhibitors. Therefore, monitor
effects on blood pressure and renal function when administering the combination, especially in the
elderly.
Dual Blockade of the Renin-angiotensin-aldosterone System: Dual blockade of the renin-angiotensin
aldosterone system (RAAS) with angiotensin receptor blockers, ACE inhibitors, or direct renin inhibitors
(such as aliskiren) is associated with increased risks of hypotension, syncope, hyperkalemia, and
changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood
pressure, renal function, and electrolytes in patients on PRINIVIL and other agents that affect the RAAS.
8
Reference ID: 3267147
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211212R008
Do not coadminister aliskiren with PRINIVIL in patients with diabetes. Avoid use of aliskiren with
PRINIVIL in patients with renal impairment (GFR <60ml/min).
Other Agents: PRINIVIL has been used concomitantly with nitrates and/or digoxin without evidence of
clinically significant adverse interactions. This included post myocardial infarction patients who were
receiving intravenous or transdermal nitroglycerin. No clinically important pharmacokinetic interactions
occurred when PRINIVIL was used concomitantly with propranolol or hydrochlorothiazide. The presence
of food in the stomach does not alter the bioavailability of PRINIVIL.
Agents Increasing Serum Potassium: PRINIVIL attenuates potassium loss caused by thiazide-type
diuretics. Use of PRINIVIL with potassium-sparing diuretics (e.g., spironolactone, eplerenone,
triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to
significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated
because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of
serum potassium. Potassium-sparing agents should generally not be used in patients with heart failure
who are receiving PRINIVIL.
Lithium: Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which
cause elimination of sodium, including ACE inhibitors. Lithium toxicity was usually reversible upon
discontinuation of lithium and the ACE inhibitor. It is recommended that serum lithium levels be monitored
frequently if PRINIVIL is administered concomitantly with lithium.
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 PRINIVIL.
Carcinogenesis, Mutagenesis, Impairment of Fertility
There was no evidence of a tumorigenic effect when lisinopril was administered orally for 105 weeks
to male and female rats at doses up to 90 mg/kg/day or for 92 weeks to male and female mice at doses
up to 135 mg/kg/day. These doses are 10 times and 7 times, respectively, the maximum recommended
human daily dose (MRHDD) when compared on a body surface area basis.
Lisinopril was not mutagenic in the Ames microbial mutagen test with or without metabolic activation.
It was also negative in a forward mutation assay using Chinese hamster lung cells. Lisinopril did not
produce single strand DNA breaks in an in vitro alkaline elution rat hepatocyte assay. In addition, lisinopril
did not produce increases in chromosomal aberrations in an in vitro test in Chinese hamster ovary cells
or in an in vivo study in mouse bone marrow.
There were no adverse effects on reproductive performance in male and female rats treated with up to
300 mg/kg/day of lisinopril (33 times the MRHDD when compared on a body surface area basis).
Nursing Mothers
Milk of lactating rats contains radioactivity following administration of 14C lisinopril. It is not known
whether this drug is secreted in human milk. Because many drugs are secreted in human milk, and
because of the potential for serious adverse reactions in nursing infants from ACE inhibitors, a decision
should be made whether to discontinue nursing or discontinue PRINIVIL, taking into account the
importance of the drug to the mother.
Pediatric Use
Neonates with a history of in utero exposure to PRINIVIL:
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. Lisinopril, which crosses the placenta, has been removed from
neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by
exchange transfusion, although there is no experience with the latter procedure.
Antihypertensive effects of PRINIVIL have been established in hypertensive pediatric patients aged 6
to 16 years.
There are no data on the effect of PRINIVIL on blood pressure in pediatric patients under the age of 6
or in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m2 (see CLINICAL
PHARMACOLOGY, Pharmacokinetics and Metabolism and Pharmacodynamics and Clinical Effects, and
DOSAGE AND ADMINISTRATION).
9
Reference ID: 3267147
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211212R008
Geriatric Use
Clinical studies of PRINIVIL in patients with hypertension and congestive heart failure did not include
sufficient numbers of subjects aged 65 and over to determine whether they respond differently from
younger subjects. Other clinical experience in this population 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.
In a clinical study of PRINIVIL in patients with myocardial infarctions 4413 (47 percent) were 65 and
over, while 1656 (18 percent) were 75 and over. No overall differences in safety or efficacy were
observed between elderly and younger patients.
Other reported clinical experience has not identified differences in responses between elderly and
younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Pharmacokinetic studies indicate that maximum blood levels and area under plasma concentration
time curve (AUC) are doubled in elderly patients.
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. Evaluation of patients with
hypertension, congestive heart failure, or myocardial infarction should always include assessment of
renal function. (See DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
PRINIVIL has been found to be generally well tolerated in controlled clinical trials involving 1969
patients with hypertension or heart failure. For the most part, adverse experiences were mild and
transient.
HYPERTENSION
In clinical trials in patients with hypertension treated with PRINIVIL, discontinuation of therapy due to
clinical adverse experiences occurred in 5.7 percent of patients. The overall frequency of adverse
experiences could not be related to total daily dosage within the recommended therapeutic dosage range.
For adverse experiences occurring in greater than one percent of patients with hypertension treated
with PRINIVIL or PRINIVIL plus hydrochlorothiazide in controlled clinical trials and more frequently with
PRINIVIL and/or PRINIVIL plus hydrochlorothiazide than placebo, comparative incidence data are listed
in table 1 below:
10
Reference ID: 3267147
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211212R008
Body As A Whole
Fatigue
Asthenia
Orthostatic
Effects
Cardiovascular
Hypotension
Digestive
Diarrhea
Nausea
Vomiting
Dyspepsia
Musculoskeletal
Muscle Cramps
Nervous/Psychiatric
Headache
Dizziness
Paresthesia
Decreased Libido
Vertigo
Respiratory
Cough
Upper Respiratory
Infection
Common Cold
Nasal Congestion
Influenza
Skin
Rash
Urogenital
Impotence
PRINIVIL
(n=1349)
Incidence
(discontinuatio
n)
2.5 (0.3)
4.0 (0.5)
1.0 (0.0)
1.3 (0.5)
2.1 (0.2)
1.0 (0.0)
1.2 (0.0)
3.5 (0.2)
1.0 (0.0)
1.2 (0.5)
1.6 (0.5)
0.5 (0.5)
2.7 (0.2)
2.7 (0.3)
2.4 (0.0)
2.0 (0.4)
2.5 (0.2)
2.4 (0.0)
1.1 (0.2)
1.4 (0.1)
0.5 (0.0)
0.9 (0.0)
1.9 (0.0)
0.0 (0.0)
0.5 (0.0)
2.9 (0.8)
0.5 (0.0)
5.7 (0.2)
4.5 (0.5)
1.9 (0.0)
5.4 (0.4)
9.2 (1.0)
1.9 (0.0)
0.8 (0.1)
2.1 (0.2)
0.0 (0.0)
0.4 (0.1)
1.3 (0.1)
0.0 (0.0)
0.2 (0.1)
1.1 (0.2)
0.0 (0.0)
3.5 (0.7)
4.6 (0.8)
1.0 (0.0)
2.1 (0.1)
2.7 (0.1)
0.0 (0.0)
1.1 (0.1)
1.3 (0.1)
0.0 (0.0)
0.4 (0.1)
1.3 (0.1)
0.0 (0.0)
0.3 (0.1)
1.1 (0.1)
0.0 (0.0)
1.3 (0.4)
1.6 (0.2)
0.5 (0.5)
1.0 (0.4)
1.6 (0.5)
0.0 (0.0)
Table 1
Percent of Patients
in Controlled Studies
PRINIVIL/
Hydrochlorothiazi
de (n=629)
Incidence
(discontinuation)
Placebo
(n=207)
Incidence
(discontinuatio
n)
Chest pain and back pain were also seen but were more common on placebo than PRINIVIL.
HEART FAILURE
In patients with heart failure treated with PRINIVIL for up to four years, discontinuation of therapy due
to clinical adverse experiences occurred in 11.0 percent of patients. In controlled studies in patients with
heart failure, therapy was discontinued in 8.1 percent of patients treated with PRINIVIL for up to 12
weeks, compared to 7.7 percent of patients treated with placebo for 12 weeks.
The following table lists those adverse experiences which occurred in greater than one percent of
patients with heart failure treated with PRINIVIL or placebo for up to 12 weeks in controlled clinical trials
and more frequently on PRINIVIL than placebo.
11
Reference ID: 3267147
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211212R008
Table 2
Controlled Trials
PRINIVIL
Placebo
(n=407)
(n=155)
Incidence
Incidence
(discontinuation)
(discontinuation)
12 weeks
12 weeks
Body As A Whole
Chest Pain
Abdominal Pain
3.4 (0.2)
2.2 (0.7)
1.3 (0.0)
1.9 (0.0)
Cardiovascular
Hypotension
4.4 (1.7)
0.6 (0.6)
Digestive
Diarrhea
3.7 (0.5)
1.9 (0.0)
Nervous/Psychiatric
Dizziness
11.8 (1.2)
4.5 (1.3)
Headache
4.4 (0.2)
3.9 (0.0)
Respiratory
Upper Respiratory
Infection
1.5 (0.0)
1.3 (0.0)
Skin
Rash
1.7 (0.5)
0.6 (0.6)
Also observed at >1% with PRINIVIL but more frequent or as frequent on placebo than PRINIVIL in
controlled trials were asthenia, angina pectoris, nausea, dyspnea, cough and pruritus.
Worsening of heart failure, anorexia, increased salivation, muscle cramps, back pain, myalgia,
depression, chest sound abnormalities and pulmonary edema were also seen in controlled clinical trials,
but were more common on placebo than PRINIVIL.
ACUTE MYOCARDIAL INFARCTION
In the GISSI - 3 trial, in patients treated with PRINIVIL for six weeks following acute myocardial
infarction, discontinuation of therapy occurred in 17.6 percent of patients.
Patients treated with PRINIVIL had a significantly higher incidence of hypotension and renal
dysfunction compared with patients not taking PRINIVIL.
In the GISSI - 3 trial, hypotension (9.7 percent), renal dysfunction (2.0 percent), cough (0.5 percent),
post-infarction angina (0.3 percent), skin rash and generalized edema (0.01 percent), and angioedema
(0.01 percent) resulted in withdrawal of treatment. In elderly patients treated with PRINIVIL,
discontinuation due to renal dysfunction was 4.2 percent.
Other clinical adverse experiences occurring in 0.3 to 1.0 percent of patients with hypertension or
heart failure treated with PRINIVIL in controlled trials and rarer, serious, possibly drug-related events
reported in uncontrolled studies or marketing experience are listed below, and within each category, are
in order of decreasing severity:
Body as a Whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid and Possibly Related
Reactions), syncope, orthostatic effects, chest discomfort, pain, pelvic pain, flank pain, edema, facial
edema, virus infection, fever, chills, malaise.
Cardiovascular: Cardiac arrest; myocardial infarction or cerebrovascular accident, possibly secondary
to excessive hypotension in high-risk patients (see WARNINGS, Hypotension); pulmonary embolism and
infarction, arrhythmias (including ventricular tachycardia, atrial tachycardia, atrial fibrillation, bradycardia
and premature ventricular contractions), palpitations, transient ischemic attacks, paroxysmal nocturnal
dyspnea, orthostatic hypotension, decreased blood pressure, peripheral edema, vasculitis.
Digestive: Pancreatitis, hepatitis (hepatocellular or cholestatic jaundice) (see WARNINGS, Hepatic
Failure), vomiting, gastritis, dyspepsia, heartburn, gastrointestinal cramps, constipation, flatulence, dry
mouth.
Hematologic: Rare cases of bone marrow depression, hemolytic anemia, leukopenia/neutropenia, and
thrombocytopenia.
Endocrine: Diabetes mellitus, syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Metabolic: Weight loss, dehydration, fluid overload, gout, weight gain. Cases of hypoglycemia in
diabetic patients on oral antidiabetic agents or insulin have been reported (see PRECAUTIONS, Drug
Interactions).
Musculoskeletal: Arthritis, arthralgia, neck pain, hip pain, low back pain, joint pain, leg pain, knee pain,
shoulder pain, arm pain, lumbago.
12
Reference ID: 3267147
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211212R008
Nervous System/Psychiatric: Stroke, ataxia, memory impairment, tremor, peripheral neuropathy (e.g.,
dysesthesia), spasm, paresthesia, confusion, insomnia, somnolence, hypersomnia, irritability, and
nervousness.
Respiratory System: Malignant lung neoplasms, hemoptysis, pulmonary infiltrates, eosinophilic
pneumonitis, bronchospasm, asthma, pleural effusion, pneumonia, bronchitis, wheezing, orthopnea,
painful respiration, epistaxis, laryngitis, sinusitis, pharyngeal pain, pharyngitis, rhinitis, rhinorrhea.
Skin: Urticaria, alopecia, herpes zoster, photosensitivity, skin lesions, skin infections, pemphigus,
erythema, flushing, diaphoresis. Other severe skin reactions (including toxic epidermal necrolysis,
Stevens-Johnson syndrome and cutaneous pseudolymphoma) have been reported rarely; causal
relationship has not been established.
Special Senses: Visual loss, diplopia, blurred vision, tinnitus, photophobia, taste disturbances.
Urogenital System: Acute renal failure, oliguria, anuria, uremia, progressive azotemia, renal
dysfunction (see PRECAUTIONS and DOSAGE AND ADMINISTRATION), pyelonephritis, dysuria,
urinary tract infection, breast pain.
Miscellaneous: A symptom complex has been reported which may include a positive ANA, an
elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia and
leukocytosis. Rash, photosensitivity or other dermatological manifestations may occur alone or in
combination with these symptoms.
Angioedema: Angioedema has been reported in patients receiving PRINIVIL (0.1%) with an incidence
higher in Black than in non-Black patients. Angioedema associated with laryngeal edema may be fatal. If
angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with PRINIVIL
should be discontinued and appropriate therapy instituted immediately. In rare cases, intestinal
angioedema has been reported with angiotensin converting enzyme inhibitors including lisinopril. (See
WARNINGS.)
Hypotension: In hypertensive patients, hypotension occurred in 1.2 percent and syncope occurred in
0.1 percent of patients. Hypotension or syncope was a cause for discontinuation of therapy in 0.5 percent
of hypertensive patients. In patients with heart failure, hypotension occurred in 5.3 percent and syncope
occurred in 1.8 percent of patients. These adverse experiences were causes for discontinuation of
therapy in 1.8 percent of these patients. In patients treated with PRINIVIL for six weeks after acute
myocardial infarction, hypotension (systolic blood pressure ≤100 mmHg) resulted in discontinuation of
therapy in 9.7 percent of the patients. (See WARNINGS.)
Fetal/Neonatal Morbidity and Mortality: See WARNINGS, Fetal/Neonatal Morbidity and Mortality.
Cough: See PRECAUTIONS, Cough.
Pediatric Patients: No relevant differences between the adverse experience profile for pediatric
patients and that previously reported for adult patients were identified.
Clinical Laboratory Test Findings
Serum Electrolytes: Hyperkalemia (see PRECAUTIONS), hyponatremia.
Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen and serum creatinine,
reversible upon discontinuation of therapy, were observed in about 2.0 percent of patients with essential
hypertension treated with PRINIVIL alone. Increases were more common in patients receiving
concomitant diuretics and in patients with renal artery stenosis. (See PRECAUTIONS.) Reversible minor
increases in blood urea nitrogen and serum creatinine were observed in approximately 11.6 percent of
patients with heart failure on concomitant diuretic therapy. Frequently, these abnormalities resolved when
the dosage of the diuretic was decreased.
Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of
approximately 0.4 g percent and 1.3 vol percent, respectively) occurred frequently in patients treated with
PRINIVIL but were rarely of clinical importance in patients without some other cause of anemia. In clinical
trials, less than 0.1 percent of patients discontinued therapy due to anemia. Hemolytic anemia has been
reported; a causal relationship to lisinopril cannot be excluded.
Liver Function Tests: Rarely, elevations of liver enzymes and/or serum bilirubin have occurred (see
WARNINGS, Hepatic Failure).
In hypertensive patients, 2.0 percent discontinued therapy due to laboratory adverse experiences,
principally elevations in blood urea nitrogen (0.6 percent), serum creatinine (0.5 percent) and serum
potassium (0.4 percent). In the heart failure trials, 3.4 percent of patients discontinued therapy due to
13
Reference ID: 3267147
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211212R008
laboratory adverse experiences, 1.8 percent due to elevations in blood urea nitrogen and/or creatinine
and 0.6 percent due to elevations in serum potassium. In the myocardial infarction trial, 2.0 percent of
patients receiving PRINIVIL discontinued therapy due to renal dysfunction (increasing creatinine
concentration to over 3 mg/dL or a doubling or more of the baseline serum creatinine concentration); less
than 1.0 percent of patients discontinued therapy due to other laboratory adverse experiences: 0.1
percent with hyperkalemia and less than 0.1 percent with hepatic enzyme alterations.
OVERDOSAGE
Following a single oral dose of 20 g/kg, no lethality occurred in rats and death occurred in one of 20
mice receiving the same dose. The most likely manifestation of overdosage would be hypotension, for
which the usual treatment would be intravenous infusion of normal saline solution.
Lisinopril can be removed by hemodialysis. (See WARNINGS, Anaphylactoid reactions during
membrane exposure.)
DOSAGE AND ADMINISTRATION
Hypertension
Initial Therapy: In patients with uncomplicated essential hypertension not on diuretic therapy, the
recommended initial dose is 10 mg once a day. Dosage should be adjusted according to blood pressure
response. The usual dosage range is 20 to 40 mg per day administered in a single daily dose. The
antihypertensive effect may diminish toward the end of the dosing interval regardless of the administered
dose, but most commonly with a dose of 10 mg daily. This can be evaluated by measuring blood
pressure just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If
it is not, an increase in dose should be considered. Doses up to 80 mg have been used but do not appear
to give a greater effect. If blood pressure is not controlled with PRINIVIL alone, a low dose of a diuretic
may be added. Hydrochlorothiazide 12.5 mg has been shown to provide an additive effect. After the
addition of a diuretic, it may be possible to reduce the dose of PRINIVIL.
Diuretic Treated Patients: In hypertensive patients who are currently being treated with a diuretic,
symptomatic hypotension may occur occasionally following the initial dose of PRINIVIL. The diuretic
should be discontinued, if possible, for two to three days before beginning therapy with PRINIVIL to
reduce the likelihood of hypotension. (See WARNINGS.) The dosage of PRINIVIL should be adjusted
according to blood pressure response. If the patient's blood pressure is not controlled with PRINIVIL
alone, diuretic therapy may be resumed as described above.
If the diuretic cannot be discontinued, an initial dose of 5 mg should be used under medical
supervision for at least two hours and until blood pressure has stabilized for at least an additional hour.
(See WARNINGS and PRECAUTIONS, Drug Interactions.)
Concomitant administration of PRINIVIL with potassium supplements, potassium salt substitutes, or
potassium-sparing diuretics may lead to increases of serum potassium (see PRECAUTIONS).
Dosage Adjustment in Renal Impairment: The usual dose of PRINIVIL (10 mg) is recommended for
patients with a creatinine clearance greater than 30 mL/min (serum creatinine of up to approximately
3 mg/dL). For patients with creatinine clearance greater than or equal to 10 mL/min and less than or
equal to 30 mL/min (serum creatinine greater than or equal to 3 mg/dL), the first dose is 5 mg once daily.
For patients with creatinine clearance less than 10 mL/min (usually on hemodialysis) the recommended
initial dose is 2.5 mg. The dosage may be titrated upward until blood pressure is controlled or to a
maximum of 40 mg daily.
14
Reference ID: 3267147
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211212R008
Table 3
Renal Status
Creatinine-
Initial Dose
Clearance
mg/day
mL/min
Normal Renal Function to Mild
>30 mL/min
10 mg
Impairment
Moderate to Severe
≥10 ≤30 mL/min
5 mg
Impairment
Dialysis Patients**
<10 mL/min
2.5 mg***
** See WARNINGS, Anaphylactoid reactions during membrane exposure.
*** Dosage or dosing interval should be adjusted depending on the blood pressure response.
Heart Failure
PRINIVIL is indicated as adjunctive therapy with diuretics and (usually) digitalis. The recommended
starting dose is 5 mg once a day.
When initiating treatment with lisinopril in patients with heart failure, the initial dose should be
administered under medical observation, especially in those patients with low blood pressure (systolic
blood pressure below 100 mmHg). The mean peak blood pressure lowering occurs six to eight hours
after dosing. Observation should continue until blood pressure is stable. The concomitant diuretic dose
should be reduced, if possible, to help minimize hypovolemia which may contribute to hypotension. (See
WARNINGS and PRECAUTIONS, Drug Interactions.) The appearance of hypotension after the initial
dose of PRINIVIL does not preclude subsequent careful dose titration with the drug, following effective
management of the hypotension.
The usual effective dosage range is 5 to 20 mg per day administered as a single daily dose.
Dosage Adjustment in Patients with Heart Failure and Renal Impairment or Hyponatremia: In patients
with heart failure who have hyponatremia (serum sodium less than 130 mEq/L) or moderate to severe
renal impairment (creatinine clearance less than or equal to 30 mL/min or serum creatinine greater than
3 mg/dL), therapy with PRINIVIL should be initiated at a dose of 2.5 mg once a day under close medical
supervision. (See WARNINGS and PRECAUTIONS, Drug Interactions.)
Acute Myocardial Infarction
In hemodynamically stable patients within 24 hours of the onset of symptoms of acute myocardial
infarction, the first dose of PRINIVIL is 5 mg given orally, followed by 5 mg after 24 hours, 10 mg after 48
hours and then 10 mg of PRINIVIL once daily. Dosing should continue for six weeks. Patients should
receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin and beta-
blockers. Patients with a low systolic blood pressure (less than or equal to 120 mmHg) when treatment is
started or during the first 3 days after the infarct should be given a lower 2.5 mg oral dose of PRINIVIL
(see WARNINGS). If hypotension occurs (systolic blood pressure less than or equal to 100 mmHg) a
daily maintenance dose of 5 mg may be given with temporary reductions to 2.5 mg if needed. If
prolonged hypotension occurs (systolic blood pressure less than 90 mmHg for more than 1 hour)
PRINIVIL should be withdrawn. For patients who develop symptoms of heart failure, see DOSAGE AND
ADMINISTRATION, Heart Failure.
Dosage Adjustment in Patients with Myocardial Infarction with Renal Impairment: In acute myocardial
infarction, treatment with PRINIVIL should be initiated with caution in patients with evidence of renal
dysfunction, defined as serum creatinine concentration exceeding 2 mg/dL. No evaluation of dosage
adjustment in myocardial infarction patients with severe renal impairment has been performed.
Use in Elderly
In general, blood pressure response and adverse experiences were similar in younger and older
patients given similar doses of PRINIVIL. Pharmacokinetic studies, however, indicate that maximum
blood levels and area under the plasma concentration time curve (AUC) are doubled in older patients, so
that dosage adjustments should be made with particular caution.
Pediatric Hypertensive Patients 6 years of age and older
The usual recommended starting dose is 0.07 mg/kg once daily (up to 5 mg total). Dosage should be
adjusted according to blood pressure response. Doses above 0.61 mg/kg (or in excess of 40 mg) have
15
Reference ID: 3267147
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRINIVIL® (Lisinopril)
USPI-T-05211212R008
not been studied in pediatric patients. (See CLINICAL PHARMACOLOGY, Pharmacokinetics and
Metabolism and Pharmacodynamics and Clinical Effects.)
PRINIVIL is not recommended in pediatric patients younger than 6 years or in pediatric patients with
glomerular
filtration
rate
less
than
30 mL/min/1.73 m2
(see
CLINICAL
PHARMACOLOGY,
Pharmacokinetics and Metabolism, Pharmacodynamics and Clinical Effects and PRECAUTIONS).
Preparation of Suspension (for 200 mL of a 1.0 mg/mL suspension)
Add 10 mL of Purified Water USP to a polyethylene terephthalate (PET) bottle containing ten 20-mg
tablets of PRINIVIL and shake for at least one minute. Add 30 mL of Bicitra® diluent and 160 mL of Ora-
Sweet SF™ to the concentrate in the PET bottle and gently shake for several seconds to disperse the
ingredients. The suspension should be stored at or below 25°C (77°F) and can be stored for up to four
weeks. Shake the suspension before each use.
HOW SUPPLIED
No. 8110 — Tablets PRINIVIL, 5 mg, are white, oval shaped compressed tablets with code MSD 19
on one side and scored on the other side. They are supplied as follows:
NDC 0006-0019-54 unit of use bottles of 90.
No. 8111 — Tablets PRINIVIL, 10 mg, are light yellow, oval shaped compressed tablets with code
MSD 106 on one side and scored on the other side. They are supplied as follows:
NDC 0006-0106-54 unit of use bottles of 90.
No. 8112 — Tablets PRINIVIL, 20 mg, are peach, oval shaped compressed tablets with code
MSD 207 on one side and scored on the other side. They are supplied as follows:
NDC 0006-0207-54 unit of use bottles of 90.
Storage
Store at controlled room temperature, 15-30°C (59-86°F), and protect from moisture.
Dispense in a tight container, if product package is subdivided. company logo
Manufactured by:
MERCK SHARP & DOHME LTD.
Cramlington, Northumberland, UK NE23 3JU
Copyright © 1988, 1989, 1992, 1993, 1995, 2005, 2006, 2011, 2012 Merck Sharp & Dohme Corp., a
subsidiary of Merck & Co., Inc.
All rights reserved.
Trademarks depicted herein are the property of their respective owners.
Revised: 02/2013
USPI-T-05211212R008
16
Reference ID: 3267147
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:28.175544
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019558s056lbl.pdf', 'application_number': 19558, 'submission_type': 'SUPPL ', 'submission_number': 56}
|
11,537
|
chem
i
c
a
l
st
ru
ct
ur
e
DERMATOP® Ointment
(prednicarbate ointment) 0.1%
FOR DERMATOLOGIC USE ONLY.
NOT FOR USE IN EYES.
DESCRIPTION
DERMATOP® Ointment (prednicarbate ointment) 0.1% contains the non-halogenated
prednisolone derivative prednicarbate. The topical corticosteroids constitute a class of
primarily synthetic steroids used topically as anti-inflammatory and anti-pruritic agents.
Each gram of DERMATOP Ointment 0.1% contains 1.0mg of prednicarbate in a base
consisting of white petrolatum, octyldodecanol, glyceryl oleate, propylene glycol, citric
acid, and propyl gallate.
Prednicarbate has the empirical formula C27H36O8 and a molecular weight of 488.58. The
CAS Registry Number is 73771-04-7. The chemical structure is:
CLINICAL PHARMACOLOGY
Like other topical corticosteroids, prednicarbate has anti-inflammatory, anti-pruritic 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 while
inflammation and/or other disease processes in the skin increase percutaneous absorption.
Reference ID: 2872737
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Studies performed with DERMATOP Ointment (prednicarbate ointment) 0.1% indicate
that it is in the medium range of potency as compared with other topical corticosteroids.
INDICATIONS AND USAGE
DERMATOP Ointment 0.1% is a medium potency corticosteroid indicated for the relief
of the inflammatory and pruritic manifestations of corticosteroid responsive dermatoses.
CONTRAINDICATIONS
DERMATOP Ointment 0.1% is contraindicated in those patients with a history of
hypersensitivity to any of the components in the 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's syndrome,
hyperglycemia, and glucosuria can also be produced in some patients by systemic
absorption of topical corticosteroids while on treatment. Patients receiving a large dose
of a higher potency topical steroid applied to a large surface area or 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.
DERMATOP Ointment 0.1% did not produce significant HPA-axis suppression when
used at a dose of 60 grams per day for a week in patients with extensive psoriasis or
atopic dermatitis.
However, 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 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 to body mass ratios. (See PRECAUTIONS-Pediatric Use.)
If irritation develops, DERMATOP Ointment 0.1% should be discontinued and
appropriate therapy instituted. Allergic contact dermatitis with corticosteroids is usually
diagnosed by observing 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 DERMATOP Ointment (prednicarbate ointment) 0.1% should be discontinued until
the infection has been adequately controlled.
Reference ID: 2872737
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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 or 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. This medication should not be used on the face, underarms, or groin areas.
6. Contact between Dermatop Ointment 0.1% and latex containing products (eg.
condoms, diaphragm etc.) should be avoided since paraffin in contact with latex can
cause damage and reduce the effectiveness of any latex containing products. If latex
products come into contact with Dermatop Ointment 0.1%, patients should be advised
to discard the latex products. Patients should be advised that this medication is to be
used externally only, not intravaginally.
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
Carcinogenesis, Mutagenesis, and Impairment of Fertility
In a study of the effect of prednicarbate on fertility, pregnancy and postnatal development
in rats, no effect was noted on the fertility or pregnancy of the parent animals or postnatal
development of the offspring after administration of up to 0.80 mg/kg of prednicarbate
subcutaneously.
Prednicarbate has been evaluated in the Salmonella reversion test (Ames test) over a wide
range of concentrations in the presence and absence of an S-9 liver microsomal fraction
and did not demonstrate mutagenic activity. Similarly, prednicarbate did not produce any
significant changes in the numbers of micronuclei seen in erythrocytes when mice were
given doses ranging from 1 to 160 mg/kg of the drug.
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.
Prednicarbate has been shown to be teratogenic and embryotoxic in Wistar rats and
Himalayan rabbits when given subcutaneously during gestation at doses 1900times and
45times, respectively, the recommended topical human dose, assuming a percutaneous
absorption of approximately 3%.
Reference ID: 2872737
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In the rats, slightly retarded fetal development and an incidence of thickened and wavy
ribs which was higher than the spontaneous rate were noted.
In rabbits, there was noted increased liver weights and slight increase in the fetal
intrauterine death rate. The fetuses delivered exhibited reduced placental weight,
increased frequency of cleft palate, ossification disorders in the sternum, omphalocele,
and anomalous posture of the forelimbs.
There are no adequate and well-controlled studies in pregnant women on teratogenic
effects of prednicarbate. Therefore, DERMATOP Ointment (prednicarbate ointment)
0.1% 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 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 DERMATOP
Ointment (prednicarbate ointment) 0.1% is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of DERMATOP Ointment 0.1% in pediatric patients below the
age of 10 years have not been established. 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
when they are treated with topical corticosteroids. They are therefore also at greater risk
of glucocorticosteroid insufficiency after withdrawal of treatment and of Cushing's
syndrome while on treatment. Adverse effects including striae have been reported with
inappropriate use of topical corticosteroids in pediatric patients. (See PRECAUTIONS.)
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. Manifesta
tions of intracranial hypertension include bulging fontanelles, headaches, and bilateral
papilledema.
ADVERSE REACTIONS
In controlled clinical studies, the incidence of adverse reactions associated with the use of
DERMATOP Ointment 0.1% was approximately 1.5%. Reported reactions including
burning, pruritis, drying, scaling, cracking and pain and irritant dermatitis.
The following additional local adverse reactions are reported infrequently with topical
corticosteroids, but may occur more frequently with the use of occlusive dressings and
especially with higher potency corticosteroids. These reactions are listed in an
approximate decreasing order of occurrence: folliculitis, hypertrichosis, acneiform
eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary
infection, skin atrophy, striae and miliaria.
Reference ID: 2872737
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
OVERDOSAGE
Topically applied corticosteroids can be absorbed in sufficient amounts to produce
systemic effects. (See PRECAUTIONS.)
DOSAGE AND ADMINISTRATION
Apply a thin film of DERMATOP Ointment 0.1% to the affected skin areas twice daily.
Rub in gently.
HOW SUPPLIED
DERMATOP Ointment (prednicarbate ointment) 0.1% is supplied in 15 gram (NDC
0066-0508-15) and 60 gram (NDC 0066-0508-60) tubes.
Store at controlled room temperature (59 to 86°F or 15 to 30°C).
Rx Only.
Dermik Laboratories
a business of sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
Revised November 2010
© 2010 sanofi-aventis U.S. LLC
Reference ID: 2872737
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:28.342490
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019568s014lbl.pdf', 'application_number': 19568, 'submission_type': 'SUPPL ', 'submission_number': 14}
|
11,536
|
NDA 19-568/S-008
Page 3
Prescribing Information as of February 2004(a).
DERMATOP Ointment
(prednicarbate ointment) 0.1%
FOR DERMATOLOGIC USE ONLY.
NOT FOR USE IN EYES.
DESCRIPTION
DERMATOP Ointment (prednicarbate ointment) 0.1% contains the non-halogenated prednisolone
derivative prednicarbate. The topical corticosteroids constitute a class of primarily synthetic steroids
used topically as anti-inflammatory and anti-pruritic agents.
Each gram of DERMATOP Ointment 0.1% contains 1.0mg of prednicarbate in a base consisting of
white petrolatum, octyldodecanol, glyceryl oleate, propylene glycol, citric acid, and propyl gallate.
Prednicarbate has the empirical formula C27H36O8 and a molecular weight of 488.58. The CAS
Registry Number is 73771-04-7. The chemical structure is:
CH3
O
H
C
H3
O
O
O
O
O
CH3
O
O
CH3
H
H
H
H
CLINICAL PHARMACOLOGY
Like other topical corticosteroids, prednicarbate has anti-inflammatory, anti-pruritic 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 while inflammation and/or other disease processes in the skin
increase percutaneous absorption.
Studies
performed
with
DERMATOP
Ointment
(prednicarbate
ointment)
0.1% indicate that it is in the medium range of potency as compared with other topical corticosteroids.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-568/S-008
Page 4
INDICATIONS AND USAGE
DERMATOP Ointment 0.1% is a medium potency corticosteroid indicated for the relief of the
inflammatory and pruritic manifestations of corticosteroid responsive dermatoses.
CONTRAINDICATIONS
DERMATOP Ointment 0.1% is contraindicated in those patients with a history of hypersensitivity to
any of the components in the 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's syndrome, hyperglycemia, and glucosuria can also be produced
in some patients by systemic absorption of topical corticosteroids while on treatment. Patients
receiving a large dose of a higher potency topical steroid applied to a large surface area or 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.
DERMATOP Ointment 0.1% did not produce significant HPA-axis suppression when used at a dose of
60 grams per day for a week in patients with exten- sive psoriasis or atopic dermatitis.
However, 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 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 to body mass ratios. (See PRECAUTIONS-Pediatric Use.)
If irritation develops, DERMATOP Ointment 0.1% should be discontinued and appropriate therapy
instituted. Allergic contact dermatitis with corticosteroids is usually diagnosed by observing 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 DERMATOP Ointment
(prednicarbate ointment) 0.1% 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. 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 or 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.
Laboratory Tests
The following tests may be helpful in evaluating patients for HPA-axis suppression:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-568/S-008
Page 5
ACTH stimulation test
A.M. plasma cortisol test
Urinary free cortisol test
Carcinogenesis, Mutagenesis, and Impairment of Fertility
In a study of the effect of prednicarbate on fertility, pregnancy and postnatal development in rats, no
effect was noted on the fertility or pregnancy of the parent animals or postnatal development of the
offspring after administration of up to 0.80 mg/kg of prednicarbate subcutaneously.
Prednicarbate has been evaluated in the Salmonella reversion test (Ames test) over a wide range of
concentrations in the presence and absence of an S-9 liver microsomal fraction and did not
demonstrate mutagenic activity. Similarly, prednicarbate did not produce any significant changes in
the numbers of micronuclei seen in erythrocytes when mice were given doses ranging from 1 to 160
mg/kg of the drug.
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.
Prednicarbate has been shown to be teratogenic and embryotoxic in Wistar rats and Himalayan rabbits
when given subcutaneously during gestation at doses 1900times and 45times, respectively, the
recommended topical human dose, assuming a percutaneous absorption of approximately 3%.
In the rats, slightly retarded fetal development and an incidence of thickened and wavy ribs which was
higher than the spontaneous rate were noted.
In rabbits, there was noted increased liver weights and slight increase in the fetal intrauterine death
rate. The fetuses delivered exhibited reduced placental weight, increased frequency of cleft palate,
ossification disorders in the sternum, omphalocele, and anomalous posture of the forelimbs.
There are no adequate and well-controlled studies in pregnant women on teratogenic effects of
prednicarbate. Therefore, DERMATOP Ointment (prednicarbate ointment) 0.1% 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 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 DERMATOP Ointment (prednicarbate ointment) 0.1% is administered to a nursing
woman.
Pediatric Use
Safety and effectiveness of DERMATOP Ointment 0.1% in pediatric patients below the age of 10
years have not been established. 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 when they are treated with topical
corticosteroids. They are therefore also at greater risk of glucocorticosteroid insufficiency after
withdrawal of treatment and of Cushing's syndrome while on treatment. Adverse effects including
striae have been reported with inappropriate use of topical corticosteroids in pediatric patients. (See
PRECAUTIONS.)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-568/S-008
Page 6
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. Manifesta- tions of intracranial hypertension include bulging
fontanelles, headaches, and bilateral papilledema.
ADVERSE REACTIONS
In controlled clinical studies, the incidence of adverse reactions associated with the use of
DERMATOP Ointment 0.1% was approximately 1.5%. Reported reactions including burning, pruritis,
drying, scaling, cracking and pain and irritant dermatitis.
The following additional local adverse reactions are reported infrequently with topical corticosteroids,
but may occur more frequently with the use of occlusive dressings and especially with higher potency
corticosteroids. These reactions are listed in an approximate decreasing order of occurrence:
folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact
dermatitis, secondary infection, skin atrophy, striae and miliaria.
OVERDOSAGE
Topically applied corticosteroids can be absorbed in sufficient amounts to produce systemic effects.
(See PRECAUTIONS.)
DOSAGE AND ADMINISTRATION
Apply a thin film of DERMATOP Ointment 0.1% to the affected skin areas twice daily. Rub in
gently.
HOW SUPPLIED
DERMATOP Ointment (prednicarbate ointment) 0.1% is supplied in 15 gram (NDC 0066-0508-15)
and 60 gram (NDC 0066-0508-60) tubes.
Store at controlled room temperature (59 to 86°F or 15 to 30°C).
Rx Only.
Prescribing information as of February 2004(a).
US Patent 4,242,334 has been extended.
Manufactured for:
Dermik Laboratories
A Division of Aventis Pharmaceuticals Inc.
Berwyn, PA 19312 USA
by:
Aventis Pharma Deutschland GmbH
D-65926 Frankfurt am Main
Germany
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:28.428930
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19568scf008_dermatop_lbl.pdf', 'application_number': 19568, 'submission_type': 'SUPPL ', 'submission_number': 8}
|
11,535
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
PRINIVIL safely and effectively. See full prescribing information for
PRINIVIL.
PRINIVIL® (lisinopril) tablets, for oral use
Initial U.S. Approval: 1987
WARNING: FETAL TOXICITY
See full prescribing information for complete boxed warning.
• When pregnancy is detected, discontinue PRINIVIL as soon as possible
(5.1).
• Drugs that act directly on the renin-angiotensin system can cause injury
and death to the developing fetus (5.1).
--------------------------- INDICATIONS AND USAGE---------------------------
PRINIVIL is an angiotensin converting enzyme (ACE) inhibitor indicated for:
•
Treatment of hypertension in adults and pediatric patients ≥6 years of age
(1.1)
•
Adjunctive therapy for heart failure (1.2)
•
Treatment of acute myocardial infarction (1.3)
-----------------------DOSAGE AND ADMINISTRATION ----------------------
• Hypertension: Initiate adults at 10 mg (monotherapy) or 5 mg (on a
diuretic) once daily. Titrate up to 40 mg daily based on response. Initial
dose in patients 6 years of age and older is 0.07 mg/kg (up to 5 mg total)
once daily (2.1)
• Heart Failure: Initiate with 5 mg once daily. Increase dose as tolerated to
40 mg daily (2.2)
• Acute Myocardial Infarction (MI): Give 5 mg within 24 hours of MI
followed by 5 mg after 24 hours, then 10 mg once daily. (2.3)
• Renal Impairment: For patients with creatine clearance 10-30 mL/min,
halve the usual initial dose. For creatinine clearance <10 mL/min or on
hemodialysis, initiate at 2.5 mg (2.4)
--------------------- DOSAGE FORMS AND STRENGTHS---------------------
•
Tablets (lisinopril content): 5 mg; 10 mg; and 20 mg (3)
------------------------------ CONTRAINDICATIONS -----------------------------
• Angioedema or a history of hereditary or idiopathic angioedema (4)
•
Hypersensitivity (4)
•
Co-administration of aliskiren with PRINIVIL in patients with diabetes
(4, 7.4)
----------------------- WARNINGS AND PRECAUTIONS ----------------------
•
Angioedema: Discontinue PRINIVIL (5.2)
•
Renal impairment: Monitor renal function periodically (5.3)
•
Hypotension: Monitor blood pressure after initiation (5.4)
•
Hyperkalemia: Monitor serum potassium periodically (5.6)
•
Cholestatic jaundice and hepatic failure: Discontinue PRINIVIL (5.7)
------------------------------ ADVERSE REACTIONS -----------------------------
Common adverse reactions (events 2% greater than on placebo):
•
Hypertension: headache, dizziness and cough (6.1)
•
Heart Failure: hypotension and chest pain (6.1)
•
Acute Myocardial Infarction: hypotension (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp
& Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or
FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------------ DRUG INTERACTIONS------------------------------
•
Diuretics: Excessive drop in blood pressure (7.1)
•
NSAIDs: Increased risk of renal impairment and loss of antihypertensive
efficacy (7.3)
•
Dual inhibition of the renin-angiotensin system: Increased risk of renal
impairment, hypotension, syncope, and hyperkalemia (7.4)
•
Lithium: Symptoms of lithium toxicity (7.7)
•
Gold: Nitritoid reactions (7.8)
----------------------- USE IN SPECIFIC POPULATIONS ----------------------
•
Pregnancy: Discontinue PRINIVIL if pregnancy is detected (5.1, 8.1)
•
Pediatrics: Safety and effectiveness have not been established in patients
<6 years of age or with glomerular filtration rate <30 mL/min/1.73m2
(8.4)
•
Race: Less antihypertensive effect in Blacks than non-Blacks (8.6)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 07/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: FETAL TOXICITY
1
INDICATIONS AND USAGE
1.1
Hypertension
1.2
Heart Failure
1.3
Acute Myocardial Infarction
2
DOSAGE AND ADMINISTRATION
2.1
Hypertension
2.2
Heart Failure
2.3
Acute Myocardial Infarction
2.4
Dose in Patients with Renal Impairment
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Fetal Toxicity
5.2
Angioedema and Anaphylactoid Reactions
5.3
Impaired Renal Function
5.4 Hypotension
5.5 Hyperkalemia
5.6 Hepatic Failure
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Diuretics
7.2
Antidiabetics
7.3
Non-Steroidal Anti-Inflammatory Agents Including Selective
Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
7.4
Dual Blockade of the Renin-Angiotensin System (RAS)
7.5 Lithium
7.6 Gold
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Race
8.7
Renal Impairment
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Hypertension
14.2 Heart Failure
14.3 Acute Myocardial Infarction
16
HOW SUPPLIED/STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information
are not listed.
Reference ID: 3789296
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: FETAL TOXICITY
When pregnancy is detected, discontinue PRINIVIL as soon as possible [see Warnings and
Precautions (5.1)].
Drugs that act directly on the renin-angiotensin system can cause injury and death to the
developing fetus [see Warnings and Precautions (5.1)].
1
INDICATIONS AND USAGE
1.1 Hypertension
PRINIVIL is indicated for the treatment of hypertension in adult patients and pediatric patients 6 years
of age and older to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non
fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been
seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes.
Control of high blood pressure should be part of comprehensive cardiovascular risk management,
including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking
cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve
blood pressure goals. For specific advice on goals and management, see published guidelines, such
as those of the National High Blood Pressure Education Program’s Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different
mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular
morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some
other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest
and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but
reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk
increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe
hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is
similar across populations with varying absolute risk, so the absolute benefit is greater in patients who
are at higher risk independent of their hypertension (for example, patients with diabetes or
hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a
lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients,
and many antihypertensive drugs have additional approved indications and effects (e.g., on angina,
heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.
PRINIVIL may be administered alone or with other antihypertensive agents [see Clinical Studies
(14.1)].
1.2 Heart Failure
PRINIVIL is indicated to reduce signs and symptoms of heart failure in patients who are not
responding adequately to diuretics and digitalis [see Clinical Studies (14.2)].
2
Reference ID: 3789296
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1.3 Acute Myocardial Infarction
PRINIVIL is indicated for the reduction of mortality in treatment of hemodynamically stable patients
within 24 hours of acute myocardial infarction. Patients should receive, as appropriate, the standard
recommended treatments such as thrombolytics, aspirin and beta-blockers [see Clinical Studies
(14.3)].
2
DOSAGE AND ADMINISTRATION
2.1 Hypertension
Initial therapy in adults: The recommended initial dose is 10 mg once a day. Adjust dosage according
to blood pressure response. The usual dosage range is 20 to 40 mg per day administered in a single
daily dose. Doses up to 80 mg have been used but do not appear to give a greater effect.
Use with Diuretics in Adults
If blood pressure is not controlled with PRINIVIL alone, a low dose of a diuretic may be added. (e.g.,
hydrochlorothiazide 12.5 mg).
The recommended starting dose in adult patients with hypertension taking diuretics is 5 mg once per
day [see Drug Interactions (7.1)].
Pediatric Patients 6 Years of Age and Older with Hypertension
For pediatric patients with glomerular filtration rate >30 mL/min/1.73m2, the recommended starting
dose is 0.07 mg/kg once daily (up to 5 mg total). Dosage should be adjusted according to blood
pressure response up to a maximum of 0.61 mg/kg (up to 40 mg) once daily. Doses above 0.61
mg/kg (or in excess of 40 mg) have not been studied in pediatric patients [see Clinical Pharmacology
(12.3)].
PRINIVIL is not recommended in pediatric patients <6 years or in pediatric patients with glomerular
filtration rate <30 mL/min/1.73m2 [see Use in Specific Populations (8.4) and Clinical Studies (14.1)].
2.2 Heart Failure
The recommended starting dose for PRINIVIL, when used with diuretics and (usually) digitalis as
adjunctive therapy is 5 mg once daily. The recommended starting dose in these patients with
hyponatremia (serum sodium <130 mEq/L) is 2.5 mg once daily. Increase as tolerated to a maximum
of 40 mg once daily.
Diuretic dose may need to be adjusted to help minimize hypovolemia, which may contribute to
hypotension [see Warnings and Precautions (5.4), and Drug Interactions (7.1)]. The appearance of
hypotension after the initial dose of PRINIVIL does not preclude subsequent careful dose titration with
the drug, following effective management of the hypotension.
2.3 Acute Myocardial Infarction
In hemodynamically stable patients within 24 hours of the onset of symptoms of acute myocardial
infarction, give PRINIVIL 5 mg orally, followed by 5 mg after 24 hours, 10 mg after 48 hours and then
10 mg once daily. Dosing should continue for at least 6 weeks.
3
Reference ID: 3789296
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Initiate therapy with 2.5 mg in patients with a low systolic blood pressure (100-120 mmHg) during the
first 3 days after the infarct [see Warnings and Precautions (5.4)]. If hypotension occurs (systolic
blood pressure ≤100 mmHg) consider doses of 2.5 or 5 mg. If prolonged hypotension occurs (systolic
blood pressure <90 mmHg for more than 1 hour) discontinue PRINIVIL.
2.4 Dose in Patients with Renal Impairment
No dose adjustment of PRINIVIL is required in patients with creatinine clearance >30 mL/min. In
patients with creatinine clearance 10-30 mL/min, reduce the initial dose of PRINIVIL to half of the
usual recommended dose (i.e., hypertension, 5 mg; heart failure or acute MI, 2.5 mg). For patients on
hemodialysis or creatinine clearance <10 mL/min, the recommended initial dose is 2.5 mg once daily
[see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
3
DOSAGE FORMS AND STRENGTHS
Tablets PRINIVIL, 5 mg, are white, oval-shaped compressed tablets with code MSD 19 on one side
and scored on the other side.
Tablets PRINIVIL, 10 mg, are light yellow, oval-shaped compressed tablets with code MSD 106 on
one side and scored on the other side.
Tablets PRINIVIL, 20 mg, are peach, oval-shaped compressed tablets with code MSD 207 on one
side and scored on the other side.
4
CONTRAINDICATIONS
PRINIVIL is contraindicated in patients with:
• a history of angioedema or hypersensitivity related to previous treatment with an angiotensin
converting enzyme inhibitor
• hereditary or idiopathic angioedema.
Do not co-administer aliskiren with PRINIVIL in patients with diabetes [see Drug Interactions (7.4)].
5
WARNINGS AND PRECAUTIONS
5.1 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 PRINIVIL as soon as possible [see Use in Specific
Populations (8.1)].
5.2 Angioedema and Anaphylactoid Reactions
Angioedema
Head and Neck Angioedema:
Angioedema of the face, extremities, lips, tongue, glottis and/or larynx, including some fatal reactions,
have occurred in patients treated with angiotensin converting enzyme inhibitors, including PRINIVIL,
at any time during treatment. Patients with involvement of the tongue, glottis or larynx are likely to
4
Reference ID: 3789296
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
experience airway obstruction, especially those with a history of airway surgery. PRINIVIL should be
promptly discontinued and appropriate therapy and monitoring should be provided until complete and
sustained resolution of signs and symptoms of angioedema has occurred.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of
angioedema while receiving an ACE inhibitor [see Contraindications (4)]. ACE inhibitors have been
associated with a higher rate of angioedema in Black than in non-Black patients.
Intestinal Angioedema:
Intestinal angioedema has occurred 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. In some cases, the angioedema was
diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms
resolved after stopping the ACE inhibitor.
Anaphylactoid Reactions
Anaphylactoid Reactions During Desensitization:
Two patients undergoing desensitizing treatment with Hymenoptera venom while receiving ACE
inhibitors sustained life-threatening anaphylactoid reactions.
Anaphylactoid Reactions During Dialysis:
Sudden and potentially life-threatening anaphylactoid reactions have occurred in some patients
dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. In such patients,
dialysis must be stopped immediately, and aggressive therapy for anaphylactoid reactions must be
initiated. Symptoms have not been relieved by antihistamines in these situations. In these patients,
consideration should be given to using a different type of dialysis membrane or a different class of
antihypertensive agent. Anaphylactoid reactions have also been reported in patients undergoing low-
density lipoprotein apheresis with dextran sulfate absorption.
5.3 Impaired Renal Function
Monitor renal function periodically in patients treated with PRINIVIL. Changes in renal function
including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system.
Patients whose renal function may depend in part on the activity of the renin-angiotensin system
(e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure,
post-myocardial infarction or volume depletion) may be at particular risk of developing acute renal
failure on PRINIVIL. Consider withholding or discontinuing therapy in patients who develop a clinically
significant decrease in renal function on PRINIVIL [see Adverse Reactions (6.1), Drug Interactions
(7.4)].
5.4 Hypotension
PRINIVIL can cause symptomatic hypotension, sometimes complicated by oliguria, progressive
azotemia, acute renal failure or death. Patients at risk of excessive hypotension include those with the
following conditions or characteristics: heart failure with systolic blood pressure below 100 mmHg,
ischemic heart disease, cerebrovascular disease, hyponatremia, high dose diuretic therapy, renal
dialysis, or severe volume and/or salt depletion of any etiology.
In these patients, start PRINIVIL under medical supervision and follow such patients for the first two
weeks of treatment and whenever the dose of PRINIVIL and/or diuretic is increased. Avoid use of
PRINIVIL in patients who are hemodynamically unstable after acute MI.
5
Reference ID: 3789296
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Symptomatic hypotension is also possible in patients with severe aortic stenosis or hypertrophic
cardiomyopathy.
Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that
produce hypotension, PRINIVIL may 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.
5.6 Hyperkalemia
Monitor serum potassium periodically in patients receiving PRINIVIL. Drugs that inhibit the renin
angiotensin system can cause hyperkalemia. Risk factors for the development of hyperkalemia
include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics,
potassium supplements and/or potassium-containing salt substitutes [see Drug Interactions (7.1)].
5.7 Hepatic Failure
ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis
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 treatment.
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of
another drug and may not reflect the rates observed in practice.
Hypertension
The following adverse reactions (events 2% greater on PRINIVIL than on placebo) were observed
with PRINIVIL vs placebo: headache (5.7% vs 1.9%), dizziness (5.4% vs 1.9%), cough (3.5% vs
1.0%).
Heart Failure
In controlled studies in patients with heart failure, therapy was discontinued in 8.1% of patients
treated with PRINIVIL for 12 weeks, compared to 7.7% of patients treated with placebo for 12 weeks.
The following adverse reactions (events 2% greater on PRINIVIL than on placebo) were observed
with PRINIVIL vs placebo: hypotension (4.4% vs 0.6%), chest pain (3.4% vs 1.3%).
In the ATLAS trial [see Clinical Studies (14.2)] in heart failure patients, withdrawals for adverse
reactions were similar in the low- and high-dose groups. The following adverse reactions, mostly
related to ACE inhibition, were reported more commonly in the high dose group:
Table 1 Dose-related Adverse Drug Reactions: ATLAS trial
High Dose
(n=1568)
Low Dose
(n=1596)
6
Reference ID: 3789296
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Dizziness
19%
12%
Hypotension
11%
7%
Creatinine increased
10%
7%
Hyperkalemia
6%
4%
Syncope
7%
5%
Acute Myocardial Infarction
Patients in the GISSI-3 study treated with PRINIVIL had a higher incidence of hypotension (9.0%% vs
3.7%%) and renal dysfunction (2.4%% vs 1.1%%) compared with patients not taking PRINIVIL.
Other clinical adverse reactions occurring in 1% or higher of patients with hypertension or heart
failure treated with PRINIVIL in controlled clinical trials and do not appear in other sections of labeling
are listed below:
Body as a whole: Fatigue, asthenia, orthostatic effects.
Digestive: Pancreatitis, constipation, flatulence, dry mouth, diarrhea.
Hematologic: Rare cases of bone marrow depression, hemolytic anemia, leukopenia/neutropenia and
thrombocytopenia.
Endocrine: Diabetes mellitus, inappropriate antidiuretic hormone secretion.
Metabolic: Gout
Skin: Urticaria, alopecia, photosensitivity, erythema, flushing, diaphoresis, cutaneous
pseudolymphoma, toxic epidermal necrolysis, Stevens - Johnson syndrome, and pruritus.
Special Senses: Visual loss, diplopia, blurred vision, tinnitus, photophobia, taste disturbances,
olfactory disturbances.
Urogenital: Impotence
Miscellaneous: A symptom complex has been reported which may include a positive ANA, an
elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia,
leukocytosis, paresthesia and vertigo. Rash, photosensitivity or other dermatological manifestations
may occur alone or in combination with these symptoms.
Clinical Laboratory Test Findings
Serum Potassium: In clinical trials hyperkalemia (serum potassium >5.7 mEq/L) occurred in 2.2% and
4.8% of PRINIVIL-treated patients with hypertension and heart failure, respectively [see Warnings
and Precautions (5.5)].
Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen and serum creatinine,
reversible upon discontinuation of therapy, were observed in about 2% of patients with hypertension
treated with PRINIVIL alone. Increases were more common in patients receiving concomitant
diuretics and in patients with renal artery stenosis [see Warnings and Precautions (5.4)]. Reversible
minor increases in blood urea nitrogen and serum creatinine were observed in 11.6% of patients with
7
Reference ID: 3789296
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
heart failure on concomitant diuretic therapy. Frequently, these abnormalities resolved when the
dosage of the diuretic was decreased.
Patients with acute myocardial infarction in the GISSI-3 trial treated with PRINIVIL had a higher (2.4%
versus 1.1% in placebo) incidence of renal dysfunction in-hospital and at 6 weeks (increasing
creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum creatinine
concentration).
Hemoglobin and Hematocrit: Small decreases in hemoglobin (mean 0.4 mg/dL) and hematocrit
(mean 1.3%) occurred frequently in patients treated with PRINIVIL but were rarely of clinical
importance in patients without some other cause of anemia. In clinical trials, fewer than 0.1% of
patients discontinued therapy for anemia.
Liver Enzymes
Rarely, elevations of liver enzymes and/or serum bilirubin have occurred [see Warnings and
Precautions (5.7)].
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of lisinopril that are not
included in other sections of labeling. 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.
Other reactions include:
Metabolism and nutrition disorders
Hyponatremia [see Warnings and Precautions (5.4)], cases of hypoglycemia in diabetic patients on
oral antidiabetic agents or insulin [see Drug Interactions (7.2)]
Nervous system and psychiatric disorders
Mood alterations (including depressive symptoms), mental confusion
7
DRUG INTERACTIONS
7.1 Diuretics
Initiation of PRINIVIL in patients on diuretics may result in excessive reduction of blood pressure. The
possibility of hypotensive effects with PRINIVIL can be minimized by either decreasing or
discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with PRINIVIL. If
this is not possible, reduce the starting dose of PRINIVIL [see Dosage and Administration (2.2) and
Warnings and Precautions (5.4)].
PRINIVIL attenuates potassium loss caused by thiazide-type diuretics. Potassium-sparing diuretics
(spironolactone, amiloride, triamterene, and others) can increase the risk of hyperkalemia. Therefore,
if concomitant use of such agents is indicated, monitor the patient’s serum potassium frequently.
7.2 Antidiabetics
Concomitant administration of PRINIVIL and antidiabetic medicines (insulins, oral hypoglycemic
agents) may cause an increased blood-glucose-lowering effect with risk of hypoglycemia.
8
Reference ID: 3789296
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7.3 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 lisinopril, may result in deterioration of renal function, including possible
acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients
receiving lisinopril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including lisinopril, may be attenuated by NSAIDs.
7.4 Dual Blockade of the Renin-Angiotensin System (RAS)
Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or direct renin inhibitors
(such as aliskiren) is associated with increased risks of hypotension, syncope, hyperkalemia, and
changes in renal function (including acute renal failure) compared to monotherapy.
The Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial enrolled 1448 patients with
type 2 diabetes, elevated urinary-albumin-to-creatinine ratio, and decreased estimated glomerular
filtration rate (GFR 30 to 89.9 ml/min), randomized them to lisinopril or placebo on a background of
losartan therapy and followed them for a median of 2.2 years. Patients receiving the combination of
losartan and lisinopril did not obtain any additional benefit compared to monotherapy for the
combined endpoint of decline in GFR, end stage renal disease, or death, but experienced an
increased incidence of hyperkalemia and acute kidney injury compared with the monotherapy group.
In general, avoid combined use of RAS inhibitors. Monitor blood pressure, renal function and
electrolytes in patients on PRINIVIL and other agents that affect the RAS.
Do not co-administer aliskiren with PRINIVIL in patients with diabetes. Avoid use of aliskiren with
PRINIVIL in patients with renal impairment (GFR <60 ml/min).
7.5 Lithium
Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs, which cause
elimination of sodium, including ACE inhibitors. Lithium toxicity was usually reversible upon
discontinuation of lithium and the ACE inhibitor. Monitor serum lithium levels during concurrent use.
7.6 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 PRINIVIL.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
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 PRINIVIL as soon as possible. These adverse
outcomes are usually associated with the use of these drugs in the second and third trimester of
9
Reference ID: 3789296
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure 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 mother and fetus.
In the unusual case that there is no appropriate alternative therapy to 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 PRINIVIL, 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 PRINIVIL for hypotension, oliguria, and
hyperkalemia [see Use in Specific Populations (8.4)].
8.3 Nursing Mothers
Milk of lactating rats contains radioactivity following administration of 14C lisinopril. It is not known
whether this drug is secreted in human milk. Because many drugs are secreted in human milk, and
because of the potential for serious adverse reactions in nursing infants from ACE inhibitors,
discontinue nursing or discontinue PRINIVIL.
8.4 Pediatric Use
Antihypertensive effects and safety of PRINIVIL have been established in pediatric patients aged 6 to
16 years [see Dosage and Administration (2.1) and Clinical Studies (14.1)]. No relevant differences
between the adverse reaction profile for pediatric patients and adult patients were identified.
Safety and effectiveness of PRINIVIL have not been established in pediatric patients under the age of
6 or in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m2 [see Clinical
Pharmacology (12.3) and Clinical Studies (14.1)].
Neonates with a History of in Utero Exposure to PRINIVIL
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.
8.5 Geriatric Use
No dosage adjustment with PRINIVIL is necessary in elderly patients. In a clinical study of PRINIVIL
in patients with myocardial infarctions (GISSI-3 Trial) 4,413 (47%) were 65 and over, while 1,656
(18%) were 75 and over. In this study, 4.8% of patients aged 75 years and older discontinued
PRINIVIL treatment because of renal dysfunction vs. 1.3% of patients younger than 75 years. No
other differences in safety or effectiveness were observed between elderly and younger patients, but
greater sensitivity of some older individuals cannot be ruled out.
8.6 Race
ACE inhibitors, including PRINIVIL, have an effect on blood pressure that is less in Black patients
than in non-Blacks.
10
Reference ID: 3789296
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8.7 Renal Impairment
Dose adjustment of PRINIVIL is required in patients undergoing hemodialysis or whose creatinine
clearance is ≤30 mL/min. No dose adjustment of PRINIVIL is required in patients with creatinine
clearance >30 mL/min [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].
10
OVERDOSAGE
Following a single oral dose of 20 g/kg, no lethality occurred in rats and death occurred in one of 20
mice receiving the same dose. The most likely manifestation of overdosage would be hypotension, for
which the usual treatment would be intravenous infusion of normal saline solution.
Lisinopril can be removed by hemodialysis [see Warnings and Precautions (5.2)].
11
DESCRIPTION
PRINIVIL contains lisinopril, a synthetic peptide derivative, and an oral, long-acting angiotensin
converting enzyme inhibitor. Lisinopril is chemically described as (S)-1-[N2-(1-carboxy-3
phenylpropyl)-L-lysyl]-L-proline dihydrate. Its empirical formula is C21H31N3O5•2H2O and its
structural formula is: structural formula
Lisinopril is a white to off-white, crystalline powder, with a molecular weight of 441.52. It is soluble in
water and sparingly soluble in methanol and practically insoluble in ethanol.
PRINIVIL is supplied as 5 mg, 10 mg, and 20 mg tablets for oral administration. In addition to the
active ingredient, lisinopril, each tablet contains the following inactive ingredients: calcium phosphate,
mannitol, magnesium stearate, and starch. The 10 mg and 20 mg tablets also contain iron oxide.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Lisinopril inhibits angiotensin converting enzyme (ACE) in human subjects and animals. ACE is a
peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance,
angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. The
beneficial effects of lisinopril in hypertension and heart failure appear to result primarily from
suppression of the renin-angiotensin-aldosterone system. Inhibition of ACE results in decreased
plasma angiotensin II which leads to decreased vasopressor activity and to decreased aldosterone
secretion. The latter decrease may result in a small increase of serum potassium. In hypertensive
patients with normal renal function treated with PRINIVIL alone for up to 24 weeks, the mean
increase in serum potassium was approximately 0.1 mEq/L; however, approximately 15% of patients
had increases greater than 0.5 mEq/L and approximately 6% had a decrease greater than 0.5 mEq/L.
In the same study, patients treated with PRINIVIL and hydrochlorothiazide for up to 24 weeks had a
mean decrease in serum potassium of 0.1 mEq/L; approximately 4% of patients had increases
greater than 0.5 mEq/L and approximately 12% had a decrease greater than 0.5 mEq/L [see
11
Reference ID: 3789296
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Warnings and Precautions (5.6)]. Removal of angiotensin II negative feedback on renin secretion
leads to increased plasma renin activity.
ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of
bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of PRINIVIL remains
to be elucidated.
While the mechanism through which PRINIVIL lowers blood pressure is believed to be primarily
suppression of the renin-angiotensin-aldosterone system, PRINIVIL is antihypertensive even in
patients with low-renin hypertension. Although PRINIVIL was antihypertensive in all races studied,
Black hypertensive patients (usually a low-renin hypertensive population) had a smaller average
response to monotherapy than non-Black patients.
Concomitant administration of PRINIVIL and hydrochlorothiazide further reduced blood pressure in
Black and non-Black patients and any racial difference in blood pressure response was no longer
evident.
12.2 Pharmacodynamics
Hypertension
Adult Patients: Administration of PRINIVIL to patients with hypertension results in a reduction of
supine and standing blood pressure to about the same extent with no compensatory tachycardia.
Symptomatic postural hypotension is usually not observed although it can occur and should be
anticipated in volume and/or salt-depleted patients [see Warnings and Precautions (5.3)]. When given
together with thiazide-type diuretics, the blood pressure lowering effects of the two drugs are
approximately additive.
In most patients studied, onset of antihypertensive activity was seen at one hour after oral
administration of an individual dose of PRINIVIL, with peak reduction of blood pressure achieved by 6
hours. Although an antihypertensive effect was observed 24 hours after dosing with recommended
single daily doses, the effect was more consistent and the mean effect was considerably larger in
some studies with doses of 20 mg or more than with lower doses. However, at all doses studied, the
mean antihypertensive effect was substantially smaller 24 hours after dosing than it was 6 hours after
dosing.
The antihypertensive effects of PRINIVIL are maintained during long-term therapy. Abrupt withdrawal
of PRINIVIL has not been associated with a rapid increase in blood pressure or a significant increase
in blood pressure compared to pretreatment levels.
12.3 Pharmacokinetics
Adult Patients: Following oral administration of PRINIVIL, peak serum concentrations of lisinopril
occur within about 7 hours, although there was a trend to a small delay in time taken to reach peak
serum concentrations in acute myocardial infarction patients. Declining serum concentrations exhibit
a prolonged terminal phase which does not contribute to drug accumulation. This terminal phase
probably represents saturable binding to ACE and is not proportional to dose. Upon multiple dosing,
lisinopril exhibits an effective half-life of 12 hours.
Lisinopril does not appear to be bound to other serum proteins. Lisinopril does not undergo
metabolism and is excreted unchanged entirely in the urine. Based on urinary recovery, the mean
12
Reference ID: 3789296
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
extent of absorption of lisinopril is approximately 25 percent, with large inter-subject variability (6-60
percent) at all doses tested (5-80 mg). Lisinopril absorption is not influenced by the presence of food
in the gastrointestinal tract. The absolute bioavailability of lisinopril is reduced to about 16 percent in
patients with stable NYHA Class II-IV congestive heart failure, and the volume of distribution appears
to be slightly smaller than that in normal subjects.
The oral bioavailability of lisinopril in patients with acute myocardial infarction is similar to that in
healthy volunteers.
Impaired renal function decreases elimination of lisinopril, which is excreted principally through the
kidneys, but this decrease becomes clinically important only when the glomerular filtration rate is
below 30 mL/min. Above this glomerular filtration rate, the elimination half-life is little changed. With
greater impairment, however, peak and trough lisinopril levels increase, time to peak concentration
increases and time to attain steady state is prolonged. Older patients, on average, have
(approximately doubled) higher blood levels and area under the plasma concentration time curve
(AUC) than younger patients [see Dosage and Administration (2.1)]. Lisinopril can be removed by
hemodialysis.
Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly. Multiple doses of lisinopril
in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity
following administration of 14C lisinopril. By whole body autoradiography, radioactivity was found in
the placenta following administration of labeled drug to pregnant rats, but none was found in the
fetuses.
Pediatric Patients: The pharmacokinetics of lisinopril were studied in 29 pediatric hypertensive
patients between 6 years and 16 years with glomerular filtration rate >30 mL/min/1.73 m2. After doses
of 0.1 to 0.2 mg/kg, steady state peak plasma concentrations of lisinopril occurred within 6 hours and
the extent of absorption based on urinary recovery was about 28%. These values are similar to those
obtained previously in adults. The typical value of lisinopril oral clearance (systemic
clearance/absolute bioavailability) in a child weighing 30 kg is 10 L/h, which increases in proportion to
renal function.
13
Reference ID: 3789296
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
There was no evidence of a tumorigenic effect when lisinopril was administered for 105 weeks to
male and female rats at doses up to 90 mg per kg per day or for 92 weeks to male and female mice
at doses up to 135 mg per kg per day. These doses are 10 times and 7 times, respectively, the
MRHDD when compared on a body surface area basis.
Lisinopril was not mutagenic in the Ames microbial mutagen test with or without metabolic activation.
It was also negative in a forward mutation assay using Chinese hamster lung cells. Lisinopril did not
produce single strand DNA breaks in an in vitro alkaline elution rat hepatocyte assay. In addition,
lisinopril did not produce increases in chromosomal aberrations in an in vitro test in Chinese hamster
ovary cells or in an in vivo study in mouse bone marrow.
There were no adverse effects on reproductive performance in male and female rats treated with up
to 300 mg/kg/day of lisinopril (33 times the MRHDD when compared on a body surface area basis).
Studies in rats indicate that lisinopril crosses the blood brain barrier poorly. Multiple doses of lisinopril
in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity
following administration of 14C lisinopril. By whole body autoradiography, radioactivity was found in
the placenta following administration of labeled drug to pregnant rats, but none was found in the
fetuses.
14
CLINICAL STUDIES
14.1 Hypertension
Adult Patients: Two dose-response studies utilizing a once daily regimen were conducted in 438 mild
to moderate hypertensive patients not on a diuretic. Blood pressure was measured 24 hours after
dosing. An antihypertensive effect of PRINIVIL was seen with 5 mg in some patients. However, in
both studies blood pressure reduction occurred sooner and was greater in patients treated with 10,
20, or 80 mg of PRINIVIL. In controlled clinical studies in patients with mild to moderate hypertension,
PRINIVIL 20-80 mg has been compared to hydrochlorothiazide 12.5-50 mg and with atenolol 50-500
mg, and in patients with moderate, to severe hypertension to metoprolol 100-200 mg. It was superior
to hydrochlorothiazide in effects on systolic and diastolic blood pressure in a population that was 75%
Caucasian. PRINIVIL was approximately equivalent to atenolol and metoprolol in effects on diastolic
blood pressure and had somewhat greater effects on systolic blood pressure.
PRINIVIL had similar effectiveness and adverse effects in younger and older (>65 years) patients. It
was less effective in Blacks than in Caucasians.
In hemodynamic studies of PRINIVIL in patients with essential hypertension, blood pressure
reduction was accompanied by a reduction in peripheral arterial resistance with little or no change in
cardiac output and in heart rate. In a study in nine hypertensive patients, following administration of
PRINIVIL, there was an increase in mean renal blood flow that was not significant. Data from several
small studies are inconsistent with respect to the effect of lisinopril on glomerular filtration rate in
hypertensive patients with normal renal function, but suggest that changes, if any, are not large.
In patients with renovascular hypertension PRINIVIL has been shown to be well tolerated and
effective in reducing blood pressure [see Warnings and Precautions (5.3)].
14
Reference ID: 3789296
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pediatric Patients: In a clinical study involving 115 hypertensive pediatric patients 6 to 16 years of
age, patients who weighed <50 kg received either 0.625, 2.5, or 20 mg of lisinopril daily and patients
who weighed ≥50 kg received either 1.25, 5, or 40 mg of lisinopril daily. At the end of 2 weeks,
lisinopril administered once daily lowered trough blood pressure in a dose-dependent manner with
consistent antihypertensive efficacy demonstrated at doses >1.25 mg (0.02 mg/kg). This effect was
confirmed in a withdrawal phase, where the diastolic pressure rose by about 9 mmHg more in
patients randomized to placebo than it did in patients who were randomized to remain on the middle
and high doses of lisinopril. The dose-dependent antihypertensive effect of lisinopril was consistent
across several demographic subgroups: age, Tanner stage, gender, and race. In this study, lisinopril
was generally well-tolerated.
In the above pediatric studies, lisinopril was given either as tablets or in a suspension for those
children and infants who were unable to swallow tablets or who required a lower dose than is
available in tablet form [see Dosage and Administration (2.5)].
14.2 Heart Failure
In two placebo controlled, 12-week clinical studies compared the addition of PRINIVIL up to 20 mg
daily to digitalis and diuretics alone. The combination of PRINIVIL, digitalis and diuretics reduced the
following signs and symptoms of heart failure: edema, rales, paroxysmal nocturnal dyspnea and
jugular venous distention. In one of the studies, the combination of PRINIVIL, digitalis and diuretics
reduced orthopnea, presence of third heart sound and the number of patients classified as NYHA
Class III and IV, and it improved exercise tolerance. A large (over 3000 patients) survival study, the
ATLAS Trial, comparing 2.5 and 35 mg of lisinopril in patients with systolic heart failure, showed that
the higher dose of lisinopril had outcomes at least as favorable as the lower dose.During baseline-
controlled clinical trials, in patients receiving digitalis and diuretics, single doses of PRINIVIL resulted
in decreases in pulmonary capillary wedge pressure, systemic vascular resistance and blood
pressure accompanied by an increase in cardiac output and no change in heart rate.
14.3 Acute Myocardial Infarction
The Gruppo Italiano per lo Studio della Sopravvienza nell’Infarto Miocardico (GISSI-3) study was a
multicenter, controlled, randomized, unblinded clinical trial conducted in 19,394 patients with acute
myocardial infarction (MI) admitted to a coronary care unit. It was designed to examine the effects of
short-term (6 week) treatment with lisinopril, nitrates, their combination, or no therapy on short-term (6
week) mortality and on long-term death and markedly impaired cardiac function. Hemodynamically
stable patients presenting within 24 hours of the onset of symptoms were randomized, in a 2 x 2
factorial design, to 6 weeks of either 1) PRINIVIL alone (n=4841), 2) nitrates alone (n=4869), 3)
PRINIVIL plus nitrates (n=4841), or 4) open control (n=4843). All patients received routine therapies,
including thrombolytics (72%), aspirin (84%), and a beta blocker (31%), as appropriate, normally
utilized in acute myocardial infarction (MI) patients.
The protocol excluded patients with hypotension (systolic blood pressure ≤100 mmHg), severe heart
failure, cardiogenic shock, and renal dysfunction (serum creatinine >2 mg/dL and/or proteinuria
>500 mg per 24 h). Patients randomized to PRINIVIL received 5 mg within 24 hours of the onset of
symptoms, 5 mg after 24 hours, and then 10 mg daily thereafter. Patients with systolic blood pressure
less than 120 mmHg at baseline received 2.5 mg of PRINIVIL. If hypotension occurred, the PRINIVIL
dose was reduced or if severe hypotension occurred PRINIVIL was stopped [see Dosage and
Administration (2.3)].
15
Reference ID: 3789296
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The primary outcomes of the trial were the overall mortality at 6 weeks and a combined endpoint at 6
months after the myocardial infarction, consisting of the number of patients who died, had late (day 4)
clinical congestive heart failure, or had extensive left ventricular damage defined as ejection fraction
≤35%, or an akinetic-dyskinetic [A-D] score ≥45%. Patients receiving PRINIVIL (n=9646), alone or
with nitrates, had an 11% lower risk of death (p =0.04) compared to patients who did not receive
PRINIVIL (n=9672) (6.4% vs. 7.2%, respectively) at 6 weeks. Although patients randomized to
receive PRINIVIL for up to 6 weeks also fared numerically better on the combined endpoint at 6
months, the open nature of the assessment of heart failure, substantial loss to follow-up
echocardiography, and substantial excess use of PRINIVIL, between 6 weeks and 6 months in the
group randomized to 6 weeks of lisinopril, preclude any conclusion about this endpoint.
Patients with acute myocardial infarction, treated with PRINIVIL, had a higher (9.0% versus 3.7%)
incidence of persistent hypotension (systolic blood pressure <90 mmHg for more than 1 hour) and
renal dysfunction (2.4% versus 1.1%) in-hospital and at 6 weeks (increasing creatinine concentration
to over 3 mg/dL or a doubling or more of the baseline serum creatinine concentration) [see Adverse
Reactions (6.1)].
16
HOW SUPPLIED/STORAGE AND HANDLING
PRINIVIL is supplied as oval-shaped, compressed tablets scored on one side.
Color
Printing
Unit of use
Bottle/90
5 mg
White
MSD 19
NDC 0006-0019
54
10 mg Light yellow
MSD 106 NDC 0006-0106
54
20 mg Peach
MSD 207 NDC 0006-0207
54
Storage
Store at controlled room temperature, 15-30°C (59-86°F), and protect from moisture.
Dispense in a tight container, if product package is subdivided.
17
PATIENT COUNSELING INFORMATION
NOTE: This information is intended to aid in the safe and effective use of this medication. It is not a
disclosure of all possible adverse or intended effects.
Pregnancy: Tell female patients of childbearing age about the consequences of exposure to PRINIVIL
during pregnancy. Discuss treatment options with women planning to become pregnant. Tell patients
to report pregnancies to their physicians as soon as possible.
Angioedema: Angioedema, including laryngeal edema, may occur at any time during treatment with
angiotensin converting enzyme inhibitors, including PRINIVIL. Tell patients to report immediately any
signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty
16
Reference ID: 3789296
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
in swallowing or breathing) and to take no more drug until they have consulted with the prescribing
physician.
Symptomatic Hypotension: Tell patients to report light-headedness especially during the first few days
of therapy. If actual syncope occurs, tell the patient to discontinue the drug until they have consulted
with the prescribing physician.
Tell patients 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; advise patients accordingly.
Hyperkalemia: Tell patients not to use salt substitutes containing potassium without consulting their
physician.
Hypoglycemia: Tell diabetic patients treated with oral antidiabetic agents or insulin starting an ACE
inhibitor to monitor for hypoglycemia closely, especially during the first month of combined use [see
Drug Interactions (7.2)].
Leukopenia/Neutropenia: Tell patients to report promptly any indication of infection (e.g., sore throat,
fever), which may be a sign of leukopenia/neutropenia. company logo
For patent information: www.merck.com/product/patent/home.html
The trademarks depicted herein are owned by their respective companies.
Copyright © 1988, 1989, 1992, 1993, 1995, 2005, 2006, 2011, 2012, 2013 Merck Sharp & Dohme
Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.
uspi-mk0521-t-XXXXrXXX
17
Reference ID: 3789296
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:28.637076
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019558s057lbl.pdf', 'application_number': 19558, 'submission_type': 'SUPPL ', 'submission_number': 57}
|
11,539
|
TERAZOL
7(terconazole) Vaginal Cream 0.4%
TERAZOL
3(terconazole) Vaginal Cream 0.8%
TERAZOL® 3 (terconazole) Vaginal Suppositories 80 mg
DESCRIPTION
TERAZOL® 7(terconazole) Vaginal Cream 0.4% is a white to off-white, water washable
cream for intravaginal administration containing 0.4% of the antifungal agent
terconazole, cis-1-[p-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-
dioxolan-4-yl]methoxy]phenyl]-4-isopropylpiperazine, compounded in a cream base
consisting of butylated hydroxyanisole, cetyl alcohol, isopropyl myristate, polysorbate
60, polysorbate 80, propylene glycol, stearyl alcohol, and purified water.
TERAZOL® 3 (terconazole) Vaginal Cream 0.8% is a white to off-white, water washable
cream for intravaginal administration containing 0.8% of the antifungal agent
terconazole, cis-1-[p-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-
dioxolan-4-yl]methoxy]phenyl]-4-isopropylpiperazine, compounded in a cream base
consisting of butylated hydroxyanisole, cetyl alcohol, isopropyl myristate, polysorbate
60, polysorbate 80, propylene glycol, stearyl alcohol, and purified water.
TERAZOL® 3 (terconazole) Vaginal Suppositories are white to off-white suppositories
for intravaginal administration containing 80 mg of the antifungal agent terconazole, cis-
1-[p-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-
yl]methoxy]phenyl]-4-isopropylpiperazine, in triglycerides derived from coconut and/or
palm kernel oil (a base of hydrogenated vegetable oils) and butylated hydroxyanisole.
The structural formula of terconazole is as follows:
TERCONAZOLE
C26H31Cl2N5O3
[INSERT STRUCTURE HERE]
Terconazole, a triazole derivative, is a white to almost white powder with a molecular
weight of 532.47. It is insoluble in water; sparingly soluble in ethanol; and soluble in
butanol.
CLINICAL PHARMACOLOGY
Following intravaginal administration of terconazole in humans, absorption ranged from
5-8% in three hysterectomized subjects and 12-16% in two non-hysterectomized subjects
with tubal ligations.
Following daily intravaginal administration of 0.8% terconazole 40 mg
(0.8% cream x 5 g) for seven days to normal humans, plasma concentrations were low
and gradually rose to a daily peak (mean of 5.9 ng/mL or 0.006 mcg/mL) at 6.6 hours.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Results from similar studies in patients with vulvovaginal candidiasis indicate that the
slow rate of absorption, the lack of accumulation, and the mean peak plasma
concentration of terconazole was not different from that observed in healthy women. The
absorption characteristics of terconazole 0.8% in pregnant or non-pregnant patients with
vulvovaginal candidiasis were also similar to those found in normal volunteers.
Following oral (30 mg) administration of 14C-labelled terconazole, the harmonic half-life
of elimination from the blood for the parent terconazole was 6.9 hours (range 4.0-11.3).
Terconazole is extensively metabolized; the plasma AUC for terconazole compared to the
AUC for total radioactivity was 0.6%. Total radioactivity was eliminated from the blood
with a harmonic half-life of 52.2 hours (range 44-60). Excretion of radioactivity was both
by renal (32-56%) and fecal (47-52%) routes.
In vitro, terconazole is highly protein bound (94.9%) and the degree of binding is
independent of drug concentration.
Photosensitivity reactions were observed in some normal volunteers following repeated
dermal application of terconazole 2.0% and 0.8% creams under conditions of filtered
artificial ultraviolet light.
Photosensitivity reactions have not been observed in U.S. and foreign clinical trials in
patients who were treated with terconazole suppositories or vaginal cream (0.4% and
0.8%).
Microbiology: Terconazole exhibits fungicidal activity in vitro against Candida
albicans. Antifungal activity has also been demonstrated against other fungi. The MIC
values of terconazole against most Lactobacillus spp. typically found in the human
vagina were ≥128 mcg/mL; therefore these beneficial bacteria were not affected by drug
treatment.
The exact pharmacologic mode of action of terconazole is uncertain; however, it may
exert its antifungal activity by the disruption of normal fungal cell membrane
permeability. No resistance to terconazole has developed during successive passages of
C. albicans.
INDICATIONS AND USAGE
TERAZOL 7 Vaginal Cream 0.4%, TERAZOL 3 Vaginal Cream 0.8% and TERAZOL 3
Vaginal Suppositories 80 mg are indicated for the local treatment of vulvovaginal
candidiasis (moniliasis). As these products are effective only for vulvovaginitis caused by
the genus Candida, the diagnosis should be confirmed by KOH smears and/or cultures.
CONTRAINDICATIONS
Patients known to be hypersensitive to terconazole or to any of the components of the
cream or suppositories.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WARNINGS
None.
PRECAUTIONS
General: Discontinue use and do not retreat with terconazole if sensitization, irritation,
fever, chills or flu-like symptoms are reported during use.
The base contained in the suppository formulation may interact with certain rubber or
latex products, such as those used in vaginal contraceptive diaphragms, therefore
concurrent use is not recommended.
Laboratory Tests: If there is lack of response to terconazole, appropriate microbiologic
studies (standard KOH smear and/or cultures) should be repeated to confirm the
diagnosis and rule out other pathogens.
Drug Interactions:
TERAZOL 7 Vaginal Cream 0.4% and TERAZOL 3 Vaginal Suppositories80mg:
The therapeutic effect of these products is not affected by oral contraceptive usage.
TERAZOL 3 Vaginal Cream 0.8%:
The levels of estradiol (E2) and progesterone did not differ significantly when 0.8%
terconazole vaginal cream was administered to healthy female volunteers established on a
low dose oral contraceptive.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Carcinogenesis: Studies to determine the carcinogenic potential of terconazole have not
been performed.
Mutagenicity: Terconazole was not mutagenic when tested in vitro for induction of
microbial point mutations (Ames test), or for inducing cellular transformation, or in vivo
for chromosome breaks (micronucleus test) or dominant lethal mutations in mouse germ
cells.
Impairment of Fertility: No impairment of fertility occurred when female rats were
administered terconazole orally up to 40 mg/kg/day for a three month period.
Pregnancy:
Teratogenic Effects:
Pregnancy Category C.
There was no evidence of teratogenicity when terconazole was administered orally up to
40 mg/kg/day (25x the recommended intravaginal human dose of the suppository
formulation, 50x the recommended intravaginal human dose of the 0.8% vaginal cream
formulation, and 100x the intravaginal human dose of the 0.4% vaginal cream
formulation) in rats, or 20 mg/kg/day in rabbits, or subcutaneously up to 20 mg/kg/day in
rats.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Dosages at or below 10 mg/kg/day produced no embryotoxicity; however, there was a
delay in fetal ossification at 10 mg/kg/day in rats. There was some evidence of
embryotoxicity in rabbits and rats at 20-40 mg/kg. In rats, this was reflected as a decrease
in litter size and number of viable young and reduced fetal weight. There was also delay
in ossification and an increased incidence of skeletal variants.
The no-effect dose of 10 mg/kg/day resulted in a mean peak plasma level of terconazole
in pregnant rats of 0.176 mcg/mL which exceeds by 44 times the mean peak plasma level
(0.004 mcg/mL) seen in normal subjects after intravaginal administration of terconazole
0.4% vaginal cream, by 30 times the mean peak plasma level (0.006 mcg/mL) seen in
normal subjects after intravaginal administration of terconazole 0.8% vaginal cream, and
by 17 times the mean peak plasma level (0.010 mcg/mL) seen in normal subjects after
intravaginal administration of terconazole 80 mg vaginal suppository. This safety
assessment does not account for possible exposure of the fetus through direct transfer to
terconazole from the irritated vagina by diffusion across amniotic membranes.
Since terconazole is absorbed from the human vagina, it should not be used in the first
trimester of pregnancy unless the physician considers it essential to the welfare of the
patient.
Nursing Mothers:
It is not known whether this drug is excreted in human milk. Animal studies have shown
that rat offspring exposed via the milk of treated (40 mg/kg/orally) dams showed
decreased survival during the first few post-partum days, but overall pup weight and
weight gain were comparable to or greater than controls throughout lactation. Because
many drugs are excreted in human milk, and because of the potential for adverse reaction
in nursing infants from terconazole, 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 efficacy in children have not been established.
Geriatric Use:
Clinical studies of TERAZOL 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.
ADVERSE REACTIONS
TERAZOL 7 Vaginal Cream 0.4%:
During controlled clinical studies conducted in the United States, 521 patients with
vulvovaginal candidiasis were treated with terconazole 0.4% vaginal cream. Based on
comparative analyses with placebo, the adverse experiences considered most likely
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
related to terconazole 0.4% vaginal cream were headache (26% vs. 17% with placebo)
and body pain (2.1% vs. 0% with placebo). Vulvovaginal burning (5.2%), itching (2.3%)
or irritation (3.1%) occurred less frequently with terconazole 0.4% vaginal cream than
with the vehicle placebo. Fever (1.7% vs. 0.5% with placebo) and chills (0.4% vs. 0.0%
with placebo) have also been reported. The therapy-related dropout rate was 1.9%. The
adverse drug experience on terconazole most frequently causing discontinuation was
vulvovaginal itching (0.6%), which was lower than the incidence for placebo (0.9%).
TERAZOL 3 Vaginal Cream 0.8%:
During controlled clinical studies conducted in the United States, patients with
vulvovaginal candidiasis were treated with terconazole 0.8% vaginal cream for three
days. Based on comparative analyses with placebo and a standard agent, the adverse
experiences considered most likely related to terconazole 0.8% vaginal cream were
headache (21% vs. 16% with placebo) and dysmenorrhea (6% vs. 2% with placebo).
Genital complaints in general, and burning and itching in particular, occurred less
frequently in the terconazole 0.8% vaginal cream 3 day regimen (5% vs. 6%-9% with
placebo). Other adverse experiences reported with terconazole 0.8% vaginal cream were
abdominal pain (3.4% vs. 1% with placebo) and fever (1% vs. 0.3% with placebo). The
therapy-related dropout rate was 2.0% for the terconazole 0.8% vaginal cream. The
adverse drug experience most frequently causing discontinuation of therapy was
vulvovaginal itching, 0.7% with the terconazole 0.8% vaginal cream group and 0.3%
with the placebo group.
TERAZOL 3 Vaginal Suppositories 80 mg:
During controlled clinical studies conducted in the United States, 284 patients with
vulvovaginal candidiasis were treated with terconazole 80 mg vaginal suppositories.
Based on comparative analyses with placebo (295 patients), the adverse experiences
considered adverse reactions most likely related to terconazole 80 mg vaginal
suppositories were headache (30.3% vs. 20.7% with placebo) and pain of the female
genitalia (4.2% vs. 0.7% with placebo). Adverse reactions that were reported but were
not statistically significantly different from placebo were burning (15.2% vs. 11.2% with
placebo) and body pain (3.9% vs. 1.7% with placebo). Fever (2.8% v. 1.4% with placebo)
and chills (1.8% vs. 0.7% with placebo) have also been reported. The therapy-related
dropout rate was 3.5% and the placebo therapy-related dropout rate was 2.7%. The
adverse drug experience on terconazole most frequently causing discontinuation was
burning (2.5% vs. 1.4% with placebo) and pruritus (1.8% vs. 1.4% with placebo).
OVERDOSAGE
Overdose of terconazole in humans has not been reported to date. In the rat, the oral LD
50 values were found to be 1741 and 849 mg/kg for the male and female, respectively.
The oral LD 50 values for the male and female dog were ~1280 and ≥640 mg/kg,
respectively.
DOSAGE AND ADMINISTRATION
TERAZOL 7 Vaginal Cream 0.4%:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
One full applicator (5 g) of TERAZOL 7 Vaginal Cream (20 mg terconazole) should be
administered intravaginally once daily at bedtime for seven consecutive days.
TERAZOL 3 Vaginal Cream 0.8%:
One full applicator (5 g) of TERAZOL 3 Vaginal Cream (40 mg terconazole) should be
administered intravaginally once daily at bedtime for three consecutive days.
TERAZOL 3 Vaginal Suppositories 80 mg
One TERAZOL 3 Vaginal Suppository (80 mg terconazole) should be administered
intravaginally once daily at bedtime for three consecutive days.
Before prescribing another course of therapy, the diagnosis should be reconfirmed by
smears and/or cultures and other pathogens commonly associated with vulvovaginitis
ruled out. The therapeutic effect of these products is not affected by menstruation.
HOW SUPPLIED
TERAZOL® 7 (terconazole) Vaginal Cream 0.4% is available in 45 g
(NDC 0062-5350-01) tubes with an ORTHO* Measured-Dose Applicator. Store at
Controlled Room Temperature 15 - 30° C (59 - 86° F).
TERAZOL® 3 (terconazole) Vaginal Cream 0.8% is available in 20 g
(NDC 0062-5356-01) tubes with an ORTHO* Measured-Dose Applicator. Store at
Controlled Room Temperature 15 - 30° C (59 - 86° F).
TERAZOL® 3 (terconazole) Vaginal Suppositories 80 mg are available as 2.5 g,
elliptically shaped white to off-white suppositories in packages of three
(NDC 0062-5351-01) with a vaginal applicator. Store at controlled room temperature 15 -
30° C (59 - 86° F).
Rx only *Trademark
ORTHO McNEIL
ORTHO McNEIL PHARMACEUTICAL, INC.
Raritan, New Jersey 08869
OMP 1998 Printed in U.S.A.
Issued March 2001
642-10-300-1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
TERAZOL
7 (terconazole) Vaginal Cream 0.4%
TERAZOL
3 (terconazole) Vaginal Cream 0.8%
PATIENT INSTRUCTIONS
Filling the applicator:
1. Remove the cap from the tube.
2. Use the pointed tip on the top of the cap to puncture the seal on the tube.
3. Screw the applicator onto the tube.
4. Squeeze the tube from the bottom and fill the applicator until the plunger stops.
5. Unscrew the applicator from the tube.
Illustration of cap puncturing tube
Illustration of applicator screwed onto tube
Using the applicator:
1. Lie on your back with your knees drawn up toward your chest.
Illustration of lower extremities.
2. Holding the applicator by the ribbed end of the barrel, insert the filled applicator into
the vagina as far as it will comfortably go.
3. Slowly press the plunger of the applicator to release the cream into the vagina.
4. Remove the applicator from the vagina.
5. Apply one applicatorful each night for as many days at bedtime, as directed by your
doctor.
Cleaning the applicator: (Does not apply to sample applicators, which are for one
time use only)
After each use, you should thoroughly clean the applicator by following the procedure
below:
1. Pull the plunger out of the barrel.
2. Wash the pieces with lukewarm, soapy water, and dry them thoroughly.
3. Put the applicator back together by gently pushing the plunger into the barrel as far as
it will go.
Illustration – separate plunger from barrel
NOTE: Store the cream at Controlled Room Temperature 15-30oC (59-86oF). See end
flap for lot number and expiration date.
U.S. Patent No. D-279,504
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
TERAZOL
3 (terconazole) Vaginal Suppositories 80 mg
Three oval suppositories, for use inside the vagina only.
Designed to be inserted into the vagina.
HOW TO USE:
Place one suppository into the vagina each night at bedtime, for 3 nights, as directed by
your doctor. The TERAZOL Suppository is self-lubricating and may be inserted with or
without the applicator.
A. Insertion with the applicator
1. Filling the applicator
• Break off suppository from the plastic strip.
• Pull the plastic completely apart at the notched end.
• Place the flat end of the suppository into the open end of the applicator
as shown. You are now ready to insert the suppository into the vagina.
Illustration 1
Illustration 2
2. Using the applicator
• Lie on your back with your knees drawn up toward your chest.
• Holding the applicator by the ribbed end of the barrel, gently insert it
into the vagina as far as it will comfortably go.
• Press the plunger to release the suppository into the vagina.
• Remove the applicator from the vagina.
Illustration of lower extremities
3. Cleaning the applicator (Does not apply to sample applicators, which
are for one time use only)
After each use, you should thoroughly clean the applicator by following
the procedure below:
• Pull the plunger out of the barrel.
• Wash both pieces with lukewarm, soapy water, and dry them
thoroughly.
• Put the applicator back together by gently pushing the plunger into the
barrel as far as it will go.
B. Insertion without the applicator
• Lie on your back with your knees drawn up toward your chest.
• Place the suppository on the tip of your finger as shown.
• Insert the suppository gently into the vagina as far as it will comfortably go.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NOTE: Store the suppositories at Controlled Room Temperature 15-30°C (59-86°F). See
end flap for lot number and expiration date.
U.S. Patent No. D-279,504
A WORD ABOUT YEAST INFECTIONS
Why do yeast infections occur?
Yeast infections are caused by an organism called Candida (KAN di duh). It may be
present in small and harmless amounts in the mouth, digestive tract, and vagina.
Sometimes the natural balance of the vagina becomes upset. This may lead to rapid
growth of Candida, which results in a yeast infection. Symptoms of a yeast infection
include itching, burning, redness, and an abnormal discharge.
Your doctor can make the diagnosis of a yeast infection by evaluating your symptoms
and looking at a sample of the discharge under the microscope.
How can I prevent yeast infections?
Certain factors may increase your chance of developing a yeast infection. These factors
don’t actually cause the problem, but they may create a situation that allows the yeast to
grow rapidly.
• Clothing: Tight jeans, nylon underwear, pantyhose, and wet bathing suits can hold in
heat and moisture (two conditions in which yeast organisms thrive). Looser pants or
skirts, 100% cotton underwear, and stockings may help avoid this problem.
• Diet: Cutting down on sweets, milk products, and artificial sweeteners may reduce
the risk of yeast infections.
• Antibiotics: Antibiotics work by eliminating disease-causing organisms. While
they are helpful in curing other problems, antibiotics may lead to an overgrowth of
Candida in the vagina.
• Pregnancy: Hormonal changes in the body during pregnancy encourage the growth
of yeast. This is a very common time for an infection to occur. Until the baby is
born, it may be hard to completely eliminate yeast infections. If you believe you are
pregnant, tell your doctor.
• Menstruation: Sometimes monthly changes in hormone levels may lead to yeast
infections.
• Diabetes: In addition to heat and moisture, yeast thrives on sugar. Because diabetics
often have sugar in their urine, their vaginas are rich in this substance. Careful
control of diabetes may help prevent yeast infection.
Controlling these factors can help eliminate yeast infections and may prevent them from
coming back.
Some other helpful tips:
1. For best results, be sure to use the medication as prescribed by your doctor, even if
you feel better quickly.
2. Avoid sexual intercourse, if your doctor advises you to do so. The suppository
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
formulation (not the cream) may damage the diaphragm. Therefore, use of the
diaphragm during therapy with the suppository is not recommended. Consult your
physician.
3. If your partner has any penile itching, redness, or discomfort, he should consult his
physician and mention that you are being treated for a yeast infection.
4. You can use the medication even if you are having your menstrual period. However,
you should not use tampons because they may absorb the medication. Instead, use
external pads or napkins until you have finished your medication. You may also wish
to wear a sanitary napkin if the vaginal medication leaks.
5. Dry the genital area thoroughly after showering, bathing, or swimming. Change out
of a wet bathing suit or damp exercise clothes as soon as possible. A dry
environment is less likely to encourage the growth of yeast.
6. Wipe from front to rear (away from the vagina) after a bowel movement.
7. Don’t douche unless your doctor specifically tells you to do so. Douching may
disturb the vaginal balance.
8. Don’t scratch if you can help it. Scratching can cause more irritation and spread the
infection.
9. Discuss with your physician any medication you are already taking. Certain types of
medication can make your vagina more susceptible to infection.
10. Eat nutritious meals to promote your general health.
ORTHO McNEIL
ORTHO McNEIL PHARMACEUTICAL, INC.
Raritan, New Jersey 08869
OMP 1998 Printed in U.S.A.
Issued March 2001
642-10-300-1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:28.669905
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/019641s016lbl.pdf', 'application_number': 19579, 'submission_type': 'SUPPL ', 'submission_number': 16}
|
11,541
|
TERAZOL® 7 VAGINAL CREAM 0.4%
(terconazole)
TERAZOL® 3 VAGINAL CREAM 0.8%
(terconazole)
TERAZOL® 3 VAGINAL SUPPOSITORIES 80 MG
(terconazole)
DESCRIPTION
TERAZOL® 7 (terconazole) Vaginal Cream 0.4% is a white to off-white, water
washable cream for intravaginal administration containing 0.4% of the antifungal
agent
terconazole,
cis-1-[p-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1
ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-isopropylpiperazine, compounded
in a cream base consisting of butylated hydroxyanisole, cetyl alcohol, isopropyl
myristate, polysorbate 60, polysorbate 80, propylene glycol, stearyl alcohol, and
purified water.
TERAZOL® 3 (terconazole) Vaginal Cream 0.8% is a white to off-white, water
washable cream for intravaginal administration containing 0.8% of the antifungal
agent
terconazole,
cis-1-[p-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1
ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-isopropylpiperazine, compounded
in a cream base consisting of butylated hydroxyanisole, cetyl alcohol, isopropyl
myristate, polysorbate 60, polysorbate 80, propylene glycol, stearyl alcohol, and
purified water.
TERAZOL® 3 (terconazole) Vaginal Suppositories are white to off-white
suppositories for intravaginal administration containing 80 mg of the antifungal
agent
terconazole,
cis-1-[p-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1
ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-isopropylpiperazine,
in
triglycerides derived from coconut and/or palm kernel oil (a base of hydrogenated
vegetable oils) and butylated hydroxyanisole.
The structural formula of terconazole is as follows:
Reference ID: 3598383
1
structural formula
Terconazole, a triazole derivative, is a white to almost white powder with a
molecular weight of 532.47. It is insoluble in water; sparingly soluble in ethanol;
and soluble in butanol.
CLINICAL PHARMACOLOGY
Absorption
Following a single intravaginal application of a suppository containing 240 mg 14C
terconazole to healthy women, approximately 70% (range: 64-76%) of terconazole
remains in the vaginal area during the suppository retention period (16 hours);
approximately 10% (range: 5-16%) of the administered radioactivity was absorbed
systemically over 7 days. Maximum plasma concentrations of terconazole occur 5
to 10 hours after intravaginal application of the cream or suppository. Systemic
exposure to terconazole is approximately proportional to the applied dose, whether
as the cream or suppository. The rate and extent of absorption of terconazole are
similar in patients with vulvovaginal candidiasis (pregnant or non-pregnant) and
healthy subjects.
Distribution
Terconazole is highly protein bound (94.9%) in human plasma and the degree of
binding is independent of drug concentration over the range of 0.01 to 5.0 mcg/mL.
Metabolism
Systemically absorbed terconazole is extensively metabolized (>95%).
Elimination
Across various studies in healthy women, after single or multiple intravaginal
administration of terconazole as the cream or suppository/ovule, the mean
elimination half-life of unchanged terconazole ranged from 6.4 to 8.5 hours.
Following a single intravaginal administration of a suppository containing 240 mg
14C-terconazole to hysterectomized or tubal ligated women, approximately 3 to 10%
(mean ± SD: 5.7 ± 3.0%) of the administered radioactivity was eliminated in the
Reference ID: 3598383
2
urine and 2 to 6% (mean ± SD: 4.2 ± 1.6%) was eliminated in the feces during the
7-day collection period.
Multiple Dosing
There is no significant increase in maximum plasma concentration or overall
exposure (AUC) after multiple daily applications of the cream for 7 days or
suppositories for 3 days.
Photosensitivity reactions were observed in some normal volunteers following
repeated dermal application of terconazole 2.0% and 0.8% creams under conditions
of filtered artificial ultraviolet light.
Photosensitivity reactions have not been observed in U.S. and foreign clinical trials
in patients who were treated with terconazole suppositories or vaginal cream (0.4%
and 0.8%).
Microbiology
Mechanism of action
Terconazole, an azole antifungal agent, inhibits fungal cytochrome P-450-mediated
14 alpha-lanosterol demethylase enzyme. This enzyme functions to convert
lanosterol to ergosterol. The accumulation of 14 alpha-methyl sterols correlates with
the subsequent loss of ergosterol in the fungal cell wall and may be responsible for
the antifungal activity of terconazole. Mammalian cell demethylation is less
sensitive to terconazole inhibition.
Activity in vitro
Terconazole exhibits antifungal activity in vitro against Candida albicans and other
Candida species. The MIC values of terconazole against most Lactobacillus spp.
typically found in the human vagina were ≥128 mcg/mL; therefore these beneficial
bacteria are not affected by drug treatment.
INDICATIONS AND USAGE
TERAZOL® 7 (terconazole) Vaginal Cream 0.4%, TERAZOL® 3 (terconazole)
Vaginal Cream 0.8% and TERAZOL® 3 (terconazole) Vaginal Suppositories 80 mg
are indicated for the local treatment of vulvovaginal candidiasis (moniliasis). As
these products are effective only for vulvovaginitis caused by the genus Candida,
the diagnosis should be confirmed by KOH smears and/or cultures.
CONTRAINDICATIONS
Patients known to be hypersensitive to terconazole or to any of the components of
the cream or suppositories.
Reference ID: 3598383
3
WARNINGS
Anaphylaxis and toxic epidermal necrolysis have been reported during terconazole
therapy. TERAZOL® therapy should be discontinued if anaphylaxis or toxic
epidermal necrolysis develops.
PRECAUTIONS
General: For vulvovaginal use only. TERAZOL® is not for ophthalmic or oral use.
Discontinue use and do not retreat with terconazole if sensitization, irritation, fever,
chills or flu-like symptoms are reported during use.
The base contained in the suppository formulation may interact with certain rubber or
latex products, such as those used in vaginal contraceptive diaphragms or latex
condoms; therefore concurrent use is not recommended.
Laboratory Tests: If there is lack of response to terconazole, appropriate
microbiologic studies (standard KOH smear and/or cultures) should be repeated to
confirm the diagnosis and rule out other pathogens.
Drug Interactions:
The therapeutic effect of terconazole is not affected by oral contraceptive usage.
The levels of estradiol and progesterone did not differ significantly when 0.8%
terconazole vaginal cream was administered to healthy female volunteers established
on a low dose oral contraceptive.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Carcinogenesis: Studies to determine the carcinogenic potential of terconazole have
not been performed.
Mutagenicity: Terconazole was not mutagenic when tested in vitro for induction of
microbial point mutations (Ames test), or for inducing cellular transformation, or in
vivo for chromosome breaks (micronucleus test) or dominant lethal mutations in
mouse germ cells.
Impairment of Fertility: No impairment of fertility occurred when female rats were
administered terconazole orally up to 40 mg/kg/day for a three month period.
Pregnancy:
Teratogenic Effects:
Pregnancy Category C.
There was no evidence of teratogenicity when terconazole was administered orally up
to 40 mg/kg/day (25x the recommended intravaginal human dose of the suppository
formulation, 50x the recommended intravaginal human dose of the 0.8% vaginal
Reference ID: 3598383
4
cream formulation, and 100x the intravaginal human dose of the 0.4% vaginal cream
formulation) in rats, or 20 mg/kg/day in rabbits, or subcutaneously up to
20 mg/kg/day in rats.
Dosages at or below 10 mg/kg/day produced no embryotoxicity; however, there was a
delay in fetal ossification at 10 mg/kg/day in rats. There was some evidence of
embryotoxicity in rabbits and rats at 20-40 mg/kg. In rats, this was reflected as a
decrease in litter size and number of viable young and reduced fetal weight. There
was also delay in ossification and an increased incidence of skeletal variants.
The no-effect dose of 10 mg/kg/day resulted in a mean peak plasma level of
terconazole in pregnant rats of 0.176 mcg/mL which exceeds by 44 times the mean
peak plasma level (0.004 mcg/mL) seen in normal subjects after intravaginal
administration of terconazole 0.4% vaginal cream, by 30 times the mean peak plasma
level (0.006 mcg/mL) seen in normal subjects after intravaginal administration of
terconazole 0.8% vaginal cream, and by 17 times the mean peak plasma level
(0.010 mcg/mL) seen in normal subjects after intravaginal administration of
terconazole 80 mg vaginal suppository. This safety assessment does not account for
possible exposure of the fetus through direct transfer to terconazole from the irritated
vagina by diffusion across amniotic membranes.
Since terconazole is absorbed from the human vagina, it should not be used in the
first trimester of pregnancy unless the physician considers it essential to the welfare
of the patient.
Terconazole may be used during the second and third trimester if the potential benefit
outweighs the possible risks to the fetus.
Nursing Mothers:
It is not known whether this drug is excreted in human milk. Animal studies have
shown that rat offspring exposed via the milk of treated (40 mg/kg/orally) dams
showed decreased survival during the first few post-partum days, but overall pup
weight and weight gain were comparable to or greater than controls throughout
lactation. Because many drugs are excreted in human milk, and because of the
potential for adverse reaction in nursing infants from terconazole, 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 efficacy in children have not been established.
Reference ID: 3598383
5
Geriatric Use:
Clinical studies of TERAZOL® 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.
ADVERSE REACTIONS
Adverse Reactions from Clinical Trials
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
clinical practice.
TERAZOL® 7 (terconazole) Vaginal Cream 0.4%:
During controlled clinical studies conducted in the United States, 521 patients with
vulvovaginal candidiasis were treated with terconazole 0.4% vaginal cream. Based on
comparative analyses with placebo, the adverse experiences considered most likely
related to terconazole 0.4% vaginal cream were headache (26% vs. 17% with
placebo) and body pain (2.1% vs. 0% with placebo). Fever (1.7% vs. 0.5% with
placebo) and chills (0.4% vs. 0.0% with placebo), vulvovaginal burning, itching and
irritation have also been reported. The adverse drug experience on terconazole most
frequently causing discontinuation was vulvovaginal itching.
TERAZOL® 3 (terconazole) Vaginal Cream 0.8%:
During controlled clinical studies conducted in the United States, patients with
vulvovaginal candidiasis were treated with terconazole 0.8% vaginal cream for three
days. Based on comparative analyses with placebo and a standard agent, the adverse
experiences considered most likely related to terconazole 0.8% vaginal cream were
headache (21% vs. 16% with placebo) and dysmenorrhea (6% vs. 2% with placebo).
Other adverse experiences reported with terconazole 0.8% vaginal cream were
abdominal pain (3.4% vs. 1% with placebo) and fever (1% vs. 0.3% with placebo).
The adverse drug experience most frequently causing discontinuation of therapy was
vulvovaginal itching, 0.7% with the terconazole 0.8% vaginal cream group and 0.3%
with the placebo group.
TERAZOL® 3 (terconazole) Vaginal Suppositories 80 mg:
During controlled clinical studies conducted in the United States, 284 patients with
vulvovaginal candidiasis were treated with terconazole 80 mg vaginal suppositories.
Based on comparative analyses with placebo (295 patients), the adverse experiences
considered adverse reactions most likely related to terconazole 80 mg vaginal
suppositories were headache (30.3% vs. 20.7% with placebo) and pain of the female
Reference ID: 3598383
6
genitalia (4.2% vs. 0.7% with placebo). Adverse reactions that have also been
reported but were not statistically significantly different from placebo were burning
(15.2% vs. 11.2% with placebo) and body pain (3.9% vs. 1.7% with placebo). Fever
(2.8% vs. 1.4% with placebo) and chills (1.8% vs. 0.7% with placebo) have also been
reported. The adverse drug experience on terconazole most frequently causing
discontinuation was burning (2.5% vs. 1.4% with placebo) and pruritus (1.8% vs.
1.4% with placebo).
Post-marketing Experience
The following adverse drug reactions have been first identified during post-marketing
experience with TERAZOL®:. 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.
General: Asthenia, Influenza-Like Illness consisting of multiple listed reactions
including fever and chills, nausea, vomiting, myalgia, arthralgia, malaise
Immune: Hypersensitivity, Anaphylaxis, Face Edema
Nervous: Dizziness
Respiratory: Bronchospasm
Skin: Rash, Toxic Epidermal Necrolysis, Urticaria
OVERDOSAGE
In the rat, the oral LD 50 values were found to be 1741 and 849 mg/kg for the male
and female, respectively. The oral LD 50 values for the male and female dog were
≅1280 and ≥640 mg/kg, respectively.
In the event of oral ingestion of suppository or cream, supportive and symptomatic
measures should be carried out. If the cream is accidentally applied to the eyes, wash
with clean water or saline and seek medical attention if symptoms persist.
DOSAGE AND ADMINISTRATION
TERAZOL® 7 (terconazole) Vaginal Cream 0.4%:
One full applicator (5 g) of TERAZOL® 7 Vaginal Cream (20 mg terconazole) should
be administered intravaginally once daily at bedtime for seven consecutive days.
TERAZOL® 3 (terconazole) Vaginal Cream 0.8%:
One full applicator (5 g) of TERAZOL® 3 Vaginal Cream (40 mg terconazole) should
be administered intravaginally once daily at bedtime for three consecutive days.
Reference ID: 3598383
7
TERAZOL® 3 (terconazole) Vaginal Suppositories 80 mg:
One TERAZOL® 3 Vaginal Suppository (80 mg terconazole) should be administered
intravaginally once daily at bedtime for three consecutive days.
Before prescribing another course of therapy, the diagnosis should be reconfirmed by
smears and/or cultures and other pathogens commonly associated with vulvovaginitis
ruled out. The therapeutic effect of these products is not affected by menstruation.
HOW SUPPLIED
TERAZOL®
7 (terconazole) Vaginal Cream 0.4% is available in 45 g
(NDC 50458-535-01) tubes with an ORTHO* Measured-Dose Applicator. Store at
Controlled Room Temperature 15–30°C (59–86°F).
TERAZOL®
3 (terconazole) Vaginal Cream 0.8% is available in 20 g
(NDC 50458-536-01) tubes with an ORTHO* Measured-Dose Applicator. Store at
Controlled Room Temperature 15–30°C (59–86°F).
TERAZOL® 3 (terconazole) Vaginal Suppositories 80 mg are available as 2.5 g,
elliptically-shaped white to off-white suppositories in packages of three
(NDC 50458-531-01) with a vaginal applicator. Store at Controlled Room
Temperature 15–30°C (59–86°F).
*Trademark
Manufactured by:
• Janssen Ortho, LLC, Manati, Puerto Rico 00674 (for the Vaginal
Cream)
• Jubilant HollisterStier General Partnership, Kirkland, Quebec, Canada
H9H 4J4 (for the Vaginal Cream and Vaginal Suppositories)
Manufactured for:
(logo)
Janssen Pharmaceuticals, Inc. Titusville, New Jersey 08560
© Janssen Pharmaceuticals, Inc. 1998
Revised July 2014
TERAZOL® 7 VAGINAL CREAM 0.4%
(terconazole)
Reference ID: 3598383
8
TERAZOL® 3 VAGINAL CREAM 0.8%
(terconazole)
PATIENT INSTRUCTIONS
FILLING THE APPLICATOR:
1. Remove the cap from the tube. usage illustration
2. Use the pointed tip on the top of the cap to puncture the seal on the tube.
3. Screw the applicator onto the tube. usage illustration
4. Squeeze the tube from the bottom and fill the applicator until the plunger
stops.
5. Unscrew the applicator from the tube.
USING THE APPLICATOR:
1. Lie on your back with your knees drawn up toward your chest.
2. Holding the applicator by the ribbed end of the barrel, insert the filled
applicator into the vagina as far as it will comfortably go.
3. Slowly press the plunger of the applicator to release the cream into the vagina.
Reference ID: 3598383
9
usage illustration
4. Remove the applicator from the vagina.
5. Apply one applicatorful each night for as many days at bedtime, as directed by
your doctor.
CLEANING THE APPLICATOR: (DOES NOT APPLY TO SAMPLE
APPLICATORS, WHICH ARE FOR ONE TIME USE ONLY)
After each use, you should thoroughly clean the applicator by following the
procedure below:
1. Pull the plunger out of the barrel. usage illustration
2. Wash the pieces with lukewarm, soapy water, and dry them thoroughly.
3. Put the applicator back together by gently pushing the plunger into the barrel
as far as it will go.
NOTE: Store the cream at Controlled Room Temperature 15–30°C (59–86°F). See
end flap for lot number and expiration date.
TERAZOL® 3 VAGINAL SUPPOSITORIES 80 mg
(terconazole)
Three oval suppositories, for use inside the vagina only.
Designed to be inserted into the vagina.
Reference ID: 3598383
10
HOW TO USE:
Place one suppository into the vagina each night at bedtime, for 3 nights, as directed
by your doctor. The TERAZOL Suppository is self-lubricating and may be inserted
with or without the applicator.
A. Insertion with the applicator
1. Filling the applicator
• Break off suppository from the plastic strip.
• Pull the plastic completely apart at the notched end. usage illustration
• Place the flat end of the suppository into the open end of the
applicator as shown. You are now ready to insert the
suppository into the vagina. usage illustration
2. Using the applicator
• Lie on your back with your knees drawn up toward your chest.
• Holding the applicator by the ribbed end of the barrel, gently
insert it into the vagina as far as it will comfortably go.
Reference ID: 3598383
11
• Press the plunger to release the suppository into the vagina. usage illustration
• Remove the applicator from the vagina.
3. Cleaning the applicator (Does not apply to sample applicators, which
are for one time use only)
After each use, you should thoroughly clean the applicator by
following the procedure below:
• Pull the plunger out of the barrel.
• Wash both pieces with lukewarm, soapy water, and dry them
thoroughly.
• Put the applicator back together by gently pushing the
plunger into the barrel as far as it will go.
B. Insertion without the applicator
• Lie on your back with your knees drawn up toward your
chest.
• Place the suppository on the tip of your finger as shown.
Reference ID: 3598383
12
usage illustration
• Insert the suppository gently into the vagina as far as it will
comfortably go.
NOTE: Store the suppositories at Controlled Room Temperature 15–30°C (59–86°F).
See end flap for lot number and expiration date.
A WORD ABOUT YEAST INFECTIONS
Why do yeast infections occur?
Yeast infections are caused by an organism called Candida (KAN di duh). It may be
present in small and harmless amounts in the mouth, digestive tract, and vagina.
Sometimes the natural balance of the vagina becomes upset. This may lead to rapid
growth of Candida, which results in a yeast infection. Symptoms of a yeast infection
include itching, burning, redness, and an abnormal discharge.
Your doctor can make the diagnosis of a yeast infection by evaluating your symptoms
and looking at a sample of the discharge under the microscope.
How can I prevent yeast infections?
Certain factors may increase your chance of developing a yeast infection. These
factors don’t actually cause the problem, but they may create a situation that allows
the yeast to grow rapidly.
• Clothing: Tight jeans, nylon underwear, pantyhose, and wet bathing suits can
hold in heat and moisture (two conditions in which yeast organisms thrive).
Looser pants or skirts, 100% cotton underwear, and stockings may help avoid
this problem.
• Diet: Cutting down on sweets, milk products, and artificial sweeteners may
reduce the risk of yeast infections.
Reference ID: 3598383
13
• Antibiotics: Antibiotics work by eliminating disease-causing organisms.
While they are helpful in curing other problems, antibiotics may lead to an
overgrowth of Candida in the vagina.
• Pregnancy: Hormonal changes in the body during pregnancy encourage the
growth of yeast. This is a very common time for an infection to occur. Until
the baby is born, it may be hard to completely eliminate yeast infections. If
you believe you are pregnant, tell your doctor.
• Menstruation: Sometimes monthly changes in hormone levels may lead to
yeast infections.
• Diabetes: In addition to heat and moisture, yeast thrives on sugar. Because
diabetics often have sugar in their urine, their vaginas are rich in this
substance. Careful control of diabetes may help prevent yeast infection.
Controlling these factors can help eliminate yeast infections and may prevent them
from coming back.
Some other helpful tips:
1. For best results, be sure to use the medication as prescribed by your doctor,
even if you feel better quickly.
2. Avoid sexual intercourse, if your doctor advises you to do so. The suppository
formulation (not the cream) may damage the diaphragm or latex condom.
Therefore, use of the diaphragm or latex condom during therapy with the
suppository is not recommended. Consult your physician.
3. If your partner has any penile itching, redness, or discomfort, he should
consult his physician and mention that you are being treated for a yeast
infection.
4. You can use the medication even if you are having your menstrual period.
However, you should not use tampons because they may absorb the
medication. Instead, use external pads or napkins until you have finished your
medication. You may also wish to wear a sanitary napkin if the vaginal
medication leaks.
5. Dry the genital area thoroughly after showering, bathing, or swimming.
Change out of a wet bathing suit or damp exercise clothes as soon as possible.
A dry environment is less likely to encourage the growth of yeast.
6. Wipe from front to rear (away from the vagina) after a bowel movement.
7. Don’t douche unless your doctor specifically tells you to do so. Douching may
disturb the vaginal balance.
Reference ID: 3598383
14
8. Don’t scratch if you can help it. Scratching can cause more irritation and
spread the infection.
9. Discuss with your physician any medication you are already taking. Certain
types of medication can make your vagina more susceptible to infection.
10. Eat nutritious meals to promote your general health.
Manufactured by:
• Janssen Ortho, LLC, Manati, Puerto Rico 00674 (for the Vaginal Cream)
• Jubilant HollisterStier General Partnership, Kirkland, Quebec, Canada H9H
4J4 (for the Vaginal Cream and Vaginal Suppositories)
Manufactured for:
(logo)
Janssen Pharmaceuticals, Inc. Titusville, New Jersey 08560
© Janssen Pharmaceuticals, Inc. 1998
Revised July 2014
Reference ID: 3598383
15
|
custom-source
|
2025-02-12T13:45:28.954116
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019579s037,019641s030,019964s032lbl.pdf', 'application_number': 19579, 'submission_type': 'SUPPL ', 'submission_number': 37}
|
11,540
|
TERAZOL 7(terconazole) Vaginal Cream 0.4%
TERAZOL 3(terconazole) Vaginal Cream 0.8%
TERAZOL® 3 (terconazole) Vaginal Suppositories 80 mg
DESCRIPTION
TERAZOL® 7(terconazole) Vaginal Cream 0.4% is a white to off-white, water washable
cream for intravaginal administration containing 0.4% of the antifungal agent
terconazole, cis-1-[p-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-
dioxolan-4-yl]methoxy]phenyl]-4-isopropylpiperazine, compounded in a cream base
consisting of butylated hydroxyanisole, cetyl alcohol, isopropyl myristate, polysorbate
60, polysorbate 80, propylene glycol, stearyl alcohol, and purified water.
TERAZOL® 3 (terconazole) Vaginal Cream 0.8% is a white to off-white, water washable
cream for intravaginal administration containing 0.8% of the antifungal agent
terconazole, cis-1-[p-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-
dioxolan-4-yl]methoxy]phenyl]-4-isopropylpiperazine, compounded in a cream base
consisting of butylated hydroxyanisole, cetyl alcohol, isopropyl myristate, polysorbate
60, polysorbate 80, propylene glycol, stearyl alcohol, and purified water.
TERAZOL® 3 (terconazole) Vaginal Suppositories are white to off-white suppositories
for intravaginal administration containing 80 mg of the antifungal agent terconazole, cis-
1-[p-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-
yl]methoxy]phenyl]-4-isopropylpiperazine, in triglycerides derived from coconut and/or
palm kernel oil (a base of hydrogenated vegetable oils) and butylated hydroxyanisole.
The structural formula of terconazole is as follows:
TERCONAZOLE
C26H31Cl2N5O3
[INSERT STRUCTURE HERE]
Terconazole, a triazole derivative, is a white to almost white powder with a molecular
weight of 532.47. It is insoluble in water; sparingly soluble in ethanol; and soluble in
butanol.
CLINICAL PHARMACOLOGY
Following intravaginal administration of terconazole in humans, absorption ranged from
5-8% in three hysterectomized subjects and 12-16% in two non-hysterectomized subjects
with tubal ligations.
Following daily intravaginal administration of 0.8% terconazole 40 mg
(0.8% cream x 5 g) for seven days to normal humans, plasma concentrations were low
and gradually rose to a daily peak (mean of 5.9 ng/mL or 0.006 mcg/mL) at 6.6 hours.
Results from similar studies in patients with vulvovaginal candidiasis indicate that the
slow rate of absorption, the lack of accumulation, and the mean peak plasma
concentration of terconazole was not different from that observed in healthy women. The
absorption characteristics of terconazole 0.8% in pregnant or non-pregnant patients with
vulvovaginal candidiasis were also similar to those found in normal volunteers.
Following oral (30 mg) administration of 14C-labelled terconazole, the harmonic half-life
of elimination from the blood for the parent terconazole was 6.9 hours (range 4.0-11.3).
Terconazole is extensively metabolized; the plasma AUC for terconazole compared to the
AUC for total radioactivity was 0.6%. Total radioactivity was eliminated from the blood
with a harmonic half-life of 52.2 hours (range 44-60). Excretion of radioactivity was both
by renal (32-56%) and fecal (47-52%) routes.
In vitro, terconazole is highly protein bound (94.9%) and the degree of binding is
independent of drug concentration.
Photosensitivity reactions were observed in some normal volunteers following repeated
dermal application of terconazole 2.0% and 0.8% creams under conditions of filtered
artificial ultraviolet light.
Photosensitivity reactions have not been observed in U.S. and foreign clinical trials in
patients who were treated with terconazole suppositories or vaginal cream (0.4% and
0.8%).
Microbiology: Terconazole exhibits fungicidal activity in vitro against Candida
albicans. Antifungal activity has also been demonstrated against other fungi. The MIC
values of terconazole against most Lactobacillus spp. typically found in the human
vagina were ≥128 mcg/mL; therefore these beneficial bacteria were not affected by drug
treatment.
The exact pharmacologic mode of action of terconazole is uncertain; however, it may
exert its antifungal activity by the disruption of normal fungal cell membrane
permeability. No resistance to terconazole has developed during successive passages of
C. albicans.
INDICATIONS AND USAGE
TERAZOL 7 Vaginal Cream 0.4%, TERAZOL 3 Vaginal Cream 0.8% and TERAZOL 3
Vaginal Suppositories 80 mg are indicated for the local treatment of vulvovaginal
candidiasis (moniliasis). As these products are effective only for vulvovaginitis caused by
the genus Candida, the diagnosis should be confirmed by KOH smears and/or cultures.
CONTRAINDICATIONS
Patients known to be hypersensitive to terconazole or to any of the components of the
cream or suppositories.
WARNINGS
None.
PRECAUTIONS
General: Discontinue use and do not retreat with terconazole if sensitization, irritation,
fever, chills or flu-like symptoms are reported during use.
The base contained in the suppository formulation may interact with certain rubber or
latex products, such as those used in vaginal contraceptive diaphragms, therefore
concurrent use is not recommended.
Laboratory Tests: If there is lack of response to terconazole, appropriate microbiologic
studies (standard KOH smear and/or cultures) should be repeated to confirm the
diagnosis and rule out other pathogens.
Drug Interactions:
TERAZOL 7 Vaginal Cream 0.4% and TERAZOL 3 Vaginal Suppositories 80mg:
The therapeutic effect of these products is not affected by oral contraceptive usage.
TERAZOL 3 Vaginal Cream 0.8%:
The levels of estradiol (E2) and progesterone did not differ significantly when 0.8%
terconazole vaginal cream was administered to healthy female volunteers established on a
low dose oral contraceptive.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Carcinogenesis: Studies to determine the carcinogenic potential of terconazole have not
been performed.
Mutagenicity: Terconazole was not mutagenic when tested in vitro for induction of
microbial point mutations (Ames test), or for inducing cellular transformation, or in vivo
for chromosome breaks (micronucleus test) or dominant lethal mutations in mouse germ
cells.
Impairment of Fertility: No impairment of fertility occurred when female rats were
administered terconazole orally up to 40 mg/kg/day for a three month period.
Pregnancy:
Teratogenic Effects:
Pregnancy Category C.
There was no evidence of teratogenicity when terconazole was administered orally up to
40 mg/kg/day (25x the recommended intravaginal human dose of the suppository
formulation, 50x the recommended intravaginal human dose of the 0.8% vaginal cream
formulation, and 100x the intravaginal human dose of the 0.4% vaginal cream
formulation) in rats, or 20 mg/kg/day in rabbits, or subcutaneously up to 20 mg/kg/day in
rats.
Dosages at or below 10 mg/kg/day produced no embryotoxicity; however, there was a
delay in fetal ossification at 10 mg/kg/day in rats. There was some evidence of
embryotoxicity in rabbits and rats at 20-40 mg/kg. In rats, this was reflected as a decrease
in litter size and number of viable young and reduced fetal weight. There was also delay
in ossification and an increased incidence of skeletal variants.
The no-effect dose of 10 mg/kg/day resulted in a mean peak plasma level of terconazole
in pregnant rats of 0.176 mcg/mL which exceeds by 44 times the mean peak plasma level
(0.004 mcg/mL) seen in normal subjects after intravaginal administration of terconazole
0.4% vaginal cream, by 30 times the mean peak plasma level (0.006 mcg/mL) seen in
normal subjects after intravaginal administration of terconazole 0.8% vaginal cream, and
by 17 times the mean peak plasma level (0.010 mcg/mL) seen in normal subjects after
intravaginal administration of terconazole 80 mg vaginal suppository. This safety
assessment does not account for possible exposure of the fetus through direct transfer to
terconazole from the irritated vagina by diffusion across amniotic membranes.
Since terconazole is absorbed from the human vagina, it should not be used in the first
trimester of pregnancy unless the physician considers it essential to the welfare of the
patient.
Nursing Mothers:
It is not known whether this drug is excreted in human milk. Animal studies have shown
that rat offspring exposed via the milk of treated (40 mg/kg/orally) dams showed
decreased survival during the first few post-partum days, but overall pup weight and
weight gain were comparable to or greater than controls throughout lactation. Because
many drugs are excreted in human milk, and because of the potential for adverse reaction
in nursing infants from terconazole, 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 efficacy in children have not been established.
Geriatric Use:
Clinical studies of TERAZOL 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.
ADVERSE REACTIONS
TERAZOL 7 Vaginal Cream 0.4%:
During controlled clinical studies conducted in the United States, 521 patients with
vulvovaginal candidiasis were treated with terconazole 0.4% vaginal cream. Based on
comparative analyses with placebo, the adverse experiences considered most likely
related to terconazole 0.4% vaginal cream were headache (26% vs. 17% with placebo)
and body pain (2.1% vs. 0% with placebo). Vulvovaginal burning (5.2%), itching (2.3%)
or irritation (3.1%) occurred less frequently with terconazole 0.4% vaginal cream than
with the vehicle placebo. Fever (1.7% vs. 0.5% with placebo) and chills (0.4% vs. 0.0%
with placebo) have also been reported. The therapy-related dropout rate was 1.9%. The
adverse drug experience on terconazole most frequently causing discontinuation was
vulvovaginal itching (0.6%), which was lower than the incidence for placebo (0.9%).
TERAZOL 3 Vaginal Cream 0.8%:
During controlled clinical studies conducted in the United States, patients with
vulvovaginal candidiasis were treated with terconazole 0.8% vaginal cream for three
days. Based on comparative analyses with placebo and a standard agent, the adverse
experiences considered most likely related to terconazole 0.8% vaginal cream were
headache (21% vs. 16% with placebo) and dysmenorrhea (6% vs. 2% with placebo).
Genital complaints in general, and burning and itching in particular, occurred less
frequently in the terconazole 0.8% vaginal cream 3 day regimen (5% vs. 6%-9% with
placebo). Other adverse experiences reported with terconazole 0.8% vaginal cream were
abdominal pain (3.4% vs. 1% with placebo) and fever (1% vs. 0.3% with placebo). The
therapy-related dropout rate was 2.0% for the terconazole 0.8% vaginal cream. The
adverse drug experience most frequently causing discontinuation of therapy was
vulvovaginal itching, 0.7% with the terconazole 0.8% vaginal cream group and 0.3%
with the placebo group.
TERAZOL 3 Vaginal Suppositories 80 mg:
During controlled clinical studies conducted in the United States, 284 patients with
vulvovaginal candidiasis were treated with terconazole 80 mg vaginal suppositories.
Based on comparative analyses with placebo (295 patients), the adverse experiences
considered adverse reactions most likely related to terconazole 80 mg vaginal
suppositories were headache (30.3% vs. 20.7% with placebo) and pain of the female
genitalia (4.2% vs. 0.7% with placebo). Adverse reactions that were reported but were
not statistically significantly different from placebo were burning (15.2% vs. 11.2% with
placebo) and body pain (3.9% vs. 1.7% with placebo). Fever (2.8% v. 1.4% with placebo)
and chills (1.8% vs. 0.7% with placebo) have also been reported. The therapy-related
dropout rate was 3.5% and the placebo therapy-related dropout rate was 2.7%. The
adverse drug experience on terconazole most frequently causing discontinuation was
burning (2.5% vs. 1.4% with placebo) and pruritus (1.8% vs. 1.4% with placebo).
OVERDOSAGE
Overdose of terconazole in humans has not been reported to date. In the rat, the oral LD
50 values were found to be 1741 and 849 mg/kg for the male and female, respectively.
The oral LD 50 values for the male and female dog were ~1280 and ≥640 mg/kg,
respectively.
DOSAGE AND ADMINISTRATION
TERAZOL 7 Vaginal Cream 0.4%:
One full applicator (5 g) of TERAZOL 7 Vaginal Cream (20 mg terconazole) should be
administered intravaginally once daily at bedtime for seven consecutive days.
TERAZOL 3 Vaginal Cream 0.8%:
One full applicator (5 g) of TERAZOL 3 Vaginal Cream (40 mg terconazole) should be
administered intravaginally once daily at bedtime for three consecutive days.
TERAZOL 3 Vaginal Suppositories 80 mg
One TERAZOL 3 Vaginal Suppository (80 mg terconazole) should be administered
intravaginally once daily at bedtime for three consecutive days.
Before prescribing another course of therapy, the diagnosis should be reconfirmed by
smears and/or cultures and other pathogens commonly associated with vulvovaginitis
ruled out. The therapeutic effect of these products is not affected by menstruation.
HOW SUPPLIED
TERAZOL® 7 (terconazole) Vaginal Cream 0.4% is available in 45 g
(NDC 0062-5350-01) tubes with an ORTHO* Measured-Dose Applicator. Store at
Controlled Room Temperature 15 - 30° C (59 - 86° F).
TERAZOL® 3 (terconazole) Vaginal Cream 0.8% is available in 20 g
(NDC 0062-5356-01) tubes with an ORTHO* Measured-Dose Applicator. Store at
Controlled Room Temperature 15 - 30° C (59 - 86° F).
TERAZOL® 3 (terconazole) Vaginal Suppositories 80 mg are available as 2.5 g,
elliptically shaped white to off-white suppositories in packages of three
(NDC 0062-5351-01) with a vaginal applicator. Store at controlled room temperature 15 -
30° C (59 - 86° F).
Rx only *Trademark
ORTHO McNEIL
ORTHO McNEIL PHARMACEUTICAL, INC.
Raritan, New Jersey 08869
OMP 1998 Printed in U.S.A.
Issued March 2001
642-10-300-1
TERAZOL 7 (terconazole) Vaginal Cream 0.4%
TERAZOL 3 (terconazole) Vaginal Cream 0.8%
PATIENT INSTRUCTIONS
Filling the applicator:
1. Remove the cap from the tube.
2. Use the pointed tip on the top of the cap to puncture the seal on the tube.
3. Screw the applicator onto the tube.
4. Squeeze the tube from the bottom and fill the applicator until the plunger stops.
5. Unscrew the applicator from the tube.
Illustration of cap puncturing tube
Illustration of applicator screwed onto tube
Using the applicator:
1. Lie on your back with your knees drawn up toward your chest.
Illustration of lower extremities.
2. Holding the applicator by the ribbed end of the barrel, insert the filled applicator into
the vagina as far as it will comfortably go.
3. Slowly press the plunger of the applicator to release the cream into the vagina.
4. Remove the applicator from the vagina.
5. Apply one applicatorful each night for as many days at bedtime, as directed by your
doctor.
Cleaning the applicator: (Does not apply to sample applicators, which are for one
time use only)
After each use, you should thoroughly clean the applicator by following the procedure
below:
1. Pull the plunger out of the barrel.
2. Wash the pieces with lukewarm, soapy water, and dry them thoroughly.
3. Put the applicator back together by gently pushing the plunger into the barrel as far as
it will go.
Illustration – separate plunger from barrel
NOTE: Store the cream at Controlled Room Temperature 15-30oC (59-86oF). See end
flap for lot number and expiration date.
U.S. Patent No. D-279,504
TERAZOL 3 (terconazole) Vaginal Suppositories 80 mg
Three oval suppositories, for use inside the vagina only.
Designed to be inserted into the vagina.
HOW TO USE:
Place one suppository into the vagina each night at bedtime, for 3 nights, as directed by
your doctor. The TERAZOL Suppository is self-lubricating and may be inserted with or
without the applicator.
A. Insertion with the applicator
1. Filling the applicator
• Break off suppository from the plastic strip.
• Pull the plastic completely apart at the notched end.
• Place the flat end of the suppository into the open end of the applicator
as shown. You are now ready to insert the suppository into the vagina.
Illustration 1
Illustration 2
2. Using the applicator
• Lie on your back with your knees drawn up toward your chest.
• Holding the applicator by the ribbed end of the barrel, gently insert it
into the vagina as far as it will comfortably go.
• Press the plunger to release the suppository into the vagina.
• Remove the applicator from the vagina.
Illustration of lower extremities
3. Cleaning the applicator (Does not apply to sample applicators, which
are for one time use only)
After each use, you should thoroughly clean the applicator by following
the procedure below:
• Pull the plunger out of the barrel.
• Wash both pieces with lukewarm, soapy water, and dry them
thoroughly.
• Put the applicator back together by gently pushing the plunger into the
barrel as far as it will go.
B. Insertion without the applicator
• Lie on your back with your knees drawn up toward your chest.
• Place the suppository on the tip of your finger as shown.
• Insert the suppository gently into the vagina as far as it will comfortably go.
NOTE: Store the suppositories at Controlled Room Temperature 15-30°C (59-86°F). See
end flap for lot number and expiration date.
U.S. Patent No. D-279,504
A WORD ABOUT YEAST INFECTIONS
Why do yeast infections occur?
Yeast infections are caused by an organism called Candida (KAN di duh). It may be
present in small and harmless amounts in the mouth, digestive tract, and vagina.
Sometimes the natural balance of the vagina becomes upset. This may lead to rapid
growth of Candida, which results in a yeast infection. Symptoms of a yeast infection
include itching, burning, redness, and an abnormal discharge.
Your doctor can make the diagnosis of a yeast infection by evaluating your symptoms
and looking at a sample of the discharge under the microscope.
How can I prevent yeast infections?
Certain factors may increase your chance of developing a yeast infection. These factors
don’t actually cause the problem, but they may create a situation that allows the yeast to
grow rapidly.
• Clothing: Tight jeans, nylon underwear, pantyhose, and wet bathing suits can hold in
heat and moisture (two conditions in which yeast organisms thrive). Looser pants or
skirts, 100% cotton underwear, and stockings may help avoid this problem.
• Diet: Cutting down on sweets, milk products, and artificial sweeteners may reduce
the risk of yeast infections.
• Antibiotics: Antibiotics work by eliminating disease-causing organisms. While
they are helpful in curing other problems, antibiotics may lead to an overgrowth of
Candida in the vagina.
• Pregnancy: Hormonal changes in the body during pregnancy encourage the growth
of yeast. This is a very common time for an infection to occur. Until the baby is
born, it may be hard to completely eliminate yeast infections. If you believe you are
pregnant, tell your doctor.
• Menstruation: Sometimes monthly changes in hormone levels may lead to yeast
infections.
• Diabetes: In addition to heat and moisture, yeast thrives on sugar. Because diabetics
often have sugar in their urine, their vaginas are rich in this substance. Careful
control of diabetes may help prevent yeast infection.
Controlling these factors can help eliminate yeast infections and may prevent them from
coming back.
Some other helpful tips:
1. For best results, be sure to use the medication as prescribed by your doctor, even if
you feel better quickly.
2. Avoid sexual intercourse, if your doctor advises you to do so. The suppository
formulation (not the cream) may damage the diaphragm. Therefore, use of the
diaphragm during therapy with the suppository is not recommended. Consult your
physician.
3. If your partner has any penile itching, redness, or discomfort, he should consult his
physician and mention that you are being treated for a yeast infection.
4. You can use the medication even if you are having your menstrual period. However,
you should not use tampons because they may absorb the medication. Instead, use
external pads or napkins until you have finished your medication. You may also wish
to wear a sanitary napkin if the vaginal medication leaks.
5. Dry the genital area thoroughly after showering, bathing, or swimming. Change out
of a wet bathing suit or damp exercise clothes as soon as possible. A dry
environment is less likely to encourage the growth of yeast.
6. Wipe from front to rear (away from the vagina) after a bowel movement.
7. Don’t douche unless your doctor specifically tells you to do so. Douching may
disturb the vaginal balance.
8. Don’t scratch if you can help it. Scratching can cause more irritation and spread the
infection.
9. Discuss with your physician any medication you are already taking. Certain types of
medication can make your vagina more susceptible to infection.
10. Eat nutritious meals to promote your general health.
ORTHO McNEIL
ORTHO McNEIL PHARMACEUTICAL, INC.
Raritan, New Jersey 08869
OMP 1998 Printed in U.S.A.
Issued March 2001
642-10-300-1
|
custom-source
|
2025-02-12T13:45:28.983577
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19579slr026,19641slr022,19964slr021_terazol_lbl.pdf', 'application_number': 19579, 'submission_type': 'SUPPL ', 'submission_number': 26}
|
11,542
|
NDA 19-583/S-023
Page 3
RL:L15
PRESCRIBING INFORMATION
RELAFEN®
(nabumetone)
Tablets
DESCRIPTION
RELAFEN (nabumetone) is a naphthylalkanone designated chemically as 4-(6-methoxy-2-
naphthalenyl)-2-butanone. It has the following structure:
Nabumetone is a white to off-white crystalline substance with a molecular weight of 228.3. It is
nonacidic and practically insoluble in water, but soluble in alcohol and most organic solvents. It has an
n-octanol:phosphate buffer partition coefficient of 2400 at pH 7.4.
Tablets for Oral Administration: Each oval-shaped, film-coated tablet contains 500 mg or 750 mg
of nabumetone. Inactive ingredients consist of hypromellose, microcrystalline cellulose, polyethylene
glycol, polysorbate 80, sodium lauryl sulfate, sodium starch glycolate, and titanium dioxide. The
750-mg tablets also contain iron oxides.
CLINICAL PHARMACOLOGY
RELAFEN is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory,
analgesic, and antipyretic properties in pharmacologic studies. As with other nonsteroidal
anti-inflammatory agents, its mode of action is not known; however, the ability to inhibit prostaglandin
synthesis may be involved in the anti-inflammatory effect.
The parent compound is a prodrug, which undergoes hepatic biotransformation to the active
component, 6-methoxy-2-naphthylacetic acid (6MNA), that is a potent inhibitor of prostaglandin
synthesis.
It is acidic and has an n-octanol:phosphate buffer partition coefficient of 0.5 at pH 7.4.
Pharmacokinetics: After oral administration, approximately 80% of a radiolabeled dose of
nabumetone is found in the urine, indicating that nabumetone is well absorbed from the gastrointestinal
tract. Nabumetone itself is not detected in the plasma because, after absorption, it undergoes rapid
biotransformation to the principal active metabolite, 6-methoxy-2-naphthylacetic acid (6MNA).
Approximately 35% of a 1,000-mg oral dose of nabumetone is converted to 6MNA and 50% is
converted into unidentified metabolites which are subsequently excreted in the urine. Following oral
administration of RELAFEN, 6MNA exhibits pharmacokinetic characteristics that generally follow a
one-compartment model with first order input and first order elimination.
6MNA is more than 99% bound to plasma proteins. The free fraction is dependent on total
concentration of 6MNA and is proportional to dose over the range of 1,000 mg to 2,000 mg. It is 0.2%
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-583/S-023
Page 4
to 0.3% at concentrations typically achieved following administration of 1,000 mg of RELAFEN and
is approximately 0.6% to 0.8% of the total concentrations at steady state following daily administration
of 2,000 mg.
Steady-state plasma concentrations of 6MNA are slightly lower than predicted from
single-dose data. This may result from the higher fraction of unbound 6MNA which undergoes greater
hepatic clearance.
Coadministration of food increases the rate of absorption and subsequent appearance of 6MNA
in the plasma but does not affect the extent of conversion of nabumetone into 6MNA. Peak plasma
concentrations of 6MNA are increased by approximately one third.
Coadministration with an aluminum-containing antacid had no significant effect on the
bioavailability of 6MNA.
Table 1. Mean Pharmacokinetic Parameters of Nabumetone Active Metabolite (6MNA) at
Steady State Following Oral Administration of 1,000-mg or 2,000-mg Doses of RELAFEN
Abbreviation
(units)
Young Adults
Mean ± SD
1,000 mg
n = 31
Young Adults
Mean ± SD
2,000 mg
n = 12
Elderly
Mean ± SD
1,000 mg
n = 27
Tmax (hr)
3.0 (1.0 to 12.0)
2.5 (1.0 to 8.0)
4.0 (1.0 to 10.0)
t½ (hr)
22.5 ± 3.7
26.2 ± 3.7
29.8 ± 8.1
CLss/F (mL/min)
26.1 ± 17.3
21.0 ± 4.0
18.6 ± 13.4
Vdss/F (L)
55.4 ± 26.4
53.4 ± 11.3
50.2 ± 25.3
The simulated curves in the graph below illustrate the range of active metabolite plasma
concentrations that would be expected from 95% of patients following 1,000-mg to 2,000-mg doses to
steady state. The cross-hatched area represents the expected overlap in plasma concentrations due to
intersubject variation following oral administration of 1,000 mg to 2,000 mg of RELAFEN.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-583/S-023
Page 5
6MNA undergoes biotransformation in the liver, producing inactive metabolites that are
eliminated as both free metabolites and conjugates. None of the known metabolites of 6MNA has been
detected in plasma. Preliminary in vivo and in vitro studies suggest that unlike other NSAIDs, there is
no evidence of enterohepatic recirculation of the active metabolite. Approximately 75% of a
radiolabeled dose was recovered in urine in 48 hours. Approximately 80% was recovered in 168 hours.
A further 9% appeared in the feces. In the first 48 hours, metabolites consisted of:
–nabumetone, unchanged
not detectable
–6-methoxy-2-naphthylacetic acid
<1%
(6MNA), unchanged
–6MNA, conjugated
11%
–6-hydroxy-2-naphthylacetic acid
5%
(6HNA), unchanged
–6HNA, conjugated
7%
–4-(6-hydroxy-2-naphthyl)-butan-2-ol,
9%
conjugated
–O-desmethyl-nabumetone, conjugated
7%
–unidentified minor metabolites
34%
Total % Dose:
73%
Following oral administration of dosages of 1,000 mg to 2,000 mg to steady state, the mean
plasma clearance of 6MNA is 20 to 30 mL/min and the elimination half-life is approximately 24 hours.
Elderly Patients: Steady-state plasma concentrations in elderly patients were generally
higher than in young healthy subjects (see Table 1 for summary of pharmacokinetic parameters).
Renal Insufficiency: In moderate renal insufficiency patients (creatinine clearance 30 to
49 mL/min), the terminal half-life of 6MNA was increased by approximately 50% (39.2 ± 7.8 hrs,
N=12) compared to the normal subjects (26.9 ± 3.3 hrs, N=13), and there was a 50% increase in the
plasma levels of unbound 6MNA.
Additionally, the renal excretion of 6MNA in the moderate renal impaired patients decreased
on average by 33% compared to that in the normal patients. A similar increase in the mean terminal
half-life of 6MNA was seen in a small study of patients with severe renal dysfunction (creatine
clearance <30 mL/min). In patients undergoing hemodialysis, steady-state plasma concentrations of the
active metabolite 6MNA were similar to those observed in healthy subjects. Due to extensive protein
binding, 6MNA is not dialyzable.
Dosage adjustment of RELAFEN generally is not necessary in patients with mild renal
insufficiency (≥50 mL/min). Caution should be used in prescribing RELAFEN to patients with
moderate or severe renal insufficiency. The maximum starting doses of RELAFEN in patients with
moderate or severe renal insufficiency should not exceed 750 mg or 500 mg, respectively once daily.
Following careful monitoring of renal function in patients with moderate or severe renal insufficiency,
daily doses may be increased to a maximum of 1,500 mg and 1,000 mg, respectively (see
PRECAUTIONS: Renal Effects).
Hepatic Impairment: Data in patients with severe hepatic impairment are limited.
Biotransformation of nabumetone to 6MNA and the further metabolism of 6MNA to inactive
metabolites is dependent on hepatic function and could be reduced in patients with severe hepatic
impairment (history of or biopsy-proven cirrhosis).
Special Studies: Gastrointestinal: RELAFEN was compared to aspirin in inducing
gastrointestinal blood loss. Food intake was not monitored. Studies utilizing 51Cr-tagged red blood
cells in healthy males showed no difference in fecal blood loss after 3 or 4 weeks’ administration of
1,000 mg or 2,000 mg of RELAFEN daily when compared to either placebo-treated or nontreated
subjects. In contrast, aspirin 3,600 mg daily produced an increase in fecal blood loss when compared to
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-583/S-023
Page 6
subjects who received RELAFEN, placebo, or no treatment. The clinical relevance of the data is
unknown.
The following endoscopy trials entered patients who had been previously treated with NSAIDs.
These patients had varying baseline scores and different courses of treatment. The trials were not
designed to correlate symptoms and endoscopy scores. The clinical relevance of these endoscopy
trials, i.e., either G.I. symptoms or serious G.I. events, is not known.
Ten endoscopy studies were conducted in 488 patients who had baseline and post-treatment
endoscopy. In 5 clinical trials that compared a total of 194 patients on 1,000 mg of RELAFEN daily or
naproxen 250 mg or 500 mg twice daily for 3 to 12 weeks, treatment with RELAFEN resulted in fewer
patients with endoscopically detected lesions (>3 mm). In 2 trials a total of 101 patients administered
1,000 mg or 2,000 mg of RELAFEN daily or piroxicam 10 mg to 20 mg for 7 to 10 days, there were
fewer patients treated with RELAFEN with endoscopically detected lesions. In 3 trials of a total of
47 patients on 1,000 mg of RELAFEN daily or indomethacin 100 mg to 150 mg daily for 3 to 4 weeks,
the endoscopy scores were higher with indomethacin. Another 12-week trial in a total of 171 patients
compared the results of treatment with 1,000 mg of RELAFEN daily to ibuprofen 2,400 mg/day and
ibuprofen 2,400 mg/day plus misoprostol 800 mcg/day. The results showed that patients treated with
RELAFEN had a lower number of endoscopically detected lesions (>5 mm) than patients treated with
ibuprofen alone but comparable to the combination of ibuprofen plus misoprostol. The results did not
correlate with abdominal pain.
Other: In 1-week, repeat-dose studies in healthy volunteers, 1,000 mg of RELAFEN daily had
little effect on collagen-induced platelet aggregation and no effect on bleeding time. In comparison,
naproxen 500 mg daily suppressed collagen-induced platelet aggregation and significantly increased
bleeding time.
CLINICAL TRIALS
Osteoarthritis: The use of RELAFEN in relieving the signs and symptoms of osteoarthritis (OA)
was assessed in double-blind, controlled trials in which 1,047 patients were treated for 6 weeks to
6 months. In these trials, RELAFEN in a dose of 1,000 mg/day administered at night was comparable
to naproxen 500 mg/day and to aspirin 3,600 mg/day.
Rheumatoid Arthritis: The use of RELAFEN in relieving the signs and symptoms of rheumatoid
arthritis (RA) was assessed in double-blind, randomized, controlled trials in which 770 patients were
treated for 3 weeks to 6 months. RELAFEN, in a dose of 1,000 mg/day administered at night, was
comparable to naproxen 500 mg/day and to aspirin 3,600 mg/day.
In controlled clinical trials of rheumatoid arthritis patients, RELAFEN has been used in
combination with gold, d-penicillamine, and corticosteroids.
Individualization of Dosing: There is considerable interpatient variation in response to RELAFEN.
Therapy is usually initiated at 1,000 mg daily, then adjusted, if needed, based on clinical response.
In clinical trials with osteoarthritis and rheumatoid arthritis patients, most patients responded to
RELAFEN in doses of 1,000 mg/day administered nightly; total daily dosages up to 2,000 mg were
used. In open-labeled studies, 1,490 patients were permitted dosage increases and were followed for
approximately 1 year (mode). Twenty percent of patients (n = 294) were withdrawn for lack of
effectiveness during the first year of these open-labeled studies. The following table provides patient-
exposure to doses used in the US clinical trials:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-583/S-023
Page 7
Table 2. Clinical Double-Blinded and Open-Labeled Trials of
RELAFEN in Osteoarthritis and Rheumatoid Arthritis
Number of Patients
Mean/Mode Duration
of Treatment (yr)
Dose of
RELAFEN
OA
RA
OA
RA
500 mg
17
6
0.4/–
0.2/–
1,000 mg
917
701
1.2/1
1.4/1
1,500 mg
645
224
2.3/1
1.7/1
2,000 mg
15
100
0.6/1
1.3/1
As with other NSAIDs, the lowest dose should be sought for each patient. Patients weighing
under 50 kg may be less likely to require dosages beyond 1,000 mg; therefore, after observing the
response to initial therapy, the dose should be adjusted to meet individual patients’ requirements.
INDICATIONS AND USAGE
RELAFEN is indicated for acute and chronic treatment of signs and symptoms of osteoarthritis
and rheumatoid arthritis.
CONTRAINDICATIONS
RELAFEN is contraindicated in patients who have previously exhibited hypersensitivity to it.
RELAFEN is contraindicated in patients in whom RELAFEN, aspirin, or other NSAIDs induce
asthma, urticaria, or other allergic-type reactions. Fatal asthmatic reactions have been reported in such
patients receiving NSAIDs.
WARNINGS
Risk of G.I. Ulceration, Bleeding, and Perforation with NSAID Therapy: Serious
gastrointestinal toxicity such as bleeding, ulceration, and perforation can occur at any time, with or
without warning symptoms, in patients treated chronically with NSAID therapy. Although minor upper
gastrointestinal problems, such as dyspepsia, are common, usually developing early in therapy,
physicians should remain alert for ulceration and bleeding in patients treated chronically with NSAIDs
even in the absence of previous G.I. tract symptoms.
In controlled clinical trials involving 1,677 patients treated with RELAFEN (1,140 followed for
1 year and 927 for 2 years), the cumulative incidence of peptic ulcers was 0.3% (95% CI; 0%, 0.6%) at
3 to 6 months, 0.5% (95% CI; 0.1%, 0.9%) at 1 year and 0.8% (95% CI; 0.3%, 1.3%) at 2 years.
Physicians should inform patients about the signs and symptoms of serious G.I. toxicity and what steps
to take if they occur. In patients with active peptic ulcer, physicians must weigh the benefits of therapy
with RELAFEN against possible hazards, institute an appropriate ulcer treatment regimen and monitor
the patients’ progress carefully.
Studies to date have not identified any subset of patients not at risk of developing peptic
ulceration and bleeding. Except for a prior history of serious G.I. events and other risk factors known
to be associated with peptic ulcer disease, such as alcoholism, smoking, other medications known to
increase the risk of gastrointestinal ulcer (e.g., oral corticosteroids), etc., no risk factors (e.g., age, sex)
have been associated with increased risk. Elderly or debilitated patients seem to tolerate ulceration or
bleeding less well than other individuals and most spontaneous reports of fatal G.I. events are in this
population.
High doses of any NSAID probably carry a greater risk of these reactions, although controlled
clinical trials showing this do not exist in most cases. In considering the use of relatively large doses
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-583/S-023
Page 8
(within the recommended dosage range), sufficient benefit should be anticipated to offset the potential
increased risk of G.I. toxicity.
PRECAUTIONS
General: Renal Effects: As a class, NSAIDs have been associated with renal papillary necrosis and
other abnormal renal pathology during long-term administration to animals.
A second form of renal toxicity often associated with NSAIDs is seen in patients with
conditions leading to a reduction in renal blood flow or blood volume, where renal prostaglandins have
a supportive role in the maintenance of renal perfusion. In these patients, administration of an NSAID
results in a dose-dependent decrease in prostaglandin synthesis and, secondarily, in a reduction of 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 the
elderly. Discontinuation of NSAID therapy is typically followed by recovery to the pretreatment state.
Nabumetone undergoes extensive hepatic metabolism to the active component, 6-methoxy-2-
naphthylacetic acid (6MNA). The oxidized and conjugated metabolites of 6MNA are eliminated
primarily by the kidneys. The extent to which these largely inactive metabolites may accumulate in
patients with renal failure has not been studied. As with other drugs whose metabolites are excreted by
the kidneys, the possibility that adverse reactions (not listed in ADVERSE REACTIONS) may be
attributable to these metabolites should be considered (see CLINICAL PHARMACOLGY: Renal
Insufficiency). No adjustment of the dosage of RELAFEN is generally necessary in patients with mild
renal insufficiency. In patients with moderate renal impairment (creatine clearance 30 to 49 mL/min)
there is a 50% increase in unbound plasma 6MNA concentrations. Caution should be used in
prescribing RELAFEN to patients with moderate or severe renal insufficiency. The maximum starting
doses of RELAFEN in patients with moderate or severe renal insufficiency should not exceed 750 mg
or 500 mg, respectively once daily. Following careful monitoring of renal function in patients with
moderate or severe renal insufficiency, daily doses may be increased to a maximum of 1,500 mg and
1,000 mg, respectively. Laboratory tests of renal function should be performed at baseline and within
weeks of starting therapy. As with all NSAIDs, patients with impaired renal function should be
monitored more closely than patients with normal renal function (see CLINICAL
PHARMACOLOGY: Renal Insufficiency). Further tests should be carried out as necessary; if the
impairment worsens, discontinuation of therapy may be warranted.
Hepatic Function: As with other NSAIDs, borderline elevations of 1 or more liver function
tests may occur in up to 15% of patients. These abnormalities may progress, may remain essentially
unchanged, or may return to normal with continued therapy. The ALT (SGPT) test is probably the
most sensitive indicator of liver dysfunction. Meaningful (3 times the upper limit of normal) elevations
of ALT (SGPT) or AST (SGOT) have occurred in controlled clinical trials of RELAFEN in less than
1% of patients. 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 RELAFEN. Severe hepatic reactions, including jaundice and
fatal hepatitis, have been reported with RELAFEN and other NSAIDs. Although such reactions are
rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver
disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), RELAFEN should
be discontinued. Because nabumetone’s biotransformation to 6MNA is dependent upon hepatic
function, the biotransformation could be decreased in patients with severe hepatic dysfunction;
therefore, RELAFEN should be used with caution in patients with severe hepatic impairment (see
Pharmacokinetics: Hepatic Impairment).
Fluid Retention and Edema: Fluid retention and edema have been observed in some
patients taking RELAFEN; therefore, as with other NSAIDs, RELAFEN should be used cautiously in
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-583/S-023
Page 9
patients with a history of congestive heart failure, hypertension, or other conditions predisposing to
fluid retention.
Photosensitivity: Based on ultraviolet (U.V.) light photosensitivity testing, RELAFEN may
be associated with more reactions to sun exposure than might be expected based on skin tanning types.
Information for Patients: RELAFEN, like other drugs of its class, is not free of side effects. The
side effects of these drugs can cause discomfort and, rarely, there are more serious side effects, such as
gastrointestinal bleeding, which may result in hospitalization and even fatal outcome.
NSAIDs are often essential agents in the management of arthritis, but they also may be
commonly employed for conditions that are less serious. Physicians may wish to discuss with their
patients the potential risks (see WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS) and
likely benefits of NSAID treatment, particularly when the drugs are used for less serious conditions
where treatment without NSAIDs may represent an acceptable alternative to both the patient and the
physician.
Laboratory Tests: Because severe G.I. tract ulceration and bleeding can occur without warning
symptoms, physicians should follow chronically-treated patients for signs and symptoms of ulceration
and bleeding, and should inform them of the importance of this follow-up (see WARNINGS: Risk of
G.I. Ulceration, Bleeding, and Perforation with NSAID Therapy).
Drug Interactions: In vitro studies have shown that, because of its affinity for protein, 6MNA may
displace other protein-bound drugs from their binding site. Caution should be exercised when
administering RELAFEN with warfarin since interactions have been seen with other NSAIDs.
Concomitant administration of an aluminum-containing antacid had no significant effect on the
bioavailability of 6MNA. When administered with food or milk, there is more rapid absorption;
however, the total amount of 6MNA in the plasma is unchanged (see CLINICAL
PHARMACOLOGY: Pharmacokinetics).
Carcinogenesis, Mutagenesis: In 2-year studies conducted in mice and rats, nabumetone had no
statistically significant tumorigenic effect. Nabumetone did not show mutagenic potential in the Ames
test and mouse micronucleus test in vivo; however, nabumetone- and 6MNA-treated lymphocytes in
culture showed chromosomal aberrations at 80 mcg/mL and higher concentrations (equal to the
average human exposure to RELAFEN at the maximum recommended dose).
Impairment of Fertility: Nabumetone did not impair fertility of male or female rats treated orally at
doses of 320 mg/kg/day (1,888 mg/m2) before mating.
Pregnancy: Teratogenic Effects: Pregnancy Category C. Nabumetone did not cause any
teratogenic effect in rats given up to 400 mg/kg (2,360 mg/m2) and in rabbits up to 300 mg/kg
(3,540 mg/m2) orally; however, increased post-implantation loss was observed in rats at 100 mg/kg
(590 mg/m2) orally and at higher doses (equal to the average human exposure to 6MNA at the
maximum recommended human dose). There are no adequate, well-controlled studies in pregnant
women. This drug should be used during pregnancy only if clearly needed.
Because of the known effect of prostaglandin-synthesis-inhibiting drugs on the human fetal
cardiovascular system (closure of ductus arteriosus), use of RELAFEN during the third trimester of
pregnancy is not recommended.
Labor and Delivery: The effects of RELAFEN on labor and delivery in women are not known. As
with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia and
delayed parturition occurred in rats treated throughout pregnancy.
Nursing Mothers: RELAFEN is not recommended for use in nursing mothers because of the
possible adverse effects of prostaglandin-synthesis–inhibiting drugs on neonates. It is not known
whether nabumetone or its metabolites are excreted in human milk; however, 6MNA is excreted in the
milk of lactating rats.
Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-583/S-023
Page 10
Geriatric Use: Of the 1,677 patients in US clinical studies who were treated with RELAFEN,
411 patients (24%) were 65 years or older; 22 patients (1%) were 75 years or older. No overall
differences in efficacy or safety were observed between these older patients and younger ones. Similar
results were observed in a 1-year, non-US postmarketing surveillance study of 10,800 patients treated
with RELAFEN, of whom 4,577 patients (42%) were 65 years or older.
ADVERSE REACTIONS
Adverse reaction information was derived from blinded-controlled and open-labeled clinical
trials and from worldwide marketing experience. In the description below, rates of the more common
events (greater than 1%) and many of the less common events (less than 1%) represent results of US
clinical studies.
Of the 1,677 patients who received RELAFEN during US clinical trials, 1,524 were treated for
at least 1 month, 1,327 for at least 3 months, 929 for at least a year, and 750 for at least 2 years. More
than 300 patients have been treated for 5 years or longer.
The most frequently reported adverse reactions were related to the
gastrointestinal tract and included diarrhea, dyspepsia, and abdominal pain.
Incidence ≥1%—Probably Causally Related
Gastrointestinal: Diarrhea (14%), dyspepsia (13%), abdominal pain (12%), constipation*,
flatulence*, nausea*, positive stool guaiac*, dry mouth, gastritis, stomatitis, vomiting.
Central Nervous System: Dizziness*, headache*, fatigue, increased sweating, insomnia,
nervousness, somnolence.
Dermatologic: Pruritus*, rash*.
Special Senses: Tinnitus*.
Miscellaneous: Edema*.
*Incidence of reported reaction between 3% and 9%. Reactions occurring in 1% to 3% of the patients
are unmarked.
Incidence <1%—Probably Causally Related†
Gastrointestinal: Anorexia, jaundice, duodenal ulcer, dysphagia, gastric ulcer,
gastroenteritis, gastrointestinal bleeding, increased appetite, liver function abnormalities,
melena, hepatic failure.
Central Nervous System: Asthenia, agitation, anxiety, confusion, depression, malaise,
paresthesia, tremor, vertigo.
Dermatologic: Bullous eruptions, photosensitivity, urticaria, pseudoporphyria cutanea tarda,
toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome.
Cardiovascular: Vasculitis.
Metabolic: Weight gain.
Respiratory: Dyspnea, eosinophilic pneumonia, hypersensitivity pneumonitis, idiopathic
interstitial pneumonitis.
Genitourinary: Albuminuria, azotemia, hyperuricemia, interstitial nephritis, nephrotic
syndrome, vaginal bleeding, renal failure.
Special Senses: Abnormal vision.
Hematologic/Lymphatic: Thrombocytopenia.
Hypersensitivity: Anaphylactoid reaction, anaphylaxis, angioneurotic edema.
†Adverse reactions reported only in worldwide postmarketing experience or in the literature, not seen
in clinical trials, are considered rarer and are italicized.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-583/S-023
Page 11
Incidence <1%—Causal Relationship Unknown
Gastrointestinal: Bilirubinuria, duodenitis, eructation, gallstones, gingivitis, glossitis,
pancreatitis, rectal bleeding.
Central Nervous System: Nightmares.
Dermatologic: Acne, alopecia.
Cardiovascular: Angina, arrhythmia, hypertension, myocardial infarction, palpitations,
syncope, thrombophlebitis.
Respiratory: Asthma, cough.
Genitourinary: Dysuria, hematuria, impotence, renal stones.
Special Senses: Taste disorder.
Body as a Whole: Fever, chills.
Hematologic/Lymphatic: Anemia, leukopenia, granulocytopenia.
Metabolic/Nutritional: Hyperglycemia, hypokalemia, weight loss.
OVERDOSAGE
Symptoms following acute NSAIDs overdoses are usually limited to lethargy, drowsiness,
nausea, vomiting, and epigastric pain, which are generally reversible with supportive care.
Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, and
coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion
of NSAIDs, and may occur following an overdose.
Patients should be managed by symptomatic and supportive care following a NSAIDs
overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 grams in adults,
1 to 2 g/kg in children), and/or osmotic cathartic may be indicated in patients seen within 4 hours of
ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). Forced diuresis,
alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.
There have been overdoses of up to 25 grams of RELAFEN reported with no long-term
sequelae following standard emergency treatment (i.e., activated charcoal, gastric lavage, IV
H2-blockers, etc.).
DOSAGE AND ADMINISTRATION
Osteoarthritis and Rheumatoid Arthritis: The recommended starting dose is 1,000 mg taken as a
single dose with or without food. Some patients may obtain more symptomatic relief from 1,500 mg to
2,000 mg per day. RELAFEN can be given in either a single or twice-daily dose. Dosages greater than
2,000 mg per day have not been studied. The lowest effective dose should be used for chronic
treatment (see PRECAUTIONS). Caution should be used in prescribing RELAFEN to patients with
moderate or severe renal insufficiency. The maximum starting doses of RELAFEN in patients with
moderate or severe renal insufficiency should not exceed 750 mg or 500 mg, respectively once daily.
Following careful monitoring of renal function in patients with moderate or severe renal insufficiency,
daily doses may be increased to a maximum of 1,500 mg and 1,000 mg, respectively (see
PRECAUTIONS: Renal Effects).
HOW SUPPLIED
Tablets: Oval-shaped, film-coated: 500 mg–white, imprinted with the product name RELAFEN and
500, in bottles of 100, and in Single-Unit Packages of 100 (intended for institutional use only). 750
mg–beige, imprinted with the product name RELAFEN and 750, in bottles of 100.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) in well-closed container;
dispense in light-resistant container.
500 mg 100’s: NDC 0029-4851-20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-583/S-023
Page 12
500 mg SUP 100’s: NDC 0029-4851-21
750 mg 100’s: NDC 0029-4852-20
750 mg SUP 100’s: NDC 0029-4852-21
GlaxoSmithKline
Research Triangle Park, NC 27709
©2005, GlaxoSmithKline. All rights reserved.
March 2005
RL:L15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:29.256406
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/019583s023lbl.pdf', 'application_number': 19583, 'submission_type': 'SUPPL ', 'submission_number': 23}
|
11,543
|
HLR 07/10/02
C:\Data\My Documents\Lariam\Oct02approvedlabel.doc
1
LARIAM
brand of
mefloquine hydrochloride
TABLETS
DESCRIPTION
Lariam (mefloquine hydrochloride) is an antimalarial agent available as 250-mg tablets of
mefloquine hydrochloride (equivalent to 228.0 mg of the free base) for oral administration.
Mefloquine hydrochloride is a 4-quinolinemethanol derivative with the specific chemical name of
(R*, S*)-(±)-α-2-piperidinyl-2,8-bis (trifluoromethyl)-4-quinolinemethanol hydrochloride. It is
a 2-aryl substituted chemical structural analog of quinine. The drug is a white to almost white
crystalline compound, slightly soluble in water.
Mefloquine hydrochloride has a calculated molecular weight of 414.78 and the following
structural formula:
The inactive ingredients are ammonium-calcium alginate, corn starch, crospovidone, lactose,
magnesium stearate, microcrystalline cellulose, poloxamer #331, and talc.
CLINICAL PHARMACOLOGY
Mefloquine is an antimalarial agent which acts as a blood schizonticide. Its exact mechanism of
action is not known.
Pharmacokinetic studies of mefloquine in healthy male subjects showed that a significant lagtime
occurred after drug administration, and the terminal elimination half-life varied widely (13 to 24
days) with a mean of about 3 weeks. Mefloquine is a mixture of enantiomeric molecules whose
rates of release, absorption, transport, action, degradation and elimination may differ. A valid
pharmacokinetic model may not exist in such a case.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 07/10/02
LARIAM
(mefloquine hydrochloride)
2
Additional studies in European subjects showed slightly greater concentrations of drug for
longer periods of time. The absorption half-life was 0.36 to 2 hours, and the terminal elimination
half-life was 15 to 33 days. The primary metabolite was identified and its concentrations were
found to surpass the concentrations of mefloquine.
Multiple-dose kinetic studies confirmed the long elimination half-lives previously observed. The
mean metabolite to mefloquine ratio measured at steady-state was found to range between 2.3
and 8.6.
The total clearance of the drug, which is essentially all hepatic, is approximately 30 mL/min. The
volume of distribution, approximately 20 L/kg, indicates extensive distribution. The drug is highly
bound (98%) to plasma proteins and concentrated in blood erythrocytes, the target cells in
malaria, at a relatively constant erythrocyte-to-plasma concentration ratio of about 2.
The pharmacokinetics of mefloquine in patients with compromised renal function and
compromised hepatic function have not been studied.
In vitro and in vivo studies showed no hemolysis associated with glucose-6-phosphate
dehydrogenase deficiency (see ANIMAL TOXICOLOGY).
Microbiology: Strains of Plasmodium falciparum resistant to mefloquine have been reported.
INDICATIONS AND USAGE
Treatment of Acute Malaria Infections: Lariam is indicated for the treatment of mild to
moderate acute malaria caused by mefloquine-susceptible strains of P. falciparum (both
chloroquine-susceptible and resistant strains) or by Plasmodium vivax. There are insufficient
clinical data to document the effect of mefloquine in malaria caused by P. ovale or P. malariae.
Note: Patients with acute P. vivax malaria, treated with Lariam, are at high risk of relapse
because Lariam does not eliminate exoerythrocytic (hepatic phase) parasites. To avoid
relapse, after initial treatment of the acute infection with Lariam, patients should
subsequently be treated with an 8-aminoquinoline (eg, primaquine).
Prevention of Malaria: Lariam is indicated for the prophylaxis of P. falciparum and P.
vivax malaria infections, including prophylaxis of chloroquine-resistant strains of P. falciparum.
CONTRAINDICATIONS
Use of Lariam is contraindicated in patients with a known hypersensitivity to mefloquine or
related compounds (eg, quinine and quinidine). Lariam should not be prescribed for prophylaxis
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 07/10/02
LARIAM
(mefloquine hydrochloride)
3
in patients with active depression, a recent history of depression, generalized anxiety disorder,
psychosis, or schizophrenia or other major psychiatric disorders, or with a history of
convulsions.
WARNINGS
In case of life-threatening, serious or overwhelming malaria infections due to P.
falciparum, patients should be treated with an intravenous antimalarial drug. Following
completion of intravenous treatment, Lariam may be given to complete the course of
therapy.
Data on the use of halofantrine subsequent to administration of Lariam suggest a
significant, potentially fatal prolongation of the QTc interval of the ECG. Therefore,
halofantrine must not be given simultaneously with or subsequent to Lariam. No data
are available on the use of Lariam after halofantrine (see PRECAUTIONS: Drug
Interactions).
Mefloquine may cause psychiatric symptoms in a number of patients, ranging from
anxiety, paranoia, and depression to hallucinations and psychotic behavior. On
occasions, these symptoms have been reported to continue long after mefloquine has
been stopped. Rare cases of suicidal ideation and suicide have been reported though
no relationship to drug administration has been confirmed. To minimize the chances of
these adverse events, mefloquine should not be taken for prophylaxis in patients with
active depression or with a recent history of depression, generalized anxiety disorder,
psychosis, or schizophrenia or other major psychiatric disorders. Lariam should be
used with caution in patients with a previous history of depression.
During prophylactic use, if psychiatric symptoms such as acute anxiety, depression,
restlessness or confusion occur, these may be considered prodromal to a more serious
event. In these cases, the drug must be discontinued and an alternative medication
should be substituted.
Concomitant administration of Lariam and quinine or quinidine may produce
electrocardiographic abnormalities.
Concomitant administration of Lariam and quinine or chloroquine may increase the
risk of convulsions.
PRECAUTIONS
General: In patients with epilepsy, Lariam may increase the risk of convulsions. The drug
should therefore be prescribed only for curative treatment in such patients and only if there are
compelling medical reasons for its use (see PRECAUTIONS: Drug Interactions).
Caution should be exercised with regard to activities requiring alertness and fine motor
coordination such as driving, piloting aircraft and operating machinery, as dizziness, a loss of
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 07/10/02
LARIAM
(mefloquine hydrochloride)
4
balance, or other disorders of the central or peripheral nervous system have been reported
during and following the use of Lariam. These effects may occur after therapy is discontinued
due to the long half-life of the drug. Lariam should be used with caution in patients with
psychiatric disturbances because mefloquine use has been associated with emotional
disturbances (see ADVERSE REACTIONS).
In patients with impaired liver function the elimination of mefloquine may be prolonged, leading
to higher plasma levels.
This drug has been administered for longer than 1 year. If the drug is to be administered for a
prolonged period, periodic evaluations including liver function tests should be performed.
Although retinal abnormalities seen in humans with long-term chloroquine use have not been
observed with mefloquine use, long-term feeding of mefloquine to rats resulted in dose-related
ocular lesions (retinal degeneration, retinal edema and lenticular opacity at 12.5 mg/kg/day and
higher) (see ANIMAL TOXICOLOGY). Therefore, periodic ophthalmic examinations are
recommended.
Parenteral studies in animals show that mefloquine, a myocardial depressant, possesses 20% of
the antifibrillatory action of quinidine and produces 50% of the increase in the PR interval
reported with quinine. The effect of mefloquine on the compromised cardiovascular system has
not been evaluated. However, transitory and clinically silent ECG alterations have been reported
during the use of mefloquine. Alterations included sinus bradycardia, sinus arrhythmia, first
degree AV-block, prolongation of the QTc interval and abnormal T waves (see also
cardiovascular effects under PRECAUTIONS: Drug Interactions and ADVERSE
REACTIONS). The benefits of Lariam therapy should be weighed against the possibility of
adverse effects in patients with cardiac disease.
Laboratory Tests: Periodic evaluation of hepatic function should be performed during
prolonged prophylaxis.
Information for Patients:
Patients should be advised:
• that malaria can be a life-threatening infection in the traveler;
• that Lariam is being prescribed to help prevent or treat this serious infection;
• 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 Lariam should be taken one week prior to
departure;
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 07/10/02
LARIAM
(mefloquine hydrochloride)
5
• that if the patients experience psychiatric symptoms such as acute anxiety, depression,
restlessness or confusion, these may be considered prodromal to a more serious event. In
these cases, the drug must be discontinued and an alternative medication should be
substituted;
• 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.
Drug Interactions: Drug-drug interactions with Lariam have not been explored in detail.
There is one report of cardiopulmonary arrest, with full recovery, in a patient who was taking a
beta blocker (propranolol) (see PRECAUTIONS: General). The effects of mefloquine on the
compromised cardiovascular system have not been evaluated. The benefits of Lariam therapy
should be weighed against the possibility of adverse effects in patients with cardiac disease.
Because of the danger of a potentially fatal prolongation of the QTc interval, halofantrine should
not be given simultaneously with or subsequent to Lariam (see WARNINGS).
Concomitant administration of Lariam and other related compounds (eg, quinine, quinidine and
chloroquine) may produce electrocardiographic abnormalities and increase the risk of
convulsions (see WARNINGS). If these drugs are to be used in the initial treatment of severe
malaria, Lariam administration should be delayed at least 12 hours after the last dose. There is
evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc
interval. Clinically significant QTc prolongation has not been found with mefloquine alone.
This appears to be the only clinically relevant interaction of this kind with Lariam, although
theoretically, coadministration of other drugs known to alter cardiac conduction (eg, anti-
arrhythmic or beta-adrenergic blocking agents, calcium channel blockers, antihistamines or H1-
blocking agents, tricyclic antidepressants and phenothiazines) might also contribute to a
prolongation of the QTc interval. There are no data that conclusively establish whether the
concomitant administration of mefloquine and the above listed agents has an effect on cardiac
function.
In patients taking an anticonvulsant (eg, valproic acid, carbamazepine, phenobarbital or
phenytoin), the concomitant use of Lariam may reduce seizure control by lowering the plasma
levels of the anticonvulsant. Therefore, patients concurrently taking antiseizure medication and
Lariam should have the blood level of their antiseizure medication monitored and the dosage
adjusted appropriately (see PRECAUTIONS: General).
When Lariam is taken concurrently with oral live typhoid vaccines, attenuation of immunization
cannot be excluded. Vaccinations with attenuated live bacteria should therefore be completed at
least 3 days before the first dose of Lariam.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 07/10/02
LARIAM
(mefloquine hydrochloride)
6
No other drug interactions are known. Nevertheless, the effects of Lariam on travelers receiving
comedication, particularly those on anticoagulants or antidiabetics, should be checked before
departure.
In clinical trials, the concomitant administration of sulfadoxine and pyrimethamine did not alter
the adverse reaction profile.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Carcinogenesis: The carcinogenic potential of mefloquine was studied in rats and mice in 2-
year feeding studies at doses of up to 30 mg/kg/day. No treatment-related increases in tumors
of any type were noted.
Mutagenesis: The mutagenic potential of mefloquine was studied in a variety of assay systems
including: Ames test, a host-mediated assay in mice, fluctuation tests and a mouse micronucleus
assay. Several of these assays were performed with and without prior metabolic activation. In
no instance was evidence obtained for the mutagenicity of mefloquine.
Impairment of Fertility: Fertility studies in rats at doses of 5, 20, and 50 mg/kg/day of
mefloquine have demonstrated adverse effects on fertility in the male at the high dose of 50
mg/kg/day, and in the female at doses of 20 and 50 mg/kg/day. Histopathological lesions were
noted in the epididymides from male rats at doses of 20 and 50 mg/kg/day. Administration of
250 mg/week of mefloquine (base) in adult males for 22 weeks failed to reveal any deleterious
effects on human spermatozoa.
Pregnancy: Teratogenic Effects. Pregnancy Category C. Mefloquine has been demonstrated
to be teratogenic in rats and mice at a dose of 100 mg/kg/day. In rabbits, a high dose of 160
mg/kg/day was embryotoxic and teratogenic, and a dose of 80 mg/kg/day was teratogenic but
not embryotoxic. There are no adequate and well-controlled studies in pregnant women.
However, clinical experience with Lariam has not revealed an embryotoxic or teratogenic effect.
Mefloquine 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. Women of childbearing potential should
also be advised to practice contraception during malaria prophylaxis with Lariam.
Nursing Mothers: Mefloquine is excreted in human milk. Based on a study in a few subjects,
low concentrations (3% to 4%) of mefloquine were excreted in human milk following a dose
equivalent to 250 mg of the free base. Because of the potential for serious adverse reactions in
nursing infants from mefloquine, a decision should be made whether 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
HLR 07/10/02
LARIAM
(mefloquine hydrochloride)
7
Pediatric Use: Use of Lariam to treat acute, uncomplicated P. falciparum malaria in pediatric
patients is supported by evidence from adequate and well-controlled studies of Lariam in adults
with additional data from published open-label and comparative trials using Lariam to treat
malaria caused by P. falciparum in patients younger than 16 years of age. The safety and
effectiveness of Lariam for the treatment of malaria in pediatric patients below the age of 6
months have not been established.
In several studies, the administration of Lariam for the treatment of malaria was associated with
early vomiting in pediatric patients. Early vomiting was cited in some reports as a possible cause
of treatment failure. If a second dose is not tolerated, the patient should be monitored closely
and alternative malaria treatment considered if improvement is not observed within a reasonable
period of time (see DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
Clinical: At the doses used for treatment of acute malaria infections, the symptoms possibly
attributable to drug administration cannot be distinguished from those symptoms usually
attributable to the disease itself.
Among subjects who received mefloquine for prophylaxis of malaria, the most frequently
observed adverse experience was vomiting (3%). Dizziness, syncope, extrasystoles and other
complaints affecting less than 1% were also reported.
Among subjects who received mefloquine for treatment, the most frequently observed adverse
experiences included: dizziness, myalgia, nausea, fever, headache, vomiting, chills, diarrhea, skin
rash, abdominal pain, fatigue, loss of appetite, and tinnitus. Those side effects occurring in less
than 1% included bradycardia, hair loss, emotional problems, pruritus, asthenia, transient
emotional disturbances and telogen effluvium (loss of resting hair). Seizures have also been
reported.
Two serious adverse reactions were cardiopulmonary arrest in one patient shortly after ingesting
a single prophylactic dose of mefloquine while concomitantly using propranolol (see
PRECAUTIONS), and encephalopathy of unknown etiology during prophylactic mefloquine
administration. The relationship of encephalopathy to drug administration could not be clearly
established.
Postmarketing: Postmarketing surveillance indicates that the same kind of adverse experiences
are reported during prophylaxis, as well as acute treatment.
The most frequently reported adverse events are nausea, vomiting, loose stools or diarrhea,
abdominal pain, dizziness or vertigo, loss of balance, and neuropsychiatric events such as
headache, somnolence, and sleep disorders (insomnia, abnormal dreams). These are usually
mild and may decrease despite continued use.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 07/10/02
LARIAM
(mefloquine hydrochloride)
8
Occasionally, more severe neuropsychiatric disorders have been reported such as: sensory and
motor neuropathies (including paresthesia, tremor and ataxia), convulsions, agitation or
restlessness, anxiety, depression, mood changes, panic attacks, forgetfulness, confusion,
hallucinations, aggression, psychotic or paranoid reactions and encephalopathy. Rare cases of
suicidal ideation and suicide have been reported though no relationship to drug administration
has been confirmed.
Other infrequent adverse events include:
Cardiovascular Disorders: circulatory disturbances (hypotension, hypertension, flushing,
syncope), chest pain, tachycardia or palpitation, bradycardia, irregular pulse, extrasystoles, A-V
block, and other transient cardiac conduction alterations.
Skin Disorders: rash, exanthema, erythema, urticaria, pruritus, edema, hair loss, erythema
multiforme, and Stevens-Johnson syndrome.
Musculoskeletal Disorders: muscle weakness, muscle cramps, myalgia, and arthralgia.
Other Symptoms: visual disturbances, vestibular disorders including tinnitus and hearing
impairment, dyspnea, asthenia, malaise, fatigue, fever, sweating, chills, dyspepsia and loss of
appetite.
Laboratory: The most frequently observed laboratory alterations which could be possibly
attributable to drug administration were decreased hematocrit, transient elevation of
transaminases, leukopenia and thrombocytopenia. These alterations were observed in patients
with acute malaria who received treatment doses of the drug and were attributed to the disease
itself.
During prophylactic administration of mefloquine to indigenous populations in malaria-endemic
areas, the following occasional alterations in laboratory values were observed: transient
elevation of transaminases, leukocytosis or thrombocytopenia.
Because of the long half-life of mefloquine, adverse reactions to Lariam may occur or persist up
to several weeks after the last dose.
OVERDOSAGE
In cases of overdosage with Lariam, the symptoms mentioned under ADVERSE
REACTIONS may be more pronounced. The following procedure is recommended in case of
overdosage: Induce vomiting or perform gastric lavage, as appropriate. Monitor cardiac
function (if possible by ECG) and neurologic and psychiatric status for at least 24 hours.
Provide symptomatic and intensive supportive treatment as required, particularly for
cardiovascular disturbances. Treat vomiting or diarrhea with standard fluid therapy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 07/10/02
LARIAM
(mefloquine hydrochloride)
9
DOSAGE AND ADMINISTRATION (see INDICATIONS AND USAGE)
Adult Patients: Treatment of mild to moderate malaria in adults caused by P. vivax or
mefloquine-susceptible strains of P. falciparum: Five tablets (1250 mg) mefloquine
hydrochloride to be given as a single oral dose. The drug should not be taken on an empty
stomach and should be administered with at least 8 oz (240 mL) of water.
If a full-treatment course has been administered without clinical cure, alternative treatment
should be given. Similarly, if previous prophylaxis with mefloquine has failed, Lariam should not
be used for curative treatment.
Note: Patients with acute P. vivax malaria, treated with Lariam, are at high risk of relapse
because Lariam does not eliminate exoerythrocytic (hepatic phase) parasites. To avoid
relapse after initial treatment of the acute infection with Lariam, patients should subsequently
be treated with an 8-aminoquinoline (eg, primaquine).
Malaria prophylaxis: One 250 mg Lariam tablet once weekly.
Prophylactic drug administration should begin 1 week before departure to an endemic area.
Subsequent weekly doses should always be taken on the same day of the week. To reduce the
risk of malaria after leaving an endemic area, prophylaxis should be continued for 4 additional
weeks. Tablets should not be taken on an empty stomach and should be administered with at
least 8 oz (240 mL) of water.
In certain cases, eg, when a traveler is taking other medication, it may be desirable to start
prophylaxis 2 to 3 weeks prior to departure, in order to ensure that the combination of drugs is
well tolerated.
Pediatric Patients: Treatment of mild to moderate malaria in pediatric patients caused
by mefloquine-susceptible strains of P. falciparum: 20 to 25 mg/kg for non-immune patients.
Splitting the total curative dose into 2 doses taken 6 to 8 hours apart may reduce the
occurrence or severity of adverse effects. Experience with Lariam in infants less than 3 months
old or weighing less than 5 kg is limited. The drug should not be taken on an empty stomach and
should be administered with ample water. For very young patients, the dose may be crushed,
mixed with water or sugar water and may be administered via an oral syringe.
If a full-treatment course has been administered without clinical cure, alternative treatment
should be given. Similarly, if previous prophylaxis with mefloquine has failed, Lariam should not
be used for curative treatment.
In pediatric patients, the administration of Lariam for the treatment of malaria has been
associated with early vomiting. In some cases, early vomiting has been cited as a possible cause
of treatment failure (see PRECAUTIONS). If a significant loss of drug product is observed or
suspected because of vomiting, a second full dose of Lariam should be administered to patients
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 07/10/02
LARIAM
(mefloquine hydrochloride)
10
who vomit less than 30 minutes after receiving the drug. If vomiting occurs 30 to 60 minutes
after a dose, an additional half-dose should be given. If vomiting recurs, the patient should be
monitored closely and alternative malaria treatment considered if improvement is not observed
within a reasonable period of time.
The safety and effectiveness of Lariam to treat malaria in pediatric patients below the age of 6
months have not been established.
Malaria Prophylaxis: The following doses have been extrapolated from the recommended
adult dose. Neither the pharmacokinetics, nor the clinical efficacy of these doses have been
determined in children owing to the difficulty of acquiring this information in pediatric subjects.
The recommended prophylactic dose of Lariam is 3 to 5 mg/kg once weekly. One 250 mg
Lariam tablet should be taken once weekly in pediatric patients weighing over 45 kg. In
pediatric patients weighing less than 45 kg, the weekly dose decreases in proportion to body
weight:
>30 to 45 kg:
¾ tablet
>20 to 30 kg:
½ tablet
up to 20 kg:
¼ tablet
Experience with Lariam in infants less than 3 months old or weighing less than 5 kg is limited.
HOW SUPPLIED
Lariam is available as scored, white, round tablets, containing 250 mg of mefloquine
hydrochloride in unit-dose packages of 25 (NDC 0004-0172-02). Imprint on tablets:
LARIAM 250 ROCHE
Tablets should be stored at 15° to 30°C (59° to 86°F).
ANIMAL TOXICOLOGY
Ocular lesions were observed in rats fed mefloquine daily for 2 years. All surviving rats given 30
mg/kg/day had ocular lesions in both eyes characterized by retinal degeneration, opacity of the
lens, and retinal edema. Similar but less severe lesions were observed in 80% of female and
22% of male rats fed 12.5 mg/kg/day for 2 years. At doses of 5 mg/kg/day, only corneal lesions
were observed. They occurred in 9% of rats studied.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 07/10/02
LARIAM
(mefloquine hydrochloride)
11
Rx only
Manufactured by:
F. HOFFMANN-LA ROCHE LTD
Basel, Switzerland
Distributed by:
27898311-0702
Revised: July 2002
Printed in USA
Copyright © 1999-2002 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
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
Renata Albrecht
10/3/02 02:31:28 PM
N 19-591/S020
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:29.294942
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19591s20lbl.pdf', 'application_number': 19591, 'submission_type': 'ORIG ', 'submission_number': 1}
|
11,544
|
HLR 07/10/02
C:\Data\My Documents\Lariam\Oct02approvedlabel.doc
1
LARIAM
brand of
mefloquine hydrochloride
TABLETS
DESCRIPTION
Lariam (mefloquine hydrochloride) is an antimalarial agent available as 250-mg tablets of
mefloquine hydrochloride (equivalent to 228.0 mg of the free base) for oral administration.
Mefloquine hydrochloride is a 4-quinolinemethanol derivative with the specific chemical name of
(R*, S*)-(±)-α-2-piperidinyl-2,8-bis (trifluoromethyl)-4-quinolinemethanol hydrochloride. It is
a 2-aryl substituted chemical structural analog of quinine. The drug is a white to almost white
crystalline compound, slightly soluble in water.
Mefloquine hydrochloride has a calculated molecular weight of 414.78 and the following
structural formula:
The inactive ingredients are ammonium-calcium alginate, corn starch, crospovidone, lactose,
magnesium stearate, microcrystalline cellulose, poloxamer #331, and talc.
CLINICAL PHARMACOLOGY
Mefloquine is an antimalarial agent which acts as a blood schizonticide. Its exact mechanism of
action is not known.
Pharmacokinetic studies of mefloquine in healthy male subjects showed that a significant lagtime
occurred after drug administration, and the terminal elimination half-life varied widely (13 to 24
days) with a mean of about 3 weeks. Mefloquine is a mixture of enantiomeric molecules whose
rates of release, absorption, transport, action, degradation and elimination may differ. A valid
pharmacokinetic model may not exist in such a case.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 07/10/02
LARIAM
(mefloquine hydrochloride)
2
Additional studies in European subjects showed slightly greater concentrations of drug for
longer periods of time. The absorption half-life was 0.36 to 2 hours, and the terminal elimination
half-life was 15 to 33 days. The primary metabolite was identified and its concentrations were
found to surpass the concentrations of mefloquine.
Multiple-dose kinetic studies confirmed the long elimination half-lives previously observed. The
mean metabolite to mefloquine ratio measured at steady-state was found to range between 2.3
and 8.6.
The total clearance of the drug, which is essentially all hepatic, is approximately 30 mL/min. The
volume of distribution, approximately 20 L/kg, indicates extensive distribution. The drug is highly
bound (98%) to plasma proteins and concentrated in blood erythrocytes, the target cells in
malaria, at a relatively constant erythrocyte-to-plasma concentration ratio of about 2.
The pharmacokinetics of mefloquine in patients with compromised renal function and
compromised hepatic function have not been studied.
In vitro and in vivo studies showed no hemolysis associated with glucose-6-phosphate
dehydrogenase deficiency (see ANIMAL TOXICOLOGY).
Microbiology: Strains of Plasmodium falciparum resistant to mefloquine have been reported.
INDICATIONS AND USAGE
Treatment of Acute Malaria Infections: Lariam is indicated for the treatment of mild to
moderate acute malaria caused by mefloquine-susceptible strains of P. falciparum (both
chloroquine-susceptible and resistant strains) or by Plasmodium vivax. There are insufficient
clinical data to document the effect of mefloquine in malaria caused by P. ovale or P. malariae.
Note: Patients with acute P. vivax malaria, treated with Lariam, are at high risk of relapse
because Lariam does not eliminate exoerythrocytic (hepatic phase) parasites. To avoid
relapse, after initial treatment of the acute infection with Lariam, patients should
subsequently be treated with an 8-aminoquinoline (eg, primaquine).
Prevention of Malaria: Lariam is indicated for the prophylaxis of P. falciparum and P.
vivax malaria infections, including prophylaxis of chloroquine-resistant strains of P. falciparum.
CONTRAINDICATIONS
Use of Lariam is contraindicated in patients with a known hypersensitivity to mefloquine or
related compounds (eg, quinine and quinidine). Lariam should not be prescribed for prophylaxis
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 07/10/02
LARIAM
(mefloquine hydrochloride)
3
in patients with active depression, a recent history of depression, generalized anxiety disorder,
psychosis, or schizophrenia or other major psychiatric disorders, or with a history of
convulsions.
WARNINGS
In case of life-threatening, serious or overwhelming malaria infections due to P.
falciparum, patients should be treated with an intravenous antimalarial drug. Following
completion of intravenous treatment, Lariam may be given to complete the course of
therapy.
Data on the use of halofantrine subsequent to administration of Lariam suggest a
significant, potentially fatal prolongation of the QTc interval of the ECG. Therefore,
halofantrine must not be given simultaneously with or subsequent to Lariam. No data
are available on the use of Lariam after halofantrine (see PRECAUTIONS: Drug
Interactions).
Mefloquine may cause psychiatric symptoms in a number of patients, ranging from
anxiety, paranoia, and depression to hallucinations and psychotic behavior. On
occasions, these symptoms have been reported to continue long after mefloquine has
been stopped. Rare cases of suicidal ideation and suicide have been reported though
no relationship to drug administration has been confirmed. To minimize the chances of
these adverse events, mefloquine should not be taken for prophylaxis in patients with
active depression or with a recent history of depression, generalized anxiety disorder,
psychosis, or schizophrenia or other major psychiatric disorders. Lariam should be
used with caution in patients with a previous history of depression.
During prophylactic use, if psychiatric symptoms such as acute anxiety, depression,
restlessness or confusion occur, these may be considered prodromal to a more serious
event. In these cases, the drug must be discontinued and an alternative medication
should be substituted.
Concomitant administration of Lariam and quinine or quinidine may produce
electrocardiographic abnormalities.
Concomitant administration of Lariam and quinine or chloroquine may increase the
risk of convulsions.
PRECAUTIONS
General: In patients with epilepsy, Lariam may increase the risk of convulsions. The drug
should therefore be prescribed only for curative treatment in such patients and only if there are
compelling medical reasons for its use (see PRECAUTIONS: Drug Interactions).
Caution should be exercised with regard to activities requiring alertness and fine motor
coordination such as driving, piloting aircraft and operating machinery, as dizziness, a loss of
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 07/10/02
LARIAM
(mefloquine hydrochloride)
4
balance, or other disorders of the central or peripheral nervous system have been reported
during and following the use of Lariam. These effects may occur after therapy is discontinued
due to the long half-life of the drug. Lariam should be used with caution in patients with
psychiatric disturbances because mefloquine use has been associated with emotional
disturbances (see ADVERSE REACTIONS).
In patients with impaired liver function the elimination of mefloquine may be prolonged, leading
to higher plasma levels.
This drug has been administered for longer than 1 year. If the drug is to be administered for a
prolonged period, periodic evaluations including liver function tests should be performed.
Although retinal abnormalities seen in humans with long-term chloroquine use have not been
observed with mefloquine use, long-term feeding of mefloquine to rats resulted in dose-related
ocular lesions (retinal degeneration, retinal edema and lenticular opacity at 12.5 mg/kg/day and
higher) (see ANIMAL TOXICOLOGY). Therefore, periodic ophthalmic examinations are
recommended.
Parenteral studies in animals show that mefloquine, a myocardial depressant, possesses 20% of
the antifibrillatory action of quinidine and produces 50% of the increase in the PR interval
reported with quinine. The effect of mefloquine on the compromised cardiovascular system has
not been evaluated. However, transitory and clinically silent ECG alterations have been reported
during the use of mefloquine. Alterations included sinus bradycardia, sinus arrhythmia, first
degree AV-block, prolongation of the QTc interval and abnormal T waves (see also
cardiovascular effects under PRECAUTIONS: Drug Interactions and ADVERSE
REACTIONS). The benefits of Lariam therapy should be weighed against the possibility of
adverse effects in patients with cardiac disease.
Laboratory Tests: Periodic evaluation of hepatic function should be performed during
prolonged prophylaxis.
Information for Patients:
Patients should be advised:
• that malaria can be a life-threatening infection in the traveler;
• that Lariam is being prescribed to help prevent or treat this serious infection;
• 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 Lariam should be taken one week prior to
departure;
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 07/10/02
LARIAM
(mefloquine hydrochloride)
5
• that if the patients experience psychiatric symptoms such as acute anxiety, depression,
restlessness or confusion, these may be considered prodromal to a more serious event. In
these cases, the drug must be discontinued and an alternative medication should be
substituted;
• 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.
Drug Interactions: Drug-drug interactions with Lariam have not been explored in detail.
There is one report of cardiopulmonary arrest, with full recovery, in a patient who was taking a
beta blocker (propranolol) (see PRECAUTIONS: General). The effects of mefloquine on the
compromised cardiovascular system have not been evaluated. The benefits of Lariam therapy
should be weighed against the possibility of adverse effects in patients with cardiac disease.
Because of the danger of a potentially fatal prolongation of the QTc interval, halofantrine should
not be given simultaneously with or subsequent to Lariam (see WARNINGS).
Concomitant administration of Lariam and other related compounds (eg, quinine, quinidine and
chloroquine) may produce electrocardiographic abnormalities and increase the risk of
convulsions (see WARNINGS). If these drugs are to be used in the initial treatment of severe
malaria, Lariam administration should be delayed at least 12 hours after the last dose. There is
evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc
interval. Clinically significant QTc prolongation has not been found with mefloquine alone.
This appears to be the only clinically relevant interaction of this kind with Lariam, although
theoretically, coadministration of other drugs known to alter cardiac conduction (eg, anti-
arrhythmic or beta-adrenergic blocking agents, calcium channel blockers, antihistamines or H1-
blocking agents, tricyclic antidepressants and phenothiazines) might also contribute to a
prolongation of the QTc interval. There are no data that conclusively establish whether the
concomitant administration of mefloquine and the above listed agents has an effect on cardiac
function.
In patients taking an anticonvulsant (eg, valproic acid, carbamazepine, phenobarbital or
phenytoin), the concomitant use of Lariam may reduce seizure control by lowering the plasma
levels of the anticonvulsant. Therefore, patients concurrently taking antiseizure medication and
Lariam should have the blood level of their antiseizure medication monitored and the dosage
adjusted appropriately (see PRECAUTIONS: General).
When Lariam is taken concurrently with oral live typhoid vaccines, attenuation of immunization
cannot be excluded. Vaccinations with attenuated live bacteria should therefore be completed at
least 3 days before the first dose of Lariam.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 07/10/02
LARIAM
(mefloquine hydrochloride)
6
No other drug interactions are known. Nevertheless, the effects of Lariam on travelers receiving
comedication, particularly those on anticoagulants or antidiabetics, should be checked before
departure.
In clinical trials, the concomitant administration of sulfadoxine and pyrimethamine did not alter
the adverse reaction profile.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Carcinogenesis: The carcinogenic potential of mefloquine was studied in rats and mice in 2-
year feeding studies at doses of up to 30 mg/kg/day. No treatment-related increases in tumors
of any type were noted.
Mutagenesis: The mutagenic potential of mefloquine was studied in a variety of assay systems
including: Ames test, a host-mediated assay in mice, fluctuation tests and a mouse micronucleus
assay. Several of these assays were performed with and without prior metabolic activation. In
no instance was evidence obtained for the mutagenicity of mefloquine.
Impairment of Fertility: Fertility studies in rats at doses of 5, 20, and 50 mg/kg/day of
mefloquine have demonstrated adverse effects on fertility in the male at the high dose of 50
mg/kg/day, and in the female at doses of 20 and 50 mg/kg/day. Histopathological lesions were
noted in the epididymides from male rats at doses of 20 and 50 mg/kg/day. Administration of
250 mg/week of mefloquine (base) in adult males for 22 weeks failed to reveal any deleterious
effects on human spermatozoa.
Pregnancy: Teratogenic Effects. Pregnancy Category C. Mefloquine has been demonstrated
to be teratogenic in rats and mice at a dose of 100 mg/kg/day. In rabbits, a high dose of 160
mg/kg/day was embryotoxic and teratogenic, and a dose of 80 mg/kg/day was teratogenic but
not embryotoxic. There are no adequate and well-controlled studies in pregnant women.
However, clinical experience with Lariam has not revealed an embryotoxic or teratogenic effect.
Mefloquine 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. Women of childbearing potential should
also be advised to practice contraception during malaria prophylaxis with Lariam.
Nursing Mothers: Mefloquine is excreted in human milk. Based on a study in a few subjects,
low concentrations (3% to 4%) of mefloquine were excreted in human milk following a dose
equivalent to 250 mg of the free base. Because of the potential for serious adverse reactions in
nursing infants from mefloquine, a decision should be made whether 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
HLR 07/10/02
LARIAM
(mefloquine hydrochloride)
7
Pediatric Use: Use of Lariam to treat acute, uncomplicated P. falciparum malaria in pediatric
patients is supported by evidence from adequate and well-controlled studies of Lariam in adults
with additional data from published open-label and comparative trials using Lariam to treat
malaria caused by P. falciparum in patients younger than 16 years of age. The safety and
effectiveness of Lariam for the treatment of malaria in pediatric patients below the age of 6
months have not been established.
In several studies, the administration of Lariam for the treatment of malaria was associated with
early vomiting in pediatric patients. Early vomiting was cited in some reports as a possible cause
of treatment failure. If a second dose is not tolerated, the patient should be monitored closely
and alternative malaria treatment considered if improvement is not observed within a reasonable
period of time (see DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
Clinical: At the doses used for treatment of acute malaria infections, the symptoms possibly
attributable to drug administration cannot be distinguished from those symptoms usually
attributable to the disease itself.
Among subjects who received mefloquine for prophylaxis of malaria, the most frequently
observed adverse experience was vomiting (3%). Dizziness, syncope, extrasystoles and other
complaints affecting less than 1% were also reported.
Among subjects who received mefloquine for treatment, the most frequently observed adverse
experiences included: dizziness, myalgia, nausea, fever, headache, vomiting, chills, diarrhea, skin
rash, abdominal pain, fatigue, loss of appetite, and tinnitus. Those side effects occurring in less
than 1% included bradycardia, hair loss, emotional problems, pruritus, asthenia, transient
emotional disturbances and telogen effluvium (loss of resting hair). Seizures have also been
reported.
Two serious adverse reactions were cardiopulmonary arrest in one patient shortly after ingesting
a single prophylactic dose of mefloquine while concomitantly using propranolol (see
PRECAUTIONS), and encephalopathy of unknown etiology during prophylactic mefloquine
administration. The relationship of encephalopathy to drug administration could not be clearly
established.
Postmarketing: Postmarketing surveillance indicates that the same kind of adverse experiences
are reported during prophylaxis, as well as acute treatment.
The most frequently reported adverse events are nausea, vomiting, loose stools or diarrhea,
abdominal pain, dizziness or vertigo, loss of balance, and neuropsychiatric events such as
headache, somnolence, and sleep disorders (insomnia, abnormal dreams). These are usually
mild and may decrease despite continued use.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 07/10/02
LARIAM
(mefloquine hydrochloride)
8
Occasionally, more severe neuropsychiatric disorders have been reported such as: sensory and
motor neuropathies (including paresthesia, tremor and ataxia), convulsions, agitation or
restlessness, anxiety, depression, mood changes, panic attacks, forgetfulness, confusion,
hallucinations, aggression, psychotic or paranoid reactions and encephalopathy. Rare cases of
suicidal ideation and suicide have been reported though no relationship to drug administration
has been confirmed.
Other infrequent adverse events include:
Cardiovascular Disorders: circulatory disturbances (hypotension, hypertension, flushing,
syncope), chest pain, tachycardia or palpitation, bradycardia, irregular pulse, extrasystoles, A-V
block, and other transient cardiac conduction alterations.
Skin Disorders: rash, exanthema, erythema, urticaria, pruritus, edema, hair loss, erythema
multiforme, and Stevens-Johnson syndrome.
Musculoskeletal Disorders: muscle weakness, muscle cramps, myalgia, and arthralgia.
Other Symptoms: visual disturbances, vestibular disorders including tinnitus and hearing
impairment, dyspnea, asthenia, malaise, fatigue, fever, sweating, chills, dyspepsia and loss of
appetite.
Laboratory: The most frequently observed laboratory alterations which could be possibly
attributable to drug administration were decreased hematocrit, transient elevation of
transaminases, leukopenia and thrombocytopenia. These alterations were observed in patients
with acute malaria who received treatment doses of the drug and were attributed to the disease
itself.
During prophylactic administration of mefloquine to indigenous populations in malaria-endemic
areas, the following occasional alterations in laboratory values were observed: transient
elevation of transaminases, leukocytosis or thrombocytopenia.
Because of the long half-life of mefloquine, adverse reactions to Lariam may occur or persist up
to several weeks after the last dose.
OVERDOSAGE
In cases of overdosage with Lariam, the symptoms mentioned under ADVERSE
REACTIONS may be more pronounced. The following procedure is recommended in case of
overdosage: Induce vomiting or perform gastric lavage, as appropriate. Monitor cardiac
function (if possible by ECG) and neurologic and psychiatric status for at least 24 hours.
Provide symptomatic and intensive supportive treatment as required, particularly for
cardiovascular disturbances. Treat vomiting or diarrhea with standard fluid therapy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 07/10/02
LARIAM
(mefloquine hydrochloride)
9
DOSAGE AND ADMINISTRATION (see INDICATIONS AND USAGE)
Adult Patients: Treatment of mild to moderate malaria in adults caused by P. vivax or
mefloquine-susceptible strains of P. falciparum: Five tablets (1250 mg) mefloquine
hydrochloride to be given as a single oral dose. The drug should not be taken on an empty
stomach and should be administered with at least 8 oz (240 mL) of water.
If a full-treatment course has been administered without clinical cure, alternative treatment
should be given. Similarly, if previous prophylaxis with mefloquine has failed, Lariam should not
be used for curative treatment.
Note: Patients with acute P. vivax malaria, treated with Lariam, are at high risk of relapse
because Lariam does not eliminate exoerythrocytic (hepatic phase) parasites. To avoid
relapse after initial treatment of the acute infection with Lariam, patients should subsequently
be treated with an 8-aminoquinoline (eg, primaquine).
Malaria prophylaxis: One 250 mg Lariam tablet once weekly.
Prophylactic drug administration should begin 1 week before departure to an endemic area.
Subsequent weekly doses should always be taken on the same day of the week. To reduce the
risk of malaria after leaving an endemic area, prophylaxis should be continued for 4 additional
weeks. Tablets should not be taken on an empty stomach and should be administered with at
least 8 oz (240 mL) of water.
In certain cases, eg, when a traveler is taking other medication, it may be desirable to start
prophylaxis 2 to 3 weeks prior to departure, in order to ensure that the combination of drugs is
well tolerated.
Pediatric Patients: Treatment of mild to moderate malaria in pediatric patients caused
by mefloquine-susceptible strains of P. falciparum: 20 to 25 mg/kg for non-immune patients.
Splitting the total curative dose into 2 doses taken 6 to 8 hours apart may reduce the
occurrence or severity of adverse effects. Experience with Lariam in infants less than 3 months
old or weighing less than 5 kg is limited. The drug should not be taken on an empty stomach and
should be administered with ample water. For very young patients, the dose may be crushed,
mixed with water or sugar water and may be administered via an oral syringe.
If a full-treatment course has been administered without clinical cure, alternative treatment
should be given. Similarly, if previous prophylaxis with mefloquine has failed, Lariam should not
be used for curative treatment.
In pediatric patients, the administration of Lariam for the treatment of malaria has been
associated with early vomiting. In some cases, early vomiting has been cited as a possible cause
of treatment failure (see PRECAUTIONS). If a significant loss of drug product is observed or
suspected because of vomiting, a second full dose of Lariam should be administered to patients
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 07/10/02
LARIAM
(mefloquine hydrochloride)
10
who vomit less than 30 minutes after receiving the drug. If vomiting occurs 30 to 60 minutes
after a dose, an additional half-dose should be given. If vomiting recurs, the patient should be
monitored closely and alternative malaria treatment considered if improvement is not observed
within a reasonable period of time.
The safety and effectiveness of Lariam to treat malaria in pediatric patients below the age of 6
months have not been established.
Malaria Prophylaxis: The following doses have been extrapolated from the recommended
adult dose. Neither the pharmacokinetics, nor the clinical efficacy of these doses have been
determined in children owing to the difficulty of acquiring this information in pediatric subjects.
The recommended prophylactic dose of Lariam is 3 to 5 mg/kg once weekly. One 250 mg
Lariam tablet should be taken once weekly in pediatric patients weighing over 45 kg. In
pediatric patients weighing less than 45 kg, the weekly dose decreases in proportion to body
weight:
>30 to 45 kg:
¾ tablet
>20 to 30 kg:
½ tablet
up to 20 kg:
¼ tablet
Experience with Lariam in infants less than 3 months old or weighing less than 5 kg is limited.
HOW SUPPLIED
Lariam is available as scored, white, round tablets, containing 250 mg of mefloquine
hydrochloride in unit-dose packages of 25 (NDC 0004-0172-02). Imprint on tablets:
LARIAM 250 ROCHE
Tablets should be stored at 15° to 30°C (59° to 86°F).
ANIMAL TOXICOLOGY
Ocular lesions were observed in rats fed mefloquine daily for 2 years. All surviving rats given 30
mg/kg/day had ocular lesions in both eyes characterized by retinal degeneration, opacity of the
lens, and retinal edema. Similar but less severe lesions were observed in 80% of female and
22% of male rats fed 12.5 mg/kg/day for 2 years. At doses of 5 mg/kg/day, only corneal lesions
were observed. They occurred in 9% of rats studied.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 07/10/02
LARIAM
(mefloquine hydrochloride)
11
Rx only
Manufactured by:
F. HOFFMANN-LA ROCHE LTD
Basel, Switzerland
Distributed by:
27898311-0702
Revised: July 2002
Printed in USA
Copyright © 1999-2002 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
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
Renata Albrecht
10/3/02 02:31:28 PM
N 19-591/S020
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:29.358753
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19591s20lbl.pdf', 'application_number': 19591, 'submission_type': 'SUPPL ', 'submission_number': 20}
|
11,545
|
HLR 15aug2003
1
Rx only
LARIAM
brand of
mefloquine hydrochloride
TABLETS
DESCRIPTION
Lariam (mefloquine hydrochloride) is an antimalarial agent available as 250-mg tablets
of mefloquine hydrochloride (equivalent to 228.0 mg of the free base) for oral
administration.
Mefloquine hydrochloride is a 4-quinolinemethanol derivative with the specific chemical
name of (R*, S*)-(±)-α-2-piperidinyl-2,8-bis (trifluoromethyl)-4-quinolinemethanol
hydrochloride. It is a 2-aryl substituted chemical structural analog of quinine. The drug is
a white to almost white crystalline compound, slightly soluble in water.
Mefloquine hydrochloride has a calculated molecular weight of 414.78 and the following
structural formula:
The inactive ingredients are ammonium-calcium alginate, corn starch, crospovidone,
lactose, magnesium stearate, microcrystalline cellulose, poloxamer #331, and talc.
CLINICAL PHARMACOLOGY
Pharmacokinetics
Absorption
The absolute oral bioavailability of mefloquine has not been determined since an
intravenous formulation is not available. The bioavailability of the tablet formation
compared with an oral solution was over 85%. The presence of food significantly
enhances the rate and extent of absorption, leading to about a 40% increase in
bioavailability. In healthy volunteers, plasma concentrations peak 6 to 24 hours (median,
about 17 hours) after a single dose of Lariam. In a similar group of volunteers, maximum
plasma concentrations in µg/L are roughly equivalent to the dose in milligrams (for
example, a single 1000 mg dose produces a maximum concentration of about 1000 µg/L).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 15aug2003
LARIAM (mefloquine hydrochloride)
2
In healthy volunteers, a dose of 250 mg once weekly, produces maximum steady-state
plasma concentrations of 1000 to 2000 µg/L, which are reached after 7 to 10 weeks.
Distribution
In healthy adults, the apparent volume of distribution is approximately 20 L/kg,
indicating extensive tissue distribution. Mefloquine may accumulate in parasitized
erythrocytes. Experiments conducted in vitro with human blood using concentrations
between 50 and 1000 mg/mL showed a relatively constant erythrocyte-to-plasma
concentration ratio of about 2 to 1. The equilibrium reached in less than 30 minutes, was
found to be reversible. Protein binding is about 98%.
Mefloquine crosses the placenta. Excretion into breast milk appears to be minimal (see
PRECAUTIONS: Nursing Mothers).
Metabolism
Two metabolites have been identified in humans. The main metabolite, 2,8-bis-
trifluoromethyl-4-quinoline carboxylic acid, is inactive in Plasmodium falciparum. In a
study in healthy volunteers, the carboxylic acid metabolite appeared in plasma 2 to 4
hours after a single oral dose. Maximum plasma concentrations, which were about 50%
higher than those of mefloquine, were reached after 2 weeks. Thereafter, plasma levels of
the main metabolite and mefloquine declined at a similar rate. The area under the plasma
concentration-time curve (AUC) of the main metabolite was 3 to 5 times larger than that
of the parent drug. The other metabolite, an alcohol, was present in minute quantities
only.
Elimination
In several studies in healthy adults, the mean elimination half-life of mefloquine varied
between 2 and 4 weeks, with an average of about 3 weeks. Total clearance, which is
essentially hepatic, is in the order of 30 mL/min. There is evidence that mefloquine is
excreted mainly in the bile and feces. In volunteers, urinary excretion of unchanged
mefloquine and its main metabolite under steady-state condition accounted for about 9%
and 4% of the dose, respectively. Concentrations of other metabolites could not be
measured in the urine.
Pharmacokinetics in Special Clinical Situations
Children and the Elderly
No relevant age-related changes have been observed in the pharmacokinetics of
mefloquine. Therefore, the dosage for children has been extrapolated from the
recommended adult dose.
No pharmacokinetic studies have been performed in patients with renal insufficiency
since only a small proportion of the drug is eliminated renally. Mefloquine and its main
metabolite are not appreciably removed by hemodialysis. No special chemoprophylactic
dosage adjustments are indicated for dialysis patients to achieve concentrations in plasma
similar to those in healthy persons.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 15aug2003
LARIAM (mefloquine hydrochloride)
3
Although clearance of mefloquine may increase in late pregnancy, in general, pregnancy
has no clinically relevant effect on the pharmacokinetics of mefloquine.
The pharmacokinetics of mefloquine may be altered in acute malaria.
Pharmacokinetic differences have been observed between various ethnic populations. In
practice, however, these are of minor importance compared with host immune status and
sensitivity of the parasite.
During long-term prophylaxis (>2 years), the trough concentrations and the elimination
half-life of mefloquine were similar to those obtained in the same population after 6
months of drug use, which is when they reached steady state.
In vitro and in vivo studies showed no hemolysis associated with glucose-6-phosphate
dehydrogenase deficiency (see ANIMAL TOXICOLOGY).
Microbiology
Mechanism of Action
Mefloquine is an antimalarial agent which acts as a blood schizonticide. Its exact
mechanism of action is not known.
Activity In Vitro and In Vivo
Mefloquine is active against the erythrocytic stages of Plasmodium species (see
INDICATIONS AND USAGE). However, the drug has no effect against the
exoerythrocytic (hepatic) stages of the parasite. Mefloquine is effective against malaria
parasites resistant to chloroquine (see INDICATIONS AND USAGE).
Drug Resistance
Strains of P. falciparum with decreased susceptibility to mefloquine can be selected in
vitro or in vivo. Resistance of P. falciparum to mefloquine has been reported in areas of
multi-drug resistance in South East Asia. Increased incidences of resistance have also
been reported in other parts of the world.
Cross Resistance
Cross-resistance between mefloquine and halofantrine and cross-resistance between
mefloquine and quinine have been observed in some regions.
INDICATIONS AND USAGE
Treatment of Acute Malaria Infections
Lariam is indicated for the treatment of mild to moderate acute malaria caused by
mefloquine-susceptible strains of P. falciparum (both chloroquine-susceptible and
resistant strains) or by Plasmodium vivax. There are insufficient clinical data to document
the effect of mefloquine in malaria caused by P. ovale or P. malariae.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 15aug2003
LARIAM (mefloquine hydrochloride)
4
Note: Patients with acute P. vivax malaria, treated with Lariam, are at high risk of
relapse because Lariam does not eliminate exoerythrocytic (hepatic phase)
parasites. To avoid relapse, after initial treatment of the acute infection with
Lariam, patients should subsequently be treated with an 8-aminoquinoline
derivative (eg, primaquine).
Prevention of Malaria
Lariam is indicated for the prophylaxis of P. falciparum and P. vivax malaria infections,
including prophylaxis of chloroquine-resistant strains of P. falciparum.
CONTRAINDICATIONS
Use of Lariam is contraindicated in patients with a known hypersensitivity to mefloquine
or related compounds (eg, quinine and quinidine) or to any of the excipients contained in
the formulation. Lariam should not be prescribed for prophylaxis in patients with active
depression, a recent history of depression, generalized anxiety disorder, psychosis, or
schizophrenia or other major psychiatric disorders, or with a history of convulsions.
WARNINGS
In case of life-threatening, serious or overwhelming malaria infections due to P.
falciparum, patients should be treated with an intravenous antimalarial drug.
Following completion of intravenous treatment, Lariam may be given to complete
the course of therapy.
Data on the use of halofantrine subsequent to administration of Lariam suggest a
significant, potentially fatal prolongation of the QTc interval of the ECG. Therefore,
halofantrine must not be given simultaneously with or subsequent to Lariam. No
data are available on the use of Lariam after halofantrine (see PRECAUTIONS:
Drug Interactions).
Mefloquine may cause psychiatric symptoms in a number of patients, ranging from
anxiety, paranoia, and depression to hallucinations and psychotic behavior. On
occasions, these symptoms have been reported to continue long after mefloquine has
been stopped. Rare cases of suicidal ideation and suicide have been reported though
no relationship to drug administration has been confirmed. To minimize the
chances of these adverse events, mefloquine should not be taken for prophylaxis in
patients with active depression or with a recent history of depression, generalized
anxiety disorder, psychosis, or schizophrenia or other major psychiatric disorders.
Lariam should be used with caution in patients with a previous history of
depression.
During prophylactic use, if psychiatric symptoms such as acute anxiety, depression,
restlessness or confusion occur, these may be considered prodromal to a more
serious event. In these cases, the drug must be discontinued and an alternative
medication should be substituted.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 15aug2003
LARIAM (mefloquine hydrochloride)
5
Concomitant administration of Lariam and quinine or quinidine may produce
electrocardiographic abnormalities.
Concomitant administration of Lariam and quinine or chloroquine may increase
the risk of convulsions.
PRECAUTIONS
General
Hypersensitivity reactions ranging from mild cutaneous events to anaphylaxis cannot be
predicted.
In patients with epilepsy, Lariam may increase the risk of convulsions. The drug should
therefore be prescribed only for curative treatment in such patients and only if there are
compelling medical reasons for its use (see PRECAUTIONS: Drug Interactions).
Caution should be exercised with regard to activities requiring alertness and fine motor
coordination such as driving, piloting aircraft, operating machinery, and deep-sea diving,
as dizziness, a loss of balance, or other disorders of the central or peripheral nervous
system have been reported during and following the use of Lariam. These effects may
occur after therapy is discontinued due to the long half-life of the drug. Lariam should be
used with caution in patients with psychiatric disturbances because mefloquine use has
been associated with emotional disturbances (see ADVERSE REACTIONS).
In patients with impaired liver function the elimination of mefloquine may be prolonged,
leading to higher plasma levels.
This drug has been administered for longer than 1 year. If the drug is to be administered
for a prolonged period, periodic evaluations including liver function tests should be
performed. Although retinal abnormalities seen in humans with long-term chloroquine
use have not been observed with mefloquine use, long-term feeding of mefloquine to rats
resulted in dose-related ocular lesions (retinal degeneration, retinal edema and lenticular
opacity at 12.5 mg/kg/day and higher) (see ANIMAL TOXICOLOGY). Therefore,
periodic ophthalmic examinations are recommended.
Parenteral studies in animals show that mefloquine, a myocardial depressant, possesses
20% of the antifibrillatory action of quinidine and produces 50% of the increase in the PR
interval reported with quinine. The effect of mefloquine on the compromised
cardiovascular system has not been evaluated. However, transitory and clinically silent
ECG alterations have been reported during the use of mefloquine. Alterations included
sinus bradycardia, sinus arrhythmia, first degree AV-block, prolongation of the QTc
interval and abnormal T waves (see also cardiovascular effects under PRECAUTIONS:
Drug Interactions and ADVERSE REACTIONS). The benefits of Lariam therapy
should be weighed against the possibility of adverse effects in patients with cardiac
disease.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 15aug2003
LARIAM (mefloquine hydrochloride)
6
Laboratory Tests
Periodic evaluation of hepatic function should be performed during prolonged
prophylaxis.
Information for Patients
Medication Guide: As required by law, a Lariam Medication Guide is supplied to patients
when Lariam is dispensed. Patients should be instructed to read the MedGuide when
Lariam is received. The complete text of the MedGuide is reprinted at the end of this
document.
Patients should be advised:
• that malaria can be a life-threatening infection in the traveler;
• that Lariam is being prescribed to help prevent or treat this serious infection;
• 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 Lariam should be taken 1 week prior
to arrival in an endemic area;
• that if the patients experience psychiatric symptoms such as acute anxiety,
depression, restlessness or confusion, these may be considered prodromal to a more
serious event. In these cases, the drug must be discontinued and an alternative
medication should be substituted;
• 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 to inform their physician that they may have been exposed to
malaria.
Drug Interactions
Drug-drug interactions with Lariam have not been explored in detail. There is one report
of cardiopulmonary arrest, with full recovery, in a patient who was taking a beta blocker
(propranolol) (see PRECAUTIONS: General). The effects of mefloquine on the
compromised cardiovascular system have not been evaluated. The benefits of Lariam
therapy should be weighed against the possibility of adverse effects in patients with
cardiac disease.
Because of the danger of a potentially fatal prolongation of the QTc interval, halofantrine
must not be given simultaneously with or subsequent to Lariam (see WARNINGS).
Concomitant administration of Lariam and other related compounds (eg, quinine,
quinidine and chloroquine) may produce electrocardiographic abnormalities and increase
the risk of convulsions (see WARNINGS). If these drugs are to be used in the initial
treatment of severe malaria, Lariam administration should be delayed at least 12 hours
after the last dose. There is evidence that the use of halofantrine after mefloquine causes a
significant lengthening of the QTc interval. Clinically significant QTc prolongation has
not been found with mefloquine alone.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 15aug2003
LARIAM (mefloquine hydrochloride)
7
This appears to be the only clinically relevant interaction of this kind with Lariam,
although theoretically, coadministration of other drugs known to alter cardiac conduction
(eg, anti-arrhythmic or beta-adrenergic blocking agents, calcium channel blockers,
antihistamines or H1-blocking agents, tricyclic antidepressants and phenothiazines) might
also contribute to a prolongation of the QTc interval. There are no data that conclusively
establish whether the concomitant administration of mefloquine and the above listed
agents has an effect on cardiac function.
In patients taking an anticonvulsant (eg, valproic acid, carbamazepine, phenobarbital or
phenytoin), the concomitant use of Lariam may reduce seizure control by lowering the
plasma levels of the anticonvulsant. Therefore, patients concurrently taking antiseizure
medication and Lariam should have the blood level of their antiseizure medication
monitored and the dosage adjusted appropriately (see PRECAUTIONS: General).
When Lariam is taken concurrently with oral live typhoid vaccines, attenuation of
immunization cannot be excluded. Vaccinations with attenuated live bacteria should
therefore be completed at least 3 days before the first dose of Lariam.
No other drug interactions are known. Nevertheless, the effects of Lariam on travelers
receiving comedication, particularly diabetics or patients using anticoagulants, should be
checked before departure.
In clinical trials, the concomitant administration of sulfadoxine and pyrimethamine did
not alter the adverse reaction profile.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
The carcinogenic potential of mefloquine was studied in rats and mice in 2-year feeding
studies at doses of up to 30 mg/kg/day. No treatment-related increases in tumors of any
type were noted.
Mutagenesis
The mutagenic potential of mefloquine was studied in a variety of assay systems
including: Ames test, a host-mediated assay in mice, fluctuation tests and a mouse
micronucleus assay. Several of these assays were performed with and without prior
metabolic activation. In no instance was evidence obtained for the mutagenicity of
mefloquine.
Impairment of Fertility
Fertility studies in rats at doses of 5, 20, and 50 mg/kg/day of mefloquine have
demonstrated adverse effects on fertility in the male at the high dose of 50 mg/kg/day,
and in the female at doses of 20 and 50 mg/kg/day. Histopathological lesions were noted
in the epididymides from male rats at doses of 20 and 50 mg/kg/day. Administration of
250 mg/week of mefloquine (base) in adult males for 22 weeks failed to reveal any
deleterious effects on human spermatozoa.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 15aug2003
LARIAM (mefloquine hydrochloride)
8
Pregnancy
Teratogenic Effects
Pregnancy Category C. Mefloquine has been demonstrated to be teratogenic in rats and
mice at a dose of 100 mg/kg/day. In rabbits, a high dose of 160 mg/kg/day was
embryotoxic and teratogenic, and a dose of 80 mg/kg/day was teratogenic but not
embryotoxic. There are no adequate and well-controlled studies in pregnant women.
However, clinical experience with Lariam has not revealed an embryotoxic or teratogenic
effect. Mefloquine 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. Women of
childbearing potential should also be advised to practice contraception during malaria
prophylaxis with Lariam and for up to 3 months thereafter. However, in the case of
unplanned pregnancy, malaria chemoprophylaxis with Lariam is not considered an
indication for pregnancy termination.
Nursing Mothers
Mefloquine is excreted in human milk in small amounts, the activity of which is
unknown. Based on a study in a few subjects, low concentrations (3% to 4%) of
mefloquine were excreted in human milk following a dose equivalent to 250 mg of the
free base. Because of the potential for serious adverse reactions in nursing infants from
mefloquine, a decision should be made whether to discontinue the drug, taking into
account the importance of the drug to the mother.
Pediatric Use
Use of Lariam to treat acute, uncomplicated P. falciparum malaria in pediatric patients is
supported by evidence from adequate and well-controlled studies of Lariam in adults with
additional data from published open-label and comparative trials using Lariam to treat
malaria caused by P. falciparum in patients younger than 16 years of age. The safety and
effectiveness of Lariam for the treatment of malaria in pediatric patients below the age of
6 months have not been established.
In several studies, the administration of Lariam for the treatment of malaria was
associated with early vomiting in pediatric patients. Early vomiting was cited in some
reports as a possible cause of treatment failure. If a second dose is not tolerated, the
patient should be monitored closely and alternative malaria treatment considered if
improvement is not observed within a reasonable period of time (see DOSAGE AND
ADMINISTRATION).
Geriatric Use
Clinical studies of Lariam 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. Since electrocardiographic abnormalities have been observed in
individuals treated with Lariam (see PRECAUTIONS) and underlying cardiac disease is
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 15aug2003
LARIAM (mefloquine hydrochloride)
9
more prevalent in elderly than in younger patients, the benefits of Lariam therapy should
be weighed against the possibility of adverse cardiac effects in elderly patients.
ADVERSE REACTIONS
Clinical
At the doses used for treatment of acute malaria infections, the symptoms possibly
attributable to drug administration cannot be distinguished from those symptoms usually
attributable to the disease itself.
Among subjects who received mefloquine for prophylaxis of malaria, the most frequently
observed adverse experience was vomiting (3%). Dizziness, syncope, extrasystoles and
other complaints affecting less than 1% were also reported.
Among subjects who received mefloquine for treatment, the most frequently observed
adverse experiences included: dizziness, myalgia, nausea, fever, headache, vomiting,
chills, diarrhea, skin rash, abdominal pain, fatigue, loss of appetite, and tinnitus. Those
side effects occurring in less than 1% included bradycardia, hair loss, emotional
problems, pruritus, asthenia, transient emotional disturbances and telogen effluvium (loss
of resting hair). Seizures have also been reported.
Two serious adverse reactions were cardiopulmonary arrest in one patient shortly after
ingesting a single prophylactic dose of mefloquine while concomitantly using propranolol
(see PRECAUTIONS: Drug Interactions), and encephalopathy of unknown etiology
during prophylactic mefloquine administration. The relationship of encephalopathy to
drug administration could not be clearly established.
Postmarketing
Postmarketing surveillance indicates that the same kind of adverse experiences are
reported during prophylaxis, as well as acute treatment.
The most frequently reported adverse events are nausea, vomiting, loose stools or
diarrhea, abdominal pain, dizziness or vertigo, loss of balance, and neuropsychiatric
events such as headache, somnolence, and sleep disorders (insomnia, abnormal dreams).
These are usually mild and may decrease despite continued use.
Occasionally, more severe neuropsychiatric disorders have been reported such as:
sensory and motor neuropathies (including paresthesia, tremor and ataxia), convulsions,
agitation or restlessness, anxiety, depression, mood changes, panic attacks, forgetfulness,
confusion,
hallucinations,
aggression,
psychotic
or
paranoid
reactions
and
encephalopathy. Rare cases of suicidal ideation and suicide have been reported though no
relationship to drug administration has been confirmed.
Other infrequent adverse events include:
Cardiovascular Disorders: circulatory disturbances (hypotension, hypertension, flushing,
syncope), chest pain, tachycardia or palpitation, bradycardia, irregular pulse,
extrasystoles, A-V block, and other transient cardiac conduction alterations
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 15aug2003
LARIAM (mefloquine hydrochloride)
10
Skin Disorders: rash, exanthema, erythema, urticaria, pruritus, edema, hair loss, erythema
multiforme, and Stevens-Johnson syndrome
Musculoskeletal Disorders: muscle weakness, muscle cramps, myalgia, and arthralgia
Other Symptoms: visual disturbances, vestibular disorders including tinnitus and hearing
impairment, dyspnea, asthenia, malaise, fatigue, fever, sweating, chills, dyspepsia and
loss of appetite
Laboratory
The most frequently observed laboratory alterations which could be possibly attributable
to drug administration were decreased hematocrit, transient elevation of transaminases,
leukopenia and thrombocytopenia. These alterations were observed in patients with acute
malaria who received treatment doses of the drug and were attributed to the disease itself.
During prophylactic administration of mefloquine to indigenous populations in malaria-
endemic areas, the following occasional alterations in laboratory values were observed:
transient elevation of transaminases, leukocytosis or thrombocytopenia.
Because of the long half-life of mefloquine, adverse reactions to Lariam may occur or
persist up to several weeks after the last dose.
OVERDOSAGE
In cases of overdosage with Lariam, the symptoms mentioned under ADVERSE
REACTIONS may be more pronounced. The following procedure is recommended in
case of overdosage: Induce vomiting or perform gastric lavage, as appropriate. Monitor
cardiac function (if possible by ECG) and neuropsychiatric status for at least 24 hours.
Provide symptomatic and intensive supportive treatment as required, particularly for
cardiovascular disturbances.
DOSAGE AND ADMINISTRATION (see INDICATIONS AND USAGE)
Adult Patients
Treatment of mild to moderate malaria in adults caused by P. vivax or
mefloquine-susceptible strains of P. falciparum
Five tablets (1250 mg) mefloquine hydrochloride to be given as a single oral dose. The
drug should not be taken on an empty stomach and should be administered with at least 8
oz (240 mL) of water.
If a full-treatment course with Lariam does not lead to improvement within 48 to 72
hours, Lariam should not be used for retreatment. An alternative therapy should be used.
Similarly, if previous prophylaxis with mefloquine has failed, Lariam should not be used
for curative treatment.
Note: Patients with acute P. vivax malaria, treated with Lariam, are at high risk of
relapse because Lariam does not eliminate exoerythrocytic (hepatic phase)
parasites. To avoid relapse after initial treatment of the acute infection with
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 15aug2003
LARIAM (mefloquine hydrochloride)
11
Lariam, patients should subsequently be treated with an 8-aminoquinoline
derivative (eg, primaquine).
Malaria Prophylaxis
One 250 mg Lariam tablet once weekly.
Prophylactic drug administration should begin 1 week before arrival in an endemic area.
Subsequent weekly doses should be taken regularly, always on the same day of each
week, preferably after the main meal. To reduce the risk of malaria after leaving an
endemic area, prophylaxis must be continued for 4 additional weeks to ensure
suppressive blood levels of the drug when merozoites emerge from the liver. Tablets
should not be taken on an empty stomach and should be administered with at least 8 oz
(240 mL) of water.
In certain cases, eg, when a traveler is taking other medication, it may be desirable to
start prophylaxis 2 to 3 weeks prior to departure, in order to ensure that the combination
of drugs is well tolerated (see PRECAUTIONS: Drug Interactions).
When prophylaxis with Lariam fails, physicians should carefully evaluate which
antimalarial to use for therapy.
Pediatric Patients
Treatment of mild to moderate malaria in pediatric patients caused by
mefloquine-susceptible strains of P. falciparum
Twenty (20) to 25 mg/kg body weight. Splitting the total therapeutic dose into 2 doses
taken 6 to 8 hours apart may reduce the occurrence or severity of adverse effects.
Experience with Lariam in infants less than 3 months old or weighing less than 5 kg is
limited. The drug should not be taken on an empty stomach and should be administered
with ample water. The tablets may be crushed and suspended in a small amount of water,
milk or other beverage for administration to small children and other persons unable to
swallow them whole.
If a full-treatment course with Lariam does not lead to improvement within 48 to 72
hours, Lariam should not be used for retreatment. An alternative therapy should be used.
Similarly, if previous prophylaxis with mefloquine has failed, Lariam should not be used
for curative treatment.
In pediatric patients, the administration of Lariam for the treatment of malaria has been
associated with early vomiting. In some cases, early vomiting has been cited as a possible
cause of treatment failure (see PRECAUTIONS). If a significant loss of drug product is
observed or suspected because of vomiting, a second full dose of Lariam should be
administered to patients who vomit less than 30 minutes after receiving the drug. If
vomiting occurs 30 to 60 minutes after a dose, an additional half-dose should be given. If
vomiting recurs, the patient should be monitored closely and alternative malaria treatment
considered if improvement is not observed within a reasonable period of time.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 15aug2003
LARIAM (mefloquine hydrochloride)
12
The safety and effectiveness of Lariam to treat malaria in pediatric patients below the age
of 6 months have not been established.
Malaria Prophylaxis
The following doses have been extrapolated from the recommended adult dose. Neither
the pharmacokinetics, nor the clinical efficacy of these doses have been determined in
children owing to the difficulty of acquiring this information in pediatric subjects. The
recommended prophylactic dose of Lariam is approximately 5 mg/kg body weight once
weekly. One 250 mg Lariam tablet should be taken once weekly in pediatric patients
weighing over 45 kg. In pediatric patients weighing less than 45 kg, the weekly dose
decreases in proportion to body weight:
30 to 45 kg:
3/4 tablet
20 to 30 kg:
1/2 tablet
10 to 20 kg:
1/4 tablet
5 to 10 kg:
1/8 tablet*
*Approximate tablet fraction based on a dosage of 5 mg/kg body weight. Exact doses for
children weighing less than 10 kg may best be prepared and dispensed by pharmacists.
Experience with Lariam in infants less than 3 months old or weighing less than 5 kg is
limited.
HOW SUPPLIED
Lariam is available as scored, white, round tablets, containing 250 mg of mefloquine
hydrochloride in unit-dose packages of 25 (NDC 0004-0172-02). Imprint on tablets:
LARIAM 250 ROCHE
Tablets should be stored at 25°C (77°F); excursions permitted to 15° to 30°C (59° to
86°F).
ANIMAL TOXICOLOGY
Ocular lesions were observed in rats fed mefloquine daily for 2 years. All surviving rats
given 30 mg/kg/day had ocular lesions in both eyes characterized by retinal degeneration,
opacity of the lens, and retinal edema. Similar but less severe lesions were observed in
80% of female and 22% of male rats fed 12.5 mg/kg/day for 2 years. At doses of 5
mg/kg/day, only corneal lesions were observed. They occurred in 9% of rats studied.
Revised: August 2003
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 15aug2003
LARIAM (mefloquine hydrochloride)
13
MEDICATION GUIDE
This Medication Guide is intended only for travelers who are taking Lariam to
prevent malaria. The information may not apply to patients who are sick with malaria
and who are taking Lariam to treat malaria.
An information wallet card is provided at the end of this Medication Guide. Cut it out and
carry it with you when you are taking Lariam.
This Medication Guide was revised in August 2003. Please read it before you start taking
Lariam and each time you get a refill. There may be new information. This Medication
Guide does not take the place of talking with your prescriber (doctor or other health care
provider) about Lariam and malaria prevention. Only you and your prescriber can decide
if Lariam is right for you. If you cannot take Lariam, you may be able to take a different
medicine to prevent malaria.
What is the most important information I should know about Lariam?
1. Take Lariam exactly as prescribed to prevent malaria.
Malaria is an infection that can cause death and is spread to humans through mosquito
bites. If you travel to parts of the world where the mosquitoes carry the malaria
parasite, you must take a malaria prevention medicine. Lariam is one of a small
number of medications approved to prevent and to treat malaria. If taken correctly,
Lariam is effective at preventing malaria but, like all medications, it may produce
side effects in some patients.
2. Lariam can rarely cause serious mental problems in some patients.
The most frequently reported side effects with Lariam, such as nausea, difficulty
sleeping, and bad dreams are usually mild and do not cause people to stop taking the
medicine. However, people taking Lariam occasionally experience severe anxiety,
feelings that people are against them, hallucinations (seeing or hearing things that are
not there, for example), depression, unusual behavior, or feeling disoriented. There
have been reports that in some patients these side effects continue after Lariam is
stopped. Some patients taking Lariam think about killing themselves, and there have
been rare reports of suicides. It is not known whether Lariam was responsible for
these suicides.
3. You need to take malaria prevention medicine before you travel to a malaria
area, while you are in a malaria area, and after you return from a malaria area.
Medicines approved in the United States for malaria prevention include Lariam,
doxycycline, atovaquone/proguanil, hydroxychloroquine, and chloroquine. Not all of
these drugs work equally as well in all areas of the world where there is malaria. The
chloroquines, for example, do not work in areas where the malaria parasite has
developed resistance to chloroquine. Lariam may be effective against malaria that is
resistant to chloroquine or other drugs. All drugs to treat malaria have side effects that
are different for each one. For example, some may make your skin more sensitive to
sunlight (Lariam does not do this). However, if you use Lariam to prevent malaria
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 15aug2003
LARIAM (mefloquine hydrochloride)
14
and you develop a sudden onset of anxiety, depression, restlessness, confusion
(possible signs of more serious mental problems), or you develop other serious side
effects, contact a doctor or other health care provider. It may be necessary to stop
taking Lariam and use another malaria prevention medicine instead. If you can’t get
another medicine, leave the malaria area. However, be aware that leaving the malaria
area may not protect you from getting malaria. You still need to take a malaria
prevention medicine.
Who should not take Lariam?
Do not take Lariam to prevent malaria if you
• have depression or had depression recently
• have had recent mental illness or problems, including anxiety disorder,
schizophrenia (a severe type of mental illness), or psychosis (losing touch with
reality)
• have or had seizures (epilepsy or convulsions)
• are allergic to quinine or quinidine (medicines related to Lariam)
Tell your prescriber about all your medical conditions. Lariam may not be right for
you if you have certain conditions, especially the ones listed below:
• Heart disease. Lariam may not be right for you.
• Pregnancy. Tell your prescriber if you are pregnant or plan to become pregnant. It is
dangerous for the mother and for the unborn baby (fetus) to get malaria during
pregnancy. Therefore, ask your prescriber if you should take Lariam or another
medicine to prevent malaria while you are pregnant.
• Breast feeding. Lariam can pass through your milk and may harm the baby.
Therefore, ask your prescriber whether you will need to stop breast feeding or use
another medicine.
• Liver problems.
Tell your prescriber about all the medicines you take, including prescription and
non-prescription medicines, vitamins, and herbal supplements. Some medicines may
give you a higher chance of having serious side effects from Lariam.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 15aug2003
LARIAM (mefloquine hydrochloride)
15
How should I take Lariam?
Take Lariam exactly as prescribed. If you are an adult or pediatric patient weighing
45 kg (99 pounds) or less, your prescriber will tell you the correct dose based on
your weight.
To prevent malaria
• For adults and pediatric patients weighing over 45 kg, take 1 tablet of Lariam at least
1 week before you travel to a malaria area (or 2 to 3 weeks before you travel to a
malaria area, if instructed by your prescriber). This starts the prevention and also
helps you see how Lariam affects you and the other medicines you take. Take 1
Lariam tablet once a week, on the same day each week, while in a malaria area.
• Continue taking Lariam for 4 weeks after returning from a malaria area. If you
cannot continue taking Lariam due to side effects or for other reasons, contact your
prescriber.
• Take Lariam just after a meal and with at least 1 cup (8 ounces) of water.
• For children, Lariam can be given with water or crushed and mixed with water or
sugar water. The prescriber will tell you the correct dose for children based on the
child’s weight.
• If you are told by a doctor or other health care provider to stop taking Lariam due to
side effects or for other reasons, it will be necessary to take another malaria medicine.
You must take malaria prevention medicine before you travel to a malaria area,
while you are in a malaria area, and after you return from a malaria area. If you
don’t have access to a doctor or other health care provider or to another
medicine besides Lariam and have to stop taking it, leave the malaria area.
However, be aware that leaving the malaria area may not protect you from
getting malaria. You still need to take a malaria prevention medicine.
What should I avoid while taking Lariam?
• Halofantrine (marketed under various brand names), a medicine used to treat
malaria. Taking both of these medicines together can cause serious heart problems
that can cause death.
• Do not become pregnant. Women should use effective birth control while taking
Lariam.
• Quinine, quinidine, or chloroquine (other medicines used to treat malaria).
Taking these medicines with Lariam could cause changes in your heart rate or
increase the risk of seizures.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 15aug2003
LARIAM (mefloquine hydrochloride)
16
In addition:
• Be careful driving or in other activities needing alertness and careful movements
(fine motor coordination). Lariam can cause dizziness or loss of balance, even after
you stop taking it.
• Be aware that certain vaccines may not work if given while you are taking
Lariam. Your prescriber may want you to finish taking your vaccines at least 3 days
before starting Lariam.
What are the possible side effects of Lariam?
Lariam, like all medicines, may cause side effects in some patients. The most frequently
reported side effects with Lariam when used for prevention of malaria include nausea,
vomiting, diarrhea, dizziness, difficulty sleeping, and bad dreams. These are usually mild
and do not cause people to stop taking the medicine.
Lariam may cause serious mental problems in some patients. (See “What is the most
important information I should know about Lariam?”).
Lariam may affect your liver and your eyes if you take it for a long time. Your prescriber
will tell you if you should have your eyes and liver checked while taking Lariam.
What else should I know about preventing malaria?
• Find out whether you need malaria prevention. Before you travel, talk with your
prescriber about your travel plans to determine whether you need to take medicine to
prevent malaria. Even in those countries where malaria is present, there may be areas
of the country that are free of malaria. In general, malaria is more common in rural
(country) areas than in big cities, and it is more common during rainy seasons, when
mosquitoes are most common. You can get information about the areas of the world
where malaria occurs from the Centers for Disease Control and Prevention (CDC)
and from local authorities in the countries you visit. If possible, plan your travel to
reduce the risk of malaria.
• Take medicine to prevent malaria infection. Without malaria prevention medicine,
you have a higher risk of getting malaria. Malaria starts with flu-like symptoms, such
as chills, fever, muscle pains, and headaches. However, malaria can make you very
sick or cause death if you don’t seek medical help immediately. These symptoms may
disappear for a while, and you may think you are well. But, the symptoms return later
and then it may be too late for successful treatment.
Malaria can cause confusion, coma, and seizures. It can cause kidney failure,
breathing problems, and severe damage to red blood cells. However, malaria can
be easily diagnosed with a blood test, and if caught in time, can be effectively
treated.
If you get flu-like symptoms (chills, fever, muscle pains, or headaches) after
you return from a malaria area, get medical help right away and tell your
prescriber that you may have been exposed to malaria.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 15aug2003
LARIAM (mefloquine hydrochloride)
17
People who have lived for many years in areas with malaria may have some
immunity to malaria (they do not get it as easily) and may not take malaria
prevention medicine. This does not mean that you don’t need to take malaria
prevention medicine.
• Protect against mosquito bites. Medicines do not always completely prevent your
catching malaria from mosquito bites. So protect yourself very well against
mosquitoes. Cover your skin with long sleeves and long pants, and use mosquito
repellent and bednets while in malaria areas. If you are out in the bush, you may want
to pre-wash your clothes with permethrin. This is a mosquito repellent that may be
effective for weeks after use. Ask your prescriber for other ways to protect yourself.
General information about the safe and effective use of Lariam.
Medicines are sometimes prescribed for conditions not listed in Medication Guides. If
you have any concerns about Lariam, ask your prescriber. This Medication Guide
contains certain important information for travelers visiting areas with malaria. Your
prescriber or pharmacist can give you information about Lariam that was written for
health care professionals. Do not use Lariam for a condition for which it was not
prescribed. Do not share Lariam with other people.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: August 2003
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 15aug2003
LARIAM (mefloquine hydrochloride)
18
Information wallet card to carry when you are taking Lariam.
Lariam (mefloquine hydrochloride) Tablets
You need to take malaria prevention
medicine before you travel to a malaria
area, while you are in a malaria area,
and after you return from a malaria
area.
If taken correctly, Lariam is effective
at preventing malaria but, like all
medications, it may produce side
effects in some patients.
If you use Lariam to prevent malaria
and you develop a sudden onset of
anxiety, depression, restlessness,
confusion (possible signs of more
serious mental problems), or you
develop other serious side effects,
contact a doctor or other health care
provider. It may be necessary to stop
taking Lariam and use another malaria
prevention medicine instead.
Revised: August 2003
Other medicines approved in the
United States for malaria prevention
include: doxycycline,
atovaquone/proguanil,
hydroxychloroquine, and
chloroquine. Not all malaria
medicines work equally well in
malaria areas. The chloroquines, for
example, do not work in many parts
of the world. If you can’t get another
medicine, leave the malaria area.
However, be aware that leaving the
malaria area may not protect you
from getting malaria. You still need
to take a malaria prevention
medicine.
Please read the Medication Guide for
additional information on Lariam.
Manufactured by:
F. HOFFMANN-LA ROCHE LTD
Basel, Switzerland
Distributed by:
27898582
Copyright 1999-2003 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
HLR 15aug2003
1
Rx only
MEDICATION GUIDE
LARIAM (LAH-ree-am)
(mefloquine hydrochloride) Tablets
to Prevent Malaria
This Medication Guide is intended only for travelers who are taking Lariam to
prevent malaria. The information may not apply to patients who are sick with malaria
and who are taking Lariam to treat malaria.
An information wallet card is provided at the end of this Medication Guide. Cut it out and
carry it with you when you are taking Lariam.
This Medication Guide was revised in August 2003. Please read it before you start taking
Lariam and each time you get a refill. There may be new information. This Medication
Guide does not take the place of talking with your prescriber (doctor or other health care
provider) about Lariam and malaria prevention. Only you and your prescriber can decide
if Lariam is right for you. If you cannot take Lariam, you may be able to take a different
medicine to prevent malaria.
What is the most important information I should know about Lariam?
1. Take Lariam exactly as prescribed to prevent malaria.
Malaria is an infection that can cause death and is spread to humans through mosquito
bites. If you travel to parts of the world where the mosquitoes carry the malaria
parasite, you must take a malaria prevention medicine. Lariam is one of a small
number of medications approved to prevent and to treat malaria. If taken correctly,
Lariam is effective at preventing malaria but, like all medications, it may produce
side effects in some patients.
2. Lariam can rarely cause serious mental problems in some patients.
The most frequently reported side effects with Lariam, such as nausea, difficulty
sleeping, and bad dreams are usually mild and do not cause people to stop taking the
medicine. However, people taking Lariam occasionally experience severe anxiety,
feelings that people are against them, hallucinations (seeing or hearing things that are
not there, for example), depression, unusual behavior, or feeling disoriented. There
have been reports that in some patients these side effects continue after Lariam is
stopped. Some patients taking Lariam think about killing themselves, and there have
been rare reports of suicides. It is not known whether Lariam was responsible for
these suicides.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 15aug2003
LARIAM (mefloquine hydrochloride)
2
3. You need to take malaria prevention medicine before you travel to a malaria
area, while you are in a malaria area, and after you return from a malaria area.
Medicines approved in the United States for malaria prevention include Lariam,
doxycycline, atovaquone/proguanil, hydroxychloroquine, and chloroquine. Not all of
these drugs work equally as well in all areas of the world where there is malaria. The
chloroquines, for example, do not work in areas where the malaria parasite has
developed resistance to chloroquine. Lariam may be effective against malaria that is
resistant to chloroquine or other drugs. All drugs to treat malaria have side effects that
are different for each one. For example, some may make your skin more sensitive to
sunlight (Lariam does not do this). However, if you use Lariam to prevent malaria
and you develop a sudden onset of anxiety, depression, restlessness, confusion
(possible signs of more serious mental problems), or you develop other serious side
effects, contact a doctor or other health care provider. It may be necessary to stop
taking Lariam and use another malaria prevention medicine instead. If you can’t get
another medicine, leave the malaria area. However, be aware that leaving the malaria
area may not protect you from getting malaria. You still need to take a malaria
prevention medicine.
Who should not take Lariam?
Do not take Lariam to prevent malaria if you
• have depression or had depression recently
• have had recent mental illness or problems, including anxiety disorder,
schizophrenia (a severe type of mental illness), or psychosis (losing touch with
reality)
• have or had seizures (epilepsy or convulsions)
• are allergic to quinine or quinidine (medicines related to Lariam)
Tell your prescriber about all your medical conditions. Lariam may not be right for
you if you have certain conditions, especially the ones listed below:
• Heart disease. Lariam may not be right for you.
• Pregnancy. Tell your prescriber if you are pregnant or plan to become pregnant. It is
dangerous for the mother and for the unborn baby (fetus) to get malaria during
pregnancy. Therefore, ask your prescriber if you should take Lariam or another
medicine to prevent malaria while you are pregnant.
• Breast feeding. Lariam can pass through your milk and may harm the baby.
Therefore, ask your prescriber whether you will need to stop breast feeding or use
another medicine.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 15aug2003
LARIAM (mefloquine hydrochloride)
3
• Liver problems.
Tell your prescriber about all the medicines you take, including prescription and
non-prescription medicines, vitamins, and herbal supplements. Some medicines may
give you a higher chance of having serious side effects from Lariam.
How should I take Lariam?
Take Lariam exactly as prescribed. If you are an adult or pediatric patient weighing
45 kg (99 pounds) or less, your prescriber will tell you the correct dose based on
your weight.
To prevent malaria
• For adults and pediatric patients weighing over 45 kg, take 1 tablet of Lariam at least
1 week before you travel to a malaria area (or 2 to 3 weeks before you travel to a
malaria area, if instructed by your prescriber). This starts the prevention and also
helps you see how Lariam affects you and the other medicines you take. Take 1
Lariam tablet once a week, on the same day each week, while in a malaria area.
• Continue taking Lariam for 4 weeks after returning from a malaria area. If you
cannot continue taking Lariam due to side effects or for other reasons, contact your
prescriber.
• Take Lariam just after a meal and with at least 1 cup (8 ounces) of water.
• For children, Lariam can be given with water or crushed and mixed with water or
sugar water. The prescriber will tell you the correct dose for children based on the
child’s weight.
• If you are told by a doctor or other health care provider to stop taking Lariam due to
side effects or for other reasons, it will be necessary to take another malaria medicine.
You must take malaria prevention medicine before you travel to a malaria area,
while you are in a malaria area, and after you return from a malaria area. If you
don’t have access to a doctor or other health care provider or to another
medicine besides Lariam and have to stop taking it, leave the malaria area.
However, be aware that leaving the malaria area may not protect you from
getting malaria. You still need to take a malaria prevention medicine.
What should I avoid while taking Lariam?
• Halofantrine (marketed under various brand names), a medicine used to treat
malaria. Taking both of these medicines together can cause serious heart problems
that can cause death.
• Do not become pregnant. Women should use effective birth control while taking
Lariam.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 15aug2003
LARIAM (mefloquine hydrochloride)
4
• Quinine, quinidine, or chloroquine (other medicines used to treat malaria).
Taking these medicines with Lariam could cause changes in your heart rate or
increase the risk of seizures.
In addition:
• Be careful driving or in other activities needing alertness and careful movements
(fine motor coordination). Lariam can cause dizziness or loss of balance, even after
you stop taking it.
• Be aware that certain vaccines may not work if given while you are taking
Lariam. Your prescriber may want you to finish taking your vaccines at least 3 days
before starting Lariam.
What are the possible side effects of Lariam?
Lariam, like all medicines, may cause side effects in some patients. The most frequently
reported side effects with Lariam when used for prevention of malaria include nausea,
vomiting, diarrhea, dizziness, difficulty sleeping, and bad dreams. These are usually mild
and do not cause people to stop taking the medicine.
Lariam may cause serious mental problems in some patients. (See “What is the most
important information I should know about Lariam?”).
Lariam may affect your liver and your eyes if you take it for a long time. Your prescriber
will tell you if you should have your eyes and liver checked while taking Lariam.
What else should I know about preventing malaria?
• Find out whether you need malaria prevention. Before you travel, talk with your
prescriber about your travel plans to determine whether you need to take medicine to
prevent malaria. Even in those countries where malaria is present, there may be areas
of the country that are free of malaria. In general, malaria is more common in rural
(country) areas than in big cities, and it is more common during rainy seasons, when
mosquitoes are most common. You can get information about the areas of the world
where malaria occurs from the Centers for Disease Control and Prevention (CDC)
and from local authorities in the countries you visit. If possible, plan your travel to
reduce the risk of malaria.
• Take medicine to prevent malaria infection. Without malaria prevention medicine,
you have a higher risk of getting malaria. Malaria starts with flu-like symptoms, such
as chills, fever, muscle pains, and headaches. However, malaria can make you very
sick or cause death if you don’t seek medical help immediately. These symptoms may
disappear for a while, and you may think you are well. But, the symptoms return later
and then it may be too late for successful treatment.
Malaria can cause confusion, coma, and seizures. It can cause kidney failure,
breathing problems, and severe damage to red blood cells. However, malaria can
be easily diagnosed with a blood test, and if caught in time, can be effectively
treated.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HLR 15aug2003
LARIAM (mefloquine hydrochloride)
5
If you get flu-like symptoms (chills, fever, muscle pains, or headaches) after
you return from a malaria area, get medical help right away and tell your
prescriber that you may have been exposed to malaria.
People who have lived for many years in areas with malaria may have some
immunity to malaria (they do not get it as easily) and may not take malaria
prevention medicine. This does not mean that you don’t need to take malaria
prevention medicine.
• Protect against mosquito bites. Medicines do not always completely prevent your
catching malaria from mosquito bites. So protect yourself very well against
mosquitoes. Cover your skin with long sleeves and long pants, and use mosquito
repellent and bednets while in malaria areas. If you are out in the bush, you may want
to pre-wash your clothes with permethrin. This is a mosquito repellent that may be
effective for weeks after use. Ask your prescriber for other ways to protect yourself.
General information about the safe and effective use of Lariam.
Medicines are sometimes prescribed for conditions not listed in Medication Guides. If
you have any concerns about Lariam, ask your prescriber. This Medication Guide
contains certain important information for travelers visiting areas with malaria. Your
prescriber or pharmacist can give you information about Lariam that was written for
health care professionals. Do not use Lariam for a condition for which it was not
prescribed. Do not share Lariam with other people.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Manufactured by:
F. HOFFMANN-LA ROCHE LTD
Basel, Switzerland
Distributed by:
27898583
Revised: August 2003
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
HLR 15aug2003
LARIAM (mefloquine hydrochloride)
6
Information wallet card to carry when you are taking Lariam.
Lariam (mefloquine hydrochloride) Tablets
You need to take malaria prevention
medicine before you travel to a malaria
area, while you are in a malaria area,
and after you return from a malaria
area.
If taken correctly, Lariam is effective
at preventing malaria but, like all
medications, it may produce side
effects in some patients.
If you use Lariam to prevent malaria
and you develop a sudden onset of
anxiety, depression, restlessness,
confusion (possible signs of more
serious mental problems), or you
develop other serious side effects,
contact a doctor or other health care
provider. It may be necessary to stop
taking Lariam and use another malaria
prevention medicine instead.
Revised: August 2003
Other medicines approved in the
United States for malaria prevention
include: doxycycline,
atovaquone/proguanil,
hydroxychloroquine, and
chloroquine. Not all malaria
medicines work equally well in
malaria areas. The chloroquines, for
example, do not work in many parts
of the world. If you can’t get another
medicine, leave the malaria area.
However, be aware that leaving the
malaria area may not protect you
from getting malaria. You still need
to take a malaria prevention
medicine.
Please read the Medication Guide for
additional information on Lariam.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:29.421758
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19591slr022_lariam_lbl.pdf', 'application_number': 19591, 'submission_type': 'SUPPL ', 'submission_number': 22}
|
11,548
|
Company logo
LARIAM®
brand of
mefloquine hydrochloride
TABLETS
Rx only
DESCRIPTION
Lariam (mefloquine hydrochloride) is an antimalarial agent available as 250-
mg tablets of mefloquine hydrochloride (equivalent to 228.0 mg of the free
base) for oral administration.
Mefloquine hydrochloride is a 4-quinolinemethanol derivative with the
specific
chemical
name
of
(R*,
S*)-(±)-α-2-piperidinyl-2,8-bis
(trifluoromethyl)-4-quinolinemethanol hydrochloride. It is a 2-aryl substituted
chemical structural analog of quinine. The drug is a white to almost white
crystalline compound, slightly soluble in water.
Mefloquine hydrochloride has a calculated molecular weight of 414.78 and
the following structural formula: Structural Formula
The inactive ingredients are ammonium-calcium alginate, corn starch,
crospovidone, lactose, magnesium stearate, microcrystalline cellulose,
poloxamer #331, and talc.
CLINICAL PHARMACOLOGY
Pharmacokinetics
Absorption
The absolute oral bioavailability of mefloquine has not been determined since
an intravenous formulation is not available. The bioavailability of the tablet
formation compared with an oral solution was over 85%. The presence of
food significantly enhances the rate and extent of absorption, leading to about
a 40% increase in bioavailability. In healthy volunteers, plasma concentrations
peak 6 to 24 hours (median, about 17 hours) after a single dose of Lariam. In a
similar group of volunteers, maximum plasma concentrations in μg/L are
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
roughly equivalent to the dose in milligrams (for example, a single 1000 mg
dose produces a maximum concentration of about 1000 μg/L). In healthy
volunteers, a dose of 250 mg once weekly produces maximum steady-state
plasma concentrations of 1000 to 2000 μg/L, which are reached after 7 to 10
weeks.
Distribution
In healthy adults, the apparent volume of distribution is approximately 20
L/kg, indicating extensive tissue distribution. Mefloquine may accumulate in
parasitized erythrocytes. Experiments conducted in vitro with human blood
using concentrations between 50 and 1000 mg/mL showed a relatively
constant erythrocyte-to-plasma concentration ratio of about 2 to 1. The
equilibrium reached in less than 30 minutes was found to be reversible.
Protein binding is about 98%.
Mefloquine crosses the placenta. Excretion into breast milk appears to be
minimal (see PRECAUTIONS: Nursing Mothers).
Metabolism
Two metabolites have been identified in humans. The main metabolite, 2,8-
bis-trifluoromethyl-4-quinoline carboxylic acid, is inactive in Plasmodium
falciparum. In a study in healthy volunteers, the carboxylic acid metabolite
appeared in plasma 2 to 4 hours after a single oral dose. Maximum plasma
concentrations, which were about 50% higher than those of mefloquine, were
reached after 2 weeks. Thereafter, plasma levels of the main metabolite and
mefloquine declined at a similar rate. The area under the plasma
concentration-time curve (AUC) of the main metabolite was 3 to 5 times
larger than that of the parent drug. The other metabolite, an alcohol, was
present in minute quantities only.
Elimination
In several studies in healthy adults, the mean elimination half-life of
mefloquine varied between 2 and 4 weeks, with an average of about 3 weeks.
Total clearance, which is essentially hepatic, is in the order of 30 mL/min.
There is evidence that mefloquine is excreted mainly in the bile and feces. In
volunteers, urinary excretion of unchanged mefloquine and its main
metabolite under steady-state condition accounted for about 9% and 4% of the
dose, respectively. Concentrations of other metabolites could not be measured
in the urine.
Pharmacokinetics in Special Clinical Situations
Children and the Elderly
No relevant age-related changes have been observed in the pharmacokinetics
of mefloquine. Therefore, the dosage for children has been extrapolated from
the recommended adult dose.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
No pharmacokinetic studies have been performed in patients with renal
insufficiency since only a small proportion of the drug is eliminated renally.
Mefloquine and its main metabolite are not appreciably removed by
hemodialysis. No special chemoprophylactic dosage adjustments are indicated
for dialysis patients to achieve concentrations in plasma similar to those in
healthy persons.
Although clearance of mefloquine may increase in late pregnancy, in general,
pregnancy has no clinically relevant effect on the pharmacokinetics of
mefloquine.
The pharmacokinetics of mefloquine may be altered in acute malaria.
Pharmacokinetic differences have been observed between various ethnic
populations. In practice, however, these are of minor importance compared
with host immune status and sensitivity of the parasite.
During long-term prophylaxis (>2 years), the trough concentrations and the
elimination half-life of mefloquine were similar to those obtained in the same
population after 6 months of drug use, which is when they reached steady
state.
In vitro and in vivo studies showed no hemolysis associated with glucose-6-
phosphate dehydrogenase deficiency (see ANIMAL TOXICOLOGY).
Microbiology
Mechanism of Action
Mefloquine is an antimalarial agent which acts as a blood schizonticide. Its
exact mechanism of action is not known.
Activity In Vitro and In Vivo
Mefloquine is active against the erythrocytic stages of Plasmodium species
(see INDICATIONS AND USAGE). However, the drug has no effect against
the exoerythrocytic (hepatic) stages of the parasite. Mefloquine is effective
against malaria parasites resistant to chloroquine (see INDICATIONS AND
USAGE).
Drug Resistance
Strains of P. falciparum with decreased susceptibility to mefloquine can be
selected in vitro or in vivo. Resistance of P. falciparum to mefloquine has
been reported in areas of multi-drug resistance in South East Asia. Increased
incidences of resistance have also been reported in other parts of the world.
Cross-Resistance
Cross-resistance between mefloquine and halofantrine and cross-resistance
between mefloquine and quinine have been observed in some regions.
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
INDICATIONS AND USAGE
Treatment of Acute Malaria Infections
Lariam is indicated for the treatment of mild to moderate acute malaria caused
by mefloquine-susceptible strains of P. falciparum (both chloroquine-
susceptible and resistant strains) or by Plasmodium vivax. There are
insufficient clinical data to document the effect of mefloquine in malaria
caused by P. ovale or P. malariae.
Note: Patients with acute P. vivax malaria, treated with Lariam, are at
high risk of relapse because Lariam does not eliminate exoerythrocytic
(hepatic phase) parasites. To avoid relapse, after initial treatment of the
acute infection with Lariam, patients should subsequently be treated
with an 8-aminoquinoline derivative (eg, primaquine).
Prevention of Malaria
Lariam is indicated for the prophylaxis of P. falciparum and P. vivax malaria
infections, including prophylaxis of chloroquine-resistant strains of P.
falciparum.
CONTRAINDICATIONS
Use of Lariam is contraindicated in patients with a known hypersensitivity to
mefloquine or related compounds (eg, quinine and quinidine) or to any of the
excipients contained in the formulation. Lariam should not be prescribed for
prophylaxis in patients with active depression, a recent history of depression,
generalized anxiety disorder, psychosis, or schizophrenia or other major
psychiatric disorders, or with a history of convulsions.
WARNINGS
In case of life-threatening, serious or overwhelming malaria infections
due to P. falciparum, patients should be treated with an intravenous
antimalarial drug. Following completion of intravenous treatment,
Lariam may be given to complete the course of therapy.
Data on the use of halofantrine subsequent to administration of Lariam
suggest a significant, potentially fatal prolongation of the QTc interval of
the ECG. Therefore, halofantrine must not be given simultaneously with
or subsequent to Lariam. No data are available on the use of Lariam after
halofantrine (see PRECAUTIONS: Drug Interactions).
Mefloquine may cause psychiatric symptoms in a number of patients,
ranging from anxiety, paranoia, and depression to hallucinations and
psychotic behavior. On occasions, these symptoms have been reported to
continue long after mefloquine has been stopped. Rare cases of suicidal
ideation and suicide have been reported though no relationship to drug
administration has been confirmed. To minimize the chances of these
adverse events, mefloquine should not be taken for prophylaxis in
patients with active depression or with a recent history of depression,
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
generalized anxiety disorder, psychosis, or schizophrenia or other major
psychiatric disorders. Lariam should be used with caution in patients
with a previous history of depression.
During prophylactic use, if psychiatric symptoms such as acute anxiety,
depression, restlessness or confusion occur, these may be considered
prodromal to a more serious event. In these cases, the drug must be
discontinued and an alternative medication should be substituted.
Concomitant administration of Lariam and quinine or quinidine may
produce electrocardiographic abnormalities.
Concomitant administration of Lariam and quinine or chloroquine may
increase the risk of convulsions.
PRECAUTIONS
Hypersensitivity Reactions
Hypersensitivity reactions ranging from mild cutaneous events to anaphylaxis
cannot be predicted.
In patients with epilepsy, Lariam may increase the risk of convulsions. The
drug should therefore be prescribed only for curative treatment in such
patients and only if there are compelling medical reasons for its use (see
PRECAUTIONS: Drug Interactions).
Central and Peripheral Nervous System Effects
Caution should be exercised with regard to activities requiring alertness and
fine motor coordination such as driving, piloting aircraft, operating
machinery, and deep-sea diving, as dizziness, a loss of balance, or other
disorders of the central or peripheral nervous system have been reported
during and following the use of Lariam. These effects may occur after therapy
is discontinued due to the long half-life of the drug. In a small number of
patients, dizziness and loss of balance have been reported to continue for
months after mefloquine has been stopped (see ADVERSE REACTIONS:
Postmarketing).
Lariam should be used with caution in patients with psychiatric disturbances
because mefloquine use has been associated with emotional disturbances (see
ADVERSE REACTIONS).
Use in Patients with Hepatic Impairment
In patients with impaired liver function the elimination of mefloquine may be
prolonged, leading to higher plasma levels.
Long-Term Use
This drug has been administered for longer than 1 year. If the drug is to be
administered for a prolonged period, periodic evaluations including liver
function tests should be performed.
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
Although retinal abnormalities seen in humans with long-term chloroquine
use have not been observed with mefloquine use, long-term feeding of
mefloquine to rats resulted in dose-related ocular lesions (retinal degeneration,
retinal edema and lenticular opacity at 12.5 mg/kg/day and higher) (see
ANIMAL TOXICOLOGY). Therefore, periodic ophthalmic examinations
are recommended.
Cardiac Effects
Parenteral studies in animals show that mefloquine, a myocardial depressant,
possesses 20% of the anti-fibrillatory action of quinidine and produces 50% of
the increase in the PR interval reported with quinine. The effect of mefloquine
on the compromised cardiovascular system has not been evaluated. However,
transitory and clinically silent ECG alterations have been reported during the
use of mefloquine. Alterations included sinus bradycardia, sinus arrhythmia,
first degree AV-block, prolongation of the QTc interval and abnormal T
waves (see also cardiovascular effects under PRECAUTIONS: Drug
Interactions and ADVERSE REACTIONS). The benefits of Lariam therapy
should be weighed against the possibility of adverse effects in patients with
cardiac disease.
Laboratory Tests
Periodic evaluation of hepatic function should be performed during prolonged
prophylaxis.
Information for Patients
Medication Guide: As required by law, a Lariam Medication Guide is
supplied to patients when Lariam is dispensed. An information wallet card is
also supplied to patients when Lariam is dispensed. Patients should be
instructed to read the Medication Guide when Lariam is received and to carry
the information wallet card with them when they are taking Lariam. The
complete texts of the Medication Guide and information wallet card are
reprinted at the end of this document.
Patients should be advised:
• that malaria can be a life-threatening infection in the traveler;
• that Lariam is being prescribed to help prevent or treat this serious
infection;
• that in a small percentage of cases, patients are unable to take this
medication because of side effects, including dizziness and loss of
balance, and it may be necessary to change medications. Although side
effects of dizziness and loss of balance are usually mild and do not cause
people to stop taking the medication, in a small number of patients it has
been reported that these symptoms may continue for months after
discontinuation of the drug.
• that when used as prophylaxis, the first dose of Lariam should be taken 1
week prior to arrival in an endemic area;
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
• that if the patients experience psychiatric symptoms such as acute anxiety,
depression, restlessness or confusion, these may be considered prodromal
to a more serious event. In these cases, the drug must be discontinued and
an alternative medication should be substituted;
• 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 to inform their physician that they may have
been exposed to malaria.
Drug Interactions
Drug-drug interactions with Lariam have not been explored in detail. There is
one report of cardiopulmonary arrest, with full recovery, in a patient who was
taking a beta blocker (propranolol) (see PRECAUTIONS: Cardiac Effects).
The effects of mefloquine on the compromised cardiovascular system have
not been evaluated. The benefits of Lariam therapy should be weighed against
the possibility of adverse effects in patients with cardiac disease.
Because of the danger of a potentially fatal prolongation of the QTc interval,
halofantrine must not be given simultaneously with or subsequent to Lariam
(see WARNINGS).
Concomitant administration of Lariam and other related compounds (eg,
quinine, quinidine and chloroquine) may produce electrocardiographic
abnormalities and increase the risk of convulsions (see WARNINGS). If
these drugs are to be used in the initial treatment of severe malaria, Lariam
administration should be delayed at least 12 hours after the last dose. There is
evidence that the use of halofantrine after mefloquine causes a significant
lengthening of the QTc interval. Clinically significant QTc prolongation has
not been found with mefloquine alone.
This appears to be the only clinically relevant interaction of this kind with
Lariam, although theoretically, coadministration of other drugs known to alter
cardiac conduction (eg, anti-arrhythmic or beta-adrenergic blocking agents,
calcium channel blockers, antihistamines or H1-blocking agents, tricyclic
antidepressants and phenothiazines) might also contribute to a prolongation of
the QTc interval. There are no data that conclusively establish whether the
concomitant administration of mefloquine and the above listed agents has an
effect on cardiac function.
In patients taking an anticonvulsant (eg, valproic acid, carbamazepine,
phenobarbital or phenytoin), the concomitant use of Lariam may reduce
seizure control by lowering the plasma levels of the anticonvulsant. Therefore,
patients concurrently taking antiseizure medication and Lariam should have
the blood level of their antiseizure medication monitored and the dosage
adjusted appropriately (see PRECAUTIONS).
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
When Lariam is taken concurrently with oral live typhoid vaccines,
attenuation of immunization cannot be excluded. Vaccinations with attenuated
live bacteria should therefore be completed at least 3 days before the first dose
of Lariam.
No other drug interactions are known. Nevertheless, the effects of Lariam on
travelers receiving comedication, particularly diabetics or patients using
anticoagulants, should be checked before departure.
In clinical trials, the concomitant administration of sulfadoxine and
pyrimethamine did not alter the adverse reaction profile.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
The carcinogenic potential of mefloquine was studied in rats and mice in 2-
year feeding studies at doses of up to 30 mg/kg/day. No treatment-related
increases in tumors of any type were noted.
Mutagenesis
The mutagenic potential of mefloquine was studied in a variety of assay
systems including: Ames test, a host-mediated assay in mice, fluctuation tests
and a mouse micronucleus assay. Several of these assays were performed with
and without prior metabolic activation. In no instance was evidence obtained
for the mutagenicity of mefloquine.
Impairment of Fertility
Fertility studies in rats at doses of 5, 20, and 50 mg/kg/day of mefloquine have
demonstrated adverse effects on fertility in the male at the high dose of 50
mg/kg/day, and in the female at doses of 20 and 50 mg/kg/day.
Histopathological lesions were noted in the epididymides from male rats at
doses of 20 and 50 mg/kg/day. Administration of 250 mg/week of mefloquine
(base) in adult males for 22 weeks failed to reveal any deleterious effects on
human spermatozoa.
Pregnancy
Teratogenic Effects
Pregnancy Category C. Mefloquine has been demonstrated to be teratogenic
in rats and mice at a dose of 100 mg/kg/day. In rabbits, a high dose of 160
mg/kg/day was embryotoxic and teratogenic, and a dose of 80 mg/kg/day was
teratogenic but not embryotoxic. There are no adequate and well-controlled
studies in pregnant women. However, clinical experience with Lariam has not
revealed an embryotoxic or teratogenic effect. Mefloquine 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. Women of
childbearing potential should also be advised to practice contraception during
malaria prophylaxis with Lariam and for up to 3 months thereafter. However,
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
in the case of unplanned pregnancy, malaria chemoprophylaxis with Lariam is
not considered an indication for pregnancy termination.
Nursing Mothers
Mefloquine is excreted in human milk in small amounts, the activity of which
is unknown. Based on a study in a few subjects, low concentrations (3% to
4%) of mefloquine were excreted in human milk following a dose equivalent
to 250 mg of the free base. Because of the potential for serious adverse
reactions in nursing infants from mefloquine, a decision should be made
whether to discontinue the drug, taking into account the importance of the
drug to the mother.
Pediatric Use
Use of Lariam to treat acute, uncomplicated P. falciparum malaria in pediatric
patients is supported by evidence from adequate and well-controlled studies of
Lariam in adults with additional data from published open-label and
comparative trials using Lariam to treat malaria caused by P. falciparum in
patients younger than 16 years of age. The safety and effectiveness of Lariam
for the treatment of malaria in pediatric patients below the age of 6 months
have not been established.
In several studies, the administration of Lariam for the treatment of malaria
was associated with early vomiting in pediatric patients. Early vomiting was
cited in some reports as a possible cause of treatment failure. If a second dose
is not tolerated, the patient should be monitored closely and alternative
malaria treatment considered if improvement is not observed within a
reasonable period of time (see DOSAGE AND ADMINISTRATION).
Geriatric Use
Clinical studies of Lariam 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.
Since
electrocardiographic abnormalities have been observed in individuals treated
with Lariam (see PRECAUTIONS) and underlying cardiac disease is more
prevalent in elderly than in younger patients, the benefits of Lariam therapy
should be weighed against the possibility of adverse cardiac effects in elderly
patients.
ADVERSE REACTIONS
Clinical
At the doses used for treatment of acute malaria infections, the symptoms
possibly attributable to drug administration cannot be distinguished from
those symptoms usually attributable to the disease itself.
Among subjects who received mefloquine for prophylaxis of malaria, the
most frequently observed adverse experience was vomiting (3%). Dizziness,
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
syncope, extrasystoles and other complaints affecting less than 1% were also
reported.
Among subjects who received mefloquine for treatment, the most frequently
observed adverse experiences included: dizziness, myalgia, nausea, fever,
headache, vomiting, chills, diarrhea, skin rash, abdominal pain, fatigue, loss of
appetite, and tinnitus. Those side effects occurring in less than 1% included
bradycardia, hair loss, emotional problems, pruritus, asthenia, transient
emotional disturbances and telogen effluvium (loss of resting hair). Seizures
have also been reported.
Two serious adverse reactions were cardiopulmonary arrest in one patient
shortly after ingesting a single prophylactic dose of mefloquine while
concomitantly using propranolol (see PRECAUTIONS: Drug Interactions),
and encephalopathy of unknown etiology during prophylactic mefloquine
administration. The relationship of encephalopathy to drug administration
could not be clearly established.
Postmarketing
Postmarketing surveillance indicates that the same kind of adverse
experiences are reported during prophylaxis, as well as acute treatment.
Because these experiences 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 Lariam exposure.
The most frequently reported adverse events are nausea, vomiting, loose
stools or diarrhea, abdominal pain, dizziness or vertigo, loss of balance, and
neuropsychiatric events such as headache, somnolence, and sleep disorders
(insomnia, abnormal dreams). These are usually mild and may decrease
despite continued use. In a small number of patients it has been reported that
dizziness or vertigo and loss of balance may continue for months after
discontinuation of the drug.
Occasionally, more severe neuropsychiatric disorders have been reported such
as: sensory and motor neuropathies (including paresthesia, tremor and ataxia),
convulsions, agitation or restlessness, anxiety, depression, mood changes,
panic attacks, forgetfulness, confusion, hallucinations, aggression, psychotic
or paranoid reactions and encephalopathy. Rare cases of suicidal ideation and
suicide have been reported though no relationship to drug administration has
been confirmed.
Other infrequent adverse events include:
Cardiovascular
Disorders:
circulatory
disturbances
(hypotension,
hypertension, flushing, syncope), chest pain, tachycardia or palpitation,
bradycardia, irregular pulse, extrasystoles, A-V block, and other transient
cardiac conduction alterations
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
Skin Disorders: rash, exanthema, erythema, urticaria, pruritus, edema, hair
loss, erythema multiforme, and Stevens-Johnson syndrome
Musculoskeletal Disorders: muscle weakness, muscle cramps, myalgia, and
arthralgia
Respiratory Disorders: dyspnea, pneumonitis of possible allergic etiology
Other Symptoms: visual disturbances, vestibular disorders including tinnitus
and hearing impairment, asthenia, malaise, fatigue, fever, sweating, chills,
dyspepsia and loss of appetite
Laboratory
The most frequently observed laboratory alterations which could be possibly
attributable to drug administration were decreased hematocrit, transient
elevation of transaminases, leukopenia and thrombocytopenia. These
alterations were observed in patients with acute malaria who received
treatment doses of the drug and were attributed to the disease itself.
During prophylactic administration of mefloquine to indigenous populations
in malaria-endemic areas, the following occasional alterations in laboratory
values were observed: transient elevation of transaminases, leukocytosis or
thrombocytopenia.
Because of the long half-life of mefloquine, adverse reactions to Lariam may
occur or persist up to several weeks after the last dose.
OVERDOSAGE
Symptoms and Signs
In cases of overdosage with Lariam, the symptoms mentioned under
ADVERSE REACTIONS may be more pronounced.
Treatment
Patients should be managed by symptomatic and supportive care following
Lariam overdose. There are no specific antidotes. Monitor cardiac function (if
possible by ECG) and neuropsychiatric status for at least 24 hours. Provide
symptomatic and intensive supportive treatment as required, particularly for
cardiovascular disturbances.
DOSAGE AND ADMINISTRATION (see INDICATIONS AND USAGE)
Adult Patients
Treatment of mild to moderate malaria in adults caused by P. vivax or
mefloquine-susceptible strains of P. falciparum
Five tablets (1250 mg) mefloquine hydrochloride to be given as a single oral
dose. The drug should not be taken on an empty stomach and should be
administered with at least 8 oz (240 mL) of water.
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
If a full-treatment course with Lariam does not lead to improvement within 48
to 72 hours, Lariam should not be used for retreatment. An alternative therapy
should be used. Similarly, if previous prophylaxis with mefloquine has failed,
Lariam should not be used for curative treatment.
Note: Patients with acute P. vivax malaria, treated with Lariam, are at
high risk of relapse because Lariam does not eliminate exoerythrocytic
(hepatic phase) parasites. To avoid relapse after initial treatment of the
acute infection with Lariam, patients should subsequently be treated
with an 8-aminoquinoline derivative (eg, primaquine).
Malaria Prophylaxis
One 250 mg Lariam tablet once weekly.
Prophylactic drug administration should begin 1 week before arrival in an
endemic area. Subsequent weekly doses should be taken regularly, always on
the same day of each week, preferably after the main meal. To reduce the risk
of malaria after leaving an endemic area, prophylaxis must be continued for 4
additional weeks to ensure suppressive blood levels of the drug when
merozoites emerge from the liver. Tablets should not be taken on an empty
stomach and should be administered with at least 8 oz (240 mL) of water.
In certain cases, eg, when a traveler is taking other medication, it may be
desirable to start prophylaxis 2 to 3 weeks prior to departure, in order to
ensure that the combination of drugs is well tolerated (see PRECAUTIONS:
Drug Interactions).
When prophylaxis with Lariam fails, physicians should carefully evaluate
which antimalarial to use for therapy.
Pediatric Patients
Treatment of mild to moderate malaria in pediatric patients caused by
mefloquine-susceptible strains of P. falciparum
Twenty (20) to 25 mg/kg body weight. Splitting the total therapeutic dose into
2 doses taken 6 to 8 hours apart may reduce the occurrence or severity of
adverse effects. Experience with Lariam in pediatric patients weighing less
than 20 kg is limited. The drug should not be taken on an empty stomach and
should be administered with ample water. The tablets may be crushed and
suspended in a small amount of water, milk or other beverage for
administration to small children and other persons unable to swallow them
whole.
If a full-treatment course with Lariam does not lead to improvement within 48
to 72 hours, Lariam should not be used for retreatment. An alternative therapy
should be used. Similarly, if previous prophylaxis with mefloquine has failed,
Lariam should not be used for curative treatment.
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
In pediatric patients, the administration of Lariam for the treatment of malaria
has been associated with early vomiting. In some cases, early vomiting has
been cited as a possible cause of treatment failure (see PRECAUTIONS). If a
significant loss of drug product is observed or suspected because of vomiting,
a second full dose of Lariam should be administered to patients who vomit
less than 30 minutes after receiving the drug. If vomiting occurs 30 to 60
minutes after a dose, an additional half-dose should be given. If vomiting
recurs, the patient should be monitored closely and alternative malaria
treatment considered if improvement is not observed within a reasonable
period of time.
The safety and effectiveness of Lariam to treat malaria in pediatric patients
below the age of 6 months have not been established.
Malaria Prophylaxis
The recommended prophylactic dose of Lariam is approximately 5 mg/kg
body weight once weekly. One 250 mg Lariam tablet should be taken once
weekly in pediatric patients weighing over 45 kg. In pediatric patients
weighing less than 45 kg, the weekly dose decreases in proportion to body
weight:
30 to 45 kg:
3/4 tablet
20 to 30 kg:
1/2 tablet
Experience with Lariam in pediatric patients weighing less than 20 kg is
limited.
HOW SUPPLIED
Lariam is available as scored, white, round tablets, containing 250 mg of
mefloquine hydrochloride in unit-dose packages of 25 (NDC 0004-0172-02).
Imprint on tablets: LARIAM 250 ROCHE
Tablets should be stored at 25°C (77°F); excursions permitted to 15° to 30°C
(59° to 86°F).
ANIMAL TOXICOLOGY
Ocular lesions were observed in rats fed mefloquine daily for 2 years. All
surviving rats given 30 mg/kg/day had ocular lesions in both eyes
characterized by retinal degeneration, opacity of the lens, and retinal edema.
Similar but less severe lesions were observed in 80% of female and 22% of
male rats fed 12.5 mg/kg/day for 2 years. At doses of 5 mg/kg/day, only
corneal lesions were observed. They occurred in 9% of rats studied.
Revised: Month/Year
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
MEDICATION GUIDE
This Medication Guide is intended only for travelers who are taking
Lariam to prevent malaria. The information may not apply to patients who
are sick with malaria and who are taking Lariam to treat malaria.
An information wallet card is provided with this Medication Guide. Carry it
with you when you are taking Lariam.
This Medication Guide was revised in September 2008. Please read it before
you start taking Lariam and each time you get a refill. There may be new
information. This Medication Guide does not take the place of talking with
your prescriber (doctor or other health care provider) about Lariam and
malaria prevention. Only you and your prescriber can decide if Lariam is right
for you. If you cannot take Lariam, you may be able to take a different
medicine to prevent malaria.
What is the most important information I should know about Lariam?
1. Take Lariam exactly as prescribed to prevent malaria.
Malaria is an infection that can cause death and is spread to humans
through mosquito bites. If you travel to parts of the world where the
mosquitoes carry the malaria parasite, you must take a malaria prevention
medicine. Lariam is one of a small number of medications approved to
prevent and to treat malaria. If taken correctly, Lariam is effective at
preventing malaria but, like all medications, it may produce side effects in
some patients.
2. Lariam can rarely cause serious mental problems in some patients.
The most frequently reported side effects with Lariam, such as nausea,
difficulty sleeping, and bad dreams are usually mild and do not cause
people to stop taking the medicine. However, people taking Lariam
occasionally experience severe anxiety, feelings that people are against
them, hallucinations (seeing or hearing things that are not there, for
example), depression, unusual behavior, or feeling disoriented. There have
been reports that in some patients these side effects continue after Lariam
is stopped. Some patients taking Lariam think about killing themselves,
and there have been rare reports of suicides. It is not known whether
Lariam was responsible for these suicides.
3. You need to take malaria prevention medicine before you travel to a
malaria area, while you are in a malaria area, and after you return
from a malaria area.
Medicines approved in the United States for malaria prevention include
Lariam, doxycycline, atovaquone/proguanil, hydroxychloroquine, and
chloroquine. Not all of these drugs work equally as well in all areas of the
world where there is malaria. The chloroquines, for example, do not work
in areas where the malaria parasite has developed resistance to
chloroquine. Lariam may be effective against malaria that is resistant to
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
chloroquine or other drugs. All drugs to treat malaria have side effects that
are different for each one. For example, some may make your skin more
sensitive to sunlight (Lariam does not do this). However, if you use
Lariam to prevent malaria and you develop a sudden onset of anxiety,
depression, restlessness, confusion (possible signs of more serious mental
problems), or you develop other serious side effects, contact a doctor or
other health care provider. It may be necessary to stop taking Lariam and
use another malaria prevention medicine instead. If you can’t get another
medicine, leave the malaria area. However, be aware that leaving the
malaria area may not protect you from getting malaria. You still need to
take a malaria prevention medicine.
Who should not take Lariam?
Do not take Lariam to prevent malaria if you
• have depression or had depression recently
• have had recent mental illness or problems, including anxiety disorder,
schizophrenia (a severe type of mental illness), or psychosis (losing touch
with reality)
• have or had seizures (epilepsy or convulsions)
• are allergic to quinine or quinidine (medicines related to Lariam)
Tell your prescriber about all your medical conditions. Lariam may not be
right for you if you have certain conditions, especially the ones listed below:
• Heart disease. Lariam may not be right for you.
• Pregnancy. Tell your prescriber if you are pregnant or plan to become
pregnant. It is dangerous for the mother and for the unborn baby (fetus) to
get malaria during pregnancy. Therefore, ask your prescriber if you should
take Lariam or another medicine to prevent malaria while you are
pregnant.
• Breast-feeding. Lariam can pass through your milk and may harm the
baby. Therefore, ask your prescriber whether you will need to stop breast-
feeding or use another medicine.
• Liver problems.
Tell your prescriber about all the medicines you take, including
prescription and non-prescription medicines, vitamins, and herbal
supplements. Some medicines may give you a higher chance of having
serious side effects from Lariam.
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
How should I take Lariam?
Take Lariam exactly as prescribed. If you are an adult or pediatric
patient weighing 45 kg (99 pounds) or less, your prescriber will tell you
the correct dose based on your weight.
To prevent malaria
• For adults and pediatric patients weighing over 45 kg, take 1 tablet of
Lariam at least 1 week before you travel to a malaria area (or 2 to 3 weeks
before you travel to a malaria area, if instructed by your prescriber). This
starts the prevention and also helps you see how Lariam affects you and
the other medicines you take. Take 1 Lariam tablet once a week, on the
same day each week, while in a malaria area.
• Continue taking Lariam for 4 weeks after returning from a malaria
area. If you cannot continue taking Lariam due to side effects or for other
reasons, contact your prescriber.
• Take Lariam just after a meal and with at least 1 cup (8 ounces) of water.
• For children, Lariam can be given with water or crushed and mixed with
water or sugar water. The prescriber will tell you the correct dose for
children based on the child’s weight.
• If you are told by a doctor or other health care provider to stop taking
Lariam due to side effects or for other reasons, it will be necessary to take
another malaria medicine. You must take malaria prevention medicine
before you travel to a malaria area, while you are in a malaria area,
and after you return from a malaria area. If you don’t have access to
a doctor or other health care provider or to another medicine besides
Lariam and have to stop taking it, leave the malaria area. However, be
aware that leaving the malaria area may not protect you from getting
malaria. You still need to take a malaria prevention medicine.
What should I avoid while taking Lariam?
• Halofantrine (marketed under various brand names), a medicine used
to treat malaria. Taking both of these medicines together can cause serious
heart problems that can cause death.
• Do not become pregnant. Women should use effective birth control
while taking Lariam.
• Quinine, quinidine, or chloroquine (other medicines used to treat
malaria). Taking these medicines with Lariam could cause changes in
your heart rate or increase the risk of seizures.
In addition:
• Be careful driving or in other activities needing alertness and careful
movements (fine motor coordination). Lariam can cause dizziness or loss
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
of balance, even after you stop taking Lariam (see “What are the possible
side effects of Lariam?”).
• Be aware that certain vaccines may not work if given while you are
taking Lariam. Your prescriber may want you to finish taking your
vaccines at least 3 days before starting Lariam.
What are the possible side effects of Lariam?
Lariam, like all medicines, may cause side effects in some patients. The most
frequently reported side effects with Lariam when used for prevention of
malaria include nausea, vomiting, diarrhea, dizziness, loss of balance,
difficulty sleeping, and bad dreams. These side effects are usually mild and do
not cause people to stop taking the medicine. However, in a small number of
patients, it has been reported that dizziness and loss of balance may continue
for months after stopping Lariam.
Lariam may cause serious mental problems in some patients (see “What is the
most important information I should know about Lariam?”).
Lariam may affect your liver and your eyes if you take it for a long time. Your
prescriber will tell you if you should have your eyes and liver checked while
taking Lariam.
Call your doctor for medical advice about side effects. You may report side
effects to FDA at 1-800-FDA-1088.
What else should I know about preventing malaria?
• Find out whether you need malaria prevention. Before you travel, talk
with your prescriber about your travel plans to determine whether you
need to take medicine to prevent malaria. Even in those countries where
malaria is present, there may be areas of the country that are free of
malaria. In general, malaria is more common in rural (country) areas than
in big cities, and it is more common during rainy seasons, when
mosquitoes are most common. You can get information about the areas of
the world where malaria occurs from the Centers for Disease Control and
Prevention (CDC) and from local authorities in the countries you visit. If
possible, plan your travel to reduce the risk of malaria.
• Take medicine to prevent malaria infection. Without malaria prevention
medicine, you have a higher risk of getting malaria. Malaria starts with
flu-like symptoms, such as chills, fever, muscle pains, and headaches.
However, malaria can make you very sick or cause death if you don’t seek
medical help immediately. These symptoms may disappear for a while,
and you may think you are well. But, the symptoms return later and then it
may be too late for successful treatment.
Malaria can cause confusion, coma, and seizures. It can cause kidney
failure, breathing problems, and severe damage to red blood cells.
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
However, malaria can be easily diagnosed with a blood test, and if
caught in time, can be effectively treated.
If you get flu-like symptoms (chills, fever, muscle pains, or
headaches) after you return from a malaria area, get medical help
right away and tell your prescriber that you may have been exposed to
malaria.
People who have lived for many years in areas with malaria may have
some immunity to malaria (they do not get it as easily) and may not
take malaria prevention medicine. This does not mean that you don’t
need to take malaria prevention medicine.
• Protect against mosquito bites. Medicines do not always completely
prevent your catching malaria from mosquito bites. So protect yourself
very well against mosquitoes. Cover your skin with long sleeves and long
pants, and use mosquito repellent and bednets while in malaria areas. If
you are out in the bush, you may want to pre-wash your clothes with
permethrin. This is a mosquito repellent that may be effective for weeks
after use. Ask your prescriber for other ways to protect yourself.
General information about the safe and effective use of Lariam.
Medicines are sometimes prescribed for conditions not listed in Medication
Guides. If you have any concerns about Lariam, ask your prescriber. This
Medication Guide contains certain important information for travelers visiting
areas with malaria. Your prescriber or pharmacist can give you information
about Lariam that was written for health care professionals. Do not use
Lariam for a condition for which it was not prescribed. Do not share Lariam
with other people.
This Medication Guide has been approved by the U.S. Food and Drug
Administration.
Medication Guide Revised: September 2008
Reprint of information wallet card:
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
19
Company logo
Lariam® (mefloquine hydrochloride) Tablets
Carry this information wallet card with you when you are taking Lariam.
You need to take malaria prevention
medicine before you travel to a malaria
area, while you are in a malaria area, and
after you return from a malaria area.
If taken correctly, Lariam is effective at
preventing malaria but, like all
medications, it may produce side effects
in some patients.
If you use Lariam to prevent malaria and
you develop a sudden onset of anxiety,
depression, restlessness, confusion
(possible signs of more serious mental
problems), or you develop other serious
side effects, contact a doctor or other
health care provider. It may be necessary
to stop taking Lariam and use another
malaria prevention medicine instead.
Other medicines approved in the United
States for malaria prevention include:
doxycycline, atovaquone/proguanil,
hydroxychloroquine, and chloroquine.
Not all malaria medicines work equally
well in malaria areas. The chloroquines,
for example, do not work in many parts
of the world. If you can’t get another
medicine, leave the malaria area.
However, be aware that leaving the
malaria area may not protect you from
getting malaria. You still need to take a
malaria prevention medicine.
Please read the Medication Guide for
additional information on Lariam.
Call your doctor for medical advice
about side effects. You may report side
effects to FDA at 1-800-FDA-1088.
Card Revised: September 2008
Manufactured by:
F. HOFFMANN-LA ROCHE LTD
Basel, Switzerland
Distributed by: Company logo
Copyright © 1999-2008 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
|
2025-02-12T13:45:29.694071
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019591slr027_lbl.pdf', 'application_number': 19591, 'submission_type': 'SUPPL ', 'submission_number': 27}
|
11,546
|
1 Roche Logo
2
LARIAM®
3
brand of
4
mefloquine hydrochloride
5
TABLETS
6
Rx only
7
DESCRIPTION
8
Lariam (mefloquine hydrochloride) is an antimalarial agent available as 250
9
mg tablets of mefloquine hydrochloride (equivalent to 228.0 mg of the free
10
base) for oral administration.
11
Mefloquine hydrochloride is a 4-quinolinemethanol derivative with the
12
specific
chemical
name
of
(R*,
S*)-(±)-α-2-piperidinyl-2,8-bis
13
(trifluoromethyl)-4-quinolinemethanol hydrochloride. It is a 2-aryl substituted
14
chemical structural analog of quinine. The drug is a white to almost white
15
crystalline compound, slightly soluble in water.
16
Mefloquine hydrochloride has a calculated molecular weight of 414.78 and
17
the following structural formula: Chemical Structure
18
19
The inactive ingredients are ammonium-calcium alginate, corn starch,
20
crospovidone, lactose, magnesium stearate, microcrystalline cellulose,
21
poloxamer #331, and talc.
22
CLINICAL PHARMACOLOGY
23
Pharmacokinetics
24
Absorption
25
The absolute oral bioavailability of mefloquine has not been determined since
26
an intravenous formulation is not available. The bioavailability of the tablet
27
formation compared with an oral solution was over 85%. The presence of
28
food significantly enhances the rate and extent of absorption, leading to about
29
a 40% increase in bioavailability. In healthy volunteers, plasma concentrations
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
30
peak 6 to 24 hours (median, about 17 hours) after a single dose of Lariam. In a
31
similar group of volunteers, maximum plasma concentrations in μg/L are
32
roughly equivalent to the dose in milligrams (for example, a single 1000 mg
33
dose produces a maximum concentration of about 1000 μg/L). In healthy
34
volunteers, a dose of 250 mg once weekly produces maximum steady-state
35
plasma concentrations of 1000 to 2000 μg/L, which are reached after 7 to 10
36
weeks.
37
Distribution
38
In healthy adults, the apparent volume of distribution is approximately 20
39
L/kg, indicating extensive tissue distribution. Mefloquine may accumulate in
40
parasitized erythrocytes. Experiments conducted in vitro with human blood
41
using concentrations between 50 and 1000 mg/mL showed a relatively
42
constant erythrocyte-to-plasma concentration ratio of about 2 to 1. The
43
equilibrium reached in less than 30 minutes was found to be reversible.
44
Protein binding is about 98%.
45
Mefloquine crosses the placenta. Excretion into breast milk appears to be
46
minimal (see PRECAUTIONS: Nursing Mothers).
47
Metabolism
48
Two metabolites have been identified in humans. The main metabolite, 2,8
49
bis-trifluoromethyl-4-quinoline carboxylic acid, is inactive in Plasmodium
50
falciparum. In a study in healthy volunteers, the carboxylic acid metabolite
51
appeared in plasma 2 to 4 hours after a single oral dose. Maximum plasma
52
concentrations, which were about 50% higher than those of mefloquine, were
53
reached after 2 weeks. Thereafter, plasma levels of the main metabolite and
54
mefloquine declined at a similar rate. The area under the plasma
55
concentration-time curve (AUC) of the main metabolite was 3 to 5 times
56
larger than that of the parent drug. The other metabolite, an alcohol, was
57
present in minute quantities only.
58
Elimination
59
In several studies in healthy adults, the mean elimination half-life of
60
mefloquine varied between 2 and 4 weeks, with an average of about 3 weeks.
61
Total clearance, which is essentially hepatic, is in the order of 30 mL/min.
62
There is evidence that mefloquine is excreted mainly in the bile and feces. In
63
volunteers, urinary excretion of unchanged mefloquine and its main
64
metabolite under steady-state condition accounted for about 9% and 4% of the
65
dose, respectively. Concentrations of other metabolites could not be measured
66
in the urine.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
67
Pharmacokinetics in Special Clinical Situations
68
Children and the Elderly
69
No relevant age-related changes have been observed in the pharmacokinetics
70
of mefloquine. Therefore, the dosage for children has been extrapolated from
71
the recommended adult dose.
72
No pharmacokinetic studies have been performed in patients with renal
73
insufficiency since only a small proportion of the drug is eliminated renally.
74
Mefloquine and its main metabolite are not appreciably removed by
75
hemodialysis. No special chemoprophylactic dosage adjustments are indicated
76
for dialysis patients to achieve concentrations in plasma similar to those in
77
healthy persons.
78
Although clearance of mefloquine may increase in late pregnancy, in general,
79
pregnancy has no clinically relevant effect on the pharmacokinetics of
80
mefloquine.
81
The pharmacokinetics of mefloquine may be altered in acute malaria.
82
Pharmacokinetic differences have been observed between various ethnic
83
populations. In practice, however, these are of minor importance compared
84
with host immune status and sensitivity of the parasite.
85
During long-term prophylaxis (>2 years), the trough concentrations and the
86
elimination half-life of mefloquine were similar to those obtained in the same
87
population after 6 months of drug use, which is when they reached steady
88
state.
89
In vitro and in vivo studies showed no hemolysis associated with glucose-6
90
phosphate dehydrogenase deficiency (see ANIMAL TOXICOLOGY).
91
Microbiology
92
Mechanism of Action
93
Mefloquine is an antimalarial agent which acts as a blood schizonticide. Its
94
exact mechanism of action is not known.
95
Activity In Vitro and In Vivo
96
Mefloquine is active against the erythrocytic stages of Plasmodium species
97
(see INDICATIONS AND USAGE). However, the drug has no effect against
98
the exoerythrocytic (hepatic) stages of the parasite. Mefloquine is effective
99
against malaria parasites resistant to chloroquine (see INDICATIONS AND
100
USAGE).
101
Drug Resistance
102
Strains of P. falciparum with decreased susceptibility to mefloquine can be
103
selected in vitro or in vivo. Resistance of P. falciparum to mefloquine has
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
104
been reported in areas of multi-drug resistance in South East Asia. Increased
105
incidences of resistance have also been reported in other parts of the world.
106
Cross-Resistance
107
Cross-resistance between mefloquine and halofantrine and cross-resistance
108
between mefloquine and quinine have been observed in some regions.
109
INDICATIONS AND USAGE
110
Treatment of Acute Malaria Infections
111
Lariam is indicated for the treatment of mild to moderate acute malaria caused
112
by mefloquine-susceptible strains of P. falciparum (both chloroquine
113
susceptible and resistant strains) or by Plasmodium vivax. There are
114
insufficient clinical data to document the effect of mefloquine in malaria
115
caused by P. ovale or P. malariae.
116
Note: Patients with acute P. vivax malaria, treated with Lariam, are at
117
high risk of relapse because Lariam does not eliminate exoerythrocytic
118
(hepatic phase) parasites. To avoid relapse, after initial treatment of the
119
acute infection with Lariam, patients should subsequently be treated
120
with an 8-aminoquinoline derivative (eg, primaquine).
121
Prevention of Malaria
122
Lariam is indicated for the prophylaxis of P. falciparum and P. vivax malaria
123
infections, including prophylaxis of chloroquine-resistant strains of P.
124
falciparum.
125
CONTRAINDICATIONS
126
Use of Lariam is contraindicated in patients with a known hypersensitivity to
127
mefloquine or related compounds (eg, quinine and quinidine) or to any of the
128
excipients contained in the formulation. Lariam should not be prescribed for
129
prophylaxis in patients with active depression, a recent history of depression,
130
generalized anxiety disorder, psychosis, or schizophrenia or other major
131
psychiatric disorders, or with a history of convulsions.
132
WARNINGS
133
In case of life-threatening, serious or overwhelming malaria infections
134
due to P. falciparum, patients should be treated with an intravenous
135
antimalarial drug. Following completion of intravenous treatment,
136
Lariam may be given to complete the course of therapy.
137
Data on the use of halofantrine subsequent to administration of Lariam
138
suggest a significant, potentially fatal prolongation of the QTc interval of
139
the ECG. Therefore, halofantrine must not be given simultaneously with
140
or subsequent to Lariam. No data are available on the use of Lariam after
141
halofantrine (see PRECAUTIONS: Drug Interactions).
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
142
Mefloquine may cause psychiatric symptoms in a number of patients,
143
ranging from anxiety, paranoia, and depression to hallucinations and
144
psychotic behavior. On occasions, these symptoms have been reported to
145
continue long after mefloquine has been stopped. Rare cases of suicidal
146
ideation and suicide have been reported though no relationship to drug
147
administration has been confirmed. To minimize the chances of these
148
adverse events, mefloquine should not be taken for prophylaxis in
149
patients with active depression or with a recent history of depression,
150
generalized anxiety disorder, psychosis, or schizophrenia or other major
151
psychiatric disorders. Lariam should be used with caution in patients
152
with a previous history of depression.
153
During prophylactic use, if psychiatric symptoms such as acute anxiety,
154
depression, restlessness or confusion occur, these may be considered
155
prodromal to a more serious event. In these cases, the drug must be
156
discontinued and an alternative medication should be substituted.
157
Concomitant administration of Lariam and quinine or quinidine may
158
produce electrocardiographic abnormalities.
159
Concomitant administration of Lariam and quinine or chloroquine may
160
increase the risk of convulsions.
161
PRECAUTIONS
162
General
163
Hypersensitivity reactions ranging from mild cutaneous events to anaphylaxis
164
cannot be predicted.
165
In patients with epilepsy, Lariam may increase the risk of convulsions. The
166
drug should therefore be prescribed only for curative treatment in such
167
patients and only if there are compelling medical reasons for its use (see
168
PRECAUTIONS: Drug Interactions).
169
Caution should be exercised with regard to activities requiring alertness and
170
fine motor coordination such as driving, piloting aircraft, operating
171
machinery, and deep-sea diving, as dizziness, a loss of balance, or other
172
disorders of the central or peripheral nervous system have been reported
173
during and following the use of Lariam. These effects may occur after therapy
174
is discontinued due to the long half-life of the drug. Lariam should be used
175
with caution in patients with psychiatric disturbances because mefloquine use
176
has been associated with emotional disturbances (see ADVERSE
177
REACTIONS).
178
In patients with impaired liver function the elimination of mefloquine may be
179
prolonged, leading to higher plasma levels.
180
This drug has been administered for longer than 1 year. If the drug is to be
181
administered for a prolonged period, periodic evaluations including liver
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
182
function tests should be performed. Although retinal abnormalities seen in
183
humans with long-term chloroquine use have not been observed with
184
mefloquine use, long-term feeding of mefloquine to rats resulted in dose
185
related ocular lesions (retinal degeneration, retinal edema and lenticular
186
opacity at 12.5 mg/kg/day and higher) (see ANIMAL TOXICOLOGY).
187
Therefore, periodic ophthalmic examinations are recommended.
188
Parenteral studies in animals show that mefloquine, a myocardial depressant,
189
possesses 20% of the antifibrillatory action of quinidine and produces 50% of
190
the increase in the PR interval reported with quinine. The effect of mefloquine
191
on the compromised cardiovascular system has not been evaluated. However,
192
transitory and clinically silent ECG alterations have been reported during the
193
use of mefloquine. Alterations included sinus bradycardia, sinus arrhythmia,
194
first degree AV-block, prolongation of the QTc interval and abnormal T
195
waves (see also cardiovascular effects under PRECAUTIONS: Drug
196
Interactions and ADVERSE REACTIONS). The benefits of Lariam therapy
197
should be weighed against the possibility of adverse effects in patients with
198
cardiac disease.
199
Laboratory Tests
200
Periodic evaluation of hepatic function should be performed during prolonged
201
prophylaxis.
202
Information for Patients
203
Medication Guide: As required by law, a Lariam Medication Guide is
204
supplied to patients when Lariam is dispensed. An information wallet card is
205
also supplied to patients when Lariam is dispensed. Patients should be
206
instructed to read the Medication Guide when Lariam is received and to carry
207
the information wallet card with them when they are taking Lariam. The
208
complete texts of the Medication Guide and information wallet card are
209
reprinted at the end of this document.
210
Patients should be advised:
211
• that malaria can be a life-threatening infection in the traveler;
212
• that Lariam is being prescribed to help prevent or treat this serious
213
infection;
214
• that in a small percentage of cases, patients are unable to take this
215
medication because of side effects, and it may be necessary to change
216
medications;
217
• that when used as prophylaxis, the first dose of Lariam should be taken 1
218
week prior to arrival in an endemic area;
219
• that if the patients experience psychiatric symptoms such as acute anxiety,
220
depression, restlessness or confusion, these may be considered prodromal
221
to a more serious event. In these cases, the drug must be discontinued and
222
an alternative medication should be substituted;
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
223
• that no chemoprophylactic regimen is 100% effective, and protective
224
clothing, insect repellents, and bednets are important components of
225
malaria prophylaxis;
226
• to seek medical attention for any febrile illness that occurs after return
227
from a malarious area and to inform their physician that they may have
228
been exposed to malaria.
229
Drug Interactions
230
Drug-drug interactions with Lariam have not been explored in detail. There is
231
one report of cardiopulmonary arrest, with full recovery, in a patient who was
232
taking a beta blocker (propranolol) (see PRECAUTIONS: General). The
233
effects of mefloquine on the compromised cardiovascular system have not
234
been evaluated. The benefits of Lariam therapy should be weighed against the
235
possibility of adverse effects in patients with cardiac disease.
236
Because of the danger of a potentially fatal prolongation of the QTc interval,
237
halofantrine must not be given simultaneously with or subsequent to Lariam
238
(see WARNINGS).
239
Concomitant administration of Lariam and other related compounds (eg,
240
quinine, quinidine and chloroquine) may produce electrocardiographic
241
abnormalities and increase the risk of convulsions (see WARNINGS). If
242
these drugs are to be used in the initial treatment of severe malaria, Lariam
243
administration should be delayed at least 12 hours after the last dose. There is
244
evidence that the use of halofantrine after mefloquine causes a significant
245
lengthening of the QTc interval. Clinically significant QTc prolongation has
246
not been found with mefloquine alone.
247
This appears to be the only clinically relevant interaction of this kind with
248
Lariam, although theoretically, coadministration of other drugs known to alter
249
cardiac conduction (eg, anti-arrhythmic or beta-adrenergic blocking agents,
250
calcium channel blockers, antihistamines or H1-blocking agents, tricyclic
251
antidepressants and phenothiazines) might also contribute to a prolongation of
252
the QTc interval. There are no data that conclusively establish whether the
253
concomitant administration of mefloquine and the above listed agents has an
254
effect on cardiac function.
255
In patients taking an anticonvulsant (eg, valproic acid, carbamazepine,
256
phenobarbital or phenytoin), the concomitant use of Lariam may reduce
257
seizure control by lowering the plasma levels of the anticonvulsant. Therefore,
258
patients concurrently taking antiseizure medication and Lariam should have
259
the blood level of their antiseizure medication monitored and the dosage
260
adjusted appropriately (see PRECAUTIONS: General).
261
When Lariam is taken concurrently with oral live typhoid vaccines,
262
attenuation of immunization cannot be excluded. Vaccinations with attenuated
263
live bacteria should therefore be completed at least 3 days before the first dose
264
of Lariam.
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
265
No other drug interactions are known. Nevertheless, the effects of Lariam on
266
travelers receiving comedication, particularly diabetics or patients using
267
anticoagulants, should be checked before departure.
268
In clinical trials, the concomitant administration of sulfadoxine and
269
pyrimethamine did not alter the adverse reaction profile.
270
Carcinogenesis, Mutagenesis, Impairment of Fertility
271
Carcinogenesis
272
The carcinogenic potential of mefloquine was studied in rats and mice in 2
273
year feeding studies at doses of up to 30 mg/kg/day. No treatment-related
274
increases in tumors of any type were noted.
275
Mutagenesis
276
The mutagenic potential of mefloquine was studied in a variety of assay
277
systems including: Ames test, a host-mediated assay in mice, fluctuation tests
278
and a mouse micronucleus assay. Several of these assays were performed with
279
and without prior metabolic activation. In no instance was evidence obtained
280
for the mutagenicity of mefloquine.
281
Impairment of Fertility
282
Fertility studies in rats at doses of 5, 20, and 50 mg/kg/day of mefloquine have
283
demonstrated adverse effects on fertility in the male at the high dose of 50
284
mg/kg/day, and in the female at doses of 20 and 50 mg/kg/day.
285
Histopathological lesions were noted in the epididymides from male rats at
286
doses of 20 and 50 mg/kg/day. Administration of 250 mg/week of mefloquine
287
(base) in adult males for 22 weeks failed to reveal any deleterious effects on
288
human spermatozoa.
289
Pregnancy
290
Teratogenic Effects
291
Pregnancy Category C. Mefloquine has been demonstrated to be teratogenic
292
in rats and mice at a dose of 100 mg/kg/day. In rabbits, a high dose of 160
293
mg/kg/day was embryotoxic and teratogenic, and a dose of 80 mg/kg/day was
294
teratogenic but not embryotoxic. There are no adequate and well-controlled
295
studies in pregnant women. However, clinical experience with Lariam has not
296
revealed an embryotoxic or teratogenic effect. Mefloquine should be used
297
during pregnancy only if the potential benefit justifies the potential risk to the
298
fetus. Women of childbearing potential who are traveling to areas where
299
malaria is endemic should be warned against becoming pregnant. Women of
300
childbearing potential should also be advised to practice contraception during
301
malaria prophylaxis with Lariam and for up to 3 months thereafter. However,
302
in the case of unplanned pregnancy, malaria chemoprophylaxis with Lariam is
303
not considered an indication for pregnancy termination.
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
304
Nursing Mothers
305
Mefloquine is excreted in human milk in small amounts, the activity of which
306
is unknown. Based on a study in a few subjects, low concentrations (3% to
307
4%) of mefloquine were excreted in human milk following a dose equivalent
308
to 250 mg of the free base. Because of the potential for serious adverse
309
reactions in nursing infants from mefloquine, a decision should be made
310
whether to discontinue the drug, taking into account the importance of the
311
drug to the mother.
312
Pediatric Use
313
Use of Lariam to treat acute, uncomplicated P. falciparum malaria in pediatric
314
patients is supported by evidence from adequate and well-controlled studies of
315
Lariam in adults with additional data from published open-label and
316
comparative trials using Lariam to treat malaria caused by P. falciparum in
317
patients younger than 16 years of age. The safety and effectiveness of Lariam
318
for the treatment of malaria in pediatric patients below the age of 6 months
319
have not been established.
320
In several studies, the administration of Lariam for the treatment of malaria
321
was associated with early vomiting in pediatric patients. Early vomiting was
322
cited in some reports as a possible cause of treatment failure. If a second dose
323
is not tolerated, the patient should be monitored closely and alternative
324
malaria treatment considered if improvement is not observed within a
325
reasonable period of time (see DOSAGE AND ADMINISTRATION).
326
Geriatric Use
327
Clinical studies of Lariam did not include sufficient numbers of subjects aged
328
65 and over to determine whether they respond differently from younger
329
subjects. Other reported clinical experience has not identified differences in
330
responses
between
the
elderly
and
younger
patients.
Since
331
electrocardiographic abnormalities have been observed in individuals treated
332
with Lariam (see PRECAUTIONS) and underlying cardiac disease is more
333
prevalent in elderly than in younger patients, the benefits of Lariam therapy
334
should be weighed against the possibility of adverse cardiac effects in elderly
335
patients.
336
ADVERSE REACTIONS
337
Clinical
338
At the doses used for treatment of acute malaria infections, the symptoms
339
possibly attributable to drug administration cannot be distinguished from
340
those symptoms usually attributable to the disease itself.
341
Among subjects who received mefloquine for prophylaxis of malaria, the
342
most frequently observed adverse experience was vomiting (3%). Dizziness,
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
343
syncope, extrasystoles and other complaints affecting less than 1% were also
344
reported.
345
Among subjects who received mefloquine for treatment, the most frequently
346
observed adverse experiences included: dizziness, myalgia, nausea, fever,
347
headache, vomiting, chills, diarrhea, skin rash, abdominal pain, fatigue, loss of
348
appetite, and tinnitus. Those side effects occurring in less than 1% included
349
bradycardia, hair loss, emotional problems, pruritus, asthenia, transient
350
emotional disturbances and telogen effluvium (loss of resting hair). Seizures
351
have also been reported.
352
Two serious adverse reactions were cardiopulmonary arrest in one patient
353
shortly after ingesting a single prophylactic dose of mefloquine while
354
concomitantly using propranolol (see PRECAUTIONS: Drug Interactions),
355
and encephalopathy of unknown etiology during prophylactic mefloquine
356
administration. The relationship of encephalopathy to drug administration
357
could not be clearly established.
358
Postmarketing
359
Postmarketing surveillance indicates that the same kind of adverse
360
experiences are reported during prophylaxis, as well as acute treatment.
361
The most frequently reported adverse events are nausea, vomiting, loose
362
stools or diarrhea, abdominal pain, dizziness or vertigo, loss of balance, and
363
neuropsychiatric events such as headache, somnolence, and sleep disorders
364
(insomnia, abnormal dreams). These are usually mild and may decrease
365
despite continued use.
366
Occasionally, more severe neuropsychiatric disorders have been reported such
367
as: sensory and motor neuropathies (including paresthesia, tremor and ataxia),
368
convulsions, agitation or restlessness, anxiety, depression, mood changes,
369
panic attacks, forgetfulness, confusion, hallucinations, aggression, psychotic
370
or paranoid reactions and encephalopathy. Rare cases of suicidal ideation and
371
suicide have been reported though no relationship to drug administration has
372
been confirmed.
373
Other infrequent adverse events include:
374
Cardiovascular
Disorders:
circulatory
disturbances
(hypotension,
375
hypertension, flushing, syncope), chest pain, tachycardia or palpitation,
376
bradycardia, irregular pulse, extrasystoles, A-V block, and other transient
377
cardiac conduction alterations
378
Skin Disorders: rash, exanthema, erythema, urticaria, pruritus, edema, hair
379
loss, erythema multiforme, and Stevens-Johnson syndrome
380
Musculoskeletal Disorders: muscle weakness, muscle cramps, myalgia, and
381
arthralgia
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
382
Respiratory Disorders: dyspnea, pneumonitis of possible allergic etiology
383
Other Symptoms: visual disturbances, vestibular disorders including tinnitus
384
and hearing impairment, asthenia, malaise, fatigue, fever, sweating, chills,
385
dyspepsia and loss of appetite
386
Laboratory
387
The most frequently observed laboratory alterations which could be possibly
388
attributable to drug administration were decreased hematocrit, transient
389
elevation of transaminases, leukopenia and thrombocytopenia. These
390
alterations were observed in patients with acute malaria who received
391
treatment doses of the drug and were attributed to the disease itself.
392
During prophylactic administration of mefloquine to indigenous populations
393
in malaria-endemic areas, the following occasional alterations in laboratory
394
values were observed: transient elevation of transaminases, leukocytosis or
395
thrombocytopenia.
396
Because of the long half-life of mefloquine, adverse reactions to Lariam may
397
occur or persist up to several weeks after the last dose.
398
OVERDOSAGE
399
Symptoms and Signs
400
In cases of overdosage with Lariam, the symptoms mentioned under
401
ADVERSE REACTIONS may be more pronounced.
402
Treatment
403
Patients should be managed by symptomatic and supportive care following
404
Lariam overdose. There are no specific antidotes. Monitor cardiac function (if
405
possible by ECG) and neuropsychiatric status for at least 24 hours. Provide
406
symptomatic and intensive supportive treatment as required, particularly for
407
cardiovascular disturbances.
408
DOSAGE AND ADMINISTRATION (see INDICATIONS AND USAGE)
409
Adult Patients
410
Treatment of mild to moderate malaria in adults caused by P. vivax or
411
mefloquine-susceptible strains of P. falciparum
412
Five tablets (1250 mg) mefloquine hydrochloride to be given as a single oral
413
dose. The drug should not be taken on an empty stomach and should be
414
administered with at least 8 oz (240 mL) of water.
415
If a full-treatment course with Lariam does not lead to improvement within 48
416
to 72 hours, Lariam should not be used for retreatment. An alternative therapy
417
should be used. Similarly, if previous prophylaxis with mefloquine has failed,
418
Lariam should not be used for curative treatment.
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
419
Note: Patients with acute P. vivax malaria, treated with Lariam, are at
420
high risk of relapse because Lariam does not eliminate exoerythrocytic
421
(hepatic phase) parasites. To avoid relapse after initial treatment of the
422
acute infection with Lariam, patients should subsequently be treated
423
with an 8-aminoquinoline derivative (eg, primaquine).
424
Malaria Prophylaxis
425
One 250 mg Lariam tablet once weekly.
426
Prophylactic drug administration should begin 1 week before arrival in an
427
endemic area. Subsequent weekly doses should be taken regularly, always on
428
the same day of each week, preferably after the main meal. To reduce the risk
429
of malaria after leaving an endemic area, prophylaxis must be continued for 4
430
additional weeks to ensure suppressive blood levels of the drug when
431
merozoites emerge from the liver. Tablets should not be taken on an empty
432
stomach and should be administered with at least 8 oz (240 mL) of water.
433
In certain cases, eg, when a traveler is taking other medication, it may be
434
desirable to start prophylaxis 2 to 3 weeks prior to departure, in order to
435
ensure that the combination of drugs is well tolerated (see PRECAUTIONS:
436
Drug Interactions).
437
When prophylaxis with Lariam fails, physicians should carefully evaluate
438
which antimalarial to use for therapy.
439
Pediatric Patients
440
Treatment of mild to moderate malaria in pediatric patients caused by
441
mefloquine-susceptible strains of P. falciparum
442
Twenty (20) to 25 mg/kg body weight. Splitting the total therapeutic dose into
443
2 doses taken 6 to 8 hours apart may reduce the occurrence or severity of
444
adverse effects. Experience with Lariam in infants less than 3 months old or
445
weighing less than 5 kg is limited. The drug should not be taken on an empty
446
stomach and should be administered with ample water. The tablets may be
447
crushed and suspended in a small amount of water, milk or other beverage for
448
administration to small children and other persons unable to swallow them
449
whole.
450
If a full-treatment course with Lariam does not lead to improvement within 48
451
to 72 hours, Lariam should not be used for retreatment. An alternative therapy
452
should be used. Similarly, if previous prophylaxis with mefloquine has failed,
453
Lariam should not be used for curative treatment.
454
In pediatric patients, the administration of Lariam for the treatment of malaria
455
has been associated with early vomiting. In some cases, early vomiting has
456
been cited as a possible cause of treatment failure (see PRECAUTIONS). If a
457
significant loss of drug product is observed or suspected because of vomiting,
458
a second full dose of Lariam should be administered to patients who vomit
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
459
less than 30 minutes after receiving the drug. If vomiting occurs 30 to 60
460
minutes after a dose, an additional half-dose should be given. If vomiting
461
recurs, the patient should be monitored closely and alternative malaria
462
treatment considered if improvement is not observed within a reasonable
463
period of time.
464
The safety and effectiveness of Lariam to treat malaria in pediatric patients
465
below the age of 6 months have not been established.
466
Malaria Prophylaxis
467
The following doses have been extrapolated from the recommended adult
468
dose. Neither the pharmacokinetics, nor the clinical efficacy of these doses
469
have been determined in children owing to the difficulty of acquiring this
470
information in pediatric subjects. The recommended prophylactic dose of
471
Lariam is approximately 5 mg/kg body weight once weekly. One 250 mg
472
Lariam tablet should be taken once weekly in pediatric patients weighing over
473
45 kg. In pediatric patients weighing less than 45 kg, the weekly dose
474
decreases in proportion to body weight:
475
30 to 45 kg:
3/4 tablet
476
20 to 30 kg:
1/2 tablet
477
10 to 20 kg:
1/4 tablet
478
5 to 10 kg:
1/8 tablet*
479
*Approximate tablet fraction based on a dosage of 5 mg/kg body weight.
480
Exact doses for children weighing less than 10 kg may best be prepared and
481
dispensed by pharmacists.
482
Experience with Lariam in infants less than 3 months old or weighing less
483
than 5 kg is limited.
484
HOW SUPPLIED
485
Lariam is available as scored, white, round tablets, containing 250 mg of
486
mefloquine hydrochloride in unit-dose packages of 25 (NDC 0004-0172-02).
487
Imprint on tablets: LARIAM 250 ROCHE
488
Tablets should be stored at 25°C (77°F); excursions permitted to 15° to 30°C
489
(59° to 86°F).
490
ANIMAL TOXICOLOGY
491
Ocular lesions were observed in rats fed mefloquine daily for 2 years. All
492
surviving rats given 30 mg/kg/day had ocular lesions in both eyes
493
characterized by retinal degeneration, opacity of the lens, and retinal edema.
494
Similar but less severe lesions were observed in 80% of female and 22% of
495
male rats fed 12.5 mg/kg/day for 2 years. At doses of 5 mg/kg/day, only
496
corneal lesions were observed. They occurred in 9% of rats studied.
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
497
Revised: Month Year
498
MEDICATION GUIDE
499
This Medication Guide is intended only for travelers who are taking
500
Lariam to prevent malaria. The information may not apply to patients who
501
are sick with malaria and who are taking Lariam to treat malaria.
502
An information wallet card is provided with this Medication Guide. Carry it
503
with you when you are taking Lariam.
504
This Medication Guide was revised in May 2004. Please read it before you
505
start taking Lariam and each time you get a refill. There may be new
506
information. This Medication Guide does not take the place of talking with
507
your prescriber (doctor or other health care provider) about Lariam and
508
malaria prevention. Only you and your prescriber can decide if Lariam is right
509
for you. If you cannot take Lariam, you may be able to take a different
510
medicine to prevent malaria.
511
What is the most important information I should know about Lariam?
512
1. Take Lariam exactly as prescribed to prevent malaria.
513
Malaria is an infection that can cause death and is spread to humans
514
through mosquito bites. If you travel to parts of the world where the
515
mosquitoes carry the malaria parasite, you must take a malaria prevention
516
medicine. Lariam is one of a small number of medications approved to
517
prevent and to treat malaria. If taken correctly, Lariam is effective at
518
preventing malaria but, like all medications, it may produce side effects in
519
some patients.
520
2. Lariam can rarely cause serious mental problems in some patients.
521
The most frequently reported side effects with Lariam, such as nausea,
522
difficulty sleeping, and bad dreams are usually mild and do not cause
523
people to stop taking the medicine. However, people taking Lariam
524
occasionally experience severe anxiety, feelings that people are against
525
them, hallucinations (seeing or hearing things that are not there, for
526
example), depression, unusual behavior, or feeling disoriented. There have
527
been reports that in some patients these side effects continue after Lariam
528
is stopped. Some patients taking Lariam think about killing themselves,
529
and there have been rare reports of suicides. It is not known whether
530
Lariam was responsible for these suicides.
531
3. You need to take malaria prevention medicine before you travel to a
532
malaria area, while you are in a malaria area, and after you return
533
from a malaria area.
534
Medicines approved in the United States for malaria prevention include
535
Lariam, doxycycline, atovaquone/proguanil, hydroxychloroquine, and
536
chloroquine. Not all of these drugs work equally as well in all areas of the
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
537
world where there is malaria. The chloroquines, for example, do not work
538
in areas where the malaria parasite has developed resistance to
539
chloroquine. Lariam may be effective against malaria that is resistant to
540
chloroquine or other drugs. All drugs to treat malaria have side effects that
541
are different for each one. For example, some may make your skin more
542
sensitive to sunlight (Lariam does not do this). However, if you use
543
Lariam to prevent malaria and you develop a sudden onset of anxiety,
544
depression, restlessness, confusion (possible signs of more serious mental
545
problems), or you develop other serious side effects, contact a doctor or
546
other health care provider. It may be necessary to stop taking Lariam and
547
use another malaria prevention medicine instead. If you can’t get another
548
medicine, leave the malaria area. However, be aware that leaving the
549
malaria area may not protect you from getting malaria. You still need to
550
take a malaria prevention medicine.
551
Who should not take Lariam?
552
Do not take Lariam to prevent malaria if you
553
• have depression or had depression recently
554
• have had recent mental illness or problems, including anxiety disorder,
555
schizophrenia (a severe type of mental illness), or psychosis (losing touch
556
with reality)
557
• have or had seizures (epilepsy or convulsions)
558
• are allergic to quinine or quinidine (medicines related to Lariam)
559
Tell your prescriber about all your medical conditions. Lariam may not be
560
right for you if you have certain conditions, especially the ones listed below:
561
• Heart disease. Lariam may not be right for you.
562
• Pregnancy. Tell your prescriber if you are pregnant or plan to become
563
pregnant. It is dangerous for the mother and for the unborn baby (fetus) to
564
get malaria during pregnancy. Therefore, ask your prescriber if you should
565
take Lariam or another medicine to prevent malaria while you are
566
pregnant.
567
• Breast-feeding. Lariam can pass through your milk and may harm the
568
baby. Therefore, ask your prescriber whether you will need to stop breast
569
feeding or use another medicine.
570
• Liver problems.
571
Tell your prescriber about all the medicines you take, including
572
prescription and non-prescription medicines, vitamins, and herbal
573
supplements. Some medicines may give you a higher chance of having
574
serious side effects from Lariam.
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
575
How should I take Lariam?
576
Take Lariam exactly as prescribed. If you are an adult or pediatric
577
patient weighing 45 kg (99 pounds) or less, your prescriber will tell you
578
the correct dose based on your weight.
579
To prevent malaria
580
• For adults and pediatric patients weighing over 45 kg, take 1 tablet of
581
Lariam at least 1 week before you travel to a malaria area (or 2 to 3 weeks
582
before you travel to a malaria area, if instructed by your prescriber). This
583
starts the prevention and also helps you see how Lariam affects you and
584
the other medicines you take. Take 1 Lariam tablet once a week, on the
585
same day each week, while in a malaria area.
586
• Continue taking Lariam for 4 weeks after returning from a malaria
587
area. If you cannot continue taking Lariam due to side effects or for other
588
reasons, contact your prescriber.
589
• Take Lariam just after a meal and with at least 1 cup (8 ounces) of water.
590
• For children, Lariam can be given with water or crushed and mixed with
591
water or sugar water. The prescriber will tell you the correct dose for
592
children based on the child’s weight.
593
• If you are told by a doctor or other health care provider to stop taking
594
Lariam due to side effects or for other reasons, it will be necessary to take
595
another malaria medicine. You must take malaria prevention medicine
596
before you travel to a malaria area, while you are in a malaria area,
597
and after you return from a malaria area. If you don’t have access to
598
a doctor or other health care provider or to another medicine besides
599
Lariam and have to stop taking it, leave the malaria area. However, be
600
aware that leaving the malaria area may not protect you from getting
601
malaria. You still need to take a malaria prevention medicine.
602
What should I avoid while taking Lariam?
603
• Halofantrine (marketed under various brand names), a medicine used
604
to treat malaria. Taking both of these medicines together can cause serious
605
heart problems that can cause death.
606
• Do not become pregnant. Women should use effective birth control
607
while taking Lariam.
608
• Quinine, quinidine, or chloroquine (other medicines used to treat
609
malaria). Taking these medicines with Lariam could cause changes in
610
your heart rate or increase the risk of seizures.
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
611
In addition:
612
• Be careful driving or in other activities needing alertness and careful
613
movements (fine motor coordination). Lariam can cause dizziness or loss
614
of balance, even after you stop taking it.
615
• Be aware that certain vaccines may not work if given while you are
616
taking Lariam. Your prescriber may want you to finish taking your
617
vaccines at least 3 days before starting Lariam.
618
What are the possible side effects of Lariam?
619
Lariam, like all medicines, may cause side effects in some patients. The most
620
frequently reported side effects with Lariam when used for prevention of
621
malaria include nausea, vomiting, diarrhea, dizziness, difficulty sleeping, and
622
bad dreams. These are usually mild and do not cause people to stop taking the
623
medicine.
624
Lariam may cause serious mental problems in some patients (see “What is the
625
most important information I should know about Lariam?”).
626
Lariam may affect your liver and your eyes if you take it for a long time. Your
627
prescriber will tell you if you should have your eyes and liver checked while
628
taking Lariam.
629
What else should I know about preventing malaria?
630
• Find out whether you need malaria prevention. Before you travel, talk
631
with your prescriber about your travel plans to determine whether you
632
need to take medicine to prevent malaria. Even in those countries where
633
malaria is present, there may be areas of the country that are free of
634
malaria. In general, malaria is more common in rural (country) areas than
635
in big cities, and it is more common during rainy seasons, when
636
mosquitoes are most common. You can get information about the areas of
637
the world where malaria occurs from the Centers for Disease Control and
638
Prevention (CDC) and from local authorities in the countries you visit. If
639
possible, plan your travel to reduce the risk of malaria.
640
• Take medicine to prevent malaria infection. Without malaria prevention
641
medicine, you have a higher risk of getting malaria. Malaria starts with
642
flu-like symptoms, such as chills, fever, muscle pains, and headaches.
643
However, malaria can make you very sick or cause death if you don’t seek
644
medical help immediately. These symptoms may disappear for a while,
645
and you may think you are well. But, the symptoms return later and then it
646
may be too late for successful treatment.
647
Malaria can cause confusion, coma, and seizures. It can cause kidney
648
failure, breathing problems, and severe damage to red blood cells.
649
However, malaria can be easily diagnosed with a blood test, and if
650
caught in time, can be effectively treated.
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LARIAM® (mefloquine hydrochloride)
651
If you get flu-like symptoms (chills, fever, muscle pains, or
652
headaches) after you return from a malaria area, get medical help
653
right away and tell your prescriber that you may have been exposed to
654
malaria.
655
People who have lived for many years in areas with malaria may have
656
some immunity to malaria (they do not get it as easily) and may not
657
take malaria prevention medicine. This does not mean that you don’t
658
need to take malaria prevention medicine.
659
• Protect against mosquito bites. Medicines do not always completely
660
prevent your catching malaria from mosquito bites. So protect yourself
661
very well against mosquitoes. Cover your skin with long sleeves and long
662
pants, and use mosquito repellent and bednets while in malaria areas. If
663
you are out in the bush, you may want to pre-wash your clothes with
664
permethrin. This is a mosquito repellent that may be effective for weeks
665
after use. Ask your prescriber for other ways to protect yourself.
666
General information about the safe and effective use of Lariam.
667
Medicines are sometimes prescribed for conditions not listed in Medication
668
Guides. If you have any concerns about Lariam, ask your prescriber. This
669
Medication Guide contains certain important information for travelers visiting
670
areas with malaria. Your prescriber or pharmacist can give you information
671
about Lariam that was written for health care professionals. Do not use
672
Lariam for a condition for which it was not prescribed. Do not share Lariam
673
with other people.
674
This Medication Guide has been approved by the U.S. Food and Drug
675
Administration.
676
Medication Guide Revised: May 2004
677
678
Reprint of information wallet card:
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
679
LARIAM® (mefloquine hydrochloride)
Lariam® (mefloquine hydrochloride) Tablets
Carry this information wallet card with you when you are taking Lariam.
You need to take malaria prevention
Other medicines approved in the United
medicine before you travel to a malaria
States for malaria prevention include:
area, while you are in a malaria area, and
doxycycline, atovaquone/proguanil,
after you return from a malaria area.
hydroxychloroquine, and chloroquine.
If taken correctly, Lariam is effective at
preventing malaria but, like all
medications, it may produce side effects
in some patients.
Not all malaria medicines work equally
well in malaria areas. The chloroquines,
for example, do not work in many parts
of the world. If you can’t get another
medicine, leave the malaria area.
If you use Lariam to prevent malaria and
However, be aware that leaving the
you develop a sudden onset of anxiety,
malaria area may not protect you from
depression, restlessness, confusion
getting malaria. You still need to take a
(possible signs of more serious mental
malaria prevention medicine.
problems), or you develop other serious
side effects, contact a doctor or other
health care provider. It may be necessary
Please read the Medication Guide for
additional information on Lariam.
to stop taking Lariam and use another
malaria prevention medicine instead.
Card Revised: May 2004
680
681
682
683
684
Manufactured by:
F. HOFFMANN-LA ROCHE LTD
Basel, Switzerland
685
Distributed by: Roche Logo & Address
686
687
xxxxxxxx
688
Copyright © 1999-200x by Roche Laboratories Inc. All rights reserved.
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:29.844176
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019591s023lbl.pdf', 'application_number': 19591, 'submission_type': 'SUPPL ', 'submission_number': 23}
|
11,547
|
NDA 19-591/S-026
NDA 19-591/S-028
Page 9 Roche Logo
LARIAM®
brand of
mefloquine hydrochloride
TABLETS
RX ONLY
DESCRIPTION
Lariam (mefloquine hydrochloride) is an antimalarial agent available as 250-mg tablets of mefloquine
hydrochloride (equivalent to 228.0 mg of the free base) for oral administration.
Mefloquine hydrochloride is a 4-quinolinemethanol derivative with the specific chemical name of (R*,
S*)-(±)-α-2-piperidinyl-2,8-bis (trifluoromethyl)-4-quinolinemethanol hydrochloride. It is a 2-aryl
substituted chemical structural analog of quinine. The drug is a white to almost white crystalline
compound, slightly soluble in water.
Mefloquine hydrochloride has a calculated molecular weight of 414.78 and the following structural
formula: Structural Formula of Mefloquine hydrochloride
The inactive ingredients are ammonium-calcium alginate, corn starch, crospovidone, lactose,
magnesium stearate, microcrystalline cellulose, poloxamer #331, and talc.
CLINICAL PHARMACOLOGY
Pharmacokinetics
Absorption
The absolute oral bioavailability of mefloquine has not been determined since an intravenous
formulation is not available. The bioavailability of the tablet formation compared with an oral solution
was over 85%. The presence of food significantly enhances the rate and extent of absorption, leading
to about a 40% increase in bioavailability. In healthy volunteers, plasma concentrations peak 6 to 24
hours (median, about 17 hours) after a single dose of Lariam. In a similar group of volunteers,
maximum plasma concentrations in µg/L are roughly equivalent to the dose in milligrams (for
example, a single 1000 mg dose produces a maximum concentration of about 1000 µg/L). In healthy
volunteers, a dose of 250 mg once weekly produces maximum steady-state plasma concentrations of
1000 to 2000 µg/L, which are reached after 7 to 10 weeks.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 10
Distribution
In healthy adults, the apparent volume of distribution is approximately 20 L/kg, indicating extensive
tissue distribution. Mefloquine may accumulate in parasitized erythrocytes. Experiments conducted in
vitro with human blood using concentrations between 50 and 1000 mg/mL showed a relatively
constant erythrocyte-to-plasma concentration ratio of about 2 to 1. The equilibrium reached in less than
30 minutes was found to be reversible. Protein binding is about 98%.
Mefloquine crosses the placenta. Excretion into breast milk appears to be minimal (see
PRECAUTIONS: Nursing Mothers).
Metabolism
Mefloquine is extensively metabolized in the liver by the cytochrome P450 system. In vitro and in vivo
studies strongly suggested that CYP3A4 is the major isoform involved.
Two metabolites of mefloquine have been identified in humans. The main metabolite, 2,8-bis
trifluoromethyl-4-quinoline carboxylic acid, is inactive in Plasmodium falciparum. In a study in
healthy volunteers, the carboxylic acid metabolite appeared in plasma 2 to 4 hours after a single oral
dose. Maximum plasma concentrations of the metabolite, which were about 50% higher than those of
mefloquine, were reached after 2 weeks. Thereafter, plasma levels of the main metabolite and
mefloquine declined at a similar rate. The area under the plasma concentration-time curve (AUC) of
the main metabolite was 3 to 5 times larger than that of the parent drug. The other metabolite, an
alcohol, was present in minute quantities only.
Elimination
In several studies in healthy adults, the mean elimination half-life of mefloquine varied between 2 and
4 weeks, with an average of about 3 weeks. Total clearance, which is essentially hepatic, is in the order
of 30 mL/min. There is evidence that mefloquine is excreted mainly in the bile and feces. In
volunteers, urinary excretion of unchanged mefloquine and its main metabolite under steady-state
condition accounted for about 9% and 4% of the dose, respectively. Concentrations of other
metabolites could not be measured in the urine.
Pharmacokinetics in Special Clinical Situations
Children and the Elderly
No relevant age-related changes have been observed in the pharmacokinetics of mefloquine. Therefore,
the dosage for children has been extrapolated from the recommended adult dose.
No pharmacokinetic studies have been performed in patients with renal insufficiency since only a
small proportion of the drug is eliminated renally. Mefloquine and its main metabolite are not
appreciably removed by hemodialysis. No special chemoprophylactic dosage adjustments are indicated
for dialysis patients to achieve concentrations in plasma similar to those in healthy persons.
Although clearance of mefloquine may increase in late pregnancy, in general, pregnancy has no
clinically relevant effect on the pharmacokinetics of mefloquine.
The pharmacokinetics of mefloquine may be altered in acute malaria.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 11
Pharmacokinetic differences have been observed between various ethnic populations. In practice,
however, these are of minor importance compared with host immune status and sensitivity of the
parasite.
During long-term prophylaxis (>2 years), the trough concentrations and the elimination half-life of
mefloquine were similar to those obtained in the same population after 6 months of drug use, which is
when they reached steady state.
In vitro and in vivo studies showed no hemolysis associated with glucose-6-phosphate dehydrogenase
deficiency (see ANIMAL TOXICOLOGY).
Microbiology
Mechanism of Action
Mefloquine is an antimalarial agent which acts as a blood schizonticide. Its exact mechanism of action
is not known.
Activity In Vitro and In Vivo
Mefloquine is active against the erythrocytic stages of Plasmodium species (see INDICATIONS AND
USAGE). However, the drug has no effect against the exoerythrocytic (hepatic) stages of the parasite.
Mefloquine is effective against malaria parasites resistant to chloroquine (see INDICATIONS AND
USAGE).
Drug Resistance
Strains of P. falciparum with decreased susceptibility to mefloquine can be selected in vitro or in vivo.
Resistance of P. falciparum to mefloquine has been reported in areas of multi-drug resistance in South
East Asia. Increased incidences of resistance have also been reported in other parts of the world.
Cross-Resistance
Cross-resistance between mefloquine and halofantrine and cross-resistance between mefloquine and
quinine have been observed in some regions.
INDICATIONS AND USAGE
Treatment of Acute Malaria Infections
Lariam is indicated for the treatment of mild to moderate acute malaria caused by mefloquine
susceptible strains of P. falciparum (both chloroquine-susceptible and resistant strains) or by
Plasmodium vivax. There are insufficient clinical data to document the effect of mefloquine in malaria
caused by P. ovale or P. malariae.
Note: Patients with acute P. vivax malaria, treated with Lariam, are at high risk of relapse
because Lariam does not eliminate exoerythrocytic (hepatic phase) parasites. To avoid relapse,
after initial treatment of the acute infection with Lariam, patients should subsequently be
treated with an 8-aminoquinoline derivative (eg, primaquine).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 12
Prevention of Malaria
Lariam is indicated for the prophylaxis of P. falciparum and P. vivax malaria infections, including
prophylaxis of chloroquine-resistant strains of P. falciparum.
CONTRAINDICATIONS
Use of Lariam is contraindicated in patients with a known hypersensitivity to mefloquine or related
compounds (eg, quinine and quinidine) or to any of the excipients contained in the formulation. Lariam
should not be prescribed for prophylaxis in patients with active depression, a recent history of
depression, generalized anxiety disorder, psychosis, or schizophrenia or other major psychiatric
disorders, or with a history of convulsions.
WARNINGS
In case of life-threatening, serious or overwhelming malaria infections due to P. falciparum,
patients should be treated with an intravenous antimalarial drug. Following completion of
intravenous treatment, Lariam may be given to complete the course of therapy.
Halofantrine should not be administered with Lariam or within 15 weeks of the last dose of
Lariam due to the risk of a potentially fatal prolongation of the QTc interval (see CLINICAL
PHARMACOLOGY: Pharmacokinetics: Elimination).
Ketoconazole should not be administered with Lariam or within 15 weeks of the last dose of
Lariam due to the risk of a potentially fatal prolongation of the QTc interval. Ketoconazole
increases plasma concentrations and elimination half-life of mefloquine following co
administration (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Elimination and
PRECAUTIONS: Drug Interactions).
Mefloquine may cause psychiatric symptoms in a number of patients, ranging from anxiety,
paranoia, and depression to hallucinations and psychotic behavior. On occasions, these
symptoms have been reported to continue long after mefloquine has been stopped. Rare cases of
suicidal ideation and suicide have been reported though no relationship to drug administration
has been confirmed. To minimize the chances of these adverse events, mefloquine should not be
taken for prophylaxis in patients with active depression or with a recent history of depression,
generalized anxiety disorder, psychosis, or schizophrenia or other major psychiatric disorders.
Lariam should be used with caution in patients with a previous history of depression.
During prophylactic use, if psychiatric symptoms such as acute anxiety, depression, restlessness
or confusion occur, these may be considered prodromal to a more serious event. In these cases,
the drug must be discontinued and an alternative medication should be substituted.
Concomitant administration of Lariam and quinine or quinidine may produce
electrocardiographic abnormalities.
Concomitant administration of Lariam and quinine or chloroquine may increase the risk of
convulsions.
PRECAUTIONS
Hypersensitivity Reactions
Hypersensitivity reactions ranging from mild cutaneous events to anaphylaxis cannot be predicted.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 13
In patients with epilepsy, Lariam may increase the risk of convulsions. The drug should therefore be
prescribed only for curative treatment in such patients and only if there are compelling medical reasons
for its use (see PRECAUTIONS: Drug Interactions).
Central and Peripheral Nervous System Effects
Caution should be exercised with regard to activities requiring alertness and fine motor coordination
such as driving, piloting aircraft, operating machinery, and deep-sea diving, as dizziness or vertigo, a
loss of balance, or other disorders of the central or peripheral nervous system have been reported
during and following the use of Lariam. These effects may occur after therapy is discontinued due to
the long half-life of the drug. In a small number of patients, dizziness or vertigo and loss of balance
have been reported to continue for months after discontinuation of the drug (see ADVERSE
REACTIONS: Postmarketing).
Lariam should be used with caution in patients with psychiatric disturbances because mefloquine use
has been associated with emotional disturbances (see ADVERSE REACTIONS).
Use in Patients with Hepatic Impairment
In patients with impaired liver function the elimination of mefloquine may be prolonged, leading to
higher plasma levels.
Long-Term Use
This drug has been administered for longer than 1 year. If the drug is to be administered for a
prolonged period, periodic evaluations including liver function tests should be performed.
Although retinal abnormalities seen in humans with long-term chloroquine use have not been observed
with mefloquine use, long-term feeding of mefloquine to rats resulted in dose-related ocular lesions
(retinal degeneration, retinal edema and lenticular opacity at 12.5 mg/kg/day and higher) (see
ANIMAL TOXICOLOGY). Therefore, periodic ophthalmic examinations are recommended.
Cardiac Effects
Parenteral studies in animals show that mefloquine, a myocardial depressant, possesses 20% of the
anti-fibrillatory action of quinidine and produces 50% of the increase in the PR interval reported with
quinine. The effect of mefloquine on the compromised cardiovascular system has not been evaluated.
However, transitory and clinically silent ECG alterations have been reported during the use of
mefloquine. Alterations included sinus bradycardia, sinus arrhythmia, first degree AV-block,
prolongation of the QTc interval and abnormal T waves (see also cardiovascular effects under
PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS). The benefits of Lariam
therapy should be weighed against the possibility of adverse effects in patients with cardiac disease.
Laboratory Tests
Periodic evaluation of hepatic function should be performed during prolonged prophylaxis.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 14
Information for Patients
Medication Guide: As required by law, a Lariam Medication Guide is supplied to patients when
Lariam is dispensed. An information wallet card is also supplied to patients when Lariam is dispensed.
Patients should be instructed to read the Medication Guide when Lariam is received and to carry the
information wallet card with them when they are taking Lariam. The complete texts of the Medication
Guide and information wallet card are reprinted at the end of this document.
Patients should be advised:
• that malaria can be a life-threatening infection in the traveler;
• that Lariam is being prescribed to help prevent or treat this serious infection;
• that in a small percentage of cases, patients are unable to take this medication because of side
effects, including dizziness or vertigo and loss of balance, and it may be necessary to change
medications. Although side effects of dizziness or vertigo and loss of balance are usually mild and
do not cause people to stop taking the medication, in a small number of patients it has been
reported that these symptoms may continue for months after discontinuation of the drug;
• that when used as prophylaxis, the first dose of Lariam should be taken 1 week prior to arrival in an
endemic area;
• that if the patients experience psychiatric symptoms such as acute anxiety, depression, restlessness
or confusion, these may be considered prodromal to a more serious event. In these cases, the drug
must be discontinued and an alternative medication should be substituted;
• 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 to
inform their physician that they may have been exposed to malaria.
Drug Interactions
Drug-drug interactions with Lariam have not been explored in detail. There is one report of
cardiopulmonary arrest, with full recovery, in a patient who was taking a beta blocker (propranolol)
(see PRECAUTIONS: Cardiac Effects). The effects of mefloquine on the compromised
cardiovascular system have not been evaluated. The benefits of Lariam therapy should be weighed
against the possibility of adverse effects in patients with cardiac disease.
Halofantrine and Other Antimalarials
Halofantrine should not be administered with Lariam or within 15 weeks of the last dose of Lariam due
to the risk of a potentially fatal prolongation of the QTc interval (see WARNINGS).
Concomitant administration of Lariam and other related antimalarial compounds (eg, quinine,
quinidine and chloroquine) may produce electrocardiographic abnormalities and increase the risk of
convulsions (see WARNINGS). If these drugs are to be used in the initial treatment of severe malaria,
Lariam administration should be delayed at least 12 hours after the last dose. Clinically significant
QTc prolongation has not been found with mefloquine alone.
Ketoconazole (Potent Inhibitor of CYP3A4)
Co-administration of a single 500 mg oral dose of Lariam with 400 mg of ketoconazole once daily for
10 days in 8 healthy volunteers resulted in an increase in the mean Cmax and AUC of mefloquine by
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 15
64% and 79%, respectively, and an increase in the mean elimination half-life of mefloquine from 322
hours to 448 hours. Ketoconazole should not be administered with Lariam or within 15 weeks of the
last dose of Lariam due to the risk of a potentially fatal prolongation of the QTc interval (see
WARNINGS).
Other Drugs that Prolong the QTc Interval
Co-administration of other drugs known to alter cardiac conduction (eg, anti-arrhythmic or beta-
adrenergic blocking agents, calcium channel blockers, antihistamines or H1-blocking agents, tricyclic
antidepressants and phenothiazines) might also contribute to a prolongation of the QTc interval. There
are no data that conclusively establish whether the concomitant administration of mefloquine and the
above listed agents has an effect on cardiac function.
Anticonvulsants
In patients taking an anticonvulsant (eg, valproic acid, carbamazepine, phenobarbital or phenytoin), the
concomitant use of Lariam may reduce seizure control by lowering the plasma levels of the
anticonvulsant. Therefore, patients concurrently taking antiseizure medication and Lariam should have
the blood level of their antiseizure medication monitored and the dosage adjusted appropriately (see
PRECAUTIONS).
Vaccines
When Lariam is taken concurrently with oral live typhoid vaccines, attenuation of immunization
cannot be excluded. Vaccinations with attenuated live bacteria should therefore be completed at least 3
days before the first dose of Lariam.
Rifampin (Potent Inducer of CYP3A4)
Co-administration of a single 500 mg oral dose of Lariam and 600 mg of rifampin once daily for 7
days in 7 healthy Thai volunteers resulted in a decrease in the mean Cmax and AUC of mefloquine by
19% and 68%, respectively, and a decrease in the mean elimination half-life of mefloquine from 305
hours to 113 hours. Rifampin should be used cautiously in patients taking Lariam.
Inhibitors and Inducers of CYP3A4
Mefloquine does not inhibit or induce the CYP 450 enzyme system. Thus, concomitant administration
of Lariam and substrates of the CYP 450 enzyme system is not expected to result in a drug interaction.
However, co-administration of CYP 450 inhibitors or inducers may increase or decrease mefloquine
plasma concentrations, respectively.
Substrates and Inhibitors of P-glycoprotein
It has been shown in vitro that mefloquine is a substrate and an inhibitor of P-glycoprotein. Therefore,
drug-drug interactions could also occur with drugs that are substrates or are known to modify the
expression of this transporter. The clinical relevance of these interactions is not known to date.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 16
Other Potential Interactions
No other drug interactions are known. Nevertheless, the effects of Lariam on travelers receiving co
medication, particularly diabetics or patients using anticoagulants, should be checked before departure.
In clinical trials, the concomitant administration of sulfadoxine and pyrimethamine did not alter the
adverse reaction profile of mefloquine.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
The carcinogenic potential of mefloquine was studied in rats and mice in 2-year feeding studies at
doses of up to 30 mg/kg/day. No treatment-related increases in tumors of any type were noted.
Mutagenesis
The mutagenic potential of mefloquine was studied in a variety of assay systems including: Ames test,
a host-mediated assay in mice, fluctuation tests and a mouse micronucleus assay. Several of these
assays were performed with and without prior metabolic activation. In no instance was evidence
obtained for the mutagenicity of mefloquine.
Impairment of Fertility
Fertility studies in rats at doses of 5, 20, and 50 mg/kg/day of mefloquine have demonstrated adverse
effects on fertility in the male at the high dose of 50 mg/kg/day, and in the female at doses of 20 and
50 mg/kg/day. Histopathological lesions were noted in the epididymides from male rats at doses of 20
and 50 mg/kg/day. Administration of 250 mg/week of mefloquine (base) in adult males for 22 weeks
failed to reveal any deleterious effects on human spermatozoa.
Pregnancy
Teratogenic Effects
Pregnancy Category C. Mefloquine has been demonstrated to be teratogenic in rats and mice at a dose
of 100 mg/kg/day. In rabbits, a high dose of 160 mg/kg/day was embryotoxic and teratogenic, and a
dose of 80 mg/kg/day was teratogenic but not embryotoxic. There are no adequate and well-controlled
studies in pregnant women. However, clinical experience with Lariam has not revealed an embryotoxic
or teratogenic effect. Mefloquine 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. Women of childbearing potential
should also be advised to practice contraception during malaria prophylaxis with Lariam and for up to
3 months thereafter. However, in the case of unplanned pregnancy, malaria chemoprophylaxis with
Lariam is not considered an indication for pregnancy termination.
Nursing Mothers
Mefloquine is excreted in human milk in small amounts, the activity of which is unknown. Based on a
study in a few subjects, low concentrations (3% to 4%) of mefloquine were excreted in human milk
following a dose equivalent to 250 mg of the free base. Because of the potential for serious adverse
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 17
reactions in nursing infants from mefloquine, a decision should be made whether to discontinue the
drug, taking into account the importance of the drug to the mother.
Pediatric Use
Use of Lariam to treat acute, uncomplicated P. falciparum malaria in pediatric patients is supported by
evidence from adequate and well-controlled studies of Lariam in adults with additional data from
published open-label and comparative trials using Lariam to treat malaria caused by P. falciparum in
patients younger than 16 years of age. The safety and effectiveness of Lariam for the treatment of
malaria in pediatric patients below the age of 6 months have not been established.
In several studies, the administration of Lariam for the treatment of malaria was associated with early
vomiting in pediatric patients. Early vomiting was cited in some reports as a possible cause of
treatment failure. If a second dose is not tolerated, the patient should be monitored closely and
alternative malaria treatment considered if improvement is not observed within a reasonable period of
time (see DOSAGE AND ADMINISTRATION).
Geriatric Use
Clinical studies of Lariam 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. Since
electrocardiographic abnormalities have been observed in individuals treated with Lariam (see
PRECAUTIONS) and underlying cardiac disease is more prevalent in elderly than in younger
patients, the benefits of Lariam therapy should be weighed against the possibility of adverse cardiac
effects in elderly patients.
ADVERSE REACTIONS
Clinical
At the doses used for treatment of acute malaria infections, the symptoms possibly attributable to drug
administration cannot be distinguished from those symptoms usually attributable to the disease itself.
Among subjects who received mefloquine for prophylaxis of malaria, the most frequently observed
adverse experience was vomiting (3%). Dizziness, syncope, extrasystoles and other complaints
affecting less than 1% were also reported.
Among subjects who received mefloquine for treatment, the most frequently observed adverse
experiences included: dizziness, myalgia, nausea, fever, headache, vomiting, chills, diarrhea, skin rash,
abdominal pain, fatigue, loss of appetite, and tinnitus. Those side effects occurring in less than 1%
included bradycardia, hair loss, emotional problems, pruritus, asthenia, transient emotional
disturbances and telogen effluvium (loss of resting hair). Seizures have also been reported.
Two serious adverse reactions were cardiopulmonary arrest in one patient shortly after ingesting a
single prophylactic dose of mefloquine while concomitantly using propranolol (see PRECAUTIONS:
Drug Interactions), and encephalopathy of unknown etiology during prophylactic mefloquine
administration. The relationship of encephalopathy to drug administration could not be clearly
established.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 18
Postmarketing
Postmarketing surveillance indicates that the same kind of adverse experiences are reported during
prophylaxis, as well as acute treatment. Because these experiences 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 Lariam exposure.
The most frequently reported adverse events are nausea, vomiting, loose stools or diarrhea, abdominal
pain, dizziness or vertigo, loss of balance, and neuropsychiatric events such as headache, somnolence,
and sleep disorders (insomnia, abnormal dreams). These are usually mild and may decrease despite
continued use. In a small number of patients it has been reported that dizziness or vertigo and loss of
balance may continue for months after discontinuation of the drug.
Occasionally, more severe neuropsychiatric disorders have been reported such as: sensory and motor
neuropathies (including paresthesia, tremor and ataxia), convulsions, agitation or restlessness, anxiety,
depression, mood swings, panic attacks, memory impairment, confusion, hallucinations, aggression,
psychotic or paranoid reactions and encephalopathy. Rare cases of suicidal ideation and suicide have
been reported though no relationship to drug administration has been confirmed.
Other less frequently reported adverse events include:
Cardiovascular Disorders: circulatory disturbances (hypotension, hypertension, flushing, syncope),
chest pain, tachycardia or palpitation, bradycardia, irregular heart rate, extrasystoles, A-V block, and
other transient cardiac conduction alterations
Skin Disorders: rash, exanthema, erythema, urticaria, pruritus, edema, hair loss, erythema multiforme,
and Stevens-Johnson syndrome
Musculoskeletal Disorders: muscle weakness, muscle cramps, myalgia, and arthralgia
Respiratory Disorders: dyspnea, pneumonitis of possible allergic etiology
Other Symptoms: visual disturbances, vestibular disorders including tinnitus and hearing impairment,
asthenia, malaise, fatigue, fever, hyperhidrosis, chills, dyspepsia and loss of appetite
Laboratory
The most frequently observed laboratory alterations which could be possibly attributable to drug
administration were decreased hematocrit, transient elevation of transaminases, leukopenia and
thrombocytopenia. These alterations were observed in patients with acute malaria who received
treatment doses of the drug and were attributed to the disease itself.
During prophylactic administration of mefloquine to indigenous populations in malaria-endemic areas,
the following occasional alterations in laboratory values were observed: transient elevation of
transaminases, leukocytosis or thrombocytopenia.
Because of the long half-life of mefloquine, adverse reactions to Lariam may occur or persist up to
several weeks after discontinuation of the drug.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 19
OVERDOSAGE
Symptoms and Signs
In cases of overdosage with Lariam, the symptoms mentioned under ADVERSE REACTIONS may
be more pronounced.
Treatment
Patients should be managed by symptomatic and supportive care following Lariam overdose. There are
no specific antidotes. Monitor cardiac function (if possible by ECG) and neuropsychiatric status for at
least 24 hours. Provide symptomatic and intensive supportive treatment as required, particularly for
cardiovascular disturbances.
DOSAGE AND ADMINISTRATION (SEE INDICATIONS AND USAGE)
Adult Patients
Treatment of mild to moderate malaria in adults caused by P. vivax or mefloquine
susceptible strains of P. falciparum
Five tablets (1250 mg) mefloquine hydrochloride to be given as a single oral dose. The drug should not
be taken on an empty stomach and should be administered with at least 8 oz (240 mL) of water.
If a full-treatment course with Lariam does not lead to improvement within 48 to 72 hours, Lariam
should not be used for retreatment. An alternative therapy should be used. Similarly, if previous
prophylaxis with mefloquine has failed, Lariam should not be used for curative treatment.
Note: Patients with acute P. vivax malaria, treated with Lariam, are at high risk of relapse
because Lariam does not eliminate exoerythrocytic (hepatic phase) parasites. To avoid relapse
after initial treatment of the acute infection with Lariam, patients should subsequently be
treated with an 8-aminoquinoline derivative (eg, primaquine).
Malaria Prophylaxis
One 250 mg Lariam tablet once weekly.
Prophylactic drug administration should begin 1 week before arrival in an endemic area. Subsequent
weekly doses should be taken regularly, always on the same day of each week, preferably after the
main meal. To reduce the risk of malaria after leaving an endemic area, prophylaxis must be continued
for 4 additional weeks to ensure suppressive blood levels of the drug when merozoites emerge from the
liver. Tablets should not be taken on an empty stomach and should be administered with at least 8 oz
(240 mL) of water.
In certain cases, eg, when a traveler is taking other medication, it may be desirable to start prophylaxis
2 to 3 weeks prior to departure, in order to ensure that the combination of drugs is well tolerated (see
PRECAUTIONS: Drug Interactions).
When prophylaxis with Lariam fails, physicians should carefully evaluate which antimalarial to use for
therapy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 20
Pediatric Patients
Treatment of mild to moderate malaria in pediatric patients caused by mefloquine
susceptible strains of P. falciparum
Twenty (20) to 25 mg/kg body weight. Splitting the total therapeutic dose into 2 doses taken 6 to 8
hours apart may reduce the occurrence or severity of adverse effects. Experience with Lariam in
pediatric patients weighing less than 20 kg is limited. The drug should not be taken on an empty
stomach and should be administered with ample water. The tablets may be crushed and suspended in a
small amount of water, milk or other beverage for administration to small children and other persons
unable to swallow them whole.
If a full-treatment course with Lariam does not lead to improvement within 48 to 72 hours, Lariam
should not be used for retreatment. An alternative therapy should be used. Similarly, if previous
prophylaxis with mefloquine has failed, Lariam should not be used for curative treatment.
In pediatric patients, the administration of Lariam for the treatment of malaria has been associated with
early vomiting. In some cases, early vomiting has been cited as a possible cause of treatment failure
(see PRECAUTIONS). If a significant loss of drug product is observed or suspected because of
vomiting, a second full dose of Lariam should be administered to patients who vomit less than 30
minutes after receiving the drug. If vomiting occurs 30 to 60 minutes after a dose, an additional half-
dose should be given. If vomiting recurs, the patient should be monitored closely and alternative
malaria treatment considered if improvement is not observed within a reasonable period of time.
The safety and effectiveness of Lariam to treat malaria in pediatric patients below the age of 6 months
have not been established.
Malaria Prophylaxis
The recommended prophylactic dose of Lariam is approximately 5 mg/kg body weight once weekly.
One 250 mg Lariam tablet should be taken once weekly in pediatric patients weighing over 45 kg. In
pediatric patients weighing less than 45 kg, the weekly dose decreases in proportion to body weight:
30 to 45 kg:
3/4 tablet
20 to 30 kg:
1/2 tablet
Experience with Lariam in pediatric patients weighing less than 20 kg is limited.
HOW SUPPLIED
Lariam is available as scored, white, round tablets, containing 250 mg of mefloquine hydrochloride in
unit-dose packages of 25 (NDC 0004-0172-02). Imprint on tablets: LARIAM 250 ROCHE
Tablets should be stored at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
ANIMAL TOXICOLOGY
Ocular lesions were observed in rats fed mefloquine daily for 2 years. All surviving rats given 30
mg/kg/day had ocular lesions in both eyes characterized by retinal degeneration, opacity of the lens,
and retinal edema. Similar but less severe lesions were observed in 80% of female and 22% of male
rats fed 12.5 mg/kg/day for 2 years. At doses of 5 mg/kg/day, only corneal lesions were observed.
They occurred in 9% of rats studied.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 21
Revised: Month/Year Roche Logo
MEDICATION GUIDE
Lariam (LAH-ree-am)
(mefloquine hydrochloride)
Tablets
Read this entire Medication Guide before you start taking Lariam and each time you get a
refill. There may be new information. This information does not take the place of talking to
your doctor about your medical condition or your treatment.
What is the most important information I should know about Lariam?
Your doctor or pharmacist will give you an Information Wallet Card
along with this Medication Guide. It has important information
about Lariam and should be carried with you at all times while you
take Lariam.
Lariam can cause serious mental problems.
• Some people who take Lariam have sudden serious mental problems, including:
• severe anxiety
• paranoia (feelings of mistrust towards others)
• hallucinations (seeing or hearing things that are not there)
• depression
• feeling restless
• unusual behavior
• feeling confused
In some patients these serious side effects can go on after Lariam is stopped.
• Some people who take Lariam think about suicide (putting an end to their life). Some
people who were taking Lariam committed suicide. It is not known whether Lariam was
responsible for those suicides.
If you have any of these serious mental problems, or you develop other serious side
effects or mental problems, you should call your doctor right away as it may be necessary
to stop taking Lariam and use another medicine to prevent malaria.
You need to take malaria prevention medicine before you travel to a malaria
area, while you are in a malaria area, and after you return from a malaria area.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 22
If you are told by a doctor to stop taking Lariam because of the side effects or for other
reasons, you will need to take another malaria medicine.
If you do not have access to a doctor or to another medicine and have to stop taking
Lariam, leave the malaria area and contact a doctor as soon as possible because leaving
the malaria area may not protect you from getting malaria. You will still need to take a
malaria prevention medicine for another 4 weeks.
• Do not take halofantrine (used to treat malaria) or ketoconazole (used for fungal
infections) with Lariam or within 15 weeks of your last dose of Lariam. You may have
serious heart problems that can lead to death. Do not take quinine (Qualaquin) or
quinidine (used to treat malaria or irregular heart beat) with Lariam. You may have
serious heart problems.
• Do not take quinine (Qualaquin) or chloroquine (Aralen) (used to treat malaria) with
Lariam. You may have a greater risk for convulsions (seizures).
What is Lariam?
Lariam is a prescription medicine used to prevent and treat malaria. Malaria can be a life-
threatening infection. Lariam does not work for all types of malaria.
It is not known if Lariam is safe and effective in children under 6 months old for the
treatment of malaria.
It is not known how well Lariam works to prevent malaria in infants weighing less than 44 lbs
(20 kg).
Who should not take Lariam?
Do not take Lariam if you have:
• depression or had depression recently
• had recent mental problems, including anxiety disorder, schizophrenia, or psychosis
(losing touch with reality)
• seizures or had seizures (epilepsy or convulsions)
• an allergy to quinine, quinidine, Lariam or any ingredients in Lariam. See the end of this
Medication Guide for a complete list of ingredients in Lariam.
Talk to your doctor before you take Lariam if you have any of the conditions listed above.
What should I tell my doctor before taking Lariam?
Before taking Lariam, tell your doctor about all your medical conditions, including
if you have:
• heart disease
• liver problems
• seizures or epilepsy
• diabetes
• blood clotting problems or take blood thinner medicines (anticoagulants)
• mental problems
• are pregnant or plan to become pregnant. It is not known if Lariam will harm your unborn
baby. Talk to you doctor if you are pregnant or plan to become pregnant.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 23
• use birth control while you take Lariam and for 3 months after you stop Lariam. If you
have an unplanned pregnancy, talk to your doctor right away.
• are breast-feeding or plan to breast-feed. Lariam can pass through your milk and may
harm your baby. Ask your doctor whether you will need to stop breast-feeding or use
another medicine.
After leaving a malaria area, if you have a fever contact your doctor right away.
Tell your doctor about all the medicines you take, including prescription and non
prescription medicines, vitamins, and herbal supplements. Lariam and other medicines may
affect each other causing side effects.
Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist
when you get a new medicine.
Especially tell your doctor if you take:
• ketoconazole used to treat fungal infections
• halofantrine, quinine (Qualaquin), quinidine, chloroquine (Aralen) or other medicines used
to treat malaria
• anti-arrhythmic medicines, beta-adrenergic blocking medicines and calcium channel
blockers used to treat heart problems or high blood pressure
• antihistamines or H1-blocking agents used to treat allergies
• tricyclic antidepressants used to treat depression
• phenothiazines used to treat mental problems
• anticonvulsants used to treat seizures
• vaccines containing live bacteria. Your doctor may want you to finish receiving your
vaccines at least 3 days before you start Lariam.
• rifampin and rifampin-containing products (Rifadin, Rifamate, Rifater, Rimactane) used to
treat infections
Ask your doctor or pharmacist for a list of these medicines if you are not sure.
How should I take Lariam?
• Take Lariam exactly as your doctor tells you to take it. Your doctor will tell you how many
Lariam to take and when to take them.
• You will start taking Lariam to prevent malaria between 1 to 3 weeks before you travel to
a malaria area.
• Take Lariam just after eating your main meal and with at least one cup (8 ounces) of
water.
• Do not take Lariam on an empty stomach.
• If you vomit after taking Lariam, call your healthcare provider to see if you should take
another dose.
• Continue taking Lariam for 4 weeks after returning from a malaria area.
• Lariam tablets may be crushed and mixed with a small amount of water, milk or other
beverage for children or other people unable to swallow Lariam whole. Your doctor will
tell you the correct dose for your child based on your child’s weight.
• If you take Lariam for a year or longer, your doctor should check your
• eyes, especially if you have trouble seeing while you take Lariam
• liver function to see if there has been damage to your liver
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 24
• Use protective clothing, insect repellents, and bednets to protect you from being bitten by
mosquitoes. Medicine alone does not always stop you from catching malaria from
mosquito bites.
What should I avoid while taking Lariam?
Avoid activities such as driving a car or using heavy machinery or other activities needing
alertness and careful movements (fine motor coordination) until you know how Lariam
affects you. You may feel dizzy or lose your balance. This could happen for months after you
stop taking Lariam. See “What are the possible side effects of Lariam?”
What are the possible side effects of Lariam?
Also see “What is the most important information I should know about Lariam?”
Lariam may cause serious side effects, including:
• convulsions (seizures)
• liver problems
• heart problems
The most common side effects of Lariam include:
• nausea
• vomiting
• diarrhea
• abdominal pain
• dizziness or loss of balance (vertigo), which may continue for months after Lariam is
stopped
• headache
• sleeping problems (sleepiness, unable to sleep, bad dreams)
The most common side effects in people who take Lariam for treatment include:
• muscle pain
• fever
• chills
• skin rash
• fatigue
• loss of appetite
• ringing in the ears
• irregular heart beat
Tell your doctor if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of Lariam. For more information, 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 Lariam?
• Store Lariam between 59ºF to 86ºF (15ºC to 30ºC)
• Safely throw away medicine that is out of date or no longer needed.
Keep Lariam and all medicines out of the reach of children.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 25
General information about the safe and effective use of Lariam.
Medicines are sometimes prescribed for purposes other than those listed in a Medication
Guide. Do not use Lariam for a condition for which it was not prescribed. Do not give
Lariam 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 Lariam. If you
would like more information, talk with your doctor. You can ask your pharmacist or doctor
for information about Lariam that is written for health professionals.
If you have any questions or would like more information about Lariam, you can
call Roche, the manufacturer of Lariam, at 1-800-526-6367.
What are the ingredients in Lariam?
Active ingredients: mefloquine hydrochloride
Inactive ingredients: ammonium-calcium alginate, corn starch, crospovidone, lactose,
magnesium stearate, microcrystalline cellulose, poloxamer #331, and talc.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Reprint of information wallet card:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 26
Information Wallet Card
Lariam® (mefloquine hydrochloride) Tablets
It is important that you read the entire Medication Guide for additional information on Lariam.
Carry this wallet card with you when you are taking Lariam.
You need to take malaria prevention
medicine before you travel to a malaria
area, while you are in a malaria area, and
after you return from a malaria area.
Lariam can cause serious mental
problems in some people. If you take
Lariam and you have sudden signs of serious
mental problems (such as: severe anxiety,
feelings of mistrust towards others, seeing or
hearing things that are not there, depression,
feeling restless, unusual behavior or feeling
confused), you should contact a doctor right
away as it may be necessary to stop taking
Lariam and take different medicine to prevent
malaria.
Other side effects from Lariam may
include: convulsions, liver problems, and
heart problems. The most common side
effects of Lariam include nausea, vomiting,
diarrhea, abdominal pain, dizziness or loss of
balance (vertigo) which may continue for
months after Lariam is stopped, headache, and
sleeping problems (sleepiness, unable to sleep,
bad dreams).
While you take Lariam, do not take:
•
Halofantrine (used to treat malaria)
•
Ketoconazole (used for fungal
infections)
•
Quinine (Qualaquin) or quinidine
(used to treat malaria or irregular
heart beat)
•
Chloroquine (Aralen) (used to treat
malaria)
Avoid activities such as driving a car or using
heavy machinery or other activities needing
alertness and careful movements (fine motor
coordination) until you know how Lariam
affects you.
Other medicines are approved in the United
States for malaria prevention. However, not
all malaria medicines work equally well in
different malaria areas. Before you travel,
talk to your doctor about your travel plans.
If you have any serious side effects, and
cannot get another medicine, leave the
malaria area and contact a doctor as soon as
possible because leaving the malaria area
may not protect you from getting malaria.
You will still need to take a malaria
prevention medicine.
Call your doctor for medical advice about
side effects.
You may report side effects to FDA at
1-800-FDA-1088.
Card Revised: Month/Year
Manufactured by:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 27
F. HOFFMANN-LA ROCHE LTD
Basel, Switzerland Roche Logo they are the Distributor
Revised: Month/Year
LMT_215998_MG_MMYYYY_N
Copyright © 2003-2009 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 19-591/S-026
NDA 19-591/S-028
Page 28
Appendix A: Medication Guide REMS Document
NDA 19-591 Lariam® (mefloquine hydrochloride) Tablets
Antimalarial Agent for the Treatment and Prevention of Malaria
Hoffmann-La Roche Inc.
340 Kingsland Street
Nutley, New Jersey 07110-1199
Roche Pharmaceuticals Service Center Telephone Contact Number:
1-800-526-6367
RISK EVALUATION AND MITIGATION STRATEGY (REMS)
I.
GOAL: To inform patients about the serious risks associated with the use of Lariam
(mefloquine hydrochloride).
II.
REMS ELEMENTS:
A. Medication Guide
A Medication Guide will be dispensed with each Lariam prescription in accordance with 21
CFR 208.
Pursuant to 21 CFR 208.24, the Medication Guide will be made available in sufficient
numbers to US Lariam distributors. US distributors will provide the Medication Guide with
every pharmacy shelf carton of Lariam to ensure its availability for dispensing to patients
who are dispensed Lariam. The label of each container or package of Lariam will include a
prominent instruction to authorized dispensers to provide a Medication Guide to each
patient to whom the drug is dispensed, and state how the Medication Guide is provided.
See appended Medication Guide.
B. Timetable for Submission of Assessments
The timetable for submission of assessments of the REMS will be 18 months, 3 years, and
7th years after the REMS is initially approved. The reporting interval covered by each
assessment will conclude no earlier than 60 days before the submission date for that
assessment.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 29 Roche Logo
MEDICATION GUIDE
Lariam (LAH-ree-am)
(mefloquine hydrochloride)
Tablets
Read this entire Medication Guide before you start taking Lariam and each time you get a
refill. There may be new information. This information does not take the place of talking to
your doctor about your medical condition or your treatment.
What is the most important information I should know about Lariam?
Your doctor or pharmacist will give you an Information Wallet Card
along with this Medication Guide. It has important information
about Lariam and should be carried with you at all times while you
take Lariam.
Lariam can cause serious mental problems.
• Some people who take Lariam have sudden serious mental problems, including:
• severe anxiety
• paranoia (feelings of mistrust towards others)
• hallucinations (seeing or hearing things that are not there)
• depression
• feeling restless
• unusual behavior
• feeling confused
In some patients these serious side effects can go on after Lariam is stopped.
• Some people who take Lariam think about suicide (putting an end to their life). Some
people who were taking Lariam committed suicide. It is not known whether Lariam was
responsible for those suicides.
If you have any of these serious mental problems, or you develop other serious side
effects or mental problems, you should call your doctor right away as it may be necessary
to stop taking Lariam and use another medicine to prevent malaria.
You need to take malaria prevention medicine before you travel to a malaria
area, while you are in a malaria area, and after you return from a malaria area.
If you are told by a doctor to stop taking Lariam because of the side effects or for other
reasons, you will need to take another malaria medicine.
If you do not have access to a doctor or to another medicine and have to stop taking
Lariam, leave the malaria area and contact a doctor as soon as possible because leaving
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 30
the malaria area may not protect you from getting malaria. You will still need to take a
malaria prevention medicine for another 4 weeks.
• Do not take halofantrine (used to treat malaria) or ketoconazole (used for fungal
infections) with Lariam or within 15 weeks of your last dose of Lariam. You may have
serious heart problems that can lead to death. Do not take quinine (Qualaquin) or
quinidine (used to treat malaria or irregular heart beat) with Lariam. You may have
serious heart problems.
• Do not take quinine (Qualaquin) or chloroquine (Aralen) (used to treat malaria) with
Lariam. You may have a greater risk for convulsions (seizures).
What is Lariam?
Lariam is a prescription medicine used to prevent and treat malaria. Malaria can be a life-
threatening infection. Lariam does not work for all types of malaria.
It is not known if Lariam is safe and effective in children under 6 months old for the
treatment of malaria.
It is not known how well Lariam works to prevent malaria in infants weighing less than 44 lbs
(20 kg).
Who should not take Lariam?
Do not take Lariam if you have:
• depression or had depression recently
• had recent mental problems, including anxiety disorder, schizophrenia, or psychosis
(losing touch with reality)
• seizures or had seizures (epilepsy or convulsions)
• an allergy to quinine, quinidine, Lariam or any ingredients in Lariam. See the end of this
Medication Guide for a complete list of ingredients in Lariam.
Talk to your doctor before you take Lariam if you have any of the conditions listed above.
What should I tell my doctor before taking Lariam?
Before taking Lariam, tell your doctor about all your medical conditions, including
if you have:
• heart disease
• liver problems
• seizures or epilepsy
• diabetes
• blood clotting problems or take blood thinner medicines (anticoagulants)
• mental problems
• are pregnant or plan to become pregnant. It is not known if Lariam will harm your unborn
baby. Talk to you doctor if you are pregnant or plan to become pregnant.
• use birth control while you take Lariam and for 3 months after you stop Lariam. If you
have an unplanned pregnancy, talk to 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 19-591/S-026
NDA 19-591/S-028
Page 31
• are breast-feeding or plan to breast-feed. Lariam can pass through your milk and may
harm your baby. Ask your doctor whether you will need to stop breast-feeding or use
another medicine.
After leaving a malaria area, if you have a fever contact your doctor right away.
Tell your doctor about all the medicines you take, including prescription and non
prescription medicines, vitamins, and herbal supplements. Lariam and other medicines may
affect each other causing side effects.
Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist
when you get a new medicine.
Especially tell your doctor if you take:
• ketoconazole used to treat fungal infections
• halofantrine, quinine (Qualaquin), quinidine, chloroquine (Aralen) or other medicines used
to treat malaria
• anti-arrhythmic medicines, beta-adrenergic blocking medicines and calcium channel
blockers used to treat heart problems or high blood pressure
• antihistamines or H1-blocking agents used to treat allergies
• tricyclic antidepressants used to treat depression
• phenothiazines used to treat mental problems
• anticonvulsants used to treat seizures
• vaccines containing live bacteria. Your doctor may want you to finish receiving your
vaccines at least 3 days before you start Lariam.
• rifampin and rifampin-containing products (Rifadin, Rifamate, Rifater, Rimactane) used to
treat infections
Ask your doctor or pharmacist for a list of these medicines if you are not sure.
How should I take Lariam?
• Take Lariam exactly as your doctor tells you to take it. Your doctor will tell you how many
Lariam to take and when to take them.
• You will start taking Lariam to prevent malaria between 1 to 3 weeks before you travel to
a malaria area.
• Take Lariam just after eating your main meal and with at least one cup (8 ounces) of
water.
• Do not take Lariam on an empty stomach.
• If you vomit after taking Lariam, call your healthcare provider to see if you should take
another dose.
• Continue taking Lariam for 4 weeks after returning from a malaria area.
• Lariam tablets may be crushed and mixed with a small amount of water, milk or other
beverage for children or other people unable to swallow Lariam whole. Your doctor will
tell you the correct dose for your child based on your child’s weight.
• If you take Lariam for a year or longer, your doctor should check your
• eyes, especially if you have trouble seeing while you take Lariam
• liver function to see if there has been damage to your liver
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 32
• Use protective clothing, insect repellents, and bednets to protect you from being bitten by
mosquitoes. Medicine alone does not always stop you from catching malaria from
mosquito bites.
What should I avoid while taking Lariam?
Avoid activities such as driving a car or using heavy machinery or other activities needing
alertness and careful movements (fine motor coordination) until you know how Lariam
affects you. You may feel dizzy or lose your balance. This could happen for months after you
stop taking Lariam. See “What are the possible side effects of Lariam?”
What are the possible side effects of Lariam?
Also see “What is the most important information I should know about Lariam?”
Lariam may cause serious side effects, including:
• convulsions (seizures)
• liver problems
• heart problems
The most common side effects of Lariam include:
• nausea
• vomiting
• diarrhea
• abdominal pain
• dizziness or loss of balance (vertigo), which may continue for months after Lariam is
stopped
• headache
• sleeping problems (sleepiness, unable to sleep, bad dreams)
The most common side effects in people who take Lariam for treatment include:
• muscle pain
• fever
• chills
• skin rash
• fatigue
• loss of appetite
• ringing in the ears
• irregular heart beat
Tell your doctor if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of Lariam. For more information, 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 Lariam?
• Store Lariam between 59ºF to 86ºF (15ºC to 30ºC)
• Safely throw away medicine that is out of date or no longer needed.
Keep Lariam and all medicines out of the reach of children.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 33
General information about the safe and effective use of Lariam.
Medicines are sometimes prescribed for purposes other than those listed in a Medication
Guide. Do not use Lariam for a condition for which it was not prescribed. Do not give
Lariam 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 Lariam. If you
would like more information, talk with your doctor. You can ask your pharmacist or doctor
for information about Lariam that is written for health professionals.
If you have any questions or would like more information about Lariam, you can
call Roche, the manufacturer of Lariam, at 1-800-526-6367.
What are the ingredients in Lariam?
Active ingredients: mefloquine hydrochloride
Inactive ingredients: ammonium-calcium alginate, corn starch, crospovidone, lactose,
magnesium stearate, microcrystalline cellulose, poloxamer #331, and talc.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Reprint of information wallet card:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 34
Information Wallet Card
Lariam® (mefloquine hydrochloride) Tablets
It is important that you read the entire Medication Guide for additional information on Lariam.
Carry this wallet card with you when you are taking Lariam.
You need to take malaria prevention
medicine before you travel to a malaria
area, while you are in a malaria area, and
after you return from a malaria area.
Lariam can cause serious mental
problems in some people. If you take
Lariam and you have sudden signs of serious
mental problems (such as: severe anxiety,
feelings of mistrust towards others, seeing or
hearing things that are not there, depression,
feeling restless, unusual behavior or feeling
confused), you should contact a doctor right
away as it may be necessary to stop taking
Lariam and take different medicine to prevent
malaria.
Other side effects from Lariam may
include: convulsions, liver problems, and
heart problems. The most common side
effects of Lariam include nausea, vomiting,
diarrhea, abdominal pain, dizziness or loss of
balance (vertigo) which may continue for
months after Lariam is stopped, headache, and
sleeping problems (sleepiness, unable to sleep,
bad dreams).
While you take Lariam, do not take:
•
Halofantrine (used to treat malaria)
•
Ketoconazole (used for fungal
infections)
•
Quinine (Qualaquin) or quinidine
(used to treat malaria or irregular
heart beat)
•
Chloroquine (Aralen) (used to treat
malaria)
Avoid activities such as driving a car or using
heavy machinery or other activities needing
alertness and careful movements (fine motor
coordination) until you know how Lariam
affects you.
Other medicines are approved in the United
States for malaria prevention. However, not
all malaria medicines work equally well in
different malaria areas. Before you travel,
talk to your doctor about your travel plans.
If you have any serious side effects, and
cannot get another medicine, leave the
malaria area and contact a doctor as soon as
possible because leaving the malaria area
may not protect you from getting malaria.
You will still need to take a malaria
prevention medicine.
Call your doctor for medical advice about
side effects.
You may report side effects to FDA at
1-800-FDA-1088.
Card Revised: Month/Year
Manufactured by:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 35
F. HOFFMANN-LA ROCHE LTD
Basel, Switzerland Roche Logo
Revised: Month/Year
LMT_215998_MG_MMYYYY_N
Copyright © 2003-2009 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
|
2025-02-12T13:45:29.877359
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019591s026s028lbl.pdf', 'application_number': 19591, 'submission_type': 'SUPPL ', 'submission_number': 26}
|
11,549
|
NDA 19-591/S-026
NDA 19-591/S-028
Page 9 Roche Logo
LARIAM®
brand of
mefloquine hydrochloride
TABLETS
RX ONLY
DESCRIPTION
Lariam (mefloquine hydrochloride) is an antimalarial agent available as 250-mg tablets of mefloquine
hydrochloride (equivalent to 228.0 mg of the free base) for oral administration.
Mefloquine hydrochloride is a 4-quinolinemethanol derivative with the specific chemical name of (R*,
S*)-(±)-α-2-piperidinyl-2,8-bis (trifluoromethyl)-4-quinolinemethanol hydrochloride. It is a 2-aryl
substituted chemical structural analog of quinine. The drug is a white to almost white crystalline
compound, slightly soluble in water.
Mefloquine hydrochloride has a calculated molecular weight of 414.78 and the following structural
formula: Structural Formula of Mefloquine hydrochloride
The inactive ingredients are ammonium-calcium alginate, corn starch, crospovidone, lactose,
magnesium stearate, microcrystalline cellulose, poloxamer #331, and talc.
CLINICAL PHARMACOLOGY
Pharmacokinetics
Absorption
The absolute oral bioavailability of mefloquine has not been determined since an intravenous
formulation is not available. The bioavailability of the tablet formation compared with an oral solution
was over 85%. The presence of food significantly enhances the rate and extent of absorption, leading
to about a 40% increase in bioavailability. In healthy volunteers, plasma concentrations peak 6 to 24
hours (median, about 17 hours) after a single dose of Lariam. In a similar group of volunteers,
maximum plasma concentrations in µg/L are roughly equivalent to the dose in milligrams (for
example, a single 1000 mg dose produces a maximum concentration of about 1000 µg/L). In healthy
volunteers, a dose of 250 mg once weekly produces maximum steady-state plasma concentrations of
1000 to 2000 µg/L, which are reached after 7 to 10 weeks.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 10
Distribution
In healthy adults, the apparent volume of distribution is approximately 20 L/kg, indicating extensive
tissue distribution. Mefloquine may accumulate in parasitized erythrocytes. Experiments conducted in
vitro with human blood using concentrations between 50 and 1000 mg/mL showed a relatively
constant erythrocyte-to-plasma concentration ratio of about 2 to 1. The equilibrium reached in less than
30 minutes was found to be reversible. Protein binding is about 98%.
Mefloquine crosses the placenta. Excretion into breast milk appears to be minimal (see
PRECAUTIONS: Nursing Mothers).
Metabolism
Mefloquine is extensively metabolized in the liver by the cytochrome P450 system. In vitro and in vivo
studies strongly suggested that CYP3A4 is the major isoform involved.
Two metabolites of mefloquine have been identified in humans. The main metabolite, 2,8-bis
trifluoromethyl-4-quinoline carboxylic acid, is inactive in Plasmodium falciparum. In a study in
healthy volunteers, the carboxylic acid metabolite appeared in plasma 2 to 4 hours after a single oral
dose. Maximum plasma concentrations of the metabolite, which were about 50% higher than those of
mefloquine, were reached after 2 weeks. Thereafter, plasma levels of the main metabolite and
mefloquine declined at a similar rate. The area under the plasma concentration-time curve (AUC) of
the main metabolite was 3 to 5 times larger than that of the parent drug. The other metabolite, an
alcohol, was present in minute quantities only.
Elimination
In several studies in healthy adults, the mean elimination half-life of mefloquine varied between 2 and
4 weeks, with an average of about 3 weeks. Total clearance, which is essentially hepatic, is in the order
of 30 mL/min. There is evidence that mefloquine is excreted mainly in the bile and feces. In
volunteers, urinary excretion of unchanged mefloquine and its main metabolite under steady-state
condition accounted for about 9% and 4% of the dose, respectively. Concentrations of other
metabolites could not be measured in the urine.
Pharmacokinetics in Special Clinical Situations
Children and the Elderly
No relevant age-related changes have been observed in the pharmacokinetics of mefloquine. Therefore,
the dosage for children has been extrapolated from the recommended adult dose.
No pharmacokinetic studies have been performed in patients with renal insufficiency since only a
small proportion of the drug is eliminated renally. Mefloquine and its main metabolite are not
appreciably removed by hemodialysis. No special chemoprophylactic dosage adjustments are indicated
for dialysis patients to achieve concentrations in plasma similar to those in healthy persons.
Although clearance of mefloquine may increase in late pregnancy, in general, pregnancy has no
clinically relevant effect on the pharmacokinetics of mefloquine.
The pharmacokinetics of mefloquine may be altered in acute malaria.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 11
Pharmacokinetic differences have been observed between various ethnic populations. In practice,
however, these are of minor importance compared with host immune status and sensitivity of the
parasite.
During long-term prophylaxis (>2 years), the trough concentrations and the elimination half-life of
mefloquine were similar to those obtained in the same population after 6 months of drug use, which is
when they reached steady state.
In vitro and in vivo studies showed no hemolysis associated with glucose-6-phosphate dehydrogenase
deficiency (see ANIMAL TOXICOLOGY).
Microbiology
Mechanism of Action
Mefloquine is an antimalarial agent which acts as a blood schizonticide. Its exact mechanism of action
is not known.
Activity In Vitro and In Vivo
Mefloquine is active against the erythrocytic stages of Plasmodium species (see INDICATIONS AND
USAGE). However, the drug has no effect against the exoerythrocytic (hepatic) stages of the parasite.
Mefloquine is effective against malaria parasites resistant to chloroquine (see INDICATIONS AND
USAGE).
Drug Resistance
Strains of P. falciparum with decreased susceptibility to mefloquine can be selected in vitro or in vivo.
Resistance of P. falciparum to mefloquine has been reported in areas of multi-drug resistance in South
East Asia. Increased incidences of resistance have also been reported in other parts of the world.
Cross-Resistance
Cross-resistance between mefloquine and halofantrine and cross-resistance between mefloquine and
quinine have been observed in some regions.
INDICATIONS AND USAGE
Treatment of Acute Malaria Infections
Lariam is indicated for the treatment of mild to moderate acute malaria caused by mefloquine
susceptible strains of P. falciparum (both chloroquine-susceptible and resistant strains) or by
Plasmodium vivax. There are insufficient clinical data to document the effect of mefloquine in malaria
caused by P. ovale or P. malariae.
Note: Patients with acute P. vivax malaria, treated with Lariam, are at high risk of relapse
because Lariam does not eliminate exoerythrocytic (hepatic phase) parasites. To avoid relapse,
after initial treatment of the acute infection with Lariam, patients should subsequently be
treated with an 8-aminoquinoline derivative (eg, primaquine).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 12
Prevention of Malaria
Lariam is indicated for the prophylaxis of P. falciparum and P. vivax malaria infections, including
prophylaxis of chloroquine-resistant strains of P. falciparum.
CONTRAINDICATIONS
Use of Lariam is contraindicated in patients with a known hypersensitivity to mefloquine or related
compounds (eg, quinine and quinidine) or to any of the excipients contained in the formulation. Lariam
should not be prescribed for prophylaxis in patients with active depression, a recent history of
depression, generalized anxiety disorder, psychosis, or schizophrenia or other major psychiatric
disorders, or with a history of convulsions.
WARNINGS
In case of life-threatening, serious or overwhelming malaria infections due to P. falciparum,
patients should be treated with an intravenous antimalarial drug. Following completion of
intravenous treatment, Lariam may be given to complete the course of therapy.
Halofantrine should not be administered with Lariam or within 15 weeks of the last dose of
Lariam due to the risk of a potentially fatal prolongation of the QTc interval (see CLINICAL
PHARMACOLOGY: Pharmacokinetics: Elimination).
Ketoconazole should not be administered with Lariam or within 15 weeks of the last dose of
Lariam due to the risk of a potentially fatal prolongation of the QTc interval. Ketoconazole
increases plasma concentrations and elimination half-life of mefloquine following co
administration (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Elimination and
PRECAUTIONS: Drug Interactions).
Mefloquine may cause psychiatric symptoms in a number of patients, ranging from anxiety,
paranoia, and depression to hallucinations and psychotic behavior. On occasions, these
symptoms have been reported to continue long after mefloquine has been stopped. Rare cases of
suicidal ideation and suicide have been reported though no relationship to drug administration
has been confirmed. To minimize the chances of these adverse events, mefloquine should not be
taken for prophylaxis in patients with active depression or with a recent history of depression,
generalized anxiety disorder, psychosis, or schizophrenia or other major psychiatric disorders.
Lariam should be used with caution in patients with a previous history of depression.
During prophylactic use, if psychiatric symptoms such as acute anxiety, depression, restlessness
or confusion occur, these may be considered prodromal to a more serious event. In these cases,
the drug must be discontinued and an alternative medication should be substituted.
Concomitant administration of Lariam and quinine or quinidine may produce
electrocardiographic abnormalities.
Concomitant administration of Lariam and quinine or chloroquine may increase the risk of
convulsions.
PRECAUTIONS
Hypersensitivity Reactions
Hypersensitivity reactions ranging from mild cutaneous events to anaphylaxis cannot be predicted.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 13
In patients with epilepsy, Lariam may increase the risk of convulsions. The drug should therefore be
prescribed only for curative treatment in such patients and only if there are compelling medical reasons
for its use (see PRECAUTIONS: Drug Interactions).
Central and Peripheral Nervous System Effects
Caution should be exercised with regard to activities requiring alertness and fine motor coordination
such as driving, piloting aircraft, operating machinery, and deep-sea diving, as dizziness or vertigo, a
loss of balance, or other disorders of the central or peripheral nervous system have been reported
during and following the use of Lariam. These effects may occur after therapy is discontinued due to
the long half-life of the drug. In a small number of patients, dizziness or vertigo and loss of balance
have been reported to continue for months after discontinuation of the drug (see ADVERSE
REACTIONS: Postmarketing).
Lariam should be used with caution in patients with psychiatric disturbances because mefloquine use
has been associated with emotional disturbances (see ADVERSE REACTIONS).
Use in Patients with Hepatic Impairment
In patients with impaired liver function the elimination of mefloquine may be prolonged, leading to
higher plasma levels.
Long-Term Use
This drug has been administered for longer than 1 year. If the drug is to be administered for a
prolonged period, periodic evaluations including liver function tests should be performed.
Although retinal abnormalities seen in humans with long-term chloroquine use have not been observed
with mefloquine use, long-term feeding of mefloquine to rats resulted in dose-related ocular lesions
(retinal degeneration, retinal edema and lenticular opacity at 12.5 mg/kg/day and higher) (see
ANIMAL TOXICOLOGY). Therefore, periodic ophthalmic examinations are recommended.
Cardiac Effects
Parenteral studies in animals show that mefloquine, a myocardial depressant, possesses 20% of the
anti-fibrillatory action of quinidine and produces 50% of the increase in the PR interval reported with
quinine. The effect of mefloquine on the compromised cardiovascular system has not been evaluated.
However, transitory and clinically silent ECG alterations have been reported during the use of
mefloquine. Alterations included sinus bradycardia, sinus arrhythmia, first degree AV-block,
prolongation of the QTc interval and abnormal T waves (see also cardiovascular effects under
PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS). The benefits of Lariam
therapy should be weighed against the possibility of adverse effects in patients with cardiac disease.
Laboratory Tests
Periodic evaluation of hepatic function should be performed during prolonged prophylaxis.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 14
Information for Patients
Medication Guide: As required by law, a Lariam Medication Guide is supplied to patients when
Lariam is dispensed. An information wallet card is also supplied to patients when Lariam is dispensed.
Patients should be instructed to read the Medication Guide when Lariam is received and to carry the
information wallet card with them when they are taking Lariam. The complete texts of the Medication
Guide and information wallet card are reprinted at the end of this document.
Patients should be advised:
• that malaria can be a life-threatening infection in the traveler;
• that Lariam is being prescribed to help prevent or treat this serious infection;
• that in a small percentage of cases, patients are unable to take this medication because of side
effects, including dizziness or vertigo and loss of balance, and it may be necessary to change
medications. Although side effects of dizziness or vertigo and loss of balance are usually mild and
do not cause people to stop taking the medication, in a small number of patients it has been
reported that these symptoms may continue for months after discontinuation of the drug;
• that when used as prophylaxis, the first dose of Lariam should be taken 1 week prior to arrival in an
endemic area;
• that if the patients experience psychiatric symptoms such as acute anxiety, depression, restlessness
or confusion, these may be considered prodromal to a more serious event. In these cases, the drug
must be discontinued and an alternative medication should be substituted;
• 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 to
inform their physician that they may have been exposed to malaria.
Drug Interactions
Drug-drug interactions with Lariam have not been explored in detail. There is one report of
cardiopulmonary arrest, with full recovery, in a patient who was taking a beta blocker (propranolol)
(see PRECAUTIONS: Cardiac Effects). The effects of mefloquine on the compromised
cardiovascular system have not been evaluated. The benefits of Lariam therapy should be weighed
against the possibility of adverse effects in patients with cardiac disease.
Halofantrine and Other Antimalarials
Halofantrine should not be administered with Lariam or within 15 weeks of the last dose of Lariam due
to the risk of a potentially fatal prolongation of the QTc interval (see WARNINGS).
Concomitant administration of Lariam and other related antimalarial compounds (eg, quinine,
quinidine and chloroquine) may produce electrocardiographic abnormalities and increase the risk of
convulsions (see WARNINGS). If these drugs are to be used in the initial treatment of severe malaria,
Lariam administration should be delayed at least 12 hours after the last dose. Clinically significant
QTc prolongation has not been found with mefloquine alone.
Ketoconazole (Potent Inhibitor of CYP3A4)
Co-administration of a single 500 mg oral dose of Lariam with 400 mg of ketoconazole once daily for
10 days in 8 healthy volunteers resulted in an increase in the mean Cmax and AUC of mefloquine by
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 15
64% and 79%, respectively, and an increase in the mean elimination half-life of mefloquine from 322
hours to 448 hours. Ketoconazole should not be administered with Lariam or within 15 weeks of the
last dose of Lariam due to the risk of a potentially fatal prolongation of the QTc interval (see
WARNINGS).
Other Drugs that Prolong the QTc Interval
Co-administration of other drugs known to alter cardiac conduction (eg, anti-arrhythmic or beta-
adrenergic blocking agents, calcium channel blockers, antihistamines or H1-blocking agents, tricyclic
antidepressants and phenothiazines) might also contribute to a prolongation of the QTc interval. There
are no data that conclusively establish whether the concomitant administration of mefloquine and the
above listed agents has an effect on cardiac function.
Anticonvulsants
In patients taking an anticonvulsant (eg, valproic acid, carbamazepine, phenobarbital or phenytoin), the
concomitant use of Lariam may reduce seizure control by lowering the plasma levels of the
anticonvulsant. Therefore, patients concurrently taking antiseizure medication and Lariam should have
the blood level of their antiseizure medication monitored and the dosage adjusted appropriately (see
PRECAUTIONS).
Vaccines
When Lariam is taken concurrently with oral live typhoid vaccines, attenuation of immunization
cannot be excluded. Vaccinations with attenuated live bacteria should therefore be completed at least 3
days before the first dose of Lariam.
Rifampin (Potent Inducer of CYP3A4)
Co-administration of a single 500 mg oral dose of Lariam and 600 mg of rifampin once daily for 7
days in 7 healthy Thai volunteers resulted in a decrease in the mean Cmax and AUC of mefloquine by
19% and 68%, respectively, and a decrease in the mean elimination half-life of mefloquine from 305
hours to 113 hours. Rifampin should be used cautiously in patients taking Lariam.
Inhibitors and Inducers of CYP3A4
Mefloquine does not inhibit or induce the CYP 450 enzyme system. Thus, concomitant administration
of Lariam and substrates of the CYP 450 enzyme system is not expected to result in a drug interaction.
However, co-administration of CYP 450 inhibitors or inducers may increase or decrease mefloquine
plasma concentrations, respectively.
Substrates and Inhibitors of P-glycoprotein
It has been shown in vitro that mefloquine is a substrate and an inhibitor of P-glycoprotein. Therefore,
drug-drug interactions could also occur with drugs that are substrates or are known to modify the
expression of this transporter. The clinical relevance of these interactions is not known to date.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 16
Other Potential Interactions
No other drug interactions are known. Nevertheless, the effects of Lariam on travelers receiving co
medication, particularly diabetics or patients using anticoagulants, should be checked before departure.
In clinical trials, the concomitant administration of sulfadoxine and pyrimethamine did not alter the
adverse reaction profile of mefloquine.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
The carcinogenic potential of mefloquine was studied in rats and mice in 2-year feeding studies at
doses of up to 30 mg/kg/day. No treatment-related increases in tumors of any type were noted.
Mutagenesis
The mutagenic potential of mefloquine was studied in a variety of assay systems including: Ames test,
a host-mediated assay in mice, fluctuation tests and a mouse micronucleus assay. Several of these
assays were performed with and without prior metabolic activation. In no instance was evidence
obtained for the mutagenicity of mefloquine.
Impairment of Fertility
Fertility studies in rats at doses of 5, 20, and 50 mg/kg/day of mefloquine have demonstrated adverse
effects on fertility in the male at the high dose of 50 mg/kg/day, and in the female at doses of 20 and
50 mg/kg/day. Histopathological lesions were noted in the epididymides from male rats at doses of 20
and 50 mg/kg/day. Administration of 250 mg/week of mefloquine (base) in adult males for 22 weeks
failed to reveal any deleterious effects on human spermatozoa.
Pregnancy
Teratogenic Effects
Pregnancy Category C. Mefloquine has been demonstrated to be teratogenic in rats and mice at a dose
of 100 mg/kg/day. In rabbits, a high dose of 160 mg/kg/day was embryotoxic and teratogenic, and a
dose of 80 mg/kg/day was teratogenic but not embryotoxic. There are no adequate and well-controlled
studies in pregnant women. However, clinical experience with Lariam has not revealed an embryotoxic
or teratogenic effect. Mefloquine 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. Women of childbearing potential
should also be advised to practice contraception during malaria prophylaxis with Lariam and for up to
3 months thereafter. However, in the case of unplanned pregnancy, malaria chemoprophylaxis with
Lariam is not considered an indication for pregnancy termination.
Nursing Mothers
Mefloquine is excreted in human milk in small amounts, the activity of which is unknown. Based on a
study in a few subjects, low concentrations (3% to 4%) of mefloquine were excreted in human milk
following a dose equivalent to 250 mg of the free base. Because of the potential for serious adverse
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 17
reactions in nursing infants from mefloquine, a decision should be made whether to discontinue the
drug, taking into account the importance of the drug to the mother.
Pediatric Use
Use of Lariam to treat acute, uncomplicated P. falciparum malaria in pediatric patients is supported by
evidence from adequate and well-controlled studies of Lariam in adults with additional data from
published open-label and comparative trials using Lariam to treat malaria caused by P. falciparum in
patients younger than 16 years of age. The safety and effectiveness of Lariam for the treatment of
malaria in pediatric patients below the age of 6 months have not been established.
In several studies, the administration of Lariam for the treatment of malaria was associated with early
vomiting in pediatric patients. Early vomiting was cited in some reports as a possible cause of
treatment failure. If a second dose is not tolerated, the patient should be monitored closely and
alternative malaria treatment considered if improvement is not observed within a reasonable period of
time (see DOSAGE AND ADMINISTRATION).
Geriatric Use
Clinical studies of Lariam 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. Since
electrocardiographic abnormalities have been observed in individuals treated with Lariam (see
PRECAUTIONS) and underlying cardiac disease is more prevalent in elderly than in younger
patients, the benefits of Lariam therapy should be weighed against the possibility of adverse cardiac
effects in elderly patients.
ADVERSE REACTIONS
Clinical
At the doses used for treatment of acute malaria infections, the symptoms possibly attributable to drug
administration cannot be distinguished from those symptoms usually attributable to the disease itself.
Among subjects who received mefloquine for prophylaxis of malaria, the most frequently observed
adverse experience was vomiting (3%). Dizziness, syncope, extrasystoles and other complaints
affecting less than 1% were also reported.
Among subjects who received mefloquine for treatment, the most frequently observed adverse
experiences included: dizziness, myalgia, nausea, fever, headache, vomiting, chills, diarrhea, skin rash,
abdominal pain, fatigue, loss of appetite, and tinnitus. Those side effects occurring in less than 1%
included bradycardia, hair loss, emotional problems, pruritus, asthenia, transient emotional
disturbances and telogen effluvium (loss of resting hair). Seizures have also been reported.
Two serious adverse reactions were cardiopulmonary arrest in one patient shortly after ingesting a
single prophylactic dose of mefloquine while concomitantly using propranolol (see PRECAUTIONS:
Drug Interactions), and encephalopathy of unknown etiology during prophylactic mefloquine
administration. The relationship of encephalopathy to drug administration could not be clearly
established.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 18
Postmarketing
Postmarketing surveillance indicates that the same kind of adverse experiences are reported during
prophylaxis, as well as acute treatment. Because these experiences 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 Lariam exposure.
The most frequently reported adverse events are nausea, vomiting, loose stools or diarrhea, abdominal
pain, dizziness or vertigo, loss of balance, and neuropsychiatric events such as headache, somnolence,
and sleep disorders (insomnia, abnormal dreams). These are usually mild and may decrease despite
continued use. In a small number of patients it has been reported that dizziness or vertigo and loss of
balance may continue for months after discontinuation of the drug.
Occasionally, more severe neuropsychiatric disorders have been reported such as: sensory and motor
neuropathies (including paresthesia, tremor and ataxia), convulsions, agitation or restlessness, anxiety,
depression, mood swings, panic attacks, memory impairment, confusion, hallucinations, aggression,
psychotic or paranoid reactions and encephalopathy. Rare cases of suicidal ideation and suicide have
been reported though no relationship to drug administration has been confirmed.
Other less frequently reported adverse events include:
Cardiovascular Disorders: circulatory disturbances (hypotension, hypertension, flushing, syncope),
chest pain, tachycardia or palpitation, bradycardia, irregular heart rate, extrasystoles, A-V block, and
other transient cardiac conduction alterations
Skin Disorders: rash, exanthema, erythema, urticaria, pruritus, edema, hair loss, erythema multiforme,
and Stevens-Johnson syndrome
Musculoskeletal Disorders: muscle weakness, muscle cramps, myalgia, and arthralgia
Respiratory Disorders: dyspnea, pneumonitis of possible allergic etiology
Other Symptoms: visual disturbances, vestibular disorders including tinnitus and hearing impairment,
asthenia, malaise, fatigue, fever, hyperhidrosis, chills, dyspepsia and loss of appetite
Laboratory
The most frequently observed laboratory alterations which could be possibly attributable to drug
administration were decreased hematocrit, transient elevation of transaminases, leukopenia and
thrombocytopenia. These alterations were observed in patients with acute malaria who received
treatment doses of the drug and were attributed to the disease itself.
During prophylactic administration of mefloquine to indigenous populations in malaria-endemic areas,
the following occasional alterations in laboratory values were observed: transient elevation of
transaminases, leukocytosis or thrombocytopenia.
Because of the long half-life of mefloquine, adverse reactions to Lariam may occur or persist up to
several weeks after discontinuation of the drug.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 19
OVERDOSAGE
Symptoms and Signs
In cases of overdosage with Lariam, the symptoms mentioned under ADVERSE REACTIONS may
be more pronounced.
Treatment
Patients should be managed by symptomatic and supportive care following Lariam overdose. There are
no specific antidotes. Monitor cardiac function (if possible by ECG) and neuropsychiatric status for at
least 24 hours. Provide symptomatic and intensive supportive treatment as required, particularly for
cardiovascular disturbances.
DOSAGE AND ADMINISTRATION (SEE INDICATIONS AND USAGE)
Adult Patients
Treatment of mild to moderate malaria in adults caused by P. vivax or mefloquine
susceptible strains of P. falciparum
Five tablets (1250 mg) mefloquine hydrochloride to be given as a single oral dose. The drug should not
be taken on an empty stomach and should be administered with at least 8 oz (240 mL) of water.
If a full-treatment course with Lariam does not lead to improvement within 48 to 72 hours, Lariam
should not be used for retreatment. An alternative therapy should be used. Similarly, if previous
prophylaxis with mefloquine has failed, Lariam should not be used for curative treatment.
Note: Patients with acute P. vivax malaria, treated with Lariam, are at high risk of relapse
because Lariam does not eliminate exoerythrocytic (hepatic phase) parasites. To avoid relapse
after initial treatment of the acute infection with Lariam, patients should subsequently be
treated with an 8-aminoquinoline derivative (eg, primaquine).
Malaria Prophylaxis
One 250 mg Lariam tablet once weekly.
Prophylactic drug administration should begin 1 week before arrival in an endemic area. Subsequent
weekly doses should be taken regularly, always on the same day of each week, preferably after the
main meal. To reduce the risk of malaria after leaving an endemic area, prophylaxis must be continued
for 4 additional weeks to ensure suppressive blood levels of the drug when merozoites emerge from the
liver. Tablets should not be taken on an empty stomach and should be administered with at least 8 oz
(240 mL) of water.
In certain cases, eg, when a traveler is taking other medication, it may be desirable to start prophylaxis
2 to 3 weeks prior to departure, in order to ensure that the combination of drugs is well tolerated (see
PRECAUTIONS: Drug Interactions).
When prophylaxis with Lariam fails, physicians should carefully evaluate which antimalarial to use for
therapy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 20
Pediatric Patients
Treatment of mild to moderate malaria in pediatric patients caused by mefloquine
susceptible strains of P. falciparum
Twenty (20) to 25 mg/kg body weight. Splitting the total therapeutic dose into 2 doses taken 6 to 8
hours apart may reduce the occurrence or severity of adverse effects. Experience with Lariam in
pediatric patients weighing less than 20 kg is limited. The drug should not be taken on an empty
stomach and should be administered with ample water. The tablets may be crushed and suspended in a
small amount of water, milk or other beverage for administration to small children and other persons
unable to swallow them whole.
If a full-treatment course with Lariam does not lead to improvement within 48 to 72 hours, Lariam
should not be used for retreatment. An alternative therapy should be used. Similarly, if previous
prophylaxis with mefloquine has failed, Lariam should not be used for curative treatment.
In pediatric patients, the administration of Lariam for the treatment of malaria has been associated with
early vomiting. In some cases, early vomiting has been cited as a possible cause of treatment failure
(see PRECAUTIONS). If a significant loss of drug product is observed or suspected because of
vomiting, a second full dose of Lariam should be administered to patients who vomit less than 30
minutes after receiving the drug. If vomiting occurs 30 to 60 minutes after a dose, an additional half-
dose should be given. If vomiting recurs, the patient should be monitored closely and alternative
malaria treatment considered if improvement is not observed within a reasonable period of time.
The safety and effectiveness of Lariam to treat malaria in pediatric patients below the age of 6 months
have not been established.
Malaria Prophylaxis
The recommended prophylactic dose of Lariam is approximately 5 mg/kg body weight once weekly.
One 250 mg Lariam tablet should be taken once weekly in pediatric patients weighing over 45 kg. In
pediatric patients weighing less than 45 kg, the weekly dose decreases in proportion to body weight:
30 to 45 kg:
3/4 tablet
20 to 30 kg:
1/2 tablet
Experience with Lariam in pediatric patients weighing less than 20 kg is limited.
HOW SUPPLIED
Lariam is available as scored, white, round tablets, containing 250 mg of mefloquine hydrochloride in
unit-dose packages of 25 (NDC 0004-0172-02). Imprint on tablets: LARIAM 250 ROCHE
Tablets should be stored at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
ANIMAL TOXICOLOGY
Ocular lesions were observed in rats fed mefloquine daily for 2 years. All surviving rats given 30
mg/kg/day had ocular lesions in both eyes characterized by retinal degeneration, opacity of the lens,
and retinal edema. Similar but less severe lesions were observed in 80% of female and 22% of male
rats fed 12.5 mg/kg/day for 2 years. At doses of 5 mg/kg/day, only corneal lesions were observed.
They occurred in 9% of rats studied.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 21
Revised: Month/Year Roche Logo
MEDICATION GUIDE
Lariam (LAH-ree-am)
(mefloquine hydrochloride)
Tablets
Read this entire Medication Guide before you start taking Lariam and each time you get a
refill. There may be new information. This information does not take the place of talking to
your doctor about your medical condition or your treatment.
What is the most important information I should know about Lariam?
Your doctor or pharmacist will give you an Information Wallet Card
along with this Medication Guide. It has important information
about Lariam and should be carried with you at all times while you
take Lariam.
Lariam can cause serious mental problems.
• Some people who take Lariam have sudden serious mental problems, including:
• severe anxiety
• paranoia (feelings of mistrust towards others)
• hallucinations (seeing or hearing things that are not there)
• depression
• feeling restless
• unusual behavior
• feeling confused
In some patients these serious side effects can go on after Lariam is stopped.
• Some people who take Lariam think about suicide (putting an end to their life). Some
people who were taking Lariam committed suicide. It is not known whether Lariam was
responsible for those suicides.
If you have any of these serious mental problems, or you develop other serious side
effects or mental problems, you should call your doctor right away as it may be necessary
to stop taking Lariam and use another medicine to prevent malaria.
You need to take malaria prevention medicine before you travel to a malaria
area, while you are in a malaria area, and after you return from a malaria area.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 22
If you are told by a doctor to stop taking Lariam because of the side effects or for other
reasons, you will need to take another malaria medicine.
If you do not have access to a doctor or to another medicine and have to stop taking
Lariam, leave the malaria area and contact a doctor as soon as possible because leaving
the malaria area may not protect you from getting malaria. You will still need to take a
malaria prevention medicine for another 4 weeks.
• Do not take halofantrine (used to treat malaria) or ketoconazole (used for fungal
infections) with Lariam or within 15 weeks of your last dose of Lariam. You may have
serious heart problems that can lead to death. Do not take quinine (Qualaquin) or
quinidine (used to treat malaria or irregular heart beat) with Lariam. You may have
serious heart problems.
• Do not take quinine (Qualaquin) or chloroquine (Aralen) (used to treat malaria) with
Lariam. You may have a greater risk for convulsions (seizures).
What is Lariam?
Lariam is a prescription medicine used to prevent and treat malaria. Malaria can be a life-
threatening infection. Lariam does not work for all types of malaria.
It is not known if Lariam is safe and effective in children under 6 months old for the
treatment of malaria.
It is not known how well Lariam works to prevent malaria in infants weighing less than 44 lbs
(20 kg).
Who should not take Lariam?
Do not take Lariam if you have:
• depression or had depression recently
• had recent mental problems, including anxiety disorder, schizophrenia, or psychosis
(losing touch with reality)
• seizures or had seizures (epilepsy or convulsions)
• an allergy to quinine, quinidine, Lariam or any ingredients in Lariam. See the end of this
Medication Guide for a complete list of ingredients in Lariam.
Talk to your doctor before you take Lariam if you have any of the conditions listed above.
What should I tell my doctor before taking Lariam?
Before taking Lariam, tell your doctor about all your medical conditions, including
if you have:
• heart disease
• liver problems
• seizures or epilepsy
• diabetes
• blood clotting problems or take blood thinner medicines (anticoagulants)
• mental problems
• are pregnant or plan to become pregnant. It is not known if Lariam will harm your unborn
baby. Talk to you doctor if you are pregnant or plan to become pregnant.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 23
• use birth control while you take Lariam and for 3 months after you stop Lariam. If you
have an unplanned pregnancy, talk to your doctor right away.
• are breast-feeding or plan to breast-feed. Lariam can pass through your milk and may
harm your baby. Ask your doctor whether you will need to stop breast-feeding or use
another medicine.
After leaving a malaria area, if you have a fever contact your doctor right away.
Tell your doctor about all the medicines you take, including prescription and non
prescription medicines, vitamins, and herbal supplements. Lariam and other medicines may
affect each other causing side effects.
Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist
when you get a new medicine.
Especially tell your doctor if you take:
• ketoconazole used to treat fungal infections
• halofantrine, quinine (Qualaquin), quinidine, chloroquine (Aralen) or other medicines used
to treat malaria
• anti-arrhythmic medicines, beta-adrenergic blocking medicines and calcium channel
blockers used to treat heart problems or high blood pressure
• antihistamines or H1-blocking agents used to treat allergies
• tricyclic antidepressants used to treat depression
• phenothiazines used to treat mental problems
• anticonvulsants used to treat seizures
• vaccines containing live bacteria. Your doctor may want you to finish receiving your
vaccines at least 3 days before you start Lariam.
• rifampin and rifampin-containing products (Rifadin, Rifamate, Rifater, Rimactane) used to
treat infections
Ask your doctor or pharmacist for a list of these medicines if you are not sure.
How should I take Lariam?
• Take Lariam exactly as your doctor tells you to take it. Your doctor will tell you how many
Lariam to take and when to take them.
• You will start taking Lariam to prevent malaria between 1 to 3 weeks before you travel to
a malaria area.
• Take Lariam just after eating your main meal and with at least one cup (8 ounces) of
water.
• Do not take Lariam on an empty stomach.
• If you vomit after taking Lariam, call your healthcare provider to see if you should take
another dose.
• Continue taking Lariam for 4 weeks after returning from a malaria area.
• Lariam tablets may be crushed and mixed with a small amount of water, milk or other
beverage for children or other people unable to swallow Lariam whole. Your doctor will
tell you the correct dose for your child based on your child’s weight.
• If you take Lariam for a year or longer, your doctor should check your
• eyes, especially if you have trouble seeing while you take Lariam
• liver function to see if there has been damage to your liver
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 24
• Use protective clothing, insect repellents, and bednets to protect you from being bitten by
mosquitoes. Medicine alone does not always stop you from catching malaria from
mosquito bites.
What should I avoid while taking Lariam?
Avoid activities such as driving a car or using heavy machinery or other activities needing
alertness and careful movements (fine motor coordination) until you know how Lariam
affects you. You may feel dizzy or lose your balance. This could happen for months after you
stop taking Lariam. See “What are the possible side effects of Lariam?”
What are the possible side effects of Lariam?
Also see “What is the most important information I should know about Lariam?”
Lariam may cause serious side effects, including:
• convulsions (seizures)
• liver problems
• heart problems
The most common side effects of Lariam include:
• nausea
• vomiting
• diarrhea
• abdominal pain
• dizziness or loss of balance (vertigo), which may continue for months after Lariam is
stopped
• headache
• sleeping problems (sleepiness, unable to sleep, bad dreams)
The most common side effects in people who take Lariam for treatment include:
• muscle pain
• fever
• chills
• skin rash
• fatigue
• loss of appetite
• ringing in the ears
• irregular heart beat
Tell your doctor if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of Lariam. For more information, 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 Lariam?
• Store Lariam between 59ºF to 86ºF (15ºC to 30ºC)
• Safely throw away medicine that is out of date or no longer needed.
Keep Lariam and all medicines out of the reach of children.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 25
General information about the safe and effective use of Lariam.
Medicines are sometimes prescribed for purposes other than those listed in a Medication
Guide. Do not use Lariam for a condition for which it was not prescribed. Do not give
Lariam 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 Lariam. If you
would like more information, talk with your doctor. You can ask your pharmacist or doctor
for information about Lariam that is written for health professionals.
If you have any questions or would like more information about Lariam, you can
call Roche, the manufacturer of Lariam, at 1-800-526-6367.
What are the ingredients in Lariam?
Active ingredients: mefloquine hydrochloride
Inactive ingredients: ammonium-calcium alginate, corn starch, crospovidone, lactose,
magnesium stearate, microcrystalline cellulose, poloxamer #331, and talc.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Reprint of information wallet card:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 26
Information Wallet Card
Lariam® (mefloquine hydrochloride) Tablets
It is important that you read the entire Medication Guide for additional information on Lariam.
Carry this wallet card with you when you are taking Lariam.
You need to take malaria prevention
medicine before you travel to a malaria
area, while you are in a malaria area, and
after you return from a malaria area.
Lariam can cause serious mental
problems in some people. If you take
Lariam and you have sudden signs of serious
mental problems (such as: severe anxiety,
feelings of mistrust towards others, seeing or
hearing things that are not there, depression,
feeling restless, unusual behavior or feeling
confused), you should contact a doctor right
away as it may be necessary to stop taking
Lariam and take different medicine to prevent
malaria.
Other side effects from Lariam may
include: convulsions, liver problems, and
heart problems. The most common side
effects of Lariam include nausea, vomiting,
diarrhea, abdominal pain, dizziness or loss of
balance (vertigo) which may continue for
months after Lariam is stopped, headache, and
sleeping problems (sleepiness, unable to sleep,
bad dreams).
While you take Lariam, do not take:
•
Halofantrine (used to treat malaria)
•
Ketoconazole (used for fungal
infections)
•
Quinine (Qualaquin) or quinidine
(used to treat malaria or irregular
heart beat)
•
Chloroquine (Aralen) (used to treat
malaria)
Avoid activities such as driving a car or using
heavy machinery or other activities needing
alertness and careful movements (fine motor
coordination) until you know how Lariam
affects you.
Other medicines are approved in the United
States for malaria prevention. However, not
all malaria medicines work equally well in
different malaria areas. Before you travel,
talk to your doctor about your travel plans.
If you have any serious side effects, and
cannot get another medicine, leave the
malaria area and contact a doctor as soon as
possible because leaving the malaria area
may not protect you from getting malaria.
You will still need to take a malaria
prevention medicine.
Call your doctor for medical advice about
side effects.
You may report side effects to FDA at
1-800-FDA-1088.
Card Revised: Month/Year
Manufactured by:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 27
F. HOFFMANN-LA ROCHE LTD
Basel, Switzerland Roche Logo they are the Distributor
Revised: Month/Year
LMT_215998_MG_MMYYYY_N
Copyright © 2003-2009 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 19-591/S-026
NDA 19-591/S-028
Page 28
Appendix A: Medication Guide REMS Document
NDA 19-591 Lariam® (mefloquine hydrochloride) Tablets
Antimalarial Agent for the Treatment and Prevention of Malaria
Hoffmann-La Roche Inc.
340 Kingsland Street
Nutley, New Jersey 07110-1199
Roche Pharmaceuticals Service Center Telephone Contact Number:
1-800-526-6367
RISK EVALUATION AND MITIGATION STRATEGY (REMS)
I.
GOAL: To inform patients about the serious risks associated with the use of Lariam
(mefloquine hydrochloride).
II.
REMS ELEMENTS:
A. Medication Guide
A Medication Guide will be dispensed with each Lariam prescription in accordance with 21
CFR 208.
Pursuant to 21 CFR 208.24, the Medication Guide will be made available in sufficient
numbers to US Lariam distributors. US distributors will provide the Medication Guide with
every pharmacy shelf carton of Lariam to ensure its availability for dispensing to patients
who are dispensed Lariam. The label of each container or package of Lariam will include a
prominent instruction to authorized dispensers to provide a Medication Guide to each
patient to whom the drug is dispensed, and state how the Medication Guide is provided.
See appended Medication Guide.
B. Timetable for Submission of Assessments
The timetable for submission of assessments of the REMS will be 18 months, 3 years, and
7th years after the REMS is initially approved. The reporting interval covered by each
assessment will conclude no earlier than 60 days before the submission date for that
assessment.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 29 Roche Logo
MEDICATION GUIDE
Lariam (LAH-ree-am)
(mefloquine hydrochloride)
Tablets
Read this entire Medication Guide before you start taking Lariam and each time you get a
refill. There may be new information. This information does not take the place of talking to
your doctor about your medical condition or your treatment.
What is the most important information I should know about Lariam?
Your doctor or pharmacist will give you an Information Wallet Card
along with this Medication Guide. It has important information
about Lariam and should be carried with you at all times while you
take Lariam.
Lariam can cause serious mental problems.
• Some people who take Lariam have sudden serious mental problems, including:
• severe anxiety
• paranoia (feelings of mistrust towards others)
• hallucinations (seeing or hearing things that are not there)
• depression
• feeling restless
• unusual behavior
• feeling confused
In some patients these serious side effects can go on after Lariam is stopped.
• Some people who take Lariam think about suicide (putting an end to their life). Some
people who were taking Lariam committed suicide. It is not known whether Lariam was
responsible for those suicides.
If you have any of these serious mental problems, or you develop other serious side
effects or mental problems, you should call your doctor right away as it may be necessary
to stop taking Lariam and use another medicine to prevent malaria.
You need to take malaria prevention medicine before you travel to a malaria
area, while you are in a malaria area, and after you return from a malaria area.
If you are told by a doctor to stop taking Lariam because of the side effects or for other
reasons, you will need to take another malaria medicine.
If you do not have access to a doctor or to another medicine and have to stop taking
Lariam, leave the malaria area and contact a doctor as soon as possible because leaving
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 30
the malaria area may not protect you from getting malaria. You will still need to take a
malaria prevention medicine for another 4 weeks.
• Do not take halofantrine (used to treat malaria) or ketoconazole (used for fungal
infections) with Lariam or within 15 weeks of your last dose of Lariam. You may have
serious heart problems that can lead to death. Do not take quinine (Qualaquin) or
quinidine (used to treat malaria or irregular heart beat) with Lariam. You may have
serious heart problems.
• Do not take quinine (Qualaquin) or chloroquine (Aralen) (used to treat malaria) with
Lariam. You may have a greater risk for convulsions (seizures).
What is Lariam?
Lariam is a prescription medicine used to prevent and treat malaria. Malaria can be a life-
threatening infection. Lariam does not work for all types of malaria.
It is not known if Lariam is safe and effective in children under 6 months old for the
treatment of malaria.
It is not known how well Lariam works to prevent malaria in infants weighing less than 44 lbs
(20 kg).
Who should not take Lariam?
Do not take Lariam if you have:
• depression or had depression recently
• had recent mental problems, including anxiety disorder, schizophrenia, or psychosis
(losing touch with reality)
• seizures or had seizures (epilepsy or convulsions)
• an allergy to quinine, quinidine, Lariam or any ingredients in Lariam. See the end of this
Medication Guide for a complete list of ingredients in Lariam.
Talk to your doctor before you take Lariam if you have any of the conditions listed above.
What should I tell my doctor before taking Lariam?
Before taking Lariam, tell your doctor about all your medical conditions, including
if you have:
• heart disease
• liver problems
• seizures or epilepsy
• diabetes
• blood clotting problems or take blood thinner medicines (anticoagulants)
• mental problems
• are pregnant or plan to become pregnant. It is not known if Lariam will harm your unborn
baby. Talk to you doctor if you are pregnant or plan to become pregnant.
• use birth control while you take Lariam and for 3 months after you stop Lariam. If you
have an unplanned pregnancy, talk to 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 19-591/S-026
NDA 19-591/S-028
Page 31
• are breast-feeding or plan to breast-feed. Lariam can pass through your milk and may
harm your baby. Ask your doctor whether you will need to stop breast-feeding or use
another medicine.
After leaving a malaria area, if you have a fever contact your doctor right away.
Tell your doctor about all the medicines you take, including prescription and non
prescription medicines, vitamins, and herbal supplements. Lariam and other medicines may
affect each other causing side effects.
Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist
when you get a new medicine.
Especially tell your doctor if you take:
• ketoconazole used to treat fungal infections
• halofantrine, quinine (Qualaquin), quinidine, chloroquine (Aralen) or other medicines used
to treat malaria
• anti-arrhythmic medicines, beta-adrenergic blocking medicines and calcium channel
blockers used to treat heart problems or high blood pressure
• antihistamines or H1-blocking agents used to treat allergies
• tricyclic antidepressants used to treat depression
• phenothiazines used to treat mental problems
• anticonvulsants used to treat seizures
• vaccines containing live bacteria. Your doctor may want you to finish receiving your
vaccines at least 3 days before you start Lariam.
• rifampin and rifampin-containing products (Rifadin, Rifamate, Rifater, Rimactane) used to
treat infections
Ask your doctor or pharmacist for a list of these medicines if you are not sure.
How should I take Lariam?
• Take Lariam exactly as your doctor tells you to take it. Your doctor will tell you how many
Lariam to take and when to take them.
• You will start taking Lariam to prevent malaria between 1 to 3 weeks before you travel to
a malaria area.
• Take Lariam just after eating your main meal and with at least one cup (8 ounces) of
water.
• Do not take Lariam on an empty stomach.
• If you vomit after taking Lariam, call your healthcare provider to see if you should take
another dose.
• Continue taking Lariam for 4 weeks after returning from a malaria area.
• Lariam tablets may be crushed and mixed with a small amount of water, milk or other
beverage for children or other people unable to swallow Lariam whole. Your doctor will
tell you the correct dose for your child based on your child’s weight.
• If you take Lariam for a year or longer, your doctor should check your
• eyes, especially if you have trouble seeing while you take Lariam
• liver function to see if there has been damage to your liver
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 32
• Use protective clothing, insect repellents, and bednets to protect you from being bitten by
mosquitoes. Medicine alone does not always stop you from catching malaria from
mosquito bites.
What should I avoid while taking Lariam?
Avoid activities such as driving a car or using heavy machinery or other activities needing
alertness and careful movements (fine motor coordination) until you know how Lariam
affects you. You may feel dizzy or lose your balance. This could happen for months after you
stop taking Lariam. See “What are the possible side effects of Lariam?”
What are the possible side effects of Lariam?
Also see “What is the most important information I should know about Lariam?”
Lariam may cause serious side effects, including:
• convulsions (seizures)
• liver problems
• heart problems
The most common side effects of Lariam include:
• nausea
• vomiting
• diarrhea
• abdominal pain
• dizziness or loss of balance (vertigo), which may continue for months after Lariam is
stopped
• headache
• sleeping problems (sleepiness, unable to sleep, bad dreams)
The most common side effects in people who take Lariam for treatment include:
• muscle pain
• fever
• chills
• skin rash
• fatigue
• loss of appetite
• ringing in the ears
• irregular heart beat
Tell your doctor if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of Lariam. For more information, 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 Lariam?
• Store Lariam between 59ºF to 86ºF (15ºC to 30ºC)
• Safely throw away medicine that is out of date or no longer needed.
Keep Lariam and all medicines out of the reach of children.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 33
General information about the safe and effective use of Lariam.
Medicines are sometimes prescribed for purposes other than those listed in a Medication
Guide. Do not use Lariam for a condition for which it was not prescribed. Do not give
Lariam 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 Lariam. If you
would like more information, talk with your doctor. You can ask your pharmacist or doctor
for information about Lariam that is written for health professionals.
If you have any questions or would like more information about Lariam, you can
call Roche, the manufacturer of Lariam, at 1-800-526-6367.
What are the ingredients in Lariam?
Active ingredients: mefloquine hydrochloride
Inactive ingredients: ammonium-calcium alginate, corn starch, crospovidone, lactose,
magnesium stearate, microcrystalline cellulose, poloxamer #331, and talc.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Reprint of information wallet card:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 34
Information Wallet Card
Lariam® (mefloquine hydrochloride) Tablets
It is important that you read the entire Medication Guide for additional information on Lariam.
Carry this wallet card with you when you are taking Lariam.
You need to take malaria prevention
medicine before you travel to a malaria
area, while you are in a malaria area, and
after you return from a malaria area.
Lariam can cause serious mental
problems in some people. If you take
Lariam and you have sudden signs of serious
mental problems (such as: severe anxiety,
feelings of mistrust towards others, seeing or
hearing things that are not there, depression,
feeling restless, unusual behavior or feeling
confused), you should contact a doctor right
away as it may be necessary to stop taking
Lariam and take different medicine to prevent
malaria.
Other side effects from Lariam may
include: convulsions, liver problems, and
heart problems. The most common side
effects of Lariam include nausea, vomiting,
diarrhea, abdominal pain, dizziness or loss of
balance (vertigo) which may continue for
months after Lariam is stopped, headache, and
sleeping problems (sleepiness, unable to sleep,
bad dreams).
While you take Lariam, do not take:
•
Halofantrine (used to treat malaria)
•
Ketoconazole (used for fungal
infections)
•
Quinine (Qualaquin) or quinidine
(used to treat malaria or irregular
heart beat)
•
Chloroquine (Aralen) (used to treat
malaria)
Avoid activities such as driving a car or using
heavy machinery or other activities needing
alertness and careful movements (fine motor
coordination) until you know how Lariam
affects you.
Other medicines are approved in the United
States for malaria prevention. However, not
all malaria medicines work equally well in
different malaria areas. Before you travel,
talk to your doctor about your travel plans.
If you have any serious side effects, and
cannot get another medicine, leave the
malaria area and contact a doctor as soon as
possible because leaving the malaria area
may not protect you from getting malaria.
You will still need to take a malaria
prevention medicine.
Call your doctor for medical advice about
side effects.
You may report side effects to FDA at
1-800-FDA-1088.
Card Revised: Month/Year
Manufactured by:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-591/S-026
NDA 19-591/S-028
Page 35
F. HOFFMANN-LA ROCHE LTD
Basel, Switzerland Roche Logo
Revised: Month/Year
LMT_215998_MG_MMYYYY_N
Copyright © 2003-2009 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
|
2025-02-12T13:45:29.959237
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019591s026s028lbl.pdf', 'application_number': 19591, 'submission_type': 'SUPPL ', 'submission_number': 28}
|
11,550
|
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
|
custom-source
|
2025-02-12T13:45:30.225574
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/1999/019593s028lbl.pdf', 'application_number': 19593, 'submission_type': 'SUPPL ', 'submission_number': 28}
|
11,552
|
PRESCRIBING INFORMATION
ZANTAC®
(ranitidine hydrochloride)
Injection
ZANTAC®
(ranitidine hydrochloride)
Injection Premixed
DESCRIPTION
The active ingredient in ZANTAC Injection and ZANTAC Injection Premixed is ranitidine
hydrochloride (HCl), 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,
hydrochloride. 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.
ZANTAC Injection is a clear, colorless to yellow, nonpyrogenic liquid. The yellow color of
the liquid tends to intensify without adversely affecting potency. The pH of the injection solution
is 6.7 to 7.3.
Sterile Injection for Intramuscular or Intravenous Administration: Each 1 mL of
aqueous solution contains ranitidine 25 mg (as the hydrochloride); phenol 5 mg as preservative;
and 0.96 mg of monobasic potassium phosphate and 2.4 mg of dibasic sodium phosphate as
buffers.
Sterile, Premixed Solution for Intravenous Administration in Single-Dose, Flexible
Plastic Containers: Each 50 mL contains ranitidine HCl equivalent to 50 mg of ranitidine,
sodium chloride 225 mg, and citric acid 15 mg and dibasic sodium phosphate 90 mg as buffers in
water for injection. It contains no preservatives. The osmolarity of this solution is 180 mOsm/L
(approx.), and the pH is 6.7 to 7.3.
The flexible plastic container is fabricated from a specially formulated, nonplasticized,
thermoplastic co-polyester (CR3). Water can permeate from inside the container into the
overwrap but not in amounts sufficient to affect the solution significantly. Solutions inside the
plastic container also can leach out certain of the chemical components in very small amounts
before the expiration period is attained. However, the safety of the plastic has been confirmed by
tests in animals according to USP biological standards for plastic containers.
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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 absorbed very rapidly after intramuscular (IM)
injection. Mean peak levels of 576 ng/mL occur within 15 minutes or less following a 50-mg IM
dose. Absorption from IM sites is virtually complete, with a bioavailability of 90% to 100%
compared with intravenous (IV) administration. Following oral administration, the bioavailability
of ZANTAC Tablets is 50%.
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: Following IV injection, approximately 70% of the dose is recovered in the urine
as unchanged drug. Renal clearance averages 530 mL/min, with a total clearance of 760 mL/min.
The elimination half-life is 2.0 to 2.5 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 3.1 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 pharmacokinetics of ZANTAC in pediatric patients are
summarized in Table 1.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1. Ranitidine Pharmacokinetics in Pediatric Patients Following IV Dosing
Population
(age)
n
Dose
(mg/kg)
t½
(hours)
Vd
(L/kg)
CLp
(mL/min/kg)
Peptic ulcer disease
(<6 years)
(6–11.9 years)
(>12 years)
Adults
6
11
6
6
1.25 or 2.5
1.25 or 2.5
1.25 or 2.5
2.5
2.2
2.1
1.7
1.9
1.29
1.14
0.98
1.04
11.41
8.96
9.89
8.77
Peptic ulcer disease
(3.5–16 years)
12
0.13–0.80
1.8
2.3
795 mL/min/1.73/m2
Children in intensive care
(1 day–12.6 years)
17
1.0
2.4
2
11.7
Neonates receiving
ECMO
12
2
6.6
1.8
4.3
T½ = Terminal half-life; CLp = Plasma clearance of ranitidine.
ECMO = extracorporeal membrane oxygenation.
Plasma clearance in neonatal patients (less than 1 month of age) receiving ECMO was
considerably lower (3 to 4 mL/min/kg) than observed in children or adults. The elimination half-
life in neonates averaged 6.6 hours as compared to approximately 2 hours in adults and pediatric
patients.
Pharmacodynamics: Serum concentrations necessary to inhibit 50% of stimulated gastric
acid secretion are estimated to be 36 to 94 ng/mL. Following single IV or IM 50-mg doses, serum
concentrations of ranitidine are in this range for 6 to 8 hours.
Antisecretory Activity: 1. Effects on Acid Secretion: ZANTAC Injection inhibits
basal gastric acid secretion as well as gastric acid secretion stimulated by betazole and
pentagastrin, as shown in Table 2.
Table 2. Effect of Intravenous ZANTAC on Gastric Acid Secretion
Time After Dose,
hours
% Inhibition of Gastric Acid Output
by Intravenous Dose, mg
20 mg
60 mg
100 mg
Betazole
Pentagastrin
Up to 2
Up to 3
93
47
99
66
99
77
In a group of 10 known hypersecretors, ranitidine plasma levels of 71, 180, and 376 ng/mL
inhibited basal acid secretion by 76%, 90%, and 99.5%, respectively.
It appears that basal- and betazole-stimulated secretions are most sensitive to inhibition by
ZANTAC, while pentagastrin-stimulated secretion is more difficult to suppress.
2. Effects on Other Gastrointestinal Secretions:
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pepsin: ZANTAC does not affect pepsin secretion. Total pepsin output is reduced in
proportion to the decrease in volume of gastric juice.
Intrinsic Factor: 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: The ranitidine concentration necessary to suppress basal acid secretion by at least
90% has been reported to be 40 to 60 ng/mL in pediatric patients with duodenal or gastric ulcers.
In a study of 20 critically ill pediatric patients receiving ranitidine IV at 1 mg/kg every
6 hours, 10 patients with a baseline pH ≥4 maintained this baseline throughout the study. Eight of
the remaining 10 patients with a baseline of pH ≤2 achieved pH ≥4 throughout varying periods
after dosing. It should be noted, however, that because these pharmacodynamic parameters were
assessed in critically ill pediatric patients, the data should be interpreted with caution when
dosing recommendations are made for a less seriously ill pediatric population.
In another small study of neonatal patients (n = 5) receiving ECMO, gastric pH <4
pretreatment increased to >4 after a 2-mg/kg dose and remained above 4 for at least 15 hours.
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
oral ZANTAC as shown in Table 3.
Table 3. Duodenal Ulcer Patient Healing Rates
Oral ZANTAC*
Oral Placebo*
Number
Entered
Healed/
Evaluable
Number
Entered
Healed/
Evaluable
Outpatients
Week 2
Week 4
195
69/182
(38%)†
137/187
(73%)†
188
31/164
(19%)
76/168
(45%)
*All patients were permitted antacids as needed for relief of pain.
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
†P<0.0001.
In these studies, patients treated with oral 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
Oral ZANTAC
Oral placebo
0.06
0.71
0.71
1.43
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 oral ZANTAC was followed by healing of ulcers in 8 of 19 (42%)
patients who were intractable to previous therapy.
In a retrospective review of 52 Zollinger-Ellison patients given ZANTAC as a continuous IV
infusion for up to 15 days, no patients developed complications of acid-peptic disease such as
bleeding or perforation. Acid output was controlled to ≤10 mEq/h.
INDICATIONS AND USAGE
ZANTAC Injection and ZANTAC Injection Premixed are indicated in some hospitalized
patients with pathological hypersecretory conditions or intractable duodenal ulcers, or as an
alternative to the oral dosage form for short-term use in patients who are unable to take oral
medication.
CONTRAINDICATIONS
ZANTAC Injection and ZANTAC Injection Premixed are contraindicated for patients known
to have hypersensitivity to the drug.
PRECAUTIONS
General:
1. Symptomatic response to therapy with ZANTAC does not preclude the presence of gastric
malignancy.
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. In controlled studies in normal volunteers, elevations in SGPT have been observed when
H2-antagonists have been administered intravenously at greater-than-recommended dosages
for 5 days or longer. Therefore, it seems prudent in patients receiving IV ranitidine at
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
dosages ≥100 mg 4 times daily for periods of 5 days or longer to monitor SGPT daily (from
day 5) for the remainder of IV therapy.
4. Bradycardia in association with rapid administration of ZANTAC Injection has been reported
rarely, usually in patients with factors predisposing to cardiac rhythm disturbances.
Recommended rates of administration should not be exceeded (see DOSAGE AND
ADMINISTRATION).
5. 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.
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.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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 oral 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 oral doses up to 160 times the human oral dose and have revealed
no evidence of impaired fertility or harm to the fetus due to ranitidine. 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 Injection have been established in
the age-group of 1 month to 16 years for the treatment of duodenal 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.
Safety and effectiveness in pediatric patients for the treatment of pathological hypersecretory
conditions have not been established.
Limited data in neonatal patients (less than 1 month of age) receiving ECMO suggest that
ZANTAC may be useful and safe for increasing gastric pH for patients at risk of gastrointestinal
hemorrhage.
Geriatric Use: Clinical studies of ZANTAC Injection did not include sufficient numbers of
subjects aged 65 and over to determine whether they responded differently from younger
subjects. However, in clinical studies of oral formulations of ZANTAC, of the total number of
subjects enrolled in US and foreign controlled clinical trials, for which there were subgroup
analyses, 4,197 were 65 and over, while 899 were 75 and over. No overall differences in safety or
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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.
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: Geriatric Use and DOSAGE AND ADMINISTRATION: Dosage Adjustment
for Patients With Impaired Renal Function).
ADVERSE REACTIONS
Transient pain at the site of IM injection has been reported. Transient local burning or itching
has been reported with IV administration of ZANTAC.
The following have been reported as events in clinical trials or in the routine management of
patients treated with oral or parenteral 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, asystole, atrioventricular block, and premature ventricular beats.
Gastrointestinal: Constipation, diarrhea, nausea/vomiting, abdominal discomfort/pain, and
rare reports of pancreatitis.
Hepatic: 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. 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.
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 humans have shown no stimulation of any
pituitary hormone by ZANTAC and no antiandrogenic activity, and cimetidine-induced
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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 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 virtually no experience with overdosage with ZANTAC Injection and limited
experience with oral doses of ranitidine. 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, 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
Parenteral Administration: In some hospitalized patients with pathological hypersecretory
conditions or intractable duodenal ulcers, or in patients who are unable to take oral medication,
ZANTAC may be administered parenterally according to the following recommendations:
Intramuscular Injection: 50 mg (2 mL) every 6 to 8 hours. (No dilution necessary.)
Intermittent Intravenous Injection:
a. Intermittent Bolus: 50 mg (2 mL) every 6 to 8 hours. Dilute ZANTAC Injection,
50 mg, in 0.9% sodium chloride injection or other compatible IV solution (see Stability) to a
concentration no greater than 2.5 mg/mL (20 mL). Inject at a rate no greater than 4 mL/min
(5 minutes).
b. Intermittent Infusion: 50 mg (2 mL) every 6 to 8 hours. Dilute ZANTAC Injection,
50 mg, in 5% dextrose injection or other compatible IV solution (see Stability) to a concentration
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
no greater than 0.5 mg/mL (100 mL). Infuse at a rate no greater than 5 to 7 mL/min (15 to
20 minutes).
ZANTAC Injection Premixed solution, 50 mg, in 0.45% sodium chloride, 50 mL, requires no
dilution and should be infused over 15 to 20 minutes.
In some patients it may be necessary to increase dosage. When this is necessary, the increases
should be made by more frequent administration of the dose, but generally should not exceed
400 mg/day.
Continuous Intravenous Infusion: Add ZANTAC Injection to 5% dextrose injection or
other compatible IV solution (see Stability). Deliver at a rate of 6.25 mg/hour (e.g., 150 mg
[6 mL] of ZANTAC Injection in 250 mL of 5% dextrose injection at 10.7 mL/hour).
For Zollinger-Ellison patients, dilute ZANTAC Injection in 5% dextrose injection or other
compatible IV solution (see Stability) to a concentration no greater than 2.5 mg/mL. Start the
infusion at a rate of 1.0 mg/kg/hour. If after 4 hours either a measured gastric acid output is
>10 mEq/hour or the patient becomes symptomatic, the dose should be adjusted upward in
0.5-mg/kg/hour increments, and the acid output should be remeasured. Dosages up to
2.5 mg/kg/hour and infusion rates as high as 220 mg/hour have been used.
Pediatric Use: While limited data exist on the administration of IV ranitidine to children, the
recommended dose in pediatric patients is for a total daily dose of 2 to 4 mg/kg, to be divided and
administered every 6 to 8 hours, up to a maximum of 50 mg given every 6 to 8 hours. This
recommendation is derived from adult clinical studies and pharmacokinetic data in pediatric
patients. Limited data in neonatal patients (less than 1 month of age) receiving ECMO have
shown that a dose of 2 mg/kg is usually sufficient to increase gastric pH to >4 for at least
15 hours. Therefore, doses of 2 mg/kg given every 12 to 24 hours or as a continuous infusion
should be considered.
ZANTAC Injection Premixed in Flexible Plastic Containers: Instructions for Use:
To Open: Tear outer wrap at notch and remove solution container. Check for minute leaks by
squeezing container firmly. If leaks are found, discard unit as sterility may be impaired.
Preparation for Administration: Use aseptic technique.
1. Close flow control clamp of administration set.
2. Remove cover from outlet port at bottom of container.
3. Insert piercing pin of administration set into port with a twisting motion until the pin is
firmly seated. NOTE: See full directions on administration set carton.
4. Suspend container from hanger.
5. Squeeze and release drip chamber to establish proper fluid level in chamber during
infusion of ZANTAC Injection Premixed.
6. Open flow control clamp to expel air from set. Close clamp.
7. Attach set to venipuncture device. If device is not indwelling, prime and make
venipuncture.
8. Perform venipuncture.
9. Regulate rate of administration with flow control clamp.
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Caution: ZANTAC Injection Premixed in flexible plastic containers is to be administered by
slow IV drip infusion only. Additives should not be introduced into this solution. If used with
a primary IV fluid system, the primary solution should be discontinued during infusion of
ZANTAC Injection Premixed.
Do not administer unless solution is clear and container is undamaged.
Warning: Do not use flexible plastic container in series connections.
Dosage Adjustment for Patients With Impaired Renal Function: The administration of
ranitidine as a continuous infusion has not been evaluated in 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 50 mg every 18 to 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.
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: Geriatric Use and PRECAUTIONS: Geriatric Use).
Stability: Undiluted, ZANTAC Injection tends to exhibit a yellow color that may intensify over
time without adversely affecting potency. ZANTAC Injection is stable for 48 hours at room
temperature when added to or diluted with most commonly used IV solutions, e.g., 0.9% sodium
chloride injection, 5% dextrose injection, 10% dextrose injection, lactated ringer's injection, or
5% sodium bicarbonate injection.
ZANTAC Injection Premixed in flexible plastic containers is sterile through the expiration
date on the label when stored under recommended conditions.
Note: Parenteral drug products should be inspected visually for particulate matter and
discoloration before administration whenever solution and container permit.
HOW SUPPLIED
ZANTAC Injection, 25 mg/mL, containing phenol 0.5% as preservative, is available as
follows:
NDC 0173-0362-38, 2-mL single-dose vials (Tray of 10)
NDC 0173-0363-01, 6-mL multidose vials (Singles)
Store between 4° and 25°C (39° and 77°F); excursions permitted to 30°C (86°F). Protect
from light.
ZANTAC Injection Premixed, 50 mg/50 mL, in 0.45% sodium chloride, is available as a
sterile, premixed solution for IV administration in single-dose, flexible plastic containers
(NDC 0173-0441-00) (case of 24). It contains no preservatives.
Store between 2° and 25°C (36° and 77°F). Protect from light.
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat;
however, brief exposure up to 40°C does not adversely affect the product. Protect from freezing.
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Company logo
GlaxoSmithKline
Research Triangle Park, NC 27709
ZANTAC® Injection:
GlaxoSmithKline
Research Triangle Park, NC 27709
ZANTAC® Injection Premixed:
Manufactured for GlaxoSmithKline
Research Triangle Park, NC 27709
by Hospira, Inc., Lake Forest, IL 60045
ZANTAC is a registered trademark of Warner-Lambert Company, used under license.
MULTISTIX is a registered trademark of Bayer Healthcare LLC.
©2009, GlaxoSmithKline. All rights reserved.
April 2009
ZNJ:5PI
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:30.279488
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019090s053,019593s042lbl.pdf', 'application_number': 19593, 'submission_type': 'SUPPL ', 'submission_number': 42}
|
11,551
|
PRESCRIBING INFORMATION
ZANTAC®
(ranitidine hydrochloride)
Injection
ZANTAC®
(ranitidine hydrochloride)
Injection Premixed
DESCRIPTION
The active ingredient in ZANTAC Injection and ZANTAC Injection Premixed is ranitidine
hydrochloride (HCl), 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,
hydrochloride. It has the following structure: Chemcial 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.
ZANTAC Injection is a clear, colorless to yellow, nonpyrogenic liquid. The yellow color of
the liquid tends to intensify without adversely affecting potency. The pH of the injection solution
is 6.7 to 7.3.
Sterile Injection for Intramuscular or Intravenous Administration: Each 1 mL of
aqueous solution contains ranitidine 25 mg (as the hydrochloride); phenol 5 mg as preservative;
and 0.96 mg of monobasic potassium phosphate and 2.4 mg of dibasic sodium phosphate as
buffers.
Sterile, Premixed Solution for Intravenous Administration in Single-Dose, Flexible
Plastic Containers: Each 50 mL contains ranitidine HCl equivalent to 50 mg of ranitidine,
sodium chloride 225 mg, and citric acid 15 mg and dibasic sodium phosphate 90 mg as buffers in
water for injection. It contains no preservatives. The osmolarity of this solution is 180 mOsm/L
(approx.), and the pH is 6.7 to 7.3.
The flexible plastic container is fabricated from a specially formulated, nonplasticized,
thermoplastic co-polyester (CR3). Water can permeate from inside the container into the
overwrap but not in amounts sufficient to affect the solution significantly. Solutions inside the
plastic container also can leach out certain of the chemical components in very small amounts
before the expiration period is attained. However, the safety of the plastic has been confirmed by
tests in animals according to USP biological standards for plastic containers.
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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 absorbed very rapidly after intramuscular (IM)
injection. Mean peak levels of 576 ng/mL occur within 15 minutes or less following a 50-mg IM
dose. Absorption from IM sites is virtually complete, with a bioavailability of 90% to 100%
compared with intravenous (IV) administration. Following oral administration, the bioavailability
of ZANTAC Tablets is 50%.
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: Following IV injection, approximately 70% of the dose is recovered in the urine
as unchanged drug. Renal clearance averages 530 mL/min, with a total clearance of 760 mL/min.
The elimination half-life is 2.0 to 2.5 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 3.1 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 pharmacokinetics of ZANTAC in pediatric patients are
summarized in Table 1.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1. Ranitidine Pharmacokinetics in Pediatric Patients Following IV Dosing
Population
(age)
n
Dose
(mg/kg)
t½
(hours)
Vd
(L/kg)
CLp
(mL/min/kg)
Peptic ulcer disease
(<6 years)
(6–11.9 years)
(>12 years)
Adults
6
11
6
6
1.25 or 2.5
1.25 or 2.5
1.25 or 2.5
2.5
2.2
2.1
1.7
1.9
1.29
1.14
0.98
1.04
11.41
8.96
9.89
8.77
Peptic ulcer disease
(3.5–16 years)
12
0.13–0.80
1.8
2.3
795 mL/min/1.73/m2
Children in intensive care
(1 day–12.6 years)
17
1.0
2.4
2
11.7
Neonates receiving
ECMO
12
2
6.6
1.8
4.3
T½ = Terminal half-life; CLp = Plasma clearance of ranitidine.
ECMO = extracorporeal membrane oxygenation.
Plasma clearance in neonatal patients (less than 1 month of age) receiving ECMO was
considerably lower (3 to 4 mL/min/kg) than observed in children or adults. The elimination half-
life in neonates averaged 6.6 hours as compared to approximately 2 hours in adults and pediatric
patients.
Pharmacodynamics: Serum concentrations necessary to inhibit 50% of stimulated gastric
acid secretion are estimated to be 36 to 94 ng/mL. Following single IV or IM 50-mg doses, serum
concentrations of ranitidine are in this range for 6 to 8 hours.
Antisecretory Activity: 1. Effects on Acid Secretion: ZANTAC Injection inhibits
basal gastric acid secretion as well as gastric acid secretion stimulated by betazole and
pentagastrin, as shown in Table 2.
Table 2. Effect of Intravenous ZANTAC on Gastric Acid Secretion
Time After Dose,
hours
% Inhibition of Gastric Acid Output
by Intravenous Dose, mg
20 mg
60 mg
100 mg
Betazole
Pentagastrin
Up to 2
Up to 3
93
47
99
66
99
77
In a group of 10 known hypersecretors, ranitidine plasma levels of 71, 180, and 376 ng/mL
inhibited basal acid secretion by 76%, 90%, and 99.5%, respectively.
It appears that basal- and betazole-stimulated secretions are most sensitive to inhibition by
ZANTAC, while pentagastrin-stimulated secretion is more difficult to suppress.
2. Effects on Other Gastrointestinal Secretions:
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pepsin: ZANTAC does not affect pepsin secretion. Total pepsin output is reduced in
proportion to the decrease in volume of gastric juice.
Intrinsic Factor: 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: The ranitidine concentration necessary to suppress basal acid secretion by at least
90% has been reported to be 40 to 60 ng/mL in pediatric patients with duodenal or gastric ulcers.
In a study of 20 critically ill pediatric patients receiving ranitidine IV at 1 mg/kg every
6 hours, 10 patients with a baseline pH ≥4 maintained this baseline throughout the study. Eight of
the remaining 10 patients with a baseline of pH ≤2 achieved pH ≥4 throughout varying periods
after dosing. It should be noted, however, that because these pharmacodynamic parameters were
assessed in critically ill pediatric patients, the data should be interpreted with caution when
dosing recommendations are made for a less seriously ill pediatric population.
In another small study of neonatal patients (n = 5) receiving ECMO, gastric pH <4
pretreatment increased to >4 after a 2-mg/kg dose and remained above 4 for at least 15 hours.
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
oral ZANTAC as shown in Table 3.
Table 3. Duodenal Ulcer Patient Healing Rates
Oral ZANTAC*
Oral Placebo*
Number
Entered
Healed/
Evaluable
Number
Entered
Healed/
Evaluable
Outpatients
Week 2
Week 4
195
69/182
(38%)†
137/187
(73%)†
188
31/164
(19%)
76/168
(45%)
*All patients were permitted antacids as needed for relief of pain.
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
†P<0.0001.
In these studies, patients treated with oral 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
Oral ZANTAC
Oral placebo
0.06
0.71
0.71
1.43
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 oral ZANTAC was followed by healing of ulcers in 8 of 19 (42%)
patients who were intractable to previous therapy.
In a retrospective review of 52 Zollinger-Ellison patients given ZANTAC as a continuous IV
infusion for up to 15 days, no patients developed complications of acid-peptic disease such as
bleeding or perforation. Acid output was controlled to ≤10 mEq/h.
INDICATIONS AND USAGE
ZANTAC Injection and ZANTAC Injection Premixed are indicated in some hospitalized
patients with pathological hypersecretory conditions or intractable duodenal ulcers, or as an
alternative to the oral dosage form for short-term use in patients who are unable to take oral
medication.
CONTRAINDICATIONS
ZANTAC Injection and ZANTAC Injection Premixed are contraindicated for patients known
to have hypersensitivity to the drug.
PRECAUTIONS
General:
1. Symptomatic response to therapy with ZANTAC does not preclude the presence of gastric
malignancy.
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. In controlled studies in normal volunteers, elevations in SGPT have been observed when
H2-antagonists have been administered intravenously at greater-than-recommended dosages
for 5 days or longer. Therefore, it seems prudent in patients receiving IV ranitidine at
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
dosages ≥100 mg 4 times daily for periods of 5 days or longer to monitor SGPT daily (from
day 5) for the remainder of IV therapy.
4. Bradycardia in association with rapid administration of ZANTAC Injection has been reported
rarely, usually in patients with factors predisposing to cardiac rhythm disturbances.
Recommended rates of administration should not be exceeded (see DOSAGE AND
ADMINISTRATION).
5. 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.
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.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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 oral 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 oral doses up to 160 times the human oral dose and have revealed
no evidence of impaired fertility or harm to the fetus due to ranitidine. 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 Injection have been established in
the age-group of 1 month to 16 years for the treatment of duodenal 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.
Safety and effectiveness in pediatric patients for the treatment of pathological hypersecretory
conditions have not been established.
Limited data in neonatal patients (less than 1 month of age) receiving ECMO suggest that
ZANTAC may be useful and safe for increasing gastric pH for patients at risk of gastrointestinal
hemorrhage.
Geriatric Use: Clinical studies of ZANTAC Injection did not include sufficient numbers of
subjects aged 65 and over to determine whether they responded differently from younger
subjects. However, in clinical studies of oral formulations of ZANTAC, of the total number of
subjects enrolled in US and foreign controlled clinical trials, for which there were subgroup
analyses, 4,197 were 65 and over, while 899 were 75 and over. No overall differences in safety or
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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.
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: Geriatric Use and DOSAGE AND ADMINISTRATION: Dosage Adjustment
for Patients With Impaired Renal Function).
ADVERSE REACTIONS
Transient pain at the site of IM injection has been reported. Transient local burning or itching
has been reported with IV administration of ZANTAC.
The following have been reported as events in clinical trials or in the routine management of
patients treated with oral or parenteral 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, asystole, atrioventricular block, and premature ventricular beats.
Gastrointestinal: Constipation, diarrhea, nausea/vomiting, abdominal discomfort/pain, and
rare reports of pancreatitis.
Hepatic: 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. 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.
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 humans have shown no stimulation of any
pituitary hormone by ZANTAC and no antiandrogenic activity, and cimetidine-induced
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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.
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 virtually no experience with overdosage with ZANTAC Injection and limited
experience with oral doses of ranitidine. 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, 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
Parenteral Administration: In some hospitalized patients with pathological hypersecretory
conditions or intractable duodenal ulcers, or in patients who are unable to take oral medication,
ZANTAC may be administered parenterally according to the following recommendations:
Intramuscular Injection: 50 mg (2 mL) every 6 to 8 hours. (No dilution necessary.)
Intermittent Intravenous Injection:
a. Intermittent Bolus: 50 mg (2 mL) every 6 to 8 hours. Dilute ZANTAC Injection,
50 mg, in 0.9% sodium chloride injection or other compatible IV solution (see Stability) to a
concentration no greater than 2.5 mg/mL (20 mL). Inject at a rate no greater than 4 mL/min
(5 minutes).
b. Intermittent Infusion: 50 mg (2 mL) every 6 to 8 hours. Dilute ZANTAC Injection,
50 mg, in 5% dextrose injection or other compatible IV solution (see Stability) to a concentration
no greater than 0.5 mg/mL (100 mL). Infuse at a rate no greater than 5 to 7 mL/min (15 to
20 minutes).
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ZANTAC Injection Premixed solution, 50 mg, in 0.45% sodium chloride, 50 mL, requires no
dilution and should be infused over 15 to 20 minutes.
In some patients it may be necessary to increase dosage. When this is necessary, the increases
should be made by more frequent administration of the dose, but generally should not exceed
400 mg/day.
Continuous Intravenous Infusion: Add ZANTAC Injection to 5% dextrose injection or
other compatible IV solution (see Stability). Deliver at a rate of 6.25 mg/hour (e.g., 150 mg
[6 mL] of ZANTAC Injection in 250 mL of 5% dextrose injection at 10.7 mL/hour).
For Zollinger-Ellison patients, dilute ZANTAC Injection in 5% dextrose injection or other
compatible IV solution (see Stability) to a concentration no greater than 2.5 mg/mL. Start the
infusion at a rate of 1.0 mg/kg/hour. If after 4 hours either a measured gastric acid output is
>10 mEq/hour or the patient becomes symptomatic, the dose should be adjusted upward in
0.5-mg/kg/hour increments, and the acid output should be remeasured. Dosages up to
2.5 mg/kg/hour and infusion rates as high as 220 mg/hour have been used.
Pediatric Use: While limited data exist on the administration of IV ranitidine to children, the
recommended dose in pediatric patients is for a total daily dose of 2 to 4 mg/kg, to be divided and
administered every 6 to 8 hours, up to a maximum of 50 mg given every 6 to 8 hours. This
recommendation is derived from adult clinical studies and pharmacokinetic data in pediatric
patients. Limited data in neonatal patients (less than 1 month of age) receiving ECMO have
shown that a dose of 2 mg/kg is usually sufficient to increase gastric pH to >4 for at least
15 hours. Therefore, doses of 2 mg/kg given every 12 to 24 hours or as a continuous infusion
should be considered.
ZANTAC Injection Premixed in Flexible Plastic Containers: Instructions for Use:
To Open: Tear outer wrap at notch and remove solution container. Check for minute leaks by
squeezing container firmly. If leaks are found, discard unit as sterility may be impaired.
Preparation for Administration: Use aseptic technique.
1. Close flow control clamp of administration set.
2. Remove cover from outlet port at bottom of container.
3. Insert piercing pin of administration set into port with a twisting motion until the pin is
firmly seated. NOTE: See full directions on administration set carton.
4. Suspend container from hanger.
5. Squeeze and release drip chamber to establish proper fluid level in chamber during
infusion of ZANTAC Injection Premixed.
6. Open flow control clamp to expel air from set. Close clamp.
7. Attach set to venipuncture device. If device is not indwelling, prime and make
venipuncture.
8. Perform venipuncture.
9. Regulate rate of administration with flow control clamp.
Caution: ZANTAC Injection Premixed in flexible plastic containers is to be administered by
slow IV drip infusion only. Additives should not be introduced into this solution. If used with
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
a primary IV fluid system, the primary solution should be discontinued during infusion of
ZANTAC Injection Premixed.
Do not administer unless solution is clear and container is undamaged.
Warning: Do not use flexible plastic container in series connections.
Dosage Adjustment for Patients With Impaired Renal Function: The administration of
ranitidine as a continuous infusion has not been evaluated in 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 50 mg every 18 to 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.
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: Geriatric Use and PRECAUTIONS: Geriatric Use).
Stability: Undiluted, ZANTAC Injection tends to exhibit a yellow color that may intensify over
time without adversely affecting potency. ZANTAC Injection is stable for 48 hours at room
temperature when added to or diluted with most commonly used IV solutions, e.g., 0.9% sodium
chloride injection, 5% dextrose injection, 10% dextrose injection, lactated ringer's injection, or
5% sodium bicarbonate injection.
ZANTAC Injection Premixed in flexible plastic containers is sterile through the expiration
date on the label when stored under recommended conditions.
Note: Parenteral drug products should be inspected visually for particulate matter and
discoloration before administration whenever solution and container permit.
HOW SUPPLIED
ZANTAC Injection, 25 mg/mL, containing phenol 0.5% as preservative, is available as
follows:
NDC 0173-0362-38, 2-mL single-dose vials (Tray of 10)
NDC 0173-0363-01, 6-mL multidose vials (Singles)
Store between 4° and 25°C (39° and 77°F); excursions permitted to 30°C (86°F). Protect
from light.
ZANTAC Injection Premixed, 50 mg/50 mL, in 0.45% sodium chloride, is available as a
sterile, premixed solution for IV administration in single-dose, flexible plastic containers
(NDC 0173-0441-00) (case of 24). It contains no preservatives.
Store between 2° and 25°C (36° and 77°F). Protect from light.
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat;
however, brief exposure up to 40°C does not adversely affect the product. Protect from freezing.
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Company Logo
GlaxoSmithKline
Research Triangle Park, NC 27709
ZANTAC® Injection:
GlaxoSmithKline
Research Triangle Park, NC 27709
ZANTAC® Injection Premixed:
Manufactured for GlaxoSmithKline
Research Triangle Park, NC 27709
by Hospira, Inc., Lake Forest, IL 60045
ZANTAC is a registered trademark of Warner-Lambert Company, used under license.
MULTISTIK is a registered trademark of Bayer Healthcare LLC.
©2009, GlaxoSmithKline. All rights reserved.
(Date of Issue)
ZNJ:4PI
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:30.334805
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019090s051,019593s039lbl.pdf', 'application_number': 19593, 'submission_type': 'SUPPL ', 'submission_number': 39}
|
11,555
|
MAGNEVIST®
(brand of gadopentetate dimeglumine)
Injection
FOR INTRAVENOUS ADMINISTRATION
Rx only
WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)
Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with
impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic
information is essential and not available with non-contrasted MRI or other modalities. NSF may
result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs.
• Do not administer MAGNEVIST to patients with:
o chronic, severe kidney disease (GFR < 30 mL/min/1.73m2), or
o acute kidney injury (see CONTRAINDICATIONS).
• Screen patients for acute kidney injury and other conditions that may reduce renal
function. For patients at risk for chronically reduced renal function (for example, age
>60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR)
through laboratory testing.
Do not exceed the recommended MAGNEVIST dose and allow a sufficient period of time for
elimination of the drug from the body prior to any re-administration (see WARNINGS AND
PRECAUTIONS).
DESCRIPTION
MAGNEVIST® (brand of gadopentetate dimeglumine) Injection is the N-methylglucamine salt of
the gadolinium complex of diethylenetriamine pentaacetic acid, and is an injectable contrast
medium for magnetic resonance imaging (MRI). MAGNEVIST Injection is provided as a sterile,
clear, colorless to slightly yellow aqueous solution for intravenous injection.
MAGNEVIST Injection is a 0.5-mol/L solution of 1-deoxy-1-(methylamino)-D-glucitol
dihydrogen [N,N-bis[2-[bis(carboxymethyl)amino]ethyl] glycinato (5-) ]gadolinate(2-)(2:1) with
a molecular weight of 938, an empirical formula of C28H54GdN5O20, and has the following
structural formula: structural formula
Each mL of MAGNEVIST Injection contains 469.01 mg gadopentetate dimeglumine, 0.99 mg
meglumine, 0.40 mg diethylenetriamine pentaacetic acid and water for injection. MAGNEVIST
Injection contains no antimicrobial preservative.
MAGNEVIST Injection has a pH of 6.5 to 8.0. Pertinent physicochemical data are noted below:
Reference ID: 2881079
Bayer Response NDA 019596 Magnevist Inj 14 Dec 10
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PARAMETER Osmolality (mOsmol/ kg water) at 37° C 1,960 Viscosity (CP) at 20° C 4.9 at 37°
C 2.9 Density (g/mL) at 25° C 1.195 Specific gravity at 25° C 1.208 Octanol: H2O at 25° C and
pH7 log Pow = - 5.4
MAGNEVIST Injection has an osmolality 6.9 times that of plasma which has an osmolality of
285 mOsmol/ kg water. MAGNEVIST Injection is hypertonic under conditions of use.
CLINICAL PHARMACOLOGY
Pharmacokinetics
The pharmacokinetics of intravenously administered gadopentetate dimeglumine in normal
subjects conforms to a two compartment open-model with mean distribution and elimination half-
lives (reported as mean ± SD) of about 0.2 ± 0.13 hours and 1.6 ± 0.13 hours, respectively.
Upon injection, the meglumine salt is completely dissociated from the gadopentetate
dimeglumine complex. Gadopentetate is exclusively eliminated in the urine with 83 ± 14% (mean
± SD) of the dose excreted within 6 hours and 91 ± 13% (mean ± SD) by 24 hours, post-injection.
There was no detectable biotransformation or decomposition of gadopentetate dimeglumine.
The renal and plasma clearance rates (1.76 ± 0.39 mL/min/kg and 1.94 ± 0.28 mL/min/kg,
respectively) of gadopentetate are essentially identical, indicating no alteration in elimination
kinetics on passage through the kidneys and that the drug is essentially cleared through the
kidney. The volume of distribution (266 ± 43 mL/kg) is equal to that of extracellular water and
clearance is similar to that of substances which are subject to glomerular filtration.
In vitro laboratory results indicate that gadopentetate does not bind to human plasma protein. In
vivo protein binding studies have not been done.
Pharmacodynamics
Gadopentetate dimeglumine is a paramagnetic agent and, as such, it develops a magnetic moment
when placed in a magnetic field. The relatively large magnetic moment produced by the
paramagnetic agent results in a relatively large local magnetic field, which can enhance the
relaxation rates of water protons in the vicinity of the paramagnetic agent.
In magnetic resonance imaging (MRI), visualization of normal and pathological brain tissue
depends in part on variations in the radiofrequency signal intensity that occur with 1) changes in
proton density; 2) alteration of the spin- lattice or longitudinal relaxation time (T1); and 3)
variation of the spin- spin or transverse relaxation time (T2). When placed in a magnetic field,
gadopentetate dimeglumine decreases the T1 and T2 relaxation time in tissues where it
accumulates. At usual doses the effect is primarily on the T1 relaxation time.
Gadopentetate dimeglumine does not cross the intact blood-brain barrier and, therefore, does not
accumulate in normal brain or in lesions that do not have an abnormal blood- brain barrier, e. g.,
cysts, mature post-operative scars, etc. However, disruption of the blood- brain barrier or
abnormal vascularity allows accumulation of gadopentetate dimeglumine in lesions such as
neoplasms, abscesses, and subacute infarcts. The pharmacokinetic parameters of MAGNEVIST
in various lesions are not known.
CLINICAL TRIALS
MAGNEVIST Injection was administered to 1272 patients in open label controlled clinical
studies. The mean age of these patients was 46.4 years (range 2 to 93 years). Of these patients,
55% (700) were male and 45% (572) were female. Of the 1271 patients who received
MAGNEVIST Injection and for whom race was reported, 82.1% (1043) were Caucasian, 9.7%
(123) were Black, 5.3% (67) were Hispanic, 2.1% (27) were Oriental/Asian, and 0.9% (11) were
Reference ID: 2881079
Bayer Response NDA 019596 Magnevist Inj 14 Dec 10
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
other. Of the 1272 patients, 550 patients were evaluated in blinded reader studies. These
evaluated the use of contrast enhancement in magnetic resonance imaging of lesions in the head
and neck, brain, spine and associated tissues, and body (excluding the heart). Of the 550 patients,
all patients had a reason for an MRI and efficacy assessments were based on pre-and post-
MAGNEVIST injection film quality, film contrast, lesion configuration (border, size, and
location), and the number of lesions. The protocols did not include systematic verification of
specific diseases or histopathologic confirmation of findings.
Of the above 550 patients, 97 patients received 0.1 mmol/kg MAGNEVIST Injection IV in two
clinical trials of MAGNEVIST MRI contrast enhancement for body imaging. Of these 97, 68 had
MRIs of the internal organs/ structures of the abdomen or thorax (excluding the heart); 8 had
breast images and 22 had images of appendages. The results of MRIs before and after
MAGNEVIST use were compared blindly. Overall additional lesions were identified in 22/ 97
(23%) of the patients after MAGNEVIST Injection. The mean number of lesions identified before
(1.49/patient) and after MAGNEVIST (1.75/patient) were similar. Seven (8%) of the patients had
lesions seen before MAGNEVIST that were not seen after MAGNEVIST. Overall, after
MAGNEVIST Injection, 41% of the images had a higher contrast score than before injection; and
18% of the images had a higher contrast score before MAGNEVIST Injection than after
MAGNEVIST Injection. MAGNEVIST MRI of the 8 patients with breast images were not
systematically compared to the results to mammography, breast biopsy or other modalities. In the
22 patients with appendage images (e. g., muscle, bone and intraarticular structures),
MAGNEVIST MRI was not systematically evaluated to determine the effects of contrast
biodistribution in these different areas.
Of the above 550 patients, 66 patients received MAGNEVIST 0.1 mmol/ kg IV in clinical trials
of MAGNEVIST MRl contrast enhancement of lesions in the head and neck. A total of 66 MRI
images were evaluated blindly by comparing each pair of MRI images, before and after
MAGNEVIST Injection. In these paired images, 56/66 (85%) had greater enhancement after
MAGNEVIST and 40/66 (61%) had better lesion configuration or border delineation after
MAGNEVIST. Overall, there was better contrast after MAGNEVIST in 55% of the images,
comparable enhancement in 44 (36%) before and after MAGNEVIST, and better enhancement in
9% without MAGNEVIST.
In the studies of the brain and spinal cord, MAGNEVIST 0.1 mmol/kg IV provided contrast
enhancement in lesions with an abnormal blood brain barrier.
In two studies, a total of 108 patients were evaluated to compare the dose response effects of 0.1
mmol/kg and 0.3 mmol/kg of MAGNEVIST in CNS MRI. Both dosing regimens had similar
imaging and general safety profiles; however, the 0.3 mmoL/kg dose did not provide additional
benefit to the final diagnosis (defined as number of lesions, location and characterization).
INDICATIONS AND USAGE
Central Nervous System
MAGNEVIST Injection is indicated for use with magnetic resonance imaging (MRI) in adults,
and pediatric patients (2 years of age and older) to visualize lesions with abnormal vascularity in
the brain (intracranial lesions), spine and associated tissues. MAGNEVIST Injection has been
shown to facilitate visualization of intracranial lesions including but not limited to tumors.
Extracranial/Extraspinal Tissues
MAGNEVIST is indicated for use with MRI in adults and pediatric patients (2 years of age and
older) to facilitate the visualization of lesions with abnormal vascularity in the head and neck.
Reference ID: 2881079
Bayer Response NDA 019596 Magnevist Inj 14 Dec 10
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Body
MAGNEVIST Injection is indicated for use in MRI in adults and pediatric patients (2 years of
age and older) to facilitate the visualization of lesions with abnormal vascularity in the body
(excluding the heart).
CONTRAINDICATIONS
MAGNEVIST is contraindicated in patients with:
•
Chronic, severe kidney disease (glomerular filtration rate, GFR < 30 mL/min/1.73m2), or
•
Acute kidney injury.
WARNINGS AND PRECAUTIONS
Nephrogenic Systemic Fibrosis (NSF)
Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis
(NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these
patients unless the diagnostic information is essential and not available with non-contrast
enhanced MRI or other modalities. The GBCA-associated NSF risk appears highest for patients
with chronic, severe kidney disease (GFR < 30 mL/min/1.73m2) as well as patients with acute
kidney injury. Do not administer MAGNEVIST to these patients. The risk appears lower for
patients with chronic, moderate kidney disease (GFR 30- 59 mL/min/1.73m2) and little, if any, for
patients with chronic, mild kidney disease (GFR 60- 89 mL/min/1.73m2). NSF may result in fatal
or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of
NSF following MAGNEVIST administration to Bayer Healthcare (1-888-842-2937) or FDA (1
800-FDA-1088 or www.fda.gov/medwatch).
Screen patients for acute kidney injury and other conditions that may reduce renal function.
Features of acute kidney injury consist of rapid (over hours to days) and usually reversible
decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-
induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal
function in the setting of acute kidney injury. For patients at risk for chronically reduced renal
function (for example, age > 60 years, diabetes mellitus or chronic hypertension), estimate the
GFR through laboratory testing.
Among the factors that may increase the risk for NSF are repeated or higher than recommended
doses of a GBCA and degree of renal impairment at the time of exposure. Record the specific
GBCA and the dose administered to a patient. When administering Magnevist, do not exceed the
recommended dose and allow a sufficient period of time for elimination of the drug prior to any
re-administration (See CLINICAL PHARMACOLOGY and DOSAGE AND
ADMINISTRATION).
Hypersensitivity Reactions
Anaphylactoid and anaphylactic reactions with cardiovascular, respiratory and/or cutaneous
manifestations rarely resulting in death have occurred. If such a reaction occurs, stop
MAGNEVIST Injection and immediately begin appropriate therapy, including resuscitation.
Observe closely patients with a history of drug reactions, allergy or other hypersensitivity
disorders, during and up to several hours after MAGNEVIST Injection.
Acute Renal Failure
In patients with renal insufficiency, acute renal failure requiring dialysis or worsening renal
function have occurred, mostly within 48 hrs of MAGNEVIST Injection. The risk of these events
Reference ID: 2881079
Bayer Response NDA 019596 Magnevist Inj 14 Dec 10
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
is higher with increasing dose of contrast. Use the lowest possible dose and evaluate renal
function in patients with renal insufficiency. (See CLINICAL PHARMACOLOGY,
Pharmacokinetics.)
MAGNEVIST is cleared by glomerular filtration and is dialyzable.
Injection Site Reactions
Skin and soft tissue necrosis, thrombosis, fasciitis, and compartment syndrome requiring surgical
intervention (e.g., compartment release or amputation) have occurred very rarely at the site of
contrast injection or the dosed limb. Total volume and rate of MAGNEVIST Injection,
extravasation of contrast agent, and patient susceptibility might contribute to these reactions.
Phlebitis and thrombophlebitis may be observed generally within 24 hours after MAGNEVIST
Injection and resolve with supportive treatment. Determine the patency and integrity of the
intravenous line before administration of MAGNEVIST Injection. Assessment of the dosed limb
for the development of injection site reactions is recommended.
Interference with Visualization of Lesions Visible with Non-Contrast MRI
As with any paramagnetic contrast agent, MAGNEVIST Injection might impair the visualization
of lesions seen on non-contrast MRI. Therefore, caution should be exercised when MAGNEVIST
MRI scans are interpreted without a companion non-contrast MRI scan.
Patient Counseling Information
Patients scheduled to receive MAGNEVIST Injection should be instructed to inform their
physician if they are pregnant, breastfeeding, or have a history of renal insufficiency, asthma or
allergic respiratory disorders. Additionally instruct patients to inform their physician if they:
•
Have a history of kidney and/or liver disease, or
•
Have recently received a GBCA.
GBCAs increase the risk of NSF among patients with impaired elimination of drugs. To counsel
patients at risk of NSF:
•
Describe the clinical manifestation of NSF
•
Describe procedures to screen for the detection of renal impairment
Instruct the patients to contact their physician if they develop signs or symptoms of NSF
following MAGNEVIST administration, such as burning, itching, swelling, scaling, hardening
and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving,
bending or straightening the arms, hands, legs or feet; pain in the hip bones or ribs; or muscle
weakness.
LABORATORY TEST FINDINGS
Transitory changes in serum iron, bilirubin and transaminase levels were observed in clinical
trials.
MAGNEVIST Injection does not interfere with serum and plasma calcium measurements
determined by colorimetric assays.
CARCINOGENESIS, MUTAGENESIS AND IMPAIRMENT OF FERTILITY
Long term animal studies have not been performed to evaluate the carcinogenic potential of
gadopentetate dimeglumine.
A comprehensive battery of in vitro and in vivo studies in bacterial and mammalian systems
suggest that gadopentetate dimeglumine is not mutagenic or clastogenic and does not induce
Reference ID: 2881079
Bayer Response NDA 019596 Magnevist Inj 14 Dec 10
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
unscheduled DNA repair in rat hepatocytes or cause cellular transformation of mouse embryo
fibroblasts. However, the drug did show some evidence of mutagenic potential in vivo in the
mouse dominant lethal assay at doses of 6 mmol/kg, but did not show any such potential in the
mouse and dog micronucleus tests at intravenous doses of 9 mmol/kg and 2.5 mmol/kg,
respectively.
When administered intra-peritoneally to male and female rats daily prior to mating, during mating
and during embryonic development for up to 74 days (males) or 35 days (females), gadopentetate
caused a decrease in number of corpora lutea at the 0.1 mmol/ kg dose level. After daily dosing
with 2.5 mmol/kg suppression of food consumption and body weight gain (males and females)
and a decrease in the weights of testes and epididymis were also observed.
In a separate experiment in rats, daily injections of gadopentetate dimeglumine over 16 days
caused spermatogenic cell atrophy at a dose level of 5 mmol/kg but not at a dose level of 2.5
mmol/kg. This atrophy was not reversed within a 16-day observation period following the
discontinuation of the drug.
PREGNANCY CATEGORY C.
Gadopentetate dimeglumine retarded fetal development slightly when given intravenously for 10
consecutive days to pregnant rats at daily doses of 0.25, 0.75, and 1.25 mmol/kg (2.5, 7.5 and
12.5 times the human dose based on body weight) and when given intravenously for 13
consecutive days to pregnant rabbits at daily doses of 0.75 and 1.25 mmol/kg (7.5 and 12.5 times
the human dose respectively, based on body weight) but not at daily doses of 0.25 mmol/kg. No
congenital anomalies were noted in rats or rabbits.
Adequate and well controlled studies were not conducted in pregnant women. MAGNEVIST
Injection should be used during pregnancy only if the potential benefit justifies the potential risk
to the fetus.
NURSING WOMEN
MAGNEVIST is excreted in human milk. MAGNEVIST Injection was administered
intravenously to 18 lactating women with normal renal function at a dose of 0.1 mmol/kg body
weight. In these women, less than 0.04% of the administered gadolinium was excreted into the
breast milk during the 24-hour period following dosing. Breast milk obtained during the 24 hours
following dosing revealed the average cumulative amount of gadolinium excreted in breast milk
was 0.57+/- 0.71 micromol. The amount transferred from a 70 kg woman (receiving 0.1 mmol/kg
body weight) to an infant by breast feeding over a period of 24 hrs translates into less than 3
micromol of gadolinium.
The overall duration of excretion of gadolinium into breast milk is unknown. The extent of the
absorption of MAGNEVIST Injection in infants and its effect on the breast-fed child remains
unknown. Caution should be exercised when MAGNEVIST Injection is administered to a nursing
woman.
PEDIATRIC USE
The use of MAGNEVIST in imaging the central nervous system, extracranial/extraspinal tissues,
and body have been established in the pediatric population from the ages of 2 to 16 years on the
basis of adequate and well controlled clinical trials in adults and safety studies in this pediatric
population. (See CLINICAL TRIALS for details.)
Safety and efficacy in the pediatric population under the age of 2 years have not been established.
MAGNEVIST is eliminated primarily by the kidney. The pharmacokinetics of MAGNEVIST in
neonates and infants with immature renal function have not been studied. (See INDICATIONS
and DOSAGE AND ADMINISTRATION.)
Reference ID: 2881079
Bayer Response NDA 019596 Magnevist Inj 14 Dec 10
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ADVERSE REACTIONS
Clinical Trial 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 to rates in the clinical trials of
another drug and may not reflect the rates observed in practice.
The mean age of the 1272 patients who received MAGNEVIST Injection in pre-market clinical
trials was 46.4 years (range 2 to 93 years). Of these patients, 55% (700) were male and 45% (572)
were female. Of the 1271 patients who received MAGNEVIST Injection and for whom race was
reported, 82.1% (1043) were Caucasian, 9.7% (123) were Black, 5.3% (67) were Hispanic, 2.1%
(27) were Oriental/Asian, and 0.9% (11) were other.
The most common adverse reaction was headache (4.8%). The majority of headaches were
transient and of mild to moderate severity. Other adverse reactions that occurred in ≥ 1% of
patients included: nausea (2.7%), injection site coldness/localized coldness (2.3%) and dizziness
(1%).
The following additional adverse reactions occurred in less than 1% of the patients:
General Disorders: Injection site symptoms, namely, pain, localized warmth, and burning
sensation; substernal chest pain, back pain, pyrexia, asthenia, feeling cold, generalized warmth,
localized edema, fatigue, and chest tightness, and anaphylactoid reactions characterized by
cardiovascular, respiratory and/or cutaneous symptoms.
Cardiovascular: Hypotension, hypertension, tachycardia, migraine, syncope, vasodilatation,
pallor, angina pectoris, phlebitis.
Digestive: Abdominal discomfort, teeth pain, increased salivation, abdominal pain, vomiting,
constipation, diarrhea.
Nervous System: Agitation, anxiety, thirst, anorexia, nystagmus, somnolence, diplopia, loss of
consciousness, convulsions (including grand mal), paresthesia.
Respiratory System: Throat irritation, rhinitis, sneezing, dyspnea, bronchospasm, cough.
Skin: Rash, sweating (hyperhidrosis), pruritus, urticaria (hives), facial edema, epidermal
necrolysis.
Special Senses: Tinnitus, conjunctivitis, visual field defect, taste abnormality, dry mouth,
lacrimation, eye irritation, eye pain, ear pain.
Postmarketing Experience
The following additional adverse reactions have been identified during postmarketing use of
Magnevist. 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.
The most serious reactions were nephrogenic systemic fibrosis (see Boxed Warning) and acute
reactions including cardiac or respiratory arrest, anaphylactic shock, shock, respiratory distress,
and laryngeal edema. The most frequently reported adverse reactions in the postmarketing
experience were nausea, vomiting, urticaria and rash.
General Disorders and Administration Site Conditions: Nephrogenic systemic fibrosis (see
Warnings and Precautions), body temperature decreased, tremor, shivering (chills), regional
lymphangitis (lymphangitis), pelvic pain.
Reference ID: 2881079
Bayer Response NDA 019596 Magnevist Inj 14 Dec 10
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Hypersensitivity Reactions: Fatal cardiac or respiratory arrest, respiratory distress, cyanosis,
laryngeal edema, laryngospasm, pharyngeal edema, angioedema, and anaphylactoid reactions
characterized by cardiovascular, respiratory and/or cutaneous symptoms, rarely resulting in death.
(see Warnings and Precautions).
Cardiac Disorders: Cardiac arrest, heart rate decreased, arrhythmia, non-specific ECG changes,
death related to myocardial infarction or other undetermined causes.
Renal and Urinary Disorders: Acute renal failure, increased serum creatinine in patients with
renal insufficiency (see Warnings and Precautions) urinary incontinence, urinary urgency.
Ear and Labyrinth Disorders: Hearing impaired.
Eye Disorders: Visual disturbance.
Musculoskeletal and Connective Tissue Disorder: Arthralgia.
Nervous System Disorders: Coma, parosmia, speech disorder.
Respiratory System: Respiratory arrest, pulmonary edema.
Vascular Disorders: Thrombophlebitis, deep vein thrombophlebitis, compartment syndrome
requiring surgical intervention.
Skin Disorders: Erythema multiforme, pustules (rash pustular).
OVERDOSAGE
Systemic consequences associated with overdosage of MAGNEVIST Injection have not been
reported.
DOSAGE AND ADMINISTRATION
The recommended dosage of MAGNEVIST Injection is 0.2 mL/kg (0.1 mmol/ kg) administered
intravenously, at a rate not to exceed 10 mL per 15 seconds. Dosing for patients in excess of 286
lbs has not been studied systematically.
DOSE AND DURATION OF MAGNEVIST INJECTION BY BODY WEIGHT
BODY WEIGHT
Total Volume, mL*
lb
kg
22
10
2
44
20
4
66
30
6
88
40
8
110
50
10
132
60
12
154
70
14
176
80
16
198
90
18
220
100
20
242
110
22
264
120
24
286
130
26
*Rate of Injection: 10 mL/15sec
Reference ID: 2881079
Bayer Response NDA 019596 Magnevist Inj 14 Dec 10
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Drug Handling: To ensure complete injection of the contrast medium, the injection should be
followed by a 5-mL normal saline flush. The imaging procedure should be completed within 1
hour of injection of MAGNEVIST Injection.
As with other gadolinium contrast agents, MAGNEVIST Injection has not been established for
use in magnetic resonance angiography.
Parenteral products should be inspected visually for particulate matter and discoloration prior to
administration. Do not use the solution if it is discolored or particulate matter is present.
Any unused portion must be discarded in accordance with regulations dealing with the disposal of
such materials.
HOW SUPPLIED
MAGNEVIST Injection is a clear, colorless to slightly yellow solution containing 469.01 mg/ mL
of gadopentetate dimeglumine. MAGNEVIST Injection is supplied in the following sizes:
5 mL single- dose vials, rubber stoppered, in individual cartons, Boxes of 20
NDC 50419-188-05
5 mL single-dose vials (RFID), rubber stoppered, in individual cartons,
Boxes of 20
NDC 50419-188-40
10 mL single-dose vials, rubber stoppered, in individual cartons,
Boxes of 20
NDC 50419-188-01
10 mL single-dose vials (RFID), rubber stoppered, in individual cartons,
Boxes of 20
NDC 50419-188-42
10 mL pre-filled disposable syringe,
Boxes of 5
NDC 50419-188-36
10 mL pre-filled disposable syringe (RFID),
Boxes of 5
NDC 50419-188-43
15 mL single-dose vials, rubber stoppered, in individual cartons,
Boxes of 20
NDC 50419-188-15
15 mL single-dose vials (RFID), rubber stoppered, in individual cartons,
Boxes of 20
NDC 50419-188-44
15 mL pre-filled disposable syringe,
Boxes of 5
NDC 50419-188-37
15 mL pre-filled disposable syringe (RFID),
Boxes of 5
NDC 50419-188-45
20 mL single-dose vials, rubber stoppered, in individual cartons,
Boxes of 20
NDC 50419-188-02
20 mL single-dose vials (RFID), rubber stoppered, in individual cartons,
Boxes of 20
NDC 50419-188-46
20 mL pre-filled disposable syringe,
Boxes of 5
NDC 50419-188-38
20 mL pre-filled disposable syringe (RFID),
Boxes of 5
NDC 50419-188-47
Reference ID: 2881079
Bayer Response NDA 019596 Magnevist Inj 14 Dec 10
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
STORAGE
MAGNEVIST Injection should be stored at controlled room temperature, between 15-30° C (59-
86° F) and protected from light. DO NOT FREEZE. Should freezing occur in the vial
MAGNEVIST Injection should be brought to room temperature before use. If allowed to stand at
room temperature for a minimum of 90 minutes, MAGNEVIST Injection should return to a clear,
colorless to slightly yellow solution. Before use, examine the product to assure that all solids are
redissolved and that the container and closure have not been damaged. Should solids persist,
discard vial.
U. S. Patent Nos. 5,362,475; 5,560,903 and, 5,876,695 relate to this product
Manufactured for: Bayer HealthCare Pharmaceuticals
Manufactured in Germany
© 2010, Bayer HealthCare Pharmaceuticals Inc., All Rights Reserved.
US
December 2010
Bayer Response NDA 019596 Magnevist Inj 14 Dec 10
Reference ID: 2881079
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:30.613144
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019596s049lbl.pdf', 'application_number': 19596, 'submission_type': 'SUPPL ', 'submission_number': 49}
|
11,553
|
NDA 19-596/S-033
Page 3
Rx only
DESCRIPTION
MAGNEVIST® (BRAND OF GADOPENTETATE DIMEGLUMINE) INJECTION IS THE N- METHYLGLUCAMINE
SALT OF THE GADOLINIUM COMPLEX OF DIETHYLENETRIAMINE PENTAACETIC ACID, AND IS AN
INJECTABLE CONTRAST MEDIUM FOR MAGNETIC RESONANCE IMAGING (MRI). MAGNEVIST® INJECTION
IS PROVIDED AS A STERILE, CLEAR, COLORLESS TO SLIGHTLY YELLOW AQUEOUS SOLUTION FOR
INTRAVENOUS INJECTION.
MAGNEVIST® INJECTION IS A 0.5-MOL/L SOLUTION OF 1-DEOXY-1-(METHYLAMINO)-D-GLUCITOL
DIHYDROGEN [N, N-BIS[2-[BIS(CARBOXYMETHYL)AMINO]ETHYL]-GLYCINATO-(5-)-]GADOLINATE(2--)
(2:1) WITH A MOLECULAR WEIGHT OF 938, AN EMPIRICAL FORMULA OF C28H54GDN5O20, AND HAS THE
FOLLOWING STRUCTURAL FORMULA:
Each mL of MAGNEVIST® Injection contains 469.01 mg gadopentetate dimeglumine, 0.99 mg
meglumine, 0.40 mg diethylenetriamine pentaacetic acid and water for injection. MAGNEVIST®
Injection contains no antimicrobial preservative.
MAGNEVIST® Injection has a pH of 6.5 to 8.0. Pertinent physicochemical data are noted below:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596/S-033
Page 4
MAGNEVIST® Injection has an osmolality 6.9 times that of plasma which has an osmolality of 285
mOsmol/kg water. MAGNEVIST® Injection is hypertonic under conditions of use.
CLINICAL PHARMACOLOGY
Pharmacokinetics
The pharmacokinetics of intravenously administered gadopentetate dimeglumine in normal subjects
conforms to a two compartment open-model with mean distribution and elimination half-lives
(reported as mean ± SD) of about 0.2 ± 0.13 hours and 1.6 ± 0.13 hours, respectively.
Upon injection, the meglumine salt is completely dissociated from the gadopentetate dimeglumine
complex. Gadopentetate is exclusively eliminated in the urine with 83 ± 14% (mean ± SD) of the dose
excreted within 6 hours and 91 ± 13% (mean ± SD) by 24 hours, post-injection. There was no
detectable biotransformation or decomposition of gadopentetate dimeglumine.
The renal and plasma clearance rates (1.76 ± 0.39 mL/min/kg and 1.94 ± 0.28 mL/min/kg,
respectively) of gadopentetate are essentially identical, indicating no alteration in elimination kinetics
on passage through the kidneys and that the drug is essentially cleared through the kidney. The volume
of distribution (266 ± 43 mL/kg) is equal to that of extracellular water and clearance is similar to that
of substances which are subject to glomerular filtration.
In vitro laboratory results indicate that gadopentetate does not bind to human plasma protein. In vivo
protein binding studies have not been done.
Pharmacodynamics
Gadopentetate dimeglumine is a paramagnetic agent and, as such, it develops a magnetic moment
when placed in a magnetic field. The relatively large magnetic moment produced by the paramagnetic
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596/S-033
Page 5
agent results in a relatively large local magnetic field, which can enhance the relaxation rates of water
protons in the vicinity of the paramagnetic agent.
In magnetic resonance imaging (MRI), visualization of normal and pathological brain tissue depends in
part on variations in the radiofrequency signal intensity that occur with 1) changes in proton density; 2)
alteration of the spin-lattice or longitudinal relaxation time (T1); and 3) variation of the spin-spin or
transverse relaxation time (T2). When placed in a magnetic field, gadopentetate dimeglumine
decreases the T1 and T2 relaxation time in tissues where it accumulates. At usual doses the effect is
primarily on the T1 relaxation time.
Gadopentetate dimeglumine does not cross the intact blood-brain barrier and, therefore, does not
accumulate in normal brain or in lesions that do not have an abnormal blood-brain barrier, e. g., cysts,
mature post-operative scars, etc. However, disruption of the blood-brain barrier or abnormal
vascularity allows accumulation of gadopentetate dimeglumine in lesions such as neoplasms,
abscesses, and subacute infarcts. The pharmacokinetic parameters of MAGNEVIST® in various lesions
are not known.
CLINICAL TRIALS
MAGNEVIST® Injection was administered to 1272 patients in open label controlled clinical studies.
The mean age of these patients was 46.4 years (range 2 to 93 years). Of these patients, 55% (700) were
male and 45% (572) were female. Of the 1271 patients who received MAGNEVIST® Injection and for
whom race was reported, 82.1% (1043) were Caucasian, 9.7% (123) were Black, 5.3% (67) were
Hispanic, 2.1% (27) were Oriental/Asian, and 0.9% (11) were other. Of the 1272 patients, 550 patients
were evaluated in blinded reader studies. These evaluated the use of contrast enhancement in magnetic
resonance imaging of lesions in the head and neck, brain, spine and associated tissues, and body
(excluding the heart). Of the 550 patients, all patients had a reason for an MRI and efficacy
assessments were based on pre- and post-MAGNEVIST® injection film quality, film contrast, lesion
configuration (border, size, and location), and the number of lesions. The protocols did not include
systematic verification of specific diseases or histopathologic confirmation of findings.
Of the above 550 patients, 97 patients received 0.1 mmol/kg MAGNEVIST® Injection I. V. in two
clinical trials of MAGNEVIST® MRI contrast enhancement for body imaging. Of these 97, 68 had
MRIs of the internal organs/structures of the abdomen or thorax (excluding the heart); 8 had breast
images and 22 had images of appendages. The results of MRIs before and after MAGNEVIST® use
were compared blindly. Overall additional lesions were identified in 22/97 (23%) of the patients after
MAGNEVIST® Injection. The mean number of lesions identified before (1.49/patient) and after
MAGNEVIST® (1.75/patient) were similar. Seven (8%) of the patients had lesions seen before
MAGNEVIST® that were not seen after MAGNEVIST.® Overall, after MAGNEVIST® Injection, 41%
of the images had a higher contrast score than before injection; and 18% of the images had a higher
contrast score before MAGNEVIST® Injection than after MAGNEVIST® Injection. MAGNEVIST®
MRI of the 8 patients with breast images were not systematically compared to the results to
mammography, breast biopsy or other modalities. In the 22 patients with appendage images (e. g.,
muscle, bone and intraarticular structures), MAGNEVIST® MRI was not systematically evaluated to
determine the effects of contrast biodistribution in these different areas.
Of the above 550 patients, 66 patients received MAGNEVIST® 0.1 mmol/kg I. V. in clinical trials of
MAGNEVIST® MRl contrast enhancement of lesions in the head and neck. A total of 66 MRI images
were evaluated blindly by comparing each pair of MRI images, before and after MAGNEVIST®
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596/S-033
Page 6
Injection. In these paired images, 56/66 (85%) had greater enhancement after MAGNEVIST® and
40/66 (61%) had better lesion configuration or border delineation after MAGNEVIST.® Overall, there
was better contrast after MAGNEVIST® in 55% of the images, comparable enhancement in 44 (36%)
before and after MAGNEVIST,® and better enhancement in 9% without MAGNEVIST®
In the studies of the brain and spinal cord, MAGNEVIST® 0.1 mmol/kg I. V. provided contrast
enhancement in lesions with an abnormal blood brain barrier.
In two studies, a total of 108 patients were evaluated to compare the dose response effects of 0.1
mmol/kg and 0.3 mmol/kg of MAGNEVIST® in CNS MRI. Both dosing regimens had similar imaging
and general safety profiles; however, the 0.3 mmoL/kg dose did not provide additional benefit to the
final diagnosis (defined as number of lesions, location and characterization).
INDICATIONS AND USAGE
Central Nervous System:
MAGNEVIST® Injection is indicated for use with magnetic resonance imaging (MRI) in adults, and
pediatric patients (2 years of age and older) to visualize lesions with abnormal vascularity in the brain
(intracranial lesions), spine and associated tissues. MAGNEVIST® Injection has been shown to
facilitate visualization of intracranial lesions including but not limited to tumors.
Extracranial/Extraspinal Tissues:
MAGNEVIST® is indicated for use with MRI in adults and pediatric patients (2 years of age and older)
to facilitate the visualization of lesions with abnormal vascularity in the head and neck.
Body:
MAGNEVIST® Injection is indicated for use in MRI in adults and pediatric patients (2 years of age
and older) to facilitate the visualization of lesions with abnormal vascularity in the body (excluding the
heart).
CONTRAINDICATIONS
None.
WARNINGS
As with various other intravenous administrations, caution must be used when administering
MAGNEVIST® Injection in patients with predisposition to the development of thrombotic syndromes.
(See PRECAUTIONS).
Deoxygenated sickle erythrocytes have been shown by in vitro studies to align perpendicular to a
magnetic field which may result in vaso-occlusive complications in vivo. The enhancement of
magnetic moment by gadopentetate dimeglumine may possibly potentiate sickle erythrocyte
alignment. MAGNEVIST® Injection in patients with sickle cell anemia and other hemoglobinopathies
has not been studied.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596/S-033
Page 7
Patients with other hemolytic anemias have not been adequately evaluated following administration of
MAGNEVIST® Injection to exclude the possibility of increased hemolysis.
Hypotension may occur in some patients after injection of MAGNEVIST® Injection. In clinical trials
two cases were reported and in addition, there was one case of vasovagal reaction and two cases of
pallor with dizziness, sweating and nausea in one and substernal pain and flushing in the other. These
were reported within 25 to 85 minutes after injection except for the vasovagal reaction which was
described as mild by the patient and occurred after 6-1/2 hours. In a study in normal volunteers one
subject experienced syncope after arising from a sitting position two hours after administration of the
drug. Although the relationship of gadopentetate dimeglumine to these events is uncertain, patients
should be observed for several hours after drug administration.
Patients with a history of allergy, drug reactions, or other hypersensitivity-like disorders, should be
closely observed during the procedure and for several hours after drug administration. (See
PRECAUTIONS – General.)
PRECAUTIONS – General
As with various other injectable products, cases of phlebitis and thrombophlebitis have been reported
also in association with MAGNEVIST® Injection. In most cases, symptoms presented during or shortly
after injection, and generally within 24 hours of injection and responded to supportive treatment.
However, in very rare cases of patients who may have underlying potential to develop thrombotic
syndromes, thrombosis with fasciitis and surgical intervention (e. g., compartment release or
amputation) of the dosed limb have been reported. The relationship of these events to pre-existing
disease, concomitant medications, pre-existing vascular fragility, MAGNEVIST® Injection, or the
injection procedure was not established. Patency and integrity of the intravenous line should be
determined before administration. As with other intravenous injections, appropriate surveillance of the
dosing limb for the development of local injection site reactions following administration of
MAGNEVIST® Injection is recommended.
AS WITH ANY PARAMAGNETIC CONTRAST AGENT, MRI WITH MAGNEVIST® CONTRAST
ENHANCEMENT MAY IMPAIR THE VISUALIZATION OF EXISTING LESIONS. SOME OF
THESE LESIONS MAY BE SEEN ON UNENHANCED, NON-CONTRAST MRI. THEREFORE,
CAUTION SHOULD BE EXERCISED WHEN CONTRAST ENHANCED SCAN
INTERPRETATION IS MADE IN THE ABSENCE OF A COMPANION UNENHANCED MRI.
Diagnostic procedures that involve the use of contrast agents should be carried out under direction of a
physician with the prerequisite training and a thorough knowledge of the procedure to be performed.
In a patient with a history of grand mal seizure, MAGNEVIST® Injection was reported to induce such
a seizure.
Since gadopentetate dimeglumine is cleared from the body by glomerular filtration, caution should be
exercised in patients with impaired renal function. MAGNEVIST® is not significantly eliminated by
the hepatobiliary enteric pathway, but is dialyzable (See Pharmacodynamics Section). Caution should
be exercised in patients with either renal or hepatic impairment.
The possibility of a reaction, including serious, life-threatening, or fatal anaphylactoid or
cardiovascular reactions or other idiosyncratic reactions (see ADVERSE REACTIONS), should
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596/S-033
Page 8
always be considered, especially in those patients with a known clinical hypersensitivity or a history of
asthma or other allergic respiratory disorders.
Animal studies suggest that gadopentetate dimeglumine may alter red cell membrane morphology
resulting in a slight degree of extravascular (splenic) hemolysis. In clinical trials 15-30% of the
patients experienced an asymptomatic transient rise in serum iron. Serum bilirubin levels were slightly
elevated in approximately 3.4% of patients. Levels generally returned to baseline within 24 to 48
hours. Hematocrit and red blood cell count were unaffected and liver enzymes were not elevated in
these patients. While the effects of gadopentetate dimeglumine on serum iron and bilirubin have not
been associated with clinical manifestations, the effect of the drug in patients with hepatic disease is
not known and caution is therefore advised.
When MAGNEVIST® Injection is to be injected using nondisposable equipment, scrupulous care
should be taken to prevent residual contamination with traces of cleansing agents. After
MAGNEVIST® Injection is drawn into the syringe the solution should be used immediately.
Repeat Procedures: Data for repeated procedures are not available. If in the clinical judgment of the
physician sequential or repeat procedures are required, a suitable interval of time between
administrations should be observed to allow for normal clearance of the drug from the body.
Repeat Injections: (See DOSAGE AND ADMINISTRATION)
Information for Patients:
Patients scheduled to receive MAGNEVIST® Injection should be instructed to inform their physician if
the patient:
1. Is pregnant or breast feeding.
2. Has any blood disorders; i. e., anemia, hemoglobinopathies, or diseases that affect red blood cells.
3. Has a history of renal or hepatic disease, seizure, asthma or allergic respiratory disorders.
LABORATORY TEST FINDINGS
Transitory changes in serum iron, bilirubin and transaminase levels have been reported in patients with
normal and abnormal liver function (See PRECAUTIONS – General). Magnevist® Injection does
not interfere with serum and plasma calcium measurements determined by colorimetric assay.
CARCINOGENESIS, MUTAGENESIS AND IMPAIRMENT OF FERTILITY
Long term animal studies have not been performed to evaluate the carcinogenic potential of
gadopentetate dimeglumine.
A comprehensive battery of in vitro and in vivo studies in bacterial and mammalian systems
suggest that gadopentetate dimeglumine is not mutagenic or clastogenic and does not induce
unscheduled DNA repair in rat hepatocytes or cause cellular transformation of mouse embryo
fibroblasts.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596/S-033
Page 9
However, the drug did show some evidence of mutagenic potential in vivo in the mouse
dominant lethal assay at doses of 6 mmol/kg, but did not show any such potential in the
mouse and dog micronucleus tests at intravenous doses of 9 mmol/kg and 2.5 mmol/kg,
respectively.
When administered intra-peritoneally to male and female rats daily prior to mating, during mating and
during embryonic development for up to 74 days (males) or 35 days (females), gadopentetate caused a
decrease in number of corpora lutea at the 0.1 mmol/kg dose level. After daily dosing with 2.5
mmol/kg suppression of food consumption and body weight gain (males and females) and a decrease
in the weights of testes and epididymis were also observed.
In a separate experiment in rats, daily injections of gadopentetate dimeglumine over 16 days caused
spermatogenic cell atrophy at a dose level of 5 mmol/kg but not at a dose level of 2.5 mmol/kg. This
atrophy was not reversed within a 16-day observation period following the discontinuation of the drug.
PREGNANCY CATEGORY C
Gadopentetate dimeglumine retarded fetal development slightly when given intravenously for 10
consecutive days to pregnant rats at daily doses of 0.25, 0.75, and 1.25 mmol/kg ( 2.5, 7.5 and 12.5
times the human dose based on body weight) and when given intravenously for 13 consecutive days to
pregnant rabbits at daily doses of 0.75 and 1.25 mmol/kg (7.5 and 12.5 times the human dose
respectively, based on body weight) but not at daily doses of 0.25 mmol/kg. No congenital anomalies
were noted in rats or rabbits.
Adequate and well controlled studies were not conducted in pregnant women. MAGNEVIST®
Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the
fetus.
NURSING WOMEN
Magnevist® Injection is excreted in human milk. Magnevist® Injection was administered
intravenously to 18 lactating women with normal renal function at a dose of 0.1 mmol/kg
body weight. In these women, less than 0.04% of the administered gadolinium was
excreted into the breast milk during the 24-hour period following dosing. Breast milk
obtained during the 24 hours following dosing revealed the average cumulative amount of
gadolinium excreted in breast milk was 0.57+ 0.71 micromol. The amount transferred
from a 70 kg woman (receiving 0.1 mmol/kg body weight) to an infant by breast feeding
over a period of 24 hrs translates into less than 3 micromol of gadolinium.
The overall duration of excretion of gadolinium into breast milk is unknown. The extent
of absorption of Magnevist® Injection in infants and its effect on the breast-fed child
remains unknown. Caution should be exercised when Magnevist® Injection is
administered to a nursing woman.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596/S-033
Page 10
PEDIATRIC USE
The use of MAGNEVIST® in imaging the Central Nervous System, Extracranial/ Extraspinal tissues,
and Body have been established in the pediatric population from the ages of 2 to 16 years on the basis
of adequate and well controlled clinical trials in adults and safety studies in this pediatric population.
(See Clinical Trials for details.)
Safety and efficacy in the pediatric population under the age of 2 years have not been established.
MAGNEVIST® is eliminated primarily by the kidney. The pharmacokinetics of MAGNEVIST® in
neonates and infants with immature renal function have not been studied. (See INDICATIONS and
the DOSAGE AND ADMINISTRATION)
ADVERSE REACTIONS
The mean age of the 1272 patients who received MAGNEVIST® Injection was 46.4 years (range 2 to
93 years). Of these patients, 55% (700) were male and 45% (572) were female. Of the 1271 patients
who received MAGNEVIST® Injection and for whom race was reported, 82.1% (1043) were
Caucasian, 9.7% (123) were Black, 5.3% (67) were Hispanic, 2.1% (27) were Oriental/ Asian, and
0.9% (11) were other. The most common noted adverse event is headache with an incidence of 4.8%.
The majority of headaches are transient and of mild to moderate severity. Nausea is the second most
common adverse experience at 2.7%. Injection site coldness/ localized coldness is the third most
common adverse experience at 2.3%. Dizziness occurred in 1% of the patients.
The following additional adverse events occurred in fewer than 1% of the patients:
Body as a Whole: Injection site symptoms, namely, pain, localized warmth, and burning sensation;
substernal chest pain, back pain, fever, weakness, generalized coldness, generalized warmth, localized
edema, tiredness, chest tightness, trembling, shivering, tension in extremities, regional lymphangitis,
pelvic pain, and anaphylactoid reactions (characterized by cardiovascular, respiratory and cutaneous
symptoms) rarely resulting in death.
Cardiovascular: Hypotension, hypertension, arrhythmia, tachycardia, migraine, syncope, vasodilation,
pallor, non-specific ECG changes, angina pectoris, death related to myocardial infarction or other
undetermined causes, phlebitis, thrombophlebitis, deep vein thrombophlebitis, compartment syndrome
requiring surgical intervention.
Digestive: Gastrointestinal distress, stomach pain, teeth pain, increased salivation, abdominal pain,
vomiting, constipation, diarrhea.
Nervous System: Agitation, anxiety, thirst, anorexia, nystagmus, drowsiness, diplopia, stupor,
convulsions (including grand mal), paresthesia.
Respiratory System: Throat irritation, rhinorrhea, sneezing, dyspnea, wheezing, laryngismus, cough,
respiratory complaints.
Skin: Rash, sweating, pruritus, urticaria (hives), facial edema, erythema multiforme, epidermal
necrolysis, pustules.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596/S-033
Page 11
Special Senses: Tinnitus, conjunctivitis, visual field defect, taste abnormality, dry mouth, lacrimation
dis-order (tearing), eye irritation, eye pain, ear pain.
OVERDOSAGE
Systemic consequences associated with overdosage of MAGNEVIST® Injection have not been
reported.
DOSAGE AND ADMINISTRATION
The recommended dosage of MAGNEVIST® Injection is 0.2 mL/kg (0.1mmol/ kg) administered
intravenously, at a rate not to exceed 10 mL per 15 seconds. Dosing for patients in excess of 286 lbs
have not been studied systematically.
Drug Handling: To ensure complete injection of the contrast medium, the injection should be followed
by a 5-mL normal saline flush. The imaging procedure should be completed within 1 hour of injection
of MAGNEVIST® Injection.
As with other gadolinium contrast agents, MAGNEVIST® Injection has not been established for use in
magnetic resonance angiography.
PARENTERAL PRODUCTS SHOULD BE INSPECTED VISUALLY FOR PARTICULATE MATTER AND
DISCOLORATION PRIOR TO ADMINISTRATION. DO NOT USE THE SOLUTION IF IT IS DISCOLORED OR
PARTICULATE MATTER IS PRESENT.
Any unused portion must be discarded in accordance with regulations dealing with the disposal of such
materials.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596/S-033
Page 12
HOW SUPPLIED
MAGNEVIST® Injection is a clear, colorless to slightly yellow solution containing 469.01 mg/mL of
gadopentetate dimeglumine in rubber stoppered vials. MAGNEVIST® Injection is supplied in the
following sizes:
5 mL single-dose vials, rubber stoppered, in individual cartons,
Boxes of 20
NDC 50419-188-05
10 mL single-dose vials, rubber stoppered, in individual cartons,
Boxes of 20
NDC 50419-188-01
10 mL pre-filled disposable syringe,
Boxes of 5
NDC 50419-188-30
15 mL single- dose vials, rubber stoppered, in individual cartons,
Boxes of 20
NDC 50419-188-15
15 mL pre- filled disposable syringe,
Boxes of 5
NDC 50419-188-31
20 mL single- dose vials, rubber stoppered, in individual cartons,
Boxes of 20
NDC 50419-188-02
20 mL pre- filled disposable syringe,
Boxes of 5
NDC 50419- 188- 32
STORAGE
MAGNEVIST® Injection should be stored at controlled room temperature, between 15°-30°C (59°-
86°F) and protected from light. DO NOT FREEZE. Should freezing occur in the vial MAGNEVIST®
Injection should be brought to room temperature before use. If allowed to stand at room temperature
for a minimum of 90 minutes, MAGNEVIST® Injection should return to a clear, colorless to slightly
yellow solution. Before use, examine the product to assure that all solids are redissolved and that the
container and closure have not been damaged. Should solids persist, discard vial.
THIS PRODUCT IS COVERED BY U. S. PATENT NO. 4,957,939. THE USE OF THIS PRODUCT IS COVERED BY
U. S. PATENT NOS. 4,647,447 AND 4,963,344.
©2004, BERLEX, INC. ALL RIGHTS RESERVED.
MANUFACTURED FOR:BERLEX MONTVILLE, NEW JERSEY 07045 MANUFACTURED IN GERMANY 6062605
REVISED JUNE2004 USA/ BERLEX COMPONENT CODE
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:30.787976
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/19596s033lbl.pdf', 'application_number': 19596, 'submission_type': 'SUPPL ', 'submission_number': 33}
|
11,554
|
NDA 19-596-S-045/21-037/S-019
Page 3
MAGNEVIST ®
(brand of gadopentetate dimeglumine)
Injection
6703001
FOR INTRAVENOUS ADMINISTRATION
Rx only
WARNING: NEPHROGENIC SYSTEMIC FIBROSIS
Gadolinium-based contrast agents increase the risk for nephrogenic systemic fibrosis
(NSF) in patients with:
• Acute or chronic severe renal insufficiency (glomerular filtration rate < 30
mL/min/1.73m2), or
• Acute renal insufficiency of any severity due to the hepato-renal syndrome or in
the perioperative liver transplantation period.
In these patients, avoid use of gadolinium-based contrast agents unless the diagnostic
information is essential and not available with non-contrast enhanced magnetic resonance
imaging (MRI). NSF may result in fatal or debilitating systemic fibrosis affecting the
skin, muscle and internal organs. Screen all patients for renal dysfunction by obtaining a
history and/or laboratory tests. When administering a gadolinium-based contrast agent,
do not exceed the recommended dose and allow a sufficient period of time for
elimination of the agent from the body prior to any readminstration (See WARNINGS).
DESCRIPTION
MAGNEVIST ® (brand of gadopentetate dimeglumine) Injection is the
N- methylglucamine salt of the gadolinium complex of diethylenetriamine pentaacetic acid, and is an
injectable contrast medium for magnetic resonance imaging (MRI).
MAGNEVIST Injection is provided as a sterile, clear, colorless to slightly yellow aqueous solution for
intravenous injection.
MAGNEVIST Injection is a 0.5-mol/L solution of 1-deoxy-1-(methylamino)-D-glucitol dihydrogen
[N,N-bis[2-[bis(carboxymethyl)amino]ethyl]-glycinato-(5--)-]gadolinate(2-)(2:1) with a molecular
weight of 938, an empirical formula of C28H54GdN5O20, and has the following structural formula: Structural Formula
Each mL of MAGNEVIST Injection contains 469.01 mg gadopentetate dimeglumine, 0.99 mg
meglumine, 0.40 mg diethylenetriamine pentaacetic acid and water for injection. MAGNEVIST
Injection contains no antimicrobial preservative.
MAGNEVIST Injection has a pH of 6.5 to 8.0. Pertinent physicochemical data are noted below:
PARAMETER Osmolality (mOsmol/ kg water) at 37° C 1,960 Viscosity (CP) at 20° C 4.9 at 37° C 2.9
Density (g/mL) at 25° C 1.195 Specific gravity at 25° C 1.208 Octanol: H2O at 25° C and pH7 log Pow
= - 5.4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596-S-045/21-037/S-019
Page 4
MAGNEVIST Injection has an osmolality 6.9 times that of plasma which has an osmolality of 285
mOsmol/ kg water. MAGNEVIST Injection is hypertonic under conditions of use.
CLINICAL PHARMACOLOGY
Pharmacokinetics
The pharmacokinetics of intravenously administered gadopentetate dimeglumine in normal subjects
conforms to a two compartment open-model with mean distribution and elimination half-lives
(reported as mean ± SD) of about 0.2 ± 0.13 hours and 1.6 ± 0.13 hours, respectively.
Upon injection, the meglumine salt is completely dissociated from the gadopentetate dimeglumine
complex. Gadopentetate is exclusively eliminated in the urine with
83 ± 14% (mean ± SD) of the dose excreted within 6 hours and 91 ± 13% (mean ± SD) by 24 hours,
post-injection. There was no detectable biotransformation or decomposition of gadopentetate
dimeglumine.
The renal and plasma clearance rates (1.76 ± 0.39 mL/min/kg and
1.94 ± 0.28 mL/min/kg, respectively) of gadopentetate are essentially identical, indicating no alteration
in elimination kinetics on passage through the kidneys and that the drug is essentially cleared through
the kidney. The volume of distribution (266 ± 43 mL/kg) is equal to that of extracellular water and
clearance is similar to that of substances which are subject to glomerular filtration.
In vitro laboratory results indicate that gadopentetate does not bind to human plasma protein. In vivo
protein binding studies have not been done.
Pharmacodynamics
Gadopentetate dimeglumine is a paramagnetic agent and, as such, it develops a magnetic moment
when placed in a magnetic field. The relatively large magnetic moment produced by the paramagnetic
agent results in a relatively large local magnetic field, which can enhance the relaxation rates of water
protons in the vicinity of the paramagnetic agent.
In magnetic resonance imaging (MRI), visualization of normal and pathological brain tissue depends in
part on variations in the radiofrequency signal intensity that occur with 1) changes in proton density; 2)
alteration of the spin- lattice or longitudinal relaxation time (T1); and 3) variation of the spin- spin or
transverse relaxation time (T2). When placed in a magnetic field, gadopentetate dimeglumine
decreases the T1 and T2 relaxation time in tissues where it accumulates. At usual doses the effect is
primarily on the T1 relaxation time.
Gadopentetate dimeglumine does not cross the intact blood-brain barrier and, therefore, does not
accumulate in normal brain or in lesions that do not have an abnormal blood- brain barrier, e. g., cysts,
mature post-operative scars, etc. However, disruption of the blood- brain barrier or abnormal
vascularity allows accumulation of gadopentetate dimeglumine in lesions such as neoplasms,
abscesses, and subacute infarcts. The pharmacokinetic parameters of MAGNEVIST in various lesions
are not known.
CLINICAL TRIALS
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596-S-045/21-037/S-019
Page 5
MAGNEVIST Injection was administered to 1272 patients in open label controlled clinical studies.
The mean age of these patients was 46.4 years (range 2 to 93 years). Of these patients, 55% (700) were
male and 45% (572) were female. Of the 1271 patients who received MAGNEVIST Injection and for
whom race was reported, 82.1% (1043) were Caucasian, 9.7% (123) were Black, 5.3% (67) were
Hispanic, 2.1% (27) were Oriental/ Asian, and 0.9% (11) were other. Of the 1272 patients, 550 patients
were evaluated in blinded reader studies. These evaluated the use of contrast enhancement in magnetic
resonance imaging of lesions in the head and neck, brain, spine and associated tissues, and body
(excluding the heart). Of the 550 patients, all patients had a reason for an MRI and efficacy
assessments were based on pre-and post- MAGNEVIST injection film quality, film contrast, lesion
configuration (border, size, and location), and the number of lesions. The protocols did not include
systematic verification of specific diseases or histopathologic confirmation of findings.
Of the above 550 patients, 97 patients received 0.1 mmol/kg MAGNEVIST Injection
I. V. in two clinical trials of MAGNEVIST MRI contrast enhancement for body imaging. Of these 97,
68 had MRIs of the internal organs/ structures of the abdomen or thorax
(excluding the heart); 8 had breast images and 22 had images of appendages. The results of MRIs
before and after MAGNEVIST use were compared blindly. Overall additional lesions were identified
in 22/ 97 (23%) of the patients after MAGNEVIST Injection. The mean number of lesions identified
before (1.49/ patient) and after MAGNEVIST
(1.75/ patient) were similar. Seven (8%) of the patients had lesions seen before MAGNEVIST that
were not seen after MAGNEVIST. Overall, after MAGNEVIST Injection, 41% of the images had a
higher contrast score than before injection; and 18% of the images had a higher contrast score before
MAGNEVIST Injection than after MAGNEVIST Injection. MAGNEVIST MRI of the 8 patients with
breast images were not systematically compared to the results to mammography, breast biopsy or other
modalities. In the 22 patients with appendage images (e. g., muscle, bone and intraarticular structures),
MAGNEVIST MRI was not systematically evaluated to determine the effects of contrast
biodistribution in these different areas.
Of the above 550 patients, 66 patients received MAGNEVIST 0.1 mmol/ kg I. V. in clinical trials of
MAGNEVIST MRl contrast enhancement of lesions in the head and neck. A total of 66 MRI images
were evaluated blindly by comparing each pair of MRI images, before and after MAGNEVIST
Injection. In these paired images, 56/66 (85%) had greater enhancement after MAGNEVIST and 40/66
(61%) had better lesion configuration or border delineation after MAGNEVIST. Overall, there was
better contrast after MAGNEVIST in 55% of the images, comparable enhancement in 44 (36%) before
and after MAGNEVIST, and better enhancement in 9% without MAGNEVIST.
In the studies of the brain and spinal cord, MAGNEVIST 0.1 mmol/kg I. V. provided contrast
enhancement in lesions with an abnormal blood brain barrier.
In two studies, a total of 108 patients were evaluated to compare the dose response effects of 0.1
mmol/kg and 0.3 mmol/kg of MAGNEVIST in CNS MRI. Both dosing regimens had similar imaging
and general safety profiles; however, the 0.3 mmoL/kg dose did not provide additional benefit to the
final diagnosis (defined as number of lesions, location and characterization).
INDICATIONS AND USAGE
Central Nervous System:
MAGNEVIST Injection is indicated for use with magnetic resonance imaging (MRI) in adults, and
pediatric patients (2 years of age and older) to visualize lesions with abnormal vascularity in the brain
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596-S-045/21-037/S-019
Page 6
(intracranial lesions), spine and associated tissues. MAGNEVIST Injection has been shown to facilitate
visualization of intracranial lesions including but not limited to tumors.
Extracranial/ Extraspinal Tissues:
MAGNEVIST is indicated for use with MRI in adults and pediatric patients (2 years of age and older)
to facilitate the visualization of lesions with abnormal vascularity in the head and neck.
Body:
MAGNEVIST Injection is indicated for use in MRI in adults and pediatric patients (2 years of age and
older) to facilitate the visualization of lesions with abnormal vascularity in the body (excluding the
heart).
CONTRAINDICATIONS
None.
WARNINGS AND PRECAUTIONS
Nephrogenic Systemic Fibrosis (NSF)
Gadolinium-based contrast agents increase the risk for nephrogenic systemic fibrosis (NSF) in patients
with acute or chronic severe renal insufficiency (glomerular filtration rate < 30 mL/min/1.73 m2) and
in patients with acute renal insufficiency of any severity due to the hepato-renal syndrome or in the
perioperative liver transplantation period. In these patients, avoid use of gadolinium-based contrast
agents unless the diagnostic information is essential and not available with non-contrast enhanced
MRI. For patients receiving hemodialysis, physicians may consider the prompt initiation of
hemodialysis following the administration of a gadolinium-based contrast agent in order to enhance the
contrast agent’s elimination. The usefulness of hemodialysis in the prevention of NSF is unknown.
Among the factors that may increase the risk for NSF are repeated or higher than recommended doses
of a gadolinium-based contrast agent and the degree of renal function impairment at the time of
exposure.
Post-marketing reports have identified the development of NSF following single and multiple
administrations of gadolinium-based contrast agents. These reports have not always identified a
specific agent. Where a specific agent was identified, the most commonly reported agent was
gadodiamide (OmniscanTM), followed by gadopentetate dimeglumine (Magnevist®) and
gadoversetamide (OptiMARK®). NSF has also developed following sequential administrations of
gadodiamide with gadobenate dimeglumine (MultiHance®) or gadoteridol (ProHance®). The number
of post-marketing reports is subject to change over time and may not reflect the true proportion of
cases associated with any specific gadolinium-based contrast agent.
The extent of risk for NSF following exposure to any specific gadolinium-based contrast agent is
unknown and may vary among the agents. Published reports are limited and predominantly estimate
NSF risks with gadodiamide. In one retrospective study of 370 patients with severe renal insufficiency
who received gadodiamide, the estimated risk for development of NSF was 4% (J Am Soc Nephrol
2006; 17:2359). The risk, if any, for the development of NSF among patients with mild to moderate
renal insufficiency or normal renal function is unknown.
Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. When
administering a gadolinium-based contrast agent, do not exceed the recommended dose and allow a
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596-S-045/21-037/S-019
Page 7
sufficient period of time for elimination of the agent prior to any readministration. (See CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Hypersensitivity reactions
Anaphylactoid and anaphylactic reactions with cardiovascular, respiratory and/or cutaneous
manifestations rarely resulting in death have occurred. If such a reaction occurs, stop MAGNEVIST
Injection and immediately begin appropriate therapy, including resuscitation.
Observe closely patients with a history of drug reactions, allergy or other hypersensitivity disorders,
during and up to several hours after MAGNEVIST Injection.
Acute renal failure
In patients with renal insufficiency, acute renal failure requiring dialysis or worsening renal function
have occurred, mostly within 48 hrs of MAGNEVIST Injection. The risk of these events is higher with
increasing dose of contrast. Use the lowest possible dose and evaluate renal function in patients with
renal insufficiency.
MAGNEVIST is cleared by glomerular filtration and is dialyzable.
Injection site reactions
Skin and soft tissue necrosis, thrombosis, fasciitis, and compartment syndrome requiring surgical
intervention (e.g. compartment release or amputation) have occurred very rarely at the site of contrast
injection or the dosed limb. Total volume and rate of MAGNEVIST Injection, extravasation of contrast
agent, and patient susceptibility might contribute to these reactions. Phlebitis and thrombophlebitis
may be observed generally within 24 hours after MAGNEVIST Injection and resolve with supportive
treatment. Determine the patency and integrity of the intravenous line before administration of
MAGNEVIST Injection. Assessment of the dosed limb for the development of injection site reactions
is recommended.
Interference with Visualization of lesions visible with non-contrast MRI
As with any paramagnetic contrast agent, MAGNEVIST Injection might impair the visualization of
lesions seen on non-contrast MRI. Therefore, caution should be exercised when MAGNEVIST MRI
scans are interpreted without a companion non-contrast MRI scan.
Patient counseling information
Patients scheduled to receive MAGNEVIST Injection should be instructed to inform their physician if
they are pregnant, breast feed, or have a history of renal insufficiency, asthma or allergic respiratory
disorders.
LABORATORY TEST FINDINGS
Transitory changes in serum iron, bilirubin and transaminase levels were observed in clinical trials.
MAGNEVIST Injection does not interfere with serum and plasma calcium measurements determined
by colorimetric assays.
CARCINOGENESIS, MUTAGENESIS AND IMPAIRMENT OF FERTILITY Long term animal
studies have not been performed to evaluate the carcinogenic potential of gadopentetate dimeglumine.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596-S-045/21-037/S-019
Page 8
A comprehensive battery of in vitro and in vivo studies in bacterial and mammalian systems suggest
that gadopentetate dimeglumine is not mutagenic or clastogenic and does not induce unscheduled
DNA repair in rat hepatocytes or cause cellular transformation of mouse embryo fibroblasts. However,
the drug did show some evidence of mutagenic potential in vivo in the mouse dominant lethal assay at
doses of 6 mmol/kg, but did not show any such potential in the mouse and dog micronucleus tests at
intravenous doses of 9 mmol/kg and 2.5 mmol/kg, respectively.
When administered intra-peritoneally to male and female rats daily prior to mating, during mating and
during embryonic development for up to 74 days (males) or 35 days
(females), gadopentetate caused a decrease in number of corpora lutea at the 0.1 mmol/ kg dose level.
After daily dosing with 2.5 mmol/kg suppression of food consumption and body weight gain (males
and females) and a decrease in the weights of testes and epididymis were also observed.
In a separate experiment in rats, daily injections of gadopentetate dimeglumine over 16 days caused
spermatogenic cell atrophy at a dose level of 5 mmol/kg but not at a dose level of 2.5 mmol/kg. This
atrophy was not reversed within a 16-day observation period following the discontinuation of the drug.
PREGNANCY CATEGORY C.
Gadopentetate dimeglumine retarded fetal development slightly when given intravenously for 10
consecutive days to pregnant rats at daily doses of 0.25, 0.75, and 1.25 mmol/kg (2.5, 7.5 and 12.5
times the human dose based on body weight) and when given intravenously for 13 consecutive days to
pregnant rabbits at daily doses of 0.75 and 1.25 mmol/kg (7.5 and 12.5 times the human dose
respectively, based on body weight) but not at daily doses of 0.25 mmol/kg. No congenital anomalies
were noted in rats or rabbits.
Adequate and well controlled studies were not conducted in pregnant women. MAGNEVIST Injection
should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
NURSING WOMEN
MAGNEVIST is excreted in human milk. MAGNEVIST Injection was administered intravenously to
18 lactating women with normal renal function at a dose of 0.1 mmol/kg body weight. In these women,
less than 0.04% of the administered gadolinium was excreted into the breast milk during the 24-hour
period following dosing. Breast milk obtained during the 24 hours following dosing revealed the
average cumulative amount of gadolinium excreted in breast milk was 0.57+/- 0.71 micromol. The
amount transferred from a 70 kg woman (receiving 0.1 mmol/kg body weight) to an infant by breast
feeding over a period of 24 hrs translates into less than 3 micromol of gadolinium.
The overall duration of excretion of gadolinium into breast milk is unknown. The extent of the
absorption of MAGNEVIST Injection in infants and its effect on the breast-fed child remains
unknown. Caution should be exercised when MAGNEVIST Injection is administered to a nursing
woman.
PEDIATRIC USE
The use of MAGNEVIST in imaging the Central Nervous System, Extracranial/ Extraspinal tissues,
and Body have been established in the pediatric population from the ages of 2 to 16 years on the basis
of adequate and well controlled clinical trials in adults and safety studies in this pediatric population.
(See Clinical Trials for details.)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596-S-045/21-037/S-019
Page 9
Safety and efficacy in the pediatric population under the age of 2 years have not been established.
MAGNEVIST is eliminated primarily by the kidney. The pharmacokinetics of MAGNEVIST in
neonates and infants with immature renal function have not been studied. (See INDICATIONS and
DOSAGE AND ADMINISTRATION)
ADVERSE REACTIONS
The mean age of the 1272 patients who received MAGNEVIST Injection in clinical trials was 46.4
years (range 2 to 93 years). Of these patients, 55% (700) were male and 45%
(572) were female. Of the 1271 patients who received MAGNEVIST Injection and for whom race was
reported, 82.1% (1043) were Caucasian, 9.7% (123) were Black, 5.3%
(67) were Hispanic, 2.1% (27) were Oriental/ Asian, and 0.9% (11) were other. The most common
noted adverse event is headache with an incidence of 4.8%. The majority of headaches are transient
and of mild to moderate severity. Nausea is the second most common adverse experience at 2.7%.
Injection site coldness/localized coldness is the third most common adverse experience at 2.3%.
Dizziness occurred in 1% of the patients.
The following additional adverse events occurred in fewer than 1% of the patients:
Body as a Whole: Injection site symptoms, namely, pain, localized warmth, and burning sensation;
substernal chest pain, back pain, fever, weakness, generalized coldness, generalized warmth, localized
edema, tiredness, chest tightness, trembling, shivering, tension in extremities, regional lymphangitis,
pelvic pain, and anaphylactoid reactions
(characterized by cardiovascular, respiratory and cutaneous symptoms) rarely resulting in death.
Cardiovascular: Hypotension, hypertension, arrhythmia, tachycardia, migraine, syncope,
vasodilation, pallor, non- specific ECG changes, angina pectoris, death related to myocardial infarction
or other undetermined causes, phlebitis, thrombophlebitis, deep vein thrombophlebitis, compartment
syndrome requiring surgical intervention.
Digestive: Gastrointestinal distress, stomach pain, teeth pain, increased salivation, abdominal pain,
vomiting, constipation, diarrhea.
Nervous System: Agitation, anxiety, thirst, anorexia, nystagmus, drowsiness, diplopia, stupor,
convulsions (including grand mal), paresthesia.
Respiratory System: Throat irritation, rhinorrhea, sneezing, dyspnea, wheezing, laryngismus, cough,
respiratory complaints.
Skin: Rash, sweating, pruritus, urticaria (hives), facial edema, erythema multiforme, epidermal
necrolysis, pustules.
Special Senses: Tinnitus, conjunctivitis, visual field defect, taste abnormality, dry mouth, lacrimation
disorder (tearing), eye irritation, eye pain, ear pain.
OVERDOSAGE
Systemic consequences associated with overdosage of MAGNEVIST Injection have not been reported.
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 19-596-S-045/21-037/S-019
Page 10
The recommended dosage of MAGNEVIST Injection is 0.2 mL/kg (0.1 mmol/ kg) administered
intravenously, at a rate not to exceed 10 mL per 15 seconds. Dosing for patients in excess of 286 lbs
has not been studied systematically.
DOSE AND DURATION OF MAGNEVIST INJECTION BY BODY WEIGHT
BODY WEIGHT
Total Volume, mL*
lb
kg
22
10
2
44
20
4
66
30
6
88
40
8
110
50
10
132
60
12
154
70
14
176
80
16
198
90
18
220
100
20
242
110
22
264
120
24
286
130
26
*Rate of Injection: 10 mL/15sec
Drug Handling: To ensure complete injection of the contrast medium, the injection should be followed
by a 5-mL normal saline flush. The imaging procedure should be completed within 1 hour of injection
of MAGNEVIST Injection.
As with other gadolinium contrast agents, MAGNEVIST Injection has not been established for use in
magnetic resonance angiography.
Parenteral products should be inspected visually for particulate matter and discoloration prior to
administration. Do not use the solution if it is discolored or particulate matter is present.
Any unused portion must be discarded in accordance with regulations dealing with the disposal of such
materials.
HOW SUPPLIED
MAGNEVIST Injection is a clear, colorless to slightly yellow solution containing 469.01 mg/ mL of
gadopentetate dimeglumine. MAGNEVIST Injection is supplied in the following sizes:
5 mL single- dose vials, rubber stoppered, in individual cartons, Boxes of 20
NDC 50419- 188- 05
5 mL single- dose vials (RFID), rubber stoppered, in individual cartons, Boxes of 20
NDC 50419- 188- 40
10 mL single- dose vials, rubber stoppered, in individual cartons, Boxes of 20
NDC 50419- 188- 01
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596-S-045/21-037/S-019
Page 11
10 mL single- dose vials (RFID), rubber stoppered, in individual cartons, Boxes of 20
NDC 50419- 188- 42
10 mL pre- filled disposable syringe, Boxes of 5
NDC 50419- 188- 36
10 mL pre- filled disposable syringe (RFID), Boxes of 5
NDC 50419- 188- 43
15 mL single- dose vials, rubber stoppered, in individual cartons, Boxes of 20
NDC 50419- 188- 15
15 mL single- dose vials (RFID), rubber stoppered, in individual cartons, Boxes of 20
NDC 50419- 188- 44
15 mL pre- filled disposable syringe, Boxes of 5
NDC 50419- 188- 37
15 mL pre- filled disposable syringe (RFID), Boxes of 5
NDC 50419- 188-45
20 mL single- dose vials, rubber stoppered, in individual cartons, Boxes of 20
NDC 50419- 188- 02
20 mL single- dose vials (RFID), rubber stoppered, in individual cartons, Boxes of 20
NDC 50419- 188- 46
20 mL pre- filled disposable syringe, Boxes of 5
NDC 50419- 188- 38
20 mL pre- filled disposable syringe (RFID), Boxes of 5
NDC 50419- 188- 47
STORAGE
MAGNEVIST Injection should be stored at controlled room temperature, between
15-30° C (59- 86° F) and protected from light. DO NOT FREEZE. Should freezing occur in the vial
MAGNEVIST Injection should be brought to room temperature before use. If allowed to stand at room
temperature for a minimum of 90 minutes, MAGNEVIST Injection should return to a clear, colorless
to slightly yellow solution. Before use, examine the product to assure that all solids are redissolved and
that the container and closure have not been damaged. Should solids persist, discard vial.
U. S. Patent Nos. 5,362,475; 5,560,903 and, 5,876,695 relate to this product
Manufactured for: Company logo
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596-S-045/21-037/S-019
Page 12
Manufactured in Germany
© 2009, Bayer HealthCare Pharmaceuticals Inc., All Rights Reserved.
Revised January 2008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596-S-045/21-037/S-019
Page 13
MAGNEVIST ®
(brand of gadopentetate dimeglumine)
Injection
FOR INTRAVENOUS ADMINISTRATION
Pharmacy Bulk Package – Not For Direct Infusion
Rx only
WARNING: NEPHROGENIC SYSTEMIC FIBROSIS
Gadolinium-based contrast agents increase the risk for nephrogenic systemic fibrosis
(NSF) in patients with:
• Acute or chronic severe renal insufficiency (glomerular filtration rate < 30
mL/min/1.73m2), or
• Acute renal insufficiency of any severity due to the hepato-renal syndrome or in
the perioperative liver transplantation period.
In these patients, avoid use of gadolinium-based contrast agents unless the diagnostic
information is essential and not available with non-contrast enhanced magnetic resonance
imaging (MRI). NSF may result in fatal or debilitating systemic fibrosis affecting the
skin, muscle and internal organs. Screen all patients for renal dysfunction by obtaining a
history and/or laboratory tests. When administering a gadolinium-based contrast agent,
do not exceed the recommended dose and allow a sufficient period of time for
elimination of the agent from the body prior to any readminstration (See WARNINGS).
DESCRIPTION
MAGNEVIST ® (brand of gadopentetate dimeglumine) Injection is the
N- methylglucamine salt of the gadolinium complex of diethylenetriamine pentaacetic acid, and is an
injectable contrast medium for magnetic resonance imaging (MRI).
MAGNEVIST Injection is provided as a sterile, clear, colorless to slightly yellow aqueous solution for
intravenous injection.
MAGNEVIST Injection is a 0.5- mol/L solution of 1-deoxy-1-(methylamino)-D-glucitol dihydrogen
[N,N-bis[2-[bis(carboxymethyl)amino]ethyl]-glycinato-(5-)-]gadolinate(2--)
(2:1) with a molecular weight of 938, an empirical formula of C28H54GdN5O20, and has the following
structural formula: Structural Formula
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596-S-045/21-037/S-019
Page 14
Each mL of MAGNEVIST Injection contains 469.01 mg gadopentetate dimeglumine, 0.99 mg
meglumine, 0.40 mg diethylenetriamine pentaacetic acid and water for injection. MAGNEVIST
Injection contains no antimicrobial preservative.
MAGNEVIST Injection has a pH of 6.5 to 8.0. Pertinent physicochemical data are noted below:
PARAMETER
Osmolality (mOsmol/kg water)
at 37° C
1,960
Viscosity (CP)
at 20° C
4.9
at 37° C
2.9
Density (g/mL)
at 25° C
1.195
Specific gravity
at 25° C
1.208
Octanol: H2O
at 25° C
and pH7
log Pow = - 5.4
MAGNEVIST Injection has an osmolality 6.9 times that of plasma which has an osmolality of 285
mOsmol/kg water. MAGNEVIST Injection is hypertonic under conditions of use.
CLINICAL PHARMACOLOGY
Pharmacokinetics
The pharmacokinetics of intravenously administered gadopentetate dimeglumine in normal subjects
conforms to a two compartment open-model with mean distribution and elimination half-lives
(reported as mean ± SD) of about 0.2 ± 0.13 hours and 1.6 ± 0.13 hours, respectively.
Upon injection, the meglumine salt is completely dissociated from the gadopentetate dimeglumine
complex. Gadopentetate is exclusively eliminated in the urine with
83 ± 14% (mean ± SD) of the dose excreted within 6 hours and 91 ± 13% (mean ± SD) by 24 hours,
post-injection. There was no detectable biotransformation or decomposition of gadopentetate
dimeglumine.
The renal and plasma clearance rates (1.76 ± 0.39 mL/min/kg and
1.94 ± 0.28 mL/min/kg, respectively) of gadopentetate are essentially identical, indicating no alteration
in elimination kinetics on passage through the kidneys and that the drug is essentially cleared through
the kidney. The volume of distribution (266 ± 43 mL/kg) is equal to that of extracellular water and
clearance is similar to that of substances which are subject to glomerular filtration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596-S-045/21-037/S-019
Page 15
In vitro laboratory results indicate that gadopentetate does not bind to human plasma protein. In vivo
protein binding studies have not been done.
Pharmacodynamics
Gadopentetate dimeglumine is a paramagnetic agent and, as such, it develops a magnetic moment
when placed in a magnetic field. The relatively large magnetic moment produced by the paramagnetic
agent results in a relatively large local magnetic field, which can enhance the relaxation rates of water
protons in the vicinity of the paramagnetic agent.
In magnetic resonance imaging (MRI), visualization of normal and pathological brain tissue depends in
part on variations in the radiofrequency signal intensity that occur with 1) changes in proton density; 2)
alteration of the spin- lattice or longitudinal relaxation time (T1); and 3) variation of the spin- spin or
transverse relaxation time (T2). When placed in a magnetic field, gadopentetate dimeglumine
decreases the T1 and T2 relaxation time in tissues where it accumulates. At usual doses the effect is
primarily on the T1 relaxation time.
Gadopentetate dimeglumine does not cross the intact blood-brain barrier and, therefore, does not
accumulate in normal brain or in lesions that do not have an abnormal blood- brain barrier, e. g., cysts,
mature post-operative scars, etc. However, disruption of the blood-brain barrier or abnormal
vascularity allows accumulation of gadopentetate dimeglumine in lesions such as neoplasms,
abscesses, and subacute infarcts. The pharmacokinetic parameters of MAGNEVIST in various lesions
are not known.
CLINICAL TRIALS
MAGNEVIST Injection was administered to 1272 patients in open label controlled clinical studies.
The mean age of these patients was 46.4 years (range 2 to 93 years). Of these patients, 55% (700) were
male and 45% (572) were female. Of the 1271 patients who received MAGNEVIST Injection and for
whom race was reported, 82.1% (1043) were Caucasian, 9.7% (123) were Black, 5.3% (67) were
Hispanic, 2.1% (27) were Oriental/Asian, and 0.9% (11) were other. Of the 1272 patients, 550 patients
were evaluated in blinded reader studies. These evaluated the use of contrast enhancement in magnetic
resonance imaging of lesions in the head and neck, brain, spine and associated tissues, and body
(excluding the heart). Of the 550 patients, all patients had a reason for an MRI and efficacy
assessments were based on pre-and post- MAGNEVIST injection film quality, film contrast, lesion
configuration (border, size, and location), and the number of lesions. The protocols did not include
systematic verification of specific diseases or histopathologic confirmation of findings.
Of the above 550 patients, 97 patients received 0.1 mmol/kg MAGNEVIST Injection
I. V. in two clinical trials of MAGNEVIST MRI contrast enhancement for body imaging. Of these 97,
68 had MRIs of the internal organs/structures of the abdomen or thorax
(excluding the heart); 8 had breast images and 22 had images of appendages. The results of MRIs
before and after MAGNEVIST use were compared blindly. Overall additional lesions were identified
in 22/97 (23%) of the patients after MAGNEVIST Injection. The mean number of lesions identified
before (1.49/patient) and after MAGNEVIST
(1.75/patient) were similar. Seven (8%) of the patients had lesions seen before MAGNEVIST that were
not seen after MAGNEVIST. Overall, after MAGNEVIST Injection, 41% of the images had a higher
contrast score than before injection; and 18% of the images had a higher contrast score before
MAGNEVIST Injection than after MAGNEVIST Injection. MAGNEVIST MRI of the 8 patients with
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596-S-045/21-037/S-019
Page 16
breast images were not systematically compared to the results to mammography, breast biopsy or other
modalities. In the 22 patients with appendage images (e. g., muscle, bone and intraarticular structures),
MAGNEVIST MRI was not systematically evaluated to determine the effects of contrast
biodistribution in these different areas.
Of the above 550 patients, 66 patients received MAGNEVIST 0.1 mmol/kg I. V. in clinical trials of
MAGNEVIST MRl contrast enhancement of lesions in the head and neck. A total of 66 MRI images
were evaluated blindly by comparing each pair of MRI images, before and after MAGNEVIST
Injection. In these paired images, 56/66 (85%) had greater enhancement after MAGNEVIST and 40/66
(61%) had better lesion configuration or border delineation after MAGNEVIST. Overall, there was
better contrast after MAGNEVIST in 55% of the images, comparable enhancement in 44 (36%) before
and after MAGNEVIST, and better enhancement in 9% without MAGNEVIST.
In the studies of the brain and spinal cord, MAGNEVIST 0.1 mmol/kg I. V. provided contrast
enhancement in lesions with an abnormal blood brain barrier.
In two studies, a total of 108 patients were evaluated to compare the dose response effects of 0.1
mmol/kg and 0.3 mmol/kg of MAGNEVIST in CNS MRI. Both dosing regimens had similar imaging
and general safety profiles; however, the 0.3 mmoL/kg dose did not provide additional benefit to the
final diagnosis (defined as number of lesions, location and characterization).
INDICATIONS AND USAGE
Central Nervous System:
MAGNEVIST Injection is indicated for use with magnetic resonance imaging (MRI) in adults, and
pediatric patients (2 years of age and older) to visualize lesions with abnormal vascularity in the brain
(intracranial lesions), spine and associated tissues. MAGNEVIST Injection has been shown to facilitate
visualization of intracranial lesions including but not limited to tumors.
Extracranial/ Extraspinal Tissues:
MAGNEVIST is indicated for use with MRI in adults and pediatric patients (2 years of age and older)
to facilitate the visualization of lesions with abnormal vascularity in the head and neck.
Body:
MAGNEVIST Injection is indicated for use in MRI in adults and pediatric patients (2 years of age and
older) to facilitate the visualization of lesions with abnormal vascularity in the body (excluding the
heart).
CONTRAINDICATIONS
None.
WARNINGS AND PRECAUTIONS
Nephrogenic Systemic Fibrosis (NSF)
Gadolinium-based contrast agents increase the risk for nephrogenic systemic fibrosis (NSF) in patients
with acute or chronic severe renal insufficiency (glomerular filtration rate < 30 mL/min/1.73 m2) and
in patients with acute renal insufficiency of any severity due to the hepato-renal syndrome or in the
perioperative liver transplantation period. In these patients, avoid use of gadolinium-based contrast
agents unless the diagnostic information is essential and not available with non-contrast enhanced
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596-S-045/21-037/S-019
Page 17
MRI. For patients receiving hemodialysis, physicians may consider the prompt initiation of
hemodialysis following the administration of a gadolinium-based contrast agent in order to enhance the
contrast agent’s elimination. The usefulness of hemodialysis in the prevention of NSF is unknown.
Among the factors that may increase the risk for NSF are repeated or higher than recommended doses
of a gadolinium-based contrast agent and the degree of renal function impairment at the time of
exposure.
Post-marketing reports have identified the development of NSF following single and multiple
administrations of gadolinium-based contrast agents. These reports have not always identified a
specific agent. Where a specific agent was identified, the most commonly reported agent was
gadodiamide (OmniscanTM), followed by gadopentetate dimeglumine (Magnevist®) and
gadoversetamide (OptiMARK®). NSF has also developed following sequential administrations of
gadodiamide with gadobenate dimeglumine (MultiHance®) or gadoteridol (ProHance®). The number
of post-marketing reports is subject to change over time and may not reflect the true proportion of
cases associated with any specific gadolinium-based contrast agent.
The extent of risk for NSF following exposure to any specific gadolinium-based contrast agent is
unknown and may vary among the agents. Published reports are limited and predominantly estimate
NSF risks with gadodiamide. In one retrospective study of 370 patients with severe renal insufficiency
who received gadodiamide, the estimated risk for development of NSF was 4% (J Am Soc Nephrol
2006; 17:2359). The risk, if any, for the development of NSF among patients with mild to moderate
renal insufficiency or normal renal function is unknown.
Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. When
administering a gadolinium-based contrast agent, do not exceed the recommended dose and allow a
sufficient period of time for elimination of the agent prior to any readministration. (See CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Hypersensitivity reactions
Anaphylactoid and anaphylactic reactions with cardiovascular, respiratory and/or cutaneous
manifestations rarely resulting in death have occurred. If such a reaction occurs, stop MAGNEVIST
Injection and immediately begin appropriate therapy, including resuscitation.
Observe closely patients with a history of drug reactions, allergy or other hypersensitivity disorders,
during and up to several hours after MAGNEVIST Injection.
Acute renal failure
In patients with renal insufficiency, acute renal failure requiring dialysis or worsening renal function
have occurred, mostly within 48 hrs of MAGNEVIST Injection. The risk of these events is higher with
increasing dose of contrast. Use the lowest possible dose and evaluate renal function in patients with
renal insufficiency.
MAGNEVIST is cleared by glomerular filtration and is dialyzable.
Injection site reactions
Skin and soft tissue necrosis, thrombosis, fasciitis, and compartment syndrome requiring surgical
intervention (e.g. compartment release or amputation) have occurred very rarely at the site of contrast
injection or the dosed limb. Total volume and rate of MAGNEVIST Injection, extravasation of contrast
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596-S-045/21-037/S-019
Page 18
agent, and patient susceptibility might contribute to these reactions. Phlebitis and thrombophlebitis
may be observed generally within 24 hours after MAGNEVIST Injection and resolve with supportive
treatment. Determine the patency and integrity of the intravenous line before administration of
MAGNEVIST Injection. Assessment of the dosed limb for the development of injection site reactions
is recommended.
Interference with Visualization of lesions visible with non-contrast MRI
As with any paramagnetic contrast agent, MAGNEVIST Injection might impair the visualization of
lesions seen on non-contrast MRI. Therefore, caution should be exercised when MAGNEVIST MRI
scans are interpreted without a companion non-contrast MRI scan.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596-S-045/21-037/S-019
Page 19
Patient counseling information
Patients scheduled to receive MAGNEVIST Injection should be instructed to inform their physician if
they are pregnant, breast feed, or have a history of renal insufficiency, asthma or allergic respiratory
disorders.
LABORATORY TEST FINDINGS
Transitory changes in serum iron, bilirubin and transaminase levels were observed in clinical trials.
MAGNEVIST Injection does not interfere with serum and plasma calcium measurements determined
by colorimetric assays.
CARCINOGENESIS, MUTAGENESIS AND IMPAIRMENT OF FERTILITY Long term animal
studies have not been performed to evaluate the carcinogenic potential of gadopentetate dimeglumine.
A comprehensive battery of in vitro and in vivo studies in bacterial and mammalian systems suggest
that gadopentetate dimeglumine is not mutagenic or clastogenic and does not induce unscheduled
DNA repair in rat hepatocytes or cause cellular transformation of mouse embryo fibroblasts. However,
the drug did show some evidence of mutagenic potential in vivo in the mouse dominant lethal assay at
doses of 6 mmol/kg, but did not show any such potential in the mouse and dog micronucleus tests at
intravenous doses of 9 mmol/kg and 2.5 mmol/kg, respectively.
When administered intra-peritoneally to male and female rats daily prior to mating, during mating and
during embryonic development for up to 74 days (males) or 35 days
(females), gadopentetate caused a decrease in number of corpora lutea at the 0.1 mmol/ kg dose level.
After daily dosing with 2.5 mmol/kg suppression of food consumption and body weight gain (males
and females) and a decrease in the weights of testes and epididymis were also observed.
In a separate experiment in rats, daily injections of gadopentetate dimeglumine over 16 days caused
spermatogenic cell atrophy at a dose level of 5 mmol/kg but not at a dose level of 2.5 mmol/kg. This
atrophy was not reversed within a 16-day observation period following the discontinuation of the drug.
PREGNANCY CATEGORY C.
Gadopentetate dimeglumine retarded fetal development slightly when given intravenously for 10
consecutive days to pregnant rats at daily doses of 0.25, 0.75, and 1.25 mmol/kg (2.5, 7.5 and 12.5
times the human dose based on body weight) and when given intravenously for 13 consecutive days to
pregnant rabbits at daily doses of 0.75 and 1.25 mmol/kg (7.5 and 12.5 times the human dose
respectively, based on body weight) but not at daily doses of 0.25 mmol/kg. No congenital anomalies
were noted in rats or rabbits.
Adequate and well controlled studies were not conducted in pregnant women. MAGNEVIST Injection
should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
NURSING WOMEN
MAGNEVIST is excreted in human milk. MAGNEVIST Injection was administered intravenously to
18 lactating women with normal renal function at a dose of 0.1 mmol/kg body weight. In these women,
less than 0.04% of the administered gadolinium was excreted into the breast milk during the 24-hour
period following dosing. Breast milk obtained during the 24 hours following dosing revealed the
average cumulative amount of gadolinium excreted in breast milk was 0.57+/- 0.71 micromol. The
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596-S-045/21-037/S-019
Page 20
amount transferred from a 70 kg woman (receiving 0.1 mmol/kg body weight) to an infant by breast
feeding over a period of 24 hrs translates into less than 3 micromol of gadolinium.
The overall duration of excretion of gadolinium into breast milk is unknown. The extent of the
absorption of MAGNEVIST Injection in infants and its effect on the breast-fed child remains
unknown. Caution should be exercised when MAGNEVIST Injection is administered to a nursing
woman.
PEDIATRIC USE
The use of MAGNEVIST in imaging the Central Nervous System, Extracranial/ Extraspinal tissues,
and Body have been established in the pediatric population from the ages of 2 to 16 years on the basis
of adequate and well controlled clinical trials in adults and safety studies in this pediatric population.
(See CLINICAL TRIALS for details.)
Safety and efficacy in the pediatric population under the age of 2 years have not been established.
MAGNEVIST is eliminated primarily by the kidney. The pharmacokinetics of MAGNEVIST in
neonates and infants with immature renal function have not been studied.
(See INDICATIONS and DOSAGE AND ADMINISTRATION)
ADVERSE REACTIONS
The mean age of the 1272 patients who received MAGNEVIST Injection was 46.4 years (range 2 to 93
years). Of these patients, 55% (700) were male and 45%
(572) were female. Of the 1271 patients who received MAGNEVIST Injection and for whom race was
reported, 82.1% (1043) were Caucasian, 9.7% (123) were Black, 5.3%
(67) were Hispanic, 2.1% (27) were Oriental/Asian, and 0.9% (11) were other. The most common
noted adverse event is headache with an incidence of 4.8%. The majority of headaches are transient
and of mild to moderate severity. Nausea is the second most common adverse experience at 2.7%.
Injection site coldness/localized coldness is the third most common adverse experience at 2.3%.
Dizziness occurred in 1% of the patients.
The following additional adverse events occurred in fewer than 1% of the patients:
Body as a Whole: Injection site symptoms, namely, pain, localized warmth, and burning sensation;
substernal chest pain, back pain, fever, weakness, generalized coldness, generalized warmth, localized
edema, tiredness, chest tightness, trembling, shivering, tension in extremities, regional lymphangitis,
pelvic pain, and anaphylactoid reactions
(characterized by cardiovascular, respiratory and cutaneous symptoms) rarely resulting in death.
Cardiovascular: Hypotension, hypertension, arrhythmia, tachycardia, migraine, syncope,
vasodilation, pallor, non-specific ECG changes, angina pectoris, death related to myocardial infarction
or other undetermined causes, phlebitis, thrombophlebitis, deep vein thrombophlebitis, compartment
syndrome requiring surgical intervention.
Digestive: Gastrointestinal distress, stomach pain, teeth pain, increased salivation, abdominal pain,
vomiting, constipation, diarrhea.
Nervous System: Agitation, anxiety, thirst, anorexia, nystagmus, drowsiness, diplopia, stupor,
convulsions (including grand mal), paresthesia.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596-S-045/21-037/S-019
Page 21
Respiratory System: Throat irritation, rhinorrhea, sneezing, dyspnea, wheezing, laryngismus, cough,
respiratory complaints.
Skin: Rash, sweating, pruritus, urticaria (hives), facial edema, erythema multiforme, epidermal
necrolysis, pustules.
Special Senses: Tinnitus, conjunctivitis, visual field defect, taste abnormality, dry mouth, lacrimation
disorder (tearing), eye irritation, eye pain, ear pain.
OVERDOSAGE
Systemic consequences associated with overdosage of MAGNEVIST Injection have not been reported.
DOSAGE AND ADMINISTRATION
The recommended dosage of MAGNEVIST Injection is 0.2 mL/kg (0.1 mmol/ kg) administered
intravenously, at a rate not to exceed 10 mL per 15 seconds. Dosing for patients in excess of 286 lbs
has not been studied systematically.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596-S-045/21-037/S-019
Page 22
DOSE AND DURATION OF MAGNEVIST INJECTION BY BODY WEIGHT
BODY WEIGHT
Total Volume, mL*
lb
kg
22
10
2
44
20
4
66
30
6
88
40
8
110
50
10
132
60
12
154
70
14
176
80
16
198
90
18
220
100
20
242
110
22
264
120
24
286
130
26
*Rate of Injection: 10 mL/15sec
Drug Handling: To ensure complete injection of the contrast medium, the injection should be followed
by a 5-mL normal saline flush. The imaging procedure should be completed within 1 hour of injection
of MAGNEVIST Injection.
As with other gadolinium contrast agents, MAGNEVIST Injection has not been established for use in
magnetic resonance angiography.
Parenteral products should be inspected visually for particulate matter and discoloration prior to
administration. Do not use the solution if it is discolored or particulate matter is present.
Pharmacy Bulk Package Preparation:
NOT FOR DIRECT INFUSION
The Pharmacy Bulk Package is used as a multiple dose container with an appropriate transfer device
for filling empty sterile syringes.
a) The transfer of MAGNEVIST Injection from the Pharmacy Bulk Package must be performed in an
aseptic work area, such as a laminar flow hood, using aseptic technique.
b) Once the Pharmacy Bulk Package is punctured, it should not be removed from the aseptic work area
during the entire 24 hour period of use.
c) The contents of the Pharmacy Bulk Package after initial puncture should be used within 24 hours.
d) Any unused MAGNEVIST Injection must be discarded 24 hours after the initial puncture of the
bulk package.
IV tubing and syringes used to administer MAGNEVIST Injection must be discarded at the conclusion
of the radiological examination.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-596-S-045/21-037/S-019
Page 23
Any unused portion must be discarded in accordance with regulations dealing with the disposal of such
materials.
HOW SUPPLIED
MAGNEVIST Injection is a clear, colorless to slightly yellow solution containing
469.01 mg/mL of gadopentetate dimeglumine. MAGNEVIST Injection is supplied in the following
sizes:
50 mL Pharmacy Bulk Package, rubber stoppered, 10 per box NDC 50419- 188- 58
50 mL Pharmacy Bulk Package (RFID), rubber stoppered, 10 per box NDC 50419- 188- 48
100 mL Pharmacy Bulk Package, rubber stoppered, 10 per box
NDC 50419- 188- 11
100 mL Pharmacy Bulk Package (RFID), rubber stoppered, 10 per box NDC 50419- 188- 49
STORAGE
MAGNEVIST Injection should be stored at controlled room temperature, between
15-30° C (59- 86° F) and protected from light. DO NOT FREEZE. Should freezing occur in the bottle
MAGNEVIST Injection should be brought to room temperature before use. If allowed to stand at room
temperature for a minimum of 90 minutes, MAGNEVIST Injection should return to a clear, colorless
to slightly yellow solution. Before use, examine the product to assure that all solids are redissolved and
that the container and closure have not been damaged. Should solids persist, discard bottle.
U. S. Patent Nos. 5,362,475; 5,560,903 and, 5,876,695 relate to this product
Manufactured for: Company logo
Manufactured in Germany
© 2009, Bayer HealthCare Pharmaceuticals Inc., All Rights Reserved.
Revised January 2008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:30.810318
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019596s045,021037s019lbl.pdf', 'application_number': 19596, 'submission_type': 'SUPPL ', 'submission_number': 45}
|
11,557
|
_______________________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to
use NAFTIN® Cream, 2% safely and effectively.
See full prescribing information for NAFTIN (naftifine hydrochloride)
Cream, 2%.
NAFTIN (naftifine hydrochloride) Cream, 2% for topical use
Initial U.S. Approval: 1988
----------------------------INDICATIONS AND USAGE---------------------------
NAFTIN (naftifine hydrochloride) Cream, 2% is an allylamine antifungal
indicated for the treatment of interdigital tinea pedis, tinea cruris, and tinea
corporis caused by the organism Trichophyton rubrum in adult patients 18
years of age. (1)
----------------------DOSAGE AND ADMINISTRATION-----------------------
For topical use only. NAFTIN (naftifine hydrochloride) Cream, 2% is not for
ophthalmic, oral, or intravaginal use. (2)
Appy a thin layer of NAFTIN (naftifine hydrochloride) Cream, 2% once-daily
to the affected areas plus a ½ inch margin of healthy surrounding skin for 2
weeks. (2)
---------------------DOSAGE FORMS AND STRENGTHS----------------------
Cream: 2% (3)
-------------------------------CONTRAINDICATIONS------------------------------
None (4)
-----------------------WARNINGS AND PRECAUTIONS--------------
If redness or irritation develops with the use of NAFTIN Cream, 2% treatment
should be discontinued. (5.1)
------------------------------ADVERSE REACTIONS-------------------------------
The most common adverse reaction (1%) is pruritus. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Merz
Pharmaceuticals, LLC at 877-743-8454 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 01/2012
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Local Adverse Reactions
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
12.4
Microbiology
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1
Tinea cruris
14.2
Tinea pedis
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed
Page 1 of 5
Reference ID: 3070857
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
NAFTIN (naftifine hydrochloride) Cream, 2% is indicated for the treatment of: interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organism
Trichophyton rubrum in adult patients 18 years of age.
2
DOSAGE AND ADMINISTRATION
For topical use only. NAFTIN (naftifine hydrochloride) Cream, 2% is not for ophthalmic, oral or intravaginal use. Apply a thin layer of NAFTIN Cream, 2% once-
daily to the affected areas plus a ½ inch margin of healthy surrounding skin for 2 weeks.
3 DOSAGE FORMS AND STRENGTHS
Cream: 2%, white to off-white cream
4
CONTRAINDICATIONS
None
5 WARNINGS AND PRECAUTIONS
5.1 Local Adverse Reactions
If irritation or sensitivity develops with the use of NAFTIN (naftifine hydrochloride) Cream, 2% treatment should be discontinued. Patients should be directed to
contact their physician if these conditions develop following use of NAFTIN (naftifine hydrochloride) Cream, 2%.
6
ADVERSE REACTIONS
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 to
rates in the clinical trials of another drug and may not reflect the rates observed in practice.
During clinical trials, 760 subjects were exposed to naftifine 1% and 2% cream formulations. A total of 421 subjects with tinea pedis and/or tinea cruris were
treated with NAFTIN (naftifine hydrochloride) Cream, 2%. In two randomized, vehicle-controlled trials (400 patients were treated with NAFTIN (naftifine
hydrochloride) Cream, 2%). The population was 12 to 88 years old, primarily male (79%), 48% Caucasian, 36% Black or African American, 40% Hispanic or
Latino and had either predominantly interdigital tinea pedis or tinea cruris. Most subjects received doses once-daily, topically, for 2 weeks to cover the affected
skin areas plus a ½ inch margin of surrounding healthy skin. In the two vehicle-controlled trials, 17.5% of NAFTIN (naftifine hydrochloride) Cream, 2% treated
subjects experienced an adverse reaction compared with 19.3% of vehicle subjects. The most common adverse reaction (1%) is pruritus. Most adverse reactions
were mild in severity. The incidence of Adverse Reactions in the NAFTIN Cream, 2% treated population were not significantly different than the vehicle treated
population.
6.2
Postmarketing Experience
The following adverse reactions have been identified during postmarketing use of (naftifine hydrochloride): redness/irritation, inflammation, maceration, swelling,
burning, blisters, serous drainage, crusting, headache, dizziness, leukopenia, agranulocytosis. 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.
8 USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B. There are no adequate and well-controlled studies of NAFTIN (naftifine hydrochloride) Cream, 2% in pregnant women. Because animal
reproduction studies are not always predictive of human response, NAFTIN (naftifine hydrochloride) Cream, 2% should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
The animal multiples of human exposure calculations were based on daily dose body surface area comparison (mg/m2) for the reproductive toxicology studies
described in this section and in Section 13.1. The Maximum Recommended Human Dose (MRHD) was set at 8 g 2% cream per day (2.67 mg/kg/day for a 60 kg
individual).
Systemic embryofetal development studies were conducted in rats and rabbits. Oral doses of 30, 100 and 300 mg/kg/day naftifine hydrochloride were administered
during the period of organogenesis (gestational days 6 – 15) to pregnant female rats. No treatment-related effects on embryofetal toxicity or teratogenicity were
noted at doses up to 300 mg/kg/day (18.2X MRHD). Subcutaneous doses of 10 and 30 mg/kg/day naftifine hydrochloride were administered during the period of
organogenesis (gestational days 6 – 15) to pregnant female rats. No treatment-related effects on embryofetal toxicity or teratogenicity were noted at 30 mg/kg/day
(1.8X MRHD). Subcutaneous doses of 3, 10 and 30 mg/kg/day naftifine hydrochloride were administered during the period of organogenesis (gestational days 6 –
18) to pregnant female rabbits. No treatment related effects on embryofetal toxicity or teratogenicity were noted at 30 mg/kg/day (3.6X MRHD).
A peri- and post-natal development study was conducted in rats. Oral doses of 30, 100 and 300 mg/kg/day naftifine hydrochloride were administered to female rats
from gestational day 14 to lactation day 21. Reduced body weight gain of females during gestation and of the offspring during lactation was noted at 300
mg/kg/day (18.2X MRHD). No developmental toxicity was noted at 100 mg/kg/day (6.1X MRHD).
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 NAFTIN (naftifine
hydrochloride) Cream, 2% is administered to a nursing woman.
8.4
Pediatric Use
Safety and effectiveness in pediatric patients have not been established. The number of pediatric patients 12 years of age studied were too small to adequately
assess safety and efficacy.
8.5
Geriatric Use
Clinical studies of NAFTIN (naftifine hydrochloride) Cream, 2% did not include sufficient numbers of subjects aged 65 and over to determine whether they
respond differently from younger subjects.
Page 2 of 5
Reference ID: 3070857
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11 DESCRIPTION
structural flormula
NAFTIN (naftifine hydrochloride) Cream, 2% is a white to off-white cream for topical use only. Each gram of (naftifine hydrochloride) Cream contains 20 mg of
naftifine hydrochloride, a synthetic allylamine antifungal compound.
Chemically, naftifine HCl is (E)-N-Cinnamyl-N-methyl-1-napthalenemethylamine hydrochloride.
The structural formula of naftifine hydrochloride is:
NAFTIN (naftifine hydrochloride) Cream, 2% contains the following inactive ingredients: benzyl alcohol, cetyl alcohol, cetyl esters wax, isopropyl myristate,
polysorbate 60, purified water, sodium hydroxide, sorbitan monostearate, stearyl alcohol, and hydrochloric acid.
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
NAFTIN (naftifine hydrochloride) Cream, 2% is a topical antifungal drug [see Clinical Pharmacology(12.4)]
12.2
Pharmacodynamics
The pharmacodynamics of NAFTIN (naftifine hydrochloride) Cream, 2% have not been established.
12.3
Pharmacokinetics
In vitro and in vivo bioavailability studies have demonstrated that naftifine penetrates the stratum corneum in sufficient concentration to inhibit the growth of
dermatophytes.
The pharmacokinetics of NAFTIN Cream, 2% was evaluated following once-daily topical application for 2 weeks to twenty one adult subjects, both males and
females, with both tinea pedis and tinea cruris. The median total amount of cream applied was 6.4 g (range 5.3-7.5 g) per day. The results showed that the systemic
exposure (i.e. maximum concentration (Cmax) and area under the curve (AUC)) to naftifine increased over the 2 week treatment period in all the 21 subjects.
Geometric Mean (CV%) AUC0-24 was 117 (41.2) ng*hr/mL on Day 1, and 204 (28.5) ng*hr/mL on Day 14. Geometric Mean (CV %) Cmax was 7 ng/mL (55.6)
on Day 1 and 11 ng/mL (29.3) on day 14. Median Tmax was 8.0 hours on Day 1 (range: 4 to 24) and 6.0 hours on Day 14 (range: 0 to 16). Accumulation after 14
days of topical application was less than two fold. Trough concentrations generally increased throughout the 14 day study period. Naftifine continued to be detected
in plasma in 13/21 (62%) subjects on day 28, the mean (SD) plasma concentrations were 1.6 r 0.5 ng/mL (range below limit of quantitation (BLQ) to 3 ng/mL).
In the same pharmacokinetic study conducted in patients with tinea pedis and tinea cruris, median fraction of the dose excreted in urine during the treatment period
was 0.0016% on Day 1 versus 0.0020% on Day 14.
12.4
Microbiology
Although the exact mechanism of action against fungi is not known, naftifine hydrochloride appears to interfere with sterol biosynthesis by inhibiting the enzyme
squalene 2, 3-epoxidase.This inhibition of enzyme activity results in decreased amounts of sterols, especially ergosterol, and a corresponding accumulation of
squalene in the cells.
Naftifine has been shown to be active against most isolates of the following fungi, both in vitro and in clinical infections, as described in the INDICATIONS AND
USAGE section:
Trichophyton rubrum
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies to evaluate the carcinogenic potential of NAFTIN (naftifine hydrochloride) Cream, 2% have not been performed.
Naftifine hydrochloride revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames assay and Chinese
hamster ovary cell chromosome aberration assay) and one in vivo genotoxicity test (mouse bone marrow micronucleus assay).
Oral administration of naftifine hydrochloride to rats, throughout mating, gestation, parturition and lactation, demonstrated no effects on growth, fertility or
reproduction, at doses up to 100 mg/kg/day (6.1X MRHD).
Page 3 of 5
Reference ID: 3070857
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14 CLINICAL STUDIES
14.1 Tinea Cruris
NAFTIN (naftifine hydrochloride) Cream, 2% has been investigated for safety and efficacy in a randomized, double-blind, vehicle-controlled, multi-center study in
146 subjects with symptomatic and dermatophyte culture positive tinea cruris. Subjects were randomized to receive (naftifine hydrochloride)Cream or vehicle.
Subjects applied the study agent (naftifine hydrochloride) Cream or vehicle) to the affected area plus a ½-inch margin of healthy skin surrounding the affected area
once-daily for 2 weeks. Signs and symptoms of tinea cruris (presence or absence of erythema, pruritus, and scaling) were assessed, and KOH examination and
dermatophyte culture were performed at the primary efficacy endpoint at week 4.
The mean age of the study population was 47 years and 87% were male and 43% were white. At baseline, subjects were confirmed to have signs and symptoms of
tinea cruris, positive KOH exam, and confirmed dermatophyte presence based on culture results from a central mycology laboratory. The analysis of the intent-to
treat population was a comparison of the proportions of subjects with a complete cure at the week 4 visit (see Table 2). Complete cure was defined as both clinical
cure (absence of erythema, pruritus, and scaling) and mycological cure (negative KOH and dermatophyte culture).
The percentage of subjects experiencing clinical cure and the percentage of subjects experiencing mycological cure at week 4 are presented individually in Table 1
below
Table 1 Efficacy Results for Pivotal Tinea Cruris Trial (Week 4 Assessment)
NAFTIN
VehicleN=71
(naftifine
hydrochloride)
Cream, 2%
Endpoint
N=75
Complete Curea
19(25%)
2(3%)
Effective Treatment b
45(60%)
7(10%)
Mycological Curec
54(72%)
11(16%)
a. Complete cure is a composite endpoint of both mycological cure and clinical cure.
Clinical cure is defined as the absence of erythema, pruritus, and scaling (grade of 0).
b. Effective treatment is a negative KOH preparation and negative dermatophyte culture,
erythema, scaling, and pruritus grades of 0 or 1 (absent or nearly absent).
c. Mycological cure is defined as negative KOH and dermatophyte culture.
14.2 Interdigital Tinea Pedis
NAFTIN (naftifine hydrochloride)Cream, 2% has been investigated for efficacy in a randomized, double-blind, vehicle-controlled, multi-center study in 216
subjects with symptomatic and dermatophyte culture positive tinea pedis. Subjects were randomized to receive NAFTIN (naftifine hydrochloride)Cream, 2% or
vehicle. Subjects applied the study agent (naftifine hydrochloride)cream or vehicle) to the affected area of the foot plus a ½-inch margin of healthy skin
surrounding the affected area once-daily for 2 weeks. Signs and symptoms of tinea pedis (presence or absence of erythema, pruritus, and scaling) were assessed
and KOH examination and dermatophyte culture was performed at the primary efficacy endpoint at week 6.
The mean age of the study population was 42 years and 71% were male and 57% were white. At baseline, subjects were confirmed to have signs and symptoms of
tinea pedis, positive KOH exam, and confirmed dermatophyte culture. The primary efficacy endpoint was the proportions of subjects with a complete cure at the
week 6 visit (see Table 3). Complete cure was defined as both a clinical cure (absence of erythema, pruritus, and scaling) and mycological cure (negative KOH and
dermatophyte culture).
The efficacy results at week 6, four weeks following the end of treatment, are presented in Table 3 below. Naftin Cream demonstrated complete cure in subjects
with interdigital tinea pedis, but complete cure in subjects with only moccasin type tinea pedis was not demonstrated.
Table 2 Efficacy Results for Pivotal Tinea Pedis Trial (Week 6 Assessment)
NAFTIN
Vehicle
(naftifine
N=70
hydrochloride)
Cream, 2%
Endpoint
N=147
Complete Curea
26(18%)
5(7%)
Effective Treatment b
83(57%)
14(20%)
Mycological Curec
99(67%)
15(21%)
a. Complete cure is a composite endpoint of both mycological cure and clinical cure.
Clinical cure is defined as absence of erythema, pruritus, and scaling (grade of 0).
b. Effective treatment is a negative KOH preparation and negative dermatophyte culture,
erythema, scaling, and pruritus grades of 0 or 1 (absent or near absent).
c. Mycological cure is defined as negative KOH and dermatophyte culture.
16 HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
NAFTIN (naftifine hydrochloride) Cream, 2% is a white to off-white cream supplied in collapsible tubes in the following sizes:
30g – NDC 0259-1102-30
45g – NDC 0259-1102-45
60g – NDC 0259-1102-60
Storage
Store NAFTIN (naftifine hydrochloride) Cream, 2% at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
17 PATIENT COUNSELING INFORMATION
Page 4 of 5
Reference ID: 3070857
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
x
Inform patients that NAFTIN (naftifine hydrochloride) Cream, 2% is for topical use only. NAFTIN (naftifine hydrochloride) Cream, 2% is not intended for
intravaginal or ophthalmic use.
x
If irritation or sensitivity develops with the use of NAFTIN (naftifine hydrochloride) Cream, 2% treatment should be discontinued and appropriate therapy
instituted. Patients should be directed to contact their physician if these conditions develop following use of NAFTIN (naftifine hydrochloride) Cream, 2%.
NAFTIN (naftifine hydrochloride) Cream, 2% is manufactured for Merz Pharmaceuticals, LLC, Greensboro, NC 27410
NAFTIN (naftifine hydrochloride) Cream, 2% is a registered trademark of Merz Pharmaceuticals, LLC
Page 5 of 5
Reference ID: 3070857
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:30.953467
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019599s011lbl.pdf', 'application_number': 19599, 'submission_type': 'SUPPL ', 'submission_number': 11}
|
11,556
|
MAGNEVIST®
(brand of gadopentetate dimeglumine)
Injection
FOR INTRAVENOUS ADMINISTRATION
Rx only
WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)
Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with
impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic
information is essential and not available with non-contrasted MRI or other modalities. NSF
may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs.
• Do not administer MAGNEVIST to patients with:
o chronic, severe kidney disease (GFR < 30 mL/min/1.73m2), or
o acute kidney injury (see CONTRAINDICATIONS).
• Screen patients for acute kidney injury and other conditions that may reduce renal function.
For patients at risk for chronically reduced renal function (for example, age >60 years,
hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory
testing.
Do not exceed the recommended MAGNEVIST dose and allow a sufficient period of time for
elimination of the drug from the body prior to any re-administration (see WARNINGS AND
PRECAUTIONS).
DESCRIPTION
MAGNEVIST® (brand of gadopentetate dimeglumine) Injection is the N-methylglucamine salt
of the gadolinium complex of diethylenetriamine pentaacetic acid, and is an injectable contrast
medium for magnetic resonance imaging (MRI). MAGNEVIST Injection is provided as a sterile,
clear, colorless to slightly yellow aqueous solution for intravenous injection.
MAGNEVIST Injection is a 0.5-mol/L solution of 1-deoxy-1-(methylamino)-D-glucitol
dihydrogen [N,N-bis[2-[bis(carboxymethyl)amino]ethyl] glycinato (5-) ]gadolinate(2-)(2:1) with
a molecular weight of 938, an empirical formula of C28H54GdN5O20, and has the following
structural formula: structural formula
Reference ID: 3391342
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 MAGNEVIST Injection contains 469.01 mg gadopentetate dimeglumine, 0.99 mg
meglumine, 0.40 mg diethylenetriamine pentaacetic acid and water for injection. MAGNEVIST
Injection contains no antimicrobial preservative.
MAGNEVIST Injection has a pH of 6.5 to 8.0. Pertinent physicochemical data are noted below:
PARAMETER
Osmolality (mOsmol/kg water)
at 37° C
1,960
Viscosity (CP)
at 20° C
4.9
at 37° C
2.9
Density (g/mL)
at 25° C
1.195
Specific Gravity
at 25° C
1.208
Octanol: H2O Coefficient
at 25° C, pH7 log Pow = - 5.4
MAGNEVIST Injection has an osmolality 6.9 times that of plasma which has an osmolality of
285 mOsmol/kg water. MAGNEVIST Injection is hypertonic under conditions of use.
CLINICAL PHARMACOLOGY
Pharmacokinetics
The pharmacokinetics of intravenously administered gadopentetate dimeglumine in normal
subjects conforms to a two compartment open-model with mean distribution and elimination
half-lives (reported as mean ± SD) of about 0.2 ± 0.13 hours and 1.6 ± 0.13 hours, respectively.
Upon injection, the meglumine salt is completely dissociated from the gadopentetate
dimeglumine complex. Gadopentetate is exclusively eliminated in the urine with 83 ± 14%
(mean ± SD) of the dose excreted within 6 hours and 91 ± 13% (mean ± SD) by 24 hours, post-
injection. There was no detectable biotransformation or decomposition of gadopentetate
dimeglumine.
The renal and plasma clearance rates (1.76 ± 0.39 mL/min/kg and 1.94 ± 0.28 mL/min/kg,
respectively) of gadopentetate are essentially identical, indicating no alteration in elimination
kinetics on passage through the kidneys and that the drug is essentially cleared through the
kidney. The volume of distribution (266 ± 43 mL/kg) is equal to that of extracellular water and
clearance is similar to that of substances which are subject to glomerular filtration.
In vitro laboratory results indicate that gadopentetate does not bind to human plasma protein. In
vivo protein binding studies have not been done.
Renal Impairment
Gadopentetate dimeglumine is excreted via the kidneys, even in patients with impaired renal
function. In patients with impaired renal function, the serum half-life of gadopentetate
Reference ID: 3391342
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
dimeglumine is prolonged. Mean serum elimination half-lives of a single intravenous dose of
gadopentetate dimeglumine (0.1 mmol/kg) were 2.6 ± 1.2 h, 4.2 ± 2.0 h and 10.8 ± 6.9 h, for
mildly (creatinine clearance, CLCR = 60 to < 90 mL/min), moderately (CLCR = 30 to < 60
mL/min) and severely (CLCR = < 30 mL/min) impaired patients, respectively, as compared with
1.6 ± 0.1 h in healthy subjects.
Pharmacodynamics
Gadopentetate dimeglumine is a paramagnetic agent and, as such, it develops a magnetic
moment when placed in a magnetic field. The relatively large magnetic moment produced by the
paramagnetic agent results in a relatively large local magnetic field, which can enhance the
relaxation rates of water protons in the vicinity of the paramagnetic agent.
In magnetic resonance imaging (MRI), visualization of normal and pathological brain tissue
depends in part on variations in the radiofrequency signal intensity that occur with 1) changes in
proton density; 2) alteration of the spin-lattice or longitudinal relaxation time (T1); and 3)
variation of the spin-spin or transverse relaxation time (T2). When placed in a magnetic field,
gadopentetate dimeglumine decreases the T1 and T2 relaxation time in tissues where it
accumulates. At usual doses the effect is primarily on the T1 relaxation time.
Gadopentetate dimeglumine does not cross the intact blood-brain barrier and, therefore, does not
accumulate in normal brain or in lesions that do not have an abnormal blood-brain barrier, e.g.,
cysts, mature post-operative scars, etc. However, disruption of the blood-brain barrier or
abnormal vascularity allows accumulation of gadopentetate dimeglumine in lesions such as
neoplasms, abscesses, and subacute infarcts. The pharmacokinetic parameters of MAGNEVIST
in various lesions are not known.
CLINICAL TRIALS
MAGNEVIST Injection was administered to 1272 patients in open label controlled clinical
studies. The mean age of these patients was 46.4 years (range 2 to 93 years). Of these patients,
55% (700) were male and 45% (572) were female. Of the 1271 patients who received
MAGNEVIST Injection and for whom race was reported, 82.1% (1043) were Caucasian, 9.7%
(123) were Black, 5.3% (67) were Hispanic, 2.1% (27) were Oriental/Asian, and 0.9% (11) were
other. Of the 1272 patients, 550 patients were evaluated in blinded reader studies. These
evaluated the use of contrast enhancement in magnetic resonance imaging of lesions in the head
and neck, brain, spine and associated tissues, and body (excluding the heart). Of the 550 patients,
all patients had a reason for an MRI and efficacy assessments were based on pre-and post-
MAGNEVIST injection film quality, film contrast, lesion configuration (border, size, and
location), and the number of lesions. The protocols did not include systematic verification of
specific diseases or histopathologic confirmation of findings.
Reference ID: 3391342
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Of the above 550 patients, 97 patients received 0.1 mmol/kg MAGNEVIST Injection IV in two
clinical trials of MAGNEVIST MRI contrast enhancement for body imaging. Of these 97, 68 had
MRIs of the internal organs/structures of the abdomen or thorax (excluding the heart); 8 had
breast images and 22 had images of appendages. The results of MRIs before and after
MAGNEVIST use were compared blindly. Overall additional lesions were identified in 22/97
(23%) of the patients after MAGNEVIST Injection. The mean number of lesions identified
before (1.49/patient) and after MAGNEVIST (1.75/patient) were similar. Seven (8%) of the
patients had lesions seen before MAGNEVIST that were not seen after MAGNEVIST. Overall,
after MAGNEVIST Injection, 41% of the images had a higher contrast score than before
injection; and 18% of the images had a higher contrast score before MAGNEVIST Injection than
after MAGNEVIST Injection. MAGNEVIST MRI of the 8 patients with breast images were not
systematically compared to the results to mammography, breast biopsy or other modalities. In
the 22 patients with appendage images (e.g., muscle, bone and intraarticular structures),
MAGNEVIST MRI was not systematically evaluated to determine the effects of contrast
biodistribution in these different areas.
Of the above 550 patients, 66 patients received MAGNEVIST 0.1 mmol/kg IV in clinical trials
of MAGNEVIST MRl contrast enhancement of lesions in the head and neck. A total of 66 MRI
images were evaluated blindly by comparing each pair of MRI images, before and after
MAGNEVIST Injection. In these paired images, 56/66 (85%) had greater enhancement after
MAGNEVIST and 40/66 (61%) had better lesion configuration or border delineation after
MAGNEVIST. Overall, there was better contrast after MAGNEVIST in 55% of the images,
comparable enhancement in 44 (36%) before and after MAGNEVIST, and better enhancement in
9% without MAGNEVIST.
In the studies of the brain and spinal cord, MAGNEVIST 0.1 mmol/kg IV provided contrast
enhancement in lesions with an abnormal blood brain barrier.
In two studies, a total of 108 patients were evaluated to compare the dose response effects of 0.1
mmol/kg and 0.3 mmol/kg of MAGNEVIST in CNS MRI. Both dosing regimens had similar
imaging and general safety profiles; however, the 0.3 mmoL/kg dose did not provide additional
benefit to the final diagnosis (defined as number of lesions, location and characterization).
INDICATIONS AND USAGE
Central Nervous System
MAGNEVIST Injection is indicated for use with magnetic resonance imaging (MRI) in adults,
and pediatric patients (2 years of age and older) to visualize lesions with abnormal vascularity in
the brain (intracranial lesions), spine and associated tissues. MAGNEVIST Injection has been
shown to facilitate visualization of intracranial lesions including but not limited to tumors.
Reference ID: 3391342
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Extracranial/Extraspinal Tissues
MAGNEVIST is indicated for use with MRI in adults and pediatric patients (2 years of age and
older) to facilitate the visualization of lesions with abnormal vascularity in the head and neck.
Body
MAGNEVIST Injection is indicated for use in MRI in adults and pediatric patients (2 years of
age and older) to facilitate the visualization of lesions with abnormal vascularity in the body
(excluding the heart).
CONTRAINDICATIONS
MAGNEVIST is contraindicated in patients with:
• Chronic, severe kidney disease (glomerular filtration rate, GFR < 30 mL/min/1.73m2), or
• Acute kidney injury, or
• History of severe hypersensitivity reactions to MAGNEVIST.
WARNINGS AND PRECAUTIONS
Nephrogenic Systemic Fibrosis (NSF)
Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis
(NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these
patients unless the diagnostic information is essential and not available with non-contrast
enhanced MRI or other modalities. The GBCA-associated NSF risk appears highest for patients
with chronic, severe kidney disease (GFR < 30 mL/min/1.73m2) as well as patients with acute
kidney injury. Do not administer MAGNEVIST to these patients. The risk appears lower for
patients with chronic, moderate kidney disease (GFR 30- 59 mL/min/1.73m2) and little, if any,
for patients with chronic, mild kidney disease (GFR 60- 89 mL/min/1.73m2). NSF may result in
fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis
of NSF following MAGNEVIST administration to Bayer Healthcare (1-888-842-2937) or FDA
(1-800-FDA-1088 or www.fda.gov/medwatch).
Screen patients for acute kidney injury and other conditions that may reduce renal function.
Features of acute kidney injury consist of rapid (over hours to days) and usually reversible
decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-
induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess
renal function in the setting of acute kidney injury. For patients at risk for chronically reduced
renal function (for example, age > 60 years, diabetes mellitus or chronic hypertension), estimate
the GFR through laboratory testing.
Among the factors that may increase the risk for NSF are repeated or higher than recommended
doses of a GBCA and degree of renal impairment at the time of exposure. Record the specific
Reference ID: 3391342
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
GBCA and the dose administered to a patient. When administering Magnevist, do not exceed the
recommended dose and allow a sufficient period of time for elimination of the drug prior to re-
administration (See CLINICAL PHARMACOLOGY and DOSAGE AND
ADMINISTRATION).
Hypersensitivity Reactions
Anaphylactoid and anaphylactic reactions with cardiovascular, respiratory and/or cutaneous
manifestations rarely resulting in death have occurred. The risk of hypersensitivity reactions is
higher in patients with a history of reaction to contrast media, bronchial asthma, or allergic
disorders. Hypersensitivity reactions can occur with or without prior exposure to GBCAs.
Have appropriately trained personnel administer MAGNEVIST in a facility that has immediate
availability of resuscitative equipment. If a hypersensitivity reaction occurs, stop MAGNEVIST
Injection and immediately begin appropriate therapy.
Observe closely patients with a history of drug reactions, allergy or other hypersensitivity
disorders, during and up to several hours after MAGNEVIST Injection.
Renal Failure
In patients with renal impairment, acute renal failure (acute kidney injury) requiring dialysis or
worsening renal function has occurred, mostly within 48 hrs of MAGNEVIST Injection. The
risk of acute renal failure is higher with increasing dose of contrast. Use the lowest possible dose,
evaluate renal function in patients with renal impairment, and allow sufficient time for contrast
elimination before re-administration. Elimination half-life in patients with mild or moderate
renal impairment is 3 to 4 hours. Elimination half-life in patients with severe renal impairment is
about 11 hours. MAGNEVIST is cleared by glomerular filtration and is dialyzable. After 3
dialysis sessions of 3 hours each, about 97% of the administered dose is eliminated from the
body; each dialysis session removes about 70% of the circulating drug (See CLINICAL
PHARMACOLOGY, Pharmacokinetics).
Injection Site Reactions
Skin and soft tissue necrosis, thrombosis, fasciitis, and compartment syndrome requiring surgical
intervention (e.g., compartment release or amputation) have occurred very rarely at the site of
contrast injection or the dosed limb. Total volume and rate of MAGNEVIST Injection,
extravasation of contrast agent, and patient susceptibility might contribute to these reactions.
Phlebitis and thrombophlebitis may be observed generally within 24 hours after MAGNEVIST
Injection and resolve with supportive treatment. Determine the patency and integrity of the
intravenous line before administration of MAGNEVIST Injection. Assessment of the dosed limb
for the development of injection site reactions is recommended.
Reference ID: 3391342
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Interference with Visualization of Lesions Visible with Non-Contrast MRI
As with any paramagnetic contrast agent, MAGNEVIST Injection might impair the visualization
of lesions seen on non-contrast MRI. Therefore, caution should be exercised when
MAGNEVIST MRI scans are interpreted without a companion non-contrast MRI scan.
Patient Counseling Information
Patients scheduled to receive MAGNEVIST Injection should be instructed to inform their
physician if they are pregnant, breastfeeding, or have a history of renal insufficiency, asthma or
allergic respiratory disorders. Additionally instruct patients to inform their physician if they:
• Have a history of kidney and/or liver disease, or
• Have recently received a GBCA.
GBCAs increase the risk of NSF among patients with impaired elimination of drugs. To counsel
patients at risk of NSF:
• Describe the clinical manifestation of NSF
• Describe procedures to screen for the detection of renal impairment
Instruct the patients to contact their physician if they develop signs or symptoms of NSF
following MAGNEVIST administration, such as burning, itching, swelling, scaling, hardening
and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble
moving, bending or straightening the arms, hands, legs or feet; pain in the hip bones or ribs; or
muscle weakness.
LABORATORY TEST FINDINGS
Transitory changes in serum iron, bilirubin and transaminase levels were observed in clinical
trials.
MAGNEVIST Injection does not interfere with serum and plasma calcium measurements
determined by colorimetric assays.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long term animal studies have not been performed to evaluate the carcinogenic potential of
gadopentetate dimeglumine.
A comprehensive battery of in vitro and in vivo studies in bacterial and mammalian systems
suggest that gadopentetate dimeglumine is not mutagenic or clastogenic and does not induce
unscheduled DNA repair in rat hepatocytes or cause cellular transformation of mouse embryo
fibroblasts. However, the drug did show some evidence of mutagenic potential in vivo in the
mouse dominant lethal assay at doses of 6 mmol/kg, but did not show any such potential in the
Reference ID: 3391342
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
mouse and dog micronucleus tests at intravenous doses of 9 mmol/kg and 2.5 mmol/kg,
respectively.
When administered intra-peritoneally to male and female rats daily prior to mating, during
mating and during embryonic development for up to 74 days (males) or 35 days (females),
gadopentetate caused a decrease in number of corpora lutea at the 0.1 mmol/kg dose level. After
daily dosing with 2.5 mmol/kg suppression of food consumption and body weight gain (males
and females) and a decrease in the weights of testes and epididymis were also observed.
In a separate experiment in rats, daily injections of gadopentetate dimeglumine over 16 days
caused spermatogenic cell atrophy at a dose level of 5 mmol/kg but not at a dose level of 2.5
mmol/kg. This atrophy was not reversed within a 16-day observation period following the
discontinuation of the drug.
Pregnancy
Category C
Gadopentetate dimeglumine retarded fetal development slightly when given intravenously for 10
consecutive days to pregnant rats at daily doses of 0.25, 0.75, and 1.25 mmol/kg (2.5, 7.5 and
12.5 times the human dose based on body weight) and when given intravenously for 13
consecutive days to pregnant rabbits at daily doses of 0.75 and 1.25 mmol/kg (7.5 and 12.5 times
the human dose respectively, based on body weight) but not at daily doses of 0.25 mmol/kg. No
congenital anomalies were noted in rats or rabbits.
Adequate and well controlled studies were not conducted in pregnant women. MAGNEVIST
Injection should be used during pregnancy only if the potential benefit justifies the potential risk
to the fetus.
Nursing Mothers
MAGNEVIST is excreted in human milk. MAGNEVIST Injection was administered
intravenously to 18 lactating women with normal renal function at a dose of 0.1 mmol/kg body
weight. In these women, less than 0.04% of the administered gadolinium was excreted into the
breast milk during the 24-hour period following dosing. Breast milk obtained during the 24 hours
following dosing revealed the average cumulative amount of gadolinium excreted in breast milk
was 0.57+/-0.71 micromoles. The amount transferred from a 70 kg woman (receiving 0.1
mmol/kg body weight) to an infant by breastfeeding over a period of 24 hrs translates into less
than 3 micromoles of gadolinium.
The overall duration of excretion of gadolinium into breast milk is unknown. The extent of the
absorption of MAGNEVIST Injection in infants and its effect on the breast-fed child remains
unknown.
Reference ID: 3391342
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pediatric Use
The use of MAGNEVIST in imaging the central nervous system, extracranial/extraspinal tissues,
and body have been established in the pediatric population from the ages of 2 to 16 years on the
basis of adequate and well controlled clinical trials in adults and safety studies in this pediatric
population. (See CLINICAL TRIALS for details.)
Safety and efficacy in the pediatric population under the age of 2 years have not been
established. MAGNEVIST is eliminated primarily by the kidney. In a study with pediatric
patients aged 2 months to < 2 years the pharmacokinetics (body weight-normalized clearance,
body weight-normalized distribution volume, and terminal half-life) of gadopentetate were
similar to adults. (See INDICATIONS and DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
Clinical Trial 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 to rates in the clinical trials
of another drug and may not reflect the rates observed in practice.
The mean age of the 1272 patients who received MAGNEVIST Injection in pre-market clinical
trials was 46.4 years (range 2 to 93 years). Of these patients, 55% (700) were male and 45%
(572) were female. Of the 1271 patients who received MAGNEVIST Injection and for whom
race was reported, 82.1% (1043) were Caucasian, 9.7% (123) were Black, 5.3% (67) were
Hispanic, 2.1% (27) were Oriental/Asian, and 0.9% (11) were other.
The most common adverse reaction was headache (4.8%). The majority of headaches were
transient and of mild to moderate severity. Other adverse reactions that occurred in ≥ 1% of
patients included: nausea (2.7%), injection site coldness/localized coldness (2.3%) and dizziness
(1%).
The following additional adverse reactions occurred in less than 1% of the patients:
General Disorders: Injection site reactions, including phlebitis, pain, localized warmth,
localized edema, and burning sensation; substernal chest pain, back pain, pyrexia, asthenia,
feeling cold, generalized warmth, fatigue, and chest tightness, and anaphylactoid reactions
characterized by cardiovascular, respiratory and/or cutaneous symptoms, such as dyspnea,
bronchospasm, and cough. (See WARNINGS AND PRECAUTIONS.)
Cardiovascular: Hypotension, hypertension, tachycardia, migraine, syncope, vasodilatation,
pallor.
Gastrointestinal: Abdominal discomfort, teeth pain, increased salivation, abdominal pain,
vomiting, diarrhea.
Reference ID: 3391342
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Nervous System: Agitation, anxiety, thirst, somnolence, diplopia, loss of consciousness,
convulsions (including grand mal), paresthesia.
Respiratory System: Throat irritation, rhinitis, sneezing.
Skin: Rash, sweating (hyperhidrosis), pruritus, urticaria (hives), facial edema.
Special Senses: Conjunctivitis, taste abnormality, dry mouth, lacrimation, eye irritation, eye
pain, ear pain.
Postmarketing Experience
The following additional adverse reactions have been identified during postmarketing use of
Magnevist. 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.
The most serious reactions were nephrogenic systemic fibrosis (see Boxed Warning) and acute
reactions including cardiac or respiratory arrest, anaphylactic shock, shock, respiratory distress,
and laryngeal edema. Life threatening and/or fatal adverse reactions have been reported. The
most frequently reported adverse reactions in the postmarketing experience were nausea,
vomiting, urticaria and rash.
General Disorders and Administration Site Conditions: Nephrogenic systemic fibrosis (see
Warnings and Precautions), body temperature decreased, tremor, shivering (chills).
Hypersensitivity Reactions: Anaphylactic/anaphylactoid reactions that may be fatal and include
cardiac or respiratory arrest, respiratory distress, cyanosis, laryngeal edema, laryngospasm,
pharyngeal edema, and angioedema (see Warnings and Precautions).
Delayed hypersensitivity reactions have been reported up to several hours after administration of
Magnevist.
Renal and Urinary: Acute renal failure, worsening renal impairment (see Warnings and
Precautions), urinary incontinence, urinary urgency.
Vascular: Thrombophlebitis, deep vein thrombophlebitis, compartment syndrome requiring
surgical intervention.
Cardiac: Cardiac arrest, heart rate decreased, arrhythmia.
Ear and Labyrinth Disorders: Hearing impaired.
Eye Disorders: Visual disturbance.
Musculoskeletal and Connective Tissue Disorder: Arthralgia.
Nervous System Disorders: Coma, parosmia, speech disorder.
Respiratory System: Respiratory arrest, pulmonary edema.
Skin: Erythema multiforme, pustules (rash pustular).
OVERDOSAGE
Systemic consequences associated with overdosage of MAGNEVIST Injection have not been
reported.
Reference ID: 3391342
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DOSAGE AND ADMINISTRATION
The recommended dosage of MAGNEVIST Injection is 0.2 mL/kg (0.1 mmol/kg) administered
intravenously, at a rate not to exceed 10 mL per 15 seconds. Dosing for patients in excess of 286
lbs has not been studied systematically.
DOSE AND DURATION OF MAGNEVIST INJECTION BY BODY WEIGHT
BODY WEIGHT
Total Volume, mL*
lb
kg
22
10
2
44
20
4
66
30
6
88
40
8
110
50
10
132
60
12
154
70
14
176
80
16
198
90
18
220
100
20
242
110
22
264
120
24
286
130
26
*Rate of Injection: 10 mL/15 sec
Drug Handling:
To ensure complete injection of the contrast medium, the injection should be followed by a 5-mL
normal saline flush. The imaging procedure should be completed within 1 hour of injection of
MAGNEVIST Injection.
As with other gadolinium contrast agents, MAGNEVIST Injection has not been established for
use in magnetic resonance angiography.
Parenteral products should be inspected visually for particulate matter and discoloration prior to
administration. Do not use the solution if it is discolored or particulate matter is present.
Any unused portion must be discarded in accordance with regulations dealing with the disposal
of such materials.
HOW SUPPLIED
MAGNEVIST Injection is a clear, colorless to slightly yellow solution containing 469.01 mg/
mL of gadopentetate dimeglumine. MAGNEVIST Injection is supplied in the following sizes:
5 mL single-dose vials, rubber stoppered, in individual cartons, Boxes of 20
NDC 50419-188-05
Reference ID: 3391342
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5 mL single-dose vials (RFID), rubber stoppered, in individual cartons,
Boxes of 20
NDC 50419-188-40
10 mL single-dose vials, rubber stoppered, in individual cartons,
Boxes of 20
NDC 50419-188-01
10 mL single-dose vials (RFID), rubber stoppered, in individual cartons,
Boxes of 20
NDC 50419-188-42
10 mL pre-filled disposable syringe,
Boxes of 5
NDC 50419-188-36
10 mL pre-filled disposable syringe (RFID),
Boxes of 5
NDC 50419-188-43
15 mL single-dose vials, rubber stoppered, in individual cartons,
Boxes of 20
NDC 50419-188-15
15 mL single-dose vials (RFID), rubber stoppered, in individual cartons,
Boxes of 20
NDC 50419-188-44
15 mL pre-filled disposable syringe,
Boxes of 5
NDC 50419-188-37
15 mL pre-filled disposable syringe (RFID),
Boxes of 5
NDC 50419-188-45
20 mL single-dose vials, rubber stoppered, in individual cartons,
Boxes of 20
NDC 50419-188-02
20 mL single-dose vials (RFID), rubber stoppered, in individual cartons,
Boxes of 20
NDC 50419-188-46
20 mL pre-filled disposable syringe,
Boxes of 5
NDC 50419-188-38
20 mL pre-filled disposable syringe (RFID),
Boxes of 5
NDC 50419-188-47
STORAGE
MAGNEVIST Injection should be stored at controlled room temperature, between 15-30° C (59
86° F) and protected from light. DO NOT FREEZE. Should freezing occur in the vial
MAGNEVIST Injection should be brought to room temperature before use. If allowed to stand at
room temperature for a minimum of 90 minutes, MAGNEVIST Injection should return to a
clear, colorless to slightly yellow solution. Before use, examine the product to assure that all
solids are redissolved and that the container and closure have not been damaged. Should solids
persist, discard vial.
Manufactured for:
Reference ID: 3391342
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
company logo
Manufactured in Germany
©2013, Bayer HealthCare Pharmaceuticals Inc., All Rights Reserved.
670301 US
July 2013
Reference ID: 3391342
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MAGNEVIST®
(brand of gadopentetate dimeglumine)
Injection
FOR INTRAVENOUS ADMINISTRATION
Pharmacy Bulk Package—Not For Direct Infusion
Rx only
WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)
Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with
impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic
information is essential and not available with non-contrasted MRI or other modalities. NSF
may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs.
• Do not administer MAGNEVIST to patients with:
∘ chronic, severe kidney disease (GFR < 30 mL/min/1.73m2), or
∘ acute kidney injury (see CONTRAINDICATIONS).
• Screen patients for acute kidney injury and other conditions that may reduce renal function.
For patients at risk for chronically reduced renal function (for example, age >60 years,
hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory
testing.
Do not exceed the recommended MAGNEVIST dose and allow a sufficient period of time for
elimination of the drug from the body prior to any re-administration (see WARNINGS AND
PRECAUTIONS).
DESCRIPTION
MAGNEVIST® (brand of gadopentetate dimeglumine) Injection is the N-methylglucamine salt
of the gadolinium complex of diethylenetriamine pentaacetic acid, and is an injectable contrast
medium for magnetic resonance imaging (MRI). MAGNEVIST Injection is provided as a sterile,
clear, colorless to slightly yellow aqueous solution for intravenous injection.
MAGNEVIST Injection is a 0.5- mol/L solution of 1-deoxy-1-(methylamino)-D-glucitol
dihydrogen [N,N-bis[2-[bis(carboxymethyl)amino]ethyl]- glycinato (5-)]gadolinate(2--) (2:1)
with a molecular weight of 938, an empirical formula of C28H54GdN5O20, and has the following
structural formula: structural formula
July, 2013
Reference ID: 3391342
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Each mL of MAGNEVIST Injection contains 469.01 mg gadopentetate dimeglumine, 0.99 mg
meglumine, 0.40 mg diethylenetriamine pentaacetic acid and water for injection. MAGNEVIST
Injection contains no antimicrobial preservative.
MAGNEVIST Injection has a pH of 6.5 to 8.0. Pertinent physicochemical data are noted below:
PARAMETER
Osmolality (mOsmol/kg water)
at 37° C
1,960
Viscosity (CP)
at 20° C
4.9
at 37° C
2.9
Density (g/mL)
at 25° C
1.195
Specific Gravity
at 25° C
1.208
Octanol: H2O Coefficient
at 25° C, pH7 log Pow = - 5.4
MAGNEVIST Injection has an osmolality 6.9 times that of plasma which has an osmolality of
285 mOsmol/kg water. MAGNEVIST Injection is hypertonic under conditions of use.
CLINICAL PHARMACOLOGY
Pharmacokinetics
The pharmacokinetics of intravenously administered gadopentetate dimeglumine in normal
subjects conforms to a two compartment open-model with mean distribution and elimination
half-lives (reported as mean ± SD) of about 0.2 ± 0.13 hours and 1.6 ± 0.13 hours, respectively.
Upon injection, the meglumine salt is completely dissociated from the gadopentetate
dimeglumine complex. Gadopentetate is exclusively eliminated in the urine with 83 ± 14%
(mean ± SD) of the dose excreted within 6 hours and 91 ± 13% (mean ± SD) by 24 hours, post-
injection. There was no detectable biotransformation or decomposition of gadopentetate
dimeglumine.
The renal and plasma clearance rates (1.76 ± 0.39 mL/min/kg and 1.94 ± 0.28 mL/min/kg,
respectively) of gadopentetate are essentially identical, indicating no alteration in elimination
kinetics on passage through the kidneys and that the drug is essentially cleared through the
kidney. The volume of distribution (266 ± 43 mL/kg) is equal to that of extracellular water and
clearance is similar to that of substances which are subject to glomerular filtration.
In vitro laboratory results indicate that gadopentetate does not bind to human plasma protein. In
vivo protein binding studies have not been done.
Renal Impairment
Gadopentetate dimeglumine is excreted via the kidneys, even in patients with impaired renal
function. In patients with impaired renal function, the serum half-life of gadopentetate
July, 2013
Reference ID: 3391342
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
dimeglumine is prolonged. Mean serum elimination half-lives of a single intravenous dose of
gadopentetate dimeglumine (0.1 mmol/kg) were 2.6 ± 1.2 h, 4.2 ± 2.0 h and 10.8 ± 6.9 h, for
mildly (creatinine clearance, CLCR = 60 to < 90 mL/min), moderately (CLCR = 30 to < 60
mL/min) and severely (CLCR = < 30 mL/min) impaired patients, respectively, as compared with
1.6 ± 0.1 h in healthy subjects.
Pharmacodynamics
Gadopentetate dimeglumine is a paramagnetic agent and, as such, it develops a magnetic
moment when placed in a magnetic field. The relatively large magnetic moment produced by the
paramagnetic agent results in a relatively large local magnetic field, which can enhance the
relaxation rates of water protons in the vicinity of the paramagnetic agent.
In magnetic resonance imaging (MRI), visualization of normal and pathological brain tissue
depends in part on variations in the radiofrequency signal intensity that occur with 1) changes in
proton density; 2) alteration of the spin-lattice or longitudinal relaxation time (T1); and 3)
variation of the spin-spin or transverse relaxation time (T2). When placed in a magnetic field,
gadopentetate dimeglumine decreases the T1 and T2 relaxation time in tissues where it
accumulates. At usual doses the effect is primarily on the T1 relaxation time.
Gadopentetate dimeglumine does not cross the intact blood-brain barrier and, therefore, does not
accumulate in normal brain or in lesions that do not have an abnormal blood-brain barrier, e.g.,
cysts, mature post-operative scars, etc. However, disruption of the blood-brain barrier or
abnormal vascularity allows accumulation of gadopentetate dimeglumine in lesions such as
neoplasms, abscesses, and subacute infarcts. The pharmacokinetic parameters of MAGNEVIST
in various lesions are not known.
CLINICAL TRIALS
MAGNEVIST Injection was administered to 1272 patients in open label controlled clinical
studies. The mean age of these patients was 46.4 years (range 2 to 93 years). Of these patients,
55% (700) were male and 45% (572) were female. Of the 1271 patients who received
MAGNEVIST Injection and for whom race was reported, 82.1% (1043) were Caucasian, 9.7%
(123) were Black, 5.3% (67) were Hispanic, 2.1% (27) were Oriental/Asian, and 0.9% (11) were
other. Of the 1272 patients, 550 patients were evaluated in blinded reader studies. These
evaluated the use of contrast enhancement in magnetic resonance imaging of lesions in the head
and neck, brain, spine and associated tissues, and body (excluding the heart). Of the 550 patients,
all patients had a reason for an MRI and efficacy assessments were based on pre-and post-
MAGNEVIST injection film quality, film contrast, lesion configuration (border, size, and
location), and the number of lesions. The protocols did not include systematic verification of
specific diseases or histopathologic confirmation of findings.
July, 2013
Reference ID: 3391342
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Of the above 550 patients, 97 patients received 0.1 mmol/kg MAGNEVIST Injection IV in two
clinical trials of MAGNEVIST MRI contrast enhancement for body imaging. Of these 97, 68 had
MRIs of the internal organs/structures of the abdomen or thorax (excluding the heart); 8 had
breast images and 22 had images of appendages. The results of MRIs before and after
MAGNEVIST use were compared blindly. Overall additional lesions were identified in 22/97
(23%) of the patients after MAGNEVIST Injection. The mean number of lesions identified
before (1.49/patient) and after MAGNEVIST (1.75/patient) were similar. Seven (8%) of the
patients had lesions seen before MAGNEVIST that were not seen after MAGNEVIST. Overall,
after MAGNEVIST Injection, 41% of the images had a higher contrast score than before
injection; and 18% of the images had a higher contrast score before MAGNEVIST Injection than
after MAGNEVIST Injection. MAGNEVIST MRI of the 8 patients with breast images were not
systematically compared to the results to mammography, breast biopsy or other modalities. In
the 22 patients with appendage images (e.g., muscle, bone and intraarticular structures),
MAGNEVIST MRI was not systematically evaluated to determine the effects of contrast
biodistribution in these different areas.
Of the above 550 patients, 66 patients received MAGNEVIST 0.1 mmol/kg IV in clinical trials
of MAGNEVIST MRl contrast enhancement of lesions in the head and neck. A total of 66 MRI
images were evaluated blindly by comparing each pair of MRI images, before and after
MAGNEVIST Injection. In these paired images, 56/66 (85%) had greater enhancement after
MAGNEVIST and 40/66 (61%) had better lesion configuration or border delineation after
MAGNEVIST. Overall, there was better contrast after MAGNEVIST in 55% of the images,
comparable enhancement in 44 (36%) before and after MAGNEVIST, and better enhancement in
9% without MAGNEVIST.
In the studies of the brain and spinal cord, MAGNEVIST 0.1 mmol/kg IV provided contrast
enhancement in lesions with an abnormal blood brain barrier.
In two studies, a total of 108 patients were evaluated to compare the dose response effects of 0.1
mmol/kg and 0.3 mmol/kg of MAGNEVIST in CNS MRI. Both dosing regimens had similar
imaging and general safety profiles; however, the 0.3 mmoL/kg dose did not provide additional
benefit to the final diagnosis (defined as number of lesions, location and characterization).
INDICATIONS AND USAGE
Central Nervous System
MAGNEVIST Injection is indicated for use with magnetic resonance imaging (MRI) in adults,
and pediatric patients (2 years of age and older) to visualize lesions with abnormal vascularity in
the brain (intracranial lesions), spine and associated tissues. MAGNEVIST Injection has been
shown to facilitate visualization of intracranial lesions including but not limited to tumors.
July, 2013
Reference ID: 3391342
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Extracranial/Extraspinal Tissues
MAGNEVIST is indicated for use with MRI in adults and pediatric patients (2 years of age and
older) to facilitate the visualization of lesions with abnormal vascularity in the head and neck.
Body
MAGNEVIST Injection is indicated for use in MRI in adults and pediatric patients (2 years of
age and older) to facilitate the visualization of lesions with abnormal vascularity in the body
(excluding the heart).
CONTRAINDICATIONS
MAGNEVIST is contraindicated in patients with:
• Chronic, severe kidney disease (glomerular filtration rate, GFR < 30 mL/min/1.73m2), or
• Acute kidney injury, or
• History of severe hypersensitivity reactions to MAGNEVIST.
WARNINGS AND PRECAUTIONS
Nephrogenic Systemic Fibrosis (NSF)
Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis
(NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these
patients unless the diagnostic information is essential and not available with non-contrast
enhanced MRI or other modalities. The GBCA-associated NSF risk appears highest for patients
with chronic, severe kidney disease (GFR < 30 mL/min/1.73m2) as well as patients with acute
kidney injury. Do not administer MAGNEVIST to these patients. The risk appears lower for
patients with chronic, moderate kidney disease (GFR 30- 59 mL/min/1.73m2) and little, if any,
for patients with chronic, mild kidney disease (GFR 60- 89 mL/min/1.73m2). NSF may result in
fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis
of NSF following MAGNEVIST administration to Bayer Healthcare (1-888-842-2937) or FDA
(1-800-FDA-1088 or www.fda.gov/medwatch).
Screen patients for acute kidney injury and other conditions that may reduce renal function.
Features of acute kidney injury consist of rapid (over hours to days) and usually reversible
decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-
induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess
renal function in the setting of acute kidney injury. For patients at risk for chronically reduced
renal function (for example, age > 60 years, diabetes mellitus or chronic hypertension), estimate
the GFR through laboratory testing.
Among the factors that may increase the risk for NSF are repeated or higher than recommended
doses of a GBCA and degree of renal impairment at the time of exposure. Record the specific
July, 2013
Reference ID: 3391342
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
GBCA and the dose administered to a patient. When administering MAGNEVIST, do not exceed
the recommended dose and allow a sufficient period of time for elimination of the drug prior to
re-administration (See CLINICAL PHARMACOLOGY and DOSAGE AND
ADMINISTRATION).
Hypersensitivity Reactions
Anaphylactoid and anaphylactic reactions with cardiovascular, respiratory and/or cutaneous
manifestations rarely resulting in death have occurred. The risk of hypersensitivity reactions is
higher in patients with a history of reaction to contrast media, bronchial asthma, or allergic
disorders. Hypersensitivity reactions can occur with or without prior exposure to GBCAs.
Have appropriately trained personnel administer MAGNEVIST in a facility that has immediate
availability of resuscitative equipment. If a hypersensitivity reaction occurs, stop MAGNEVIST
Injection and immediately begin appropriate therapy.
Observe closely patients with a history of drug reactions, allergy or other hypersensitivity
disorders, during and up to several hours after MAGNEVIST Injection.
Renal Failure
In patients with renal impairment, acute renal failure (acute kidney injury) requiring dialysis or
worsening renal function has occurred, mostly within 48 hrs of MAGNEVIST Injection. The
risk of acute renal failure is higher with increasing dose of contrast. Use the lowest possible dose,
evaluate renal function in patients with renal impairment, and allow sufficient time for contrast
elimination before re-administration. Elimination half-life in patients with mild or moderate
renal impairment is 3 to 4 hours. Elimination half-life in patients with severe renal impairment is
about 11 hours. MAGNEVIST is cleared by glomerular filtration and is dialyzable. After 3
dialysis sessions of 3 hours each, about 97% of the administered dose is eliminated from the
body; each dialysis session removes about 70% of the circulating drug (See CLINICAL
PHARMACOLOGY, Pharmacokinetics).
Injection Site Reactions
Skin and soft tissue necrosis, thrombosis, fasciitis, and compartment syndrome requiring surgical
intervention (e.g. compartment release or amputation) have occurred very rarely at the site of
contrast injection or the dosed limb. Total volume and rate of MAGNEVIST Injection,
extravasation of contrast agent, and patient susceptibility might contribute to these reactions.
Phlebitis and thrombophlebitis may be observed generally within 24 hours after MAGNEVIST
Injection and resolve with supportive treatment. Determine the patency and integrity of the
intravenous line before administration of MAGNEVIST Injection. Assessment of the dosed limb
for the development of injection site reactions is recommended.
July, 2013
Reference ID: 3391342
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Interference with Visualization of Lesions Visible with Non-Contrast MRI
As with any paramagnetic contrast agent, MAGNEVIST Injection might impair the visualization
of lesions seen on non-contrast MRI. Therefore, caution should be exercised when
MAGNEVIST MRI scans are interpreted without a companion non-contrast MRI scan.
Patient Counseling Information
Patients scheduled to receive MAGNEVIST Injection should be instructed to inform their
physician if they are pregnant, breastfeeding, or have a history of renal insufficiency, asthma or
allergic respiratory disorders. Additionally instruct patients to inform their physician if they:
• Have a history of kidney and/or liver disease, or
• Have recently received a GBCA.
GBCAs increase the risk of NSF among patients with impaired elimination of drugs. To counsel
patients at risk of NSF:
• Describe the clinical manifestation of NSF
• Describe procedures to screen for the detection of renal impairment
Instruct the patients to contact their physician if they develop signs or symptoms of NSF
following MAGNEVIST administration, such as burning, itching, swelling, scaling, hardening
and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble
moving, bending or straightening the arms, hands, legs or feet; pain in the hip bones or ribs; or
muscle weakness.
LABORATORY TEST FINDINGS
Transitory changes in serum iron, bilirubin and transaminase levels were observed in clinical
trials.
MAGNEVIST Injection does not interfere with serum and plasma calcium measurements
determined by colorimetric assays.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long term animal studies have not been performed to evaluate the carcinogenic potential of
gadopentetate dimeglumine.
A comprehensive battery of in vitro and in vivo studies in bacterial and mammalian systems
suggest that gadopentetate dimeglumine is not mutagenic or clastogenic and does not induce
unscheduled DNA repair in rat hepatocytes or cause cellular transformation of mouse embryo
fibroblasts. However, the drug did show some evidence of mutagenic potential in vivo in the
mouse dominant lethal assay at doses of 6 mmol/kg, but did not show any such potential in the
July, 2013
Reference ID: 3391342
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
mouse and dog micronucleus tests at intravenous doses of 9 mmol/kg and 2.5 mmol/kg,
respectively.
When administered intra-peritoneally to male and female rats daily prior to mating, during
mating and during embryonic development for up to 74 days (males) or 35 days (females),
gadopentetate caused a decrease in number of corpora lutea at the 0.1 mmol/kg dose level. After
daily dosing with 2.5 mmol/kg suppression of food consumption and body weight gain (males
and females) and a decrease in the weights of testes and epididymis were also observed.
In a separate experiment in rats, daily injections of gadopentetate dimeglumine over 16 days
caused spermatogenic cell atrophy at a dose level of 5 mmol/kg but not at a dose level of 2.5
mmol/kg. This atrophy was not reversed within a 16-day observation period following the
discontinuation of the drug.
Pregnancy
Category C
Gadopentetate dimeglumine retarded fetal development slightly when given intravenously for 10
consecutive days to pregnant rats at daily doses of 0.25, 0.75, and 1.25 mmol/kg (2.5, 7.5 and
12.5 times the human dose based on body weight) and when given intravenously for 13
consecutive days to pregnant rabbits at daily doses of 0.75 and 1.25 mmol/kg (7.5 and 12.5 times
the human dose respectively, based on body weight) but not at daily doses of 0.25 mmol/kg. No
congenital anomalies were noted in rats or rabbits.
Adequate and well controlled studies were not conducted in pregnant women. MAGNEVIST
Injection should be used during pregnancy only if the potential benefit justifies the potential risk
to the fetus.
Nursing Mothers
MAGNEVIST is excreted in human milk. MAGNEVIST Injection was administered
intravenously to 18 lactating women with normal renal function at a dose of 0.1 mmol/kg body
weight. In these women, less than 0.04% of the administered gadolinium was excreted into the
breast milk during the 24-hour period following dosing. Breast milk obtained during the 24 hours
following dosing revealed the average cumulative amount of gadolinium excreted in breast milk
was 0.57+/-0.71 micromoles. The amount transferred from a 70 kg woman (receiving 0.1
mmol/kg body weight) to an infant by breastfeeding over a period of 24 hrs translates into less
than 3 micromoles of gadolinium.
The overall duration of excretion of gadolinium into breast milk is unknown. The extent of the
absorption of MAGNEVIST Injection in infants and its effect on the breast-fed child remains
unknown.
July, 2013
Reference ID: 3391342
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pediatric Use
The use of MAGNEVIST in imaging the central nervous system, extracranial/extraspinal tissues,
and body have been established in the pediatric population from the ages of 2 to 16 years on the
basis of adequate and well controlled clinical trials in adults and safety studies in this pediatric
population. (See CLINICAL TRIALS for details.)
Safety and efficacy in the pediatric population under the age of 2 years have not been
established. MAGNEVIST is eliminated primarily by the kidney. In a study with pediatric
patients aged 2 months to < 2 years the pharmacokinetics (body weight-normalized clearance,
body weight-normalized distribution volume, and terminal half-life) of gadopentetate were
similar to adults. (See INDICATIONS and DOSAGE AND ADMINISTRATION.)
ADVERSE REACTIONS
Clinical Trial 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 to rates in the clinical trials
of another drug and may not reflect the rates observed in practice.
The mean age of the 1272 patients who received MAGNEVIST Injection in pre-market clinical
trials was 46.4 years (range 2 to 93 years). Of these patients, 55% (700) were male and 45%
(572) were female. Of the 1271 patients who received MAGNEVIST Injection and for whom
race was reported, 82.1% (1043) were Caucasian, 9.7% (123) were Black, 5.3% (67) were
Hispanic, 2.1% (27) were Oriental/Asian, and 0.9% (11) were other.
The most common adverse reaction was headache (4.8%). The majority of headaches were
transient and of mild to moderate severity. Other adverse reactions that occurred in ≥ 1% of
patients included: nausea (2.7%), injection site coldness/localized coldness (2.3%) and dizziness
(1%).
The following additional adverse reactions occurred in less than 1% of the patients:
General Disorders: Injection site reactions, including phlebitis, pain, localized warmth,
localized edema, and burning sensation; substernal chest pain, back pain, pyrexia, asthenia,
feeling cold, generalized warmth, fatigue, and chest tightness, and anaphylactoid reactions
characterized by cardiovascular, respiratory and/or cutaneous symptoms, such as dyspnea,
bronchospasm, and cough. (See WARNINGS AND PRECAUTIONS.)
Cardiovascular: Hypotension, hypertension, tachycardia, migraine, syncope, vasodilatation,
pallor.
Gastrointestinal: Abdominal discomfort, teeth pain, increased salivation, abdominal pain,
vomiting, diarrhea.
July, 2013
Reference ID: 3391342
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Nervous System: Agitation, anxiety, thirst, somnolence, diplopia, loss of consciousness,
convulsions (including grand mal), paresthesia.
Respiratory System: Throat irritation, rhinitis, sneezing.
Skin: Rash, sweating (hyperhidrosis), pruritus, urticaria (hives), facial edema.
Special Senses: Conjunctivitis, taste abnormality, dry mouth, lacrimation, eye irritation, eye
pain, ear pain.
Postmarketing Experience
The following additional adverse reactions have been identified during postmarketing use of
MAGNEVIST. 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.
The most serious reactions were nephrogenic systemic fibrosis (see Boxed Warning) and acute
reactions including cardiac or respiratory arrest, anaphylactic shock, shock, respiratory distress,
and laryngeal edema. Life threatening and/or fatal adverse reactions have been reported. The
most frequently reported adverse reactions in the postmarketing experience were nausea,
vomiting, urticaria and rash.
General Disorders and Administration Site Conditions: Nephrogenic systemic fibrosis (see
WARNINGS AND PRECAUTIONS), body temperature decreased, tremor, shivering (chills).
Hypersensitivity Reactions: Anaphylactic/anaphylactoid reactions that may be fatal and include
cardiac or respiratory arrest, respiratory distress, cyanosis, laryngeal edema, laryngospasm,
pharyngeal edema, and angioedema (see WARNINGS AND PRECAUTIONS).
Delayed hypersensitivity reactions have been reported up to several hours after administration of
MAGNEVIST.
Renal and Urinary: Acute renal failure, worsening renal impairment (see WARNINGS AND
PRECAUTIONS), urinary incontinence, urinary urgency.
Vascular: Thrombophlebitis, deep vein thrombophlebitis, compartment syndrome requiring
surgical intervention.
Cardiac: Cardiac arrest, heart rate decreased, arrhythmia.
Ear and Labyrinth Disorders: Hearing impaired.
Eye Disorders: Visual disturbance.
Musculoskeletal and Connective Tissue Disorder: Arthralgia.
Nervous System Disorders: Coma, parosmia, speech disorder.
Respiratory System Disorders: Respiratory arrest, pulmonary edema.
Skin: Erythema multiforme, pustules (rash pustular).
OVERDOSAGE
Systemic consequences associated with overdosage of MAGNEVIST Injection have not been
reported.
July, 2013
Reference ID: 3391342
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DOSAGE AND ADMINISTRATION
The recommended dosage of MAGNEVIST Injection is 0.2 mL/kg (0.1 mmol/kg) administered
intravenously, at a rate not to exceed 10 mL per 15 seconds. Dosing for patients in excess of 286
lbs has not been studied systematically.
DOSE AND DURATION OF MAGNEVIST INJECTION BY BODY WEIGHT
BODY WEIGHT
Total Volume, mL*
lb
kg
22
10
2
44
20
4
66
30
6
88
40
8
110
50
10
132
60
12
154
70
14
176
80
16
198
90
18
220
100
20
242
110
22
264
120
24
286
130
26
*Rate of Injection: 10 mL/15 sec
Drug Handling:
To ensure complete injection of the contrast medium, the injection should be followed by a 5-mL
normal saline flush. The imaging procedure should be completed within 1 hour of injection of
MAGNEVIST Injection.
As with other gadolinium contrast agents, MAGNEVIST Injection has not been established for
use in magnetic resonance angiography.
Parenteral products should be inspected visually for particulate matter and discoloration prior to
administration. Do not use the solution if it is discolored or particulate matter is present.
Pharmacy Bulk Package Preparation: NOT FOR DIRECT INFUSION
The Pharmacy Bulk Package is used as a multiple dose container with an appropriate transfer
device for filling empty sterile syringes.
a) The transfer of MAGNEVIST Injection from the Pharmacy Bulk Package must be performed
in an aseptic work area, such as a laminar flow hood, using aseptic technique.
July, 2013
Reference ID: 3391342
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
b) Once the Pharmacy Bulk Package is punctured, it should not be removed from the aseptic
work area during the entire 24 hour period of use.
c) The contents of the Pharmacy Bulk Package after initial puncture should be used within 24
hours.
d) Any unused MAGNEVIST Injection must be discarded 24 hours after the initial puncture of
the bulk package.
IV tubing and syringes used to administer MAGNEVIST Injection must be discarded at the
conclusion of the radiological examination.
Any unused portion must be discarded in accordance with regulations dealing with the disposal
of such materials.
HOW SUPPLIED
MAGNEVIST Injection is a clear, colorless to slightly yellow solution containing 469.01 mg/mL
of gadopentetate dimeglumine. MAGNEVIST Injection is supplied in the following sizes:
50 mL Pharmacy Bulk Package, rubber stoppered,
10 per box
NDC 50419-188-58
50 mL Pharmacy Bulk Package (RFID), rubber stoppered,
10 per box
NDC 50419-188-48
100 mL Pharmacy Bulk Package, rubber stoppered,
10 per box
NDC 50419-188-11
100 mL Pharmacy Bulk Package (RFID), rubber stoppered,
10 per box
NDC 50419-188-49
STORAGE
MAGNEVIST Injection should be stored at controlled room temperature, between 15–30° C
(59–86° F) and protected from light. DO NOT FREEZE. Should freezing occur in the bottle,
MAGNEVIST Injection should be brought to room temperature before use. If allowed to stand at
room temperature for a minimum of 90 minutes, MAGNEVIST Injection should return to a
clear, colorless to slightly yellow solution. Before use, examine the product to assure that all
solids are redissolved and that the container and closure have not been damaged. Should solids
persist, discard bottle.
Manufactured for:
company logo
July, 2013
Reference ID: 3391342
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
©2013, Bayer HealthCare Pharmaceuticals Inc., All Rights Reserved.
670310x US
May 2013
July, 2013
Reference ID: 3391342
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:31.071086
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019596s056,021037s029lbl.pdf', 'application_number': 19596, 'submission_type': 'SUPPL ', 'submission_number': 56}
|
11,559
|
NDA 19-600/S-006 & S-009
Page 3
OXSORALEN-ULTRA
CAPSULES
(Methoxsalen Capsules, USP, 10 mg)
Rx ONLY
CAUTION: METHOXSALEN IS A POTENT DRUG. READ ENTIRE BROCHURE PRIOR TO PRESCRIBING
OR DISPENSING THIS MEDICATION.
Methoxsalen with UV radiation should be used only by physicians who have special competence in the
diagnosis and treatment of psoriasis and who have special training and experience in photochemotherapy. The
use of Psoralen and ultraviolent radiation therapy should be under constant supervision of such a physician.
For the treatment of patients with psoriasis, photochemotherapy should be restricted to patients with severe,
recalcitrant, disabling psoriasis which is not adequately responsive to other forms of therapy, and only when
the diagnosis is certain. Because of the possibilities of ocular damage, aging of the skin, and skin cancer
(including melanoma), the patient should be fully informed by the physician of the risks inherent in this
therapy.
CAUTION: Oxsoralen-Ultra (Methoxsalen Soft Gelatin Capsules should not be used interchangeably
with regular Oxsoralen or 8-MOP® (Methoxsalen Hard Gelatin Capsules). This new dosage form of
methoxsalen exhibits significantly greater bioavailability and earlier photosensitixation onset time than
previous methoxsalen dosage forms. Patient should be treated in accordance with the dosimetry
specifically recommended for this product. The minimum phototoxic dose (MPD) and phototoxic peak
time after drug administration prior to onset of photochemotherapy with tis dosage form should be
determined.
I. DESCRIPTION
Oxsoralen-Ultra (methoxsalen, 8-methoxypsoralen) Capsules, 10 mg. Methoxsalen is a naturally occurring
photoactive substance found in the seeds of the Ammi majus (Umbelliferae) plant and in the roots of Heracleum
Candicans. It belongs to a group of compounds known as psoralens, or furocoumarins. The chemical name of
methoxsalen is 9-methoxy-7H-furo [3,2-g] [1] benzopyran-7-one; it has the following structure:
II. CLINICAL PHARMACOLOGY
The combination treatment regimen of psoralen (P) and ultraviolet radiation of 320-400 nm wavelength commonly
referred to as UVA is known by the acronym, PUVA. Skin reactivity to UVA (320–400 nm) radiation is markedly
enhanced by the ingestion of methoxsalen. In a well controlled bioavailability study, Oxsoralen-Ultra Capsules
reached peak drug levels in the blood of test subjects between 0.5 and 4 hours (Mean = 1.8 hours) as compared to
between 1.5 and 6 hours (Mean = 3.0 hours) for regular Oxsoralen when administered with 8 ounces of milk. Peak
drug levels were 2 to 3 fold greater when the overall extent of drug absorption was approximately two fold greater
for Oxsoralen-Ultra Capsules as compared to regular Oxsoralen Capsules. Detectable methoxsalen levels were
observed up to 12 hours post dose. The drug half-life is approximately 2 hours. Photosensitivity studies
demonstrate a shorter time of peak photosensitivity of 1.5 to 2.1 hours vs. 3.9 to 4.25 hours for regular Oxsoralen
capsules. In addition, the mean minimal erythema dose (MED), J/cm2, for the Oxsoralen-Ultra Capsules is
substantially less than that required for regular Oxsoralen Capsules (Levins et al., 1984 and private
communication1).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 4
Methoxsalen is reversibly bound to serum albumin and is also preferentially taken up by epidermal cells (Artuc et
al., 19792). At a dose which is six times larger than that used in humans, it induces mixed function oxidases in the
liver of mice (Mandula et al., 19783). In both mice and man, methoxsalen is rapidly metabolized. Approximately
95% of the drug is excreted as a series of metabolites in the urine within 24 hours (Pathak et al., 19774). The exact
mechanism of action of methoxsalen with the epidermal melanocytes and keratinocytes is not known. The best
known biochemical reaction of methoxsalen is with DNA. Methoxsalen, upon photoactivation, conjugates and
forms covalent bonds with DNA which leads to the formation of both monofunctional (addition to a single strand of
DNA) and bifunctional (crosslinking of psoralen to both strands of DNA) adducts (Dall’ Acqua et al., 19715; Cole,
19706; Musajo et al., 19747; Dall’ Acqua et al., 19798). Reactions with proteins have also been described
(Yoshikawa, et al., 19799).
Methoxsalen acts as a photosensitizer. Administration of the drug and subsequent exposure to UVA can lead to cell
injury. Orally administered methoxsalen reaches the skin via the blood and UVA penetrates well into the skin. If
sufficient cell injury occurs in the skin, an inflammatory reaction occurs. The most obvious manifestation of this
reaction is delayed erythema, which may not begin for several hours and peaks at 48-72 hours. The inflammation is
followed, over several days to weeks, by repair which is manifested by increased melanization of the epidermis and
thickening of the stratum corneum. The mechanisms of therapy are not known. In the treatment of psoriasis, the
mechanism is most often assumed to be DNA photodamage and resulting decrease in cell proliferation but other
vascular, leukocyte, or cell regulatory mechanisms may also be playing some role. Psoriasis is a hyper-proliferative
disorder and other agents known to be therapeutic for psoriasis are known to inhibit DNA synthesis
III. INDICATIONS AND USAGE
Photochemotherapy (Methoxsalen with long wave UVA radiation) is indicated for the symptomatic control of
severe, recalcitrant, disabling psoriasis not adequately responsive to other forms of therapy and when the
diagnosis has been supported by biopsy. Methoxsalen is intended to be administered only in conjunction with a
schedule of controlled doses of long wave ultraviolet radiation.
IV. CONTRAINDICATIONS
A. Patients exhibiting idiosyncratic reactions to psoralen compounds.
B. Patients possessing a specific history of light sensitive disease states should not initiate methoxsalen
therapy except under special circumstances. Diseases associated with photosensitivity include lupus
erythematosus, porphyria cutanea tarda, erythropoietic protoporphyria, variegate porphyria, xeroderma
pigmentosum, and albinism.
C. Patients with melanoma or with a history of melanoma.
D. Patients with invasive squamous cell carcinomas.
E. Patients with aphakia, because of the significantly increased risk of retinal damage due to the absence of
lenses.
V. WARNINGS-GENERAL
A. SIN BURNING: Serious burns from either UVA or sunlight (even through window glass) can result if the
recommended dosage of the drug and/or exposure schedules are exceeded.
B. CARCINOGENICITY:
1. ANIMAL STUDIES: Topical or intraperitoneal methoxsalen has been reported to be a potent
photocarcinogen in albino mice and hairless mice (Hakim et al., 196010). However, methoxsalen given by
the oral route to Swiss albino mice suggests this agent exerts a protective effect against ultraviolet
carcinogenesis; mice given 8-methoxypsoralen in their diet showed 38% ear tumors 180 days after the start
of ultraviolet therapy compared to 62% for controls (O’Neal et al., 195711).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 5
2. HUMAN STUDIES: A 5.7 year prospective study of 1380 psoriasis patients treated with oral
methoxsalen and ultraviolet A photochemotherapy (PUVA) demonstrated that the risk of cutaneous
squamous-cell carcinoma developing at least 22 months following the first PUVA exposure was
approximately 12.8 times higher in the high dose patients than in the low dose patients (Stern et al., 197912,
Stern et al., 198013, and Stern et al., 198414). The substantial dose-dependent increase was observed in
patients with neither a prior history of skin cancer nor significant exposure to cutaneous carcinogens.
Reduction in PUVA dosage significantly reduces the risk. No substantial dose related increase was noted
for basal cell carcinoma according to Stern et al., 198414. Increases appear greatest in patients who have
pre-PUVA exposure to 1) prolonged tar and UVB treatment, 2) ionizing radiation, or 3) arsenic.
Roenigk et al., 198015, studied 690 patients for up to 4 years and found no increase in the risk of non-
melanoma skin cancer, although patients in this cohort had significantly less exposure to PUVA than in the
Stern et al. study. Recent analysis of new data in the Stern et al cohort (Stern et al., 199716) has shown that
these patients have an elevated relative risk of contracting melanoma. The relative risk for melanoma in
these patients was 2.3 (95 percent confidence interval 1.1 to 4.1). The risk is particularly higher in those
patients who have received more than 250 PUVA treatments and in those whose treatment has spanned
greater than 15 years earlier. These observations indicate the need for monitoring of PUVA patients for
skin tumors throughout their lives.
In a study in Indian patients treated for 4 years for vitiligo, 12 percent developed keratoses, but not
cancer, in the depigmented, vitiliginous areas (Mosher, 198017). Clinically, the keratoses were keratotic
papules, actinic keratosis-like macules, nonscaling dome-shaped papules, and lichenoid porokeratotic-like
papules.
C. CATARACTOGENICITY:
1. ANIMAL STUDIES: Exposure to large doses of UVA causes cataracts in animals, and this effect is
enhanced by the administration of methoxsalen (Cloud et al., 196018; Cloud et al., 196119 Freeman et al.,
196920).
2. HUMAN STUDIES: It has been found that the concentration of methoxsalen in the lens is proportional
to the serum level. If the lens is exposed to UVA during the time methoxsalen is present in the lens,
photochemical action may lead to irreversible binding of methoxsalen to proteins and the DNA components
of the lens (Lerman et al., 198021). However, if the lens is shielded from UVA, the methoxsalen will
diffuse out of the lens in a 24 hour period (Lerman et al., 198021). Patients should be told emphatically to
wear UVA absorbing, wrap-around sunglasses for the twenty-four (24) hour period following ingestion of
methoxsalen whether exposed to direct or indirect sunlight in the open or through a window glass.
Among patients using proper eye protection, there is no evidence for a significantly increased risk of
cataracts in association with PUVA therapy (Stern et al., 197912). Thirty-five of 1380 patients have
developed cataracts in the five years since their first PUVA treatment. This incidence is comparable to that
expected in a population of this size and age distribution. No relationship between PUVA dose and
cataract risk in this group has been noted.
D. ACTINIC DEGENERATION: Exposure to sunlight and/or ultraviolet radiation may result in “premature
aging” of the skin.
E. BASAL CELL CARCINOMAS: Patients exhibiting multiple basal cell carcinomas or having a history of
basal cell carcinomas should be diligently observed and treated.
F. RADIATION THERAPY: Patients having a history of previous x-ray therapy or grenz ray therapy
should be diligently observed for signs of carcinoma.
G. ARSENIC THERAPY: Patients having a history of previous arsenic therapy should be diligently
observed for signs of carcinoma.
H. HEPATIC DISEASES: Patients with hepatic insufficiency should be treated with caution since hepatic
biotransformation is necessary for drug urinary excretion.
I.
CARDIAC DISEASES: Patients with cardiac diseases or others who may be unable to tolerate prolonged
standing or exposure to heat stress should not be treated in a vertical UVA chamber.
J. ELDERLY PATIENTS: Caution should be used in elderly patients, especially those with a pre-existing
history of cataracts, cardiovascular conditions, kidney and/or liver dysfunction, or skin cancer.
K. TOTAL DOSAGE: The total cumulative dose of UVA that can be given over long periods of time with
safety has not as yet been established.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 6
L. CONCOMITANT THERAPY: Special care should be exercised in treating patients who are receiving
concomitant therapy (either topically or systemically) with known photosensitizing agents such as
anthralin, coal tar or coal tar derivatives, griseofulvin, phenothiazines, nalidixic acid, fluoroquinolone
antibiotics, halogenated salicylanilides (bacteriostatic soaps), sulfonamides, tetracyclines, thiazides and
certain organic staining dyes such as methylene blue, toluidine blue, rose bengal, and methyl orange.
VI. PRECAUTIONS
A. GENERAL — APPLICABLE TO PSORIASIS TREATMENT:
1. BEFORE METHOXSALEN INGESTION
Patients must not sunbathe during the 24 hours prior to methoxsalen ingestion and UV exposure. The
presence of a sunburn may prevent an accurate evaluation of the patient’s response to photochemotherapy.
2. AFTER METHOXSALEN INGESTION
a. UVA-absorbing wrap-around sunglasses should be worn during daylight for 24 hours after methoxsalen
ingestion. The protective eyewear must be designed to prevent entry of stray radiation to the eyes,
including that which may enter from the sides of the eyewear. The protective eyewear is used to prevent
the irreversible binding of methoxsalen to the proteins and DNA components of the lens. Cataracts form
when enough of the binding occurs. Visual discrimination should be permitted by the eyewear of patient
well-being and comfort.
b. Patients must avoid sun exposure, even through window glass or cloud cover, for at least 8 hours after
methoxsalen ingestion. If sun exposure cannot be avoided, the patient should wear protective devices such
as a hat and gloves, and/or apply sunscreens which contain ingredients that filter out UVA radiation (e.g.,
sunscreens containing benzophenone and/or PABA esters which exhibit a sun protective factor equal to or
greater than 15). These chemical sunscreens should be applied to all areas that might be exposed to the sun
(including lips). Sunscreens should not be applied to areas affected by psoriasis until after the patient has
been treated in the UVA chamber.
3. DURING PUVA THERAPY
a. Total UVA-absorbing/blocking goggles mechanically designed to give maximal ocular protection must
be worn. Failure to do so may increase the risk of cataract formation. A reliable radiometer can be used to
verify elimination of UVA transmission through the goggles.
b. Abdominal skin, breasts, genitalia, and other sensitive areas should be protected for approximately 1/3
of the initial exposure time until tanning occurs.
c. Unless affected by disease, male genitalia should be shielded.
4. AFTER COMBINED METHOXSALEN/UVA THERAPY
a. UVA-absorbing wrap-around sunglasses should be worn during daylight for 24 hours after combined
methoxsalen/UVA therapy.
b. Patients should not sunbathe for 48 hours after therapy. Erythema and/or burning due to
photochemotherapy and sunburn due to sun exposure are additive.
B. INFORMATION FOR PATIENTS: See accompanying Patient Package Insert.
C. LABORATORY TESTS:
1. Patients should have an ophthalmologic examination prior to start of therapy, and thence yearly.
2. Patients should have routine laboratory tests prior to the start of therapy and at regular periods thereafter
if patients are on extended treatments.
D. DRUG INTERACTIONS: See Warnings Section.
E. CARCINOGENESIS: See Warnings Section.
F. PREGNANCY:
Pregnancy Category C. Animal reproduction studies have not been conducted with methoxsalen. It is also not
known whether methoxsalen can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Methoxsalen should be given to a woman with reproductive capacity only if clearly
needed.
G. NURSING MOTHERS:
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human
milk, either methoxsalen ingestion or nursing should be discontinued.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 7
H. PEDIATRIC USE:
Safety in children has not been established. Potential hazards of long-term therapy include the possibilities of
carcinogenicity and cataractogenicity as described in the Warnings Section as well as the probability of actinic
degeneration which is also described in the Warnings Section.
I.
GERIATRIC USE:
Clinical studies with Oxsoralen-Ultra capsules did not include sufficient numbers of subjects aged 65 and over
to determine whether elderly subjects responded differently from younger subjects. Other reported clinical
experience 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.
VII. ADVERSE REACTIONS
A. METHOXSALEN:
The most commonly reported side effect of methoxsalen alone is nausea, which occurs with approximately 10%
of all patients. This effect may be minimized or avoided by instructing the patient to take methoxsalen in milk
or food, or to divide the dose into two portions, taken approximately one-half hour apart. Other effects include
nervousness, insomnia, and depression.
B. COMBINED METHOXSALEN/UVA THERAPY:
1. PRURITUS: This adverse reaction occurs with approximately 10% of all patients. In most cases, pruritus
can be alleviated with frequent application of bland emollients or other topical agents; severe pruritus may
require systemic treatment. If pruritus is unresponsive to these measures, shield pruritic areas from further
UVA exposure until the condition resolves. If intractable pruritus is generalized, UVA treatment should be
discontinued until the pruritus disappears.
2. ERYTHEMA: Mild, transient erythema at 24–48 hours after PUVA therapy is an expected reaction and
indicates that a therapeutic interaction between methoxsalen and UVA occurred. Any area showing
moderate erythema (greater than Grade 2 - See Table 1 for grades of erythema) should be shielded during
subsequent UVA exposures until the erythema has resolved. Erythema greater than Grade 2 which appears
within 24 hours after UVA treatment may signal a potentially severe burn. Erythema may become
progressively worse over the next 24 hours, since the peak erythemal reaction characteristically occurs 48
hours or later after methoxsalen ingestion. The patient should be protected from further UVA exposures
and sunlight, and should be monitored closely.
3. IMPORTANT DIFFERENCES BETWEEN PUVA ERYTHEMA AND SUNBURN: PUVA-
induced inflammation differs from sunburn or UVB phototherapy in several ways. The percent
transmission of UVB varies between 0% to 34% through skin whereas UVA varies between 1% to 80%
transmission; thus, UVA is transmitted to a larger percent through the skin. (Diffey, 198221). The DNA
lesions induced by PUVA are very different from UV-induced thymine dimers and may lead to a DNA
crosslink. This DNA lesion may be more problematic to the cell because crosslinks are more lethal and
psoralen-DNA photoproducts may be “new” or unfamiliar substrates for DNA repair enzymes. DNA
synthesis is also suppressed longer after PUVA. The time course of delayed erythema is different with
PUVA and may not involve the usual mediators seen in sunburn. PUVA-induced redness may be just
beginning at 24 hours, when UVB erythema has already passed its peak. The erythema dose-response
curve is also steeper for PUVA. Compared to equally erythemogenic doses of UVB, the histologic
alterations induced by PUVA show more dermal vessel damage and longer duration of epidermal and
dermal abnormalities.
4. OTHER ADVERSE REACTIONS: Those reported include edema, dizziness, headache, malaise,
depression, hypopigmentation, vesiculation and bullae formation, non-specific rash, herpes simplex,
miliaria, urticaria, folliculitis, gastrointestinal disturbances, cutaneous tenderness, leg cramps, hypotension,
and extension of psoriasis.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 8
VIII. OVERDOSAGE
In the event of methoxsalen overdosage, induce emesis and keep the patient in a darkened room for at least 24
hours. Emesis is most beneficial within the first 2 to 3 hours after ingestion of methoxsalen, since maximum
blood levels are reached by this time.
IX. DRUG DOSAGE & ADMINISTRATION
CAUTION: Oxsoralen-Ultra represents a new dose form of methoxsalen. This new dosage form of methoxsalen
exhibits significantly greater bioavailability and earlier photosensitization onset time than previous methoxsalen dosage
forms. Each patient should be evaluated by determining the minimum phototoxic dose (MPD) and phototoxic peak time
after drug administration prior to onset of photochemotherapy with this dosage form. Human bioavailability studies
have indicated the following drug dosage and administration directions are to be used as a guideline only.
PSORIASIS THERAPY
1. DRUG DOSAGE - INITIAL THERAPY: The methoxsalen capsules should be taken 1 1/2 to 2 hours
before UVA exposure with some low fat food or milk according to the following table:
Patient’s Weight
Dose
(kg)
(lbs)
(mg)
<30
<66
10
30-50
66-110
20
51-65
112-143
30
66-80
146-176
40
81-90
179-198
50
91-115 201-254
60
>115
>254
70
Elderly patients should generally be started at the low end of the dose recommended according to
body weight and closely monitored during PUVA therapy. Although clinical experience has not
identified differences in response between elderly and younger patients, the use of methoxsalen in
older individuals may be affected by the presence of pre-existing medical conditions.
2. INITIAL EXPOSURE: The initial UVA exposure energy level and corresponding time of exposure is
determined by the patient’s skin characteristics for sun burning and tanning as follows:
Skin Type
History
Recommen
ded
Joules/cm2
I
Always burn, never tan (patients
with erythrodermic psoriasis are
to be classed as Type I for
determination of UVA dosage.)
0.5 J/cm2
II
Always burn, but sometimes tan
1.0 J/cm2
III
Sometimes burn, but always tan
1.5 J/cm2
IV
Never burn, always tan
2.0 J/cm2
Skin Type
Physician Examination
Joules/cm2
V*
Moderately pigmented
2.5 J/cm2
VI*
Blacks
3.0 J/cm2
(*Patients with natural pigmentation of these types should be classified into a lower skin type category if the
sunburning history so indicates.)
If the MPD is done, start at 1/2 MPD.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 9
Additional drug dosage directions are as follows:
a. Weight Change: In the event that the weight of a patient changes during treatment such that he/she falls into
an adjacent weight range/dose category, no change in the dose of methoxsalen is usually required. If, in the
physician’s opinion, however, a weight change is sufficiently great to modify the drug dose, then an adjustment
in the time of exposure to UVA should be made.
b. Dose/Week: The number of doses per week of methoxsalen capsules will be determined by the patient’s
schedule of UVA exposures. In no case should treatments be given more often than once every other day
because the full extent of phototoxic reactions may not be evident until 48 hours after each exposure.
c. Dosage Increase: Dosage may be increased by 10 mg. after the fifteenth treatment under the conditions
outlined in section XI.B.4.b.
X. UVA RADIATION SOURCE SPECIFICATIONS & INFORMATION
A. IRRADIANCE UNIFORMITY:
The following specifications should be met with the window of the detector held in a vertical plane:
1.
Vertical variation: For readings taken at any point along the vertical center axis of the chamber (to
within 15 cm from the top and bottom), the lowest reading should not be less than 70 percent of the highest
reading.
2.
Horizontal variation: Throughout any specific horizontal plane, the lowest reading must be at least 80
percent of the highest reading, excluding the peripheral 3 cm of the patient treatment space.
B. PATIENT SAFETY FEATURES:
The following safety features should be present: (1) Protection from electrical hazard: All units should be
grounded and conform to applicable electrical codes. The patient or operator should not be able to touch any
live electrical parts. There should be ground fault protection. (2) Protective shielding of lamps: The patient
should not be able to come in contact with the bare lamps. In the event of lamp breakage, the patient should not
be exposed to broken lamp components. (3) Hand rails and hand holds: Appropriate supports should be
available to the patient. (4) Patient viewing window: A window which blocks UV should be provided for
viewing the patient during treatment. (5) Door and latches: Patients should be able to open the door from the
inside with only slight pressure to the door. (6) Non-skid floor: The floor should be of a non-skid nature. (7)
Thermoregulation: Sufficient air flow should be provided for patient safety and comfort, limiting temperature
within the UVA radiator cabinet to approximately less than 100°F. (8) Timer: The irradiator should be
equipped with an automatic timer which terminates the exposure at the conclusion of a pre-set time interval. (9)
Patient alarm device: An alarm device within the UVA irradiator chamber should be accessible to the patient
for emergency activation. (10) Danger label: The unit should have a label prominently displayed which reads as
follows:
DANGER - Ultraviolet radiation - Follow your physicians instructions - Failure to use protective eyewear may
result in eye injury.
C. UVA EXPOSURE DOSIMETRY MEASUREMENTS:
The maximum radiant exposure or irradiance (within ±15 percent) of UVA (320-400 nm) delivered to the
patient should be determined by using an appropriate radiometer calibrated to be read in Joules/cm2 or mW/cm2.
In the absence of a standard measuring technique approved by the National Bureau of Standards, the system
should use a detector corrected to a cosine spatial response. The use and recalibration frequency of such a
radiometer for a specific UVA irradiator chamber should be specified by the manufacturer because the UVA
dose (exposure) is determined by the design of the irradiator, the number of lamps, and the age of the lamp. If
irradiance is measured, the radiometer reading in mW/cm2 is used to calculate the exposure time in minutes to
deliver the required UVA in Joules/cm2 to a patient in the UVA irradiator cabinet. The equation is:
Exposure Time = Desired UVA Dose (J/cm2)
(minutes) 0.06 x Irradiance (mW/cm2)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 10
Overexposure due to human error should be minimized by using an accurate automatic timing device,
which is set by the operator and controlled by energizing and de-energizing the UVA irradiator lamp.
The timing device calibration interval should be specified by the manufacturer. Safety systems should
be included to minimize the possibility of delivering a UVA exposure which exceeds the prescribed
dose, in the event the timer or radiometer should malfunction.
D. UVA SPECTRAL OUTPUT DISTRIBUTION:
The spectral distributions of the lamps should meet the following specifications:
Wavelength band (nanometers)
Output1
<310
<1
310 to 320
1 to 3
320 to 330
4 to 8
330 to 340
11 to 17
340 to 350
18 to 25
350 to 360
19 to 28
360 to 370
15 to 23
370 to 380
8 to 12
380 to 390
3 to 7
390 to 400
1 to 3
1As a percentage of total irradiance between 320 and 400 nanometers.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 11
XI. PUVA TREATMENT PROTOCOL
INTRODUCTION:
The Oxsoralen-Ultra Capsules reach their maximum bioavailability in 1 1/2 to 2 hours after ingestion.
On average, the serum level achieved with Oxsoralen-Ultra is twice that obtained with 8-MOP (formerly
Oxsoralen) and reach their peak concentration in less than 1/2 the time of the 8-MOP capsules.
As a result the mean MED J/cm2 for the Oxsoralen-Ultra Capsules is substantially less than that required for 8-
MOP (Levins et al., 1984 and private communication1).
Photosensitivity studies demonstrate a shorter time of peak photosensitivity of 1.5 to 2.1 hours vs. 3.9 to 4.25
hours for regular methoxsalen capsules.
A. INITIAL EXPOSURE: The initial UVA exposures should be conducted according to the guidelines
presented previously under IX.B.1 and 2, Psoriasis therapy, Drug dosage-initial Therapy and Exposure.
B. CLEARING PHASE: Specific recommendations for patient treatment are as follows:
1. SKIN TYPES I, II, & III. Patients with skin types I, II, and III may be treated 2 or 3 times per week. UVA
exposure may be held constant or increased by up to 1.0 Joule/cm2 at each treatment, according to the
patient’s response. If erythema occurs, however, do not increase exposure time until erythema resolves.
The severity and extent of the patient’s erythema may be used to determine whether the next exposure
should be shortened, omitted, or maintained at the previous dosage. See Adverse Reactions section for
additional information.
2. SKIN TYPES IV, V, & VI. Patients with skin types IV, V, and VI may be treated 2 or 3 times per week.
UVA exposure may be held constant or increased by up to 1.5 Joules/cm2 at each treatment unless
erythema occurs. If erythema occurs, follow instructions outlined above in the procedures for patients with
skin types I, II, and III.
3. ERYTHRODERMIC PSORIASIS: Patients with erythrodermic psoriasis should be treated with special
attention because pre-existing erythema may obscure observations of possible treatment-related phototoxic
erythema. These patients may be treated 2 or 3 times per week, as a Type I patient.
4. MISCELLANEOUS SITUATIONS:
a. If there is no response after a total of 10 treatments, the exposure of UVA energy may be increased by
an additional 0.5–1.0 Joules/cm2 above the prior incremental increases for each treatment. (Example: a
patient whose exposure dosage is being increased by 1.0 Joule/cm2 may now have all subsequent doses
increased by 1.5–2.0 Joules/cm2.)
b. If there is no response, or only minimal response, after 15 treatments, the dosage of methoxsalen may be
increased by 10 mg (a one-time increase in dosage). This increased dosage may be continued for the
remainder of the course of treatment but should not be exceeded.
c. If a patient misses a treatment, the UVA exposure time of the next treatment should not be increased. If
more than one treatment is missed, reduce the exposure by 0.5 Joules/cm2 for each treatment missed.
d. If the lower extremities are not responding as well as the rest of the body and do not show erythema,
cover all other body areas and give 25 percent of the present exposure dose as an additional exposure to the
lower extremities. This additional exposure to the lower extremities should be terminated if erythema
develops on these areas.
e. Non-responsive psoriasis: If a patient’s generalized psoriasis is not responding, or if the condition
appears to be worsening during treatment, the possibility of a generalized phototoxic reaction should be
considered. This may be confirmed by the improvement of the condition following temporary
discontinuance of this therapy for two weeks. If no improvement occurs during the interruption of
treatment, this patient may be considered a treatment failure.
C. ALTERNATIVE EXPOSURE SCHEDULE:
As an alternative to increasing the UVA exposure at each treatment, the following schedule may be followed;
this schedule may reduce the total number of Joules/cm2 received by the patient over the entire course of
therapy.
1. Incremental increases in UVA exposure for all patients may range from 0.5 to 1.5 Joules/cm2, according to
the patient’s response to therapy.
2. Once Grade 2 clearing (see Table 2) has been reached and the patient is progressing adequately, UVA
dosage is held constant. This dosage is maintained until Grade 4 clearing is reached.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 12
3. If the rate of clearing significantly decreases, exposure dosage may be increased at each treatment (0.1-1.5
Joules/cm2) until Grade 3 clearing and a satisfactory progress rate is attained. The UVA exposure will be
held constant again until Grade 4 clearing is attained. These increases may be used also if the rate of
clearing significantly decreases between Grade 3 and Grade 4 response. However, the possibility of a
phototoxic reaction should be considered; see Non-responsive Psoriasis, above.
4. In summary, this schedule raises slightly the increments (Joules/cm2) of UVA dosage, but limits these
increases to those periods when the patient is not responding adequately. Otherwise, the UVA exposure is
held at the lowest effective dose.
D. MAINTENANCE PHASE:
The goal of maintenance treatment is to keep the patient as symptom-free as possible with the least amount of
UVA exposure.
1. SCHEDULE OF EXPOSURES: When patients have achieved 95 percent clearing, or Grade 4 response
(Table 2), they may be placed on the following maintenance schedules (M1 – M4), in sequence. It is
recommended that each maintenance schedule be adhered to for at least 2 treatments (unless erythema or
psoriatic flare occurs, in which case see (2a) and (2b) below).
Maintenance Schedules
M1 - once/week
M2 - once/2 weeks
M3 - once/3 weeks
M4 - p.r.n. (i.e., for
flares)
2. LENGTH OF EXPOSURE: The UVA exposure for the first maintenance treatment of any schedule
(except M4 as noted below) is the same as that of the patient’s last treatment under the previous schedule.
For skin types I–IV, however, it is recommended that the maximum UVA dosage during maintenance
treatments not exceed the following:
Skin Types
Joules/cm2/treatment
I
II
III
IV
12
14
18
22
If the patient develops erythema or new lesions of psoriasis, proceed as follows:
a. Erythema: During maintenance therapy, the patient’s tan and threshold dose for erythema may
gradually decrease. If maintenance treatments produce significant erythema, the exposure to UVA should
be decreased by 25 percent until further treatments no longer produce erythema.
b. Psoriasis: If the patient develops new areas of psoriasis during maintenance therapy (but still is
classified as having a Grade 4 response), the exposure to UVA may be increased by 0.5–1.5 Joules/cm2 at
each treatment; this is appropriate for all types of patients. These increases are continued until the psoriasis
is brought under control and the patient is again clear. The exposure being administered when this clearing
is reached should be used for further maintenance treatment.
3. FLARES DURING MAINTENANCE: If the patient flares during maintenance treatment (i.e.,
develops psoriasis on more than 5 percent of the originally involved areas of the body), his maintenance
treatment schedule may be changed to the preceding maintenance or clearing schedule. The patient may be
kept on his schedule until again 95 percent clear. If the original maintenance treatment schedule is unable
to control the psoriasis, the schedule may be changed to a more frequent regimen. If a flare occurs less
than 6 weeks after the last treatment, 25 percent of the maximum exposure received during the clearing
phase, with the clearing schedule received during the clearing phase, may be used and then proceed with
the clearing schedule previously followed for this patient. (At 95 percent clearing, follow regular
maintenance until the optimum maintenance schedule is determined for the patient.) If more than 6 weeks
have elapsed since the last treatment was given, treat patients as if they were beginning therapy insofar as
exposure dosages are concerned, since their threshold for erythema may have decreased.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 13
Table 1. Grades of Erythema
Grade
Erythema
0
1
2
3
4
No erythema
Minimally perceptible erythema -
faint pink
Marked erythema but with no edema
Fiery erythema with edema
Fiery erythema with edema and
blistering
Table 2. Response to Therapy
Grade
Criteria
Percent Improvement
(compared to original
extent of disease)
-1
0
1
2
3
4
Psoriasis worse
No change
Minimal improvement - slightly less scale
and/or erythema
Definite improvement - partial flattening
of all plaques—less scaling and less erythema
Considerable improvement - nearly complete
flattening of all plaques but borders of plaques still
palpable
Clearing; complete flattening of plaques
including borders; plaques may be outlined
by pigmentation
0
0
5-20
20-50
50-95
95
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 14
XII. HOW SUPPLIED
Oxsoralen-Ultra Capsules, each containing 10 mg of methoxsalen (8-methoxypsoralen) in a soft gelatin capsule
packaged in amber glass bottles are available as follows:
Unit Count
NDC Number
50
NDC 0187-0650-42
Store at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F).
ICN Pharmaceuticals, Inc.
3300 Hyland Ave.
Costa Mesa, CA 92626, U.S.A.
BIBLIOGRAPHY
1. Levins, P.C., Gange, R.W., Momtaz-T,K., Parrish, J.A., and Fitzpatrick, T.B.: A New Liquid Formulation
of 8-Methoxypsoralen: Bioactivity and Effect of Diet: JID, 82, No. 2, pp. 185-187 (1984) and private
communication.
2. Artuc, M., Stuettgen, G., Schalla, W., Schaefer, H., and Gazith, J.: Reversibile binding of 5- and 8-
methoxypsoralen to human serum proteins (albumin) and to epidermis in vitro: Brit. J. Dermat. 101, pp.
669-677 (1979).
3. Mandula, B. B., Pathak, M.A., Nakayama, T., and Davidson, S.J.: Induction of mixed-function oxidases in
mouse liver by psoralens., Ibid, 99, pp. 687-692 (1978).
4. Pathak, M. A., Fitzpatrick, T. B., Parrish, J. A.: PSORIASIS, Proceedings of the Second International
Symposium. Edited by E. M. Farber, A. J. Cox, Yorke Medical Books, pp. 262-265 (1977).
5. Dall’Acqua, F., Marciani, S., Ciavatta, L., Rodighiero, G.: Formation of interstrand cross-linkings in the
photoreactions between furocoumarins and DNA; Z Naturforsch (B), 26, pp. 561-569 (1971).
6. Cole, R. S.: Light-induced cross-linkings of DNA in the presence of a furocoumarin (psoralen), Biochem.
Biophys. Acta, 217, pp. 30-39 (1970).
7. Musajo, L., Rodighiero, G., Caporale, G., Dall’Acqua, F., Marciani, S., Bordin, F., Baccichetti, F.,
Bevilacqua, R.: Photoreactions between Skin-Photosensitizing Furocoumarins and Nucleic Acids,
SUNLIGHT AND MAN; Normal and Abnormal Photobiologic Responses. Edited by M. A. Pathak, L. C.
Harber, M. Seiji et al. University of Tokyo Press, pp. 369-387 (1974).
8. Dall’Acqua, F., Vedaldi, D., Bordin, F., and Rodighiero, G.: New studies in the interaction between 8-
methoxypsoralen and DNA in vitro; JID, 73, pp. 191-197 (1979).
9. Yoshikawa, K., Mori, N., Sakakibara, S., Mizuno, N., Song, P.: Photo-Conjugation of 8-methoxypsoralen
with Proteins; Photochem. & Photobiol. 29, pp. 1127-1133 (1979).
10. Hakim, R. E., Griffin, A. C.: Knox, J. M.: Erythema and tumor formation in methoxsalen treated mice
exposed to fluorescent light; Arch. Dermatol. 82, pp. 572-577 (1960).
11. O’Neal, M.A., Griffin, A.C.: The Effect of Oxypsoralen upon Ultraviolet Carcinogenesis in Albino Mice,
Cancer Res., 17, pp. 911-916 (1957).
12. Stern, R. S., Unpublished personal communication.
13. Stern, R. S., Parrish, J.A., Zierler, S.: Skin Carcinoma in Patients with Psoriasis Treated with Topical Tar
and Artificial Ultraviolet Radiation. Lancet, 1, pp. 732-735 (1980).
14. Stern, R.S., Laird, N., Melski, J., Parrish, J.A., Fitzpatrick, T.B., Bleich, H.L.: Cutaneous Squamous-
Cell Carcinoma in Patients Treated with PUVA: NEJM, 310, No. 18, pp. 1156-1161 (1984).
15. Roenigk, Jr., H. H., and 12 Cooperating Investigators: Skin Cancer in the PUVA-48 Cooperative Study
of Psoriasis. Program for Forty-First Annual Meeting for The Society of Investigative Dermatology, Inc.,
Sheraton Washington Hotel, Washington, D.C., May 12, 13, and 14, 1980. Abstract JID, 74 No. 4, pp. 250
(April 1980).
16. Stern et al., Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and
ultraviolet A radiation (PUVA). The PUVA Follow-Up Study. New England Journal of Medicine,
336:1041-1045, (April 10, 1997).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 15
17. Mosher, D. B., Pathak, M. A., Harris, T. J., Fitzpatrick, T. B.: Development of Cutaneous Lesions in
Vitiligo During Long-Term PUVA Therapy. Program for Forty-First Annual Meeting for The Society for
Investigative Dermatology, Inc., Sheraton Washington Hotel, Washington, D.C., May 12, 13, and 14,
1980. Abstracts JID, 74, No. 4, p. 259 (April, 1980).
18. Cloud, T. M., Hakim, R., Griffin, A. C.: Photosensitization of the eye with methoxsalen. I. Acute effects;
Arch. Ophthalmol. 64, pp. 346-352 (1960).
19. Cloud, T. M., Hakim, R., Griffin, A. C.: Photosensitization of the eye with methoxsalen. II. Chronic
effects, Ibid, 66, pp. 689-694 (1961).
20. Freeman, R. G., Troll, D.: Photosensitization of the eye by 8-methoxypsoralen, JID, 53, pp. 449-453
(1969).
21. Lerman, S., Megaw, J., Willis, I.: Potential ocular complications from PUVA therapy and their
prevention; JID 74, pp. 197-199 (1980).
22. Diffey, >L., Medical Physics Handbook 11, Ultraviolet Radiation In Medicine, Adam Hilger, Ltd., Bristol,
p. 86 (1982)
Revised 8-98
2400-03EL
PATIENT INFORMATION ON THE USE OF
OXSORALEN–ULTRA CAPSULES (METHOXSALEN, 10 mg)
IN THE TREATMENT OF PSORIASIS
This brochure is intended to provide you with information about the treatment of psoriasis. The entire brochure should be read so
that you are aware of the requirements on your part to ensure the effectiveness and safety of the therapy. Any additional questions
that you may have can be answered by your doctor or pharmacist. In addition, the pharmacist will have a copy of a very technical
brochure entitled the “Physician’s Package Insert” that you may wish to read.
A. What Is Oxsoralen-Ultra (Methoxsalen)?
Oxsoralen-Ultra (methoxsalen) is a drug which has been shown to be effective in the treatment of psoriasis when combined with
exposure to a very specific kind of light. The use of the drug must be combined with exposure to the special light to produce
effective therapy. Oxsoralen-Ultra represents a new dose form of methoxsalen. This new dosage form of methoxsalen exhibits
significantly greater bioavailability and earlier photosensitization onset time than previous methoxsalen dosage forms.
B. What Is The Special Light?
Light is classified into many different parts. One part is known as ultraviolet light, which is a normal component of sunlight.
Artificial or man-made light sources are now available that produce the special part of light (ultraviolet “A”) necessary for the
most effective therapy.
C. What Is “PUVA”?
“PUVA” is the name of the treatment for psoriasis and stands for the use of Psoralen drug (Oxsoralen-Ultra) in combination with
UltraViolet A light.
D. What Is Psoriasis?
Psoriasis is a skin condition associated with red and scaly patches. The cause of psoriasis is not known. PUVA (Oxsoralen–
Ultra with ultraviolet A light) is used for the treatment of severe psoriasis that has not been helped by other methods of therapy.
E. What Should The Patient Do Before PUVA Therapy?
Certain other medicines can make you more sensitive to the combination drug and light treatment. In addition, certain other
medical conditions can be aggravated by this treatment. Before starting treatment, be sure to tell your doctor if you have
experienced any of the following:
1) had a severe reaction to Oxsoralen–Ultra in the past
2) had recent x-ray treatment or planning any
3) have or ever have had skin cancer
4) have or ever have had any eye problems such as cataracts or loss of the lens of the eyes
5) have or ever have had liver problems
6) have or ever have had heart or blood pressure problems
7) have any medical condition that requires you to stay out of the sun such as lupus erythematosus
8) are taking any drugs (either prescription or nonprescription). Some drugs can increase your sensitivity to ultraviolet light
either from the sun or man-made sources. Examples of such drugs include major tranquilizers, sulfa drugs for the
treatment of infection or diabetes, tetracycline, antibiotics, griseofulvin products, thiazide-containing diuretics (blood
pressure or water elimination drugs), and certain antibacterial or deodorant soaps.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 16
F. How Should The Patient Take Oxsoralen–Ultra?
1) The number of capsules recommended by your doctor should be taken with some food or lowfat milk two hours before
ultraviolet light treatment.
2) Oxsoralen–Ultra is a potent drug. Never take more than is prescribed for you since it may result in burning and/or blistering
of your skin after exposure to ultraviolet light.
G. What Precautions Should Be Taken During And After PUVA Therapy?
1) Eye Protection — Make sure that you wear special wrap-around sunglasses that totally block or absorb ultraviolet light. Put
them on immediately after taking Oxsoralen-Ultra and continue wearing them for 24 hours if any light is present (even if
indirect such as reflection or through window glass). Ordinary sunglasses are not adequate.
2) Skin & Lip Protection — Do not allow exposure of your skin and lips to sunlight for 8 hours after treatment. In addition, do
not expose your skin to either sunlight or sun lamps (regardless of safety claims) within 24 hours of a scheduled treatment.
It is advisable to wear protective clothing (hat, gloves) to cover as much of your body as possible after treatment as well as
using a sun screen product having a protection factor of at least 15 (only use after treatment).
H. How Long Will The Treatments Last?
May take from six to eight weeks before lesions disappear. Maintenance treatments are usually needed to keep the disease
under control.
I.
What Are The Problems Associated With Pregnancy Or Breast Feeding?
1) Birth control methods should be employed since the effects of PUVA therapy on the unborn child are not known. If you
become pregnant, inform your doctor so that he can determine whether it is necessary for you to temporarily stop therapy.
2) Since it is not known whether Oxsoralen-Ultra passes into mother’s milk, it is safer not to breast feed while taking this drug.
J. What Are The Risks Of PUVA Therapy?
1) Premature skin aging may result from prolonged PUVA therapy, especially with those individuals who tan poorly. This
problem is similar to excessive exposure to sunlight.
2) There is an increased risk of developing both melanoma and non-melanoma skin cancer. This risk is greater for individuals
who fall into the following categories:
a) fair skin that burns rather than tans
b) have had prior treatment with x-rays, grenz rays, or arsenic
c) have had coal tar and UltraViolet B (UVB) treatment.
Even though your doctor will be examining you, you should routinely and completely examine yourself for small growths on
your skin or skin sores that will not heal. Immediately report such observations to your doctor.
3) Since studies have shown that animals with unprotected eyes have developed cataracts after PUVA therapy, you should
have your eyes examined by an ophthalmologist before starting PUVA therapy, after the first year of therapy and every two
years thereafter.
K. What Are The Possible Side Effects?
1) The most common side effects of PUVA therapy are nausea, itching, and redness of the skin. The use of lowfat milk or food
when ingesting the drug may prevent the nausea.
2) Tenderness or blistering of the skin may occur, but these symptoms can be helped by the use of skin products
recommended by your doctor or pharmacist.
3) Less frequent side effects include depression, dizziness, headache, swelling, rash or leg cramps.
Important: Contact your doctor if any side effect continues to bother you after 24–48 hours.
L. What Else Should The Patient Know?
1) Remember to take Oxsoralen–Ultra as directed by your doctor. If you forget to take the drug before your scheduled
treatment, be sure to call your doctor to determine what he wishes you to do.
2) Remember that the drug has been prescribed specifically for you and your diagnosed condition. Do not use the drug for any
other conditions nor give the drug to others even if they have similar symptoms.
3) If you think that you or anyone else has accidentally taken an overdose, stay out of the sunlight and immediately contact
your poison control center, doctor, pharmacist, or nearest hospital emergency room.
4)
ALWAYS KEEP THIS DRUG AND ALL OTHER DRUGS OUT OF THE REACH OF CHILDREN.
5)
Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F).
ICN Pharmaceuticals, Inc.
Printed in U.S.A.
3300 Hyland Ave.
Costa Mesa, CA 92626, U.S.A.
Revised -8-98
2401-04 EL
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:31.175881
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19600slr006,009_oxsoralen-ultra_lbl.pdf', 'application_number': 19600, 'submission_type': 'SUPPL ', 'submission_number': 6}
|
11,560
|
NDA 19-600/S-006 & S-009
Page 3
OXSORALEN-ULTRA
CAPSULES
(Methoxsalen Capsules, USP, 10 mg)
Rx ONLY
CAUTION: METHOXSALEN IS A POTENT DRUG. READ ENTIRE BROCHURE PRIOR TO PRESCRIBING
OR DISPENSING THIS MEDICATION.
Methoxsalen with UV radiation should be used only by physicians who have special competence in the
diagnosis and treatment of psoriasis and who have special training and experience in photochemotherapy. The
use of Psoralen and ultraviolent radiation therapy should be under constant supervision of such a physician.
For the treatment of patients with psoriasis, photochemotherapy should be restricted to patients with severe,
recalcitrant, disabling psoriasis which is not adequately responsive to other forms of therapy, and only when
the diagnosis is certain. Because of the possibilities of ocular damage, aging of the skin, and skin cancer
(including melanoma), the patient should be fully informed by the physician of the risks inherent in this
therapy.
CAUTION: Oxsoralen-Ultra (Methoxsalen Soft Gelatin Capsules should not be used interchangeably
with regular Oxsoralen or 8-MOP® (Methoxsalen Hard Gelatin Capsules). This new dosage form of
methoxsalen exhibits significantly greater bioavailability and earlier photosensitixation onset time than
previous methoxsalen dosage forms. Patient should be treated in accordance with the dosimetry
specifically recommended for this product. The minimum phototoxic dose (MPD) and phototoxic peak
time after drug administration prior to onset of photochemotherapy with tis dosage form should be
determined.
I. DESCRIPTION
Oxsoralen-Ultra (methoxsalen, 8-methoxypsoralen) Capsules, 10 mg. Methoxsalen is a naturally occurring
photoactive substance found in the seeds of the Ammi majus (Umbelliferae) plant and in the roots of Heracleum
Candicans. It belongs to a group of compounds known as psoralens, or furocoumarins. The chemical name of
methoxsalen is 9-methoxy-7H-furo [3,2-g] [1] benzopyran-7-one; it has the following structure:
II. CLINICAL PHARMACOLOGY
The combination treatment regimen of psoralen (P) and ultraviolet radiation of 320-400 nm wavelength commonly
referred to as UVA is known by the acronym, PUVA. Skin reactivity to UVA (320–400 nm) radiation is markedly
enhanced by the ingestion of methoxsalen. In a well controlled bioavailability study, Oxsoralen-Ultra Capsules
reached peak drug levels in the blood of test subjects between 0.5 and 4 hours (Mean = 1.8 hours) as compared to
between 1.5 and 6 hours (Mean = 3.0 hours) for regular Oxsoralen when administered with 8 ounces of milk. Peak
drug levels were 2 to 3 fold greater when the overall extent of drug absorption was approximately two fold greater
for Oxsoralen-Ultra Capsules as compared to regular Oxsoralen Capsules. Detectable methoxsalen levels were
observed up to 12 hours post dose. The drug half-life is approximately 2 hours. Photosensitivity studies
demonstrate a shorter time of peak photosensitivity of 1.5 to 2.1 hours vs. 3.9 to 4.25 hours for regular Oxsoralen
capsules. In addition, the mean minimal erythema dose (MED), J/cm2, for the Oxsoralen-Ultra Capsules is
substantially less than that required for regular Oxsoralen Capsules (Levins et al., 1984 and private
communication1).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 4
Methoxsalen is reversibly bound to serum albumin and is also preferentially taken up by epidermal cells (Artuc et
al., 19792). At a dose which is six times larger than that used in humans, it induces mixed function oxidases in the
liver of mice (Mandula et al., 19783). In both mice and man, methoxsalen is rapidly metabolized. Approximately
95% of the drug is excreted as a series of metabolites in the urine within 24 hours (Pathak et al., 19774). The exact
mechanism of action of methoxsalen with the epidermal melanocytes and keratinocytes is not known. The best
known biochemical reaction of methoxsalen is with DNA. Methoxsalen, upon photoactivation, conjugates and
forms covalent bonds with DNA which leads to the formation of both monofunctional (addition to a single strand of
DNA) and bifunctional (crosslinking of psoralen to both strands of DNA) adducts (Dall’ Acqua et al., 19715; Cole,
19706; Musajo et al., 19747; Dall’ Acqua et al., 19798). Reactions with proteins have also been described
(Yoshikawa, et al., 19799).
Methoxsalen acts as a photosensitizer. Administration of the drug and subsequent exposure to UVA can lead to cell
injury. Orally administered methoxsalen reaches the skin via the blood and UVA penetrates well into the skin. If
sufficient cell injury occurs in the skin, an inflammatory reaction occurs. The most obvious manifestation of this
reaction is delayed erythema, which may not begin for several hours and peaks at 48-72 hours. The inflammation is
followed, over several days to weeks, by repair which is manifested by increased melanization of the epidermis and
thickening of the stratum corneum. The mechanisms of therapy are not known. In the treatment of psoriasis, the
mechanism is most often assumed to be DNA photodamage and resulting decrease in cell proliferation but other
vascular, leukocyte, or cell regulatory mechanisms may also be playing some role. Psoriasis is a hyper-proliferative
disorder and other agents known to be therapeutic for psoriasis are known to inhibit DNA synthesis
III. INDICATIONS AND USAGE
Photochemotherapy (Methoxsalen with long wave UVA radiation) is indicated for the symptomatic control of
severe, recalcitrant, disabling psoriasis not adequately responsive to other forms of therapy and when the
diagnosis has been supported by biopsy. Methoxsalen is intended to be administered only in conjunction with a
schedule of controlled doses of long wave ultraviolet radiation.
IV. CONTRAINDICATIONS
A. Patients exhibiting idiosyncratic reactions to psoralen compounds.
B. Patients possessing a specific history of light sensitive disease states should not initiate methoxsalen
therapy except under special circumstances. Diseases associated with photosensitivity include lupus
erythematosus, porphyria cutanea tarda, erythropoietic protoporphyria, variegate porphyria, xeroderma
pigmentosum, and albinism.
C. Patients with melanoma or with a history of melanoma.
D. Patients with invasive squamous cell carcinomas.
E. Patients with aphakia, because of the significantly increased risk of retinal damage due to the absence of
lenses.
V. WARNINGS-GENERAL
A. SIN BURNING: Serious burns from either UVA or sunlight (even through window glass) can result if the
recommended dosage of the drug and/or exposure schedules are exceeded.
B. CARCINOGENICITY:
1. ANIMAL STUDIES: Topical or intraperitoneal methoxsalen has been reported to be a potent
photocarcinogen in albino mice and hairless mice (Hakim et al., 196010). However, methoxsalen given by
the oral route to Swiss albino mice suggests this agent exerts a protective effect against ultraviolet
carcinogenesis; mice given 8-methoxypsoralen in their diet showed 38% ear tumors 180 days after the start
of ultraviolet therapy compared to 62% for controls (O’Neal et al., 195711).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 5
2. HUMAN STUDIES: A 5.7 year prospective study of 1380 psoriasis patients treated with oral
methoxsalen and ultraviolet A photochemotherapy (PUVA) demonstrated that the risk of cutaneous
squamous-cell carcinoma developing at least 22 months following the first PUVA exposure was
approximately 12.8 times higher in the high dose patients than in the low dose patients (Stern et al., 197912,
Stern et al., 198013, and Stern et al., 198414). The substantial dose-dependent increase was observed in
patients with neither a prior history of skin cancer nor significant exposure to cutaneous carcinogens.
Reduction in PUVA dosage significantly reduces the risk. No substantial dose related increase was noted
for basal cell carcinoma according to Stern et al., 198414. Increases appear greatest in patients who have
pre-PUVA exposure to 1) prolonged tar and UVB treatment, 2) ionizing radiation, or 3) arsenic.
Roenigk et al., 198015, studied 690 patients for up to 4 years and found no increase in the risk of non-
melanoma skin cancer, although patients in this cohort had significantly less exposure to PUVA than in the
Stern et al. study. Recent analysis of new data in the Stern et al cohort (Stern et al., 199716) has shown that
these patients have an elevated relative risk of contracting melanoma. The relative risk for melanoma in
these patients was 2.3 (95 percent confidence interval 1.1 to 4.1). The risk is particularly higher in those
patients who have received more than 250 PUVA treatments and in those whose treatment has spanned
greater than 15 years earlier. These observations indicate the need for monitoring of PUVA patients for
skin tumors throughout their lives.
In a study in Indian patients treated for 4 years for vitiligo, 12 percent developed keratoses, but not
cancer, in the depigmented, vitiliginous areas (Mosher, 198017). Clinically, the keratoses were keratotic
papules, actinic keratosis-like macules, nonscaling dome-shaped papules, and lichenoid porokeratotic-like
papules.
C. CATARACTOGENICITY:
1. ANIMAL STUDIES: Exposure to large doses of UVA causes cataracts in animals, and this effect is
enhanced by the administration of methoxsalen (Cloud et al., 196018; Cloud et al., 196119 Freeman et al.,
196920).
2. HUMAN STUDIES: It has been found that the concentration of methoxsalen in the lens is proportional
to the serum level. If the lens is exposed to UVA during the time methoxsalen is present in the lens,
photochemical action may lead to irreversible binding of methoxsalen to proteins and the DNA components
of the lens (Lerman et al., 198021). However, if the lens is shielded from UVA, the methoxsalen will
diffuse out of the lens in a 24 hour period (Lerman et al., 198021). Patients should be told emphatically to
wear UVA absorbing, wrap-around sunglasses for the twenty-four (24) hour period following ingestion of
methoxsalen whether exposed to direct or indirect sunlight in the open or through a window glass.
Among patients using proper eye protection, there is no evidence for a significantly increased risk of
cataracts in association with PUVA therapy (Stern et al., 197912). Thirty-five of 1380 patients have
developed cataracts in the five years since their first PUVA treatment. This incidence is comparable to that
expected in a population of this size and age distribution. No relationship between PUVA dose and
cataract risk in this group has been noted.
D. ACTINIC DEGENERATION: Exposure to sunlight and/or ultraviolet radiation may result in “premature
aging” of the skin.
E. BASAL CELL CARCINOMAS: Patients exhibiting multiple basal cell carcinomas or having a history of
basal cell carcinomas should be diligently observed and treated.
F. RADIATION THERAPY: Patients having a history of previous x-ray therapy or grenz ray therapy
should be diligently observed for signs of carcinoma.
G. ARSENIC THERAPY: Patients having a history of previous arsenic therapy should be diligently
observed for signs of carcinoma.
H. HEPATIC DISEASES: Patients with hepatic insufficiency should be treated with caution since hepatic
biotransformation is necessary for drug urinary excretion.
I.
CARDIAC DISEASES: Patients with cardiac diseases or others who may be unable to tolerate prolonged
standing or exposure to heat stress should not be treated in a vertical UVA chamber.
J. ELDERLY PATIENTS: Caution should be used in elderly patients, especially those with a pre-existing
history of cataracts, cardiovascular conditions, kidney and/or liver dysfunction, or skin cancer.
K. TOTAL DOSAGE: The total cumulative dose of UVA that can be given over long periods of time with
safety has not as yet been established.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 6
L. CONCOMITANT THERAPY: Special care should be exercised in treating patients who are receiving
concomitant therapy (either topically or systemically) with known photosensitizing agents such as
anthralin, coal tar or coal tar derivatives, griseofulvin, phenothiazines, nalidixic acid, fluoroquinolone
antibiotics, halogenated salicylanilides (bacteriostatic soaps), sulfonamides, tetracyclines, thiazides and
certain organic staining dyes such as methylene blue, toluidine blue, rose bengal, and methyl orange.
VI. PRECAUTIONS
A. GENERAL — APPLICABLE TO PSORIASIS TREATMENT:
1. BEFORE METHOXSALEN INGESTION
Patients must not sunbathe during the 24 hours prior to methoxsalen ingestion and UV exposure. The
presence of a sunburn may prevent an accurate evaluation of the patient’s response to photochemotherapy.
2. AFTER METHOXSALEN INGESTION
a. UVA-absorbing wrap-around sunglasses should be worn during daylight for 24 hours after methoxsalen
ingestion. The protective eyewear must be designed to prevent entry of stray radiation to the eyes,
including that which may enter from the sides of the eyewear. The protective eyewear is used to prevent
the irreversible binding of methoxsalen to the proteins and DNA components of the lens. Cataracts form
when enough of the binding occurs. Visual discrimination should be permitted by the eyewear of patient
well-being and comfort.
b. Patients must avoid sun exposure, even through window glass or cloud cover, for at least 8 hours after
methoxsalen ingestion. If sun exposure cannot be avoided, the patient should wear protective devices such
as a hat and gloves, and/or apply sunscreens which contain ingredients that filter out UVA radiation (e.g.,
sunscreens containing benzophenone and/or PABA esters which exhibit a sun protective factor equal to or
greater than 15). These chemical sunscreens should be applied to all areas that might be exposed to the sun
(including lips). Sunscreens should not be applied to areas affected by psoriasis until after the patient has
been treated in the UVA chamber.
3. DURING PUVA THERAPY
a. Total UVA-absorbing/blocking goggles mechanically designed to give maximal ocular protection must
be worn. Failure to do so may increase the risk of cataract formation. A reliable radiometer can be used to
verify elimination of UVA transmission through the goggles.
b. Abdominal skin, breasts, genitalia, and other sensitive areas should be protected for approximately 1/3
of the initial exposure time until tanning occurs.
c. Unless affected by disease, male genitalia should be shielded.
4. AFTER COMBINED METHOXSALEN/UVA THERAPY
a. UVA-absorbing wrap-around sunglasses should be worn during daylight for 24 hours after combined
methoxsalen/UVA therapy.
b. Patients should not sunbathe for 48 hours after therapy. Erythema and/or burning due to
photochemotherapy and sunburn due to sun exposure are additive.
B. INFORMATION FOR PATIENTS: See accompanying Patient Package Insert.
C. LABORATORY TESTS:
1. Patients should have an ophthalmologic examination prior to start of therapy, and thence yearly.
2. Patients should have routine laboratory tests prior to the start of therapy and at regular periods thereafter
if patients are on extended treatments.
D. DRUG INTERACTIONS: See Warnings Section.
E. CARCINOGENESIS: See Warnings Section.
F. PREGNANCY:
Pregnancy Category C. Animal reproduction studies have not been conducted with methoxsalen. It is also not
known whether methoxsalen can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Methoxsalen should be given to a woman with reproductive capacity only if clearly
needed.
G. NURSING MOTHERS:
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human
milk, either methoxsalen ingestion or nursing should be discontinued.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 7
H. PEDIATRIC USE:
Safety in children has not been established. Potential hazards of long-term therapy include the possibilities of
carcinogenicity and cataractogenicity as described in the Warnings Section as well as the probability of actinic
degeneration which is also described in the Warnings Section.
I.
GERIATRIC USE:
Clinical studies with Oxsoralen-Ultra capsules did not include sufficient numbers of subjects aged 65 and over
to determine whether elderly subjects responded differently from younger subjects. Other reported clinical
experience 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.
VII. ADVERSE REACTIONS
A. METHOXSALEN:
The most commonly reported side effect of methoxsalen alone is nausea, which occurs with approximately 10%
of all patients. This effect may be minimized or avoided by instructing the patient to take methoxsalen in milk
or food, or to divide the dose into two portions, taken approximately one-half hour apart. Other effects include
nervousness, insomnia, and depression.
B. COMBINED METHOXSALEN/UVA THERAPY:
1. PRURITUS: This adverse reaction occurs with approximately 10% of all patients. In most cases, pruritus
can be alleviated with frequent application of bland emollients or other topical agents; severe pruritus may
require systemic treatment. If pruritus is unresponsive to these measures, shield pruritic areas from further
UVA exposure until the condition resolves. If intractable pruritus is generalized, UVA treatment should be
discontinued until the pruritus disappears.
2. ERYTHEMA: Mild, transient erythema at 24–48 hours after PUVA therapy is an expected reaction and
indicates that a therapeutic interaction between methoxsalen and UVA occurred. Any area showing
moderate erythema (greater than Grade 2 - See Table 1 for grades of erythema) should be shielded during
subsequent UVA exposures until the erythema has resolved. Erythema greater than Grade 2 which appears
within 24 hours after UVA treatment may signal a potentially severe burn. Erythema may become
progressively worse over the next 24 hours, since the peak erythemal reaction characteristically occurs 48
hours or later after methoxsalen ingestion. The patient should be protected from further UVA exposures
and sunlight, and should be monitored closely.
3. IMPORTANT DIFFERENCES BETWEEN PUVA ERYTHEMA AND SUNBURN: PUVA-
induced inflammation differs from sunburn or UVB phototherapy in several ways. The percent
transmission of UVB varies between 0% to 34% through skin whereas UVA varies between 1% to 80%
transmission; thus, UVA is transmitted to a larger percent through the skin. (Diffey, 198221). The DNA
lesions induced by PUVA are very different from UV-induced thymine dimers and may lead to a DNA
crosslink. This DNA lesion may be more problematic to the cell because crosslinks are more lethal and
psoralen-DNA photoproducts may be “new” or unfamiliar substrates for DNA repair enzymes. DNA
synthesis is also suppressed longer after PUVA. The time course of delayed erythema is different with
PUVA and may not involve the usual mediators seen in sunburn. PUVA-induced redness may be just
beginning at 24 hours, when UVB erythema has already passed its peak. The erythema dose-response
curve is also steeper for PUVA. Compared to equally erythemogenic doses of UVB, the histologic
alterations induced by PUVA show more dermal vessel damage and longer duration of epidermal and
dermal abnormalities.
4. OTHER ADVERSE REACTIONS: Those reported include edema, dizziness, headache, malaise,
depression, hypopigmentation, vesiculation and bullae formation, non-specific rash, herpes simplex,
miliaria, urticaria, folliculitis, gastrointestinal disturbances, cutaneous tenderness, leg cramps, hypotension,
and extension of psoriasis.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 8
VIII. OVERDOSAGE
In the event of methoxsalen overdosage, induce emesis and keep the patient in a darkened room for at least 24
hours. Emesis is most beneficial within the first 2 to 3 hours after ingestion of methoxsalen, since maximum
blood levels are reached by this time.
IX. DRUG DOSAGE & ADMINISTRATION
CAUTION: Oxsoralen-Ultra represents a new dose form of methoxsalen. This new dosage form of methoxsalen
exhibits significantly greater bioavailability and earlier photosensitization onset time than previous methoxsalen dosage
forms. Each patient should be evaluated by determining the minimum phototoxic dose (MPD) and phototoxic peak time
after drug administration prior to onset of photochemotherapy with this dosage form. Human bioavailability studies
have indicated the following drug dosage and administration directions are to be used as a guideline only.
PSORIASIS THERAPY
1. DRUG DOSAGE - INITIAL THERAPY: The methoxsalen capsules should be taken 1 1/2 to 2 hours
before UVA exposure with some low fat food or milk according to the following table:
Patient’s Weight
Dose
(kg)
(lbs)
(mg)
<30
<66
10
30-50
66-110
20
51-65
112-143
30
66-80
146-176
40
81-90
179-198
50
91-115 201-254
60
>115
>254
70
Elderly patients should generally be started at the low end of the dose recommended according to
body weight and closely monitored during PUVA therapy. Although clinical experience has not
identified differences in response between elderly and younger patients, the use of methoxsalen in
older individuals may be affected by the presence of pre-existing medical conditions.
2. INITIAL EXPOSURE: The initial UVA exposure energy level and corresponding time of exposure is
determined by the patient’s skin characteristics for sun burning and tanning as follows:
Skin Type
History
Recommen
ded
Joules/cm2
I
Always burn, never tan (patients
with erythrodermic psoriasis are
to be classed as Type I for
determination of UVA dosage.)
0.5 J/cm2
II
Always burn, but sometimes tan
1.0 J/cm2
III
Sometimes burn, but always tan
1.5 J/cm2
IV
Never burn, always tan
2.0 J/cm2
Skin Type
Physician Examination
Joules/cm2
V*
Moderately pigmented
2.5 J/cm2
VI*
Blacks
3.0 J/cm2
(*Patients with natural pigmentation of these types should be classified into a lower skin type category if the
sunburning history so indicates.)
If the MPD is done, start at 1/2 MPD.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 9
Additional drug dosage directions are as follows:
a. Weight Change: In the event that the weight of a patient changes during treatment such that he/she falls into
an adjacent weight range/dose category, no change in the dose of methoxsalen is usually required. If, in the
physician’s opinion, however, a weight change is sufficiently great to modify the drug dose, then an adjustment
in the time of exposure to UVA should be made.
b. Dose/Week: The number of doses per week of methoxsalen capsules will be determined by the patient’s
schedule of UVA exposures. In no case should treatments be given more often than once every other day
because the full extent of phototoxic reactions may not be evident until 48 hours after each exposure.
c. Dosage Increase: Dosage may be increased by 10 mg. after the fifteenth treatment under the conditions
outlined in section XI.B.4.b.
X. UVA RADIATION SOURCE SPECIFICATIONS & INFORMATION
A. IRRADIANCE UNIFORMITY:
The following specifications should be met with the window of the detector held in a vertical plane:
1.
Vertical variation: For readings taken at any point along the vertical center axis of the chamber (to
within 15 cm from the top and bottom), the lowest reading should not be less than 70 percent of the highest
reading.
2.
Horizontal variation: Throughout any specific horizontal plane, the lowest reading must be at least 80
percent of the highest reading, excluding the peripheral 3 cm of the patient treatment space.
B. PATIENT SAFETY FEATURES:
The following safety features should be present: (1) Protection from electrical hazard: All units should be
grounded and conform to applicable electrical codes. The patient or operator should not be able to touch any
live electrical parts. There should be ground fault protection. (2) Protective shielding of lamps: The patient
should not be able to come in contact with the bare lamps. In the event of lamp breakage, the patient should not
be exposed to broken lamp components. (3) Hand rails and hand holds: Appropriate supports should be
available to the patient. (4) Patient viewing window: A window which blocks UV should be provided for
viewing the patient during treatment. (5) Door and latches: Patients should be able to open the door from the
inside with only slight pressure to the door. (6) Non-skid floor: The floor should be of a non-skid nature. (7)
Thermoregulation: Sufficient air flow should be provided for patient safety and comfort, limiting temperature
within the UVA radiator cabinet to approximately less than 100°F. (8) Timer: The irradiator should be
equipped with an automatic timer which terminates the exposure at the conclusion of a pre-set time interval. (9)
Patient alarm device: An alarm device within the UVA irradiator chamber should be accessible to the patient
for emergency activation. (10) Danger label: The unit should have a label prominently displayed which reads as
follows:
DANGER - Ultraviolet radiation - Follow your physicians instructions - Failure to use protective eyewear may
result in eye injury.
C. UVA EXPOSURE DOSIMETRY MEASUREMENTS:
The maximum radiant exposure or irradiance (within ±15 percent) of UVA (320-400 nm) delivered to the
patient should be determined by using an appropriate radiometer calibrated to be read in Joules/cm2 or mW/cm2.
In the absence of a standard measuring technique approved by the National Bureau of Standards, the system
should use a detector corrected to a cosine spatial response. The use and recalibration frequency of such a
radiometer for a specific UVA irradiator chamber should be specified by the manufacturer because the UVA
dose (exposure) is determined by the design of the irradiator, the number of lamps, and the age of the lamp. If
irradiance is measured, the radiometer reading in mW/cm2 is used to calculate the exposure time in minutes to
deliver the required UVA in Joules/cm2 to a patient in the UVA irradiator cabinet. The equation is:
Exposure Time = Desired UVA Dose (J/cm2)
(minutes) 0.06 x Irradiance (mW/cm2)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 10
Overexposure due to human error should be minimized by using an accurate automatic timing device,
which is set by the operator and controlled by energizing and de-energizing the UVA irradiator lamp.
The timing device calibration interval should be specified by the manufacturer. Safety systems should
be included to minimize the possibility of delivering a UVA exposure which exceeds the prescribed
dose, in the event the timer or radiometer should malfunction.
D. UVA SPECTRAL OUTPUT DISTRIBUTION:
The spectral distributions of the lamps should meet the following specifications:
Wavelength band (nanometers)
Output1
<310
<1
310 to 320
1 to 3
320 to 330
4 to 8
330 to 340
11 to 17
340 to 350
18 to 25
350 to 360
19 to 28
360 to 370
15 to 23
370 to 380
8 to 12
380 to 390
3 to 7
390 to 400
1 to 3
1As a percentage of total irradiance between 320 and 400 nanometers.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 11
XI. PUVA TREATMENT PROTOCOL
INTRODUCTION:
The Oxsoralen-Ultra Capsules reach their maximum bioavailability in 1 1/2 to 2 hours after ingestion.
On average, the serum level achieved with Oxsoralen-Ultra is twice that obtained with 8-MOP (formerly
Oxsoralen) and reach their peak concentration in less than 1/2 the time of the 8-MOP capsules.
As a result the mean MED J/cm2 for the Oxsoralen-Ultra Capsules is substantially less than that required for 8-
MOP (Levins et al., 1984 and private communication1).
Photosensitivity studies demonstrate a shorter time of peak photosensitivity of 1.5 to 2.1 hours vs. 3.9 to 4.25
hours for regular methoxsalen capsules.
A. INITIAL EXPOSURE: The initial UVA exposures should be conducted according to the guidelines
presented previously under IX.B.1 and 2, Psoriasis therapy, Drug dosage-initial Therapy and Exposure.
B. CLEARING PHASE: Specific recommendations for patient treatment are as follows:
1. SKIN TYPES I, II, & III. Patients with skin types I, II, and III may be treated 2 or 3 times per week. UVA
exposure may be held constant or increased by up to 1.0 Joule/cm2 at each treatment, according to the
patient’s response. If erythema occurs, however, do not increase exposure time until erythema resolves.
The severity and extent of the patient’s erythema may be used to determine whether the next exposure
should be shortened, omitted, or maintained at the previous dosage. See Adverse Reactions section for
additional information.
2. SKIN TYPES IV, V, & VI. Patients with skin types IV, V, and VI may be treated 2 or 3 times per week.
UVA exposure may be held constant or increased by up to 1.5 Joules/cm2 at each treatment unless
erythema occurs. If erythema occurs, follow instructions outlined above in the procedures for patients with
skin types I, II, and III.
3. ERYTHRODERMIC PSORIASIS: Patients with erythrodermic psoriasis should be treated with special
attention because pre-existing erythema may obscure observations of possible treatment-related phototoxic
erythema. These patients may be treated 2 or 3 times per week, as a Type I patient.
4. MISCELLANEOUS SITUATIONS:
a. If there is no response after a total of 10 treatments, the exposure of UVA energy may be increased by
an additional 0.5–1.0 Joules/cm2 above the prior incremental increases for each treatment. (Example: a
patient whose exposure dosage is being increased by 1.0 Joule/cm2 may now have all subsequent doses
increased by 1.5–2.0 Joules/cm2.)
b. If there is no response, or only minimal response, after 15 treatments, the dosage of methoxsalen may be
increased by 10 mg (a one-time increase in dosage). This increased dosage may be continued for the
remainder of the course of treatment but should not be exceeded.
c. If a patient misses a treatment, the UVA exposure time of the next treatment should not be increased. If
more than one treatment is missed, reduce the exposure by 0.5 Joules/cm2 for each treatment missed.
d. If the lower extremities are not responding as well as the rest of the body and do not show erythema,
cover all other body areas and give 25 percent of the present exposure dose as an additional exposure to the
lower extremities. This additional exposure to the lower extremities should be terminated if erythema
develops on these areas.
e. Non-responsive psoriasis: If a patient’s generalized psoriasis is not responding, or if the condition
appears to be worsening during treatment, the possibility of a generalized phototoxic reaction should be
considered. This may be confirmed by the improvement of the condition following temporary
discontinuance of this therapy for two weeks. If no improvement occurs during the interruption of
treatment, this patient may be considered a treatment failure.
C. ALTERNATIVE EXPOSURE SCHEDULE:
As an alternative to increasing the UVA exposure at each treatment, the following schedule may be followed;
this schedule may reduce the total number of Joules/cm2 received by the patient over the entire course of
therapy.
1. Incremental increases in UVA exposure for all patients may range from 0.5 to 1.5 Joules/cm2, according to
the patient’s response to therapy.
2. Once Grade 2 clearing (see Table 2) has been reached and the patient is progressing adequately, UVA
dosage is held constant. This dosage is maintained until Grade 4 clearing is reached.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 12
3. If the rate of clearing significantly decreases, exposure dosage may be increased at each treatment (0.1-1.5
Joules/cm2) until Grade 3 clearing and a satisfactory progress rate is attained. The UVA exposure will be
held constant again until Grade 4 clearing is attained. These increases may be used also if the rate of
clearing significantly decreases between Grade 3 and Grade 4 response. However, the possibility of a
phototoxic reaction should be considered; see Non-responsive Psoriasis, above.
4. In summary, this schedule raises slightly the increments (Joules/cm2) of UVA dosage, but limits these
increases to those periods when the patient is not responding adequately. Otherwise, the UVA exposure is
held at the lowest effective dose.
D. MAINTENANCE PHASE:
The goal of maintenance treatment is to keep the patient as symptom-free as possible with the least amount of
UVA exposure.
1. SCHEDULE OF EXPOSURES: When patients have achieved 95 percent clearing, or Grade 4 response
(Table 2), they may be placed on the following maintenance schedules (M1 – M4), in sequence. It is
recommended that each maintenance schedule be adhered to for at least 2 treatments (unless erythema or
psoriatic flare occurs, in which case see (2a) and (2b) below).
Maintenance Schedules
M1 - once/week
M2 - once/2 weeks
M3 - once/3 weeks
M4 - p.r.n. (i.e., for
flares)
2. LENGTH OF EXPOSURE: The UVA exposure for the first maintenance treatment of any schedule
(except M4 as noted below) is the same as that of the patient’s last treatment under the previous schedule.
For skin types I–IV, however, it is recommended that the maximum UVA dosage during maintenance
treatments not exceed the following:
Skin Types
Joules/cm2/treatment
I
II
III
IV
12
14
18
22
If the patient develops erythema or new lesions of psoriasis, proceed as follows:
a. Erythema: During maintenance therapy, the patient’s tan and threshold dose for erythema may
gradually decrease. If maintenance treatments produce significant erythema, the exposure to UVA should
be decreased by 25 percent until further treatments no longer produce erythema.
b. Psoriasis: If the patient develops new areas of psoriasis during maintenance therapy (but still is
classified as having a Grade 4 response), the exposure to UVA may be increased by 0.5–1.5 Joules/cm2 at
each treatment; this is appropriate for all types of patients. These increases are continued until the psoriasis
is brought under control and the patient is again clear. The exposure being administered when this clearing
is reached should be used for further maintenance treatment.
3. FLARES DURING MAINTENANCE: If the patient flares during maintenance treatment (i.e.,
develops psoriasis on more than 5 percent of the originally involved areas of the body), his maintenance
treatment schedule may be changed to the preceding maintenance or clearing schedule. The patient may be
kept on his schedule until again 95 percent clear. If the original maintenance treatment schedule is unable
to control the psoriasis, the schedule may be changed to a more frequent regimen. If a flare occurs less
than 6 weeks after the last treatment, 25 percent of the maximum exposure received during the clearing
phase, with the clearing schedule received during the clearing phase, may be used and then proceed with
the clearing schedule previously followed for this patient. (At 95 percent clearing, follow regular
maintenance until the optimum maintenance schedule is determined for the patient.) If more than 6 weeks
have elapsed since the last treatment was given, treat patients as if they were beginning therapy insofar as
exposure dosages are concerned, since their threshold for erythema may have decreased.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 13
Table 1. Grades of Erythema
Grade
Erythema
0
1
2
3
4
No erythema
Minimally perceptible erythema -
faint pink
Marked erythema but with no edema
Fiery erythema with edema
Fiery erythema with edema and
blistering
Table 2. Response to Therapy
Grade
Criteria
Percent Improvement
(compared to original
extent of disease)
-1
0
1
2
3
4
Psoriasis worse
No change
Minimal improvement - slightly less scale
and/or erythema
Definite improvement - partial flattening
of all plaques—less scaling and less erythema
Considerable improvement - nearly complete
flattening of all plaques but borders of plaques still
palpable
Clearing; complete flattening of plaques
including borders; plaques may be outlined
by pigmentation
0
0
5-20
20-50
50-95
95
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 14
XII. HOW SUPPLIED
Oxsoralen-Ultra Capsules, each containing 10 mg of methoxsalen (8-methoxypsoralen) in a soft gelatin capsule
packaged in amber glass bottles are available as follows:
Unit Count
NDC Number
50
NDC 0187-0650-42
Store at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F).
ICN Pharmaceuticals, Inc.
3300 Hyland Ave.
Costa Mesa, CA 92626, U.S.A.
BIBLIOGRAPHY
1. Levins, P.C., Gange, R.W., Momtaz-T,K., Parrish, J.A., and Fitzpatrick, T.B.: A New Liquid Formulation
of 8-Methoxypsoralen: Bioactivity and Effect of Diet: JID, 82, No. 2, pp. 185-187 (1984) and private
communication.
2. Artuc, M., Stuettgen, G., Schalla, W., Schaefer, H., and Gazith, J.: Reversibile binding of 5- and 8-
methoxypsoralen to human serum proteins (albumin) and to epidermis in vitro: Brit. J. Dermat. 101, pp.
669-677 (1979).
3. Mandula, B. B., Pathak, M.A., Nakayama, T., and Davidson, S.J.: Induction of mixed-function oxidases in
mouse liver by psoralens., Ibid, 99, pp. 687-692 (1978).
4. Pathak, M. A., Fitzpatrick, T. B., Parrish, J. A.: PSORIASIS, Proceedings of the Second International
Symposium. Edited by E. M. Farber, A. J. Cox, Yorke Medical Books, pp. 262-265 (1977).
5. Dall’Acqua, F., Marciani, S., Ciavatta, L., Rodighiero, G.: Formation of interstrand cross-linkings in the
photoreactions between furocoumarins and DNA; Z Naturforsch (B), 26, pp. 561-569 (1971).
6. Cole, R. S.: Light-induced cross-linkings of DNA in the presence of a furocoumarin (psoralen), Biochem.
Biophys. Acta, 217, pp. 30-39 (1970).
7. Musajo, L., Rodighiero, G., Caporale, G., Dall’Acqua, F., Marciani, S., Bordin, F., Baccichetti, F.,
Bevilacqua, R.: Photoreactions between Skin-Photosensitizing Furocoumarins and Nucleic Acids,
SUNLIGHT AND MAN; Normal and Abnormal Photobiologic Responses. Edited by M. A. Pathak, L. C.
Harber, M. Seiji et al. University of Tokyo Press, pp. 369-387 (1974).
8. Dall’Acqua, F., Vedaldi, D., Bordin, F., and Rodighiero, G.: New studies in the interaction between 8-
methoxypsoralen and DNA in vitro; JID, 73, pp. 191-197 (1979).
9. Yoshikawa, K., Mori, N., Sakakibara, S., Mizuno, N., Song, P.: Photo-Conjugation of 8-methoxypsoralen
with Proteins; Photochem. & Photobiol. 29, pp. 1127-1133 (1979).
10. Hakim, R. E., Griffin, A. C.: Knox, J. M.: Erythema and tumor formation in methoxsalen treated mice
exposed to fluorescent light; Arch. Dermatol. 82, pp. 572-577 (1960).
11. O’Neal, M.A., Griffin, A.C.: The Effect of Oxypsoralen upon Ultraviolet Carcinogenesis in Albino Mice,
Cancer Res., 17, pp. 911-916 (1957).
12. Stern, R. S., Unpublished personal communication.
13. Stern, R. S., Parrish, J.A., Zierler, S.: Skin Carcinoma in Patients with Psoriasis Treated with Topical Tar
and Artificial Ultraviolet Radiation. Lancet, 1, pp. 732-735 (1980).
14. Stern, R.S., Laird, N., Melski, J., Parrish, J.A., Fitzpatrick, T.B., Bleich, H.L.: Cutaneous Squamous-
Cell Carcinoma in Patients Treated with PUVA: NEJM, 310, No. 18, pp. 1156-1161 (1984).
15. Roenigk, Jr., H. H., and 12 Cooperating Investigators: Skin Cancer in the PUVA-48 Cooperative Study
of Psoriasis. Program for Forty-First Annual Meeting for The Society of Investigative Dermatology, Inc.,
Sheraton Washington Hotel, Washington, D.C., May 12, 13, and 14, 1980. Abstract JID, 74 No. 4, pp. 250
(April 1980).
16. Stern et al., Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and
ultraviolet A radiation (PUVA). The PUVA Follow-Up Study. New England Journal of Medicine,
336:1041-1045, (April 10, 1997).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 15
17. Mosher, D. B., Pathak, M. A., Harris, T. J., Fitzpatrick, T. B.: Development of Cutaneous Lesions in
Vitiligo During Long-Term PUVA Therapy. Program for Forty-First Annual Meeting for The Society for
Investigative Dermatology, Inc., Sheraton Washington Hotel, Washington, D.C., May 12, 13, and 14,
1980. Abstracts JID, 74, No. 4, p. 259 (April, 1980).
18. Cloud, T. M., Hakim, R., Griffin, A. C.: Photosensitization of the eye with methoxsalen. I. Acute effects;
Arch. Ophthalmol. 64, pp. 346-352 (1960).
19. Cloud, T. M., Hakim, R., Griffin, A. C.: Photosensitization of the eye with methoxsalen. II. Chronic
effects, Ibid, 66, pp. 689-694 (1961).
20. Freeman, R. G., Troll, D.: Photosensitization of the eye by 8-methoxypsoralen, JID, 53, pp. 449-453
(1969).
21. Lerman, S., Megaw, J., Willis, I.: Potential ocular complications from PUVA therapy and their
prevention; JID 74, pp. 197-199 (1980).
22. Diffey, >L., Medical Physics Handbook 11, Ultraviolet Radiation In Medicine, Adam Hilger, Ltd., Bristol,
p. 86 (1982)
Revised 8-98
2400-03EL
PATIENT INFORMATION ON THE USE OF
OXSORALEN–ULTRA CAPSULES (METHOXSALEN, 10 mg)
IN THE TREATMENT OF PSORIASIS
This brochure is intended to provide you with information about the treatment of psoriasis. The entire brochure should be read so
that you are aware of the requirements on your part to ensure the effectiveness and safety of the therapy. Any additional questions
that you may have can be answered by your doctor or pharmacist. In addition, the pharmacist will have a copy of a very technical
brochure entitled the “Physician’s Package Insert” that you may wish to read.
A. What Is Oxsoralen-Ultra (Methoxsalen)?
Oxsoralen-Ultra (methoxsalen) is a drug which has been shown to be effective in the treatment of psoriasis when combined with
exposure to a very specific kind of light. The use of the drug must be combined with exposure to the special light to produce
effective therapy. Oxsoralen-Ultra represents a new dose form of methoxsalen. This new dosage form of methoxsalen exhibits
significantly greater bioavailability and earlier photosensitization onset time than previous methoxsalen dosage forms.
B. What Is The Special Light?
Light is classified into many different parts. One part is known as ultraviolet light, which is a normal component of sunlight.
Artificial or man-made light sources are now available that produce the special part of light (ultraviolet “A”) necessary for the
most effective therapy.
C. What Is “PUVA”?
“PUVA” is the name of the treatment for psoriasis and stands for the use of Psoralen drug (Oxsoralen-Ultra) in combination with
UltraViolet A light.
D. What Is Psoriasis?
Psoriasis is a skin condition associated with red and scaly patches. The cause of psoriasis is not known. PUVA (Oxsoralen–
Ultra with ultraviolet A light) is used for the treatment of severe psoriasis that has not been helped by other methods of therapy.
E. What Should The Patient Do Before PUVA Therapy?
Certain other medicines can make you more sensitive to the combination drug and light treatment. In addition, certain other
medical conditions can be aggravated by this treatment. Before starting treatment, be sure to tell your doctor if you have
experienced any of the following:
1) had a severe reaction to Oxsoralen–Ultra in the past
2) had recent x-ray treatment or planning any
3) have or ever have had skin cancer
4) have or ever have had any eye problems such as cataracts or loss of the lens of the eyes
5) have or ever have had liver problems
6) have or ever have had heart or blood pressure problems
7) have any medical condition that requires you to stay out of the sun such as lupus erythematosus
8) are taking any drugs (either prescription or nonprescription). Some drugs can increase your sensitivity to ultraviolet light
either from the sun or man-made sources. Examples of such drugs include major tranquilizers, sulfa drugs for the
treatment of infection or diabetes, tetracycline, antibiotics, griseofulvin products, thiazide-containing diuretics (blood
pressure or water elimination drugs), and certain antibacterial or deodorant soaps.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-600/S-006 & S-009
Page 16
F. How Should The Patient Take Oxsoralen–Ultra?
1) The number of capsules recommended by your doctor should be taken with some food or lowfat milk two hours before
ultraviolet light treatment.
2) Oxsoralen–Ultra is a potent drug. Never take more than is prescribed for you since it may result in burning and/or blistering
of your skin after exposure to ultraviolet light.
G. What Precautions Should Be Taken During And After PUVA Therapy?
1) Eye Protection — Make sure that you wear special wrap-around sunglasses that totally block or absorb ultraviolet light. Put
them on immediately after taking Oxsoralen-Ultra and continue wearing them for 24 hours if any light is present (even if
indirect such as reflection or through window glass). Ordinary sunglasses are not adequate.
2) Skin & Lip Protection — Do not allow exposure of your skin and lips to sunlight for 8 hours after treatment. In addition, do
not expose your skin to either sunlight or sun lamps (regardless of safety claims) within 24 hours of a scheduled treatment.
It is advisable to wear protective clothing (hat, gloves) to cover as much of your body as possible after treatment as well as
using a sun screen product having a protection factor of at least 15 (only use after treatment).
H. How Long Will The Treatments Last?
May take from six to eight weeks before lesions disappear. Maintenance treatments are usually needed to keep the disease
under control.
I.
What Are The Problems Associated With Pregnancy Or Breast Feeding?
1) Birth control methods should be employed since the effects of PUVA therapy on the unborn child are not known. If you
become pregnant, inform your doctor so that he can determine whether it is necessary for you to temporarily stop therapy.
2) Since it is not known whether Oxsoralen-Ultra passes into mother’s milk, it is safer not to breast feed while taking this drug.
J. What Are The Risks Of PUVA Therapy?
1) Premature skin aging may result from prolonged PUVA therapy, especially with those individuals who tan poorly. This
problem is similar to excessive exposure to sunlight.
2) There is an increased risk of developing both melanoma and non-melanoma skin cancer. This risk is greater for individuals
who fall into the following categories:
a) fair skin that burns rather than tans
b) have had prior treatment with x-rays, grenz rays, or arsenic
c) have had coal tar and UltraViolet B (UVB) treatment.
Even though your doctor will be examining you, you should routinely and completely examine yourself for small growths on
your skin or skin sores that will not heal. Immediately report such observations to your doctor.
3) Since studies have shown that animals with unprotected eyes have developed cataracts after PUVA therapy, you should
have your eyes examined by an ophthalmologist before starting PUVA therapy, after the first year of therapy and every two
years thereafter.
K. What Are The Possible Side Effects?
1) The most common side effects of PUVA therapy are nausea, itching, and redness of the skin. The use of lowfat milk or food
when ingesting the drug may prevent the nausea.
2) Tenderness or blistering of the skin may occur, but these symptoms can be helped by the use of skin products
recommended by your doctor or pharmacist.
3) Less frequent side effects include depression, dizziness, headache, swelling, rash or leg cramps.
Important: Contact your doctor if any side effect continues to bother you after 24–48 hours.
L. What Else Should The Patient Know?
1) Remember to take Oxsoralen–Ultra as directed by your doctor. If you forget to take the drug before your scheduled
treatment, be sure to call your doctor to determine what he wishes you to do.
2) Remember that the drug has been prescribed specifically for you and your diagnosed condition. Do not use the drug for any
other conditions nor give the drug to others even if they have similar symptoms.
3) If you think that you or anyone else has accidentally taken an overdose, stay out of the sunlight and immediately contact
your poison control center, doctor, pharmacist, or nearest hospital emergency room.
4)
ALWAYS KEEP THIS DRUG AND ALL OTHER DRUGS OUT OF THE REACH OF CHILDREN.
5)
Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F).
ICN Pharmaceuticals, Inc.
Printed in U.S.A.
3300 Hyland Ave.
Costa Mesa, CA 92626, U.S.A.
Revised -8-98
2401-04 EL
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:31.334672
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19600slr006,009_oxsoralen-ultra_lbl.pdf', 'application_number': 19600, 'submission_type': 'SUPPL ', 'submission_number': 9}
|
11,558
|
_______________________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
NAFTIN® Cream, 2% safely and effectively. See full prescribing
information for NAFTIN (naftifine hydrochloride) Cream, 2%.
NAFTIN (naftifine hydrochloride) Cream, 2% for topical use
Initial U.S. Approval: 1988
---------------------------RECENT MAJOR CHANGES--------------------------
Indications and Usage (1)
10/2014
----------------------------INDICATIONS AND USAGE--------------------------
NAFTIN Cream is an allylamine antifungal indicated for the treatment of
interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organism
Trichophyton rubrum. (1)
----------------------DOSAGE AND ADMINISTRATION----------------------
For topical use only. NAFTIN Cream is not for ophthalmic, oral, or
intravaginal use. (2)
Apply a thin layer of NAFTIN Cream once-daily to the affected areas plus a
½ inch margin of healthy surrounding skin for 2 weeks. (2)
---------------------DOSAGE FORMS AND STRENGTHS---------------------
Cream: 2% (3)
-------------------------------CONTRAINDICATIONS-----------------------------
None (4)
-----------------------WARNINGS AND PRECAUTIONS--------------
If redness or irritation develops with the use of NAFTIN Cream treatment
should be discontinued. (5.1)
------------------------------ADVERSE REACTIONS------------------------------
The most common adverse reaction (≥1%) is pruritus. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Merz
Pharmaceuticals, LLC at 877-743-8454 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 10/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Local Adverse Reactions
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
12.4
Microbiology
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1
Tinea cruris
14.2
Interdigital Tinea pedis
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed
Page 1 of 5
Reference ID: 3642374
Reference ID: 3646088
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
NAFTIN Cream is indicated for the treatment of: interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organism Trichophyton rubrum.
2 DOSAGE AND ADMINISTRATION
For topical use only. NAFTIN Cream is not for ophthalmic, oral or intravaginal use. Apply a thin layer of NAFTIN Cream once-daily to the affected areas plus a ½
inch margin of healthy surrounding skin for 2 weeks.
3 DOSAGE FORMS AND STRENGTHS
Cream: 2%, white to off-white cream
4 CONTRAINDICATIONS
None
5 WARNINGS AND PRECAUTIONS
5.1
Local Adverse Reactions
If irritation or sensitivity develops with the use of NAFTIN Cream, treatment should be discontinued. Patients should be directed to contact their physician if these
conditions develop following use of NAFTIN Cream.
6 ADVERSE REACTIONS
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 to
rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
During clinical trials, 760 subjects were exposed to naftifine 1% and 2% cream formulations. A total of 421 subjects with interdigital tinea pedis and/or tinea cruris
were treated with NAFTIN Cream.
In two randomized, vehicle-controlled trials (400 patients were treated with NAFTIN Cream). The population was 12 to 88 years old, primarily male (79%), 48%
Caucasian, 36% Black or African American, 40% Hispanic or Latino and had either predominantly interdigital tinea pedis or tinea cruris. Most subjects received
doses once-daily, topically, for 2 weeks to cover the affected skin areas plus a ½ inch margin of surrounding healthy skin. In the two vehicle-controlled trials,
17.5% of NAFTIN Cream treated subjects experienced an adverse reaction compared with 19.3% of vehicle subjects. The most common adverse reaction (≥1%) is
pruritus. Most adverse reactions were mild in severity. The incidence of Adverse Reactions in the NAFTIN Cream treated population were not significantly
different than the vehicle treated population.
In an open-label pediatric pharmacokinetics and safety trial, 22 pediatric subjects 13-17 years of age with interdigital tinea pedis and tinea cruris received NAFTIN
Cream. The incidence of adverse reactions in the pediatric population was similar to that observed in the adult population.
6.2
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of (naftifine hydrochloride): redness/irritation, inflammation, maceration, swelling,
burning, blisters, serous drainage, crusting, headache, dizziness, leukopenia, agranulocytosis. 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.
8 USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B. There are no adequate and well-controlled studies of NAFTIN Cream in pregnant women. Because animal reproduction studies are not
always predictive of human response, NAFTIN Cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
The animal multiples of human exposure calculations were based on daily dose body surface area comparison (mg/m2) for the reproductive toxicology studies
described in this section and in Section 13.1. The Maximum Recommended Human Dose (MRHD) was set at 8 g 2% cream per day (2.67 mg/kg/day for a 60 kg
individual).
Systemic embryofetal development studies were conducted in rats and rabbits. Oral doses of 30, 100 and 300 mg/kg/day naftifine hydrochloride were administered
during the period of organogenesis (gestational days 6 – 15) to pregnant female rats. No treatment-related effects on embryofetal toxicity or teratogenicity were
noted at doses up to 300 mg/kg/day (18.2X MRHD). Subcutaneous doses of 10 and 30 mg/kg/day naftifine hydrochloride were administered during the period of
organogenesis (gestational days 6 – 15) to pregnant female rats. No treatment-related effects on embryofetal toxicity or teratogenicity were noted at 30 mg/kg/day
(1.8X MRHD). Subcutaneous doses of 3, 10 and 30 mg/kg/day naftifine hydrochloride were administered during the period of organogenesis (gestational days 6 –
18) to pregnant female rabbits. No treatment related effects on embryofetal toxicity or teratogenicity were noted at 30 mg/kg/day (3.6X MRHD).
A peri- and post-natal development study was conducted in rats. Oral doses of 30, 100 and 300 mg/kg/day naftifine hydrochloride were administered to female rats
from gestational day 14 to lactation day 21. Reduced body weight gain of females during gestation and of the offspring during lactation was noted at 300
mg/kg/day (18.2X MRHD). No developmental toxicity was noted at 100 mg/kg/day (6.1X MRHD).
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 NAFTIN Cream is
administered to a nursing woman.
8.4
Pediatric Use
The safety and effectiveness of NAFTIN Cream have been established in the age group 12-17 with interdigital tinea pedis and tinea cruris.
Page 2 of 5
Reference ID: 3642374
Reference ID: 3646088
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
s
tructural formula
The molecular formula is C 21 H21 N•HCl with a molecular weight of 323.86.
Use of NAFTIN Cream in this age group is supported by evidence from adequate and well controlled studies in adults with additional safety and PK data from an
open label trial, conducted in 22 adolescents ≥12 years of age who were exposed to Naftin Cream at a dose of approximately 8 g/day [see Clinical Pharmacology
(12.3)].
Safety and effectiveness in pediatric patients < 12 years of age have not been established.
8.5
Geriatric Use
Clinical studies of NAFTIN Cream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger
subjects.
11 DESCRIPTION
NAFTIN Cream is a white to off-white cream for topical use only. Each gram of (naftifine hydrochloride) Cream contains 20 mg of naftifine hydrochloride, a
synthetic allylamine antifungal compound.
Chemically, naftifine HCl is (E)-N-Cinnamyl-N-methyl-1-napthalenemethylamine hydrochloride.
NAFTIN Cream contains the following inactive ingredients: benzyl alcohol, cetyl alcohol, cetyl esters wax, isopropyl myristate, polysorbate 60, purified water,
sodium hydroxide, sorbitan monostearate, stearyl alcohol, and hydrochloric acid.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
NAFTIN Cream is a topical antifungal drug [see Clinical Pharmacology(12.4)]
12.2 Pharmacodynamics
The pharmacodynamics of NAFTIN Cream have not been established.
12.3 Pharmacokinetics
In vitro and in vivo bioavailability studies have demonstrated that naftifine penetrates the stratum corneum in sufficient concentration to inhibit the growth of
dermatophytes.
The pharmacokinetics of NAFTIN Cream was evaluated following once-daily topical application for 2 weeks to twenty one adult subjects, both males and females,
with both tinea pedis and tinea cruris. The median total amount of cream applied was 6.4 g (range 5.3-7.5 g) per day. The results showed that the systemic exposure
(i.e., maximum concentration (Cmax) and area under the curve (AUC)) to naftifine increased over the 2 week treatment period in all the 21 subjects. Geometric
Mean (CV%) AUC0-24 was 117 (41.2) ng*hr/mL on Day 1, and 204 (28.5) ng*hr/mL on Day 14. Geometric Mean (CV %) Cmax was 7 ng/mL (55.6) on Day 1
and 11 ng/mL (29.3) on day 14. Median Tmax was 8.0 hours on Day 1 (range: 4 to 24) and 6.0 hours on Day 14 (range: 0 to 16). Accumulation after 14 days of
topical application was less than two fold. Trough concentrations generally increased throughout the 14 day study period. Naftifine continued to be detected in
plasma in 13/21 (62%) subjects on day 28, the mean (SD) plasma concentrations were 1.6 ± 0.5 ng/mL (range below limit of quantitation (BLQ) to 3 ng/mL). In the
same pharmacokinetic trial conducted in patients with tinea pedis and tinea cruris, median fraction of the dose excreted in urine during the treatment period was
0.0016% on Day 1 versus 0.0020% on Day 14.
In a second trial, that enrolled 22 subjects the pharmacokinetics of NAFTIN Cream was evaluated in 20 pediatric subjects 13 – 17 years of age with both tinea pedis
and tinea cruris. Subjects were treated with a median dose of 8.1 g (range 6.6-10.1 g) applied to the affected areas once daily for 14 days. The results showed that
the systemic exposure increased over the treatment period. Geometric Mean (CV%) AUC0-24 was 138 (50.2) ng*hr/mL on Day 1, and 192 (74.9) ng*hr/mL on Day
14. Geometric Mean (CV %) Cmax was 9.21 ng/mL (48.4) on Day 1 and 12.7 ng/mL (67.2) on day 14. Median fraction of the dose excreted in urine during the
treatment period was 0.0030% on Day 1 and 0.0033% on Day 14.
12.4 Microbiology
Although the exact mechanism of action against fungi is not known, naftifine hydrochloride appears to interfere with sterol biosynthesis by inhibiting the enzyme
squalene 2, 3-epoxidase.This inhibition of enzyme activity results in decreased amounts of sterols, especially ergosterol, and a corresponding accumulation of
squalene in the cells.
Mechanism of Resistance
To date, a mechanism of resistance to naftifine has not been identified.
Naftifine has been shown to be active against most isolates of the following fungi, both in vitro and in clinical infections, as described in the INDICATIONS AND
USAGE section:
Trichophyton rubrum
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies to evaluate the carcinogenic potential of NAFTIN Cream have not been performed.
Naftifine hydrochloride revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames assay and Chinese
hamster ovary cell chromosome aberration assay) and one in vivo genotoxicity test (mouse bone marrow micronucleus assay).
Oral administration of naftifine hydrochloride to rats, throughout mating, gestation, parturition and lactation, demonstrated no effects on growth, fertility or
reproduction, at doses up to 100 mg/kg/day (6.1X MRHD).
Page 3 of 5
Reference ID: 3642374
Reference ID: 3646088
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14 CLINICAL STUDIES
14.1 Tinea Cruris
NAFTIN Cream has been investigated for safety and efficacy in a randomized, double-blind, vehicle-controlled, multi-center study in 146 subjects with
symptomatic and dermatophyte culture positive tinea cruris. Subjects were randomized to receive (naftifine hydrochloride) Cream or vehicle. Subjects applied the
study agent (naftifine hydrochloride) Cream or vehicle to the affected area plus a ½-inch margin of healthy skin surrounding the affected area once-daily for 2
weeks. Signs and symptoms of tinea cruris (presence or absence of erythema, pruritus, and scaling) were assessed, and KOH examination and dermatophyte culture
were performed at the primary efficacy endpoint at week 4.
The mean age of the study population was 47 years and 87% were male and 43% were white. At baseline, subjects were confirmed to have signs and symptoms of
tinea cruris, positive KOH exam, and confirmed dermatophyte presence based on culture results from a central mycology laboratory. The analysis of the intent-to
treat population was a comparison of the proportions of subjects with a complete cure at the week 4 visit (see Table 1). Complete cure was defined as both clinical
cure (absence of erythema, pruritus, and scaling) and mycological cure (negative KOH and dermatophyte culture).
The percentage of subjects experiencing clinical cure and the percentage of subjects experiencing mycological cure at week 4 are presented individually in Table 1
below.
Table 1 Efficacy Results for Pivotal Tinea Cruris Trial (Week 4 Assessment)
NAFTIN
VehicleN=71
(naftifine
hydrochloride)
Cream, 2%
Endpoint
N=75
Complete Curea
19(25%)
2(3%)
Effective Treatmentb
45(60%)
7(10%)
Mycological Curec
54(72%)
11(16%)
a. Complete cure is a composite endpoint of both mycological cure and clinical cure.
Clinical cure is defined as the absence of erythema, pruritus, and scaling (grade of 0).
b. Effective treatment is a negative KOH preparation and negative dermatophyte culture,
erythema, scaling, and pruritus grades of 0 or 1 (absent or nearly absent).
c. Myco logical cure is defined as negative KOH and dermatophyte culture.
14.2 Interdigital Tinea Pedis
NAFTIN Cream has been investigated for efficacy in a randomized, double-blind, vehicle-controlled, multi-center study in 217 subjects with symptomatic and
dermatophyte culture positive interdigital tinea pedis. Subjects were randomized to receive NAFTIN Cream or vehicle. Subjects applied the study agent (naftifine
hydrochloride) Cream or vehicle to the affected area of the foot plus a ½-inch margin of healthy skin surrounding the affected area once-daily for 2 weeks. Signs
and symptoms of interdigital tinea pedis (presence or absence of erythema, pruritus, and scaling) were assessed and KOH examination and dermatophyte culture
was performed at the primary efficacy endpoint at week 6.
The mean age of the study population was 42 years and 71% were male and 57% were white. At baseline, subjects were confirmed to have signs and symptoms of
interdigital tinea pedis, positive KOH exam, and confirmed dermatophyte culture. The primary efficacy endpoint was the proportions of subjects with a complete
cure at the week 6 visit (see Table 2). Complete cure was defined as both a clinical cure (absence of erythema, pruritus, and scaling) and mycological cure (negative
KOH and dermatophyte culture).
The efficacy results at week 6, four weeks following the end of treatment, are presented in Table 2 below. Naftin Cream demonstrated complete cure in subjects
with interdigital tinea pedis, but complete cure in subjects with only moccasin type tinea pedis was not demonstrated.
Table 2 Efficacy Results for Pivotal Interdigital Tinea Pedis Trial (Week 6 Assessment)
NAFTIN
Vehicle
(naftifine
hydrochloride)
N=70
Cream, 2%
Endpoint
N=147
Complete Curea
26(18%)
5(7%)
Effective Treatmentb
83(57%)
14(20%)
Mycological Curec
99(67%)
15(21%)
a. Complete cure is a composite endpoint of both mycological cure and clinical cure.
Clinical cure is defined as absence of erythema, pruritus, and scaling (grade of 0).
b. Effective treatment is a negative KOH preparation and negative dermatophyte culture,
erythema, scaling, and pruritus grades of 0 or 1 (absent or near absent).
c. Mycological cure is defined as negative KOH and dermatophyte culture.
16 HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
NAFTIN Cream is a white to off-white cream supplied in collapsible tubes in the following sizes:
30g – NDC 0259-1102-30
45g – NDC 0259-1102-45
60g – NDC 0259-1102-60
Storage
Store NAFTIN Cream at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
17 PATIENT COUNSELING INFORMATION
•
Inform patients that NAFTIN Cream is for topical use only. NAFTIN Cream is not intended for oral, intravaginal or ophthalmic use.
•
If irritation or sensitivity develops with the use of NAFTIN Cream treatment should be discontinued and appropriate therapy instituted. Patients should be
directed to contact their physician if these conditions develop following use of NAFTIN Cream.
Page 4 of 5
Reference ID: 3642374
Reference ID: 3646088
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NAFTIN (naftifine hydrochloride) Cream, 2% is manufactured for Merz Pharmaceuticals, LLC, Greensboro, NC 27410
NAFTIN (naftifine hydrochloride) Cream, 2% is a registered trademark of Merz Pharmaceuticals, LLC
5011539
Page 5 of 5
Reference ID: 3642374
Reference ID: 3646088
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:31.369092
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019599s012lbledt.pdf', 'application_number': 19599, 'submission_type': 'SUPPL ', 'submission_number': 12}
|
11,561
|
Rx only
PC3799F Rev. 01/09
DESCRIPTION
Verelan® (verapamil hydrochloride capsules) is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist).
Verelan is available for oral administration as a 360 mg hard gelatin capsule (lavender cap/yellow body), a 240 mg hard gelatin
capsule (dark blue cap/yellow body), a 180 mg hard gelatin capsule (light grey cap/yellow body), and a 120 mg hard gelatin capsule
(yellow cap/yellow body). These pellet filled capsules provide a sustained-release of the drug in the gastrointestinal tract.
The structural formula of verapamil HCl is given below: Structural formula
Chemical name: Benzeneacetonitrile, α-[3-[[2-(3,4-dimethoxyphenyl)-ethyl]methylamino]propyl]-3,4-dimethoxy-α-(1-methylethyl),
monohydrochloride.
Verapamil HCl is an almost white, crystalline powder, practically free of odor, with a bitter taste. It is soluble in water, chloroform
and methanol. Verapamil HCl is not structurally related to other cardioactive drugs.
In addition to verapamil HCl the Verelan capsule contains the following inactive ingredients: fumaric acid, talc, sugar spheres,
povidone, shellac, gelatin, FD&C red #40, yellow iron oxide, titanium dioxide, methylparaben, propylparaben, silicon dioxide, and
sodium lauryl sulfate. In addition, the Verelan 240 mg and 360 mg capsules contain FD&C blue #1 and D&C red #28; and the Verelan
180 mg capsule contains black iron oxide.
CLINICAL PHARMACOLOGY
Verelan is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) which exerts its pharmacologic effects by
modulating the influx of ionic calcium across the cell membrane of the arterial smooth muscle as well as in conductile and contractile
myocardial cells.
Normal sinus rhythm is usually not affected by verapamil HCl. However in patients with sick sinus syndrome, verapamil HCl may
interfere with sinus node impulse generation and may induce sinus arrest or sinoatrial block. Atrioventricular block can occur in
patients without preexisting conduction defects. (See WARNINGS.) Verapamil HCl does not alter the normal atrial action potential
or intraventricular conduction time, but depresses amplitude, velocity of depolarization and conduction in depressed atrial fibers.
Verapamil HCl may shorten the antegrade effective refractory period of accessory bypass tracts. Acceleration of ventricular rate and/
or ventricular fibrillation has been reported in patients with atrial flutter or atrial fibrillation and a coexisting accessory AV pathway
following administration of verapamil. (See WARNINGS.)
Verapamil HCl has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis. It is not known whether this
action is important at the doses used in man.
Mechanism of Action
Essential Hypertension
Verapamil HCl exerts antihypertensive effects by decreasing systemic vascular resistance, usually without orthostatic decreases in
blood pressure or reflex tachycardia; bradycardia (rate less than 50 beats/minute is uncommon). Verapamil HCl 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.
Pharmacokinetics and Metabolism
With the immediate release formulations, more than 90% of the orally administered dose is absorbed, and peak plasma concentrations
of verapamil are observed 1 to 2 hours after dosing. Because of rapid biotransformation of verapamil during its first pass through the
portal circulation, the absolute bioavailability ranges from 20% to 35%. Chronic oral administration of the highest recommended dose
(120 mg every 6 hours) resulted in plasma verapamil levels ranging from 125 to 400 ng/mL with higher values reported occasionally.
A nonlinear correlation between the verapamil HCl dose administered and verapamil plasma levels does exist.
During initial dose titration with verapamil a relationship exists between verapamil plasma concentrations and the prolongation of the
PR interval. However, during chronic administration this relationship may disappear. The quantitative relationship between plasma
verapamil concentrations and blood pressure reduction has not been fully characterized.
In a multiple dose pharmacokinetic study, peak concentrations for a single daily dose of Verelan 240 mg were approximately 65% of
those obtained with an 80 mg t.i.d. dose of the conventional immediate-release tablets, and the 24 hour post-dose concentrations were
approximately 30% higher. At a total daily dose of 240 mg, Verelan was shown to have a similar extent of verapamil bioavailability
based on the AUC-24 as that obtained with the conventional immediate-release tablets. In this same study Verelan doses of 120 mg,
240 mg and 360 mg once daily were compared after multiple doses. The ratios of the verapamil and norverapamil AUCs for the
page 1 of 9
Reference ID: 3042985
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Verelan 120 mg, 240 mg and 360 mg once daily doses are 1 (565 ng·hr/mL):3 (1660 ng·hr/mL):5 (2729 ng·hr/mL) and 1 (621 ng·hr/
mL):3 (1614 ng· hr/mL):4 (2535 ng·hr/mL) respectively, indicating that the AUC increased non-proportionately with increasing doses.
Food does not affect the extent or rate of the absorption of verapamil from the controlled release Verelan capsule. The Verelan 240
mg capsule when administered with food had a Cmax of 77 ng/mL which occurred 9.0 hours after dosing, and an AUC(O-inf) of 1387
ng·hr/mL. Verelan 240 mg under fasting conditions had a Cmax of 77 ng/mL which occurred 9.8 hours after dosing, and an AUC(O
inf) of 1541 ng·hr/mL.
The bioequivalence of Verelan 240 mg, administered as the pellets sprinkled on applesauce and as the intact capsule, was
demonstrated in a single-dose, cross-over study in 32 healthy adults. Comparative ratios (sprinkled/intact) of verapamil were 0.95,
1.02, and 1.01 for Cmax, Tmax, and AUC(O-inf) respectively. When the contents of the Verelan® capsule were administered by
sprinkling onto one tablespoonful of applesauce, the rate and extent of verapamil absorption were found to be bioequivalent to the
same dose when administered as an intact capsule. Similar results were observed with norverapamil.
The time to reach maximum verapamil concentrations (Tmax) with Verelan has been found to be approximately 7-9 hours in each
of the single dose (fasting), single dose (fed), the multiple dose (steady state) studies and dose proportionality pharmacokinetic
studies. Similarly the apparent half-life (t1/2) has been found to be approximately 12 hours independent of dose. Aging may affect the
pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly.
In healthy man, orally administered verapamil HCl undergoes extensive metabolism in the liver. Twelve metabolites have been
identified in plasma; all except norverapamil are present in trace amounts only. Norverapamil can reach steady-state plasma
concentrations approximately equal to those of verapamil itself. The biologic activity of norverapamil appears to be approximately
20% that of verapamil.
Approximately 70% of an administered dose of verapamil HCl is excreted as metabolites in the urine and 16% or more in the
feces within 5 days. About 3% to 4% is excreted in the urine as unchanged drug. Approximately 90% is bound to plasma proteins.
In patients with hepatic insufficiency, metabolism is delayed and elimination half-life prolonged up to 14 to 16 hours (see
PRECAUTIONS), the volume of distribution is increased and plasma clearance reduced to about 30% of normal. Verapamil
clearance values suggest that patients with liver dysfunction may attain therapeutic verapamil plasma concentrations with one-third of
the oral daily dose required for patients with normal liver function.
After four weeks of oral dosing (120 mg q.i.d.), verapamil and norverapamil levels were noted in the cerebrospinal fluid with
estimated partition coefficient of 0.06 for verapamil and 0.04 for norverapamil.
In 10 healthy males, administration of oral verapamil (80 mg every 8 hours for 6 days) and a single oral dose of ethanol (0.8 g/kg),
resulted in a 17% increase in mean peak ethanol concentrations (106.45 ± 21.40 to 124.23 ± 24.74 mg/dL) compared with placebo.
(See PRECAUTIONS-Drug Interactions.)
The area under the blood ethanol concentration versus time curve (AUC over 12 hours) increased by 30% (365.67 ± 93.52 to 475.07 ±
97.24 mg·hr/dL). Verapamil AUCs were positively correlated (r = 0.71) to increased ethanol blood AUC values.
Geriatric Use
The pharmacokinetics of verapamil GITS were studied after 5 consecutive nights of dosing 180 mg in 30 healthy young (19-43 years)
versus 30 healthy elderly (65-80years) male and female subjects. Older subjects had significantly higher mean veapamil Cmax , Cmin
and AUC (0-24h) compared to younger subjects. Older subjects had mean AUCs that were approximately 1.7-2.0 times higher than
those of younger subjects as well as a longer average verapamil t1/2 (approximately 20 hr vs 13 hr).
Hemodynamics and Myocardial Metabolism
Verapamil HCl reduces afterload and myocardial contractility. Improved left ventricular diastolic function in patients with IHSS
and those with coronary heart disease has also been observed with verapamil HCl therapy. In most patients, including those with
organic cardiac disease, the negative inotropic action of verapamil HCl is countered by reduction of afterload and cardiac index is
usually not reduced. In patients with severe left ventricular dysfunction however, (e.g., pulmonary wedge pressure above 20 mm Hg or
ejection fraction lower than 30%), or in patients on beta-adrenergic blocking agents or other cardiodepressant drugs, deterioration of
ventricular function may occur. (See Drug Interactions.)
Pulmonary Function
Verapamil HCl does not induce broncho-constriction and hence, does not impair ventilatory function.
INDICATIONS AND USAGE
Verelan (verapamil HCl) is indicated for the management of essential hypertension.
CONTRAINDICATIONS
Verapamil HCl is contraindicated in:
1. Severe left ventricular dysfunction. (See WARNINGS.)
2. Hypotension (less than 90 mm Hg systolic pressure) or cardiogenic shock.
3. Sick sinus syndrome (except in patients with a functioning artificial ventricula pacemaker).
page 2 of 9
Reference ID: 3042985
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4. Second - or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker).
5. Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff-Parkinson-White, Lown-Ganong-Levine
syndromes). (See WARNINGS.)
6. Patients with known hypersensitivity to Verapamil hydrochloride.
WARNINGS
Heart Failure
Verapamil has a negative inotropic effect which, in most patients, is compensated by its afterload reduction (decreased systemic
vascular resistance) properties without a net impairment of ventricular performance. In clinical experience with 4,954 patients, 87
(1.8%) developed congestive heart failure or pulmonary edema. Verapamil should be avoided in patients with severe left ventricular
dysfunction (e.g., ejection fraction less than 30% or moderate to severe symptoms of cardiac failure) and in patients with any degree
of ventricular dysfunction if they are receiving a beta-adrenergic blocker. (See Drug Interactions.) Patients with milder ventricular
dysfunction should, if possible, be controlled with optimum doses of digitalis and/or diuretics before verapamil treatment (note
interactions with digoxin under: PRECAUTIONS).
Hypotension
Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels which may result
in dizziness or symptomatic hypotension. The incidence of hypotension observed in 4,954 patients enrolled in clinical trials was 2.5%.
In hypertensive patients, decreases in blood pressure below normal are unusual. Tilt table testing (60 degrees) was not able to induce
orthostatic hypotension.
Elevated Liver Enzymes
Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Such
elevations have sometimes been transient and may disappear even in the face of continued verapamil treatment. Several cases of
hepatocellular injury related to verapamil have been proven by rechallenge; half of these had clinical symptoms (malaise, fever, and/or
right upper quadrant pain) in addition to elevations of SGOT, SGPT and alkaline phosphatase. Periodic monitoring of liver function in
patients receiving verapamil is therefore prudent.
Accessory Bypass Tract (Wolff-Parkinson-White or Lown-Ganong- Levine)
Some patients with paroxysmal and/or chronic atrial flutter or atrial fibrillation and a coexisting accessory AV pathway have
developed increased antegrade conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular
response or ventricular fibrillation after receiving intravenous verapamil (or digitalis). Although a risk of this occurring with
oral verapamil has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is
contraindicated. (See CONTRAINDICATIONS.)
Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral verapamil.
Atrioventricular Block
The effect of verapamil on AV conduction and the SA node may lead to asymptomatic first-degree AV block and transient
bradycardia, sometimes accompanied by nodal escape rhythms. PR interval prolongation is correlated with verapamil plasma
concentrations, especially during the early titration phase of therapy. Higher degrees of AV block, however, were infrequently (0.8%)
observed.
Marked first-degree block or progressive development to second- or third-degree AV block requires a reduction in dosage or, in rare
instances, discontinuation of verapamil HCl and institution of appropriate therapy depending upon the clinical situation.
Patients with Hypertrophic Cardiomyopathy (IHSS)
In 120 patients with hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) who received therapy with
verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. Three patients died in pulmonary edema; all
had severe left ventricular outflow obstruction and a past history of left ventricular dysfunction. Eight other patients had pulmonary
edema and/or severe hypotension; abnormally high (over 20 mm Hg) capillary wedge pressure and a marked left ventricular outflow
obstruction were present in most of these patients. Concomitant administration of quinidine (see Drug Interactions) preceded the
severe hypotension in 3 of the 8 patients (2 of whom developed pulmonary edema). Sinus bradycardia occurred in 11% of the patients,
second-degree AV block in 4% and sinus arrest in 2%. It must be appreciated that this group of patients had a serious disease with a
high mortality rate. Most adverse effects responded well to dose reduction and only rarely did verapamil have to be discontinued.
PRECAUTIONS
THE CONTENTS OF THE VERELAN CAPSULE SHOULD NOT BE CRUSHED OR CHEWED. Verelan®CAPSULES
ARE TO BE SWALLOWED WHOLE OR THE ENTIRE CONTENTS OF THE CAPSULE SPRINKLED ONTO
APPLESAUCE (See DOSAGE AND ADMINISTRATION).
page 3 of 9
Reference ID: 3042985
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
General
Use in Patients with Impaired Hepatic Function
Since verapamil is highly metabolized by the liver, it should be administered cautiously to patients with impaired hepatic function.
Severe liver dysfunction prolongs the elimination half-life of immediate-release verapamil to about 14 to 16 hours; hence,
approximately 30% of the dose given to patients with normal liver function should be administered to these patients. Careful
monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects (see OVERDOSAGE)
should be carried out.
Use in Patients with Attenuated (Decreased) Neuromuscular Transmission
It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne's muscular dystrophy, and that
verapamil prolongs recovery from the neuromuscular blocking agent vecuronium and causes a worsening of myasthenia gravis. It may
be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission.
Use in Patients with Impaired Renal Function
About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Until further data are available, verapamil
should be administered cautiously to patients with impaired renal function. These patients should be carefully monitored for abnormal
prolongation of the PR interval or other signs of overdosage. (See OVERDOSAGE.)
Information for Patients
When the sprinkle method of administration is prescribed, details of the proper technique should be explained to the patient. (See
DOSAGE AND ADMINISTRATION.)
Drug-Drug Interactions
Drug Interactions: Effects of other drugs on verapamil pharmacokinetics
In vitro metabolic studies indicate that verapamil is metabolized by cytochrome P450, CYP3A4, CYP1A2, and CYP2C. Clinically
significant interactions have been reported with inhibitors of CYP3A4 (eg, erythromycin, ritonavir) causing elevation of plasma levels
of verapamil while inducers of CYP3A4 (eg, rifampin) have caused a lowering of plasma levels of verapamil.
HMG-CoA Reductase Inhibitors
The use of HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with verapamil has been associated with
reports of myopathy/rhabdomyolysis.
Co-administration of multiple doses of 10 mg of verapamil with 80 mg simvastatin resulted in exposure to simvastatin 2.5-fold that
following simvastatin alone. Limit the dose of simvastatin in patients on verapamil to 10 mg daily. Limit the daily dose of lovastatin
to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required as verapamil may
increase the plasma concentration of these drugs.
Beta Blockers
Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular
conduction, and/or cardiac contractility. The combination of sustained-release verapamil and beta-adrenergic blocking agents has
not been studied. However, there have been reports of excess bradycardia and AV block, including complete heart block, when the
combination has been used for the treatment of hypertension.
For hypertensive patients, the risk of combined therapy may outweigh the potential benefits. The combination should be used only
with caution and close monitoring.
Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant
timolol (a beta-adrenergic blocker) eyedrops and oral verapamil.
A decrease in metoprolol clearance has been reported when verapamil and metoprolol were administered together. A similar effect has
not been observed when verapamil and atenolol are given together.
Digitalis
Clinical use of verapamil in digitalized patients has shown the combination to be well tolerated if digoxin doses are properly
adjusted. Chronic verapamil treatment can increase serum digoxin levels by 50% to 75% during the first week of therapy, and
this can result in digitalis toxicity. In patients with hepatic cirrhosis the influence of verapamil on digoxin kinetics is magnified.
Maintenance digitalis doses should be reduced when verapamil is administered, and the patient should be carefully monitored to avoid
over- or underdigitalization. Whenever overdigitalization is suspected, the daily dose of digoxin should be reduced or temporarily
discontinued. Upon discontinuation of verapamil HCl, the patient should be reassessed to avoid underdigitalization.
page 4 of 9
Reference ID: 3042985
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Antihypertensive Agents
Verapamil administered concomitantly with oral antihypertensive agents (e.g., vasodilators, angiotensin-converting enzyme inhibitors,
diuretics, beta blockers) will usually have an additive effect on lowering blood pressure. Patients receiving these combinations
should be appropriately monitored. Concomitant use of agents that attenuate alpha-adrenergic function with verapamil may result in
reduction in blood pressure that is excessive in some patients. Such an effect was observed in one study following the concomitant
administration of verapamil and prazosin.
Antiarrhythmic Agents
Disopyramide
Until data on possible interactions between verapamil and disopyramide phosphate are obtained, disopyramide should not be
administered within 48 hours before or 24 hours after verapamil administration.
Flecainide
A study in healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on
myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide and verapamil may result in additive
negative inotropic effect and prolongation of atrioventricular conduction.
Quinidine
In a small number of patients with hypertrophic cardiomyopathy (IHSS), concomitant use of verapamil and quinidine resulted in
significant hypotension. Until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic
cardiomyopathy should probably be avoided.
The electrophysiological effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil significantly
counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during verapamil
therapy.
Nitrates
Verapamil has been given concomitantly with short- and long-acting nitrates without any undesirable drug interactions. The
pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions.
Alcohol
Verapamil has been found to significantly inhibit ethanol elimination resulting in elevated blood ethanol concentrations that may
prolong the intoxicating effects of alcohol. (See CLINICAL PHARMACOLOGY-Pharmacokinetics and Metabolism.)
Other
Aspirin
In a few reported cases, coadministration of verapamil with aspirin has led to increased bleeding times greater than observed with
aspirin alone.
Cimetidine
The interaction between cimetidine and chronically administered verapamil has not been studied. Variable results on clearance have
been obtained in acute studies of healthy volunteers; clearance of verapamil was either reduced or unchanged.
Grapefruit juice
Grapefruit juice may significantly increase concentrations of verapamil. Grapefruit juice given to nine healthy volunteers increased
S- and R- verapamil AUC0-12 by 36% and 28%, respectively. Steady state Cmax and Cmin of S-verapamil increased by 57% and
16.7%, respectively with grapefruit juice compared to control. Similarly, Cmax and Cmin of R-verapamil increased by 40% and 13%,
respectively. Grapefruit juice did not affect half-life, nor was there a significant change in AUC0-12 ratio R/S compared to control.
Grapefruit juice did not cause a significant difference in the PK of norverapamil. This increase in verapamil plasma concentration is
not expected to have any clinical consequences.
Lithium
Pharmacokinetic and pharmacodynamic interactions between oral verapamil and lithium have been reported. The former may result
in a lowering of serum lithium levels in patients receiving chronic stable oral lithium therapy. The latter may result in an increased
sensitivity to the effects of lithium. Patients receiving both drugs must be monitored carefully.
Carbamazepine
Verapamil therapy may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side
effects such as diplopia, headache, ataxia, or dizziness.
page 5 of 9
Reference ID: 3042985
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Rifampin
Therapy with rifampin may markedly reduce oral verapamil bioavailability.
Phenobarbital
Phenobarbital therapy may increase verapamil clearance.
Cyclosporine
Verapamil therapy may increase serum levels of cyclosporine.
Inhalation Anesthetics
Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of
calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, should be titrated carefully
to avoid excessive cardiovascular depression.
Neuromuscular Blocking Agents
Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and
depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the
drugs are used concomitantly.
Carcinogenesis, Mutagenesis, Impairment of Fertility
An 18-month toxicity study in rats, at a low multiple (6 fold) of the maximum recommended human dose, and not the maximum
tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of verapamil administered
in the diet of rats for two years at doses of 10, 35 and 120 mg/kg per day or approximately 1x, 3.5x and 12x, respectively, the
maximum recommended human daily dose (480 mg per day or 9.6 mg/kg/day).
Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate, with or without metabolic activation.
Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did not show
impaired fertility. Effects on male fertility have not been determined.
Pregnancy
Pregnancy Category C
Reproduction studies have been performed in rabbits and rats at oral doses up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the
maximum recommended human daily dose, respectively, and have revealed no evidence of teratogenicity. In the rat, however, this
multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects
reflected in reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats. 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. Verapamil crosses the placental barrier and can be detected in
umbilical vein blood at delivery.
Labor and Delivery
It is not known whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or
whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse
experiences have not been reported in the literature, despite a long history of use of verapamil HCl in Europe in the treatment of
cardiac side effects of beta-adrenergic agonist agents used to treat premature labor.
Nursing Mothers
Verapamil is excreted in human milk. Because of the potential for adverse reactions in nursing infants from verapamil, nursing should
be discontinued while verapamil is administered.
Pediatric Use
Safety and efficacy of verapamil in children below the age of 18 years have not been established.
Geriatric Use
Clinical studies of verapamil 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.
Aging may affect the pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly (see CLINICAL
PHARMACOLOGY, Pharmacokinetics and Metabolism).
page 6 of 9
Reference ID: 3042985
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Verapamil is highly metabolized by the liver, and about 70% of the administered dose is excreted as metabolites in the urine. Clinical
circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered
(see PRECAUTIONS, General). In general, lower initial doses of Verelan may be warranted in the elderly (see DOSAGE AND
ADMINISTRATION).
Animal Pharmacology and/or Animal Toxicology
In chronic animal toxicology studies verapamil caused lenticular and/or suture line changes at 30 mg/kg/day or greater and frank
cataracts at 62.5 mg/kg/day or greater in the beagle dog but not the rat. Development of cataracts due to verapamil has not been
reported in man.
ADVERSE REACTIONS
Serious adverse reactions are uncommon when verapamil HCl therapy is initiated with upward dose titration within the recommended
single and total daily dose. See WARNINGS for discussion of heart failure, hypotension, elevated liver enzymes, AV block, and rapid
ventricular response. Reversible (upon discontinuation of verapamil) non-obstructive, paralytic ileus has been infrequently reported in
association with the use of verapamil.
In clinical trials involving 285 hypertensive patients on Verelan for greater than 1 week the following adverse reactions were reported
in greater than 1.0% of the patients:
Constipation
7.4%
Headache
5.3%
Dizziness
4.2%
Lethargy
3.2%
Dyspepsia
2.5%
Rash
1.4%
Ankle Edema
1.4%
Sleep Disturbance
1.4%
Myalgia
1.1%
In clinical trials of other formulations of verapamil HCl (N=4,954) the following reactions have occurred at rates greater than 1.0%:
Constipation
7.3%
CHF/Pulmonary Edema
1.8%
Dizziness
3.3%
Fatigue
1.7%
Nausea
2.7%
Bradycardia (HR<50/min)
1.4%
Hypotension
2.5%
AV block-total 1°, 2°, 3°
1.2%
2° and 3°
0.8%
Edema
1.9%
Headache
2.2%
Flushing
0.6%
Rash
1.2%
Elevated Liver Enzymes (see WARNINGS)
In clinical trials related to the control of ventricular response in digitalized patients who had atrial fibrillation or atrial flutter,
ventricular rate below 50/min at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5% of patients.
The following reactions, reported in 1.0% or less of patients, occurred under conditions (open trials, marketing experience) where a
causal relationship is uncertain; they are listed to alert the physician to a possible relationship:
Cardiovascular: angina pectoris, atrioventricular dissociation, chest pain, claudication, myocardial infarction, palpitations, purpura
(vasculitis), syncope.
Digestive System: diarrhea, dry mouth, gastrointestinal distress, gingival hyperplasia.
Hemic and Lymphatic: ecchymosis or bruising.
Nervous System: cerebrovascular accident, confusion, equilibrium disorders, extrapyramidal symptoms insomnia, muscle cramps,
paresthesia, psychotic symptoms, shakiness, somnolence.
Respiratory: dyspnea.
Skin: arthralgia and rash, exanthema, hair loss, hyperkeratosis, maculae, sweating, urticaria, Stevens-Johnson syndrome, erythema
multiforme.
page 7 of 9
Reference ID: 3042985
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Special Senses: blurred vision, tinnitis.
Urogenital: gynecomastia, impotence, increased urination, spotty menstruation.
Treatment of Acute Cardiovascular Adverse Reactions
The frequency of cardiovascular adverse reactions which require therapy is rare; hence, experience with their treatment is limited.
Whenever severe hypotension or complete AV block occurs following oral administration of verapamil, the appropriate emergency
measures should be applied immediately, e.g., intravenously administered isoproterenol HCl, levarterenol bitartrate, atropine (all in
the usual doses), or calcium gluconate (10% solution). In patients with hypertrophic cardiomyopathy (IHSS), alpha-adrenergic agents
(phenylephrine, metaraminol bitartrate or methoxamine) should be used to maintain blood pressure, and isoproterenol and levarterenol
should be avoided. If further support is necessary, inotropic agents (dopamine or dobutamine) may be administered. Actual treatment
and dosage should depend on the severity and the clinical situation and the judgment and experience of the treating physician.
OVERDOSAGE
There is no specific antidote for verapamil overdosage; treatment should be supportive. Delayed pharmacodynamic consequences may
occur with sustained-release formulations, and patients should be observed for at least 48 hours, preferably under continuous hospital
care. Reported effects include hypotension, bradycardia, cardiac conduction defects, arrhythmias, hyperglycemia, and decreased
mental status. In addition, there have been literature reports of non-cardiogenic pulmonary edema in patients taking large overdoses of
verapamil (up to approximately 9g).
In acute overdosage, gastrointestinal decontamination with cathartics and whole bowel irrigation should be considered. Calcium,
inotropes (i.e., isoproterenol, dopamine, and glucagon), atropine, vasopressors (i.e., norepinephrine, and epinephrine), and cardiac
pacing have been used with variable results to reverse hypotension and myocardial depression. In a few reported cases, overdose
with calcium channel blockers that was initially refractory to atropine became more responsive to this treatment when the patients
received large doses (close to 1g/hour for more than 24 hours) of calcium chloride. Calcium chloride is preferred to calcium gluconate
since it provides 3 times more calcium per volume. Asystole should be handled by the usual measures including cardiopulmonary
resuscitation. Verapamil cannot be removed by hemodialysis.
DOSAGE AND ADMINISTRATION
Essential Hypertension
The dose of Verelan should be individualized by titration. The usual daily dose of sustained-release verapamil, Verelan, in clinical
trials has been 240 mg given by mouth once daily in the morning. However, initial doses of 120 mg a day may be warranted in
patients who may have an increased response to verapamil (e.g., elderly, small people, etc.). Upward titration should be based on
therapeutic efficacy and safety evaluated approximately 24 hours after dosing. The antihypertensive effects of Verelan are evident
within the first week of therapy.
If adequate response is not obtained with 120 mg of Verelan, the dose may be titrated upward in the following manner:
(a) 180 mg in the morning.
(b) 240 mg in the morning.
(c) 360 mg in the morning.
(d) 480 mg in the morning.
Verelan sustained-release capsules are for once-a-day administration. When switching from immediate-release verapamil to Verelan
capsules, the same total daily dose of Verelan capsules can be used.
As with immediate-release verapamil, dosages of Verelan capsules should be individualized and titration may be needed in some
patients.
Sprinkling the Capsule Contents on Food
Verelan pellet filled capsules may also be administered by carefully opening the capsule and sprinkling the pellets on a spoonful of
applesauce. The applesauce should be swallowed immediately without chewing and followed with a glass of cool water to ensure
complete swallowing of the pellets. The applesauce used should not be hot, and it should be soft enough to be swallowed without
chewing. Any pellet/applesauce mixture should be used immediately and not stored for future use. Subdividing the contents of a
Verelan capsule is not recommended.
HOW SUPPLIED
Verelan ® (verapamil hydrochloride) sustained-release pellet filled capsules are supplied in four dosage strengths:
120 mg
Two-piece, size 2 hard gelatin capsule (yellow cap/yellow body), printed with SCHWARZ above 2490 on left
and VERELAN above 120 mg on right side of the capsule in black ink, supplied as follows:
NDC 0091-2490-23 - Bottle of 100s
180 mg
Two-piece, size 1 elongated hard gelatin capsule (light grey cap/yellow body), printed with SCHWARZ above
2489 on left and VERELAN above 180 mg on right side of the capsule in black ink, supplied as follows:
NDC 0091-2489-23 - Bottle of 100s
page 8 of 9
Reference ID: 3042985
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
240 mg
Two-piece, size 0 hard gelatin capsule (dark blue cap/yellow body), printed with SCHWARZ above 2491 on left
and VERELAN above 240 mg on right side of the capsule in black ink, supplied as follows:
NDC 0091-2491-23 - Bottle of 100s
360 mg
Two-piece, size 00 hard gelatin capsule (lavender cap/yellow body), printed with SCHWARZ above 2495 on left
and VERELAN above 360 mg on right side of the capsule in black ink, supplied as follows:
NDC 0091-2495-23 - Bottle of 100s
Store at controlled room temperature 20°-25°C (68°-77°F). [See USP]. Avoid excessive heat. Brief digressions above 25°C,
while not detrimental, should be avoided. Protect from moisture. Dispense in tight, light-resistant container as defined in USP.
Call your doctor for medical advice about side effects. You may report side effects to UCB, Inc. at 1-800-477-7877 or FDA at 1-800
FDA-1088 or www.fda.gov/medwatch.
Rxonly
Manufactured for:
—Schwarz Pharma, LLC, a subsidiary of UCB, Inc. Smyrna, GA 30080
Verelan® is a registered trademark of Elan Pharma International Ltd.
by:
ELAN HOLDINGS, INC.
Gainesville, GA 30504, USA
U.S. Patent No.: 4,863,742PC3799F
Rev. 01/09
page 9 of 9
Reference ID: 3042985
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:31.463831
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019614s049lbl.pdf', 'application_number': 19614, 'submission_type': 'SUPPL ', 'submission_number': 49}
|
11,562
|
Verelan® capsules
(verapamil hydrochloride)
Sustained-release pellet filled capsules
Rx only
Rev. 06/14
DESCRIPTION
Verelan® (verapamil hydrochloride capsules) is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist).
Verelan is available for oral administration as a 360 mg hard gelatin capsule (lavender cap/yellow body), a 240 mg hard gelatin
capsule (dark blue cap/yellow body), a 180 mg hard gelatin capsule (light grey cap/yellow body), and a 120 mg hard gelatin capsule
(yellow cap/yellow body). These pellet filled capsules provide a sustained-release of the drug in the gastrointestinal tract.
The structural formula of verapamil HCl is given below: structural formula
Chemical name: Benzeneacetonitrile, -[3-[[2-(3,4-dimethoxyphenyl)-ethyl]methylamino]propyl]-3,4-dimethoxy- -(1-methylethyl),
monohydrochloride.
Verapamil HCl is an almost white, crystalline powder, practically free of odor, with a bitter taste. It is soluble in water, chloroform
and methanol. Verapamil HCl is not structurally related to other cardioactive drugs.
In addition to verapamil HCl the Verelan capsule contains the following inactive ingredients: fumaric acid, talc, sugar spheres,
povidone, shellac, gelatin, FD&C red #40, yellow iron oxide, titanium dioxide, methylparaben, propylparaben, silicon dioxide, and
sodium lauryl sulfate. In addition, the Verelan 240 mg and 360 mg capsules contain FD&C blue #1 and D&C red #28; and the Verelan
180 mg capsule contains black iron oxide.
CLINICAL PHARMACOLOGY
Verelan is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) which exerts its pharmacologic effects by
modulating the influx of ionic calcium across the cell membrane of the arterial smooth muscle as well as in conductile and contractile
myocardial cells.
Normal sinus rhythm is usually not affected by verapamil HCl. However in patients with sick sinus syndrome, verapamil HCl may
interfere with sinus node impulse generation and may induce sinus arrest or sinoatrial block. Atrioventricular block can occur in
patients without preexisting conduction defects. (See WARNINGS.) Verapamil HCl does not alter the normal atrial action potential
or intraventricular conduction time, but depresses amplitude, velocity of depolarization and conduction in depressed atrial fibers.
Verapamil HCl may shorten the antegrade effective refractory period of accessory bypass tracts. Acceleration of ventricular rate and/
or ventricular fibrillation has been reported in patients with atrial flutter or atrial fibrillation and a coexisting accessory AV pathway
following administration of verapamil. (See WARNINGS.)
Verapamil HCl has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis. It is not known whether this
action is important at the doses used in man.
Mechanism of Action
Essential Hypertension
Verapamil HCl exerts antihypertensive effects by decreasing systemic vascular resistance, usually without orthostatic decreases in
blood pressure or reflex tachycardia; bradycardia (rate less than 50 beats/minute is uncommon). Verapamil HCl 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.
Pharmacokinetics and Metabolism
With the immediate release formulations, more than 90% of the orally administered dose is absorbed, and peak plasma concentrations
of verapamil are observed 1 to 2 hours after dosing. Because of rapid biotransformation of verapamil during its first pass through the
portal circulation, the absolute bioavailability ranges from 20% to 35%. Chronic oral administration of the highest recommended dose
(120 mg every 6 hours) resulted in plasma verapamil levels ranging from 125 to 400 ng/mL with higher values reported occasionally.
A nonlinear correlation between the verapamil HCl dose administered and verapamil plasma levels does exist.
During initial dose titration with verapamil a relationship exists between verapamil plasma concentrations and the prolongation of the
Reference ID: 3641839
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PR interval. However, during chronic administration this relationship may disappear. The quantitative relationship between plasma
verapamil concentrations and blood pressure reduction has not been fully characterized.
In a multiple dose pharmacokinetic study, peak concentrations for a single daily dose of Verelan 240 mg were approximately 65% of
those obtained with an 80 mg t.i.d. dose of the conventional immediate-release tablets, and the 24 hour post-dose concentrations were
approximately 30% higher. At a total daily dose of 240 mg, Verelan was shown to have a similar extent of verapamil bioavailability
based on the AUC-24 as that obtained with the conventional immediate-release tablets. In this same study Verelan doses of 120 mg,
240 mg and 360 mg once daily were compared after multiple doses. The ratios of the verapamil and norverapamil AUCs for the
Verelan 120 mg, 240 mg and 360 mg once daily doses are 1 (565 ng·hr/mL):3 (1660 ng·hr/mL):5 (2729 ng·hr/mL) and 1 (621 ng·hr/
mL):3 (1614 ng· hr/mL):4 (2535 ng·hr/mL) respectively, indicating that the AUC increased non-proportionately with increasing doses.
Food does not affect the extent or rate of the absorption of verapamil from the controlled release Verelan capsule. The Verelan 240
mg capsule when administered with food had a Cmax of 77 ng/mL which occurred 9.0 hours after dosing, and an AUC(O-inf) of 1387
ng·hr/mL. Verelan 240 mg under fasting conditions had a Cmax of 77 ng/mL which occurred 9.8 hours after dosing, and an AUC(O
inf) of 1541 ng·hr/mL.
The bioequivalence of Verelan 240 mg, administered as the pellets sprinkled on applesauce and as the intact capsule, was
demonstrated in a single-dose, cross-over study in 32 healthy adults. Comparative ratios (sprinkled/intact) of verapamil were 0.95,
1.02, and 1.01 for Cmax, Tmax, and AUC(O-inf) respectively. When the contents of the Verelan® capsule were administered by
sprinkling onto one tablespoonful of applesauce, the rate and extent of verapamil absorption were found to be bioequivalent to the
same dose when administered as an intact capsule. Similar results were observed with norverapamil.
The time to reach maximum verapamil concentrations (Tmax) with Verelan has been found to be approximately 7-9 hours in each
of the single dose (fasting), single dose (fed), the multiple dose (steady state) studies and dose proportionality pharmacokinetic
studies. Similarly the apparent half-life (t1/2) has been found to be approximately 12 hours independent of dose. Aging may affect the
pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly.
In healthy man, orally administered verapamil HCl undergoes extensive metabolism in the liver. Twelve metabolites have been
identified in plasma; all except norverapamil are present in trace amounts only. Norverapamil can reach steady-state plasma
concentrations approximately equal to those of verapamil itself. The biologic activity of norverapamil appears to be approximately
20% that of verapamil.
Approximately 70% of an administered dose of verapamil HCl is excreted as metabolites in the urine and 16% or more in the
feces within 5 days. About 3% to 4% is excreted in the urine as unchanged drug. Approximately 90% is bound to plasma proteins. In
patients with hepatic insufficiency, metabolism is delayed and elimination half-life prolonged up to 14 to 16 hours (see
PRECAUTIONS), the volume of distribution is increased and plasma clearance reduced to about 30% of normal. Verapamil
clearance values suggest that patients with liver dysfunction may attain therapeutic verapamil plasma concentrations with one-third of
the oral daily dose required for patients with normal liver function.
After four weeks of oral dosing (120 mg q.i.d.), verapamil and norverapamil levels were noted in the cerebrospinal fluid with
estimated partition coefficient of 0.06 for verapamil and 0.04 for norverapamil.
In 10 healthy males, administration of oral verapamil (80 mg every 8 hours for 6 days) and a single oral dose of ethanol (0.8 g/kg),
resulted in a 17% increase in mean peak ethanol concentrations (106.45 ± 21.40 to 124.23 ± 24.74 mg/dL) compared with placebo.
(See PRECAUTIONS-Drug Interactions.)
The area under the blood ethanol concentration versus time curve (AUC over 12 hours) increased by 30% (365.67 ± 93.52 to 475.07 ±
97.24 mg·hr/dL). Verapamil AUCs were positively correlated (r = 0.71) to increased ethanol blood AUC values.
Geriatric Use
The pharmacokinetics of verapamil GITS were studied after 5 consecutive nights of dosing 180 mg in 30 healthy young (19-43 years)
versus 30 healthy elderly (65-80years) male and female subjects. Older subjects had significantly higher mean veapamil Cmax , Cmin
and AUC (0-24h) compared to younger subjects. Older subjects had mean AUCs that were approximately 1.7-2.0 times higher than
those of younger subjects as well as a longer average verapamil t1/2 (approximately 20 hr vs 13 hr).
Hemodynamics and Myocardial Metabolism
Verapamil HCl reduces afterload and myocardial contractility. Improved left ventricular diastolic function in patients with IHSS and
those with coronary heart disease has also been observed with verapamil HCl therapy. In most patients, including those with organic
Reference ID: 3641839
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
cardiac disease, the negative inotropic action of verapamil HCl is countered by reduction of afterload and cardiac index is usually not
reduced. In patients with severe left ventricular dysfunction however, (e.g., pulmonary wedge pressure above 20 mm Hg or ejection
fraction lower than 30%), or in patients on beta-adrenergic blocking agents or other cardiodepressant drugs, deterioration of
ventricular function may occur. (See Drug Interactions.)
Pulmonary Function
Verapamil HCl does not induce broncho-constriction and hence, does not impair ventilatory function.
INDICATIONS AND USAGE
Verelan (verapamil HCl) is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the
risk of fatal and nonfatal cardiovascular events, primarily stokes and myocardial infarctions. These benefits have been seen in
controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug.
Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid
control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will
require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines,
such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown
in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure
reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most
consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and
cardiovascular mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at
higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction
from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who
are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be
expected to benefit from more aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs
have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may
guide selection of therapy.
CONTRAINDICATIONS
Verapamil HCl is contraindicated in:
1. Severe left ventricular dysfunction. (See WARNINGS.)
2. Hypotension (less than 90 mm Hg systolic pressure) or cardiogenic shock.
3. Sick sinus syndrome (except in patients with a functioning artificial ventricula pacemaker).
4. Second - or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker).
5. Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff-Parkinson-White, Lown-Ganong-
Levine syndromes). (See WARNINGS.)
6. Patients with known hypersensitivity to Verapamil hydrochloride.
WARNINGS
Heart Failure
Verapamil has a negative inotropic effect which, in most patients, is compensated by its afterload reduction (decreased systemic
vascular resistance) properties without a net impairment of ventricular performance. In clinical experience with 4,954 patients, 87
(1.8%) developed congestive heart failure or pulmonary edema. Verapamil should be avoided in patients with severe left ventricular
dysfunction (e.g., ejection fraction less than 30% or moderate to severe symptoms of cardiac failure) and in patients with any degree
of ventricular dysfunction if they are receiving a beta-adrenergic blocker. (See Drug Interactions.) Patients with milder ventricular
dysfunction should, if possible, be controlled with optimum doses of digitalis and/or diuretics before verapamil treatment (note
interactions with digoxin under: PRECAUTIONS).
Reference ID: 3641839
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Hypotension
Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels which may result
in dizziness or symptomatic hypotension. The incidence of hypotension observed in 4,954 patients enrolled in clinical trials was 2.5%.
In hypertensive patients, decreases in blood pressure below normal are unusual. Tilt table testing (60 degrees) was not able to induce
orthostatic hypotension.
Elevated Liver Enzymes
Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Such
elevations have sometimes been transient and may disappear even in the face of continued verapamil treatment. Several cases of
hepatocellular injury related to verapamil have been proven by rechallenge; half of these had clinical symptoms (malaise, fever, and/or
right upper quadrant pain) in addition to elevations of SGOT, SGPT and alkaline phosphatase. Periodic monitoring of liver function in
patients receiving verapamil is therefore prudent.
Accessory Bypass Tract (Wolff-Parkinson-White or Lown-Ganong- Levine)
Some patients with paroxysmal and/or chronic atrial flutter or atrial fibrillation and a coexisting accessory AV pathway have
developed increased antegrade conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular
response or ventricular fibrillation after receiving intravenous verapamil (or digitalis). Although a risk of this occurring with
oral verapamil has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is
contraindicated. (See CONTRAINDICATIONS.)
Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral verapamil.
Atrioventricular Block
The effect of verapamil on AV conduction and the SA node may lead to asymptomatic first-degree AV block and transient
bradycardia, sometimes accompanied by nodal escape rhythms. PR interval prolongation is correlated with verapamil plasma
concentrations, especially during the early titration phase of therapy. Higher degrees of AV block, however, were infrequently (0.8%)
observed.
Marked first-degree block or progressive development to second- or third-degree AV block requires a reduction in dosage or, in rare
instances, discontinuation of verapamil HCl and institution of appropriate therapy depending upon the clinical situation.
Patients with Hypertrophic Cardiomyopathy (IHSS)
In 120 patients with hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) who received therapy with
verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. Three patients died in pulmonary edema; all
had severe left ventricular outflow obstruction and a past history of left ventricular dysfunction. Eight other patients had pulmonary
edema and/or severe hypotension; abnormally high (over 20 mm Hg) capillary wedge pressure and a marked left ventricular outflow
obstruction were present in most of these patients. Concomitant administration of quinidine (see Drug Interactions) preceded the
severe hypotension in 3 of the 8 patients (2 of whom developed pulmonary edema). Sinus bradycardia occurred in 11% of the patients,
second-degree AV block in 4% and sinus arrest in 2%. It must be appreciated that this group of patients had a serious disease with a
high mortality rate. Most adverse effects responded well to dose reduction and only rarely did verapamil have to be discontinued.
PRECAUTIONS
THE CONTENTS OF THE VERELAN CAPSULE SHOULD NOT BE CRUSHED OR CHEWED. Verelan®CAPSULES
ARE TO BE SWALLOWED WHOLE OR THE ENTIRE CONTENTS OF THE CAPSULE SPRINKLED ONTO
APPLESAUCE (See DOSAGE AND ADMINISTRATION).
General
Use in Patients with Impaired Hepatic Function
Since verapamil is highly metabolized by the liver, it should be administered cautiously to patients with impaired hepatic function.
Severe liver dysfunction prolongs the elimination half-life of immediate-release verapamil to about 14 to 16 hours; hence,
approximately 30% of the dose given to patients with normal liver function should be administered to these patients. Careful
monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects (see OVERDOSAGE)
should be carried out.
Reference ID: 3641839
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Use in Patients with Attenuated (Decreased) Neuromuscular Transmission
It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne's muscular dystrophy, and that
verapamil prolongs recovery from the neuromuscular blocking agent vecuronium and causes a worsening of myasthenia gravis. It may
be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission.
Use in Patients with Impaired Renal Function
About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Until further data are available, verapamil
should be administered cautiously to patients with impaired renal function. These patients should be carefully monitored for abnormal
prolongation of the PR interval or other signs of overdosage. (See OVERDOSAGE.)
Information for Patients
When the sprinkle method of administration is prescribed, details of the proper technique should be explained to the patient. (See
DOSAGE AND ADMINISTRATION.)
Drug-Drug Interactions
Drug Interactions: Effects of other drugs on verapamil pharmacokinetics
In vitro metabolic studies indicate that verapamil is metabolized by cytochrome P450, CYP3A4, CYP1A2, and CYP2C. Clinically
significant interactions have been reported with inhibitors of CYP3A4 (eg, erythromycin, ritonavir) causing elevation of plasma levels
of verapamil while inducers of CYP3A4 (eg, rifampin) have caused a lowering of plasma levels of verapamil. Hypotension,
bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent telithromycin, and antibiotic in the ketolide
class of antibiotics.
HMG-CoA Reductase Inhibitors
The use of HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with verapamil has been associated with
reports of myopathy/rhabdomyolysis.
Co-administration of multiple doses of 10 mg of verapamil with 80 mg simvastatin resulted in exposure to simvastatin 2.5-fold that
following simvastatin alone. Limit the dose of simvastatin in patients on verapamil to 10 mg daily. Limit the daily dose of lovastatin
to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required as verapamil may
increase the plasma concentration of these drugs.
Beta Blockers
Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular
conduction, and/or cardiac contractility. The combination of sustained-release verapamil and beta-adrenergic blocking agents has
not been studied. However, there have been reports of excess bradycardia and AV block, including complete heart block, when the
combination has been used for the treatment of hypertension.
For hypertensive patients, the risk of combined therapy may outweigh the potential benefits. The combination should be used only
with caution and close monitoring.
Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant
timolol (a beta-adrenergic blocker) eyedrops and oral verapamil.
A decrease in metoprolol clearance has been reported when verapamil and metoprolol were administered together. A similar effect has
not been observed when verapamil and atenolol are given together.
Clonidine
Sinus bradycardia resulting in hospitalization and peacemaker insertion has been reported in association with the use of clonidine
concurrently with verapamil. Monitor heart rate in patients receiving concomitant verapamil and clonidine.
Digitalis
Consider reducing digoxin dose when verapamil and digoxin are to be given together. Monitor digoxin level periodically
during therapy. Chronic verapamil treatment can increase serum digoxin levels by 50% to 75% during the first week of
therapy, and this can result in digitalis toxicity. In patients with hepatic cirrhosis the influence of verapamil on digoxin kinetics
Reference ID: 3641839
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
is magnified. Verapamil may reduce total body clearance and extrarenal clearance of digoxin by 27% and 29%, respectively. If
digoxin toxicity is suspected, suspend or discontinue digoxin therapy.
In previous clinical trials with other verapamil formulations related to the control of ventricular response in patients taking digoxin
who had atrial fibrillation or atrial flutter, ventricular rates below 50/min at rest occurred in 15% of patients, and asymptomatic
hypotension occurred in 5% of patients.
Antihypertensive Agents
Verapamil administered concomitantly with oral antihypertensive agents (e.g., vasodilators, angiotensin-converting enzyme inhibitors,
diuretics, beta blockers) will usually have an additive effect on lowering blood pressure. Patients receiving these combinations
should be appropriately monitored. Concomitant use of agents that attenuate alpha-adrenergic function with verapamil may result in
reduction in blood pressure that is excessive in some patients. Such an effect was observed in one study following the concomitant
administration of verapamil and prazosin.
Antiarrhythmic Agents
Disopyramide
Until data on possible interactions between verapamil and disopyramide phosphate are obtained, disopyramide should not be
administered within 48 hours before or 24 hours after verapamil administration.
Flecainide
A study in healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on
myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide and verapamil may result in additive
negative inotropic effect and prolongation of atrioventricular conduction.
Quinidine
In a small number of patients with hypertrophic cardiomyopathy (IHSS), concomitant use of verapamil and quinidine resulted in
significant hypotension. Until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic
cardiomyopathy should probably be avoided.
The electrophysiological effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil significantly
counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during verapamil
therapy.
Nitrates
Verapamil has been given concomitantly with short- and long-acting nitrates without any undesirable drug interactions. The
pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions.
Alcohol
Verapamil has been found to significantly inhibit ethanol elimination resulting in elevated blood ethanol concentrations that may
prolong the intoxicating effects of alcohol. (See CLINICAL PHARMACOLOGY-Pharmacokinetics and Metabolism.)
Other
Aspirin
In a few reported cases, coadministration of verapamil with aspirin has led to increased bleeding times greater than observed with
aspirin alone.
Cimetidine
The interaction between cimetidine and chronically administered verapamil has not been studied. Variable results on clearance have
been obtained in acute studies of healthy volunteers; clearance of verapamil was either reduced or unchanged.
Grapefruit juice
Reference ID: 3641839
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Grapefruit juice may significantly increase concentrations of verapamil. Grapefruit juice given to nine healthy volunteers increased
S- and R- verapamil AUC0-12 by 36% and 28%, respectively. Steady state Cmax and Cmin of S-verapamil increased by 57% and
16.7%, respectively with grapefruit juice compared to control. Similarly, Cmax and Cmin of R-verapamil increased by 40% and 13%,
respectively. Grapefruit juice did not affect half-life, nor was there a significant change in AUC0-12 ratio R/S compared to control.
Grapefruit juice did not cause a significant difference in the PK of norverapamil. This increase in verapamil plasma concentration is
not expected to have any clinical consequences.
Lithium
Pharmacokinetic and pharmacodynamic interactions between oral verapamil and lithium have been reported. The former may result
in a lowering of serum lithium levels in patients receiving chronic stable oral lithium therapy. The latter may result in an increased
sensitivity to the effects of lithium. Patients receiving both drugs must be monitored carefully.
Carbamazepine
Verapamil therapy may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side
effects such as diplopia, headache, ataxia, or dizziness.
Rifampin
Therapy with rifampin may markedly reduce oral verapamil bioavailability.
Phenobarbital
Phenobarbital therapy may increase verapamil clearance.
Cyclosporine
Verapamil therapy may increase serum levels of cyclosporine.
Inhalation Anesthetics
Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of
calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, should be titrated carefully
to avoid excessive cardiovascular depression.
Neuromuscular Blocking Agents
Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and
depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the
drugs are used concomitantly.
Carcinogenesis, Mutagenesis, Impairment of Fertility
An 18-month toxicity study in rats, at a low multiple (6 fold) of the maximum recommended human dose, and not the maximum
tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of verapamil administered
in the diet of rats for two years at doses of 10, 35 and 120 mg/kg per day or approximately 1x, 3.5x and 12x, respectively, the
maximum recommended human daily dose (480 mg per day or 9.6 mg/kg/day).
Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate, with or without metabolic activation.
Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did not show
impaired fertility. Effects on male fertility have not been determined.
Pregnancy
Pregnancy Category C
Reproduction studies have been performed in rabbits and rats at oral doses up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the
maximum recommended human daily dose, respectively, and have revealed no evidence of teratogenicity. In the rat, however, this
Reference ID: 3641839
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects
reflected in reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats. 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. Verapamil crosses the placental barrier and can be detected in
umbilical vein blood at delivery.
Labor and Delivery
It is not known whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or
whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse
experiences have not been reported in the literature, despite a long history of use of verapamil HCl in Europe in the treatment of
cardiac side effects of beta-adrenergic agonist agents used to treat premature labor.
Nursing Mothers
Verapamil is excreted in human milk. Because of the potential for adverse reactions in nursing infants from verapamil, nursing should
be discontinued while verapamil is administered.
Pediatric Use
Safety and efficacy of verapamil in children below the age of 18 years have not been established.
Geriatric Use
Clinical studies of verapamil 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.
Aging may affect the pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly (see CLINICAL
PHARMACOLOGY, Pharmacokinetics and Metabolism).
Verapamil is highly metabolized by the liver, and about 70% of the administered dose is excreted as metabolites in the urine. Clinical
circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered
(see PRECAUTIONS, General). In general, lower initial doses of Verelan may be warranted in the elderly (see DOSAGE AND
ADMINISTRATION).
Animal Pharmacology and/or Animal Toxicology
In chronic animal toxicology studies verapamil caused lenticular and/or suture line changes at 30 mg/kg/day or greater and frank
cataracts at 62.5 mg/kg/day or greater in the beagle dog but not the rat. Development of cataracts due to verapamil has not been
reported in man.
ADVERSE REACTIONS
Serious adverse reactions are uncommon when verapamil HCl therapy is initiated with upward dose titration within the recommended
single and total daily dose. See WARNINGS for discussion of heart failure, hypotension, elevated liver enzymes, AV block, and rapid
ventricular response. Reversible (upon discontinuation of verapamil) non-obstructive, paralytic ileus has been infrequently reported in
association with the use of verapamil.
In clinical trials involving 285 hypertensive patients on Verelan for greater than 1 week the following adverse reactions were reported
in greater than 1.0% of the patients:
Constipation
7.4%
Headache
5.3%
Dizziness
4.2%
Lethargy
3.2%
Dyspepsia
2.5%
Rash
1.4%
Ankle Edema
1.4%
Sleep Disturbance
1.4%
Myalgia
1.1%
In clinical trials of other formulations of verapamil HCl (N=4,954) the following reactions have occurred at rates greater than 1.0%:
Reference ID: 3641839
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Constipation
7.3%
CHF/Pulmonary Edema
1.8%
Dizziness
3.3%
Fatigue
1.7%
Nausea
2.7%
Bradycardia (HR<50/min)
1.4%
Hypotension
2.5%
AV block-total 1°, 2°, 3°
1.2%
2° and 3°
0.8%
Edema
1.9%
Headache
2.2%
Flushing
0.6%
Rash
1.2%
Elevated Liver Enzymes (see WARNINGS)
In clinical trials related to the control of ventricular response in digitalized patients who had atrial fibrillation or atrial flutter,
ventricular rate below 50/min at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5% of patients.
The following reactions, reported in 1.0% or less of patients, occurred under conditions (open trials, marketing experience) where a
causal relationship is uncertain; they are listed to alert the physician to a possible relationship:
Cardiovascular: angina pectoris, atrioventricular dissociation, chest pain, claudication, myocardial infarction, palpitations, purpura
(vasculitis), syncope.
Digestive System: diarrhea, dry mouth, gastrointestinal distress, gingival hyperplasia.
Hemic and Lymphatic: ecchymosis or bruising.
Nervous System: cerebrovascular accident, confusion, equilibrium disorders, extrapyramidal symptoms insomnia, muscle cramps,
paresthesia, psychotic symptoms, shakiness, somnolence.
Respiratory: dyspnea.
Skin: arthralgia and rash, exanthema, hair loss, hyperkeratosis, maculae, sweating, urticaria, Stevens-Johnson syndrome, erythema
multiforme.
Special Senses: blurred vision, tinnitis.
Urogenital: gynecomastia, impotence, increased urination, spotty menstruation.
Treatment of Acute Cardiovascular Adverse Reactions
The frequency of cardiovascular adverse reactions which require therapy is rare; hence, experience with their treatment is limited.
Whenever severe hypotension or complete AV block occurs following oral administration of verapamil, the appropriate emergency
measures should be applied immediately, e.g., intravenously administered isoproterenol HCl, levarterenol bitartrate, atropine (all in
the usual doses), or calcium gluconate (10% solution). In patients with hypertrophic cardiomyopathy (IHSS), alpha-adrenergic agents
(phenylephrine, metaraminol bitartrate or methoxamine) should be used to maintain blood pressure, and isoproterenol and levarterenol
should be avoided. If further support is necessary, inotropic agents (dopamine or dobutamine) may be administered. Actual treatment
and dosage should depend on the severity and the clinical situation and the judgment and experience of the treating physician.
OVERDOSAGE
There is no specific antidote for verapamil overdosage; treatment should be supportive. Delayed pharmacodynamic consequences may
occur with sustained-release formulations, and patients should be observed for at least 48 hours, preferably under continuous hospital
care. Reported effects include hypotension, bradycardia, cardiac conduction defects, arrhythmias, hyperglycemia, and decreased
mental status. In addition, there have been literature reports of non-cardiogenic pulmonary edema in patients taking large overdoses of
verapamil (up to approximately 9g).
In acute overdosage, gastrointestinal decontamination with cathartics and whole bowel irrigation should be considered. Calcium,
inotropes (i.e., isoproterenol, dopamine, and glucagon), atropine, vasopressors (i.e., norepinephrine, and epinephrine), and cardiac
Reference ID: 3641839
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
pacing have been used with variable results to reverse hypotension and myocardial depression. In a few reported cases, overdose
with calcium channel blockers that was initially refractory to atropine became more responsive to this treatment when the patients
received large doses (close to 1g/hour for more than 24 hours) of calcium chloride. Calcium chloride is preferred to calcium gluconate
since it provides 3 times more calcium per volume. Asystole should be handled by the usual measures including cardiopulmonary
resuscitation. Verapamil cannot be removed by hemodialysis.
DOSAGE AND ADMINISTRATION
Essential Hypertension
The dose of Verelan should be individualized by titration. The usual daily dose of sustained-release verapamil, Verelan, in clinical
trials has been 240 mg given by mouth once daily in the morning. However, initial doses of 120 mg a day may be warranted in
patients who may have an increased response to verapamil (e.g., elderly, small people, etc.). Upward titration should be based on
therapeutic efficacy and safety evaluated approximately 24 hours after dosing. The antihypertensive effects of Verelan are evident
within the first week of therapy.
If adequate response is not obtained with 120 mg of Verelan, the dose may be titrated upward in the following manner:
(a) 180 mg in the morning.
(b) 240 mg in the morning.
(c) 360 mg in the morning.
(d) 480 mg in the morning.
Verelan sustained-release capsules are for once-a-day administration. When switching from immediate-release verapamil to Verelan
capsules, the same total daily dose of Verelan capsules can be used.
As with immediate-release verapamil, dosages of Verelan capsules should be individualized and titration may be needed in some
patients.
Sprinkling the Capsule Contents on Food
Verelan pellet filled capsules may also be administered by carefully opening the capsule and sprinkling the pellets on a spoonful of
applesauce. The applesauce should be swallowed immediately without chewing and followed with a glass of cool water to ensure
complete swallowing of the pellets. The applesauce used should not be hot, and it should be soft enough to be swallowed without
chewing. Any pellet/applesauce mixture should be used immediately and not stored for future use. Subdividing the contents of a
Verelan capsule is not recommended.
HOW SUPPLIED
Verelan ® (verapamil hydrochloride) sustained-release pellet filled capsules are supplied in four dosage strengths:
120 mg -
Two-piece, size 2 hard gelatin capsule (yellow cap/yellow body), printed with SCHWARZ above 2490 on left
and VERELAN above 120 mg on right side of the capsule in black ink, supplied as follows:
NDC 0091-2490-23 - Bottle of 100s
180 mg -
Two-piece, size 1 elongated hard gelatin capsule (light grey cap/yellow body), printed with SCHWARZ above
2489 on left and VERELAN above 180 mg on right side of the capsule in black ink, supplied as follows:
NDC 0091-2489-23 - Bottle of 100s
240 mg -
Two-piece, size 0 hard gelatin capsule (dark blue cap/yellow body), printed with SCHWARZ above 2491 on left
and VERELAN above 240 mg on right side of the capsule in black ink, supplied as follows:
NDC 0091-2491-23 - Bottle of 100s
360 mg -
Two-piece, size 00 hard gelatin capsule (lavender cap/yellow body), printed with SCHWARZ above 2495 on left
and VERELAN above 360 mg on right side of the capsule in black ink, supplied as follows:
NDC 0091-2495-23 - Bottle of 100s
Store at controlled room temperature 20°-25°C (68°-77°F). [See USP]. Avoid excessive heat. Brief digressions above 25°C,
while not detrimental, should be avoided. Protect from moisture. Dispense in tight, light-resistant container as defined in USP.
Call your doctor for medical advice about side effects. You may report side effects to UCB, Inc. at 1-800-477-7877 or FDA at 1-800
FDA-1088 or www.fda.gov/medwatch.
Rxonly
Distributed by:
Kremers Urban Pharmaceutical Inc.
Princeton, NJ 08540, USA
Verelan® is a registered trademark of Alkermes Pharma Ireland Limited
Reference ID: 3641839
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Manufactured by:
Alkermes Gaineville LLC
Gaineville, GA 30504, USA
Rev. 06/2014
Reference ID: 3641839
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:31.642767
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019614s050lbl.pdf', 'application_number': 19614, 'submission_type': 'SUPPL ', 'submission_number': 50}
|
11,564
|
Prepidil® Gel
dinoprostone cervical gel
For Endocervical Use
DESCRIPTION
PREPIDIL Gel contains dinoprostone as the naturally occurring form of prostaglandin E2
(PGE2) and is designated chemically as (5Z, 11a, 13E, 15S)-11,15-Dihydroxy-9-oxo
prosta-5,13-dien-1-oic acid. The molecular formula is C20H32O5 and the molecular
weight is 352.5. Dinoprostone occurs as a white to off-white crystalline powder with a
melting point within the range of 65° to 69°C. It is soluble in ethanol, in 25% ethanol in
water, and in water to the extent of 130 mg/100 mL. The active constituent of PREPIDIL
Gel is dinoprostone 0.5 mg/3 g (2.5 mL gel); other constituents are colloidal silicon
dioxide NF (240 mg/3 g) and triacetin USP (2760 mg/3 g).
The structural formula is represented below: Structural Formula
CLINICAL PHARMACOLOGY
PREPIDIL Gel (dinoprostone) administered endocervically may stimulate the
myometrium of the gravid uterus to contract in a manner similar to contractions seen in
the term uterus during labor. Whether or not this action results from a direct effect of
dinoprostone on the myometrium has not been determined. Dinoprostone is also capable
of stimulating smooth muscle of the gastrointestinal tract in humans. This activity may be
responsible for the vomiting and/or diarrhea that is occasionally seen when dinoprostone
is used for preinduction cervical ripening.
In laboratory animals, and also in humans, large doses of dinoprostone can lower blood
pressure, probably as a result of its effect on smooth muscle of the vascular system. With
the doses of dinoprostone used for cervical ripening this effect has not been seen. In
laboratory animals, and also in humans, dinoprostone can elevate body temperature;
however, with the dosing used for cervical ripening this effect has not been seen.
In addition to an oxytocic effect, there is evidence suggesting that this agent has a local
cervical effect in initiating softening, effacement, and dilation. These changes, referred to
as cervical ripening, occur spontaneously as the normal pregnancy progresses toward
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
term and allow evacuation of uterine contents by decreasing cervical resistance at the
same time that myometrial activity increases. While not completely understood,
biochemical changes within the cervix during natural cervical ripening are similar to
those following PGE2-induced ripening. Further, it has been shown that these changes
can take place independent of myometrial activity; however, it is quite likely that PGE2
administered endocervically produces effacement and softening by combined
contraction-inducing and cervical-ripening properties. There is evidence to suggest that
the changes that take place within the cervix are due to collagen degradation resulting
from collagenase secretion as a response, at least in part, to PGE2.
Using an unvalidated assay, the following information was determined. When PREPIDIL
Gel was administered endocervically to women undergoing preinduction ripening, results
from measurement of plasma levels of the metabolite 13,14-dihydro-15-keto-PGE2
(DHK-PGE2) showed that PGE2 was relatively rapidly absorbed and the Tmax was 0.5 to
0.75 hours. Plasma mean Cmax for gel-treated subjects was 433 ± 51 pg/mL versus 137 ±
24 pg/mL for untreated controls. In those subjects in which a clinical response was
observed, mean Cmax was 484 ± 57 pg/mL versus 213 ± 69 pg/mL in nonresponders and
219 ± 92 pg/mL in control subjects who had positive clinical progression toward normal
labor. These elevated levels in gel-treated subjects appear to be largely a result of
absorption of PGE2 from the gel rather than from endogenous sources.
PGE2 is completely metabolized in humans. PGE2 is extensively metabolized in the
lungs, and the resulting metabolites are further metabolized in the liver and kidney. The
major route of elimination of the products of PGE2 metabolism is the kidneys.
INDICATIONS AND USAGE
PREPIDIL Gel is indicated for ripening an unfavorable cervix in pregnant women at or
near term with a medical or obstetrical need for labor induction.
CONTRAINDICATIONS
Endocervically administered PREPIDIL Gel is not recommended for the following:
a. Patients in whom oxytocic drugs are generally contraindicated or where prolonged
contractions of the uterus are considered inappropriate, such as:
• cases with a history of cesarean section or major uterine surgery
• cases in which cephalopelvic disproportion is present
• cases in which there is a history of difficult labor and/or traumatic delivery
• grand multiparae with six or more previous term pregnancies cases with
non-vertex presentation
• cases with hyperactive or hypertonic uterine patterns
• cases of fetal distress where delivery is not imminent
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• in obstetric emergencies where the benefit-to-risk ratio for either the fetus
or the mother favors surgical intervention
b. Patients with hypersensitivity to prostaglandins or constituents of the gel.
c. Patients with placenta previa or unexplained vaginal bleeding during this
pregnancy.
d. Patients for whom vaginal delivery is not indicated, such as vasa previa or active
herpes genitalia.
WARNINGS
FOR HOSPITAL USE ONLY
Dinoprostone, as with other potent oxytocic agents, should be used only with strict
adherence to recommended dosages. Dinoprostone should be administered by physicians
in a hospital that can provide immediate intensive care and acute surgical facilities.
Women aged 30 years or older, those with complications during pregnancy and those
with a gestational age over 40 weeks have been shown to have an increased risk of post
partum disseminated intravascular coagulation. In addition, these factors may further
increase the risk associated with labor induction (see ADVERSE REACTIONS, Post-
marketing surveillance). Therefore, in these women, use of dinoprostone should be
undertaken with caution. Measures should be applied to detect as soon as possible an
evolving fibrinolysis in the immediate post-partum phase.
The Clinician should be alert that the intracervical placement of dinoprostone gel may
result in inadvertent disruption and subsequent embolization of antigenic tissue causing
in rare circumstances the development of Anaphylactoid Syndrome of Pregnancy
(Amniotic Fluid Embolism).
PRECAUTIONS
1. General Precautions
During use, uterine activity, fetal status, and character of the cervix (dilation and
effacement) should be carefully monitored either by auscultation or electronic fetal
monitoring to detect possible evidence of undesired responses, e.g., hypertonus, sustained
uterine contractility, or fetal distress. In cases where there is a history of hypertonic
uterine contractility or tetanic uterine contractions, it is recommended that uterine activity
and the state of the fetus should be continuously monitored. The possibility of uterine
rupture should be borne in mind when high-tone myometrial contractions are sustained.
Feto-pelvic relationships should be carefully evaluated before use of PREPIDIL Gel (see
CONTRAINDICATIONS).
Caution should be exercised in administration of PREPIDIL Gel in patients with:
• asthma or history of asthma
• glaucoma or raised intraocular pressure
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Caution should be taken so as not to administer PREPIDIL Gel above the level of the
internal os. Careful vaginal examination will reveal the degree of effacement which will
regulate the size of the shielded endocervical catheter to be used. That is, the 20 mm
endocervical catheter should be used if no effacement is present, and the 10 mm catheter
should be used if the cervix is 50% effaced. Placement of PREPIDIL Gel into the extra-
amniotic space has been associated with uterine hyperstimulation.
As PREPIDIL Gel is extensively metabolized in the lung, liver, and kidney, and the
major route of elimination is the kidney, PREPIDIL Gel should be used with caution in
patients with renal and hepatic dysfunction.
2. Patients With Ruptured Membranes
Caution should be exercised in the administration of PREPIDIL Gel in patients with
ruptured membranes. The safety of use of PREPIDIL Gel in these patients has not been
determined.
3. Drug Interactions
PREPIDIL Gel may augment the activity of other oxytocic agents and their concomitant
use is not recommended. For the sequential use of oxytocin following PREPIDIL Gel
administration, a dosing interval of 6–12 hours is recommended.
4. Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenic bioassay studies have not been conducted in animals with PREPIDIL Gel
due to the limited indications for use and short duration of administration. No evidence of
mutagenicity was observed in the Micronucleus Test or Ames Assay.
5. Pregnancy, Teratogenic Effects
PREGNANCY CATEGORY C
Prostaglandin E2 produced an increase in skeletal anomalies in rats and rabbits. No effect
would be expected clinically, when used as indicated, since PREPIDIL Gel is
administered after the period of organogenesis. PREPIDIL Gel has been shown to be
embryotoxic in rats and rabbits, and any dose that produces sustained increased uterine
tone could put the embryo or fetus at risk. See statements under General Precautions.
6. Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
ADVERSE REACTIONS
PREPIDIL Gel is generally well-tolerated. In controlled trials, in which 1731 women
were entered, the following events were reported at an occurrence of ≥ 1%:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PGE2
Control*
Adverse Reaction
(N = 884)
(N = 847)
Maternal
N (%)
N (%)
Uterine contractile abnormality
58 (6.6)
34 (4.0)
Any gastrointestinal effect
50 (5.7)
22 (2.6)
Back pain
27 (3.1)
0 (0)
Warm feeling in vagina
13 (1.5)
0 (0)
Fever
12 (1.4)
10 (1.2)
Fetal
Any fetal heart rate abnormality
150 (17.0)
123 (14.5)
Bradycardia
36 (4.1)
26 (3.1)
Deceleration
Late
25 (2.8)
18 (2.1)
Variable
38 (4.3)
29 (3.4)
Unspecified
19 (2.1)
19 (2.2)
*placebo gel or no treatment
In addition, in other trials amnionitis and intrauterine fetal sepsis have been associated
with extra-amniotic intrauterine administration of PGE2. Uterine rupture has been
reported in association with the use of PREPIDIL Gel intracervically. Additional events
reported in the literature, associated by the authors with the use of PREPIDIL Gel,
included premature rupture of membranes, fetal depression (1 min Apgar < 7), and fetal
acidosis (umbilical artery pH < 7.15).
Post-marketing surveillance:
Blood and lymphatic system disorders: An increased risk of post-partum disseminated
intravascular coagulation has been described in patients whose labor was induced by
pharmacological means, either with dinoprostone or oxytocin (see section WARNINGS).
The frequency of this adverse event, however, appears to be rare (<1 per 1,000 labors).
DRUG ABUSE AND DEPENDENCE
No drug abuse or drug dependence has been seen with the use of PREPIDIL Gel.
OVERDOSAGE
Overdosage with PREPIDIL Gel may be expressed by uterine hypercontractility and
uterine hypertonus. Because of the transient nature of PGE2-induced myometrial
hyperstimulation, nonspecific, conservative management was found to be effective in the
vast majority of the cases; i.e., maternal position change and administration of oxygen to
the mother. β-adrenergic drugs may be used as a treatment of hyperstimulation following
the administration of PGE2 for cervical ripening.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DOSAGE AND ADMINISTRATION
NOTE: USE CAUTION IN HANDLING THIS PRODUCT TO PREVENT CONTACT
WITH SKIN. WASH HANDS THOROUGHLY WITH SOAP AND WATER AFTER
ADMINISTRATION.
PREPIDIL Gel should be brought to room temperature (59° to 86°F; 15° to 30°C) just
prior to administration. Do not force the warming process by using a water bath or other
source of external heat (eg, microwave oven).
To prepare the product for use remove the protective end cap (to serve as plunger
extension) and insert the protective end cap into the plunger stopper assembly in the
barrel of syringe. Choose the appropriate length shielded catheter (10 mm or 20 mm) and
aseptically remove the sterile shielded catheter from the package. Careful vaginal
examination will reveal the degree of effacement which will regulate the size of the
shielded endocervical catheter to be used. That is, the 20 mm endocervical catheter
should be used if no effacement is present, and the 10 mm catheter should be used if the
cervix is 50% effaced. Firmly attach the catheter hub to the syringe tip as evidenced by a
distinct click. Fill the catheter with sterile gel by pushing the plunger assembly to expel
air from the catheter prior to administration to the patient. Proper assembly of the dosing
apparatus is shown below. usage illustration
To properly administer the product, the patient should be in a dorsal position with the
cervix visualized using a speculum. Using sterile technique, introduce the gel with the
catheter provided into the cervical canal just below the level of the internal os.
Administer the contents of the syringe by gentle expulsion and then remove the catheter.
The gel is easily extrudable from the syringe. Use the contents of one syringe for one
patient only. No attempt should be made to administer the small amount of gel remaining
in the catheter. The syringe, catheter, and any unused package contents should be
discarded after use. Following administration of PREPIDIL Gel, the patient should
remain in the supine position for at least 15–30 minutes to minimize leakage from the
cervical canal. If the desired response is obtained from PREPIDIL Gel, the recommended
interval before giving intravenous oxytocin is 6–12 hours. If there is no cervical/uterine
response to the initial dose of PREPIDIL Gel, repeat dosing may be given. The
recommended repeat dose is 0.5 mg dinoprostone with a dosing interval of 6 hours. The
need for additional dosing and the interval must be determined by the attending physician
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
based on the course of clinical events. The maximum recommended cumulative dose for
a 24-hour period is 1.5 mg of dinoprostone (7.5 mL PREPIDIL Gel).
HOW SUPPLIED
PREPIDIL Gel is available as a sterile semitranslucent viscous preparation for
endocervical application: 0.5 mg PGE2 per 3.0 g (2.5 mL) in syringe. In addition, each
package contains two shielded catheters (10 mm and 20 mm tip) enclosed in sterile
envelopes. The contents are not guaranteed sterile if envelopes are not intact.
Each 3 gram syringe applicator contains:
dinoprostone, 0.5 mg; colloidal silicon dioxide, 240 mg; triacetin, 2760 mg.
5 × 3 gram syringes
NDC 0009-3359-02
PREPIDIL Gel needs to be stored under continuous refrigeration (36° to 46°F; 2° to 8°C).
Rx only Company logo
Revised February 2010
LAB-0062-4.1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:31.707581
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019617s010lbl.pdf', 'application_number': 19617, 'submission_type': 'SUPPL ', 'submission_number': 10}
|
11,563
|
07-19-66-240
Baxter
DOPamine Hydrochloride and 5% Dextrose Injection,
USP
in Plastic Container
VIAFLEX Plus Container
DESCRIPTION
Dopamine Hydrochloride and 5% Dextrose Injection, USP is a sterile, nonpyrogenic
solution of Dopamine Hydrochloride, USP and Dextrose, USP in Water for Injection.
Structural formulas are shown below: structural formula
Dopamine Hydrochloride and 5% Dextrose Injection, USP is intended for intravenous
use only. It contains no antimicrobial agents. The pH is adjusted with hydrochloric acid
and is 3.5 (2.5 to 4.5). Approximately 5 mEq/L sodium bisulfite is added as a stabilizer.
The solution provides a caloric content of 170 kcal/L. The solution is intended for single
use only. When smaller doses are required, the unused portion should be discarded.
Composition and osmolarity are given below:
1
Reference ID: 3146006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
800 mcg/mL Dopamine Hydrochloride and 5% Dextrose Injection, USP provides
800 mcg/mL Dopamine Hydrochloride, USP and 50 g/L Dextrose Hydrous, USP with an
osmolarity of 261 mOsmol/L (calc).
1600 mcg/mL Dopamine Hydrochloride and 5% Dextrose Injection, USP provides
1600 mcg/mL Dopamine Hydrochloride, USP and 50 g/L Dextrose Hydrous, USP with
an osmolarity of 269 mOsmol/L (calc).
3200 mcg/mL Dopamine Hydrochloride and 5% Dextrose Injection, USP provides
3200 mcg/mL Dopamine Hydrochloride, USP and 50 g/L Dextrose Hydrous, USP with
an osmolarity of 286 mOsmol/L (calc).
Dopamine administered intravenously is a myocardial inotropic agent which also may
increase mesenteric and renal blood flow plus urinary output.
Dopamine hydrochloride is designated chemically as 3,4-dihydroxyphenethylamine
hydrochloride, a white crystalline powder freely soluble in water. Dopamine (also
referred to as 3-hydroxytyramine) is a naturally occurring biochemical catecholamine
precursor of norepinephrine.
This VIAFLEX Plus plastic container is fabricated from a specially formulated polyvinyl
chloride (PL 2207 Plastic). VIAFLEX containers, including VIAFLEX Plus containers,
are made of flexible plastic and are for parenteral use. VIAFLEX Plus on the container
indicates the presence of a drug additive in a drug vehicle. 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.
CLINICAL PHARMACOLOGY
Dopamine is a natural catecholamine formed by the decarboxylation of 3,4
dihydroxyphenylalanine (DOPA). It is a precursor to norepinephrine in noradrenergic
nerves and is also a neurotransmitter in certain areas of the central nervous system,
especially in the nigrostriatal tract, and in a few peripheral sympathetic nerves.
Dopamine produces positive chronotropic and inotropic effects on the myocardium,
resulting in increased heart rate and cardiac contractility. This is accomplished directly by
2
Reference ID: 3146006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
exerting an agonist action on beta-adrenoceptors and indirectly by causing release of
norepinephrine from storage sites in sympathetic nerve endings.
Dopamine’s onset of action occurs within five minutes of intravenous administration, and
with dopamine’s plasma half-life of about two minutes, the duration of action is less than
ten minutes. If monoamine oxidase (MAO) inhibitors are present, however, the duration
may increase to one hour. The drug is widely distributed in the body but does not cross
the blood-brain barrier to a significant extent. Dopamine is metabolized in the liver,
kidney, and plasma by MAO and catechol-O-methyltransferase to the inactive
compounds homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid. About 25% of
the dose is taken up into specialized neurosecretory vesicles (the adrenergic nerve
terminals), where it is hydroxylated to form norepinephrine. It has been reported that
about 80% of the drug is excreted in the urine within 24 hours, primarily as HVA and its
sulfate and glucuronide conjugates and as 3,4-dihydroxyphenylacetic acid. A very small
portion is excreted unchanged.
The predominant effects of dopamine are dose-related, although actual response of an
individual patient will largely depend on the clinical status of the patient at the time the
drug is administered. At low rates of infusion (0.5-2 mcg/kg/min) dopamine causes
vasodilation that is presumed to be due to a specific agonist action on dopamine receptors
(distinct from alpha- and beta-adrenoceptors) in the renal, mesenteric, coronary, and
intracerebral vascular beds. At these dopamine receptors, haloperidol is an antagonist.
The vasodilation in these vascular beds is accompanied by increased glomerular filtration
rate, renal blood flow, sodium excretion, and urine flow. Hypotension sometimes occurs.
An increase in urinary output produced by dopamine is usually not associated with a
decrease in osmolarity of the urine.
At intermediate rates of infusion (2-10 mcg/kg/min) dopamine acts to stimulate the beta1
adrenoceptors, resulting in improved myocardial contractility, increased SA rate and
enhanced impulse conduction in the heart. There is little, if any, stimulation of the beta2
adrenoceptors (peripheral vasodilation). Dopamine causes less increase in myocardial
oxygen consumption than isoproterenol, and its use is not usually associated with a
tachyarrhythmia. Clinical studies indicate that it usually increases systolic and pulse
pressure with either no effect or a slight increase in diastolic pressure. Blood flow to the
peripheral vascular beds may decrease while mesenteric flow increased due to increased
cardiac output. At low and intermediate doses, total peripheral resistance (which would
be raised by alpha activity) is usually unchanged.
3
Reference ID: 3146006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
At higher rates of infusion (10-20 mcg/kg/min) there is some effect on alpha
adrenoceptors, with consequent vasoconstrictor effects and a rise in blood pressure. The
vasoconstrictor effects are first seen in the skeletal muscle vascular beds, but with
increasing doses they are also evident in the renal and mesenteric vessels. At very high
rates of infusion (above 20 mcg/kg/min), stimulation of alpha-adrenoceptors
predominates and vasoconstriction may compromise the circulation of the limbs and
override the dopaminergic effects of dopamine, reversing renal dilation and natriuresis.
Dextrose provides a source of calories. Dextrose is readily metabolized, may decrease
losses of body protein and nitrogen, promotes glycogen deposition and decreases or
prevents ketosis if sufficient doses are provided.
INDICATIONS AND USAGE
Dopamine hydrochloride is indicated for the correction of hemodynamic imbalances
present in the shock syndrome due to myocardial infarctions, trauma, endotoxic
septicemia, open heart surgery, renal failure and chronic cardiac decompensation as in
congestive failure.
Where appropriate, restoration of blood volume with a suitable plasma expander or whole
blood should be instituted or completed prior to administration of dopamine
hydrochloride.
Patients most likely to respond adequately to dopamine hydrochloride are those in whom
physiological parameters, such as urine flow, myocardial function and blood pressure
have not undergone profound deterioration. Reports indicate that the shorter the time
interval between onset of signs and symptoms and initiation of therapy with volume
correction and dopamine hydrochloride, the better the prognosis.
Poor Perfusion of Vital Organs
Urine flow appears to be one of the better diagnostic signs by which adequacy of vital
organ perfusion can be monitored. Nevertheless, the physician should also observe the
patient for signs of reversal of confusion or comatose condition. Loss of pallor, increase
in toe temperature and/or adequacy of nail bed capillary filling may also be used as
indices of adequate dosage. Reported studies indicate that when dopamine hydrochloride
is administered before urine flow has diminished to levels of approximately 0.3
mL/minute, prognosis is more favorable. Nevertheless, in a number of oliguric or anuric
patients, administration of dopamine hydrochloride has resulted in an increase in urine
flow which in some cases reached normal levels. Dopamine hydrochloride may also
4
Reference ID: 3146006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
increase urine flow in patients whose output is within normal limits and thus may be of
value in reducing the degree of preexisting fluid accumulation. It should be noted that at
doses above those optimal for the individual patient, urine flow may decrease,
necessitating reduction of dosage. Concurrent administration of dopamine hydrochloride
and diuretic agents may produce an additive or potentiating effect.
Low Cardiac Output
Increased cardiac output is related to dopamine hydrochloride’s direct inotropic effect on
the myocardium. Increased cardiac output at low or moderate doses appears to be related
to a favorable prognosis. Increase in cardiac output has been associated with either static
or decreased systemic vascular resistance (SVR). Static or decreased SVR associated
with low or moderate increments in cardiac output is believed to be a reflection of
differential effects on specific vascular beds with increased resistance in peripheral beds
(e.g., femoral) and concomitant decreases in mesenteric and renal vascular beds.
Redistribution of blood flow parallels these changes so that an increase in cardiac output
is accompanied by an increase in mesenteric and renal blood flow. In many instances the
renal fraction of the total cardiac output has been found to increase. Increase in cardiac
output produced by dopamine hydrochloride is not associated with substantial decreases
in systemic vascular resistance as may occur with isoproterenol.
Hypotension
Hypotension due to inadequate cardiac output can be managed by administration of low
to moderate doses of dopamine hydrochloride, which have little effect on SVR. At high
therapeutic doses, dopamine hydrochloride’s alpha-adrenergic activity becomes more
prominent and thus may correct hypotension due to diminished SVR. As in the case of
other circulatory decompensation states, prognosis is better in patients whose blood
pressure and urine flow have not undergone profound deterioration. Therefore, it is
suggested that the physician administer dopamine hydrochloride as soon as a definite
trend toward decreased systolic and diastolic pressure becomes evident.
CONTRAINDICATIONS
Dopamine hydrochloride should not be used in patients with pheochromocytoma.
Dopamine hydrochloride should not be administered in the presence of uncorrected
tachyarrhythmias or ventricular fibrillation.
5
Reference ID: 3146006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Solutions containing dextrose may be contraindicated in patients with known allergy to
corn or corn products.
WARNINGS
Patients who have been treated with monoamine oxidase (MAO) inhibitors prior to the
administration of dopamine hydrochloride will require substantially reduced dosage. See
Drug Interactions, below.
Evidence is inadequate for fully defining proper dosage and limitations for use in
children.
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.
Do not add Dopamine Hydrochloride and 5% Dextrose Injection, USP to any alkaline
diluent solution since dopamine hydrochloride is inactivated in alkaline solution.
Solutions containing dextrose should not be administered through the same
administration set as blood, as this may result in pseudoagglutination or hemolysis.
The intravenous administration of solutions may cause fluid overloading resulting in
dilution of serum electrolyte concentrations, overhydration, congested states or
pulmonary edema.
Excess administration of potassium-free solutions may result in significant hypokalemia.
PRECAUTIONS
General
Avoid bolus administration of dopamine hydrochloride. See Dosage and
Administration.
Avoid Hypovolemia
Prior to treatment with dopamine hydrochloride, hypovolemia should be fully corrected,
if possible, with either whole blood, plasma, or plasma expanders as indicated.
6
Reference ID: 3146006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Monitoring of central venous pressure or left ventricular filling pressure may be helpful
in detecting and treating hypovolemia.
Hypoxia, Hypercapnia, Acidosis
These conditions, which may also reduce the effectiveness and/or increase the incidence
of adverse effects of dopamine, must be identified and corrected prior to, and
concurrently with, administration of dopamine HCl.
Ventricular Arrhythmias
If an increased number of ectopic beats is observed, the dose should be reduced if
possible.
Decreased Pulse Pressure
If a disproportionate rise in the diastolic pressure (i.e., marked decrease in the pulse
pressure) is observed in patients receiving dopamine hydrochloride, the infusion rate
should be decreased and the patient observed carefully for further evidence of
predominant vasoconstrictor activity, unless such an effect is desired.
Hypotension
At lower infusion rates, if hypotension occurs, the infusion rate should be rapidly
increased until adequate blood pressure is obtained. If hypotension persists, dopamine
HCl should be discontinued and a more potent vasoconstrictor agent such as
norepinephrine should be administered.
Occlusive Vascular Disease
Patients with a history of occlusive vascular disease (for example, atherosclerosis, arterial
embolism, Raynaud’s disease, cold injury, diabetic endarteritis and Buerger’s disease)
should be closely monitored for any changes in color or temperature of the skin in the
extremities. If a change in skin color or temperature occurs and is thought to be the result
of compromised circulation to the extremities, the benefits of continued dopamine
hydrochloride infusion should be weighed against the risk of possible necrosis. This
condition may be reversed by either decreasing the rate or discontinuing the infusion.
Extravasation
Dopamine Hydrochloride and 5% Dextrose Injection, USP should be infused into a large
vein whenever possible to prevent the possibility of extravasation into tissue adjacent to
7
Reference ID: 3146006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
the infusion site. Extravasation may cause necrosis and sloughing of surrounding tissue.
Large veins of the antecubital fossa are preferred to veins in the dorsum of the hand or
ankle. Less suitable infusion sites should be used only if the patient’s condition requires
immediate attention. The physician should switch to more suitable sites as rapidly as
possible. The infusion site should be continuously monitored for free flow.
IMPORTANT – Antidote for Peripheral Ischemia
To prevent sloughing and necrosis in ischemic areas, the area should be infiltrated as
soon as possible with 10 to 15 mL of 0.9% Sodium Chloride Injection, USP containing
from 5 to 10 mg phentolamine, an adrenergic blocking agent. A syringe with a fine
hypodermic needle should be used and the solution liberally infiltrated throughout the
ischemic area. Sympathetic blockage with phentolamine causes immediate and
conspicuous local hyperemic changes if the area is infiltrated within 12 hours. Therefore,
phentolamine should be given as soon as possible after the extravasation is noted.
Weaning
When discontinuing the infusion, it may be necessary to gradually decrease the dose of
dopamine HCl while expanding blood volume with IV fluids, since sudden cessation may
result in marked hypotension.
Careful Monitoring Required
Close monitoring of the following indices - urine flow, cardiac output and blood pressure
- during dopamine hydrochloride infusion is necessary as in the case of any adrenergic
agent.
Solutions containing dextrose should be used with caution in patients with known
subclinical or overt diabetes mellitus.
Do not administer unless solution is clear and seal is intact.
If administration is controlled by a pumping device, care must be taken to discontinue
pumping action before the container runs dry or air embolism may result.
Laboratory Tests
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.
8
Reference ID: 3146006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Drug Interactions
Cyclopropane or halogenated hydrocarbon anesthetics increase cardiac autonomic
irritability and may sensitize the myocardium to the action of certain intravenously
administered catecholamines, such as dopamine. This interaction appears to be related
both to pressor activity and to the beta-adrenergic stimulating properties of these
catecholamines, and may produce ventricular arrhythmias. Therefore, EXTREME
CAUTION should be exercised when administering dopamine HCl to patients receiving
cyclopropane or halogenated hydrocarbon anesthetics. Results of studies in animals
indicate that dopamine-induced ventricular arrhythmias during anesthesia can be reversed
by propranolol.
Because dopamine is metabolized by monoamine oxidase (MAO), inhibition of this
enzyme prolongs and potentiates the effect of dopamine. Patients who have been treated
with MAO inhibitors within two to three weeks prior to the administration of dopamine
should receive initial doses of dopamine hydrochloride no greater than one-tenth (1/10)
of the usual dose.
Concurrent administration of low-dose dopamine HCl and diuretic agents may produce
an additive or potentiating effect on urine flow.
Tricyclic antidepressants may potentiate the cardiovascular effects of adrenergic agents.
Cardiac effects of dopamine are antagonized by beta-adrenergic blocking agents, such as
propranolol and metoprolol. The peripheral vasoconstriction caused by high doses of
dopamine HCl is antagonized by alpha-adrenergic blocking agents. Dopamine-induced
renal and mesenteric vasodilation is not antagonized by either alpha- or beta-adrenergic
blocking agents.
Butyrophenones (such as haloperidol) and phenothiazines can suppress the dopaminergic
renal and mesenteric vasodilation induced with low-dose dopamine infusion.
The concomitant use of vasopressors, vasoconstrictor agents (such as ergonovine) and
some oxytocic drugs may result in severe hypertension.
Administration of phenytoin to patients receiving dopamine HCl has been reported to
lead to hypotension and bradycardia. It is suggested that in patients receiving dopamine
HCl, alternatives to phenytoin should be considered if anticonvulsant therapy is needed.
9
Reference ID: 3146006
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
Long term animal studies have not been performed to evaluate the carcinogenic potential
of dopamine HCl.
Dopamine HCl at doses approaching maximal solubility showed no clear genotoxic
potential in the Ames test. Although there was a reproducible dose-dependent increase in
the number of revertant colonies with strains TA100 and TA98, both with and without
metabolic activation, the small increase was considered inconclusive evidence of
mutagenicity. In the L5178Y TK ± mouse lymphoma assay, dopamine HCl at the highest
concentrations used of 750 μg/ml without metabolic activation, and 3000 μg/ml with
activation, was toxic and associated with increases in mutant frequencies when compared
to untreated and solvent controls; at the lower concentrations no increases over controls
were noted.
No clear evidence of clastogenic potential was reported in the in vivo mouse or male rat
bone marrow micronucleus test when the animals were treated intravenously with up to
224 mg/kg and 30 mg/kg of dopamine HCl, respectively.
Pregnancy
Teratogenic Effects
Pregnancy Category C
Teratogenicity studies in rats and rabbits at dopamine HCl dosages up to 6 mg/kg/day
intravenously during organogenesis produced no detectable teratogenic or embryotoxic
effects, although maternal toxicity consisting of mortalities, decreased body weight gain,
and pharmacotoxic signs were observed in rats. In a published study, dopamine HCl
administered at 10 mg/kg subcutaneously for 30 days, markedly prolonged metestrus and
increased mean pituitary and ovary weights in female rats. Similar administration to
pregnant rats throughout gestation or for 5 days starting on gestation day 10 or 15
resulted in decreased body weight gains, increased mortalities and slight increases in
cataract formation among the offspring. There are no adequate and well-controlled
studies in pregnant women, and it is not known if dopamine HCl crosses the placental
barrier. Dopamine HCl should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
10
Reference ID: 3146006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Labor and Delivery
In obstetrics, if vasopressor drugs are used to correct hypotension or are added to a local
anesthetic solution the interaction with some oxytocic drugs may cause severe
hypertension.
Nursing Mothers
It is not known whether dopamine hydrochloride is excreted in human milk. Because
many drugs are excreted in human milk, caution should be exercised when dopamine
hydrochloride is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in children have not been established. The clearance of
dopamine is affected by age (as much as 2 fold greater in children under 2 years of age),
renal and hepatic function (decreasing by 2 fold in the presence of either). In younger
children, particularly neonates, clearance is highly variable. Newborn infants may be
more sensitive to the vasoconstrictive effects of dopamine.
The most consistent effects of dopamine in 57 publications (between the years 1966
through 1997) were increases in systolic and mean arterial pressure. Renal function was
variably affected, except that in a single publication renal function was preserved in the
face of treatment with indomethacin. No consistent effect on heart rate was described.
Because of the variability of clearance, especially in the neonate and newborn, low doses
of dopamine and slow deliberate titration should be employed (see DOSAGE and
ADMINISTRATION).
Geriatric Use
Clinical studies of dopamine injection 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.
11
Reference ID: 3146006
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 adverse reactions have been observed, but there are not enough data to
support an estimate of their frequency.
Cardiovascular System
ventricular arrhythmia
atrial fibrillation
ectopic beats
tachycardia
anginal pain
palpitation
cardiac conduction abnormalities
widened QRS complex
bradycardia
hypotension
hypertension
vasoconstriction
Respiratory System
dyspnea
Gastrointestinal System
nausea
vomiting
Metabolic/Nutritional System
azotemia
Central Nervous System
headache
anxiety
Dermatological System
piloerection
12
Reference ID: 3146006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Other
Gangrene of the extremities has occurred when high doses were administered for
prolonged periods or in patients with occlusive vascular disease receiving low doses of
dopamine HCl.
OVERDOSAGE
In case of accidental overdosage, as evidenced by excessive blood pressure elevation,
reduce rate of administration or temporarily discontinue dopamine hydrochloride until
patient’s condition stabilizes. Since dopamine hydrochloride’s duration of action is quite
short, no additional remedial measures are usually necessary. If these measures fail to
stabilize the patient’s condition, use of the short-acting alpha-adrenergic blocking agent,
phentolamine, should be considered.
DOSAGE AND ADMINISTRATION
Rate of Administration
Dopamine Hydrochloride and 5% Dextrose Injection, USP is administered intravenously
through a suitable intravenous catheter or needle. An IV drip chamber or other suitable
metering device is essential for controlling the rate of flow in drops/minute. Each patient
must be individually titrated to the desired hemodynamic and/or renal response with
dopamine hydrochloride. In titrating to the desired increase in systolic blood pressure, the
optimum dosage rate for renal response may be exceeded, thus necessitating a reduction
in rate after the hemodynamic condition is stabilized.
Administration of dopamine hydrochloride at rates greater than 50 mcg/kg/min has safely
been used in advanced circulatory decompensation states. If unnecessary fluid expansion
is of concern, use of a more concentrated solution may be preferred over increasing the
flow rate of a less concentrated solution.
Suggested Regimen
1. When appropriate, increase blood volume with whole blood, plasma, or plasma
expanders until central venous pressure is 10 to 15 cm H2O or pulmonary wedge
pressure is 14 to 18 mm Hg.
2. Begin infusion of Dopamine Hydrochloride and 5% Dextrose Injection, USP at doses
of 2 to 5 mcg/kg/min in patients who are likely to respond to modest increments of
heart force and renal perfusion.
In more seriously ill patients, begin administration of Dopamine Hydrochloride and
13
Reference ID: 3146006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5% Dextrose Injection, USP at rates of 5 mcg/kg/min and increase gradually using 5
to 10 mcg/kg/min increments up to a rate of 20 to 50 mcg/kg/min as needed. If rates
in excess of 50 mcg/kg/min are required, it is suggested that urine output be checked
frequently. Should urine flow begin to decrease in the absence of hypotension,
reduction of dopamine hydrochloride dosage should be considered. Reports have
shown that more than 50% of the patients were satisfactorily maintained on doses of
dopamine hydrochloride administered at rates of less than 20 mcg/kg/min. In patients
who do not respond to these doses with adequate arterial pressures or urine flow,
additional increments of dopamine hydrochloride may be given in an effort to
produce an appropriate arterial pressure and central perfusion.
3. Treatment of all patients requires constant evaluation of therapy in terms of blood
volume, augmentation of myocardial contractility and distribution of peripheral
perfusion. Dosage of dopamine hydrochloride should be adjusted according to the
patient’s response, with particular attention to diminution of established urine flow
rate, increasing tachycardia or development of new dysrhythmias as indices for
decreasing or temporarily suspending the dosage.
4. As with all potent intravenously administered drugs, care should be taken to control
the rate of administration so as to avoid inadvertent administration of a bolus of drug.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
Do not use Dopamine Hydrochloride and 5% Dextrose Injection, USP if darker than
slightly yellow or discolored in any other way.
All injections in VIAFLEX Plus plastic containers are intended for intravenous
administration using sterile equipment.
Drug additives should not be made to Dopamine Hydrochloride and 5% Dextrose
Injection, USP.
Pediatric Dosing and Administration
In publications, the most common starting doses were 1-5
micrograms/kilograms/minute. Particularly in neonates, such low doses require
considerable dilution of this product; careful consideration should be given to the
use of this product in such circumstances. Dosing increments that were reported
ranged from 2.5 to 5.0 micrograms/kilogram/minute. Usual maximum doses were 15-20
14
Reference ID: 3146006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
micrograms/kilogram/minute, with occasional use as great as 50
micrograms/kilogram/minute. The time course of dopamine kinetics is poorly defined.
Increasing infusion rates (or dose) should be approached cautiously and only after it is
apparent that hemodynamics (mainly systolic blood pressure) have stabilized with respect
to the current dose and/or rate of infusion.
There have been occasional reports of vasospastic events when dopamine was infused
through umbilical vessels. Due caution should be exercised if infusion of dopamine
through umbilical vessels becomes necessary.
HOW SUPPLIED
Code
Size (mL)
mcg/mL
NDC
2B0832
250
800
0338-1005-02
2B0842
250
1600
0338-1007-02
2B0833
500
800
0338-1005-03
2B0846
250
3200
0338-1009-02
2B0843
500
1600
0338-1007-03
Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat.
Protect from freezing. It is recommended the product be stored at room temperature
(25◦C); brief exposure up to 40◦C does not adversely affect the product.
Avoid contact with alkalies (including sodium bicarbonate), oxidizing agents or iron
salts.
NOTE - Do not use the injection if it is darker than slightly yellow or discolored in any
other way.
DIRECTIONS FOR USE OF VIAFLEX PLUS PLASTIC CONTAINER
The overwrap is a moisture and oxygen barrier. Do not remove unit from overwrap until
ready for use.
To open
Tear overwrap down side at notch 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
15
Reference ID: 3146006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
gradually. Check for minute leaks by squeezing inner bag firmly. If leaks are found,
discard solution as sterility may be impaired.
PREPARATION FOR ADMINISTRATION
Caution: 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.
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
071966240
©Copyright 1985, 1989, 1994, 1995, Baxter Healthcare Corporation.
All rights reserved.
Baxter and VIAFLEX are trademarks of Baxter International Inc.
07-19-66-240
Rev. March 2011
16
Reference ID: 3146006
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:31.844623
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019615s021lbl.pdf', 'application_number': 19615, 'submission_type': 'SUPPL ', 'submission_number': 21}
|
11,566
|
1
ELOCON®
brand of mometasone furoate cream
Cream 0.1%
For Dermatologic Use Only
Not for Ophthalmic Use
DESCRIPTION ELOCON® (mometasone furoate cream) Cream, 0.1%, contains mometasone
furoate, USP for dermatologic use. Mometasone furoate is a synthetic corticosteroid with anti-
inflammatory activity.
Chemically, mometasone furoate is 9α,21-dichloro-11β,17-dihydroxy-16α-
methylpregna-1,4-diene-3,20-dione 17-(2-furoate), with the empirical formula C27H30CI2O6, a
molecular weight of 521.4 and the following structural formula:
[Structure]
Mometasone furoate is a white to off-white powder practically insoluble in water, slightly
soluble in octanol, and moderately soluble in ethyl alcohol.
Each gram of ELOCON Cream, 0.1%, contains: 1 mg mometasone furoate, USP in a
cream base of hexylene glycol; phosphoric acid; propylene glycol stearate (55% monoester);
stearyl alcohol and ceteareth-20; titanium dioxide; aluminum starch octenylsuccinate (Gamma
Irradiated); white wax; white petrolatum; and purified water.
CLINICAL PHARMACOLOGY Like other topical corticosteroids, mometasone furoate 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. Studies in humans indicate that approximately 0.4% of the applied dose of
ELOCON Cream, 0.1%, enters the circulation after 8 hours of contact on normal skin without
occlusion. Inflammation and/or other disease processes in the skin may increase percutaneous
absorption.
Studies performed with ELOCON Cream indicate that it is in the medium range of
potency as compared with other topical corticosteroids.
In a study evaluating the effects of mometasone furoate cream on the hypothalamic-
pituitary-adrenal (HPA) axis, 15 grams were applied twice daily for 7 days to 6 adult patients
with psoriasis or atopic dermatitis. The cream was applied without occlusion to at least 30% of
the body surface. The results show that the drug caused a slight lowering of adrenal
corticosteroid secretion.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
In a pediatric trial, 24 atopic dermatitis patients, of which 19 patients were age 2 to 12
years, were treated with ELOCON Cream, 0.1%, once daily. The majority of patients cleared
within 3 weeks.
Ninety-seven pediatric patients ages 6 to 23 months, with atopic dermatitis, were enrolled
in an open-label, hypothalamic-pituitary-adrenal (HPA) axis safety study. ELOCON Cream was
applied once daily for approximately 3 weeks over a mean body surface area of 41% (range 15%
to 94%). In approximately 16% of patients who showed normal adrenal function by Cortrosyn
test before starting treatment, adrenal suppression was observed at the end of treatment with
ELOCON Cream. The criteria for suppression were: basal cortisol level of ≤5 mcg/dL, 30-
minute post-stimulation level of ≤18 mcg/dL, or an increase of <7 mcg/dL. Follow-up testing 2
to 4 weeks after stopping treatment, available for 5 of the patients, demonstrated suppressed
HPA axis function in one patient, using these same criteria.
INDICATIONS AND USAGE ELOCON Cream, 0.1%, is a medium potency corticosteroid
indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-
responsive dermatoses.
ELOCON (mometasone furoate cream) Cream, 0.1%, may be used in pediatric patients 2
years 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 Section). Since safety and efficacy
of ELOCON Cream have not been adequately established in pediatric patients below 2 years of
age, its use in this age group is not recommended.
CONTRAINDICATIONS ELOCON Cream is contraindicated in those patients with a history
of hypersensitivity to any of the components in the preparation.
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’s 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.
In a study evaluating the effects of mometasone furoate cream on the hypothalamic-
pituitary-adrenal (HPA) axis, 15 grams were applied twice daily for 7 days to 6 adult patients
with psoriasis or atopic dermatitis. The cream was applied without occlusion to at least 30% of
the body surface. The results show that the drug caused a slight lowering of adrenal
corticosteroid secretion.
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 to body mass ratios (see PRECAUTIONS - Pediatric Use Section).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
If irritation develops, ELOCON Cream 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
ELOCON Cream 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. 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 or 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 ELOCON Cream in the treatment
of diaper dermatitis. ELOCON Cream should not be applied in the diaper area as diapers or
plastic pants may constitute occlusive dressing (see DOSAGE AND ADMINISTRATION
Section).
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.
8. Other corticosteroid-containing products should not be used with ELOCON Cream without
first consulting with 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
Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term animal studies have not
been performed to evaluate the carcinogenic potential of ELOCON (mometasone furoate cream)
Cream, 0.1%. Long-term carcinogenicity studies of mometasone furoate were conducted by the
inhalation route in rats and mice. In a 2-year carcinogenicity study in Sprague-Dawley rats,
mometasone furoate demonstrated no statistically significant increase of tumors at inhalation
doses up to 67 mcg/kg (approximately 0.04 times the estimated maximum clinical topical dose
from ELOCON Cream on a mcg/m2 basis). In a 19-month carcinogenicity study in Swiss CD-1
mice, mometasone furoate demonstrated no statistically significant increase in the incidence of
tumors at inhalation doses up to 160 mcg/kg (approximately 0.05 times the estimated maximum
clinical topical dose from ELOCON Cream on a mcg/m2 basis).
Mometasone furoate increased chromosomal aberrations in an in vitro Chinese hamster
ovary cell assay, but did not increase chromosomal aberrations in an in vitro Chinese hamster
lung cell assay. Mometasone furoate was not mutagenic in the Ames test or mouse lymphoma
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
assay, and was not clastogenic in an in vivo mouse micronucleus assay, a rat bone marrow
chromosomal aberration assay, or a mouse male germ-cell chromosomal aberration assay.
Mometasone furoate also did not induce unscheduled DNA synthesis in vivo in rat hepatocytes.
In reproductive studies in rats, impairment of fertility was not produced in male or female
rats by subcutaneous doses up to 15 mcg/kg (approximately 0.01 times the estimated maximum
clinical topical dose from ELOCON Cream on a mcg/m2 basis).
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.
When administered to pregnant rats, rabbits, and mice, mometasone furoate increased
fetal malformations. The doses that produced malformations also decreased fetal growth, as
measured by lower fetal weights and/or delayed ossification. Mometasone furoate also caused
dystocia and related complications when administered to rats during the end of pregnancy.
In mice, mometasone furoate caused cleft palate at subcutaneous doses of 60 mcg/kg and
above. Fetal survival was reduced at 180 mcg/kg. No toxicity was observed at 20 mcg/kg.
(Doses of 20, 60 and 180 mcg/kg in the mouse are approximately 0.01, 0.02 and 0.05 times the
estimated maximum clinical topical dose from ELOCON Cream on a mcg/m2 basis).
In rats, mometasone furoate produced umbilical hernias at topical doses of 600 mcg/kg
and above. A dose of 300 mcg/kg produced delays in ossification, but no malformations.
(Doses of 300 and 600 mcg/kg in the rat are approximately 0.2 and 0.4 times the estimated
maximum clinical topical dose from ELOCON Cream on a mcg/m2 basis).
In rabbits, mometasone furoate caused multiple malformations (e.g., flexed front paws,
gallbladder agenesis, umbilical hernia, hydrocephaly) at topical doses of 150 mcg/kg and above
(approximately 0.2 times the estimated maximum clinical topical dose from ELOCON Cream on
a mcg/m2 basis). In an oral study, mometasone furoate increased resorptions and caused cleft
palate and/or head malformations (hydrocephaly and domed head) at 700 mcg/kg. At 2800
mcg/kg most litters were aborted or resorbed. No toxicity was observed at 140 mcg/kg. (Doses
of 140, 700 and 2800 mcg/kg in the rabbit are approximately 0.2, 0.9 and 3.6 times the estimated
maximum clinical topical dose from ELOCON Cream on a mcg/m2 basis).
When rats received subcutaneous doses of mometasone furoate throughout pregnancy or
during the later stages of pregnancy, 15 mcg/kg caused prolonged and difficult labor and reduced
the number of live births, birth weight and early pup survival. Similar effects were not observed
at 7.5 mcg/kg. (Doses of 7.5 and 15 mcg/kg in the rat are approximately 0.005 and 0.01 times
the estimated maximum clinical topical dose from ELOCON Cream on a mcg/m2 basis).
There are no adequate and well-controlled studies of teratogenic effects from topically
applied corticosteroids in pregnant women. Therefore, topical corticosteroids 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 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 ELOCON Cream is
administered to a nursing woman.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Pediatric Use: ELOCON Cream may be used with caution in pediatric patients 2 years of age or
older, although the safety and efficacy of drug use for longer than 3 weeks have not been
established. Use of ELOCON Cream is supported by results from adequate and well-controlled
studies in pediatric patients with corticosteroid-responsive dermatoses. Since safety and efficacy
of ELOCON Cream have not been adequately established in pediatric patients below 2 years of
age, its use in this age group is not recommended.
ELOCON Cream caused HPA axis suppression in approximately 16% of pediatric
patients ages 6 to 23 months, who showed normal adrenal function by Cortrosyn test before
starting treatment, and were treated for approximately 3 weeks over a mean body surface area of
41% (range 15% to 94%). The criteria for suppression were: basal cortisol level of ≤5 mcg/dL,
30-minute post-stimulation level of ≤18 mcg/dL, or an increase of <7 mcg/dL. Follow-up testing
2 to 4 weeks after study completion, available for 5 of the patients, demonstrated suppressed
HPA axis function in one patient, using these same criteria. Long-term use of topical
corticosteroids has not been studied in this population (see CLINICAL PHARMACOLOGY –
Pharmacokinetics Section).
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’s 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. Pediatric patients may be more susceptible than
adults to skin atrophy, including striae, when they are treated with topical corticosteroids.
Pediatric patients applying topical corticosteroids to greater than 20% of body surface are at
higher risk of HPA axis suppression.
HPA axis suppression, Cushing’s syndrome, linear growth retardation, delayed weight
gain, and intracranial hypertension have been reported in pediatric patients receiving topical
corticosteroids. Manifestations of adrenal suppression in children include low plasma cortisol
levels, and an absence of response to ACTH stimulation. Manifestations of intracranial
hypertension include bulging fontanelles, headaches, and bilateral papilledema.
ELOCON (mometasone furoate cream) Cream, 0.1%, should not be used in the treatment
of diaper dermatitis.
Geriatrics Use: Clinical studies of ELOCON Cream included 190 subjects who were 65 years of
age and over and 39 subjects who were 75 years of age and over. 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. However, greater sensitivity of some older individuals cannot be ruled out.
ADVERSE REACTIONS In controlled clinical studies involving 319 patients, the incidence of
adverse reactions associated with the use of ELOCON Cream was 1.6%. Reported reactions
included burning, pruritus, and skin atrophy. Reports of rosacea associated with the use of
ELOCON Cream have also been received. In controlled clinical studies (n=74) involving
pediatric patients 2 to 12 years of age, the incidence of adverse experiences associated with the
use of ELOCON Cream was approximately 7%. Reported reactions included stinging, pruritus,
and furunculosis.
The following adverse reactions were reported to be possibly or probably related to
treatment with ELOCON Cream during clinical studies in 4% of 182 pediatric patients 6 months
to 2 years of age: decreased glucocorticoid levels, 2; paresthesia, 2; folliculitis, 1; moniliasis, 1;
bacterial infection, 1; skin depigmentation, 1. The following signs of skin atrophy were also
observed among 97 patients treated with ELOCON Cream in a clinical study: shininess 4,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
telangiectasia 1, loss of elasticity 4, loss of normal skin markings 4, thinness 1, and bruising 1.
Striae were not observed in this study.
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 an approximate decreasing order of occurrence: irritation, dryness,
folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic
contact dermatitis, secondary infection, striae, and miliaria.
OVERDOSAGE Topically applied ELOCON Cream can be absorbed in sufficient amounts to
produce systemic effects (see PRECAUTIONS Section).
DOSAGE AND ADMINISTRATION Apply a thin film of ELOCON Cream to the affected
skin areas once daily. ELOCON Cream may be used in pediatric patients 2 years of age or older.
Since safety and efficacy of ELOCON Cream have not been adequately established in pediatric
patients below 2 years of age, its use in this age group is not recommended (see
PRECAUTIONS - Pediatric Use Section).
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. Safety
and efficacy of ELOCON Cream in pediatric patients for more than 3 weeks of use have not
been established.
ELOCON Cream should not be used with occlusive dressings unless directed by a
physician. ELOCON Cream should not be applied in the diaper area if the child still requires
diapers or plastic pants as these garments may constitute occlusive dressing.
HOW SUPPLIED ELOCON Cream 0.1%, is supplied in 15-g (NDC 0085-0567-01) and 45-g
(NDC 0085-0567-02) tubes; boxes of one.
Store ELOCON Cream between 2°° C and 25°° C (36°° F and 77°° F).
ELOCON®
brand of mometasone furoate cream
Cream 0.1%
For Dermatologic Use Only
Not for Ophthalmic Use
SP Schering Corporation
Kenilworth, NJ 07033 USA
Rev. 7/17/02
XXXXXXXX
Copyright 1987, 1996, 2001 Schering Corporation.
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/
---------------------
Jonathan Wilkin
7/17/02 06:19:24 PM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:31.893598
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19625s12s13lbl.pdf', 'application_number': 19625, 'submission_type': 'SUPPL ', 'submission_number': 12}
|
11,567
|
1
ELOCON®
brand of mometasone furoate cream
Cream 0.1%
For Dermatologic Use Only
Not for Ophthalmic Use
DESCRIPTION ELOCON® (mometasone furoate cream) Cream, 0.1%, contains mometasone
furoate, USP for dermatologic use. Mometasone furoate is a synthetic corticosteroid with anti-
inflammatory activity.
Chemically, mometasone furoate is 9α,21-dichloro-11β,17-dihydroxy-16α-
methylpregna-1,4-diene-3,20-dione 17-(2-furoate), with the empirical formula C27H30CI2O6, a
molecular weight of 521.4 and the following structural formula:
[Structure]
Mometasone furoate is a white to off-white powder practically insoluble in water, slightly
soluble in octanol, and moderately soluble in ethyl alcohol.
Each gram of ELOCON Cream, 0.1%, contains: 1 mg mometasone furoate, USP in a
cream base of hexylene glycol; phosphoric acid; propylene glycol stearate (55% monoester);
stearyl alcohol and ceteareth-20; titanium dioxide; aluminum starch octenylsuccinate (Gamma
Irradiated); white wax; white petrolatum; and purified water.
CLINICAL PHARMACOLOGY Like other topical corticosteroids, mometasone furoate 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. Studies in humans indicate that approximately 0.4% of the applied dose of
ELOCON Cream, 0.1%, enters the circulation after 8 hours of contact on normal skin without
occlusion. Inflammation and/or other disease processes in the skin may increase percutaneous
absorption.
Studies performed with ELOCON Cream indicate that it is in the medium range of
potency as compared with other topical corticosteroids.
In a study evaluating the effects of mometasone furoate cream on the hypothalamic-
pituitary-adrenal (HPA) axis, 15 grams were applied twice daily for 7 days to 6 adult patients
with psoriasis or atopic dermatitis. The cream was applied without occlusion to at least 30% of
the body surface. The results show that the drug caused a slight lowering of adrenal
corticosteroid secretion.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
In a pediatric trial, 24 atopic dermatitis patients, of which 19 patients were age 2 to 12
years, were treated with ELOCON Cream, 0.1%, once daily. The majority of patients cleared
within 3 weeks.
Ninety-seven pediatric patients ages 6 to 23 months, with atopic dermatitis, were enrolled
in an open-label, hypothalamic-pituitary-adrenal (HPA) axis safety study. ELOCON Cream was
applied once daily for approximately 3 weeks over a mean body surface area of 41% (range 15%
to 94%). In approximately 16% of patients who showed normal adrenal function by Cortrosyn
test before starting treatment, adrenal suppression was observed at the end of treatment with
ELOCON Cream. The criteria for suppression were: basal cortisol level of ≤5 mcg/dL, 30-
minute post-stimulation level of ≤18 mcg/dL, or an increase of <7 mcg/dL. Follow-up testing 2
to 4 weeks after stopping treatment, available for 5 of the patients, demonstrated suppressed
HPA axis function in one patient, using these same criteria.
INDICATIONS AND USAGE ELOCON Cream, 0.1%, is a medium potency corticosteroid
indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-
responsive dermatoses.
ELOCON (mometasone furoate cream) Cream, 0.1%, may be used in pediatric patients 2
years 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 Section). Since safety and efficacy
of ELOCON Cream have not been adequately established in pediatric patients below 2 years of
age, its use in this age group is not recommended.
CONTRAINDICATIONS ELOCON Cream is contraindicated in those patients with a history
of hypersensitivity to any of the components in the preparation.
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’s 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.
In a study evaluating the effects of mometasone furoate cream on the hypothalamic-
pituitary-adrenal (HPA) axis, 15 grams were applied twice daily for 7 days to 6 adult patients
with psoriasis or atopic dermatitis. The cream was applied without occlusion to at least 30% of
the body surface. The results show that the drug caused a slight lowering of adrenal
corticosteroid secretion.
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 to body mass ratios (see PRECAUTIONS - Pediatric Use Section).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
If irritation develops, ELOCON Cream 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
ELOCON Cream 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. 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 or 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 ELOCON Cream in the treatment
of diaper dermatitis. ELOCON Cream should not be applied in the diaper area as diapers or
plastic pants may constitute occlusive dressing (see DOSAGE AND ADMINISTRATION
Section).
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.
8. Other corticosteroid-containing products should not be used with ELOCON Cream without
first consulting with 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
Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term animal studies have not
been performed to evaluate the carcinogenic potential of ELOCON (mometasone furoate cream)
Cream, 0.1%. Long-term carcinogenicity studies of mometasone furoate were conducted by the
inhalation route in rats and mice. In a 2-year carcinogenicity study in Sprague-Dawley rats,
mometasone furoate demonstrated no statistically significant increase of tumors at inhalation
doses up to 67 mcg/kg (approximately 0.04 times the estimated maximum clinical topical dose
from ELOCON Cream on a mcg/m2 basis). In a 19-month carcinogenicity study in Swiss CD-1
mice, mometasone furoate demonstrated no statistically significant increase in the incidence of
tumors at inhalation doses up to 160 mcg/kg (approximately 0.05 times the estimated maximum
clinical topical dose from ELOCON Cream on a mcg/m2 basis).
Mometasone furoate increased chromosomal aberrations in an in vitro Chinese hamster
ovary cell assay, but did not increase chromosomal aberrations in an in vitro Chinese hamster
lung cell assay. Mometasone furoate was not mutagenic in the Ames test or mouse lymphoma
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
assay, and was not clastogenic in an in vivo mouse micronucleus assay, a rat bone marrow
chromosomal aberration assay, or a mouse male germ-cell chromosomal aberration assay.
Mometasone furoate also did not induce unscheduled DNA synthesis in vivo in rat hepatocytes.
In reproductive studies in rats, impairment of fertility was not produced in male or female
rats by subcutaneous doses up to 15 mcg/kg (approximately 0.01 times the estimated maximum
clinical topical dose from ELOCON Cream on a mcg/m2 basis).
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.
When administered to pregnant rats, rabbits, and mice, mometasone furoate increased
fetal malformations. The doses that produced malformations also decreased fetal growth, as
measured by lower fetal weights and/or delayed ossification. Mometasone furoate also caused
dystocia and related complications when administered to rats during the end of pregnancy.
In mice, mometasone furoate caused cleft palate at subcutaneous doses of 60 mcg/kg and
above. Fetal survival was reduced at 180 mcg/kg. No toxicity was observed at 20 mcg/kg.
(Doses of 20, 60 and 180 mcg/kg in the mouse are approximately 0.01, 0.02 and 0.05 times the
estimated maximum clinical topical dose from ELOCON Cream on a mcg/m2 basis).
In rats, mometasone furoate produced umbilical hernias at topical doses of 600 mcg/kg
and above. A dose of 300 mcg/kg produced delays in ossification, but no malformations.
(Doses of 300 and 600 mcg/kg in the rat are approximately 0.2 and 0.4 times the estimated
maximum clinical topical dose from ELOCON Cream on a mcg/m2 basis).
In rabbits, mometasone furoate caused multiple malformations (e.g., flexed front paws,
gallbladder agenesis, umbilical hernia, hydrocephaly) at topical doses of 150 mcg/kg and above
(approximately 0.2 times the estimated maximum clinical topical dose from ELOCON Cream on
a mcg/m2 basis). In an oral study, mometasone furoate increased resorptions and caused cleft
palate and/or head malformations (hydrocephaly and domed head) at 700 mcg/kg. At 2800
mcg/kg most litters were aborted or resorbed. No toxicity was observed at 140 mcg/kg. (Doses
of 140, 700 and 2800 mcg/kg in the rabbit are approximately 0.2, 0.9 and 3.6 times the estimated
maximum clinical topical dose from ELOCON Cream on a mcg/m2 basis).
When rats received subcutaneous doses of mometasone furoate throughout pregnancy or
during the later stages of pregnancy, 15 mcg/kg caused prolonged and difficult labor and reduced
the number of live births, birth weight and early pup survival. Similar effects were not observed
at 7.5 mcg/kg. (Doses of 7.5 and 15 mcg/kg in the rat are approximately 0.005 and 0.01 times
the estimated maximum clinical topical dose from ELOCON Cream on a mcg/m2 basis).
There are no adequate and well-controlled studies of teratogenic effects from topically
applied corticosteroids in pregnant women. Therefore, topical corticosteroids 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 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 ELOCON Cream is
administered to a nursing woman.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Pediatric Use: ELOCON Cream may be used with caution in pediatric patients 2 years of age or
older, although the safety and efficacy of drug use for longer than 3 weeks have not been
established. Use of ELOCON Cream is supported by results from adequate and well-controlled
studies in pediatric patients with corticosteroid-responsive dermatoses. Since safety and efficacy
of ELOCON Cream have not been adequately established in pediatric patients below 2 years of
age, its use in this age group is not recommended.
ELOCON Cream caused HPA axis suppression in approximately 16% of pediatric
patients ages 6 to 23 months, who showed normal adrenal function by Cortrosyn test before
starting treatment, and were treated for approximately 3 weeks over a mean body surface area of
41% (range 15% to 94%). The criteria for suppression were: basal cortisol level of ≤5 mcg/dL,
30-minute post-stimulation level of ≤18 mcg/dL, or an increase of <7 mcg/dL. Follow-up testing
2 to 4 weeks after study completion, available for 5 of the patients, demonstrated suppressed
HPA axis function in one patient, using these same criteria. Long-term use of topical
corticosteroids has not been studied in this population (see CLINICAL PHARMACOLOGY –
Pharmacokinetics Section).
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’s 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. Pediatric patients may be more susceptible than
adults to skin atrophy, including striae, when they are treated with topical corticosteroids.
Pediatric patients applying topical corticosteroids to greater than 20% of body surface are at
higher risk of HPA axis suppression.
HPA axis suppression, Cushing’s syndrome, linear growth retardation, delayed weight
gain, and intracranial hypertension have been reported in pediatric patients receiving topical
corticosteroids. Manifestations of adrenal suppression in children include low plasma cortisol
levels, and an absence of response to ACTH stimulation. Manifestations of intracranial
hypertension include bulging fontanelles, headaches, and bilateral papilledema.
ELOCON (mometasone furoate cream) Cream, 0.1%, should not be used in the treatment
of diaper dermatitis.
Geriatrics Use: Clinical studies of ELOCON Cream included 190 subjects who were 65 years of
age and over and 39 subjects who were 75 years of age and over. 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. However, greater sensitivity of some older individuals cannot be ruled out.
ADVERSE REACTIONS In controlled clinical studies involving 319 patients, the incidence of
adverse reactions associated with the use of ELOCON Cream was 1.6%. Reported reactions
included burning, pruritus, and skin atrophy. Reports of rosacea associated with the use of
ELOCON Cream have also been received. In controlled clinical studies (n=74) involving
pediatric patients 2 to 12 years of age, the incidence of adverse experiences associated with the
use of ELOCON Cream was approximately 7%. Reported reactions included stinging, pruritus,
and furunculosis.
The following adverse reactions were reported to be possibly or probably related to
treatment with ELOCON Cream during clinical studies in 4% of 182 pediatric patients 6 months
to 2 years of age: decreased glucocorticoid levels, 2; paresthesia, 2; folliculitis, 1; moniliasis, 1;
bacterial infection, 1; skin depigmentation, 1. The following signs of skin atrophy were also
observed among 97 patients treated with ELOCON Cream in a clinical study: shininess 4,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
telangiectasia 1, loss of elasticity 4, loss of normal skin markings 4, thinness 1, and bruising 1.
Striae were not observed in this study.
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 an approximate decreasing order of occurrence: irritation, dryness,
folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic
contact dermatitis, secondary infection, striae, and miliaria.
OVERDOSAGE Topically applied ELOCON Cream can be absorbed in sufficient amounts to
produce systemic effects (see PRECAUTIONS Section).
DOSAGE AND ADMINISTRATION Apply a thin film of ELOCON Cream to the affected
skin areas once daily. ELOCON Cream may be used in pediatric patients 2 years of age or older.
Since safety and efficacy of ELOCON Cream have not been adequately established in pediatric
patients below 2 years of age, its use in this age group is not recommended (see
PRECAUTIONS - Pediatric Use Section).
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. Safety
and efficacy of ELOCON Cream in pediatric patients for more than 3 weeks of use have not
been established.
ELOCON Cream should not be used with occlusive dressings unless directed by a
physician. ELOCON Cream should not be applied in the diaper area if the child still requires
diapers or plastic pants as these garments may constitute occlusive dressing.
HOW SUPPLIED ELOCON Cream 0.1%, is supplied in 15-g (NDC 0085-0567-01) and 45-g
(NDC 0085-0567-02) tubes; boxes of one.
Store ELOCON Cream between 2°° C and 25°° C (36°° F and 77°° F).
ELOCON®
brand of mometasone furoate cream
Cream 0.1%
For Dermatologic Use Only
Not for Ophthalmic Use
SP Schering Corporation
Kenilworth, NJ 07033 USA
Rev. 7/17/02
XXXXXXXX
Copyright 1987, 1996, 2001 Schering Corporation.
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/
---------------------
Jonathan Wilkin
7/17/02 06:19:24 PM
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:31.901465
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19625s12s13lbl.pdf', 'application_number': 19625, 'submission_type': 'SUPPL ', 'submission_number': 13}
|
11,565
|
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
|
custom-source
|
2025-02-12T13:45:31.910529
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019618s018lbl.pdf', 'application_number': 19618, 'submission_type': 'SUPPL ', 'submission_number': 18}
|
11,571
|
LOT
EXP
M027818/01
62934E
Twenty 50 mL vials
For Single Patient Use Only
FOR INTRAVENOUS ADMINISTRATION
Twenty 50 mL vials
For Single Patient Use Only
FOR INTRAVENOUS ADMINISTRATION
Twenty 50 mL vials
For Single Patient Use Only
FOR INTRAVENOUS ADMINISTRATION
Twenty 50 mL vials
For Single Patient Use Only
FOR INTRAVENOUS ADMINISTRATION
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5,714,520 5,731,355
5,731,356 5,908,869
30363323269501
402347C
M087920/01
Dosage: See package insert.
In addition to the active component,
propofol, the formulation contains:
soybean oil (100 mg/mL), glycerol
(22.5 mg/mL), egg lecithin (12 mg/mL)
and disodium edetate (0.005%);
with sodium hydroxide to adjust pH.
Store between 4° to 25°C (40° to 77°F).
Do not freeze.
Sterile, nonpyrogenic
SHAKE WELL BEFORE USING
Manufactured for:
Made in Austria
FOR INTRAVENOUS ADMINISTRATION
50 mL - For Single Patient Use Only
LOT
EXP
2221
US Pat
Rx only
NDC 63323-269-50 260950
(Propofol)
®
INJECTABLE
EMULSION, USP
500 mg per 50 mL
(10 mg per mL)
Reference ID: 3337787
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LOT
EXP
Ten 100 mL vials
For Single Patient Use Only
FOR INTRAVENOUS ADMINISTRATION
M027820/01
62936E
Ten 100 mL vials
For Single Patient Use Only
FOR INTRAVENOUS ADMINISTRATION
Ten 100 mL vials
For Single Patient Use Only
FOR INTRAVENOUS ADMINISTRATION
Ten 100 mL vials
For Single Patient Use Only
FOR INTRAVENOUS ADMINISTRATION
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:32.515194
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019627s60lbl.pdf', 'application_number': 19627, 'submission_type': 'SUPPL ', 'submission_number': 60}
|
11,568
|
1
PROFESSIONAL INFORMATION BROCHURE
DIPRIVAN® (propofol) Injectable Emulsion
FOR IV ADMINISTRATION
DESCRIPTION
DIPRIVAN® (propofol) Injectable Emulsion is a sterile, nonpyrogenic emulsion containing 10 mg/mL of
propofol suitable for intravenous administration. Propofol is chemically described as 2,6-diisopropylphenol and
has a molecular weight of 178.27. The structural and molecular formulas are:
Propofol is very slightly soluble in water and, thus, is formulated in a white, oil-in-water emulsion. The pKa is
11. The octanol/water partition coefficient for propofol is 6761:1 at a pH of 6-8.5. In addition to the active
component, propofol, the formulation also contains soybean oil (100 mg/mL), glycerol (22.5 mg/mL), egg
lecithin (12 mg/mL); and disodium edetate (0.005%); with sodium hydroxide to adjust pH. The DIPRIVAN
Injection emulsion is isotonic and has a pH of 7-8.5.
STRICT ASEPTIC TECHNIQUE MUST ALWAYS BE MAINTAINED DURING HANDLING.
DIPRIVAN INJECTABLE EMULSION IS A SINGLE-USE PARENTERAL PRODUCT WHICH
CONTAINS 0.005% DISODIUM EDETATE TO RETARD THE RATE OF GROWTH OF
MICROORGANISMS IN THE EVENT OF ACCIDENTAL EXTRINSIC CONTAMINATION.
HOWEVER, DIPRIVAN INJECTABLE EMULSION CAN STILL SUPPORT THE GROWTH OF
MICROORGANISMS AS IT IS NOT AN ANTIMICROBIALLY PRESERVED PRODUCT UNDER
USP STANDARDS. ACCORDINGLY, STRICT ASEPTIC TECHNIQUE MUST STILL BE ADHERED
TO. DO NOT USE IF CONTAMINATION IS SUSPECTED. DISCARD UNUSED PORTIONS AS
DIRECTED WITHIN THE REQUIRED TIME LIMITS (SEE DOSAGE AND ADMINISTRATION,
HANDLING PROCEDURES). THERE HAVE BEEN REPORTS IN WHICH FAILURE TO USE
ASEPTIC TECHNIQUE WHEN HANDLING DIPRIVAN INJECTABLE EMULSION WAS
ASSOCIATED WITH MICROBIAL CONTAMINATION OF THE PRODUCT AND WITH FEVER,
INFECTION/SEPSIS, OTHER LIFE-THREATENING ILLNESS, AND/OR DEATH.
CLINICAL PHARMACOLOGY
General
DIPRIVAN Injectable Emulsion is an intravenous sedative-hypnotic agent for use in the induction and
maintenance of anesthesia or sedation. Intravenous injection of a therapeutic dose of propofol produces
hypnosis rapidly with minimal excitation, usually within 40 seconds from the start of an injection (the time for
one arm-brain circulation). As with other rapidly acting intravenous anesthetic agents, the half-time of the
blood-brain equilibration is approximately 1 to 3 minutes, and this accounts for the rapid induction of anesthesia.
Pharmacodynamics
Pharmacodynamic properties of propofol are dependent upon the therapeutic blood propofol concentrations.
Steady state propofol blood concentrations are generally proportional to infusion rates, especially within an
individual patient. Undesirable side effects such as cardiorespiratory depression are likely to occur at higher
blood concentrations which result from bolus dosing or rapid increase in infusion rate. An adequate interval (3
to 5 minutes) must be allowed between clinical dosage adjustments in order to assess drug effects.
The hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of anesthesia vary. If
spontaneous ventilation is maintained, the major cardiovascular effects are arterial hypotension (sometimes
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
greater than a 30% decrease) with little or no change in heart rate and no appreciable decrease in cardiac output.
If ventilation is assisted or controlled (positive pressure ventilation), the degree and incidence of decrease in
cardiac output are accentuated. Addition of a potent opioid (e.g., fentanyl) when used as a premedicant further
decreases cardiac output and respiratory drive.
If anesthesia is continued by infusion of DIPRIVAN Injectable Emulsion, the stimulation of endotracheal
intubation and surgery may return arterial pressure towards normal. However, cardiac output may remain
depressed. Comparative clinical studies have shown that the hemodynamic effects of DIPRIVAN Injectable
Emulsion during induction of anesthesia are generally more pronounced than with other IV induction agents
traditionally used for this purpose.
Clinical and preclinical studies suggest that DIPRIVAN Injectable Emulsion is rarely associated with elevation
of plasma histamine levels.
Induction of anesthesia with DIPRIVAN Injectable Emulsion is frequently associated with apnea in both adult
and pediatric patients. In 1573 adult patients who received DIPRIVAN Injectable Emulsion (2 to 2.5 mg/kg),
apnea lasted less than 30 seconds in 7% of patients, 30-60 seconds in 24% of patients, and more than 60 seconds
in 12% of patients. In 218 pediatric patients from birth through 16 years of age assessable for apnea who
received bolus doses of DIPRIVAN Injectable Emulsion (1 to 3.6 mg/kg), apnea lasted less than 30 seconds in
12% of patients, 30-60 seconds in 10% of patients, and more than 60 seconds in 5% of patients.
During maintenance, DIPRIVAN Injectable Emulsion causes a decrease in ventilation usually associated with an
increase in carbon dioxide tension which may be marked depending upon the rate of administration and other
concurrent medications (e.g., opioids, sedatives, etc.).
During monitored anesthesia care (MAC) sedation, attention must be given to the cardiorespiratory effects of
DIPRIVAN Injectable Emulsion. Hypotension, oxyhemoglobin desaturation, apnea, airway obstruction, and/or
oxygen desaturation can occur, especially following a rapid bolus of DIPRIVAN Injectable Emulsion. During
initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus
administration, and during maintenance of MAC sedation, a variable rate infusion is preferable over intermittent
bolus administration in order to minimize undesirable cardiorespiratory effects. In the elderly, debilitated, or
ASA III/IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation.
(See WARNINGS.)
Clinical studies in humans and studies in animals show that DIPRIVAN Injectable Emulsion does not suppress
the adrenal response to ACTH.
Preliminary findings in patients with normal intraocular pressure indicate that DIPRIVAN Injectable Emulsion
anesthesia produces a decrease in intraocular pressure which may be associated with a concomitant decrease in
systemic vascular resistance.
Animal studies and limited experience in susceptible patients have not indicated any propensity of DIPRIVAN
Injectable Emulsion to induce malignant hyperthermia.
Studies to date indicate that DIPRIVAN Injectable Emulsion when used in combination with hypocarbia
increases cerebrovascular resistance and decreases cerebral blood flow, cerebral metabolic oxygen consumption,
and intracranial pressure. DIPRIVAN Injectable Emulsion does not affect cerebrovascular reactivity to changes
in arterial carbon dioxide tension. (see Clinical Trials - Neuroanesthesia).
Hemosiderin deposits have been observed in the livers of dogs receiving DIPRIVAN Injectable Emulsion
containing 0.005% disodium edetate over a four week period; the clinical significance is unknown.
Pharmacokinetics
The proper use of DIPRIVAN Injectable Emulsion requires an understanding of the disposition and elimination
characteristics of propofol.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
The pharmacokinetics of propofol are well described by a three compartment linear model with compartments
representing the plasma, rapidly equilibrating tissues, and slowly equilibrating tissues.
Following an IV bolus dose, there is rapid equilibration between the plasma and the highly perfused tissue of the
brain, thus accounting for the rapid onset of anesthesia. Plasma levels initially decline rapidly as a result of both
rapid distribution and high metabolic clearance. Distribution accounts for about half of this decline following a
bolus of propofol.
However, distribution is not constant over time, but decreases as body tissues equilibrate with plasma and
become saturated. The rate at which equilibration occurs is a function of the rate and duration of the infusion.
When equilibration occurs there is no longer a net transfer of propofol between tissues and plasma.
Discontinuation of the recommended doses of DIPRIVAN Injectable Emulsion after the maintenance of
anesthesia for approximately one-hour, or for sedation in the ICU for one-day, results in a prompt decrease in
blood propofol concentrations and rapid awakening. Longer infusions (10 days of ICU sedation) result in
accumulation of significant tissue stores of propofol, such that the reduction in circulating propofol is slowed and
the time to awakening is increased.
By daily titration of DIPRIVAN Injectable Emulsion dosage to achieve only the minimum effective therapeutic
concentration, rapid awakening within 10 to 15 minutes will occur even after long-term administration. If,
however, higher than necessary infusion levels have been maintained for a long time, propofol will be
redistributed from fat and muscle to the plasma, and this return of propofol from peripheral tissues will slow
recovery.
The figure below illustrates the fall of plasma propofol levels following ICU sedation infusions of various
durations.
The large contribution of distribution (about 50%) to the fall of propofol plasma levels following brief infusions
means that after very long infusions (at steady state), about half the initial rate will maintain the same plasma
levels. Failure to reduce the infusion rate in patients receiving DIPRIVAN Injectable Emulsion for extended
periods may result in excessively high blood concentrations of the drug. Thus, titration to clinical response and
daily evaluation of sedation levels are important during use of DIPRIVAN Injectable Emulsion infusion for ICU
sedation, especially of long duration.
Adults: Propofol clearance ranges from 23-50 mL/kg/min (1.6 to 3.4 L/min in 70 kg adults). It is chiefly
eliminated by hepatic conjugation to inactive metabolites which are excreted by the kidney. A glucuronide
conjugate accounts for about 50% of the administered dose. Propofol has a steady state volume of distribution
(10-day infusion) approaching 60 L/kg in healthy adults. A difference in pharmacokinetics due to gender has not
been observed. The terminal half-life of propofol after a 10-day infusion is 1 to 3 days.
Geriatrics: With increasing patient age, the dose of propofol needed to achieve a defined anesthetic end point
(dose-requirement) decreases. This does not appear to be an age-related change of pharmacodynamics or brain
sensitivity, as measured by EEG burst suppression. With increasing patient age pharmacokinetic changes are
such that for a given IV bolus dose, higher peak plasma concentrations occur, which can explain the decreased
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
dose requirement. These higher peak plasma concentrations in the elderly can predispose patients to
cardiorespiratory effects including hypotension, apnea, airway obstruction, and/or oxygen desaturation. The
higher plasma levels reflect an age-related decrease in volume of distribution and reduced intercompartmental
clearance. Lower doses are thus recommended for initiation and maintenance of sedation/anesthesia in elderly
patients. (See CLINICAL PHARMACOLOGY - Individualization of Dosage.)
Pediatrics: The pharmacokinetics of propofol were studied in 53 children between the ages of 3 and 12 years
who received DIPRIVAN Injectable Emulsion for periods of approximately 1-2 hours. The observed
distribution and clearance of propofol in these children were similar to adults.
Organ Failure: The pharmacokinetics of propofol do not appear to be different in people with chronic hepatic
cirrhosis or chronic renal impairment compared to adults with normal hepatic and renal function. The effects of
acute hepatic or renal failure on the pharmacokinetics of propofol have not been studied.
Clinical Trials
Anesthesia and Monitored Anesthesia Care (MAC) Sedation
DIPRIVAN Injectable Emulsion was compared to intravenous and inhalational anesthetic or sedative agents in
91 trials involving a total of 5,135 patients. Of these, 3,354 received DIPRIVAN Injectable Emulsion and
comprised the overall safety database for anesthesia and MAC sedation. Fifty-five of these trials, 20 for
anesthesia induction and 35 for induction and maintenance of anesthesia or MAC sedation, were carried out in
the US or Canada and provided the basis for dosage recommendations and the adverse event profile during
anesthesia or MAC sedation.
Pediatric Anesthesia
DIPRIVAN Injectable Emulsion was studied in 14 clinical trials involving 691 pediatric patients, including 42
cardiac surgical patients. Of the total 691 patients, 90 were less than 3 years of age and 601 were 3 years of age
or older. Of these, 506 were from US/Canadian clinical trials and comprised the overall safety and efficacy
database for Pediatric Anesthesia. The majority of the remaining patients were healthy ASA I/II patients.” (See
Table 1 and Appendices 1).
TABLE 1. PEDIATRIC INDUCTION OF ANESTHESIA
Patients Receiving DIPRIVAN Injectable Emulsion Median and (Range)
No. of
Induction
Injection
Age Range
Patients
Dose
Duration
Birth through
353
2.5 mg/kg
20 sec.
16 years
(1-3.6)
(6-45)
TABLE 2. PEDIATRIC MAINTENANCE OF ANESTHESIA
Patients Receiving DIPRIVAN Injectable Emulsion Median and (Range)
Maintenance
No. of
Dosage
Duration
Age Range
Patients
µg/kg/min
minutes
2 months to 2 years
68
199 (82 - 394)
65 (12 - 282)
2 to 12 years
165
188 (12 - 1041)
69 (23 - 374)
> 12 through 16 years 27
161 (84 - 359)
69 (26 - 251)
Also includes all time following induction dose.
Neuroanesthesia
DIPRIVAN Injection was studied in 50 patients undergoing craniotomy for supratentorial tumors in two clinical
trials. The mean lesion size (anterior/posterior and lateral) was 31 mm and 32 mm in one trial and 55 mm and 42
mm in the other trial respectively.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
TABLE 3. NEUROANESTHESIA CLINICAL TRIALS
Patients Receiving DIPRIVAN Injectable Emulsion Median and (Range)
Maintenance
Maintenance
No. of
Induction Bolus
Dosage
Duration
Patient Type
Patients
Dosages (mg/kg)
(µg/kg/min)_
__(min)____
Craniotomy patients
50
1.36
146
285
(0.9-6.9)
(68-425)
(48-622)
In ten of these patients, DIPRIVAN Injectable Emulsion was administered by infusion in a controlled clinical
trial to evaluate the effect of DIPRIVAN Injectable Emulsion on cerebrospinal fluid pressure (CSFP). The mean
arterial pressure was maintained relatively constant over 25 minutes with a change from baseline of -4% ± 17%
(mean ± SD), whereas the percent change in cerebrospinal fluid pressure (CSFP) was -46% ± 14%. As CSFP is
an indirect measure of intracranial pressure (ICP), when given by infusion or slow bolus, DIPRIVAN Injectable
Emulsion, in combination with hypocarbia, is capable of decreasing ICP independent of changes in arterial
pressure.
Intensive Care Unit (ICU) Sedation
Adult Patients:
DIPRIVAN Injectable Emulsion was compared to benzodiazepines and/or opioids in 14 clinical trials involving
a total of 550 ICU patients. Of these, 302 received DIPRIVAN Injectable Emulsion and comprise the overall
safety database for ICU sedation. Six of these studies were carried out in the US or Canada and provide the
basis for dosage recommendations and the adverse event profile.
Information from 193 literature reports of DIPRIVAN Injectable Emulsion used for ICU sedation in over 950
patients and information from the clinical trials are summarized below:
TABLE 4. ADULT ICU SEDATION CLINICAL TRIALS AND
LITERATURE
Patients receiving DIPRIVAN Injectable Emulsion
Median and (Range)
Sedation
Number of Patients
Sedation Dose
Duration
ICU Patient Type
Trials
Literature
µg/kg/min
mg/kg/h
_Hours_
Post-CABG
41
-
11
0.66
10
(0.1-30)
(0.006-1.8)
(2-14)
-
334
(5-100)
(0.3-6)
(4-24)
Post-Surgical
60
-
20
1.2
18
(6-53)
(0.4-3.2)
(0.3-187)
-
142
(23-82)
(1.4-4.9)
(6-96)
Neuro/Head Trauma
7
-
25
1.5
168
(13-37)
(0.8-2.2)
(112-282)
-
184
(8.3-87)
(0.5-5.2)
(8 hr-5 days)
Medical
49
-
41
2.5
72
(9-131)
(0.5-7.9)
(0.4-337)
-
76
(3.3-62)
(0.2-3.7)
(4-96)
Special Patients
ARDS/Resp. Failure
-
56
(10-142)
(0.6-8.5)
(1 hr-8 days)
COPD/Asthma
-
49
(17-75)
(1-4.5)
(1-8 days)
Status Epilepticus
-
15
(25-167)
(1.5-10)
(1-21 days)
Tetanus
-
11
(5-100)
(0.3-6)
(1-25 days)
Trials (Individual patients from clinical studies)
Literature (Individual patients from published reports)
CABG (Coronary Artery Bypass Graft)
ARDS (Adult Respiratory Distress Syndrome)
Cardiac Anesthesia
DIPRIVAN Injectable Emulsion was evaluated in 5 clinical trials conducted in the US and Canada, involving a
total of 569 patients undergoing coronary artery bypass graft (CABG). Of these, 301 patients received
DIPRIVAN Injectable Emulsion. They comprise the safety database for cardiac anesthesia and provide the basis
for dosage recommendations in this patient population, in conjunction with reports in the published literature.
Individualization of Dosage
General: STRICT ASEPTIC TECHNIQUE MUST ALWAYS BE MAINTAINED DURING HANDLING.
DIPRIVAN INJECTABLE EMULSION IS A SINGLE-USE PARENTERAL PRODUCT WHICH
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
CONTAINS 0.005% DISODIUM EDETATE TO RETARD THE RATE OF GROWTH OF
MICROORGANISMS IN THE EVENT OF ACCIDENTAL EXTRINSIC CONTAMINATION.
HOWEVER, DIPRIVAN INJECTABLE EMULSION CAN STILL SUPPORT THE GROWTH OF
MICROORGANISMS AS IT IS NOT AN ANTIMICROBIALLY PRESERVED PRODUCT UNDER
USP STANDARDS. ACCORDINGLY, STRICT ASEPTIC TECHNIQUE MUST STILL BE ADHERED
TO. DO NOT USE IF CONTAMINATION IS SUSPECTED. DISCARD UNUSED PORTIONS AS
DIRECTED WITHIN THE REQUIRED TIME LIMITS (SEE DOSAGE AND ADMINISTRATION,
HANDLING PROCEDURES). THERE HAVE BEEN REPORTS IN WHICH FAILURE TO USE
ASEPTIC TECHNIQUE WHEN HANDLING DIPRIVAN INJECTABLE EMULSION WAS
ASSOCIATED WITH MICROBIAL CONTAMINATION OF THE PRODUCT AND WITH FEVER,
INFECTION/SEPSIS, OTHER LIFE-THREATENING ILLNESS, AND/OR DEATH.
Propofol blood concentrations at steady state are generally proportional to infusion rates, especially in individual
patients. Undesirable effects such as cardiorespiratory depression are likely to occur at higher blood
concentrations which result from bolus dosing or rapid increases in the infusion rate. An adequate interval (3 to
5 minutes) must be allowed between clinical dosage adjustments in order to assess drug effects.
When administering DIPRIVAN Injectable Emulsion by infusion, syringe pumps, or volumetric pumps are
recommended to provide controlled infusion rates. When infusing DIPRIVAN Injectable Emulsion to patients
undergoing magnetic resonance imaging, metered control devices may be utilized if mechanical pumps are
impractical.
Changes in vital signs (increases in pulse rate, blood pressure, sweating, and/or tearing) that indicate a response
to surgical stimulation or lightening of anesthesia may be controlled by the administration of DIPRIVAN
Injectable Emulsion 25 mg (2.5 mL) to 50 mg (5 mL) incremental boluses and/or by increasing the infusion rate.
For minor surgical procedures (e.g., body surface) nitrous oxide (60%-70%) can be combined with a variable
rate DIPRIVAN Injectable Emulsion infusion to provide satisfactory anesthesia. With more stimulating surgical
procedures (e.g., intra-abdominal), or if supplementation with nitrous oxide is not provided, administration
rate(s) of DIPRIVAN Injectable Emulsion and/or opioids should be increased in order to provide adequate
anesthesia.
Infusion rates should always be titrated downward in the absence of clinical signs of light anesthesia until a mild
response to surgical stimulation is obtained in order to avoid administration of DIPRIVAN Injectable Emulsion
at rates higher than are clinically necessary. Generally, rates of 50 to 100 ug/kg/min in aduts should be achieved
during maintenance in order to optimize recovery times.
Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase
CNS depression induced by propofol. Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen
has been shown to decrease the necessary propofol injection maintenance infusion rate and therapeutic blood
concentrations when compared to non-narcotic (lorazepam) premedication.
Induction of General Anesthesia
Adult Patients: Most adult patients under 55 years of age and classified ASA I/II require 2 to 2.5 mg/kg of
DIPRIVAN Injectable Emulsion for induction when unpremedicated or when premedicated with oral
benzodiazepines or intramuscular opioids. For induction, DIPRIVAN Injectable Emulsion should be titrated
(approximately 40 mg every 10 seconds) against the response of the patient until the clinical signs show the
onset of anesthesia. As with other sedative-hypnotic agents, the amount of intravenous opioid and/or
benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN
Injectable Emulsion.
Elderly, Debilitated, or ASA III/IV Patients: It is important to be familiar and experienced with the
intravenous use of DIPRIVAN Injectable Emulsion before treating elderly, debilitated, or ASA III/IV patients.
Due to the reduced clearance and higher blood concentrations, most of these patients require approximately 1 to
1.5 mg/kg (approximately 20 mg every 10 seconds) of DIPRIVAN Injectable Emulsion for induction of
anesthesia according to their condition and responses. A rapid bolus should not be used, as this will increase the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
likelihood of undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or
oxygen desaturation. (See DOSAGE AND ADMINISTRATION.)
Pediatric Patients:
Most patients aged 3 years through 16 years and classified ASA I or II require 2.5 to 3.5 mg/kg of DIPRIVAN
Injectable Emulsion for induction when unpremedicated or when lightly premedicated with oral benzodiazepines
or intramuscular opioids. Within this dosage range, younger pediatric patients may require higher induction
doses than older pediatric patients. As with other sedative-hypnotic agents, the amount of intravenous opioid
and/or benzodiazepine premedication will influence the response of the patient to an induction dose of
DIPRIVAN Injectable Emulsion. A lower dosage is recommended for pediatric patients classified as ASA III or
IV. Attention should be paid to minimize pain on injection when administering DIPRIVAN Injectable Emulsion
to pediatric patients. Boluses of DIPRIVAN Injectable Emulsion may be administered via small veins if
pretreated with lidocaine or via antecubital or larger veins (See PRECAUTIONS - General).
Neurosurgical Patients: Slower induction is recommended using boluses of 20 mg every 10 seconds. Slower
boluses or infusions of DIPRIVAN Injectable Emulsion for induction of anesthesia, titrated to clinical responses,
will generally result in reduced induction dosage requirements (1 to 2 mg/kg). (See PRECAUTIONS and
DOSAGE AND ADMINISTRATION.)
Cardiac Anesthesia: DIPRIVAN Injectable Emulsion has been well-studied in patients with coronary artery
disease, but experience in patients with hemodynamically significant valvular or congenital heart disease is
limited. As with other anesthetic and sedative-hypnotic agents, DIPRIVAN Injectable Emulsion in healthy
patients causes a decrease in blood pressure that is secondary to decreases in preload (ventricular filling volume
at the end of the diastole) and afterload (arterial resistance at the beginning of the systole). The magnitude of
these changes is proportional to the blood and effect site concentrations achieved. These concentrations depend
upon the dose and speed of the induction and maintenance infusion rates.
In addition, lower heart rates are observed during maintenance with DIPRIVAN Injectable Emulsion, possibly
due to reduction of the sympathetic activity and/or resetting of the baroreceptor reflexes. Therefore,
anticholinergic agents should be administered when increases in vagal tone are anticipated.
As with other anesthetic agents, DIPRIVAN Injectable Emulsion reduces myocardial oxygen consumption.
Further studies are needed to confirm and delineate the extent of these effects on the myocardium and the
coronary vascular system.
Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the
necessary DIPRIVAN Injectable Emulsion maintenance infusion rates and therapeutic blood concentrations
when compared to non-narcotic (lorazepam) premedication. The rate of DIPRIVAN Injectable Emulsion
administration should be determined based on the patient's premedication and adjusted according to clinical
responses.
A rapid bolus induction should be avoided. A slow rate of approximately 20 mg every 10 seconds until
induction onset (0.5 to 1.5 mg/kg) should be used. In order to assure adequate anesthesia, when DIPRIVAN
Injectable Emulsion is used as the primary agent, maintenance infusion rates should not be less than 100
µg/kg/min and should be supplemented with analgesic levels of continuous opioid administration. When an
opioid is used as the primary agent, DIPRIVAN Injectable Emulsion maintenance rates should not be less than
50 µg/kg/min, and care should be taken to ensure amnesia with concomitant benzodiazepines. Higher doses of
DIPRIVAN Injectable Emulsion will reduce the opioid requirements (see Table 5). When DIPRIVAN Injectable
Emulsion is used as the primary anesthetic, it should not be administered with the high-dose opioid technique, as
this may increase the likelihood of hypotension (see PRECAUTIONS - Cardiac Anesthesia).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
Table 5. Cardiac Anesthesia Techniques
Primary Agent
Rate
Secondary Agent/Rate
(Following Induction with Primary Agent)
DIPRIVAN Injectable
OPIOIDa/0.05-0.075 µg/kg/min (no bolus)
Emulsion
Preinduction anxiolysis
25 µg/kg/min
Induction
0.5-1.5 mg/kg
over 60 sec
Maintenance
100-150 µg/kg/min
(Titrated to Clinical
Response)
OPIOIDb
DIPRIVAN Injectable Emulsion/ 50-100 µg/kg/min
(no bolus)
Induction
25-50 µg/kg
Maintenance
0.2-0.3 µg/kg/min
_________________________________________________________________________
aOPIOID is defined in terms of fentanyl equivalents, i.e.,
1 µg of fentanyl
=
5 µg of alfentanil (for bolus)
=
10 µg of alfentanil (for maintenance)
or
=
0.1 µg of sufentanil
bCare should be taken to ensure amnesia with concomitant benzodiazepine therapy
Maintenance of General Anesthesia
Adult Patients: In adults, anesthesia can be maintained by administering DIPRIVAN Injectable Emulsion by
infusion or intermittent IV bolus injection. The patient's clinical response will determine the infusion rate or the
amount and frequency of incremental injections.
Continuous Infusion: DIPRIVAN Injectable Emulsion 100 to 200 µg/kg/min administered in a variable rate
infusion with 60%-70% nitrous oxide and oxygen provides anesthesia for patients undergoing general surgery.
Maintenance by infusion of DIPRIVAN Injectable Emulsion should immediately follow the induction dose in
order to provide satisfactory or continuous anesthesia during the induction phase. During this initial period
following the induction dose, higher rates of infusion are generally required (150 to 200 µg/kg/min) for the first
10 to 15 minutes. Infusion rates should subsequently be decreased 30%-50% during the first half-hour of
maintenance. Generally, rates of 50 - 100 ug/kg/min in adults should be achieved during maintenance in order to
optimize recovery times.
Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase
the CNS depression induced by propofol.
Intermittent Bolus: Increments of DIPRIVAN Injectable Emulsion 25 mg (2.5 mL) to 50 mg (5 mL) may be
administered with nitrous oxide in adult patients undergoing general surgery. The incremental boluses should be
administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia.
Pediatric Patients: DIPRIVAN Injectable Emulsion administered as a variable rate infusion supplemented with
nitrous oxide 60% - 70% provides satisfactory anesthesia for most children 2 months of age or older, ASA class
I or II, undergoing general anesthesia.
In general, for the pediatric population, maintenance by infusion of DIPRIVAN Injectable Emulsion at a rate of
200 – 300 ug/kg/min should immediately follow the induction dose. Following the first half-hour of
maintenance, infusion rates of 125-150 ug/kg/min are typically needed. DIPRIVAN Injectable Emulsion
SHOULD BE TITRATED TO ACHIEVE THE DESIRED CLINICAL EFFECT. Younger pediatric patients
may require higher maintenance infusion rates than older pediatric patients (See Table 2 Clinical Trials.)
DIPRIVAN Injectable Emulsion has been used with a variety of agents commonly used in anesthesia such as
atropine, scopolamine, glycopyrrolate, diazepam, depolarizing and nondepolarizing muscle relaxants, and opioid
analgesics, as well as with inhalational and regional anesthetic agents.
In the elderly, debilitated, or ASA III/IV patients, rapid bolus doses should not be used, as this will increase
cardiorespiratory effects including hypotension, apnea, airway obstruction, and/or oxygen desaturation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
Monitored Anesthesia Care (MAC) Sedation
Adult Patients:
When DIPRIVAN Injectable Emulsion is administered for MAC sedation, rates of administration should be
individualized and titrated to clinical response. In most patients, the rates of DIPRIVAN Injectable Emulsion
administration will be in the range of 25-75 µg/kg/min.
During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus
administration. During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent
bolus dose administration. In the elderly, debilitated, or ASA III/IV patients, rapid (single or repeated) bolus
dose administration should not be used for MAC sedation. (See WARNINGS.) A rapid bolus injection can
result in undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction,
and/or oxygen desaturation.
Initiation of MAC Sedation: For initiation of MAC sedation, either an infusion or a slow injection method may
be utilized while closely monitoring cardiorespiratory function. With the infusion method, sedation may be
initiated by infusing DIPRIVAN Injectable Emulsion at 100 to 150 µg/kg/min (6 to 9 mg/kg/h) for a period of 3
to 5 minutes and titrating to the desired clinical effect while closely monitoring respiratory function. With the
slow injection method for initiation, patients will require approximately 0.5 mg/kg administered over 3 to 5
minutes and titrated to clinical responses. When DIPRIVAN Injectable Emulsion is administered slowly over 3
to 5 minutes, most patients will be adequately sedated, and the peak drug effect can be achieved while
minimizing undesirable cardiorespiratory effects occurring at high plasma levels.
In the elderly, debilitated, or ASA III/IV patients, rapid (single or repeated) bolus dose administration should not
be used for MAC sedation. (See WARNINGS.) The rate of administration should be over 3-5 minutes and the
dosage of DIPRIVAN Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in
these patients according to their condition, responses, and changes in vital signs. (See DOSAGE AND
ADMINISTRATION.)
Maintenance of MAC Sedation: For maintenance of sedation, a variable rate infusion method is preferable
over an intermittent bolus dose method. With the variable rate infusion method, patients will generally require
maintenance rates of 25 to 75 µg/kg/min (1.5 to 4.5 mg/kg/h) during the first 10 to 15 minutes of sedation
maintenance. Infusion rates should subsequently be decreased over time to 25 to 50 µg/kg/min and adjusted to
clinical responses. In titrating to clinical effect, allow approximately 2 minutes for onset of peak drug effect.
Infusion rates should always be titrated downward in the absence of clinical signs of light sedation until mild
responses to stimulation are obtained in order to avoid sedative administration of DIPRIVAN Injectable
Emulsion at rates higher than are clinically necessary.
If the intermittent bolus dose method is used, increments of DIPRIVAN Injectable Emulsion 10 mg (1 mL) or 20
mg (2 mL) can be administered and titrated to desired clinical effect. With the intermittent bolus method of
sedation maintenance, there is the potential for respiratory depression, transient increases in sedation depth,
and/or prolongation of recovery.
In the elderly, debilitated, or ASA III/IV patients, rapid (single or repeated) bolus dose administration should not
be used for MAC sedation. (See WARNINGS.) The rate of administration and the dosage of DIPRIVAN
Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients
according to their condition, responses, and changes in vital signs. (See DOSAGE AND ADMINISTRATION.)
DIPRIVAN Injectable Emulsion can be administered as the sole agent for maintenance of MAC sedation during
surgical/diagnostic procedures. When DIPRIVAN Injectable Emulsion sedation is supplemented with opioid
and/or benzodiazepine medications, these agents increase the sedative and respiratory effects of DIPRIVAN
Injectable Emulsion and may also result in a slower recovery profile. (See PRECAUTIONS, Drug Interactions.)
ICU Sedation: (See WARNINGS and DOSAGE AND ADMINISTRATION, Handling Procedures.)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
Adult Patients: For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation
should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize
hypotension. (See DOSAGE AND ADMINISTRATION.)
Across all 6 US/Canadian clinical studies, the mean infusion maintenance rate for all DIPRIVAN Injectable
Emulsion patients was 27 ± 21 µg/kg/min. The maintenance infusion rates required to maintain adequate
sedation ranged from 2.8 µg/kg/min to 130 µg/kg/min. The infusion rate was lower in patients over 55 years of
age (approximately 20 µg/kg/min) compared to patients under 55 years of age (approximately 38 µg/kg/min). In
these studies, morphine or fentanyl was used as needed for analgesia.
Most adult ICU patients recovering from the effects of general anesthesia or deep sedation will require
maintenance rates of 5 to 50 µg/kg/min (0.3 to 3 mg/kg/h) individualized and titrated to clinical response. (See
DOSAGE AND ADMINISTRATION.) With medical ICU patients or patients who have recovered from the
effects of general anesthesia or deep sedation, the rate of administration of 50 µg/kg/min or higher may be
required to achieve adequate sedation. These higher rates of administration may increase the likelihood of
patients developing hypotension.
Although there are reports of reduced analgesic requirements, most patients received opioids for analgesia during
maintenance of ICU sedation. Some patients also received benzodiazepines and/or neuromuscular blocking
agents. During long-term maintenance of sedation, some ICU patients were awakened once or twice every 24
hours for assessment of neurologic or respiratory function. (See Clinical Trials, Table 4.)
In post-CABG (coronary artery bypass graft) patients, the maintenance rate of propofol administration was
usually low (median 11 µg/kg/min) due to the intraoperative administration of high opioid doses. Patients
receiving DIPRIVAN Injectable Emulsion required 35% less nitroprusside than midazolam patients; this
difference was statistically significant (P<0.05). During initiation of sedation in post-CABG patients, a 15% to
20% decrease in blood pressure was seen in the first 60 minutes. It was not possible to determine cardiovascular
effects in patients with severely compromised ventricular function (See Clinical Trials, Table 4).
In Medical or Postsurgical ICU studies comparing DIPRIVAN Injectable Emulsion to benzodiazepine infusion
or bolus, there were no apparent differences in maintenance of adequate sedation, mean arterial pressure, or
laboratory findings. Like the comparators, DIPRIVAN Injectable Emulsion reduced blood cortisol during
sedation while maintaining responsivity to challenges with adrenocorticotropic hormone (ACTH). Case reports
from the published literature generally reflect that DIPRIVAN Injectable Emulsion has been used safely in
patients with a history of porphyria or malignant hyperthermia.
In hemodynamically stable head trauma patients ranging in age from 19-43 years, adequate sedation was
maintained with DIPRIVAN Injectable Emulsion or morphine (N=7 in each group). There were no apparent
differences in adequacy of sedation, intracranial pressure, cerebral perfusion pressure, or neurologic recovery
between the treatment groups. In literature reports from Neurosurgical ICU and severely head-injured patients
DIPRIVAN Injectable Emulsion infusion with or without diuretics and hyperventilation controlled intracranial
pressure while maintaining cerebral perfusion pressure. In some patients, bolus doses resulted in decreased
blood pressure and compromised cerebral perfusion pressure. (See Clinical Trials, Table 4.)
DIPRIVAN Injectable Emulsion was found to be effective in status epilepticus which was refractory to the
standard anticonvulsant therapies. For these patients as well as for ARDS/respiratory failure and tetanus
patients, sedation maintenance dosages were generally higher than those for other critically ill patient
populations. (See Clinical Trials, Table 4.)
Abrupt discontinuation of DIPRIVAN Injectable Emulsion prior to weaning or for daily evaluation of sedation
levels should be avoided. This may result in rapid awakening with associated anxiety, agitation, and resistance
to mechanical ventilation. Infusions of DIPRIVAN Injectable Emulsion should be adjusted to maintain a light
level of sedation through the weaning process or evaluation of sedation level. (See PRECAUTIONS.)
INDICATIONS AND USAGE
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
DIPRIVAN Injectable Emulsion is an IV sedative-hypnotic agent that can be used for both induction and/or
maintenance of anesthesia as part of a balanced anesthetic technique for inpatient and outpatient surgery in adult
patients and pediatric patients greater than 3 years of age. DIPRIVAN Injectable Emulsion can also be used for
maintenance of anesthesia as part of a balanced anesthetic technique for inpatient and outpatient surgery in adult
patients and in pediatric patients greater than 2 months of age. DIPRIVAN is not recommended for induction of
anesthesia below the age of 3 years or for maintenance of anesthesia below the age of 2 months because its
safety and effectiveness have not been established in those populations.
In adult patients, DIPRIVAN Injectable Emulsion, when administered intravenously as directed, can be used to
initiate and maintain monitored anesthesia care (MAC) sedation during diagnostic procedures. DIPRIVAN
Injectable Emulsion may also be used for MAC sedation in conjunction with local/regional anesthesia in patients
undergoing surgical procedures. (See PRECAUTIONS.)
Safety, effectiveness and dosing guidelines for DIPRIVAN Injectable Emulsion have not been established for
MAC Sedation/light general anesthesia in the pediatric population undergoing diagnostic or nonsurgical
procedures and therefore it is not recommended for this use. (See PRECAUTIONS, Pediatric Use).
DIPRIVAN Injectable Emulsion should only be administered to intubated, mechanically ventilated adult patients
in the Intensive Care Unit (ICU) to provide continuous sedation and control of stress responses. In this setting,
DIPRIVAN Injectable Emulsion should be administered only by persons skilled in the medical management of
critically ill patients and trained in cardiovascular resuscitation and airway management.
DIPRIVAN Injectable Emulsion is not indicated for use in Pediatric ICU sedation since the safety of this
regimen has not been established. (See PRECAUTIONS, Pediatric Use).
DIPRIVAN Injectable Emulsion is not recommended for obstetrics, including cesarean section deliveries.
DIPRIVAN Injectable Emulsion crosses the placenta, and as with other general anesthetic agents, the
administration of DIPRIVAN Injectable Emulsion may be associated with neonatal depression. (See
PRECAUTIONS.)
DIPRIVAN Injectable Emulsion is not recommended for use in nursing mothers because DIPRIVAN Injectable
Emulsion has been reported to be excreted in human milk, and the effects of oral absorption of small amounts of
propofol are not known. (See PRECAUTIONS.)
CONTRAINDICATIONS
DIPRIVAN Injectable Emulsion is contraindicated in patients with a known hypersensitivity to DIPRIVAN
Injectable Emulsion or its components, or when general anesthesia or sedation are contraindicated.
WARNINGS
For general anesthesia or monitored anesthesia care (MAC) sedation, DIPRIVAN Injectable Emulsion
should be administered only by persons trained in the administration of general anesthesia and not
involved in the conduct of the surgical/diagnostic procedure. Patients should be continuously monitored,
and facilities for maintenance of a patent airway, artificial ventilation, and oxygen enrichment and
circulatory resuscitation must be immediately available.
For sedation of intubated, mechanically ventilated adult patients in the Intensive Care Unit (ICU),
DIPRIVAN Injectable Emulsion should be administered only by persons skilled in the management of
critically ill patients and trained in cardiovascular resuscitation and airway management.
In the elderly, debilitated, or ASA III/IV patients, rapid (single or repeated) bolus administration should not be
used during general anesthesia or MAC sedation in order to minimize undesirable cardiorespiratory depression,
including hypotension, apnea, airway obstruction, and/or oxygen desaturation.
MAC sedation patients should be continuously monitored by persons not involved in the conduct of the surgical
or diagnostic procedure; oxygen supplementation should be immediately available and provided where clinically
indicated; and oxygen saturation should be monitored in all patients. Patients should be continuously monitored
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
for early signs of hypotension, apnea, airway obstruction, and/or oxygen desaturation. These cardiorespiratory
effects are more likely to occur following rapid initiation (loading) boluses or during supplemental maintenance
boluses, especially in the elderly, debilitated, or ASA III/IV patients.
DIPRIVAN Injectable Emulsion should not be coadministered through the same IV catheter with blood or
plasma because compatibility has not been established. In vitro tests have shown that aggregates of the globular
component of the emulsion vehicle have occurred with blood/plasma/serum from humans and animals. The
clinical significance is not known.
STRICT ASEPTIC TECHNIQUE MUST ALWAYS BE MAINTAINED DURING HANDLING.
DIPRIVAN INJECTABLE EMULSION IS A SINGLE-USE PARENTERAL PRODUCT WHICH
CONTAINS 0.005% DISODIUM EDETATE TO RETARD THE RATE OF GROWTH OF
MICROORGANISMS IN THE EVENT OF ACCIDENTAL EXTRINSIC CONTAMINATION.
HOWEVER, DIPRIVAN INJECTABLE EMULSION CAN STILL SUPPORT THE GROWTH OF
MICROORGANISMS AS IT IS NOT AN ANTIMICROBIALLY PRESERVED PRODUCT UNDER
USP STANDARDS. ACCORDINGLY, STRICT ASEPTIC TECHNIQUE MUST STILL BE ADHERED
TO. DO NOT USE IF CONTAMINATION IS SUSPECTED. DISCARD UNUSED PORTIONS AS
DIRECTED WITHIN THE REQUIRED TIME LIMITS (SEE DOSAGE AND ADMINISTRATION,
HANDLING PROCEDURES). THERE HAVE BEEN REPORTS IN WHICH FAILURE TO USE
ASEPTIC TECHNIQUE WHEN HANDLING DIPRIVAN INJECTABLE EMULSION WAS
ASSOCIATED WITH MICROBIAL CONTAMINATION OF THE PRODUCT AND WITH FEVER,
INFECTION/SEPSIS, OTHER LIFE-THREATENING ILLNESS, AND/OR DEATH.
PRECAUTIONS
General
Adult and Pediatric Patients:
A lower induction dose and a slower maintenance rate of administration should be used in elderly, debilitated, or
ASA III/IV patients. (See CLINICAL PHARMACOLOGY - Individualization of Dosage.) Patients should be
continuously monitored for early signs of significant hypotension and/or bradycardia. Treatment may include
increasing the rate of intravenous fluid, elevation of lower extremities, use of pressor agents, or administration of
atropine. Apnea often occurs during induction and may persist for more than 60 seconds. Ventilatory support
may be required. Because DIPRIVAN Injectable Emulsion is an emulsion, caution should be exercised in
patients with disorders of lipid metabolism such as primary hyperlipoproteinemia, diabetic hyperlipemia, and
pancreatitis.
Very rarely the use of DIPRIVAN may be associated with the development of a period of postoperative
unconsciousness which may be accompanied by an increase in muscle tone. This may or may not be preceded
by a brief period of wakefulness. Recovery is spontaneous. The clinical criteria for discharge from the
recovery/day surgery area established for each institution should be satisfied before discharge of the patient from
the care of the anesthesiologist.
When DIPRIVAN Injectable Emulsion is administered to an epileptic patient, there may be a risk of seizure
during the recovery phase.
Attention should be paid to minimize pain on administration of DIPRIVAN Injectable Emulsion. Transient local
pain can be minimized if the larger veins of the forearm or antecubital fossa are used. Pain during intravenous
injection may also be reduced by prior injection of IV lidocaine (1 mL of a 1% solution). Pain on injection
occurred frequently in pediatric patients (45%) when a small vein of the hand was utilized without lidocaine
pretreatment. With lidocaine pretreatment or when antecubital veins were utilized, pain was minimal (incidence
less than 10%) and well-tolerated.
Venous sequelae (phlebitis or thrombosis) have been reported rarely (<1%). In two well-controlled clinical
studies using dedicated intravenous catheters, no instances of venous sequelae were observed up to 14 days
following induction.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
Intra-arterial injection in animals did not induce local tissue effects. Accidental intra-arterial injection has been
reported in patients, and, other than pain, there were no major sequelae.
Intentional injection into subcutaneous or perivascular tissues of animals caused minimal tissue reaction. During
the post-marketing period, there have been rare reports of local pain, swelling, blisters, and/or tissue necrosis
following accidental extravasation of DIPRIVAN Injectable Emulsion.
Perioperative myoclonia, rarely including convulsions and opisthotonos, has occurred in temporal relationship in
cases in which DIPRIVAN Injectable Emulsion has been administered.
Clinical features of anaphylaxis, which may include angioedema, bronchospasm, erythema, and hypotension,
occur rarely following DIPRIVAN Injectable Emulsion administration, although use of other drugs in most
instances makes the relationship to DIPRIVAN Injectable Emulsion unclear.
There have been rare reports of pulmonary edema in temporal relationship to the administration of DIPRIVAN
Injectable Emulsion, although a causal relationship is unknown.
Very rarely, cases of unexplained postoperative pancreatitis (requiring hospital admission) have been reported
after anesthesia in which DIPRIVAN Injectable Emulsion was one of the induction agents used. Due to a variety
of confounding factors in these cases, including concomitant medications, a causal relationship to DIPRIVAN
Injectable Emulsion is unclear.
DIPRIVAN Injectable Emulsion has no vagolytic activity. Reports of bradycardia, asystole, and rarely, cardiac
arrest have been associated with DIPRIVAN Injectable Emulsion. Pediatric patients are susceptible to this effect,
particularly when fentanyl is given concomitantly. The intravenous administration of anticholinergic agents
(e.g., atropine or glycopyrrolate) should be considered to modify potential increases in vagal tone due to
concomitant agents (e.g., succinylcholine) or surgical stimuli.
Intensive Care Unit Sedation
Adult Patients (See WARNINGS and DOSAGE AND ADMINISTRATION, Handling Procedures.) The
administration of DIPRIVAN Injectable Emulsion should be initiated as a continuous infusion and changes in
the rate of administration made slowly (>5 min) in order to minimize hypotension and avoid acute overdosage.
(See CLINICAL PHARMACOLOGY - Individualization of Dosage.)
Patients should be monitored for early signs of significant hypotension and/or cardiovascular depression, which
may be profound. These effects are responsive to discontinuation of DIPRIVAN Injectable Emulsion, IV fluid
administration, and/or vasopressor therapy.
As with other sedative medications, there is wide interpatient variability in DIPRIVAN Injectable Emulsion
dosage requirements, and these requirements may change with time.
Failure to reduce the infusion rate in patients receiving DIPRIVAN Injectable Emulsion for extended periods
may result in excessively high blood concentrations of the drug. Thus, titration to clinical response and daily
evaluation of sedation levels are important during use of DIPRIVAN Injectable Emulsion infusion for ICU
sedation, especially of long duration.
Opioids and paralytic agents should be discontinued and respiratory function optimized prior to weaning patients
from mechanical ventilation. Infusions of DIPRIVAN Injectable Emulsion should be adjusted to maintain a
light level of sedation prior to weaning patients from mechanical ventilatory support. Throughout the weaning
process, this level of sedation may be maintained in the absence of respiratory depression. Because of the rapid
clearance of DIPRIVAN Injectable Emulsion, abrupt discontinuation of a patient's infusion may result in rapid
awakening of the patient with associated anxiety, agitation, and resistance to mechanical ventilation, making
weaning from mechanical ventilation difficult. It is therefore recommended that administration of DIPRIVAN
Injectable Emulsion be continued in order to maintain a light level of sedation throughout the weaning process
until 10-15 minutes prior to extubation, at which time the infusion can be discontinued.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
There have been very rare reports of rhdomyolysis associated with the administration of DIPRIVAN for ICU
sedation.
Since DIPRIVAN Injectable Emulsion is formulated in an oil-in-water emulsion, elevations in serum
triglycerides may occur when DIPRIVAN Injectable Emulsion is administered for extended periods of time.
Patients at risk of hyperlipidemia should be monitored for increases in serum triglycerides or serum turbidity.
Administration of DIPRIVAN Injectable Emulsion should be adjusted if fat is being inadequately cleared from
the body. A reduction in the quantity of concurrently administered lipids is indicated to compensate for the
amount of lipid infused as part of the DIPRIVAN Injectable Emulsion formulation; 1 mL of DIPRIVAN
Injectable Emulsion contains approximately 0.1 g of fat (1.1 kcal).
EDTA is a strong chelator of trace metals -- including zinc. Although with DIPRIVAN Injectable Emulsion there
are no reports of decreased zinc levels or zinc deficiency-related adverse events, DIPRIVAN Injectable
Emulsion should not be infused for longer than 5 days without providing a drug holiday to safely replace
estimated or measured urine zinc losses.
In clinical trials mean urinary zinc loss was approximately 2.5 to 3.0 mg/day in adult patients and 1.5 to 2.0
mg/day in pediatric patients.
In patients who are predisposed to zinc deficiency, such as those with burns, diarrhea, and/or major sepsis, the
need for supplemental zinc should be considered during prolonged therapy with DIPRIVAN Injectable
Emulsion.
At high doses (2-3 grams per day), EDTA has been reported, on rare occasions, to be toxic to the renal tubules.
Studies to-date, in patients with normal or impaired renal function have not shown any alteration in renal
function with DIPRIVAN Injectable Emulsion containing 0.005% disodium edetate. In patients at risk for renal
impairment, urinalysis and urine sediment should be checked before initiation of sedation and then be monitored
on alternate days during sedation.
The long-term administration of DIPRIVAN Injectable Emulsion to patients with renal failure and/or hepatic
insufficiency has not been evaluated.
Neurosurgical Anesthesia: When DIPRIVAN Injectable Emulsion is used in patients with increased
intracranial pressure or impaired cerebral circulation, significant decreases in mean arterial pressure should be
avoided because of the resultant decreases in cerebral perfusion pressure. To avoid significant hypotension and
decreases in cerebral perfusion pressure, an infusion or slow bolus of approximately 20 mg every 10 seconds
should be utilized instead of rapid, more frequent, and/or larger boluses of DIPRIVAN Injectable Emulsion.
Slower induction titrated to clinical responses, will generally result in reduced induction dosage requirements (1
to 2 mg/kg). When increased ICP is suspected, hyperventilation and hypocarbia should accompany the
administration of DIPRIVAN Injectable Emulsion. (See DOSAGE AND ADMINISTRATION.)
Cardiac Anesthesia: Slower rates of administration should be utilized in premedicated patients, geriatric
patients, patients with recent fluid shifts, or patients who are hemodynamically unstable. Any fluid deficits
should be corrected prior to administration of DIPRIVAN Injectable Emulsion. In those patients where
additional fluid therapy may be contraindicated, other measures, e.g., elevation of lower extremities, or use of
pressor agents, may be useful to offset the hypotension which is associated with the induction of anesthesia with
DIPRIVAN Injectable Emulsion.
Information for Patients: Patients should be advised that performance of activities requiring mental alertness,
such as operating a motor vehicle, or hazardous machinery or signing legal documents may be impaired for some
time after general anesthesia or sedation.
Drug Interactions: The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in
patients with intramuscular or intravenous premedication, particularly with narcotics (e.g., morphine,
meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (e.g., benzodiazepines, barbiturates,
chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial
pressures and cardiac output.
During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should
be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of
supplemental analgesic agents (e.g., nitrous oxide or opioids). The concurrent administration of potent
inhalational agents (e.g., isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable
Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the
anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion.
DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity or duration of
action of the commonly used neuromuscular blocking agents (e.g., succinylcholine and nondepolarizing muscle
relaxants).
No significant adverse interactions with commonly used premedications or drugs used during anesthesia or
sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic
agents) have been observed in adults. In pediatric patients, administration of fentanyl concomitantly with
DIPRIVAN Injectable Emulsion may result in serious bradycardia.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Animal carcinogenicity studies have not been
performed with propofol.
In vitro and in vivo animal tests failed to show any potential for mutagenicity by propofol. Tests for
mutagenicity included the Ames (using Salmonella sp) mutation test, gene mutation/gene conversion using
Saccharomyces cerevisiae, in vitro cytogenetic studies in Chinese hamsters, and a mouse micronucleus test.
Studies in female rats at intravenous doses up to 15 mg/kg/day (approximately equivalent to the recommended
human induction dose on a mg/m2 basis) for 2 weeks before pregnancy to day 7 of gestation did not show
impaired fertility. Male fertility in rats was not affected in a dominant lethal study at intravenous doses up to 15
mg/kg/day for 5 days.
Pregnancy Category B: Reproduction studies have been performed in rats and rabbits at intravenous doses of
15 mg/kg/day (approximately equivalent to the recommended human induction dose on a mg/m2 basis) and have
revealed no evidence of impaired fertility or harm to the fetus due to propofol. Propofol, however, has been
shown to cause maternal deaths in rats and rabbits and decreased pup survival during the lactating period in
dams treated with 15 mg/kg/day (approximately equivalent to the recommended human induction dose on a
mg/m2 basis). The pharmacological activity (anesthesia) of the drug on the mother is probably responsible for the
adverse effects seen in the offspring. There are, however, no adequate and well-controlled studies in pregnant
women. Because animal reproduction studies are not always predictive of human responses, this drug should be
used during pregnancy only if clearly needed.
Labor and Delivery: DIPRIVAN Injectable Emulsion is not recommended for obstetrics, including cesarean
section deliveries. DIPRIVAN Injectable Emulsion crosses the placenta, and as with other general anesthetic
agents, the administration of DIPRIVAN Injectable Emulsion may be associated with neonatal depression.
Nursing Mothers: DIPRIVAN Injectable Emulsion is not recommended for use in nursing mothers because
DIPRIVAN Injectable Emulsion has been reported to be excreted in human milk and the effects of oral
absorption of small amounts of propofol are not known.
Pediatric Use: The safety and effectiveness of DIPRIVAN Injectable Emulsion have been established for
induction of anesthesia in pediatric patients aged 3 years and older and for the maintenance of anesthesia aged 2
months and older.
DIPRIVAN Injectable Emulsion is not recommended for the induction of anesthesia in patients younger than 3
years of age and for the maintenance of anesthesia in patients younger than 2 months of age as safety and
effectiveness have not been established.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
In pediatric patients, administration of fentanyl concomitantly with DIPRIVAN Injectable Emulsion may result
in serious brady cardia. (see PRECAUTIONS – General).
DIPRIVAN Injectable Emulsion is not indicated for use in pediatric patients for ICU sedation or for MAC
sedation for surgical, nonsurgical or diagnostic procedures as safety and effectiveness have not been established.
There have been anecdotal reports of serious adverse events and death in pediatric patients with upper
respiratory tract infections receiving DIPRIVAN Injectable Emulsion for ICU sedation.
In one multicenter clinical trial of ICU sedation in critically ill pediatric patients that excluded patients with
upper respiratory tract infections, the incidence of mortality observed in patients who received DIPRIVAN
Injectable Emulsion (n=222) was 9%, while that for patients who received standard sedative agents (n=105) was
4%. While causality has not been established, DIPRIVAN Injectable Emulsion is not indicated for sedation in
pediatric patients until further studies have been performed to document its safety in that population. (See
CLINICAL PHARMACOLOGY – Pediatric Patients: and Dosage and Administration).
In pediatric patients, abrupt discontinuation following prolonged infusion may result in flushing of the hands and
feet, agitation, tremulousness and hyperirritability. Increased incidences of bradycardia (5%), agitation (4%), and
jitteriness (9%) have also been observed.
Geriatric use: A lower induction dose and a slower maintenance rate of administration of DIPRIVAN®
Injectable Emulsion should be used in elderly patients. In this group of patients, rapid (single or repeated) bolus
administration should not be used in order to minimize undesirable cardiorespiratory depression including
hypotension, apnea, airway obstruction and/or oxygen desaturation. All dosing should be titrated according to
patient condition and response. (See DOSAGE AND ADMINISTRATION - Elderly, debilitated or ASA III/IV
patients and CLINICAL PHARMACOLOGY - Geriatrics)
ADVERSE REACTIONS
General
Adverse event information is derived from controlled clinical trials and worldwide marketing experience. In the
description below, rates of the more common events represent US/Canadian clinical study results. Less frequent
events are also derived from publications and marketing experience in over 8 million patients; there are
insufficient data to support an accurate estimate of their incidence rates. These studies were conducted using a
variety of premedicants, varying lengths of surgical/diagnostic procedures, and various other anesthetic/sedative
agents. Most adverse events were mild and transient.
Anesthesia and MAC Sedation in Adults
The following estimates of adverse events for DIPRIVAN Injectable Emulsion include data from clinical trials in
general anesthesia/MAC sedation (N=2889 adult patients). The adverse events listed below as probably causally
related are those events in which the actual incidence rate in patients treated with DIPRIVAN Injectable
Emulsion was greater than the comparator incidence rate in these trials. Therefore, incidence rates for anesthesia
and MAC sedation in adults generally represent estimates of the percentage of clinical trial patients which
appeared to have probable causal relationship.
The adverse experience profile from reports of 150 patients in the MAC sedation clinical trials is similar to the
profile established with DIPRIVAN Injectable Emulsion during anesthesia (see below). During MAC sedation
clinical trials, significant respiratory events included cough, upper airway obstruction, apnea, hypoventilation,
and dyspnea.
Anesthesia in Pediatric Patients
Generally the adverse experience profile from reports of 506 DIPRIVAN Injectable Emulsion pediatric patients
from 6 days through 16 years of age in the US/Canadian anesthesia clinical trials is similar to the profile
established with DIPRIVAN Injectable Emulsion during anesthesia in adults (see Pediatric percentages [Peds %]
below). Although not reported as an adverse event in clinical trials, apnea is frequently observed in pediatric
patients.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
ICU Sedation in Adults
The following estimates of adverse events include data from clinical trials in ICU sedation (N=159 adult
patients). Probably related incidence rates for ICU sedation were determined by individual case report form
review. Probable causality was based upon an apparent dose response relationship and/or positive responses to
rechallenge. In many instances the presence of concomitant disease and concomitant therapy made the causal
relationship unknown. Therefore, incidence rates for ICU sedation generally represent estimates of the
percentage of clinical trial patients which appeared to have a probable causal relationship.
Incidence greater than 1% - Probably Causally Related
Anesthesia/MAC Sedation
ICU Sedation
Cardiovascular:
Bradycardia
Bradycardia
Arrhythmia [Peds: 1.2%]
Tachycardia Nodal [Peds: 1.6%]
Hypotension* [Peds: 17%]
Decreased Cardiac Output
(see also CLINICAL
PHARMACOLOGY)
[Hypertension Peds: 8%]
Hypotension 26%
Central Nervous
System:
Movement* [Peds: 17%]
Injection Site:
Burning/Stinging or Pain, 17.6%
[Peds: 10%]
Metabolic/Nutritional:
Hyperlipemia*
Respiratory:
Apnea
Respiratory Acidosis
(see also CLINICAL
During Weaning*
PHARMACOLOGY)
Skin and Appendages:
Rash [Peds: 5%]
Pruritus [Peds: 2%]
Events without an * or % had an incidence of 1%-3%
* Incidence of events 3% to 10%
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18
Incidence less than 1% - Probably Causally Related
Anesthesia/MAC Sedation
ICU Sedation
Body as a Whole:
Anaphylaxis/Anaphylactoid
Reaction
Perinatal Disorder
[Tachycardia]
[Bigeminy]
[Bradycardia]
[Premature Ventricular
Contractions]
[Hemorrhage]
[ECG Abnormal]
[Arrhythmia Atrial]
[Fever]
[Extremities Pain]
[Anticholinergic Syndrome]
Cardiovascular:
Premature Atrial Contractions
Syncope
Central Nervous
System:
Hypertonia/Dystonia,
Agitation
Paresthesia
Digestive:
[Hypersalivation]
[Nausea]
Hemic/Lymphatic [Leykocytosis]
Injection Site: [Phlebitis]
[Pruritus]
Metabolic: [Hypomagnesemia]
Musculoskeletal:
Myalgia
Nervous: [Dizziness]
[Agitation]
[Chills]
[Somnolence]
[Delirium]
Respiratory:
Wheezing
Decreased Lung
Function
[Cough]
[Laryngospasm]
[Hypoxia]
Skin and Appendages:
Flushing, Pruritus
Special Senses:
Amblyopia
[Vision Abnormal]
Urogenital:
Cloudy Urine
Green Urine
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19
Incidence less than 1% - Causal Relationship Unknown
Anesthesia/MAC Sedation
ICU Sedation
Body as a Whole:
Asthenia, Awareness, Chest Pain
Fever, Sepsis, Trunk Pain
Extremities Pain, Fever,
Whole Body Weakness
Increased Drug Effect,
Neck Rigidity/Stiffness, Trunk Pain
Cardiovascular:
Arrhythmia, Atrial Fibrillation,
Arrhythmia, Atrial
Atrioventricular Heart Block,
Fibrillation, Bigeminy,
Bigeminy, Bleeding, Bundle
Cardiac Arrest,
Branch Block, Cardiac Arrest,
Extrasystole, Right
ECG Abnormal, Edema,
Heart Failure, Ventricular
Extrasystole, Heart Block,
Tachycardia
Hypertension, Myocardial
Infarction, Myocardial
Ischemia, Premature Ventricular
Contractions, ST Segment
Depression, Supraventricular
Tachycardia, Tachycardia,
Ventricular Fibrillation
Central Nervous
System:
Abnormal Dreams, Agitation,
Chills/Shivering,
Amorous Behavior, Anxiety,
Intracranial Hypertension,
Bucking/Jerking/Thrashing,
Seizures, Somnolence,
Chills/Shivering, Clonic/
Thinking Abnormal
Myoclonic Movement,
Combativeness, Confusion,
Delirium, Depression,
Dizziness, Emotional
Lability, Euphoria, Fatigue,
Hallucinations, Headache,
Hypotonia, Hysteria,
Insomnia, Moaning, Neuropathy,
Opisthotonos, Rigidity,
Seizures, Somnolence, Tremor,
Twitching
Incidence less than 1% - Causal Relationship Unknown (cont’d)
Anesthesia/MAC Sedation
ICU Sedation
Digestive:
Cramping, Diarrhea, Dry Mouth,
Ileus, Liver Function
Enlarged Parotid, Nausea,
Abnormal
Swallowing, Vomiting
Hematologic/
Lymphatic:
Coagulation Disorder,
Leukocytosis
Injection Site:
Hives/Itching, Phlebitis,
Redness/Discoloration
Metabolic/
Nutritional:
Hyperkalemia, Hyperlipemia
BUN Increased,
Creatinine, Increased,
Dehydration,
Hyperglycemia,
Metabolic Acidosis,
Osmolality Increased
Respiratory:
Bronchospasm, Burning in
Hypoxia
Throat, Cough, Dyspnea,
Hiccough, Hyperventilation,
Hypoventilation, Hypoxia,
Laryngospasm, Pharyngitis,
Sneezing, Tachypnea, Upper
Airway Obstruction
Skin and Appendages:
Conjunctival Hyperemia,
Rash
Diaphoresis, Urticaria
Special Senses:
Diplopia, Ear Pain, Eye Pain,
Nystagmus, Taste Perversion,
Tinnitus
Urogenital:
Oliguria, Urine Retention
Kidney Failure
DRUG ABUSE AND DEPENDENCE
Rare cases of self-administration of DIPRIVAN Injectable Emulsion by health care professionals have been
reported, including some fatalities. DIPRIVAN Injectable Emulsion should be managed to prevent the risk of
diversion, including restriction of access and accounting procedures as appropriate to the clinical setting.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
20
OVERDOSAGE
If overdosage occurs, DIPRIVAN Injectable Emulsion administration should be discontinued immediately.
Overdosage is likely to cause cardiorespiratory depression. Respiratory depression should be treated by artificial
ventilation with oxygen. Cardiovascular depression may require repositioning of the patient by raising the
patient's legs, increasing the flow rate of intravenous fluids, and administering pressor agents and/or
anticholinergic agents.
DOSAGE AND ADMINISTRATION
Dosage and rate of administration should be individualized and titrated to the desired effect, according to
clinically relevant factors, including preinduction and concomitant medications, age, ASA physical
classification, and level of debilitation of the patient.
The following is abbreviated dosage and administration information which is only intended as a general
guide in the use of DIPRIVAN Injectable Emulsion. Prior to administering DIPRIVAN Injectable
Emulsion, it is imperative that the physician review and be completely familiar with the specific dosage
and administration information detailed in the CLINICAL PHARMACOLOGY - Individualization of
Dosage section.
In the elderly, debilitated, or ASA III/IV patients, rapid bolus doses should not be the method of
administration. (See WARNINGS.)
Intensive care unit sedation:
STRICT ASEPTIC TECHNIQUE MUST ALWAYS BE MAINTAINED DURING HANDLING.
DIPRIVAN INJECTABLE EMULSION IS A SINGLE-USE PARENTERAL PRODUCT WHICH
CONTAINS 0.005% DISODIUM EDETATE TO RETARD THE RATE OF GROWTH OF
MICROORGANISMS IN THE EVENT OF ACCIDENTAL EXTRINSIC CONTAMINATION.
HOWEVER, DIPRIVAN INJECTABLE EMULSION CAN STILL SUPPORT THE GROWTH OF
MICROORGANISMS AS IT IS NOT AN ANTIMICROBIALLY PRESERVED PRODUCT UNDER
USP STANDARDS. ACCORDINGLY, STRICT ASEPTIC TECHNIQUE MUST STILL BE ADHERED
TO. DO NOT USE IF CONTAMINATION IS SUSPECTED. (see DOSAGE AND ADMINISTRATION,
Handling Procedures.)
DIPRIVAN Injectable Emulsion should be individualized according to the patient's condition and response,
blood lipid profile, and vital signs. (see PRECAUTIONS - ICU SEDATION.) For intubated, mechanically
ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous
infusion in order to titrate to desired clinical effect and minimize hypotension. When indicated, initiation of
sedation should begin at 5 µg/kg/min (0.3 mg/kg/h). The infusion rate should be increased by increments of 5 to
10 µg/kg/min (0.3 to 0.6 mg/kg/h) until the desired level of sedation is achieved. A minimum period of 5
minutes between adjustments should be allowed for onset of peak drug effect. Most adult patients require
maintenance rates of 5 to 50 µg/kg/min (0.3 to 3 mg/kg/h) or higher. Dosages of DIPRIVAN Injectable
Emulsion should be reduced in patients who have received large dosages of narcotics. Conversely, the
DIPRIVAN Injectable Emulsion dosage requirement may be reduced by adequate management of pain with
analgesic agents. As with other sedative medications, there is interpatient variability in dosage requirements,
and these requirements may change with time. (see dosage guide.) EVALUATION OF LEVEL OF
SEDATION AND ASSESSMENT OF CNS FUNCTION SHOULD BE CARRIED OUT DAILY
THROUGHOUT MAINTENANCE TO DETERMINE THE MINIMUM DOSE OF DIPRIVAN
INJECTABLE EMULSION REQUIRED FOR SEDATION (SEE CLINICAL TRIALS, ICU
SEDATION). Bolus administration of 10 or 20 mg should only be used to rapidly increase depth of sedation in
patients where hypotension is not likely to occur. Patients with compromised myocardial function, intravascular
volume depletion, or abnormally low vascular tone (e.g. sepsis) may be more susceptible to hypotension. (See
PRECAUTIONS).
EDTA is a strong chelator of trace metals – including zinc.. Although with DIPRIVAN Injectable Emulsion
there are no reports of decreased zinc levels or zinc deficiency-related adverse events, DIPRIVAN Injectable
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
21
Emulsion should not be infused for longer than 5 days without providing a drug holiday to safely replace
estimated or measured urine zinc losses.
At high doses (2-3 grams per day), EDTA has been reported, on rare occasions, to be toxic to the renal tubules.
Studies to-date, in patients with normal or impaired renal function have not shown any alteration in renal
function with DIPRIVAN Injectable Emulsion containing 0.005% disodium edetate. In patients at risk for renal
impairment, urinalysis and urine sediment should be checked before initiation of sedation and then be monitored
on alternate days during sedation.
SUMMARY OF DOSAGE GUIDELINES -
Dosages and rates of administration in the following table should be individualized and titrated to clinical
response. Safety and dosing requirements for induction of anesthesia in pediatric patients have only been
established for children 3 years of age and older. Safety and dosing requirements for the maintenance of
anesthesia have only been established for children 2 months of age and older. For complete dosage information,
see CLINICAL PHARMACOLOGY – Individualization of Dosage.
INDICATION
DOSAGE AND ADMINISTRATION
Induction of General Anesthesia
Healthy Adults Less Than 55 Years
of Age: 40 mg every 10 seconds until
induction onset (2 to 2.5 mg/kg).
Elderly, Debilitated, or ASA III/IV
Patients: 20 mg every 10 seconds
until induction onset (1 to 1.5 mg/kg).
Cardiac Anesthesia: 20 mg every 10
seconds until induction onset (0.5 to
1.5 mg/kg).
Neurosurgical Patients: 20 mg every
10 seconds until induction onset (1 to 2
mg/kg)
Pediatric Patients - healthy, from 3
years to 16 years of age: 2.5 to 3.5
mg/kg administered over 20-30
seconds. (See PRECAUTIONS –
Pediatric Use: and CLINICAL
PHARMACOLOGY – Pediatric
patients)
_______________________________________________
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
22
Maintenance of General Anesthesia: Infusion
Healthy Adults Less Than 55
Years of Age: 100 to 200
µg/kg/min (6 to 12 mg/kg/h).
Elderly, Debilitated, ASA
III/IV Patients: 50 to 100
µg/kg/min (3 to 6 mg/kg/h).
Cardiac Anesthesia: Most
patients require:
Primary DIPRIVAN Injectable
Emulsion with Secondary Opioid
-
100 - 150 µg/kg/min
Low-Dose DIPRIVAN Injectable
Emulsion with Primary Opioid -
50 - 100 µg/kg/min
(See CLINICAL
PHARMACOLOGY, Table 6)
Neurosurgical Patients: 100 to
200 µg/kg/min (6 to 12 mg/kg/h).
Pediatric Patients - healthy,
from 2 months of age to 16
years of age: 125 to 300
µg/kg/min (7.5 to 18 mg/kg/h)
“Following the first half hour of
maintenance, if clinical signs of
light anesthesia are not present,
the infusion rate should be
decreased.” (See
PRECAUTIONS – Pediatric Use:
and CLINICAL
PHARMACOLOGY – Pediatric
patients)”
___________________________________________________________
Maintenance of General Anesthesia:
Intermittent Bolus
Healthy Adults Less Than 55
Years of Age: Increments of
20 to 50 mg as needed.
___________________________________________________________
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
Initiation of MAC Sedation
Healthy Adults Less Than 55
Years of Age: Slow infusion or
slow injection techniques are
recommended to avoid apnea or
hypotension. Most patients require
an infusion of 100 to
150 µg/kg/min (6 to 9 mg/kg/h) for
3 to 5 minutes or a slow injection of
0.5 mg/kg over 3 to 5 minutes
followed immediately by a
maintenance infusion.
Elderly, Debilitated,
Neurosurgical, or ASA III/IV
Patients: Most patients require
dosages similar to healthy adults.
Rapid boluses are to be avoided
(See WARNINGS.)
___________________________________________________________
Maintenance of MAC Sedation
Healthy Adults Less Than 55
Years of Age: A variable rate
infusion technique is preferable over
an intermittent bolus technique.
Most patients require an
infusion of 25 to 75 µg/kg/min
(1.5 to 4.5 mg/kg/h) or incremental
bolus doses of 10 mg or 20 mg.
In Elderly, Debilitated,
Neurosurgical, or ASA III/IV
Patients: Most patients require
80% of the usual adult dose. A
rapid (single or repeated) bolus dose
should not be used. (See
WARNINGS.)
___________________________________________________________
Initiation and Maintenance of ICU Sedation in Intubated,
Mechanically Ventilated
Adult Patients - Because of the residual
effects of previous anesthetic or sedative
agents, in most patients the initial infusion
should be 5 µg/kg/min (0.3 mg/kg/h) for at
least 5 minutes. Subsequent increments of
5 to 10 µg/kg/min (0.3 to 0.6 mg/kg/h) over
5 to 10 minutes may be used until desired
clinical effect is achieved. Maintenance
rates of 5 to 50 µg/kg/min (0.3 to 3
mg/kg/h) or higher may be required.
Evaluation of level of sedation and
assessment of CNS function should be
carried out daily throughout
maintenance to determine the minimum
dose of DIPRIVAN Injectable Emulsion
required for sedation.
The tubing and any unused portions of
DIPRIVAN Injectable Emulsion should
be discarded after 12 hours because
DIPRIVAN Injectable Emulsion
contains no preservatives and is capable
of supporting rapid growth of
microorganisms. (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
24
Compatibility and Stability: DIPRIVAN Injectable Emulsion should not be mixed with other therapeutic
agents prior to administration.
Dilution Prior to Administration: DIPRIVAN Injectable Emulsion is provided as a ready to use formulation.
However, should dilution be necessary, it should only be diluted with 5% Dextrose Injection, USP, and it should
not be diluted to a concentration less than 2 mg/mL because it is an emulsion. In diluted form it has been shown
to be more stable when in contact with glass than with plastic (95% potency after 2 hours of running infusion in
plastic).
Administration with Other Fluids: Compatibility of DIPRIVAN Injectable Emulsion with the
coadministration of blood/serum/plasma has not been established. (See WARNINGS.) When administered
using a y-type infusion set, DIPRIVAN Injectable Emulsion has been shown to be compatible with the following
intravenous fluids.
- 5% Dextrose Injection, USP
- Lactated Ringers Injection, USP
- Lactated Ringers and 5% Dextrose Injection
- 5% Dextrose and 0.45% Sodium Chloride Injection, USP
- 5% Dextrose and 0.2% Sodium Chloride Injection, USP
Assembly Instructions for Pre-Filled Syringe
1. Remove the Luer connector from packaging.
2. Remove glass syringe barrel from tray and check for cracks or leaks. Shake. Remove the plastic cover.
Applying moderate pressure, disinfect the surface of the rubber stopper prior to attachment of the Luer
connector.
3. Pull off needle cover from Luer connector. The bevel of the needle spike is slightly bent (c-tip) to prevent
potential coring.
Fig. 1
4. Stand the syringe barrel vertically on a hard surface and push Luer connector on to syringe barrel so needle
penetrates rubber seal and connector slides over the aluminum seal until firmly seated. (Fig. 1)
Fig. 2
5. Add plunger rod by screwing clockwise. CAUTION: the rod must be fully screwed on, otherwise it may
detach which could result in siphoning of the syringe contents. (Fig. 2)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
25
6. Unscrew Luer cover remove excess nitrogen gas from the syringe (a small nitrogen gas bubble may remain).
Assemble administration line and connect syringe.
Handling Procedures
General
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit.
Clinical experience with the use of in-line filters and DIPRIVAN Injectable Emulsion during anesthesia or
ICU/MAC sedation is limited. DIPRIVAN Injectable Emulsion should only be administered through a filter
with a pore size of 5 µm or greater unless it has been demonstrated that the filter does not restrict the flow of
DIPRIVAN Injectable Emulsion and/or cause the breakdown of the emulsion. Filters should be used with
caution and where clinically appropriate. Continuous monitoring is necessary due to the potential for restricted
flow and/or breakdown of the emulsion.
Do not use if there is evidence of separation of the phases of the emulsion.
Rare cases of self-administration of DIPRIVAN Injectable Emulsion by health care professionals have been
reported, including some fatalities (See DRUG ABUSE AND DEPENDENCE).
STRICT ASEPTIC TECHNIQUE MUST ALWAYS BE MAINTAINED DURING HANDLING.
DIPRIVAN INJECTABLE EMULSION IS A SINGLE-USE PARENTERAL PRODUCT; WHICH
CONTAINS 0.005% DISODIUM EDETATE TO RETARD THE RATE OF GROWTH OF
MICROORGANISMS IN THE EVENT OF ACCIDENTAL EXTRINSIC CONTAMINATION.
HOWEVER, DIPRIVAN INJECTABLE EMULSION CAN STILL SUPPORT THE GROWTH OF
MICROORGANISMS AS IT IS NOT ANTIMICROBIALLY PRESERVED PRODUCT UNDER USP
STANDARDS. ACCORDINGLY, STRICT ASEPTIC TECHNIQUES MUST STILL BE ADHERED
TO. DO NOT USE IF CONTAMINATION IS SUSPECTED. DISCARD UNUSED PORTIONS AS
DIRECTED WITHIN THE REQUIRED TIME LIMITS (SEE DOSAGE AND ADMINISTRATION,
HANDLING PROCEDURES). THERE HAVE BEEN REPORTS IN WHICH FAILURE TO USE
ASEPTIC TECHNIQUE WHEN HANDLING DIPRIVAN INJECTABLE EMULSION WAS
ASSOCIATED WITH MICROBIAL CONTAMINATION OF THE PRODUCT AND WITH FEVER,
INFECTION/SEPSIS, OTHER LIFE-THREATENING ILLNESS, AND/OR DEATH.
Guidelines for Aseptic Technique for General Anesthesia/MAC Sedation
DIPRIVAN Injectable Emulsion should be prepared for use just prior to initiation of each individual
anesthetic/sedative procedure. The ampule neck surface, or vial/pre-filled syringe rubber stopper should be
disinfected using 70% isopropyl alcohol. DIPRIVAN Injectable Emulsion should be drawn into sterile syringes
immediately after ampules or vials are opened. When withdrawing DIPRIVAN Injectable Emulsion from vials,
a sterile vent spike should be used. The syringe(s) should be labeled with appropriate information including the
date and time the ampule or vial was opened. Administration should commence promptly and be completed
within 6 hours after the ampules, vials, or pre-filled syringes have been opened.
DIPRIVAN Injectable Emulsion should be prepared for single-patient use only. Any unused portions of
DIPRIVAN Injectable Emulsion, reservoirs, dedicated administration tubing and/or solutions containing
DIPRIVAN Injectable Emulsion must be discarded at the end of the anesthetic procedure or at 6 hours,
whichever occurs sooner. The IV line should be flushed every 6 hours and at the end of the anesthetic procedure
to remove residual DIPRIVAN Injectable Emulsion.
Guidelines for Aseptic Technique for ICU Sedation
DIPRIVAN Injectable Emulsion should be prepared for single-patient use only. When DIPRIVAN Injectable
Emulsion is administered directly from the vial/pre-filled syringe, strict aseptic techniques must be followed.
The vial/pre-filled syringe rubber stopper should be disinfected using 70% isopropyl alcohol. A sterile vent
spike and sterile tubing must be used for administration of DIPRIVAN Injectable Emulsion. As with other lipid
emulsions, the number of IV line manipulations should be minimized. Administration should commence
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
26
promptly and must be completed within 12 hours after the vial has been spiked. The tubing and any unused
portions of DIPRIVAN Injectable Emulsion must be discarded after 12 hours.
If DIPRIVAN Injectable Emulsion is transferred to a syringe or other container prior to administration, the
handling procedures for General anesthesia/MAC sedation should be followed, and the product should be
discarded and administration lines changed after 6 hours.
HOW SUPPLIED
DIPRIVAN Injectable Emulsion is available in ready to use 20 mL ampoules, 50 mL infusion vials, 100 mL
infusion vials, and 50 mL pre-filled syringes containing 10 mg/mL of propofol.
20 mL ampoules (NDC 0310-0300-20)
50 mL infusion vials (NDC 0310-0300-50)
100 mL infusion vials (NDC 0310-0300-11)
50 mL pre-filled syringes (NDC 0310-0300-54)
Propofol undergoes oxidative degradation, in the presence of oxygen, and is therefore packaged under nitrogen
to eliminate this degradation path.
Store between 4-22°C(40-72°F). Do not freeze. Shake well before use.
Manufactured by Zeneca S.p.A. for:
Zeneca Pharmaceuticals
A business unit of ZENECA Inc.
Wilmington, DE 19850-5437 USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:32.631935
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/19627S35LBL.pdf', 'application_number': 19627, 'submission_type': 'SUPPL ', 'submission_number': 35}
|
11,569
|
NDA 19-627/S-045
Page 3
Rev
SIC 64180-03
DIPRIVAN®
(propofol) Injectable Emulsion
FOR IV ADMINISTRATION
Strict aseptic technique must always be maintained during handling. Diprivan Injectable
Emulsion is a single-use parenteral product which contains 0.005% disodium edetate to retard
the rate of growth of microorganisms in the event of accidental extrinsic contamination.
However, Diprivan Injectable Emulsion can still support the growth of microorganisms as it is
not an antimicrobially preserved product under USP standards. Accordingly, strict aseptic
technique must still be adhered to. Do not use if contamination is suspected. Discard unused
portions as directed within the required time limits (see dosage and administration, handling
procedures). There have been reports in which failure to use aseptic technique when handling
Diprivan Injectable Emulsion was associated with microbial contamination of the product and
with fever, infection/sepsis, other life-threatening illness, and/or death.
DESCRIPTION
DIPRIVAN® (propofol) Injectable Emulsion is a sterile, nonpyrogenic emulsion containing 10 mg/mL
of propofol suitable for intravenous administration. Propofol is chemically described as
2,6-diisopropylphenol and has a molecular weight of 178.27. The structural and molecular formulas
are:
Propofol is slightly soluble in water and, thus, is formulated in a white, oil-in-water emulsion. The pKa
is 11. The octanol/water partition coefficient for propofol is 6761:1 at a pH of 6-8.5. In addition to the
active component, propofol, the formulation also contains soybean oil (100 mg/mL), glycerol (22.5
mg/mL), egg lecithin (12 mg/mL); and disodium edetate (0.005%); with sodium hydroxide to adjust
pH. The DIPRIVAN Injectable Emulsion is isotonic and has a pH of 7-8.5.
CLINICAL PHARMACOLOGY
General
DIPRIVAN Injectable Emulsion is an intravenous sedative-hypnotic agent for use in the induction and
maintenance of anesthesia or sedation. Intravenous injection of a therapeutic dose of propofol induces
hypnosis, with minimal excitation, usually within 40 seconds from the start of injection (the time for
one arm-brain circulation). As with other rapidly acting intravenous anesthetic agents, the half-time of
the blood-brain equilibration is approximately 1 to 3 minutes, accounting for the rate of induction of
anesthesia.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 4
Pharmacodynamics
Pharmacodynamic properties of propofol are dependent upon the therapeutic blood propofol
concentrations. Steady-state propofol blood concentrations are generally proportional to infusion rates.
Undesirable side effects, such as cardiorespiratory depression, are likely to occur at higher blood
concentrations which result from bolus dosing or rapid increases in infusion rates. An adequate
interval (3 to 5 minutes) must be allowed between dose adjustments in order to assess clinical effects.
The hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of anesthesia vary. If
spontaneous ventilation is maintained, the major cardiovascular effect is arterial hypotension
(sometimes greater than a 30% decrease) with little or no change in heart rate and no appreciable
decrease in cardiac output. If ventilation is assisted or controlled (positive pressure ventilation), there
is an increase in the incidence and the degree of depression of cardiac output. Addition of an opioid,
used as a premedicant, further decreases cardiac output and respiratory drive.
If anesthesia is continued by infusion of DIPRIVAN Injectable Emulsion, the stimulation of
endotracheal intubation and surgery may return arterial pressure towards normal. However, cardiac
output may remain depressed. Comparative clinical studies have shown that the hemodynamic effects
of DIPRIVAN Injectable Emulsion during induction of anesthesia are generally more pronounced than
with other intravenous (IV) induction agents.
Induction of anesthesia with DIPRIVAN Injectable Emulsion is frequently associated with apnea in
both adults and pediatric patients. In adult patients who received DIPRIVAN Injectable Emulsion (2
to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30-60 seconds in 24% of patients,
and more than 60 seconds in 12% of patients. In pediatric patients from birth through 16 years of age
assessable for apnea who received bolus doses of DIPRIVAN Injectable Emulsion (1 to 3.6 mg/kg),
apnea lasted less than 30 seconds in 12% of patients, 30-60 seconds in 10% of patients, and more than
60 seconds in 5% of patients.
During maintenance of general anesthesia, DIPRIVAN Injectable Emulsion causes a decrease in
spontaneous minute ventilation usually associated with an increase in carbon dioxide tension which
may be marked depending upon the rate of administration and concurrent use of other medications
(e.g., opioids, sedatives, etc.).
During monitored anesthesia care (MAC) sedation, attention must be given to the cardiorespiratory
effects of DIPRIVAN Injectable Emulsion. Hypotension, oxyhemoglobin desaturation, apnea, and
airway obstruction can occur, especially following a rapid bolus of DIPRIVAN Injectable Emulsion.
During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over
rapid bolus administration. During maintenance of MAC sedation, a variable rate infusion is preferable
over intermittent bolus administration in order to minimize undesirable cardiorespiratory effects. In
the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose
administration should not be used for MAC sedation (see WARNINGS).
Clinical and preclinical studies suggest that DIPRIVAN Injectable Emulsion is rarely associated with
elevation of plasma histamine levels.
Preliminary findings in patients with normal intraocular pressure indicate that DIPRIVAN Injectable
Emulsion produces a decrease in intraocular pressure which may be associated with a concomitant
decrease in systemic vascular resistance.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 5
Clinical studies indicate that DIPRIVAN Injectable Emulsion when used in combination with
hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow, cerebral metabolic
oxygen consumption, and intracranial pressure. DIPRIVAN Injectable Emulsion does not affect
cerebrovascular reactivity to changes in arterial carbon dioxide tension (see Clinical Trials -
Neuroanesthesia).
Clinical studies indicate that DIPRIVAN Injectable Emulsion does not suppress the adrenal response
to ACTH.
Animal studies and limited experience in susceptible patients have not indicated any propensity of
DIPRIVAN Injectable Emulsion to induce malignant hyperthermia.
Hemosiderin deposits have been observed in the livers of dogs receiving DIPRIVAN Injectable
Emulsion containing 0.005% disodium edetate over a four-week period; the clinical significance of this
is unknown.
Pharmacokinetics
The pharmacokinetics of propofol are well described by a three compartment linear model with
compartments representing the plasma, rapidly equilibrating tissues, and slowly equilibrating tissues.
Following an IV bolus dose, there is rapid equilibration between the plasma and the brain, accounting
for the rapid onset of anesthesia. Plasma levels initially decline rapidly as a result of both distribution
and metabolic clearance. Distribution accounts for about half of this decline following a bolus of
propofol. However, distribution is not constant over time, but decreases as body tissues equilibrate
with plasma and become saturated. The rate at which equilibration occurs is a function of the rate and
duration of the infusion. When equilibration occurs there is no longer a net transfer of propofol
between tissues and plasma.
Discontinuation of the recommended doses of DIPRIVAN Injectable Emulsion after the maintenance
of anesthesia for approximately one hour, or for sedation in the ICU for one day, results in a prompt
decrease in blood propofol concentrations and rapid awakening. Longer infusions (10 days of ICU
sedation) result in accumulation of significant tissue stores of propofol, such that the reduction in
circulating propofol is slowed and the time to awakening is increased.
By daily titration of DIPRIVAN Injectable Emulsion dosage to achieve only the minimum effective
therapeutic concentration, rapid awakening within 10 to 15 minutes can occur even after long-term
administration. If, however, higher than necessary infusion levels have been maintained for a long
time, propofol redistribution from fat and muscle to the plasma can be significant and slow recovery.
The figure below illustrates the fall of plasma propofol levels following infusions of various durations
to provide ICU sedation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 6
The large contribution of distribution (about 50%) to the fall of propofol plasma levels following brief
infusions means that after very long infusions a reduction in the infusion rate is appropriate by as much
as half the initial infusion rate in order to maintain a constant plasma level. Therefore, failure to
reduce the infusion rate in patients receiving DIPRIVAN Injectable Emulsion for extended periods
may result in excessively high blood concentrations of the drug. Thus, titration to clinical response
and daily evaluation of sedation levels are important during use of DIPRIVAN Injectable Emulsion
infusion for ICU sedation..
Adults: Propofol clearance ranges from 23-50 mL/kg/min (1.6 to 3.4 L/min in 70 kg adults). It is
chiefly eliminated by hepatic conjugation to inactive metabolites which are excreted by the kidney. A
glucuronide conjugate accounts for about 50% of the administered dose. Propofol has a steady state
volume of distribution (10-day infusion) approaching 60 L/kg in healthy adults. A difference in
pharmacokinetics due to gender has not been observed. The terminal half-life of propofol after a 10-
day infusion is 1 to 3 days.
Geriatrics: With increasing patient age, the dose of propofol needed to achieve a defined anesthetic
end point (dose-requirement) decreases. This does not appear to be an age-related change in
pharmacodynamics or brain sensitivity, as measured by EEG burst suppression. With increasing
patient age, pharmacokinetic changes are such that, for a given IV bolus dose, higher peak plasma
concentrations occur, which can explain the decreased dose requirement. These higher peak plasma
concentrations in the elderly can predispose patients to cardiorespiratory effects including hypotension,
apnea, airway obstruction, and/or arterial oxygen desaturation. The higher plasma levels reflect age-
related decreased in volume of distribution and intercompartmental clearance. Lower doses are
therefore recommended for initiation and maintenance of sedation and anesthesia in elderly patients.
(See DOSAGE AND ADMINISTRATION.)
Pediatrics: The pharmacokinetics of propofol were studied in children between 3 and 12 years of age
who received DIPRIVAN Injectable Emulsion for periods of approximately 1-2 hours. The observed
distribution and clearance of propofol in these children were similar to adults.
Organ Failure: The pharmacokinetics of propofol do not appear to be different in people with
chronic hepatic cirrhosis or chronic renal impairment compared to adults with normal hepatic and renal
function. The effects of acute hepatic or renal failure on the pharmacokinetics of propofol have not
been studied.
Clinical Trials
Anesthesia and Monitored Anesthesia Care (MAC) Sedation
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 7
Pediatric Anesthesia:
DIPRIVAN Injectable Emulsion was studied in clinical trials which included cardiac surgical patients.
Most patients were 3 years of age or older. The majority of the patients were healthy ASA-PS I or II
patients The range of doses in these studies are described in Tables 1 and 2.
TABLE 1. PEDIATRIC INDUCTION OF ANESTHESIA
Age Range
Induction Dose
Injection Duration
Median (range)
Median (range)
Birth through 16 years
2.5 mg/kg
(1-3.6)
20 sec.
(6-45)
TABLE 2. PEDIATRIC MAINTENANCE OF ANESTHESIA
Age Range
Maintenance Dosage Dosage
(µg/kg/min)
Duration
(minutes)
2 months to 2 years
199 (82 – 394)
65 (12 - 282)
2 to 12 years
188 (12 – 1041)
69 (23 – 374)
>12 through 16 years
161 (84 – 359)
69 (26 – 251)
Neuroanesthesia:
DIPRIVAN Injectable Emulsion was studied in patients undergoing craniotomy for supratentorial
tumors in two clinical trials. The mean lesion size (anterior/posterior x lateral) was 31 mm x 32 mm in
one trial and 55 mm x 42 mm in the other trial respectively. Anesthesia was induced with a median
Diprivan dose of 1.4 mg/kg (range: 0.9-6.9 mg/kg) and maintained with a median maintenance
Diprivan dose of 146 µg/kg/min (range: 68-425 µg/kg/min). The median duration of the Diprivan
maintenance infusion was 285 minutes (range: 48-622 minutes).
DIPRIVAN Injectable Emulsion was administered by infusion in a controlled clinical trial to evaluate
its effect on cerebrospinal fluid pressure (CSFP). The mean arterial pressure was maintained relatively
constant over 25 minutes with a change from baseline of -4% ± 17% (mean ± SD). The change in
CSFP was -46% ± 14%. As CSFP is an indirect measure of intracranial pressure (ICP), DIPRIVAN
Injectable Emulsion, when given by infusion or slow bolus in combination with hypocarbia, is capable
of decreasing ICP independent of changes in arterial pressure.
Intensive Care Unit (ICU) Sedation
Adult Patients:
DIPRIVAN Injectable Emulsion was compared to benzodiazepines and opioids in clinical trials
involving ICU patients. Of these, 302 received DIPRIVAN Injectable Emulsion and comprise the
overall safety database for ICU sedation.
Across all clinical studies, the mean infusion maintenance rate for all DIPRIVAN Injectable Emulsion
patients was 27 ± 21 µg/kg/min. The maintenance infusion rates required to maintain adequate
sedation ranged from 2.8 µg/kg/min to 130 µg/kg/min. The infusion rate was lower in patients over 55
years of age (approximately 20 µg/kg/min) compared to patients under 55 years of age (approximately
38 µg/kg/min). Although there are reports of reduced analgesic requirements, most patients received
opioids for analgesia during maintenance of ICU sedation. In these studies, morphine or fentanyl was
used as needed for analgesia. Some patients also received benzodiazepines and/or neuromuscular
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 8
blocking agents. During long-term maintenance of sedation, some ICU patients were awakened once
or twice every 24 hours for assessment of neurologic or respiratory function. (See Table 4.)
In Medical and Postsurgical ICU studies comparing DIPRIVAN Injectable Emulsion to
benzodiazepine infusion or bolus, there were no apparent differences in maintenance of adequate
sedation, mean arterial pressure, or laboratory findings. Like the comparators, DIPRIVAN Injectable
Emulsion reduced blood cortisol during sedation while maintaining responsivity to challenges with
adrenocorticotropic hormone (ACTH). Case reports from the published literature generally reflect
that DIPRIVAN Injectable Emulsion has been used safely in patients with a history of porphyria or
malignant hyperthermia.
In hemodynamically stable head trauma patients ranging in age from 19-43 years, adequate sedation
was maintained with DIPRIVAN Injectable Emulsion or morphine. There were no apparent
differences in adequacy of sedation, intracranial pressure, cerebral perfusion pressure, or neurologic
recovery between the treatment groups. In literature reports of severely head-injured patients in
Neurosurgical ICUs, DIPRIVAN Injectable Emulsion infusion and hyperventilation, both with and
without diuretics, controlled intracranial pressure while maintaining cerebral perfusion pressure. In
some patients, bolus doses resulted in decreased blood pressure and compromised cerebral perfusion
pressure. (See Table 4.)
DIPRIVAN Injectable Emulsion was found to be effective in status epilepticus which was refractory to
the standard anticonvulsant therapies. For these patients, as well as for ARDS/respiratory failure and
tetanus patients, sedation maintenance dosages were generally higher than those for other critically ill
patient populations. (See Table 4.)
Pediatric Patients:
A single, randomized, controlled, clinical trial that evaluated the safety and effectiveness of
DIPRIVAN versus standard sedative agents (SSA) was conducted on 327 pediatric ICU patients.
Patients were randomized to receive either DIPRIVAN 2%, (113 patients), DIPRIVAN 1%, (109
patients), or an SSA (eg, lorazepam, chloral hydrate, fentanyl, ketamine, morphine, or phenobarbital).
DIPRIVAN therapy was initiated at an infusion rate of 5.5 mg/kg/hr and titrated as needed to maintain
sedation at a standardized level. The results of the study showed an increase in the number of deaths in
patients treated with DIPRIVAN as compared to SSAs. Of the 25 patients who died during the trial or
within the 28-day follow-up period: 12 (11% were) in the DIPRIVAN 2% treatment group, 9 (8%
were) in the DIPRIVAN 1% treatment group, and 4% were (4%) in the SSA treatment group. The
differences in mortality rate between the groups were not statistically significant. Review of the deaths
failed to reveal a correlation with underlying disease status or a correlation to the drug or a definitive
pattern to the causes of death.
Information from literature reports of DIPRIVAN Injectable Emulsion used for ICU sedation in over
950 patients and information from the clinical trials are summarized below:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 9
TABLE 4. ADULT ICU SEDATION (DATA FROM CLINICAL TRIALS AND LITERATURE)
Reason for ICU
sedation
Trial
Literatur
Sedation Dose
Sedation Duration
(µg/kg/min)
mg/kg/h
Hours
Post-CABG
X
-
11
(0.1-30)
0.66
(0.006-1.8)
10
(2-14)
X
(5-100)
(0.3-6)
(4-24)
60X
-
20
(6-53)
1.2
(0.4-3.2)
18
(0.3-187)
(6-96)
Post-Surgical
--
142X
(23-82)
(1.4-4.9)
Medical
X
-
41
(9-131)
2.5
(0.5-7.9)
72
(0.4-337)
X
(3.3-62)
(0.2)
(4-96)
Medical
49X
-
41
(9-131)
2.5
(0.5-7.9)
72
(0.4-337)
76X
(3.3-62)
(0.2-3.7)
(4-96)
Special Patients
ARDS/Resp. Failure
-
X
(10-142)
(0.6-8.5)
(1 hr-8 days)
COPD/Asthma
-
X
(17-75)
(1-4.5)
(1-8 days)
Status Epilepticus
-
X
(25-167)
(1.5-10)
(1-21 days)
Tetanus
-
X
(5-100)
(0.3-6)
1-25 days)
CABG (CORONARY ARTERY BYPASS GRAFT)
ARDS (ADULT RESPIRATORY DISTRESS SYNDROME)
Cardiac Anesthesia
DIPRIVAN Injectable Emulsion was evaluated in clinical trials involving patients undergoing
coronary artery bypass graft (CABG).
In post-CABG (coronary artery bypass graft) patients, the maintenance rate of propofol administration
was usually low (median 11 µg/kg/min) due to the intraoperative administration of high opioid doses.
Patients receiving DIPRIVAN Injectable Emulsion required 35% less nitroprusside than midazolam
patients. During initiation of sedation in post-CABG patients, a 15% to 20% decrease in blood
pressure was seen in the first 60 minutes. It was not possible to determine cardiovascular effects in
patients with severely compromised ventricular function. (See Table 4.)
INDICATIONS AND USAGE
DIPRIVAN Injectable Emulsion is an IV sedative-hypnotic agent that can be used as described in the
table below.
Table 3 Indications for DIPRIVAN Injectable Emulsion
Indication
Approved Patient Population
Initiation and maintenance of Monitored Anesthesia
Care (MAC) sedation
Adults only
Combined sedation and regional anesthesia
Adults only (See PRECAUTIONS)
Induction of General Anesthesia
Patients ≥ 3 years of age
Mainenance of General Anesthesia
Patients ≥ 2 months of age
Intensive Care Unit (ICU) sedation of intubated,
mechanically ventilated patients
Adults only
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 10
Safety, effectiveness and dosing guidelines for DIPRIVAN Injectable Emulsion have not been
established for MAC Sedation in the pediatric population; therefore, it is not recommended for this
use. (See PRECAUTIONS, Pediatric Use).
DIPRIVAN Injectable Emulsion is not recommended for induction of anesthesia below the age of 3
years or for maintenance of anesthesia below the age of 2 months because its safety and effectiveness
have not been established in those populations.
In the Intensive Care Unit (ICU), DIPRIVAN Injectable Emulsion can be administered to intubated,
mechanically ventilated adult patients to provide continuous sedation and control of stress responses,
only by persons skilled in the medical management of critically ill patients and trained in
cardiovascular resuscitation and airway management.
DIPRIVAN Injectable Emulsion is not indicated for use in Pediatric ICU sedation since the safety of
this regimen has not been established. (See PRECAUTIONS, Pediatric Use).
DIPRIVAN Injectable Emulsion is not recommended for obstetrics, including Cesarean section
deliveries. DIPRIVAN Injectable Emulsion crosses the placenta, and as with other general anesthetic
agents, the administration of DIPRIVAN Injectable Emulsion may be associated with neonatal
depression. (See PRECAUTIONS.)
DIPRIVAN Injectable Emulsion is not recommended for use in nursing mothers because DIPRIVAN
Injectable Emulsion has been reported to be excreted in human milk, and the effects of oral absorption
of small amounts of propofol are not known. (See PRECAUTIONS.)
CONTRAINDICATIONS
DIPRIVAN Injectable Emulsion is contraindicated in patients with a known hypersensitivity to
DIPRIVAN Injectable Emulsion or any of its components.
DIPRIVAN Injectable Emulsion is contraindicated in patients with allergies to eggs, egg products,
soybeans or soy products.
WARNINGS
Use of DIPRIVAN Injectable Emulsion has been associated with both fatal and life-threatening
anaphylactic and anaphylactoid reactions.
For general anesthesia or monitored anesthesia care (MAC) sedation, DIPRIVAN Injectable Emulsion
should be administered only by persons trained in the administration of general anesthesia and not
involved in the conduct of the surgical/diagnostic procedure. Sedated patients should be continuously
monitored, and facilities for maintenance of a patent airway, providing artificial ventilation,
administering supplemental oxygen, and instituting cardiovascular resuscitation must be immediately
available. Patients should be continuously monitored for early signs of hypotension, apnea, airway
obstruction, and/or oxygen desaturation. These cardiorespiratory effects are more likely to occur
following rapid bolus administration, especially in the elderly, debilitated, or ASA-PS III or IV
patients.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 11
For sedation of intubated, mechanically ventilated patients in the Intensive Care Unit (ICU),
DIPRIVAN Injectable Emulsion should be administered only by persons skilled in the management of
critically ill patients and trained in cardiovascular resuscitation and airway management.
Use of DIPRIVAN Injectable Emulsion infusions for both adult and pediatric ICU sedation has
been associated with a constellation of metabolic derangements and organ system failures,
referred to as Propofol Infusion Syndrome, that have resulted in death. The syndrome is
characterized
by
severe
metabolic
acidosis,
hyperkalemia,
lipemia,
rhabdomyolysis,
hepatomegaly, cardiac and renal failure. The syndrome is most often associated with prolonged,
high-dose infusions (> 5 mg/kg/h for > 48h) but has also been reported following large-dose,
short-term infusions during surgical anesthesia. In the setting of prolonged need for sedation,
increasing propofol dose requirements to maintain a constant level of sedation, or onset of
metabolic acidosis during administration of a propofol infusion, consideration should be given to
using alternative means of sedation.
Abrupt discontinuation of DIPRIVAN Injectable Emulsion prior to weaning or for daily evaluation of
sedation levels should be avoided. This may result in rapid awakening with associated anxiety,
agitation, and resistance to mechanical ventilation. Infusions of DIPRIVAN Injectable Emulsion
should be adjusted to maintain a light level of sedation through the weaning process or evaluation of
sedation level. (See PRECAUTIONS.)
DIPRIVAN Injectable Emulsion should not be coadministered through the same IV catheter with
blood or plasma because compatibility has not been established. In vitro tests have shown that
aggregates of the globular component of the emulsion vehicle have occurred with blood/plasma/serum
from humans and animals. The clinical significance of these findings is not known.
There have been reports in which failure to use aseptic technique when handling Diprivan
Injectable Emulsion was associated with microbial contamination of the product and with fever,
infection, sepsis, other life-threatening illness, and death. Do not use if contamination is
suspected. Discard unused portions as directed within the required time limits (see DOSAGE
AND ADMINISTRATION, HANDLING PROCEDURES)
PRECAUTIONS
General:
Adult and Pediatric Patients: A lower induction dose and a slower maintenance rate of
administration should be used in elderly, debilitated, or ASA-PS III or IV patients (See DOSAGE
AND ADMINISTRATION). Patients should be continuously monitored for early signs of
hypotension and/or bradycardia. Apnea requiring ventilatory support often occurs during induction
and may persist for more than 60 seconds. DIPRIVAN Injectable Emulsion use requires caution when
administered to patients with disorders of lipid metabolism such as primary hyperlipoproteinemia,
diabetic hyperlipemia, and pancreatitis.
Very rarely the use of DIPRIVAN Injectable Emulsion may be associated with the development of a
period of postoperative unconsciousness which may be accompanied by an increase in muscle tone.
This may or may not be preceded by a brief period of wakefulness. Recovery is spontaneous.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 12
When DIPRIVAN Injectable Emulsion is administered to an epileptic patient, there is a risk of seizure
during the recovery phase.
Attention should be paid to minimize pain on administration of DIPRIVAN Injectable Emulsion.
Transient local pain can be minimized if the larger veins of the forearm or antecubital fossa are used.
Pain during intravenous injection may also be reduced by prior injection of IV lidocaine (1 mL of a 1%
solution). Pain on injection occurred frequently in pediatric patients (45%) when a small vein of the
hand was utilized without lidocaine pretreatment. With lidocaine pretreatment or when antecubital
veins were utilized, pain was minimal (incidence less than 10%) and well-tolerated. There have been
reports in the literature indicating that the addition of lidocaine to DIPRIVAN in quantities greater than
20 mg lidocaine/200 mg DIPRIVAN results in instability of the emulsion which is associated with
increases in globule sizes over time and (in rat studies) a reduction in anesthetic potency. Therefore, it
is recommended that lidocaine be administered prior to DIPRIVAN administration or that it be added
to DIPRIVAN immediately before administration and in quantities not exceeding 20mg lidocaine/200
mg DIPRIVAN.
Venous sequelae, i.e., phlebitis or thrombosis, have been reported rarely (<1%). In two clinical studies
using dedicated intravenous catheters, no instances of venous sequelae were observed up to 14 days
following induction.
Intra-arterial injection in animals did not induce local tissue effects. Accidental intra-arterial injection
has been reported in patients, and, other than pain, there were no major sequelae.
Intentional injection into subcutaneous or perivascular tissues of animals caused minimal tissue
reaction. During the post-marketing period, there have been rare reports of local pain, swelling,
blisters, and/or tissue necrosis following accidental extravasation of DIPRIVAN Injectable Emulsion.
Perioperative myoclonia, rarely including convulsions and opisthotonos, has occurred in association
with DIPRIVAN Injectable Emulsion administration.
Clinical features of anaphylaxis, including angioedema, bronchospasm, erythema, and hypotension,
occur rarely following DIPRIVAN Injectable Emulsion administration.
There have been rare reports of pulmonary edema in temporal relationship to the administration of
DIPRIVAN Injectable Emulsion, although a causal relationship is unknown.
Rarely, cases of unexplained postoperative pancreatitis (requiring hospital admission) have been
reported after anesthesia in which DIPRIVAN Injectable Emulsion was one of the induction agents
used. Due to a variety of confounding factors in these cases, including concomitant medications, a
causal relationship to DIPRIVAN Injectable Emulsion is unclear.
DIPRIVAN Injectable Emulsion has no vagolytic activity. Reports of bradycardia, asystole, and
rarely, cardiac arrest have been associated with DIPRIVAN Injectable Emulsion. Pediatric patients are
susceptible to this effect, particularly when fentanyl is given concomitantly. The intravenous
administration of anticholinergic agents (e.g., atropine or glycopyrrolate) should be considered to
modify potential increases in vagal tone due to concomitant agents (e.g., succinylcholine) or surgical
stimuli.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 13
Intensive Care Unit Sedation
Adult Patients: (See WARNINGS and DOSAGE AND ADMINISTRATION, Handling
Procedures.) The administration of DIPRIVAN Injectable Emulsion should be initiated as a
continuous infusion and changes in the rate of administration made slowly (>5 min) in order to
minimize hypotension and avoid acute overdosage. (See DOSAGE AND ADMINISTRATION.)
Patients should be monitored for early signs of significant hypotension and/or cardiovascular
depression, which may be profound. These effects are responsive to discontinuation of DIPRIVAN
Injectable Emulsion, IV fluid administration, and/or vasopressor therapy. In the elderly, debilitated, or
ASA-PS III or IV patients, rapid (single or repeated) bolus administration should not be used during
sedation in order to minimize undesirable cardiorespiratory depression, including hypotension, apnea,
airway obstruction, and oxygen desaturation.
As with other sedative medications, there is wide interpatient variability in DIPRIVAN Injectable
Emulsion dosage requirements, and these requirements may change with time.
Failure to reduce the infusion rate in patients receiving DIPRIVAN Injectable Emulsion for extended
periods may result in excessively high blood concentrations of the drug. Thus, titration to clinical
response and daily evaluation of sedation levels are important during use of DIPRIVAN Injectable
Emulsion infusion for ICU sedation, especially when it is used for long durations.
Opioids and paralytic agents should be discontinued and respiratory function optimized prior to
weaning patients from mechanical ventilation. Infusions of DIPRIVAN Injectable Emulsion should be
adjusted to maintain a light level of sedation prior to weaning patients from mechanical ventilatory
support. Throughout the weaning process, this level of sedation may be maintained in the absence of
respiratory depression. Because of the rapid clearance of DIPRIVAN Injectable Emulsion, abrupt
discontinuation of a patient's infusion may result in rapid awakening with associated anxiety, agitation,
and resistance to mechanical ventilation, making weaning from mechanical ventilation difficult. It is
therefore recommended that administration of DIPRIVAN Injectable Emulsion be continued in order
to maintain a light level of sedation throughout the weaning process until 10-15 minutes prior to
extubation, at which time the infusion can be discontinued.
Since DIPRIVAN Injectable Emulsion is formulated in an oil-in-water emulsion, elevations in serum
triglycerides may occur when DIPRIVAN Injectable Emulsion is administered for extended periods of
time. Patients at risk of hyperlipidemia should be monitored for increases in serum triglycerides or
serum turbidity. Administration of DIPRIVAN Injectable Emulsion should be adjusted if fat is being
inadequately cleared from the body. A reduction in the quantity of concurrently administered lipids is
indicated to compensate for the amount of lipid infused as part of the DIPRIVAN Injectable Emulsion
formulation; 1 mL of DIPRIVAN Injectable Emulsion contains approximately 0.1 g of fat (1.1 kcal).
EDTA is a strong chelator of trace metals -- including zinc. Although with DIPRIVAN Injectable
Emulsion there are no reports of decreased zinc levels or zinc deficiency-related adverse events,
DIPRIVAN Injectable Emulsion should not be infused for longer than 5 days without providing a drug
holiday to safely replace estimated or measured urine zinc losses.
In clinical trials mean urinary zinc loss was approximately 2.5 to 3.0 mg/day in adult patients and 1.5
to 2.0 mg/day in pediatric patients.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 14
In patients who are predisposed to zinc deficiency, such as those with burns, diarrhea, and/or major
sepsis, the need for supplemental zinc should be considered during prolonged therapy with DIPRIVAN
Injectable Emulsion.
At high doses (2-3 grams per day), EDTA has been reported, on rare occasions, to be toxic to the renal
tubules. Studies to date in patients with normal or impaired renal function have not shown any
alteration in renal function with DIPRIVAN Injectable Emulsion containing 0.005% disodium edetate.
In patients at risk for renal impairment, urinalysis and urine sediment should be checked before
initiation of sedation and then be monitored on alternate days during sedation.
The long-term administration of DIPRIVAN Injectable Emulsion to patients with renal failure and/or
hepatic insufficiency has not been evaluated.
Neurosurgical Anesthesia: When DIPRIVAN Injectable Emulsion is used in patients with increased
intracranial pressure or impaired cerebral circulation, significant decreases in mean arterial pressure
should be avoided because of the resultant decreases in cerebral perfusion pressure. To avoid
significant hypotension and decreases in cerebral perfusion pressure, an infusion or slow bolus of
approximately 20 mg every 10 seconds should be utilized instead of rapid, more frequent, and/or larger
boluses of DIPRIVAN Injectable Emulsion. Slower induction, titrated to clinical responses, will
generally result in reduced induction dosage requirements (1 to 2 mg/kg). When increased ICP is
suspected, hyperventilation and hypocarbia should accompany the administration of DIPRIVAN
Injectable Emulsion. (See DOSAGE AND ADMINISTRATION.)
Cardiac Anesthesia: Slower rates of administration should be utilized in premedicated patients,
geriatric patients, patients with recent fluid shifts, and patients who are hemodynamically unstable.
Fluid deficits should be corrected prior to administration of DIPRIVAN Injectable Emulsion. In those
patients where additional fluid therapy may be contraindicated, other measures, e.g., elevation of lower
extremities, or use of pressor agents, may be useful to offset the hypotension which is associated with
the induction of anesthesia with DIPRIVAN Injectable Emulsion.
Information for Patients:
Patients should be advised that performance of activities requiring mental alertness, such as operating a
motor vehicle, or hazardous machinery or signing legal documents may be impaired for some time
after general anesthesia or sedation.
Drug Interactions:
The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with
intramuscular or intravenous premedication, particularly with narcotics (e.g., morphine, meperidine,
and fentanyl, etc.) and combinations of opioids and sedatives (e.g., benzodiazepines, barbiturates,
chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of
DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic,
diastolic, and mean arterial pressures and cardiac output.
During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion
administration should be adjusted according to the desired level of anesthesia or sedation and may be
reduced in the presence of supplemental analgesic agents (e.g., nitrous oxide or opioids). The
concurrent administration of potent inhalational agents (e.g., isoflurane, enflurane, and halothane)
during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 15
inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory
effects of DIPRIVAN Injectable Emulsion.
DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity or
duration of action of the commonly used neuromuscular blocking agents (e.g., succinylcholine and
nondepolarizing muscle relaxants).
No significant adverse interactions with commonly used premedications or drugs used during
anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and
local anesthetic agents) have been observed in adults. In pediatric patients, administration of fentanyl
concomitantly with DIPRIVAN Injectable Emulsion may result in serious bradycardia.
Carcinogenesis, mutagenesis, impairment of fertility.
Carcinogenesis: Long-term studies in animals have not been performed to evaluate the carcinogenic
potential of propofol.
Mutagenesis: Propofol was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test)
using Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538. Propofol was
not mutagenic in either the gene mutation/gene conversion test using Saccharomyces cerevisiae, or in
vitro cytogenetic studies in Chinese hamsters. In the in vivo mouse micronucleus assay with Chinese
Hamsters propofol administration did not produce chromosome aberrations.
Impairment of fertility: Female Wistar rats were administered either 0, 10, or 15 mg/kg/day propofol
intravenously from 2 weeks before pregnancy to day 7 of gestation did not show impaired fertility.
Male fertility in rats was not affected in a dominant lethal study at intravenous doses up to 15
mg/kg/day for 5 days.
Pregnancy
Teratogenic effects
Pregnancy Category B:
Reproduction studies have been performed in rats and rabbits at intravenous doses of 15 mg/kg/day
(approximately equivalent to the recommended human induction dose on a mg/m2 basis) and have
revealed no evidence of impaired fertility or harm to the fetus due to propofol. Propofol, however, has
been shown to cause maternal deaths in rats and rabbits and decreased pup survival during the lactating
period in dams treated with 15 mg/kg/day (approximately equivalent to the recommended human
induction dose on a mg/m2 basis). The pharmacological activity (anesthesia) of the drug on the mother
is probably responsible for the adverse effects seen in the offspring. There are, however, no adequate
and well-controlled studies in pregnant women. Because animal reproduction studies are not always
predictive of human responses, this drug should be used during pregnancy only if clearly needed.
Labor and Delivery:
DIPRIVAN Injectable Emulsion is not recommended for obstetrics, including cesarean section
deliveries. DIPRIVAN Injectable Emulsion crosses the placenta, and as with other general anesthetic
agents, the administration of DIPRIVAN Injectable Emulsion may be associated with neonatal
depression.
Nursing Mothers:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 16
DIPRIVAN Injectable Emulsion is not recommended for use in nursing mothers because DIPRIVAN
Injectable Emulsion has been reported to be excreted in human milk and the effects of oral absorption
of small amounts of propofol are not known.
Pediatric Use:
The safety and effectiveness of DIPRIVAN Injectable Emulsion have been established for induction of
anesthesia in pediatric patients aged 3 years and older and for the maintenance of anesthesia aged 2
months and older.
DIPRIVAN Injectable Emulsion is not recommended for the induction of anesthesia in patients
younger than 3 years of age and for the maintenance of anesthesia in patients younger than 2 months of
age as safety and effectiveness have not been established.
In pediatric patients, administration of fentanyl concomitantly with DIPRIVAN Injectable Emulsion
may result in serious bradycardia (see PRECAUTIONS – General).
DIPRIVAN Injectable Emulsion is not indicated for use in pediatric patients for ICU sedation or for
MAC sedation for surgical, nonsurgical or diagnostic procedures as safety and effectiveness have not
been established.
There have been anecdotal reports of serious adverse events and death in pediatric patients with upper
respiratory tract infections receiving DIPRIVAN Injectable Emulsion for ICU sedation.
In one multicenter clinical trial of ICU sedation in critically ill pediatric patients that excluded patients
with upper respiratory tract infections, the incidence of mortality observed in patients who received
DIPRIVAN Injectable Emulsion (n=222) was 9%, while that for patients who received standard
sedative agents (n=105) was 4%. While causality has not been established, DIPRIVAN Injectable
Emulsion is not indicated for sedation in pediatric patients until further studies have been performed to
document its safety in that population. (See CLINICAL PHARMACOLOGY – Pediatric Patients: and
Dosage and Administration).
In pediatric patients, abrupt discontinuation following prolonged infusion may result in flushing of the
hands and feet, agitation, tremulousness and hyperirritability. Increased incidences of bradycardia
(5%), agitation (4%), and jitteriness (9%) have also been observed.
Geriatric Use:
The effect of age on induction dose requirements for propofol was assessed in an open-label study
involving 211 unpremedicated patients with approximately 30 patients in each decade between the
ages of 16 and 80. The average dose to induce anesthesia was calculated for patients up to 54 years of
age and for patients 55 years of age or older. The average dose to induce anesthesia in patients up to
54 years of age was 1.99 mg/kg and in patients above 54 it was 1.66 mg/kg. Subsequent clinical
studies have demonstrated lower dosing requirements for subjects greater than 60 years of age.
A lower induction dose and a slower maintenance rate of administration of DIPRIVAN Injectable
Emulsion should be used in elderly patients. In this group of patients, rapid (single or repeated) bolus
administration should not be used in order to minimize undesirable cardiorespiratory depression
including hypotension, apnea, airway obstruction, and/or oxygen desaturation. All dosing should be
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 17
titrated according to patient condition and response. (See DOSAGE AND ADMINISTRATION –
Elderly, debilitated or ASA-PS III or IV patients and CLINICAL PHARMACOLOGY – Geriatrics.)
ADVERSE REACTIONS
General
Adverse event information is derived from controlled clinical trials and worldwide marketing
experience. In the description below, rates of the more common events represent US/Canadian clinical
study results. Less frequent events are also derived from publications and marketing experience in
over 8 million patients; there are insufficient data to support an accurate estimate of their incidence
rates. These studies were conducted using a variety of premedicants, varying lengths of
surgical/diagnostic procedures, and various other anesthetic/sedative agents. Most adverse events were
mild and transient.
Anesthesia and MAC Sedation in Adults
The following estimates of adverse events for DIPRIVAN Injectable Emulsion include data from
clinical trials in general anesthesia/MAC sedation (N=2889 adult patients). The adverse events listed
below as probably causally related are those events in which the actual incidence rate in patients
treated with DIPRIVAN Injectable Emulsion was greater than the comparator incidence rate in these
trials. Therefore, incidence rates for anesthesia and MAC sedation in adults generally represent
estimates of the percentage of clinical trial patients which appeared to have probable causal
relationship.
The adverse experience profile from reports of 150 patients in the MAC sedation clinical trials is
similar to the profile established with DIPRIVAN Injectable Emulsion during anesthesia (see below).
During MAC sedation clinical trials, significant respiratory events included cough, upper airway
obstruction, apnea, hypoventilation, and dyspnea.
Anesthesia in Pediatric Patients
Generally the adverse experience profile from reports of 506 DIPRIVAN Injectable Emulsion pediatric
patients from 6 days through 16 years of age in the US/Canadian anesthesia clinical trials is similar to
the profile established with DIPRIVAN Injectable Emulsion during anesthesia in adults (see Pediatric
percentages [Peds %] below). Although not reported as an adverse event in clinical trials, apnea is
frequently observed in pediatric patients.
ICU Sedation in Adults
The following estimates of adverse events include data from clinical trials in ICU sedation
(N=159 adult patients). Probably related incidence rates for ICU sedation were determined by
individual case report form review. Probable causality was based upon an apparent dose response
relationship and/or positive responses to rechallenge. In many instances the presence of concomitant
disease and concomitant therapy made the causal relationship unknown. Therefore, incidence rates for
ICU sedation generally represent estimates of the percentage of clinical trial patients which appeared to
have a probable causal relationship.
Incidence greater than 1% - Probably Causally Related
Anesthesia/MAC Sedation
ICU Sedation
Cardiovascular:
Bradycardia
Bradycardia
Arrhythmia [Peds: 1.2%]
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 18
Tachycardia Nodal [Peds. 1.6%]
Hypotension* [Peds 17%]
(see also CLINICAL PHARMACOLOGY
Decreased Cardiac Output
[Hypertension Peds:8%]
Hypotension 26%
Central Nervous System:
Movement* [Peds: 17%]
Injection Site:
Burning/Stinging or Pain, 17.6% [Peds: 10%]
Metabolic/Nutritional:
Hyperlipemia*
Respiratory
Apnea (see also CLINICAL PHARMACOLOGY)
Respiratory Acidosis During Weaning*
Skin and Appendages:
Rash [Peds: 5%]
Pruritus [Peds:2%]
Events without an * or % had an incidence of 1%-3%
*Incidence of events 3% to 10%
Incidence less than 1% - Probably Causally Related
Anesthesia/MAC Sedation
ICU Sedation
Body as a Whole:
Anaphylaxis/Anaphylactoid Reaction
Perinatal Disorder
[Tachycardia]
[Bigeminy]
[Bradycardia]
[Premature Ventricular Contractions]
[Hemorrhage]
[ECG Abnormal]
[Arrhythmia Atrial]
[Fever]
[Extremities Pain]
[Anticholinergic Syndrome]
Cardiovascular:
Premature Atrial Contractions
Syncope
Central Nervous System:
Hypertonia/Dystonia, Paresthesia
Agitation
Digestive:
[Hypersalivation]
[Nausea]
Hemic/Lymphatic:
[Leukocytosis]
Injection Site:
[Phlebitis]
[Pruritus]
Metabolic:
[Hypomagnesemia]
Musculoskeletal:
Myalgia
Nervous:
[Dizziness]
[Agitation]
[Chills]
[Somnolence]
[Delirium]
Respiratory:
Wheezing
[Cough]
Decreased Lung Function
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 19
[Laryngospasm]
[Hypoxia]
Skin and Appendages:
Flushing, Pruritus
Special Senses:
Amblyopia
[Vision Abnormal]
Urogenital:
Cloudy Urine
Green Urine
Incidence less than 1% - Causal Relationship Unknown
Anesthesia/MAC Sedation
ICU Sedation
Body as a Whole:
Asthenia, Awareness, Chest Pain,
Extremities Pain, Fever, Increased
Drug Effect, neck Rigidity/Stiffness,
Trunk pain
Fever, Sepsis, Trunk Pain, Whole Body Weakness
Cardiovascular:
Arrhythmia, Atrial Fibrillation,
Atrioventricular Heart Block,
Bigeminy, Bleeding, Bundle Branch
Block, Cardiac Arrest, ECG Abnormal,
Block, Hypertension, Myocardial
Infarction, Myocardial Ischemia,
Premature Ventricular Contractions,
ST Segment Depression,
Supraventricular Tachycardia,
Tachycardia, Ventricular Fibrillation
Arrhythmia, Atrial Fibrillation, Bigeminy, Cardiac
Arrest, Extrasystole, Right Heart Failure, ventricular
Tachycardia
Central Nervous System:
Abnormal Dreams, Agitation,
Amorous Behavior, Anxiety,
Bucking/Jerking/Thrashing,
Chills/Shivering/Clonic/Myoclonic
Movement, Combativeness,
Confusion, Delirium, Depression,
Dizziness, Emotional Lability,
Euphoria, Fatigue, Hallucinations,
Headache, Hypotonia, Hysteria,
Insomnia, Moaning, Neuropathy,
Opisthotonos, Rigidity, Seizures,
Somnolence, Tremor, Twitching
Chills/Shivering, Intracranial Hypertension,
Seizures, Somnolence, Thinking Abnormal
Digestive:
Cramping, Diarrhea, Dry Mouth,
Enlarged Parotid, Nausea, Swallowing,
Vomiting
Ileus, Liver Function Abnormal
Hematologic/Lymphatic:
Coagulation Disorder, Leukocytosis
Injection Site:
Hives/Itching, Phlebitis,
Redness/Discoloration
Metabolic/Nutritional:
Hyperkalemia, Hyperlipemia
BUN Increased, Creatinine Increased, Dehydration,
Hyperglycemia, Metabolic Acidosis, Osmolality
Increased
Respiratory:
Bronchospasm, Burning in Throat,
Cough, Dyspnea, Hiccough,
Hyperventilation, Hypoventilation,
Hypoxia
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 20
Hypoxia, Laryngospasm, Pharyngitis,
Sneezing, Tachypnea, Upper Airway
Obstruction
Skin and Appendages:
Conjunctival Hyperemia, Diaphoresis,
Urticaria
Rash
Special Senses:
Diplopia, Ear Pain, Eye Pain,
Nystagmus, Taste Perversion,
Tinnitus
Urogenital:
Oliguria, Urine Retention
Kidney Failure
DRUG ABUSE AND DEPENDENCE
Rare cases of self-administration of DIPRIVAN Injectable Emulsion by health care professionals have
been reported, including some fatalities. DIPRIVAN Injectable Emulsion should be managed to
prevent the risk of diversion, including restriction of access and accounting procedures as appropriate
to the clinical setting.
OVERDOSAGE
If overdosage occurs, DIPRIVAN Injectable Emulsion administration should be discontinued
immediately. Overdosage is likely to cause cardiorespiratory depression. Respiratory depression
should be treated by artificial ventilation with oxygen. Cardiovascular depression may require
repositioning of the patient by raising the patient's legs, increasing the flow rate of intravenous fluids,
and administering pressor agents and/or anticholinergic agents.
DOSAGE AND ADMINISTRATION
Propofol blood concentrations at steady state are generally proportional to infusion rates, especially in
individual patients. Undesirable effects such as cardiorespiratory depression are likely to occur at
higher blood concentrations which result from bolus dosing or rapid increases in the infusion rate. An
adequate interval (3 to 5 minutes) must be allowed between dose adjustments to allow for and assess
the clinical effects.
When administering DIPRIVAN Injectable Emulsion by infusion, syringe or volumetric pumps are
recommended to provide controlled infusion rates. When infusing DIPRIVAN Injectable Emulsion to
patients undergoing magnetic resonance imaging, metered control devices may be utilized if
mechanical pumps are impractical.
Changes in vital signs indicating a stress response to surgical stimulation or the emergence from
anesthesia may be controlled by the administration 25 mg (2.5 mL) to 50 mg (5 mL) incremental
boluses and/or by increasing the infusion rate of DIPRIVAN Injectable Emulsion.
For minor surgical procedures (e.g., body surface) nitrous oxide (60%-70%) can be combined with a
variable rate DIPRIVAN Injectable Emulsion infusion to provide satisfactory anesthesia. With more
stimulating surgical procedures (e.g., intra-abdominal), or if supplementation with nitrous oxide is not
provided, administration rate(s) of DIPRIVAN Injectable Emulsion and/or opioids should be increased
in order to provide adequate anesthesia.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 21
Infusion rates should always be titrated downward in the absence of clinical signs of light anesthesia
until a mild response to surgical stimulation is obtained in order to avoid administration of DIPRIVAN
Injectable Emulsion at rates higher than are clinically necessary. Generally, rates of 50 to 100
µg/kg/min in adults should be achieved during maintenance in order to optimize recovery times.
Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can
increase CNS depression induced by propofol. Morphine premedication (0.15 mg/kg) with nitrous
oxide 67% in oxygen has been shown to decrease the necessary propofol injection maintenance
infusion rate and therapeutic blood concentrations when compared to non-narcotic (lorazepam)
premedication.
Induction of General Anesthesia
Adult Patients: Most adult patients under 55 years of age and classified as ASA-PS I or II require 2
to 2.5 mg/kg of DIPRIVAN Injectable Emulsion for induction when unpremedicated or when
premedicated with oral benzodiazepines or intramuscular opioids. For induction, DIPRIVAN
Injectable Emulsion should be titrated (approximately 40 mg every 10 seconds) against the response of
the patient until the clinical signs show the onset of anesthesia. As with other sedative-hypnotic
agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the
response of the patient to an induction dose of DIPRIVAN Injectable Emulsion.
Elderly, Debilitated, or ASA-PS III or IV Patients: It is important to be familiar and experienced
with the intravenous use of DIPRIVAN Injectable Emulsion before treating elderly, debilitated, or
ASA-PS III or IV patients. Due to the reduced clearance and higher blood concentrations, most of
these patients require approximately 1 to 1.5 mg/kg (approximately 20 mg every 10 seconds) of
DIPRIVAN Injectable Emulsion for induction of anesthesia according to their condition and responses.
A rapid bolus should not be used, as this will increase the likelihood of undesirable cardiorespiratory
depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation (See
DOSAGE AND ADMINISTRATION).
Pediatric Patients: Most patients aged 3 years through 16 years and classified ASA-PS I or II require
2.5 to 3.5 mg/kg of DIPRIVAN Injectable Emulsion for induction when unpremedicated or when
lightly premedicated with oral benzodiazepines or intramuscular opioids. Within this dosage range,
younger pediatric patients may require higher induction doses than older pediatric patients. As with
other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication
will influence the response of the patient to an induction dose of DIPRIVAN Injectable Emulsion. A
lower dosage is recommended for pediatric patients classified as ASA-PS III or IV. Attention should
be paid to minimize pain on injection when administering DIPRIVAN Injectable Emulsion to pediatric
patients. Boluses of DIPRIVAN Injectable Emulsion may be administered via small veins if pretreated
with lidocaine or via antecubital or larger veins (See PRECAUTIONS - General).
Neurosurgical Patients: Slower induction is recommended using boluses of 20 mg every 10 seconds.
Slower boluses or infusions of DIPRIVAN Injectable Emulsion for induction of anesthesia, titrated to
clinical responses, will generally result in reduced induction dosage requirements (1 to 2 mg/kg). (See
PRECAUTIONS and DOSAGE AND ADMINISTRATION.)
Cardiac Anesthesia: DIPRIVAN Injectable Emulsion has been well-studied in patients with coronary
artery disease, but experience in patients with hemodynamically significant valvular or congenital
heart disease is limited. As with other anesthetic and sedative-hypnotic agents, DIPRIVAN Injectable
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 22
Emulsion in healthy patients causes a decrease in blood pressure that is secondary to decreases in
preload (ventricular filling volume at the end of the diastole) and afterload (arterial resistance at the
beginning of the systole). The magnitude of these changes is proportional to the blood and effect site
concentrations achieved. These concentrations depend upon the dose and speed of the induction and
maintenance infusion rates.
In addition, lower heart rates are observed during maintenance with DIPRIVAN Injectable Emulsion,
possibly due to reduction of the sympathetic activity and/or resetting of the baroreceptor reflexes.
Therefore, anticholinergic agents should be administered when increases in vagal tone are anticipated.
As with other anesthetic agents, DIPRIVAN Injectable Emulsion reduces myocardial oxygen
consumption. Further studies are needed to confirm and delineate the extent of these effects on the
myocardium and the coronary vascular system.
Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease
the necessary DIPRIVAN Injectable Emulsion maintenance infusion rates and therapeutic blood
concentrations when compared to non-narcotic (lorazepam) premedication. The rate of DIPRIVAN
Injectable Emulsion administration should be determined based on the patient's premedication and
adjusted according to clinical responses.
A rapid bolus induction should be avoided. A slow rate of approximately 20 mg every 10 seconds
until induction onset (0.5 to 1.5 mg/kg) should be used. In order to assure adequate anesthesia, when
DIPRIVAN Injectable Emulsion is used as the primary agent, maintenance infusion rates should not be
less than 100 µg/kg/min and should be supplemented with analgesic levels of continuous opioid
administration. When an opioid is used as the primary agent, DIPRIVAN Injectable Emulsion
maintenance rates should not be less than 50 µg/kg/min, and care should be taken to ensure amnesia.
Higher doses of DIPRIVAN Injectable Emulsion will reduce the opioid requirements (see Table 5).
When DIPRIVAN Injectable Emulsion is used as the primary anesthetic, it should not be administered
with the high-dose opioid technique as this may increase the likelihood of hypotension (see
PRECAUTIONS - Cardiac Anesthesia).
Table 5. Cardiac Anesthesia Techniques
Primary Agent
Rate
Secondary Agent/Rate
(Following Induction with Primary Agent)
DIPRIVAN Injectable Emulsion
OPIOIDa/0.05-0.075 µg/kg/min (no bolus)
Preinduction
Anxiolysis
25 µg/kg/min
Induction
0.5-1.5 mg/kg
over 60 sec
Maintenance
(Titrated to Clinical
Response)
100-150 µg/kg/min
OPIOIDb
DIPRIVAN Injectable Emulsion/50-100 µg/kg/min (no bolus)
Induction
25-50 µg/kg
Maintenance
0.2-0.3 µg/kg/min
AOPIOID IS DEFINED IN TERMS OF FENTANYL EQUIVALENTS, I.E.,
1 µG OF FENTANYL
= 5 µG OF ALFENTANIL (FOR BOLUS)
= 10 µG OF ALFENTANIL (FOR MAINTENANCE)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 23
OR
= 0.1 µG OF SUFENTANIL
BCARE SHOULD BE TAKEN TO ENSURE AMNESIA .
Maintenance of General Anesthesia
Adult Patients: In adults, anesthesia can be maintained by administering DIPRIVAN Injectable
Emulsion by infusion or intermittent IV bolus injection. The patient's clinical response will determine
the infusion rate or the amount and frequency of incremental injections.
Continuous Infusion: DIPRIVAN Injectable Emulsion 100 to 200 µg/kg/min administered in a
variable rate infusion with 60%-70% nitrous oxide and oxygen provides anesthesia for patients
undergoing general surgery. Maintenance by infusion of DIPRIVAN Injectable Emulsion should
immediately follow the induction dose in order to provide satisfactory or continuous anesthesia during
the induction phase. During this initial period following the induction dose, higher rates of infusion
are generally required (150 to 200 µg/kg/min) for the first 10 to 15 minutes. Infusion rates should
subsequently be decreased 30%-50% during the first half-hour of maintenance. Generally, rates of 50 -
100 µg/kg/min in adults should be achieved during maintenance in order to optimize recovery times.
Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can
increase the CNS depression induced by propofol.
Intermittent Bolus: Increments of DIPRIVAN Injectable Emulsion 25 mg (2.5 mL) to 50 mg (5 mL)
may be administered with nitrous oxide in adult patients undergoing general surgery. The incremental
boluses should be administered when changes in vital signs indicate a response to surgical stimulation
or light anesthesia.
Pediatric Patients: DIPRIVAN Injectable Emulsion administered as a variable rate infusion
supplemented with nitrous oxide 60% - 70% provides satisfactory anesthesia for most children 2
months of age or older, ASA-PS I or II, undergoing general anesthesia.
In general, for the pediatric population, maintenance by infusion of DIPRIVAN Injectable Emulsion at
a rate of 200 – 300 µg/kg/min should immediately follow the induction dose. Following the first half-
hour of maintenance, infusion rates of 125-150 µg/kg/min are typically needed. DIPRIVAN Injectable
Emulsion should be titrated to achieve the desired clinical effect. Younger pediatric patients may
require higher maintenance infusion rates than older pediatric patients. (See Table 2 Clinical Trials.)
DIPRIVAN Injectable Emulsion has been used with a variety of agents commonly used in anesthesia
such as atropine, scopolamine, glycopyrrolate, diazepam, depolarizing and nondepolarizing muscle
relaxants, and opioid analgesics, as well as with inhalational and regional anesthetic agents.
In the elderly, debilitated, or ASA-PS III or IV patients, rapid bolus doses should not be used, as this
will increase cardiorespiratory effects including hypotension, apnea, airway obstruction, and oxygen
desaturation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 24
Monitored Anesthesia Care (MAC) Sedation
Adult Patients: When DIPRIVAN Injectable Emulsion is administered for MAC sedation, rates of
administration should be individualized and titrated to clinical response. In most patients, the rates of
DIPRIVAN Injectable Emulsion administration will be in the range of 25-75 µg/kg/min.
During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over
rapid bolus administration. During maintenance of MAC sedation, a variable rate infusion is
preferable over intermittent bolus dose administration. In the elderly, debilitated, or ASA-PS III or IV
patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation.
(See WARNINGS.) A rapid bolus injection can result in undesirable cardiorespiratory depression
including hypotension, apnea, airway obstruction, and oxygen desaturation.
Initiation of MAC Sedation: For initiation of MAC sedation, either an infusion or a slow injection
method may be utilized while closely monitoring cardiorespiratory function. With the infusion
method, sedation may be initiated by infusing DIPRIVAN Injectable Emulsion at 100 to
150 µg/kg/min (6 to 9 mg/kg/h) for a period of 3 to 5 minutes and titrating to the desired clinical effect
while closely monitoring respiratory function. With the slow injection method for initiation, patients
will require approximately 0.5 mg/kg administered over 3 to 5 minutes and titrated to clinical
responses. When DIPRIVAN Injectable Emulsion is administered slowly over 3 to 5 minutes, most
patients will be adequately sedated, and the peak drug effect can be achieved while minimizing
undesirable cardiorespiratory effects occurring at high plasma levels.
In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose
administration should not be used for MAC sedation. (See WARNINGS.) The rate of administration
should be over 3-5 minutes and the dosage of DIPRIVAN Injectable Emulsion should be reduced to
approximately 80% of the usual adult dosage in these patients according to their condition, responses,
and changes in vital signs. (See DOSAGE AND ADMINISTRATION.)
Maintenance of MAC Sedation: For maintenance of sedation, a variable rate infusion method is
preferable over an intermittent bolus dose method. With the variable rate infusion method, patients
will generally require maintenance rates of 25 to 75 µg/kg/min (1.5 to 4.5 mg/kg/h) during the first 10
to 15 minutes of sedation maintenance. Infusion rates should subsequently be decreased over time to
25 to 50 µg/kg/min and adjusted to clinical responses. In titrating to clinical effect, allow
approximately 2 minutes for onset of peak drug effect.
Infusion rates should always be titrated downward in the absence of clinical signs of light sedation
until mild responses to stimulation are obtained in order to avoid sedative administration of
DIPRIVAN Injectable Emulsion at rates higher than are clinically necessary.
If the intermittent bolus dose method is used, increments of DIPRIVAN Injectable Emulsion 10 mg (1
mL) or 20 mg (2 mL) can be administered and titrated to desired clinical effect. With the intermittent
bolus method of sedation maintenance, there is increased potential for respiratory depression, transient
increases in sedation depth, and prolongation of recovery.
In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose
administration should not be used for MAC sedation. (See WARNINGS.) The rate of administration
and the dosage of DIPRIVAN Injectable Emulsion should be reduced to approximately 80% of the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 25
usual adult dosage in these patients according to their condition, responses, and changes in vital signs.
(See DOSAGE AND ADMINISTRATION.)
DIPRIVAN Injectable Emulsion can be administered as the sole agent for maintenance of MAC
sedation during surgical/diagnostic procedures. When DIPRIVAN Injectable Emulsion sedation is
supplemented with opioid and/or benzodiazepine medications, these agents increase the sedative and
respiratory effects of DIPRIVAN Injectable Emulsion and may also result in a slower recovery profile.
(See PRECAUTIONS, Drug Interactions.)
ICU Sedation: (See WARNINGS and DOSAGE AND ADMINISTRATION, Handling
Procedures.)
Abrupt discontinuation of DIPRIVAN Injectable Emulsion prior to weaning or for daily evaluation of
sedation levels should be avoided. This may result in rapid awakening with associated anxiety,
agitation, and resistance to mechanical ventilation. Infusions of DIPRIVAN Injectable Emulsion
should be adjusted to assure a minimal level of sedation is maintained throughout the weaning process
and when assessing the level of sedation. (See PRECAUTIONS.)
Adult Patients: For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU)
sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical
effect and minimize hypotension. (See DOSAGE AND ADMINISTRATION.)
Most adult ICU patients recovering from the effects of general anesthesia or deep sedation will require
maintenance rates of 5 to 50 µg/kg/min (0.3 to 3 mg/kg/h) individualized and titrated to clinical
response. (See DOSAGE AND ADMINISTRATION.) With medical ICU patients or patients who
have recovered from the effects of general anesthesia or deep sedation, the rate of administration of 50
µg/kg/min or higher may be required to achieve adequate sedation. These higher rates of
administration may increase the likelihood of patients developing hypotension.
Dosage and rate of administration should be individualized and titrated to the desired effect, according
to clinically relevant factors including the patient’s underlying medical problems, preinduction and
concomitant medications, age, ASA-PS classification, and level of debilitation of the patient. The
elderly, debilitated, and ASA-PS III or IV patients may have exaggerated hemodynamic and
respiratory responses to rapid bolus doses. (See WARNINGS.)
DIPRIVAN Injectable Emulsion should be individualized according to the patient's condition and
response, blood lipid profile, and vital signs. (See PRECAUTIONS - ICU Sedation.) For intubated,
mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly
with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension. When
indicated, initiation of sedation should begin at 5 µg/kg/min (0.3 mg/kg/h). The infusion rate should
be increased by increments of 5 to 10 µg/kg/min (0.3 to 0.6 mg/kg/h) until the desired level of sedation
is achieved. A minimum period of 5 minutes between adjustments should be allowed for onset of peak
drug effect. Most adult patients require maintenance rates of 5 to 50 µg/kg/min (0.3 to 3 mg/kg/h) or
higher. Dosages of DIPRIVAN Injectable Emulsion should be reduced in patients who have received
large dosages of narcotics. Conversely, the DIPRIVAN Injectable Emulsion dosage requirement may
be reduced by adequate management of pain with analgesic agents. As with other sedative
medications, there is interpatient variability in dosage requirements, and these requirements may
change with time. (See dosage guide.) Evaluation of level of sedation and assessment of cns function
should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 26
required for sedation (see CLINICAL TRIALS, ICU SEDATION). Bolus administration of 10 or 20
mg should only be used to rapidly increase depth of sedation in patients where hypotension is not
likely to occur. Patients with compromised myocardial function, intravascular volume depletion, or
abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension. (See
PRECAUTIONS.).
SUMMARY OF DOSAGE GUIDELINES
Dosages and rates of administration in the following table should be individualized and titrated to
clinical response. Safety and dosing requirements for induction of anesthesia in pediatric patients have
only been established for children 3 years of age or older. Safety and dosing requirements for the
maintenance of anesthesia have only been established for children 2 months of age and older.
For complete dosage information, see DOSAGE AND ADMINISTRATION.
INDICATION
DOSAGE AND ADMINISTRATION
Induction of General Anesthesia
Healthy Adults Less Than 55 Years OF Age: 40 mg every 10 seconds until
induction onset (2 to 2.5 mg/kg).
Elderly, Debilitated, or ASA-PS III or IV Patients: 20 mg every 10 seconds
induction onset (1 to 1.5 mg/kg).
Cardiac Anesthesia: 20 mg every 10 seconds until induction onset (0.5 to
1.5 mg/kg).
Neurosurgical Patients: 20 mg every 10 seconds until induction onset (1 to
2 mg/kg)
Pediatric Patients - healthy, from 3 years to 16 years of age: 2.5 to 3.5
mg/kg administered over 20-30 seconds.
See PRECAUTIONS – Pediatric Use: and CLINICAL PHARMACOLOGY
– Pediatrics )
Maintenance of General Anesthesia:
Infusion
Healthy Adults Less Than 55 Years of Age: 100 to 200 µg/kg/min
(6 to 12 mg/kg/h).
Elderly, Debilitated, ASA-PS III or IV Patients: 50 to 100 µg/kg/min
(3 to 6 mg/kg/h).
Cardiac Anesthesia: Most patients require:
Primary DIPRIVAN Injectable Emulsion with Secondary Opioid –
100 – 150 µg/kg/min
Low-Dose DIPRIVAN Injectable Emulsion with Primary Opioid –
50 - 100 µg/kg/min
(See DOSAGE AND ADMINISTRATION
, Table 5)
Neurosurgical Patients: 100 to 200 µg/kg/min (6 to 12 mg/kg/h).
Pediatric Patients - healthy, from 2 months of age to 16 years of age:
125 to 300 µg/kg/min (7.5 to 18 mg/kg/h)
Following the first half hour of maintenance, if clinical signs of light
anesthesia are not present, the infusion rate should be decreased.
(See PRECAUTIONS – Pediatric Use: and CLINICAL PHARMACOLOGY
– Pediatrics )
Maintenance of General Anesthesia:
Intermittent Bolus
Healthy Adults Less Than 55 Years Of Age: Increments of 20 to 50 mg
as needed.
Initiation of MAC Sedation:
Healthy Adults Less Than 55 Years of Age: Slow infusion or slow
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 27
injection techniques are recommended to avoid apnea or hypotension.
Most patients require an infusion of 100 to 150 µg/kg/min (6 to 9 mg/kg/h)
for 3 to 5 minutes or a slow injection of 0.5 mg/kg over 3 to 5 minutes
followed immediately by a maintenance infusion.
Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients:
Most patients require dosages similar to healthy adults. Rapid boluses are to
be avoided. (See WARNINGS.)
Maintenance of MAC Sedation
Healthy Adults Less Than 55 Years of Age: A variable rate infusion
technique is preferable over an intermittent bolus technique. Most patients
require an infusion of 25 to 75 µg/kg/min (1.5 to 4.5 mg/kg/h) or incremental
bolus doses of 10 mg or 20 mg.
In Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients:
Most patients require 80% of the usual adult dose. A rapid (single or
repeated) bolus dose should not be used. (See WARNINGS.)
Initiation and Maintenance of ICU Sedation in Intubated, Mechanically Ventilated
Adult Patients - Because of the residual effects of previous anesthetic or
sedative agents, in most patients the initial infusion should be 5 µg/kg/min
(0.3 mg/kg/h) for at least 5 minutes. Subsequent increments of 5 to 10
µg/kg/min (0.3 to 0.6 mg/kg/h) over 5 to 10 minutes may be used until
desired clinical effect is achieved. Maintenance rates of 5 to 50 µg/kg/min
(0.3 to 3 mg/kg/h) or higher may be required.
Evaluation of clinical effect and assessment of CNS function should be
carried out daily throughout maintenance to determine the minimum
dose of DIPRIVAN Injectable Emulsion required for sedation.
The tubing and any unused portions of DIPRIVAN Injectable Emulsion
should be discarded after 12 hours because DIPRIVAN Injectable
Emulsion contains no preservatives and is capable of supporting growth
of microorganisms. (See WARNINGS, and DOSAGE AND
ADMINISTRATION.)
Administration with Lidocaine: If lidocaine is to be administered to minimize pain on injection of
DIPRIVAN, it is recommended that it be administered prior to DIPRIVAN administration or that it be
added to DIPRIVAN immediately before administration and in quantities not exceeding 20 mg
lidocaine/200 mg DIPRIVAN.
Compatibility and Stability: DIPRIVAN Injectable Emulsion should not be mixed with other
therapeutic agents prior to administration.
Dilution Prior to Administration: DIPRIVAN Injectable Emulsion is provided as a ready-to-use
formulation. However, should dilution be necessary, it should only be diluted with 5% Dextrose
Injection, USP, and it should not be diluted to a concentration less than 2 mg/mL because it is an
emulsion. In diluted form it has been shown to be more stable when in contact with glass than with
plastic (95% potency after 2 hours of running infusion in plastic).
Administration with Other Fluids: Compatibility of DIPRIVAN Injectable Emulsion with the
coadministration of blood/serum/plasma has not been established. (See WARNINGS.) When
administered using a y-type infusion set, DIPRIVAN Injectable Emulsion has been shown to be
compatible with the following intravenous fluids.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 28
- 5% Dextrose Injection, USP
- Lactated Ringers Injection, USP
- Lactated Ringers and 5% Dextrose Injection
- 5% Dextrose and 0.45% Sodium Chloride Injection, USP
- 5% Dextrose and 0.2% Sodium Chloride Injection, USP
Handling Procedures
General
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration whenever solution and container permit.
Clinical experience with the use of in-line filters and DIPRIVAN Injectable Emulsion during
anesthesia or ICU/MAC sedation is limited. DIPRIVAN Injectable Emulsion should only be
administered through a filter with a pore size of 5 µm or greater unless it has been demonstrated that
the filter does not restrict the flow of DIPRIVAN Injectable Emulsion and/or cause the breakdown of
the emulsion. Filters should be used with caution and where clinically appropriate. Continuous
monitoring is necessary due to the potential for restricted flow and/or breakdown of the emulsion.
Do not use if there is evidence of separation of the phases of the emulsion.
Rare cases of self-administration of DIPRIVAN Injectable Emulsion by health care professionals have
been reported, including some fatalities (See DRUG ABUSE AND DEPENDENCE).
Strict aseptic technique must always be maintained during handling. Diprivan Injectable
Emulsion is a single-use parenteral product which contains 0.005% disodium edetate to retard
the rate of growth of microorganisms in the event of accidental extrinsic contamination.
However, Diprivan Injectable Emulsion can still support the growth of microorganisms as it is
not an antimicrobially preserved product under usp standards. Accordingly, strict aseptic
technique must still be adhered to. Do not use if contamination is suspected. Discard unused
portions as directed within the required time limits (see dosage and administration, handling
procedures). There have been reports in which failure to use aseptic technique when handling
Diprivan Injectable Emulsion was associated with microbial contamination of the product and
with fever, infection/sepsis, other life-threatening illness, and/or death.
Guidelines for Aseptic Technique for General Anesthesia/MAC Sedation:
DIPRIVAN Injectable Emulsion should be prepared for use just prior to initiation of each individual
anesthetic/sedative procedure. The vial/pre-filled syringe rubber stopper should be disinfected using
70% isopropyl alcohol. DIPRIVAN Injectable Emulsion should be drawn into sterile syringes
immediately after vials are opened. When withdrawing DIPRIVAN Injectable Emulsion from vials, a
sterile vent spike should be used. The syringe(s) should be labeled with appropriate information
including the date and time the vial was opened. Administration should commence promptly and be
completed within 6 hours after the vials or pre-filled syringes have been opened.
DIPRIVAN Injectable Emulsion should be prepared for single-patient use only. Any unused portions
of DIPRIVAN Injectable Emulsion, reservoirs, dedicated administration tubing and/or solutions
containing DIPRIVAN Injectable Emulsion must be discarded at the end of the anesthetic procedure or
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-627/S-045
Page 29
at 6 hours, whichever occurs sooner. The IV line should be flushed every 6 hours and at the end of the
anesthetic procedure to remove residual DIPRIVAN Injectable Emulsion.
Guidelines for Aseptic Technique for ICU Sedation
DIPRIVAN Injectable Emulsion should be prepared for single-patient use only. When DIPRIVAN
Injectable Emulsion is administered directly from the vial/pre-filled syringe, strict aseptic techniques
must be followed. The vial/pre-filled syringe rubber stopper should be disinfected using 70%
isopropyl alcohol. A sterile vent spike and sterile tubing must be used for administration of
DIPRIVAN Injectable Emulsion. As with other lipid emulsions, the number of IV line manipulations
should be minimized. Administration should commence promptly and must be completed within 12
hours after the vial has been spiked. The tubing and any unused portions of DIPRIVAN Injectable
Emulsion must be discarded after 12 hours.
If DIPRIVAN Injectable Emulsion is transferred to a syringe or other container prior to administration,
the handling procedures for General anesthesia/MAC sedation should be followed, and the product
should be discarded and administration lines changed after 6 hours.
HOW SUPPLIED
DIPRIVAN Injectable Emulsion is available in ready to use 20 mL infusion vials, 50 mL infusion
vials, 100 mL infusion vials, and 50 mL pre-filled syringes containing 10 mg/mL of propofol.
20 mL infusion vials (NDC 0310-0300-22)
50 mL infusion vials (NDC 0310-0300-50)
100 mL infusion vials (NDC 0310-0300-11)
50 mL pre-filled syringes (NDC 0310-0300-54)
Propofol undergoes oxidative degradation, in the presence of oxygen, and is therefore packaged under
nitrogen to eliminate this degradation path.
Store between 4-22°C (40-72°F). Do not freeze. Shake well before use.
All trademarks are the property of Abraxis BioScience Inc.
© Abraxis BioScience Inc. 2001, 2004, 2006
Manufactured for:
Abraxis BioScience Inc.
Los Angeles, CABy: AstraZeneca S.p.A.,
Caponago, Italy
Made in Italy
Rev
SIC 64180-03
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:32.766458
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/019627s045lbl.pdf', 'application_number': 19627, 'submission_type': 'SUPPL ', 'submission_number': 45}
|
11,570
|
1
451094A/Issued: February 2008
2 DIPRIVAN®
3 (propofol) Injectable Emulsion
4
FOR IV ADMINISTRATION
5
Strict aseptic technique must always be maintained during handling. Diprivan
6
Injectable Emulsion is a single-use parenteral product which contains 0.005% disodium
7
edetate to inhibit the rate of growth of microorganisms, for up to 12 hours, in the event
8
of accidental extrinsic contamination. However, Diprivan Injectable Emulsion can still
9
support the growth of microorganisms, as it is not an antimicrobially preserved product
10
under USP standards. Accordingly, strict aseptic technique must still be adhered to.
11
Do not use if contamination is suspected. Discard unused portions as directed within the
12
required time limits (see DOSAGE AND ADMINSTRATION, Handling Procedures).
13
There have been reports in which failure to use aseptic technique when handling
14
Diprivan Injectable Emulsion was associated with microbial contamination of the
15
product and with fever, infection/sepsis, other life-threatening illness, and/or death.
16
DESCRIPTION
17
DIPRIVAN® (propofol) Injectable Emulsion is a sterile, nonpyrogenic emulsion containing
18
10 mg/mL of propofol suitable for intravenous administration. Propofol is chemically
19
described as 2,6-diisopropylphenol and has a molecular weight of 178.27. The structural and
20
molecular formulas are:
21
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Chemical Structure
2
Propofol is slightly soluble in water and, thus, is formulated in a white, oil-in-water
3
emulsion. The pKa is 11. The octanol/water partition coefficient for propofol is 6761:1 at a
4
pH of 6-8.5. In addition to the active component, propofol, the formulation also contains
5
soybean oil (100 mg/mL), glycerol (22.5 mg/mL), egg lecithin (12 mg/mL); and disodium
6
edetate (0.005%); with sodium hydroxide to adjust pH. The DIPRIVAN Injectable Emulsion
7
is isotonic and has a pH of 7-8.5.
8
CLINICAL PHARMACOLOGY
9
General
10
DIPRIVAN Injectable Emulsion is an intravenous sedative-hypnotic agent for use in the
11
induction and maintenance of anesthesia or sedation. Intravenous injection of a therapeutic
12
dose of propofol induces hypnosis, with minimal excitation, usually within 40 seconds from
13
the start of injection (the time for one arm-brain circulation). As with other rapidly acting
14
intravenous anesthetic agents, the half-time of the blood-brain equilibration is approximately
15
1 to 3 minutes, accounting for the rate of induction of anesthesia.
16
Pharmacodynamics
17
Pharmacodynamic properties of propofol are dependent upon the therapeutic blood propofol
18
concentrations. Steady-state propofol blood concentrations are generally proportional to
19
infusion rates. Undesirable side effects, such as cardiorespiratory depression, are likely to
20
occur at higher blood concentrations which result from bolus dosing or rapid increases in
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
infusion rates. An adequate interval (3 to 5 minutes) must be allowed between dose
2
adjustments in order to assess clinical effects.
3
The hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of anesthesia
4
vary. If spontaneous ventilation is maintained, the major cardiovascular effect is arterial
5
hypotension (sometimes greater than a 30% decrease) with little or no change in heart rate
6
and no appreciable decrease in cardiac output. If ventilation is assisted or controlled
7
(positive pressure ventilation), there is an increase in the incidence and the degree of
8
depression of cardiac output. Addition of an opioid, used as a premedicant, further decreases
9
cardiac output and respiratory drive.
10
If anesthesia is continued by infusion of DIPRIVAN Injectable Emulsion, the stimulation of
11
endotracheal intubation and surgery may return arterial pressure towards normal. However,
12
cardiac output may remain depressed. Comparative clinical studies have shown that the
13
hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of anesthesia are
14
generally more pronounced than with other intravenous (IV) induction agents.
15
Induction of anesthesia with DIPRIVAN Injectable Emulsion is frequently associated with
16
apnea in both adults and pediatric patients. In adult patients who received DIPRIVAN
17
Injectable Emulsion (2 to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30
18
60 seconds in 24% of patients, and more than 60 seconds in 12% of patients. In pediatric
19
patients from birth through 16 years of age assessable for apnea who received bolus doses of
20
DIPRIVAN Injectable Emulsion (1 to 3.6 mg/kg), apnea lasted less than 30 seconds in 12%
21
of patients, 30-60 seconds in 10% of patients, and more than 60 seconds in 5% of patients.
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
During maintenance of general anesthesia, DIPRIVAN Injectable Emulsion causes a
2
decrease in spontaneous minute ventilation usually associated with an increase in carbon
3
dioxide tension which may be marked depending upon the rate of administration and
4
concurrent use of other medications (e.g., opioids, sedatives, etc.).
5
During monitored anesthesia care (MAC) sedation, attention must be given to the
6
cardiorespiratory effects of DIPRIVAN Injectable Emulsion. Hypotension, oxyhemoglobin
7
desaturation, apnea, and airway obstruction can occur, especially following a rapid bolus of
8
DIPRIVAN Injectable Emulsion. During initiation of MAC sedation, slow infusion or slow
9
injection techniques are preferable over rapid bolus administration. During maintenance of
10
MAC sedation, a variable rate infusion is preferable over intermittent bolus administration in
11
order to minimize undesirable cardiorespiratory effects. In the elderly, debilitated, or ASA
12
PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used
13
for MAC sedation (see WARNINGS).
14
Clinical and preclinical studies suggest that DIPRIVAN Injectable Emulsion is rarely
15
associated with elevation of plasma histamine levels.
16
Preliminary findings in patients with normal intraocular pressure indicate that DIPRIVAN
17
Injectable Emulsion produces a decrease in intraocular pressure which may be associated
18
with a concomitant decrease in systemic vascular resistance.
19
Clinical studies indicate that DIPRIVAN Injectable Emulsion when used in combination with
20
hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow, cerebral
21
metabolic oxygen consumption, and intracranial pressure. DIPRIVAN Injectable Emulsion
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension (see
2
Clinical Trials - Neuroanesthesia).
3
Clinical studies indicate that DIPRIVAN Injectable Emulsion does not suppress the adrenal
4
response to ACTH.
5
Animal studies and limited experience in susceptible patients have not indicated any
6
propensity of DIPRIVAN Injectable Emulsion to induce malignant hyperthermia.
7
Hemosiderin deposits have been observed in the livers of dogs receiving DIPRIVAN
8
Injectable Emulsion containing 0.005% disodium edetate over a four-week period; the
9
clinical significance of this is unknown.
10
Pharmacokinetics
11
The pharmacokinetics of propofol are well described by a three compartment linear model
12
with compartments representing the plasma, rapidly equilibrating tissues, and slowly
13
equilibrating tissues.
14
Following an IV bolus dose, there is rapid equilibration between the plasma and the brain,
15
accounting for the rapid onset of anesthesia. Plasma levels initially decline rapidly as a result
16
of both distribution and metabolic clearance. Distribution accounts for about half of this
17
decline following a bolus of propofol. However, distribution is not constant over time, but
18
decreases as body tissues equilibrate with plasma and become saturated. The rate at which
19
equilibration occurs is a function of the rate and duration of the infusion. When equilibration
20
occurs there is no longer a net transfer of propofol between tissues and plasma.
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Discontinuation of the recommended doses of DIPRIVAN Injectable Emulsion after the
2
maintenance of anesthesia for approximately one hour, or for sedation in the ICU for one
3
day, results in a prompt decrease in blood propofol concentrations and rapid awakening.
4
Longer infusions (10 days of ICU sedation) result in accumulation of significant tissue stores
5
of propofol, such that the reduction in circulating propofol is slowed and the time to
6
awakening is increased.
7
By daily titration of DIPRIVAN Injectable Emulsion dosage to achieve only the minimum
8
effective therapeutic concentration, rapid awakening within 10 to 15 minutes can occur even
9
after long-term administration. If, however, higher than necessary infusion levels have been
10
maintained for a long time, propofol redistribution from fat and muscle to the plasma can be
11
significant and slow recovery.
12
The figure below illustrates the fall of plasma propofol levels following infusions of various
13
durations to provide ICU sedation.
Graph
15
The large contribution of distribution (about 50%) to the fall of propofol plasma levels
16
following brief infusions means that after very long infusions a reduction in the infusion rate
17
is appropriate by as much as half the initial infusion rate in order to maintain a constant
18
plasma level. Therefore, failure to reduce the infusion rate in patients receiving DIPRIVAN
19
Injectable Emulsion for extended periods may result in excessively high blood concentrations
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
of the drug. Thus, titration to clinical response and daily evaluation of sedation levels are
2
important during use of DIPRIVAN Injectable Emulsion infusion for ICU sedation..
3
Adults: Propofol clearance ranges from 23-50 mL/kg/min (1.6 to 3.4 L/min in 70 kg adults).
4
It is chiefly eliminated by hepatic conjugation to inactive metabolites which are excreted by
5
the kidney. A glucuronide conjugate accounts for about 50% of the administered dose.
6
Propofol has a steady state volume of distribution (10-day infusion) approaching 60 L/kg in
7
healthy adults. A difference in pharmacokinetics due to gender has not been observed. The
8
terminal half-life of propofol after a 10-day infusion is 1 to 3 days.
9
Geriatrics: With increasing patient age, the dose of propofol needed to achieve a defined
10
anesthetic end point (dose-requirement) decreases. This does not appear to be an age-related
11
change in pharmacodynamics or brain sensitivity, as measured by EEG burst suppression.
12
With increasing patient age, pharmacokinetic changes are such that, for a given IV bolus
13
dose, higher peak plasma concentrations occur, which can explain the decreased dose
14
requirement. These higher peak plasma concentrations in the elderly can predispose patients
15
to cardiorespiratory effects including hypotension, apnea, airway obstruction, and/or arterial
16
oxygen desaturation. The higher plasma levels reflect age-related decreased in volume of
17
distribution and intercompartmental clearance. Lower doses are therefore recommended for
18
initiation and maintenance of sedation and anesthesia in elderly patients. (See DOSAGE
19
AND ADMINISTRATION.)
20
Pediatrics: The pharmacokinetics of propofol were studied in children between 3 and 12
21
years of age who received DIPRIVAN Injectable Emulsion for periods of approximately 1-2
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
hours. The observed distribution and clearance of propofol in these children were similar to
2
adults.
3
Organ Failure: The pharmacokinetics of propofol do not appear to be different in people
4
with chronic hepatic cirrhosis or chronic renal impairment compared to adults with normal
5
hepatic and renal function. The effects of acute hepatic or renal failure on the
6
pharmacokinetics of propofol have not been studied.
7
Clinical Trials
8
Anesthesia and Monitored Anesthesia Care (MAC) Sedation
9
Pediatric Anesthesia:
10
DIPRIVAN Injectable Emulsion was studied in clinical trials which included cardiac surgical
11
patients. Most patients were 3 years of age or older. The majority of the patients were
12
healthy ASA-PS I or II patients The range of doses in these studies are described in Tables 1
13
and 2.
14
TABLE 1. PEDIATRIC INDUCTION OF ANESTHESIA
Age Range
Induction Dose
Injection Duration
Median (range)
Median (range)
Birth through 16 years
2.5 mg/kg
20 sec.
(1-3.6)
(6-45)
15
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
2
TABLE 2. PEDIATRIC MAINTENANCE OF ANESTHESIA
Age Range
2 months to 2 years
2 to 12 years
>12 through 16 years
Neuroanesthesia:
Maintenance Dosage
Duration
(mcg/kg/min)
199 (82 – 394)
188 (12 – 1041)
161 (84 – 359)
(minutes)
65 (12 - 282)
69 (23 – 374)
69 (26 – 251)
3
DIPRIVAN Injectable Emulsion was studied in patients undergoing craniotomy for
4
supratentorial tumors in two clinical trials. The mean lesion size (anterior/posterior x lateral)
5
was 31 mm x 32 mm in one trial and 55 mm x 42 mm in the other trial respectively.
6
Anesthesia was induced with a median Diprivan dose of 1.4 mg/kg (range: 0.9-6.9 mg/kg)
7
and maintained with a median maintenance Diprivan dose of 146 mcg/kg/min (range: 68-425
8
mcg/kg/min). The median duration of the Diprivan maintenance infusion was 285 minutes
9
(range: 48-622 minutes).
10
DIPRIVAN Injectable Emulsion was administered by infusion in a controlled clinical trial to
11
evaluate its effect on cerebrospinal fluid pressure (CSFP). The mean arterial pressure was
12
maintained relatively constant over 25 minutes with a change from baseline of -4% ± 17%
13
(mean ± SD). The change in CSFP was -46% ± 14%. As CSFP is an indirect measure of
14
intracranial pressure (ICP), DIPRIVAN Injectable Emulsion, when given by infusion or slow
15
bolus in combination with hypocarbia, is capable of decreasing ICP independent of changes
16
in arterial pressure.
17
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Intensive Care Unit (ICU) Sedation
2
Adult Patients:
3
DIPRIVAN Injectable Emulsion was compared to benzodiazepines and opioids in clinical
4
trials involving ICU patients. Of these, 302 received DIPRIVAN Injectable Emulsion and
5
comprise the overall safety database for ICU sedation.
6
Across all clinical studies, the mean infusion maintenance rate for all DIPRIVAN Injectable
7
Emulsion patients was 27 ± 21 mcg/kg/min. The maintenance infusion rates required to
8
maintain adequate sedation ranged from 2.8 mcg/kg/min to 130 mcg/kg/min. The infusion
9
rate was lower in patients over 55 years of age (approximately 20 mcg/kg/min) compared to
10
patients under 55 years of age (approximately 38 mcg/kg/min). Although there are reports of
11
reduced analgesic requirements, most patients received opioids for analgesia during
12
maintenance of ICU sedation. In these studies, morphine or fentanyl was used as needed for
13
analgesia. Some patients also received benzodiazepines and/or neuromuscular blocking
14
agents. During long-term maintenance of sedation, some ICU patients were awakened once
15
or twice every 24 hours for assessment of neurologic or respiratory function.
16
In Medical and Postsurgical ICU studies comparing DIPRIVAN Injectable Emulsion to
17
benzodiazepine infusion or bolus, there were no apparent differences in maintenance of
18
adequate sedation, mean arterial pressure, or laboratory findings. Like the comparators,
19
DIPRIVAN Injectable Emulsion reduced blood cortisol during sedation while maintaining
20
responsivity to challenges with adrenocorticotropic hormone (ACTH). Case reports from
21
the published literature generally reflect that DIPRIVAN Injectable Emulsion has been used
22
safely in patients with a history of porphyria or malignant hyperthermia.
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
In hemodynamically stable head trauma patients ranging in age from 19-43 years, adequate
2
sedation was maintained with DIPRIVAN Injectable Emulsion or morphine. There were no
3
apparent differences in adequacy of sedation, intracranial pressure, cerebral perfusion
4
pressure, or neurologic recovery between the treatment groups. In literature reports of
5
severely head-injured patients in Neurosurgical ICUs, DIPRIVAN Injectable Emulsion
6
infusion and hyperventilation, both with and without diuretics, controlled intracranial
7
pressure while maintaining cerebral perfusion pressure. In some patients, bolus doses
8
resulted in decreased blood pressure and compromised cerebral perfusion pressure.
9
DIPRIVAN Injectable Emulsion was found to be effective in status epilepticus which was
10
refractory to the standard anticonvulsant therapies. For these patients, as well as for
11
ARDS/respiratory failure and tetanus patients, sedation maintenance dosages were generally
12
higher than those for other critically ill patient populations.
13
Pediatric Patients:
14
A single, randomized, controlled, clinical trial that evaluated the safety and effectiveness of
15
DIPRIVAN versus standard sedative agents (SSA) was conducted on 327 pediatric ICU
16
patients. Patients were randomized to receive either DIPRIVAN 2%, (113 patients),
17
DIPRIVAN 1%, (109 patients), or an SSA (eg, lorazepam, chloral hydrate, fentanyl,
18
ketamine, morphine, or phenobarbital). DIPRIVAN therapy was initiated at an infusion rate
19
of 5.5 mg/kg/hr and titrated as needed to maintain sedation at a standardized level. The
20
results of the study showed an increase in the number of deaths in patients treated with
21
DIPRIVAN as compared to SSAs. Of the 25 patients who died during the trial or within the
22
28-day follow-up period: 12 (11% were) in the DIPRIVAN 2% treatment group, 9 (8% were)
23
in the DIPRIVAN 1% treatment group, and 4% were (4%) in the SSA treatment group. The
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
differences in mortality rate between the groups were not statistically significant. Review of
2
the deaths failed to reveal a correlation with underlying disease status or a correlation to the
3
drug or a definitive pattern to the causes of death.
4
Cardiac Anesthesia
5
DIPRIVAN Injectable Emulsion was evaluated in clinical trials involving patients
6
undergoing coronary artery bypass graft (CABG).
7
In post-CABG (coronary artery bypass graft) patients, the maintenance rate of propofol
8
administration was usually low (median 11 mcg/kg/min) due to the intraoperative
9
administration of high opioid doses. Patients receiving DIPRIVAN Injectable Emulsion
10
required 35% less nitroprusside than midazolam patients. During initiation of sedation in
11
post-CABG patients, a 15% to 20% decrease in blood pressure was seen in the first 60
12
minutes. It was not possible to determine cardiovascular effects in patients with severely
13
compromised ventricular function.
14
INDICATIONS AND USAGE
15
DIPRIVAN Injectable Emulsion is an IV sedative-hypnotic agent that can be used as
16
described in the table below.
17
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Table 3 Indications for DIPRIVAN Injectable Emulsion
Indication
Initiation and maintenance of Monitored
Anesthesia Care (MAC) sedation
Combined sedation and regional anesthesia
Induction of General Anesthesia
Mainenance of General Anesthesia
Intensive Care Unit (ICU) sedation of intubated,
mechanically ventilated patients
Approved Patient Population
Adults only
Adults only (See PRECAUTIONS)
Patients ≥ 3 years of age
Patients ≥ 2 months of age
Adults only
2
Safety, effectiveness and dosing guidelines for DIPRIVAN Injectable Emulsion have not
3
been established for MAC Sedation in the pediatric population; therefore, it is not
4
recommended for this use. (See PRECAUTIONS, Pediatric Use).
5
DIPRIVAN Injectable Emulsion is not recommended for induction of anesthesia below the
6
age of 3 years or for maintenance of anesthesia below the age of 2 months because its safety
7
and effectiveness have not been established in those populations.
8
In the Intensive Care Unit (ICU), DIPRIVAN Injectable Emulsion can be administered to
9
intubated, mechanically ventilated adult patients to provide continuous sedation and control
10
of stress responses only by persons skilled in the medical management of critically ill
11
patients and trained in cardiovascular resuscitation and airway management.
12
DIPRIVAN Injectable Emulsion is not indicated for use in Pediatric ICU sedation since the
13
safety of this regimen has not been established. (See PRECAUTIONS, Pediatric Use).
14
DIPRIVAN Injectable Emulsion is not recommended for obstetrics, including Cesarean
15
section deliveries. DIPRIVAN Injectable Emulsion crosses the placenta, and as with other
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
general anesthetic agents, the administration of DIPRIVAN Injectable Emulsion may be
2
associated with neonatal depression. (See PRECAUTIONS.)
3
DIPRIVAN Injectable Emulsion is not recommended for use in nursing mothers because
4
DIPRIVAN Injectable Emulsion has been reported to be excreted in human milk, and the
5
effects of oral absorption of small amounts of propofol are not known. (See
6
PRECAUTIONS.)
7
CONTRAINDICATIONS
8
DIPRIVAN Injectable Emulsion is contraindicated in patients with a known hypersensitivity
9
to DIPRIVAN Injectable Emulsion or any of its components.
10
DIPRIVAN Injectable Emulsion is contraindicated in patients with allergies to eggs, egg
11
products, soybeans or soy products.
12
WARNINGS
13
Use of DIPRIVAN Injectable Emulsion has been associated with both fatal and life
14
threatening anaphylactic and anaphylactoid reactions.
15
For general anesthesia or monitored anesthesia care (MAC) sedation, DIPRIVAN Injectable
16
Emulsion should be administered only by persons trained in the administration of general
17
anesthesia and not involved in the conduct of the surgical/diagnostic procedure. Sedated
18
patients should be continuously monitored, and facilities for maintenance of a patent airway,
19
providing artificial ventilation, administering supplemental oxygen, and instituting
20
cardiovascular resuscitation must be immediately available. Patients should be continuously
21
monitored for early signs of hypotension, apnea, airway obstruction, and/or oxygen
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
desaturation. These cardiorespiratory effects are more likely to occur following rapid bolus
2
administration, especially in the elderly, debilitated, or ASA-PS III or IV patients.
3
For sedation of intubated, mechanically ventilated patients in the Intensive Care Unit (ICU),
4
DIPRIVAN Injectable Emulsion should be administered only by persons skilled in the
5
management of critically ill patients and trained in cardiovascular resuscitation and airway
6
management.
7
Use of DIPRIVAN Injectable Emulsion infusions for both adult and pediatric ICU
8
sedation has been associated with a constellation of metabolic derangements and organ
9
system failures, referred to as Propofol Infusion Syndrome, that have resulted in death.
10
The syndrome is characterized by severe metabolic acidosis, hyperkalemia, lipemia,
11
rhabdomyolysis, hepatomegaly, cardiac and renal failure. The syndrome is most often
12
associated with prolonged, high-dose infusions (> 5 mg/kg/h for > 48h) but has also been
13
reported following large-dose, short-term infusions during surgical anesthesia. In the
14
setting of prolonged need for sedation, increasing propofol dose requirements to
15
maintain a constant level of sedation, or onset of metabolic acidosis during
16
administration of a propofol infusion, consideration should be given to using alternative
17
means of sedation.
18
Abrupt discontinuation of DIPRIVAN Injectable Emulsion prior to weaning or for daily
19
evaluation of sedation levels should be avoided. This may result in rapid awakening with
20
associated anxiety, agitation, and resistance to mechanical ventilation. Infusions of
21
DIPRIVAN Injectable Emulsion should be adjusted to maintain a light level of sedation
22
through the weaning process or evaluation of sedation level. (See PRECAUTIONS.)
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
DIPRIVAN Injectable Emulsion should not be coadministered through the same IV catheter
2
with blood or plasma because compatibility has not been established. In vitro tests have
3
shown that aggregates of the globular component of the emulsion vehicle have occurred with
4
blood/plasma/serum from humans and animals. The clinical significance of these findings is
5
not known.
6
There have been reports in which failure to use aseptic technique when handling
7
Diprivan Injectable Emulsion was associated with microbial contamination of the
8
product and with fever, infection, sepsis, other life-threatening illness, and death. Do
9
not use if contamination is suspected. Discard unused portions as directed within the
10
required time limits (see DOSAGE AND ADMINISTRATION, Handling Procedures)
11
PRECAUTIONS
12
General:
13
Adult and Pediatric Patients: A lower induction dose and a slower maintenance rate of
14
administration should be used in elderly, debilitated, or ASA-PS III or IV patients. (See
15
DOSAGE AND ADMINISTRATION.) Patients should be continuously monitored for early
16
signs of hypotension and/or bradycardia. Apnea requiring ventilatory support often occurs
17
during induction and may persist for more than 60 seconds. DIPRIVAN Injectable Emulsion
18
use requires caution when administered to patients with disorders of lipid metabolism such as
19
primary hyperlipoproteinemia, diabetic hyperlipemia, and pancreatitis.
20
Very rarely the use of DIPRIVAN Injectable Emulsion may be associated with the
21
development of a period of postoperative unconsciousness which may be accompanied by an
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
increase in muscle tone. This may or may not be preceded by a brief period of wakefulness.
2
Recovery is spontaneous.
3
When DIPRIVAN Injectable Emulsion is administered to an epileptic patient, there is a risk
4
of seizure during the recovery phase.
5
Attention should be paid to minimize pain on administration of DIPRIVAN Injectable
6
Emulsion. Transient local pain can be minimized if the larger veins of the forearm or
7
antecubital fossa are used. Pain during intravenous injection may also be reduced by prior
8
injection of IV lidocaine (1 mL of a 1% solution). Pain on injection occurred frequently in
9
pediatric patients (45%) when a small vein of the hand was utilized without lidocaine
10
pretreatment. With lidocaine pretreatment or when antecubital veins were utilized, pain was
11
minimal (incidence less than 10%) and well-tolerated. There have been reports in the
12
literature indicating that the addition of lidocaine to DIPRIVAN in quantities greater than 20
13
mg lidocaine/200 mg DIPRIVAN results in instability of the emulsion which is associated
14
with increases in globule sizes over time and (in rat studies) a reduction in anesthetic
15
potency. Therefore, it is recommended that lidocaine be administered prior to DIPRIVAN
16
administration or that it be added to DIPRIVAN immediately before administration and in
17
quantities not exceeding 20 mg lidocaine/200 mg DIPRIVAN.
18
Venous sequelae, i.e., phlebitis or thrombosis, have been reported rarely (<1%). In two
19
clinical studies using dedicated intravenous catheters, no instances of venous sequelae were
20
observed up to 14 days following induction.
21
Intra-arterial injection in animals did not induce local tissue effects. Accidental intra-arterial
22
injection has been reported in patients, and, other than pain, there were no major sequelae.
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Intentional injection into subcutaneous or perivascular tissues of animals caused minimal
2
tissue reaction. During the post-marketing period, there have been rare reports of local pain,
3
swelling, blisters, and/or tissue necrosis following accidental extravasation of DIPRIVAN
4
Injectable Emulsion.
5
Perioperative myoclonia, rarely including convulsions and opisthotonos, has occurred in
6
association with DIPRIVAN Injectable Emulsion administration.
7
Clinical features of anaphylaxis, including angioedema, bronchospasm, erythema, and
8
hypotension, occur rarely following DIPRIVAN Injectable Emulsion administration.
9
There have been rare reports of pulmonary edema in temporal relationship to the
10
administration of DIPRIVAN Injectable Emulsion, although a causal relationship is
11
unknown.
12
Rarely, cases of unexplained postoperative pancreatitis (requiring hospital admission) have
13
been reported after anesthesia in which DIPRIVAN Injectable Emulsion was one of the
14
induction agents used. Due to a variety of confounding factors in these cases, including
15
concomitant medications, a causal relationship to DIPRIVAN Injectable Emulsion is unclear.
16
DIPRIVAN Injectable Emulsion has no vagolytic activity. Reports of bradycardia, asystole,
17
and rarely, cardiac arrest have been associated with DIPRIVAN Injectable Emulsion.
18
Pediatric patients are susceptible to this effect, particularly when fentanyl is given
19
concomitantly. The intravenous administration of anticholinergic agents (e.g., atropine or
20
glycopyrrolate) should be considered to modify potential increases in vagal tone due to
21
concomitant agents (e.g., succinylcholine) or surgical stimuli.
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Intensive Care Unit Sedation
2
Adult Patients: (See WARNINGS and DOSAGE AND ADMINISTRATION, Handling
3
Procedures.) The administration of DIPRIVAN Injectable Emulsion should be initiated as a
4
continuous infusion and changes in the rate of administration made slowly (>5 min) in order
5
to minimize hypotension and avoid acute overdosage. (See DOSAGE AND
6
ADMINISTRATION.)
7
Patients should be monitored for early signs of significant hypotension and/or cardiovascular
8
depression, which may be profound. These effects are responsive to discontinuation of
9
DIPRIVAN Injectable Emulsion, IV fluid administration, and/or vasopressor therapy. In the
10
elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus
11
administration should not be used during sedation in order to minimize undesirable
12
cardiorespiratory depression, including hypotension, apnea, airway obstruction, and oxygen
13
desaturation.
14
As with other sedative medications, there is wide interpatient variability in DIPRIVAN
15
Injectable Emulsion dosage requirements, and these requirements may change with time.
16
Failure to reduce the infusion rate in patients receiving DIPRIVAN Injectable Emulsion for
17
extended periods may result in excessively high blood concentrations of the drug. Thus,
18
titration to clinical response and daily evaluation of sedation levels are important during use
19
of DIPRIVAN Injectable Emulsion infusion for ICU sedation, especially when it is used for
20
long durations.
21
Opioids and paralytic agents should be discontinued and respiratory function optimized prior
22
to weaning patients from mechanical ventilation. Infusions of DIPRIVAN Injectable
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Emulsion should be adjusted to maintain a light level of sedation prior to weaning patients
2
from mechanical ventilatory support. Throughout the weaning process, this level of sedation
3
may be maintained in the absence of respiratory depression. Because of the rapid clearance
4
of DIPRIVAN Injectable Emulsion, abrupt discontinuation of a patient's infusion may result
5
in rapid awakening with associated anxiety, agitation, and resistance to mechanical
6
ventilation, making weaning from mechanical ventilation difficult. It is therefore
7
recommended that administration of DIPRIVAN Injectable Emulsion be continued in order
8
to maintain a light level of sedation throughout the weaning process until 10-15 minutes prior
9
to extubation, at which time the infusion can be discontinued.
10
Since DIPRIVAN Injectable Emulsion is formulated in an oil-in-water emulsion, elevations
11
in serum triglycerides may occur when DIPRIVAN Injectable Emulsion is administered for
12
extended periods of time. Patients at risk of hyperlipidemia should be monitored for
13
increases in serum triglycerides or serum turbidity. Administration of DIPRIVAN Injectable
14
Emulsion should be adjusted if fat is being inadequately cleared from the body. A reduction
15
in the quantity of concurrently administered lipids is indicated to compensate for the amount
16
of lipid infused as part of the DIPRIVAN Injectable Emulsion formulation; 1 mL of
17
DIPRIVAN Injectable Emulsion contains approximately 0.1 g of fat (1.1 kcal).
18
EDTA is a strong chelator of trace metals -- including zinc. Although with DIPRIVAN
19
Injectable Emulsion there are no reports of decreased zinc levels or zinc deficiency-related
20
adverse events, DIPRIVAN Injectable Emulsion should not be infused for longer than 5 days
21
without providing a drug holiday to safely replace estimated or measured urine zinc losses.
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
In clinical trials mean urinary zinc loss was approximately 2.5 to 3.0 mg/day in adult patients
2
and 1.5 to 2.0 mg/day in pediatric patients.
3
In patients who are predisposed to zinc deficiency, such as those with burns, diarrhea, and/or
4
major sepsis, the need for supplemental zinc should be considered during prolonged therapy
5
with DIPRIVAN Injectable Emulsion.
6
At high doses (2-3 grams per day), EDTA has been reported, on rare occasions, to be toxic to
7
the renal tubules. Studies to date in patients with normal or impaired renal function have not
8
shown any alteration in renal function with DIPRIVAN Injectable Emulsion containing
9
0.005% disodium edetate. In patients at risk for renal impairment, urinalysis and urine
10
sediment should be checked before initiation of sedation and then be monitored on alternate
11
days during sedation.
12
The long-term administration of DIPRIVAN Injectable Emulsion to patients with renal
13
failure and/or hepatic insufficiency has not been evaluated.
14
Neurosurgical Anesthesia: When DIPRIVAN Injectable Emulsion is used in patients with
15
increased intracranial pressure or impaired cerebral circulation, significant decreases in mean
16
arterial pressure should be avoided because of the resultant decreases in cerebral perfusion
17
pressure. To avoid significant hypotension and decreases in cerebral perfusion pressure, an
18
infusion or slow bolus of approximately 20 mg every 10 seconds should be utilized instead of
19
rapid, more frequent, and/or larger boluses of DIPRIVAN Injectable Emulsion. Slower
20
induction, titrated to clinical responses, will generally result in reduced induction dosage
21
requirements (1 to 2 mg/kg). When increased ICP is suspected, hyperventilation and
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
hypocarbia should accompany the administration of DIPRIVAN Injectable Emulsion. (See
2
DOSAGE AND ADMINISTRATION.)
3
Cardiac Anesthesia: Slower rates of administration should be utilized in premedicated
4
patients, geriatric patients, patients with recent fluid shifts, and patients who are
5
hemodynamically unstable. Fluid deficits should be corrected prior to administration of
6
DIPRIVAN Injectable Emulsion. In those patients where additional fluid therapy may be
7
contraindicated, other measures, e.g., elevation of lower extremities, or use of pressor agents,
8
may be useful to offset the hypotension which is associated with the induction of anesthesia
9
with DIPRIVAN Injectable Emulsion.
10
Information for Patients:
11
Patients should be advised that performance of activities requiring mental alertness, such as
12
operating a motor vehicle, or hazardous machinery or signing legal documents may be
13
impaired for some time after general anesthesia or sedation.
14
Drug Interactions:
15
The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in
16
patients with intramuscular or intravenous premedication, particularly with narcotics (e.g.,
17
morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (e.g.,
18
benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase
19
the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in
20
more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac
21
output.
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion
2
administration should be adjusted according to the desired level of anesthesia or sedation and
3
may be reduced in the presence of supplemental analgesic agents (e.g., nitrous oxide or
4
opioids). The concurrent administration of potent inhalational agents (e.g., isoflurane,
5
enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not
6
been extensively evaluated. These inhalational agents can also be expected to increase the
7
anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion.
8
DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset,
9
intensity or duration of action of the commonly used neuromuscular blocking agents (e.g.,
10
succinylcholine and nondepolarizing muscle relaxants).
11
No significant adverse interactions with commonly used premedications or drugs used during
12
anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic
13
agents, and local anesthetic agents) have been observed in adults. In pediatric patients,
14
administration of fentanyl concomitantly with DIPRIVAN Injectable Emulsion may result in
15
serious bradycardia.
16
Carcinogenesis, mutagenesis, impairment of fertility.
17
Carcinogenesis: Long-term studies in animals have not been performed to evaluate the
18
carcinogenic potential of propofol.
19
Mutagenesis: Propofol was not mutagenic in the in vitro bacterial reverse mutation assay
20
(Ames test) using Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and
21
TA1538. Propofol was not mutagenic in either the gene mutation/gene conversion test using
22
Saccharomyces cerevisiae, or in vitro cytogenetic studies in Chinese hamsters. In the in vivo
23
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
mouse micronucleus assay with Chinese Hamsters propofol administration did not produce
2
chromosome aberrations.
3
Impairment of fertility: Female Wistar rats were administered either 0, 10, or 15 mg/kg/day
4
propofol intravenously from 2 weeks before pregnancy to day 7 of gestation did not show
5
impaired fertility. Male fertility in rats was not affected in a dominant lethal study at
6
intravenous doses up to 15 mg/kg/day for 5 days.
7
Pregnancy
8
Teratogenic effects
9
Pregnancy Category B:
10
Reproduction studies have been performed in rats and rabbits at intravenous doses of 15
11
mg/kg/day (approximately equivalent to the recommended human induction dose on a mg/m2
12
basis) and have revealed no evidence of impaired fertility or harm to the fetus due to
13
propofol. Propofol, however, has been shown to cause maternal deaths in rats and rabbits and
14
decreased pup survival during the lactating period in dams treated with 15 mg/kg/day
15
(approximately equivalent to the recommended human induction dose on a mg/m2 basis).
16
The pharmacological activity (anesthesia) of the drug on the mother is probably responsible
17
for the adverse effects seen in the offspring. There are, however, no adequate and
18
well-controlled studies in pregnant women. Because animal reproduction studies are not
19
always predictive of human responses, this drug should be used during pregnancy only if
20
clearly needed.
21
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Labor and Delivery:
2
DIPRIVAN Injectable Emulsion is not recommended for obstetrics, including cesarean
3
section deliveries. DIPRIVAN Injectable Emulsion crosses the placenta, and as with other
4
general anesthetic agents, the administration of DIPRIVAN Injectable Emulsion may be
5
associated with neonatal depression.
6
Nursing Mothers:
7
DIPRIVAN Injectable Emulsion is not recommended for use in nursing mothers because
8
DIPRIVAN Injectable Emulsion has been reported to be excreted in human milk and the
9
effects of oral absorption of small amounts of propofol are not known.
10
Pediatric Use:
11
The safety and effectiveness of DIPRIVAN Injectable Emulsion have been established for
12
induction of anesthesia in pediatric patients aged 3 years and older and for the maintenance
13
of anesthesia aged 2 months and older.
14
DIPRIVAN Injectable Emulsion is not recommended for the induction of anesthesia in
15
patients younger than 3 years of age and for the maintenance of anesthesia in patients
16
younger than 2 months of age as safety and effectiveness have not been established.
17
In pediatric patients, administration of fentanyl concomitantly with DIPRIVAN Injectable
18
Emulsion may result in serious bradycardia (see PRECAUTIONS – General).
19
DIPRIVAN Injectable Emulsion is not indicated for use in pediatric patients for ICU
20
sedation or for MAC sedation for surgical, nonsurgical or diagnostic procedures as safety and
21
effectiveness have not been established.
25
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
There have been anecdotal reports of serious adverse events and death in pediatric patients
2
with upper respiratory tract infections receiving DIPRIVAN Injectable Emulsion for ICU
3
sedation.
4
In one multicenter clinical trial of ICU sedation in critically ill pediatric patients that
5
excluded patients with upper respiratory tract infections, the incidence of mortality observed
6
in patients who received DIPRIVAN Injectable Emulsion (n=222) was 9%, while that for
7
patients who received standard sedative agents (n=105) was 4%. While causality has not
8
been established, DIPRIVAN Injectable Emulsion is not indicated for sedation in pediatric
9
patients until further studies have been performed to document its safety in that population.
10
(See CLINICAL PHARMACOLOGY, Pharmacokinetics – Pediatric Patients: and DOSAGE
11
AND ADMINISTRATION).
12
In pediatric patients, abrupt discontinuation following prolonged infusion may result in
13
flushing of the hands and feet, agitation, tremulousness and hyperirritability. Increased
14
incidences of bradycardia (5%), agitation (4%), and jitteriness (9%) have also been observed.
15
Geriatric Use:
16
The effect of age on induction dose requirements for propofol was assessed in an open-label
17
study involving 211 unpremedicated patients with approximately 30 patients in each decade
18
between the ages of 16 and 80. The average dose to induce anesthesia was calculated for
19
patients up to 54 years of age and for patients 55 years of age or older. The average dose to
20
induce anesthesia in patients up to 54 years of age was 1.99 mg/kg and in patients above 54 it
21
was 1.66 mg/kg. Subsequent clinical studies have demonstrated lower dosing requirements
22
for subjects greater than 60 years of age.
26
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
A lower induction dose and a slower maintenance rate of administration of DIPRIVAN
2
Injectable Emulsion should be used in elderly patients. In this group of patients, rapid (single
3
or repeated) bolus administration should not be used in order to minimize undesirable
4
cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or
5
oxygen desaturation. All dosing should be titrated according to patient condition and
6
response. (See DOSAGE AND ADMINISTRATION – Elderly, Debilitated or ASA-PS III or
7
IV Patients and CLINICAL PHARMACOLOGY – Geriatrics.)
8
ADVERSE REACTIONS
9
General
10
Adverse event information is derived from controlled clinical trials and worldwide marketing
11
experience. In the description below, rates of the more common events represent
12
US/Canadian clinical study results. Less frequent events are also derived from publications
13
and marketing experience in over 8 million patients; there are insufficient data to support an
14
accurate estimate of their incidence rates. These studies were conducted using a variety of
15
premedicants, varying lengths of surgical/diagnostic procedures, and various other
16
anesthetic/sedative agents. Most adverse events were mild and transient.
17
Anesthesia and MAC Sedation in Adults
18
The following estimates of adverse events for DIPRIVAN Injectable Emulsion include data
19
from clinical trials in general anesthesia/MAC sedation (N=2889 adult patients). The
20
adverse events listed below as probably causally related are those events in which the actual
21
incidence rate in patients treated with DIPRIVAN Injectable Emulsion was greater than the
22
comparator incidence rate in these trials. Therefore, incidence rates for anesthesia and MAC
27
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
sedation in adults generally represent estimates of the percentage of clinical trial patients
2
which appeared to have probable causal relationship.
3
The adverse experience profile from reports of 150 patients in the MAC sedation clinical
4
trials is similar to the profile established with DIPRIVAN Injectable Emulsion during
5
anesthesia (see below). During MAC sedation clinical trials, significant respiratory events
6
included cough, upper airway obstruction, apnea, hypoventilation, and dyspnea.
7
Anesthesia in Pediatric Patients
8
Generally the adverse experience profile from reports of 506 DIPRIVAN Injectable
9
Emulsion pediatric patients from 6 days through 16 years of age in the US/Canadian
10
anesthesia clinical trials is similar to the profile established with DIPRIVAN Injectable
11
Emulsion during anesthesia in adults (see Pediatric percentages [Peds %] below). Although
12
not reported as an adverse event in clinical trials, apnea is frequently observed in pediatric
13
patients.
14
ICU Sedation in Adults
15
The following estimates of adverse events include data from clinical trials in ICU sedation
16
(N=159 adult patients). Probably related incidence rates for ICU sedation were determined
17
by individual case report form review. Probable causality was based upon an apparent dose
18
response relationship and/or positive responses to rechallenge. In many instances the
19
presence of concomitant disease and concomitant therapy made the causal relationship
20
unknown. Therefore, incidence rates for ICU sedation generally represent estimates of the
21
percentage of clinical trial patients which appeared to have a probable causal relationship.
22
28
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Incidence greater than 1% - Probably Causally Related
Anesthesia/MAC Sedation
ICU Sedation
Cardiovascular:
Bradycardia
Arrhythmia [Peds: 1.2%]
Tachycardia Nodal [Peds.
1.6%]
Hypotension* [Peds 17%]
(see also CLINICAL PHARMACOLOGY)
[Hypertension Peds:8%]
Bradycardia
Decreased Cardiac Output
Hypotension 26%
Central Nervous
System:
Movement* [Peds: 17%]
Injection Site:
Burning/Stinging or Pain,
17.6% [Peds: 10%]
Metabolic/Nutritional:
Hyperlipemia*
Respiratory
Apnea
(see also CLINICAL PHARMACOLOGY)
Respiratory Acidosis During
Weaning*
Skin and Appendages:
Rash [Peds: 5%]
Pruritus [Peds:2%]
Events without an * or % had an incidence of 1%-3%
*Incidence of events 3% to 10%
2
3
29
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Incidence less than 1% - Probably Causally Related
Anesthesia/MAC Sedation
ICU Sedation
Body as a Whole:
Anaphylaxis/Anaphylactoid Reaction
Perinatal Disorder
[Tachycardia]
[Bigeminy]
[Bradycardia]
[Premature Ventricular Contractions]
[Hemorrhage]
[ECG Abnormal]
[Arrhythmia Atrial]
[Fever]
[Extremities Pain]
[Anticholinergic Syndrome]
Cardiovascular:
Premature Atrial Contractions
Syncope
Central Nervous System:
Hypertonia/Dystonia, Paresthesia
Agitation
Digestive:
[Hypersalivation]
[Nausea]
Hemic/Lymphatic:
[Leukocytosis]
Injection Site:
[Phlebitis]
[Pruritus]
Metabolic:
Musculoskeletal:
Nervous:
[Hypomagnesemia]
Myalgia
[Dizziness]
[Agitation]
[Chills]
[Somnolence]
[Delirium]
Respiratory:
Wheezing
[Cough]
[Laryngospasm]
[Hypoxia]
Decreased Lung Function
Skin and Appendages:
Flushing, Pruritus
Special Senses:
Amblyopia
[Vision Abnormal]
2
Urogenital:
Cloudy Urine
Green Urine
3
30
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Incidence less than 1% - Causal Relationship Unknown
Anesthesia/MAC Sedation
ICU Sedation
Body as a Whole:
Asthenia, Awareness, Chest Pain,
Extremities Pain, Fever, Increased
Drug Effect, neck Rigidity/Stiffness,
Trunk pain
Fever, Sepsis, Trunk Pain, Whole Body Weakness
Cardiovascular:
Arrhythmia, Atrial Fibrillation,
Atrioventricular Heart Block,
Bigeminy, Bleeding, Bundle Branch
Block, Cardiac Arrest, ECG Abnormal,
Block, Hypertension, Myocardial
Infarction, Myocardial Ischemia,
Premature Ventricular Contractions,
ST Segment Depression,
Supraventricular Tachycardia,
Tachycardia, Ventricular Fibrillation
Arrhythmia, Atrial Fibrillation, Bigeminy, Cardiac
Arrest, Extrasystole, Right Heart Failure, ventricular
Tachycardia
Central Nervous System:
Abnormal Dreams, Agitation,
Amorous Behavior, Anxiety,
Bucking/Jerking/Thrashing,
Chills/Shivering/Clonic/Myoclonic
Movement, Combativeness,
Confusion, Delirium, Depression,
Dizziness, Emotional Lability,
Euphoria, Fatigue, Hallucinations,
Headache, Hypotonia, Hysteria,
Insomnia, Moaning, Neuropathy,
Opisthotonos, Rigidity, Seizures,
Somnolence, Tremor, Twitching
Chills/Shivering, Intracranial Hypertension,
Seizures, Somnolence, Thinking Abnormal
Digestive:
Cramping, Diarrhea, Dry Mouth,
Enlarged Parotid, Nausea, Swallowing,
Vomiting
Ileus, Liver Function Abnormal
Hematologic/Lymphatic:
Coagulation Disorder, Leukocytosis
Injection Site:
Hives/Itching, Phlebitis,
Redness/Discoloration
Metabolic/Nutritional:
Hyperkalemia, Hyperlipemia
BUN Increased, Creatinine Increased, Dehydration,
Hyperglycemia, Metabolic Acidosis, Osmolality
Increased
Respiratory:
Bronchospasm, Burning in Throat,
Cough, Dyspnea, Hiccough,
Hyperventilation, Hypoventilation,
Hypoxia, Laryngospasm, Pharyngitis,
Sneezing, Tachypnea, Upper Airway
Obstruction
Hypoxia
Skin and Appendages:
Conjunctival Hyperemia, Diaphoresis,
Urticaria
Rash
31
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Special Senses:
Diplopia, Ear Pain, Eye Pain,
Nystagmus, Taste Perversion,
Tinnitus
Urogenital:
Oliguria, Urine Retention
Kidney Failure
1
DRUG ABUSE AND DEPENDENCE
2
Rare cases of self-administration of DIPRIVAN Injectable Emulsion by health care
3
professionals have been reported, including some fatalities. DIPRIVAN Injectable
4
Emulsion should be managed to prevent the risk of diversion, including restriction of access
5
and accounting procedures as appropriate to the clinical setting.
6
OVERDOSAGE
7
If overdosage occurs, DIPRIVAN Injectable Emulsion administration should be discontinued
8
immediately. Overdosage is likely to cause cardiorespiratory depression. Respiratory
9
depression should be treated by artificial ventilation with oxygen. Cardiovascular depression
10
may require repositioning of the patient by raising the patient's legs, increasing the flow rate
11
of intravenous fluids, and administering pressor agents and/or anticholinergic agents.
12
DOSAGE AND ADMINISTRATION
13
Propofol blood concentrations at steady state are generally proportional to infusion rates,
14
especially in individual patients. Undesirable effects such as cardiorespiratory depression are
15
likely to occur at higher blood concentrations which result from bolus dosing or rapid
16
increases in the infusion rate. An adequate interval (3 to 5 minutes) must be allowed
17
between dose adjustments to allow for and assess the clinical effects.
18
When administering DIPRIVAN Injectable Emulsion by infusion, syringe or volumetric
19
pumps are recommended to provide controlled infusion rates. When infusing DIPRIVAN
32
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Injectable Emulsion to patients undergoing magnetic resonance imaging, metered control
2
devices may be utilized if mechanical pumps are impractical.
3
Changes in vital signs indicating a stress response to surgical stimulation or the emergence
4
from anesthesia may be controlled by the administration 25 mg (2.5 mL) to 50 mg (5 mL)
5
incremental boluses and/or by increasing the infusion rate of DIPRIVAN Injectable
6
Emulsion.
7
For minor surgical procedures (e.g., body surface) nitrous oxide (60%-70%) can be
8
combined with a variable rate DIPRIVAN Injectable Emulsion infusion to provide
9
satisfactory anesthesia. With more stimulating surgical procedures (e.g., intra-abdominal), or
10
if supplementation with nitrous oxide is not provided, administration rate(s) of DIPRIVAN
11
Injectable Emulsion and/or opioids should be increased in order to provide adequate
12
anesthesia.
13
Infusion rates should always be titrated downward in the absence of clinical signs of light
14
anesthesia until a mild response to surgical stimulation is obtained in order to avoid
15
administration of DIPRIVAN Injectable Emulsion at rates higher than are clinically
16
necessary. Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during
17
maintenance in order to optimize recovery times.
18
Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and
19
opioids) can increase CNS depression induced by propofol. Morphine premedication (0.15
20
mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary propofol
21
injection maintenance infusion rate and therapeutic blood concentrations when compared to
22
non-narcotic (lorazepam) premedication.
33
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Induction of General Anesthesia
2
Adult Patients: Most adult patients under 55 years of age and classified as ASA-PS I or II
3
require 2 to 2.5 mg/kg of DIPRIVAN Injectable Emulsion for induction when
4
unpremedicated or when premedicated with oral benzodiazepines or intramuscular opioids.
5
For induction, DIPRIVAN Injectable Emulsion should be titrated (approximately 40 mg
6
every 10 seconds) against the response of the patient until the clinical signs show the onset of
7
anesthesia. As with other sedative-hypnotic agents, the amount of intravenous opioid and/or
8
benzodiazepine premedication will influence the response of the patient to an induction dose
9
of DIPRIVAN Injectable Emulsion.
10
Elderly, Debilitated, or ASA-PS III or IV Patients: It is important to be familiar and
11
experienced with the intravenous use of DIPRIVAN Injectable Emulsion before treating
12
elderly, debilitated, or ASA-PS III or IV patients. Due to the reduced clearance and higher
13
blood concentrations, most of these patients require approximately 1 to 1.5 mg/kg
14
(approximately 20 mg every 10 seconds) of DIPRIVAN Injectable Emulsion for induction of
15
anesthesia according to their condition and responses. A rapid bolus should not be used, as
16
this will increase the likelihood of undesirable cardiorespiratory depression including
17
hypotension, apnea, airway obstruction, and/or oxygen desaturation (See DOSAGE AND
18
ADMINISTRATION).
19
Pediatric Patients: Most patients aged 3 years through 16 years and classified ASA-PS I or
20
II require 2.5 to 3.5 mg/kg of DIPRIVAN Injectable Emulsion for induction when
21
unpremedicated or when lightly premedicated with oral benzodiazepines or intramuscular
22
opioids. Within this dosage range, younger pediatric patients may require higher induction
23
doses than older pediatric patients. As with other sedative-hypnotic agents, the amount of
34
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
intravenous opioid and/or benzodiazepine premedication will influence the response of the
2
patient to an induction dose of DIPRIVAN Injectable Emulsion. A lower dosage is
3
recommended for pediatric patients classified as ASA-PS III or IV. Attention should be paid
4
to minimize pain on injection when administering DIPRIVAN Injectable Emulsion to
5
pediatric patients. Boluses of DIPRIVAN Injectable Emulsion may be administered via
6
small veins if pretreated with lidocaine or via antecubital or larger veins (See
7
PRECAUTIONS - General).
8
Neurosurgical Patients: Slower induction is recommended using boluses of 20 mg every
9
10 seconds. Slower boluses or infusions of DIPRIVAN Injectable Emulsion for induction of
10
anesthesia, titrated to clinical responses, will generally result in reduced induction dosage
11
requirements (1 to 2 mg/kg). (See PRECAUTIONS and DOSAGE AND
12
ADMINISTRATION.)
13
Cardiac Anesthesia: DIPRIVAN Injectable Emulsion has been well-studied in patients
14
with coronary artery disease, but experience in patients with hemodynamically significant
15
valvular or congenital heart disease is limited. As with other anesthetic and sedative
16
hypnotic agents, DIPRIVAN Injectable Emulsion in healthy patients causes a decrease in
17
blood pressure that is secondary to decreases in preload (ventricular filling volume at the end
18
of the diastole) and afterload (arterial resistance at the beginning of the systole). The
19
magnitude of these changes is proportional to the blood and effect site concentrations
20
achieved. These concentrations depend upon the dose and speed of the induction and
21
maintenance infusion rates.
35
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
In addition, lower heart rates are observed during maintenance with DIPRIVAN Injectable
2
Emulsion, possibly due to reduction of the sympathetic activity and/or resetting of the
3
baroreceptor reflexes. Therefore, anticholinergic agents should be administered when
4
increases in vagal tone are anticipated.
5
As with other anesthetic agents, DIPRIVAN Injectable Emulsion reduces myocardial oxygen
6
consumption. Further studies are needed to confirm and delineate the extent of these effects
7
on the myocardium and the coronary vascular system.
8
Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to
9
decrease the necessary DIPRIVAN Injectable Emulsion maintenance infusion rates and
10
therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication.
11
The rate of DIPRIVAN Injectable Emulsion administration should be determined based on
12
the patient's premedication and adjusted according to clinical responses.
13
A rapid bolus induction should be avoided. A slow rate of approximately 20 mg every 10
14
seconds until induction onset (0.5 to 1.5 mg/kg) should be used. In order to assure adequate
15
anesthesia, when DIPRIVAN Injectable Emulsion is used as the primary agent, maintenance
16
infusion rates should not be less than 100 mcg/kg/min and should be supplemented with
17
analgesic levels of continuous opioid administration. When an opioid is used as the primary
18
agent, DIPRIVAN Injectable Emulsion maintenance rates should not be less than
19
50 mcg/kg/min, and care should be taken to ensure amnesia. Higher doses of DIPRIVAN
20
Injectable Emulsion will reduce the opioid requirements (see Table 4). When DIPRIVAN
21
Injectable Emulsion is used as the primary anesthetic, it should not be administered with the
36
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
high-dose opioid technique as this may increase the likelihood of hypotension (see
2
PRECAUTIONS - Cardiac Anesthesia).
3
Table 4. Cardiac Anesthesia Techniques
Primary Agent
DIPRIVAN Injectable Emulsion
Preinduction
Anxiolysis
Induction
Maintenance
(Titrated to Clinical
Response)
OPIOIDb
Induction
Maintenance
Rate
Secondary Agent/Rate
(Following Induction with Primary Agent)
OPIOIDa/0.05-0.075 mcg/kg/min (no bolus)
25 mcg/kg/min
0.5-1.5 mg/kg
over 60 sec
100-150 mcg/kg/m
DIPRIVAN Injectable Emulsion/50-100 mcg/kg/min
(no bolus)
25-50 mcg/kg
0.2-0.3 mcg/kg/mi
4
aOPIOID is defined in terms of fentanyl equivalents, i.e.,
5
1 µg of fentanyl
= 5 mcg of alfentanil (for bolus)
6
= 10 mcg of alfentanil (for maintenance)
7
or
8
= 0.1 mcg of sufentanil
9
bCare should be taken to ensure amnesia .
10
Maintenance of General Anesthesia
11
Adult Patients: In adults, anesthesia can be maintained by administering DIPRIVAN
12
Injectable Emulsion by infusion or intermittent IV bolus injection. The patient's clinical
13
response will determine the infusion rate or the amount and frequency of incremental
14
injections.
15
Continuous Infusion: DIPRIVAN Injectable Emulsion 100 to 200 mcg/kg/min
16
administered in a variable rate infusion with 60%-70% nitrous oxide and oxygen provides
17
anesthesia for patients undergoing general surgery. Maintenance by infusion of DIPRIVAN
37
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Injectable Emulsion should immediately follow the induction dose in order to provide
2
satisfactory or continuous anesthesia during the induction phase. During this initial period
3
following the induction dose, higher rates of infusion are generally required (150 to 200
4
mcg/kg/min) for the first 10 to 15 minutes. Infusion rates should subsequently be decreased
5
30%-50% during the first half-hour of maintenance. Generally, rates of 50 - 100 mcg/kg/min
6
in adults should be achieved during maintenance in order to optimize recovery times.
7
Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and
8
opioids) can increase the CNS depression induced by propofol.
9
Intermittent Bolus: Increments of DIPRIVAN Injectable Emulsion 25 mg (2.5 mL) to 50
10
mg (5 mL) may be administered with nitrous oxide in adult patients undergoing general
11
surgery. The incremental boluses should be administered when changes in vital signs
12
indicate a response to surgical stimulation or light anesthesia.
13
Pediatric Patients: DIPRIVAN Injectable Emulsion administered as a variable rate infusion
14
supplemented with nitrous oxide 60% - 70% provides satisfactory anesthesia for most
15
children 2 months of age or older, ASA-PS I or II, undergoing general anesthesia.
16
In general, for the pediatric population, maintenance by infusion of DIPRIVAN Injectable
17
Emulsion at a rate of 200 – 300 mcg/kg/min should immediately follow the induction dose.
18
Following the first half-hour of maintenance, infusion rates of 125-150 mcg/kg/min are
19
typically needed. DIPRIVAN Injectable Emulsion should be titrated to achieve the desired
20
clinical effect. Younger pediatric patients may require higher maintenance infusion rates
21
than older pediatric patients. (See Table 2 Clinical Trials.)
38
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
DIPRIVAN Injectable Emulsion has been used with a variety of agents commonly used in
2
anesthesia such as atropine, scopolamine, glycopyrrolate, diazepam, depolarizing and
3
nondepolarizing muscle relaxants, and opioid analgesics, as well as with inhalational and
4
regional anesthetic agents.
5
In the elderly, debilitated, or ASA-PS III or IV patients, rapid bolus doses should not be used,
6
as this will increase cardiorespiratory effects including hypotension, apnea, airway
7
obstruction, and oxygen desaturation.
8
Monitored Anesthesia Care (MAC) Sedation
9
Adult Patients: When DIPRIVAN Injectable Emulsion is administered for MAC sedation,
10
rates of administration should be individualized and titrated to clinical response. In most
11
patients, the rates of DIPRIVAN Injectable Emulsion administration will be in the range of
12
25-75 mcg/kg/min.
13
During initiation of MAC sedation, slow infusion or slow injection techniques are preferable
14
over rapid bolus administration. During maintenance of MAC sedation, a variable rate
15
infusion is preferable over intermittent bolus dose administration. In the elderly, debilitated,
16
or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not
17
be used for MAC sedation. (See WARNINGS.) A rapid bolus injection can result in
18
undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction,
19
and oxygen desaturation.
20
Initiation of MAC Sedation: For initiation of MAC sedation, either an infusion or a slow
21
injection method may be utilized while closely monitoring cardiorespiratory function. With
22
the infusion method, sedation may be initiated by infusing DIPRIVAN Injectable Emulsion
39
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
at 100 to 150 mcg/kg/min (6 to 9 mg/kg/h) for a period of 3 to 5 minutes and titrating to the
2
desired clinical effect while closely monitoring respiratory function. With the slow injection
3
method for initiation, patients will require approximately 0.5 mg/kg administered over 3 to 5
4
minutes and titrated to clinical responses. When DIPRIVAN Injectable Emulsion is
5
administered slowly over 3 to 5 minutes, most patients will be adequately sedated, and the
6
peak drug effect can be achieved while minimizing undesirable cardiorespiratory effects
7
occurring at high plasma levels.
8
In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose
9
administration should not be used for MAC sedation. (See WARNINGS.) The rate of
10
administration should be over 3-5 minutes and the dosage of DIPRIVAN Injectable Emulsion
11
should be reduced to approximately 80% of the usual adult dosage in these patients according
12
to their condition, responses, and changes in vital signs. (See DOSAGE AND
13
ADMINISTRATION.)
14
Maintenance of MAC Sedation: For maintenance of sedation, a variable rate infusion
15
method is preferable over an intermittent bolus dose method. With the variable rate infusion
16
method, patients will generally require maintenance rates of 25 to 75 mcg/kg/min (1.5 to 4.5
17
mg/kg/h) during the first 10 to 15 minutes of sedation maintenance. Infusion rates should
18
subsequently be decreased over time to 25 to 50 mcg/kg/min and adjusted to clinical
19
responses. In titrating to clinical effect, allow approximately 2 minutes for onset of peak
20
drug effect.
21
Infusion rates should always be titrated downward in the absence of clinical signs of light
22
sedation until mild responses to stimulation are obtained in order to avoid sedative
40
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
administration of DIPRIVAN Injectable Emulsion at rates higher than are clinically
2
necessary.
3
If the intermittent bolus dose method is used, increments of DIPRIVAN Injectable Emulsion
4
10 mg (1 mL) or 20 mg (2 mL) can be administered and titrated to desired clinical effect.
5
With the intermittent bolus method of sedation maintenance, there is increased potential for
6
respiratory depression, transient increases in sedation depth, and prolongation of recovery.
7
In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose
8
administration should not be used for MAC sedation. (See WARNINGS.) The rate of
9
administration and the dosage of DIPRIVAN Injectable Emulsion should be reduced to
10
approximately 80% of the usual adult dosage in these patients according to their condition,
11
responses, and changes in vital signs. (See DOSAGE AND ADMINISTRATION.)
12
DIPRIVAN Injectable Emulsion can be administered as the sole agent for maintenance of
13
MAC sedation during surgical/diagnostic procedures. When DIPRIVAN Injectable
14
Emulsion sedation is supplemented with opioid and/or benzodiazepine medications, these
15
agents increase the sedative and respiratory effects of DIPRIVAN Injectable Emulsion and
16
may also result in a slower recovery profile. (See PRECAUTIONS, Drug Interactions.)
17
ICU Sedation: (See WARNINGS and DOSAGE AND ADMINISTRATION,
18
Handling Procedures.)
19
Abrupt discontinuation of DIPRIVAN Injectable Emulsion prior to weaning or for daily
20
evaluation of sedation levels should be avoided. This may result in rapid awakening with
21
associated anxiety, agitation, and resistance to mechanical ventilation. Infusions of
22
DIPRIVAN Injectable Emulsion should be adjusted to assure a minimal level of sedation is
41
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
maintained throughout the weaning process and when assessing the level of sedation. (See
2
PRECAUTIONS.)
3
Adult Patients: For intubated, mechanically ventilated adult patients, Intensive Care Unit
4
(ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to
5
desired clinical effect and minimize hypotension. (See DOSAGE AND
6
ADMINISTRATION.)
7
Most adult ICU patients recovering from the effects of general anesthesia or deep sedation
8
will require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) individualized and
9
titrated to clinical response. (See DOSAGE AND ADMINISTRATION.) With medical ICU
10
patients or patients who have recovered from the effects of general anesthesia or deep
11
sedation, the rate of administration of 50 mcg/kg/min or higher may be required to achieve
12
adequate sedation. These higher rates of administration may increase the likelihood of
13
patients developing hypotension.
14
Dosage and rate of administration should be individualized and titrated to the desired effect,
15
according to clinically relevant factors including the patient’s underlying medical problems,
16
preinduction and concomitant medications, age, ASA-PS classification, and level of
17
debilitation of the patient. The elderly, debilitated, and ASA-PS III or IV patients may have
18
exaggerated hemodynamic and respiratory responses to rapid bolus doses. (See
19
WARNINGS.)
20
DIPRIVAN Injectable Emulsion should be individualized according to the patient's condition
21
and response, blood lipid profile, and vital signs. (See PRECAUTIONS - Intensive Care
22
Unit Sedation.) For intubated, mechanically ventilated adult patients, Intensive Care Unit
42
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
(ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to
2
desired clinical effect and minimize hypotension. When indicated, initiation of sedation
3
should begin at 5 mcg/kg/min (0.3 mg/kg/h). The infusion rate should be increased by
4
increments of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/h) until the desired level of sedation is
5
achieved. A minimum period of 5 minutes between adjustments should be allowed for onset
6
of peak drug effect. Most adult patients require maintenance rates of 5 to 50 mcg/kg/min
7
(0.3 to 3 mg/kg/h) or higher. Dosages of DIPRIVAN Injectable Emulsion should be reduced
8
in patients who have received large dosages of narcotics. Conversely, the DIPRIVAN
9
Injectable Emulsion dosage requirement may be reduced by adequate management of pain
10
with analgesic agents. As with other sedative medications, there is interpatient variability in
11
dosage requirements, and these requirements may change with time. (See SUMMARY OF
12
DOSAGE GUIDELINES.) Evaluation of level of sedation and assessment of cns function
13
should be carried out daily throughout maintenance to determine the minimum dose of
14
DIPRIVAN required for sedation (see CLINICAL TRIALS, Intensive Care Unit (ICU)
15
Sedation). Bolus administration of 10 or 20 mg should only be used to rapidly increase depth
16
of sedation in patients where hypotension is not likely to occur. Patients with compromised
17
myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g.,
18
sepsis) may be more susceptible to hypotension. (See PRECAUTIONS.).
19
SUMMARY OF DOSAGE GUIDELINES
20
Dosages and rates of administration in the following table should be individualized and
21
titrated to clinical response. Safety and dosing requirements for induction of anesthesia in
22
pediatric patients have only been established for children 3 years of age or older. Safety and
43
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
dosing requirements for the maintenance of anesthesia have only been established for
2
children 2 months of age and older.
3
For complete dosage information, see DOSAGE AND ADMINISTRATION.
INDICATION
DOSAGE AND ADMINISTRATION
Induction of General Anesthesia
Healthy Adults Less Than 55 Years of Age:
40 mg every 10 seconds until induction onset (2 to 2.5 mg/kg).
Elderly, Debilitated, or ASA-PS III or IV Patients:
20 mg every 10 seconds until induction onset (1 to 1.5 mg/kg).
Cardiac Anesthesia:
20 mg every 10 seconds until induction onset (0.5 to 1.5 mg/kg).
Neurosurgical Patients:
20 mg every 10 seconds until induction onset (1 to 2 mg/kg)
Pediatric Patients - healthy, from 3 years to 16 years of age:
2.5 to 3.5 mg/kg administered over 20-30 seconds.
(See PRECAUTIONS – Pediatric Use: and CLINICAL
PHARMACOLOGY – Pediatrics )
Maintenance of General Anesthesia: Infusion
Healthy Adults Less Than 55 Years of Age:
100 to 200 mcg/kg/min (6 to 12 mg/kg/h).
Elderly, Debilitated, ASA-PS III or IV Patients:
50 to 100 mcg/kg/min (3 to 6 mg/kg/h).
Cardiac Anesthesia: Most patients require:
Primary DIPRIVAN Injectable Emulsion with Secondary Opioid –
100 – 150 mcg/kg/min
Low-Dose DIPRIVAN Injectable Emulsion with Primary Opioid –
50 - 100 mcg/kg/min
(See DOSAGE AND ADMINISTRATION, Table 4)
Neurosurgical Patients:
100 to 200 mcg/kg/min (6 to 12 mg/kg/h).
Pediatric Patients - healthy, from 2 months of age to 16 years of age:
125 to 300 mcg/kg/min (7.5 to 18 mg/kg/h)
Following the first half hour of maintenance, if clinical signs of light
anesthesia are not present, the infusion rate should be decreased.
(See PRECAUTIONS – Pediatric Use: and CLINICAL
PHARMACOLOGY – Pediatrics )
Maintenance of General Anesthesia: Intermittent Bolus
Healthy Adults Less Than 55 Years of Age:
Increments of 20 to 50 mg as needed.
Initiation of MAC Sedation:
Healthy Adults Less Than 55 Years of Age:
Slow infusion or slow injection techniques are recommended to avoid apnea
44
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
or hypotension. Most patients require an infusion of 100 to 150 mcg/kg/min
(6 to 9 mg/kg/h) for 3 to 5 minutes or a slow injection of 0.5 mg/kg over 3
to 5 minutes followed immediately by a maintenance infusion.
Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients:
Most patients require dosages similar to healthy adults.
Rapid boluses are to be avoided. (See WARNINGS.)
Maintenance of MAC Sedation
Healthy Adults Less Than 55 Years of Age:
A variable rate infusion technique is preferable over an intermittent bolus
technique. Most patients require an infusion of 25 to 75 mcg/kg/min
(1.5 to 4.5 mg/kg/h) or incremental bolus doses of 10 mg or 20 mg.
In Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients:
Most patients require 80% of the usual adult dose. A rapid (single or
repeated) bolus dose should not be used. (See WARNINGS.)
Initiation and Maintenance of ICU Sedation in Intubated, Mechanically Ventilated
Adult Patients - Because of the residual effects of previous anesthetic or
sedative agents, in most patients the initial infusion should be 5 µg/kg/min
(0.3 mg/kg/h) for at least 5 minutes. Subsequent increments of 5 to 10
mcg/kg/min (0.3 to 0.6 mg/kg/h) over 5 to 10 minutes may be used until
desired clinical effect is achieved. Maintenance rates of 5 to 50 mcg/kg/min
(0.3 to 3 mg/kg/h) or higher may be required.
Evaluation of clinical effect and assessment of CNS function should be
carried out daily throughout maintenance to determine the minimum
dose of DIPRIVAN Injectable Emulsion required for sedation.
The tubing and any unused portions of DIPRIVAN Injectable Emulsion
should be discarded after 12 hours because DIPRIVAN Injectable
Emulsion contains no preservatives and is capable of supporting growth
of microorganisms. (See WARNINGS, and DOSAGE AND
ADMINISTRATION.)
1
Administration with Lidocaine: If lidocaine is to be administered to minimize pain on
2
injection of DIPRIVAN, it is recommended that it be administered prior to DIPRIVAN
3
administration or that it be added to DIPRIVAN immediately before administration and in
4
quantities not exceeding 20 mg lidocaine/200 mg DIPRIVAN.
5
Compatibility and Stability: DIPRIVAN Injectable Emulsion should not be mixed with
6
other therapeutic agents prior to administration.
7
Dilution Prior to Administration: DIPRIVAN Injectable Emulsion is provided as a ready
8
to-use formulation. However, should dilution be necessary, it should only be diluted with
45
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
5% Dextrose Injection, USP, and it should not be diluted to a concentration less than 2
2
mg/mL because it is an emulsion. In diluted form it has been shown to be more stable when
3
in contact with glass than with plastic (95% potency after 2 hours of running infusion in
4
plastic).
5
Administration with Other Fluids: Compatibility of DIPRIVAN Injectable Emulsion with
6
the coadministration of blood/serum/plasma has not been established. (See WARNINGS.)
7
When administered using a y-type infusion set, DIPRIVAN Injectable Emulsion has been
8
shown to be compatible with the following intravenous fluids.
9
- 5% Dextrose Injection, USP
10
- Lactated Ringers Injection, USP
11
- Lactated Ringers and 5% Dextrose Injection
12
- 5% Dextrose and 0.45% Sodium Chloride Injection, USP
13
- 5% Dextrose and 0.2% Sodium Chloride Injection, USP
14
Handling Procedures
15
General
16
Parenteral drug products should be inspected visually for particulate matter and discoloration
17
prior to administration whenever solution and container permit.
18
Clinical experience with the use of in-line filters and DIPRIVAN Injectable Emulsion during
19
anesthesia or ICU/MAC sedation is limited. DIPRIVAN Injectable Emulsion should only be
20
administered through a filter with a pore size of 5 mcm or greater unless it has been
21
demonstrated that the filter does not restrict the flow of DIPRIVAN Injectable Emulsion
22
and/or cause the breakdown of the emulsion. Filters should be used with caution and where
46
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
clinically appropriate. Continuous monitoring is necessary due to the potential for restricted
2
flow and/or breakdown of the emulsion.
3
Do not use if there is evidence of separation of the phases of the emulsion.
4
Rare cases of self-administration of DIPRIVAN Injectable Emulsion by health care
5
professionals have been reported, including some fatalities (See DRUG ABUSE AND
6
DEPENDENCE).
7
Strict aseptic technique must always be maintained during handling. Diprivan
8
Injectable Emulsion is a single-use parenteral product which contains 0.005% disodium
9
edetate to inhibit the rate of growth of microorganisms, up to 12 hours, in the event of
10
accidental extrinsic contamination. However, Diprivan Injectable Emulsion can still
11
support the growth of microorganisms as it is not an antimicrobially preserved product
12
under USP standards. Accordingly, strict aseptic technique must still be adhered to.
13
Do not use if contamination is suspected. Discard unused portions as directed within
14
the required time limits (see dosage and administration, handling procedures). There
15
have been reports in which failure to use aseptic technique when handling Diprivan
16
Injectable Emulsion was associated with microbial contamination of the product and
17
with fever, infection/sepsis, other life-threatening illness, and/or death.
18
Diprivan, with EDTA, inhibits microbial growth for up to 12 hours, as demonstrated by test
19
data for representative USP microorganisms.
47
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Guidelines for Aseptic Technique for General Anesthesia/MAC Sedation:
2
DIPRIVAN Injectable Emulsion should be prepared for use just prior to initiation of each
3
individual anesthetic/sedative procedure. The vial syringe rubber stopper should be
4
disinfected using 70% isopropyl alcohol. DIPRIVAN Injectable Emulsion should be drawn
5
into sterile syringes immediately after vials are opened. When withdrawing DIPRIVAN
6
Injectable Emulsion from vials, a sterile vent spike should be used. The syringe(s) should be
7
labeled with appropriate information including the date and time the vial was opened.
8
Administration should commence promptly and be completed within 12 hours after the vials
9
have been opened.
10
DIPRIVAN Injectable Emulsion should be prepared for single-patient use only. Any unused
11
portions of DIPRIVAN Injectable Emulsion, reservoirs, dedicated administration tubing
12
and/or solutions containing DIPRIVAN Injectable Emulsion must be discarded at the end of
13
the anesthetic procedure or at 12 hours, whichever occurs sooner. The IV line should be
14
flushed every 12 hours and at the end of the anesthetic procedure to remove residual
15
DIPRIVAN Injectable Emulsion.
16
Guidelines for Aseptic Technique for ICU Sedation
17
DIPRIVAN Injectable Emulsion should be prepared for single-patient use only. When
18
DIPRIVAN Injectable Emulsion is administered directly from the vial, strict aseptic
19
techniques must be followed. The vial rubber stopper should be disinfected using 70%
20
isopropyl alcohol. A sterile vent spike and sterile tubing must be used for administration of
21
DIPRIVAN Injectable Emulsion. As with other lipid emulsions, the number of IV line
22
manipulations should be minimized. Administration should commence promptly and must
48
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
be completed within 12 hours after the vial has been spiked. The tubing and any unused
2
portions of DIPRIVAN Injectable Emulsion must be discarded after 12 hours.
3
If DIPRIVAN Injectable Emulsion is transferred to a syringe or other container prior to
4
administration, the handling procedures for General anesthesia/MAC sedation should be
5
followed, and the product should be discarded and administration lines changed after 12
6
hours.
7
HOW SUPPLIED
8
DIPRIVAN Injectable Emulsion is available as follows:
Product
No.
260920
NDC
No.
63323-269-20
260950
63323-269-50
260965
63323-269-65
Strength
1% (10 mg/mL propofol)
20 mL ready-to–use single
patient infusion vial.
1% (10 mg/mL propofol)
50 mL ready-to–use single
patient infusion vial.
1% (10 mg/mL propofol)
100 mL ready-to–use
single patient infusion vial.
9
Propofol undergoes oxidative degradation, in the presence of oxygen, and is therefore
10
packaged under nitrogen to eliminate this degradation path.
11
Store between 4-22°C (40-72°F). Do not freeze. Shake well before use.
12
All trademarks are the property of APP Pharmaceuticals, LLC.
49
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
Manufactured for:
Company Logo
3
Made in Italy
4
5
451094A
6
Issued: February 2008
50
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Packaging
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Packaging
Unvarnished Area
Place an opaque white
box behind the laser box.
Laser box should be
Letter Press or Flexo Ink Only
Packag
ing
Notes to Printer:
Software: Illus. 11
Fonts: Helvetica Regular, Bold, Bold Oblique;
Helvetica Cond. Medium, Bold, Oblique;
OCRB; Symbol
Barcode: The use of codes provided in artwork is optional;
replace if code specifications do not meet press requirements.
UPC - Magnification 85%, Bar Adjust -.002
Information encoded: 3 63323 269 20 3
AZ NDC 0310-0300-22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Packaging
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Packaging
Packag
ing
Notes to Printer:
Software: Illus. 11
Fonts: Helvetica Regular, Bold, Bold Oblique;
Helvetica Cond. Medium, Bold, Oblique;
OCRB; Symbol
Barcode: The use of codes provided in artwork is optional;
replace if code specifications do not meet press requirements.
14-digit I 2 of 5 - Magnification 18.0%, Narrow Bar .0072
Ratio 2.5, Bar Adjust -.002
Information encoded: 3 03 63323 269 50 1
AZ NDC 0310-0300-50
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Packaging
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Text in color block to be
printed in white. Number
one to be printed in white
with PMS 301 outline.
Packaging
Packaging
Notes to Printer:
Software: Illus. 11.0
Fonts: Helvetica Regular, Bold, Bold Oblique;
Helvetica Cond. Medium, Bold, Oblique; Symbol;
OCRB
Barcode: The use of codes provided in artwork is optional;
replace if code specifications do not meet press requirements.
12-digit UPC - Magnification 100%, Bar Adjust -.002
Information encoded: 3 63323 269 65 4
AZ NDC 0310-0300-11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:33.383364
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019627s046lbl.pdf', 'application_number': 19627, 'submission_type': 'SUPPL ', 'submission_number': 46}
|
11,574
|
----------
NDA 19635/S-035
Page 4
SODIUM CHLORIDE- sodium chloride injection, solution
B. Braun Medical Inc.
0.9% Sodium Chloride Injection USP
DESCRIPTION
Each 100 mL of 0.9% Sodium Chloride Injection USP contains:
Sodium Chloride USP 0.9 g; Water for Injection USP qs
pH: 5.6 (4.5-7.0)
Calculated Osmolarity: 308 mOsmol/liter
pH adjusted with Hydrochloric Acid NF
Concentration of Electrolytes (mEq/liter): Sodium 154 Chloride 154
Sodium Chloride Injection USP is sterile, nonpyrogenic, isotonic and contains no bacteriostatic
or antimicrobial agents.
The formula of the active ingredient is:
Not made with natural rubber latex, PVC, or DEHP.
The plastic container is made from a homogenous blend of polypropylene and thermoplastic
modifier specifically developed for parenteral drugs. The container is nontoxic and biologically
inert. The container is a closed system and is not dependent upon entry of external air during
administration.
Addition of medication should be accomplished using complete aseptic technique.
The closure system has two ports; one for the administration set and the other is a medication
addition site. Each port has a tamper evident cover. Refer to the Directions for Use of the
container.
CLINICAL PHARMACOLOGY
Sodium Chloride Injection USP provides electrolytes and is a source of water for hydration. It is
capable of inducing diuresis depending on the clinical condition of the patient.
Sodium, the major cation of the extracellular fluid, functions primarily in the control of water
distribution, fluid balance, and osmotic pressure of body fluids. Sodium is also associated with
chloride and bicarbonate in the regulation of the acid-base equilibrium of body fluid.
Reference ID: 3623377
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19635/S-035
Page 5
Chloride, the major extracellular anion, closely follows the metabolism of sodium, and changes
in the acid-base balance of the body are reflected by changes in the chloride concentration.
INDICATIONS AND USAGE
This intravenous solution is indicated for use in adults and pediatric patients as a source of
electrolytes and water for hydration.
0.9% Sodium Chloride Injection USP is indicated for extracellular fluid replacement, treatment
of metabolic alkalosis in the presence of fluid loss and mild sodium depletion.
0.9% Sodium Chloride Injection USP is also indicated for use as a priming solution in
hemodialysis procedures and may be used to initiate and terminate blood transfusions without
hemolyzing red blood cells.
Sodium Chloride Injection USP is also indicated as a pharmaceutic aid and diluent for the
infusion of compatible drug additives. Refer to prescribing information accompanying additive
drugs.
CONTRAINDICATIONS
This solution is contraindicated where the administration of sodium or chloride could be
clinically detrimental.
WARNINGS
The administration of intravenous solutions can cause fluid and/or solute overload resulting in
dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary
edema. The risk of dilutional states is inversely proportional to the electrolyte concentration. The
risk of solute overload causing congested states with peripheral and pulmonary edema is directly
proportional to the electrolyte concentration.
Solutions containing sodium ions should be used with great care, if at all, in patients with
congestive heart failure, severe renal insufficiency, and in clinical states in which there is sodium
retention with edema. In patients with diminished renal function, administration of solutions
containing sodium ions may result in sodium retention.
Infusion of isotonic (0.9%) sodium chloride during or immediately after surgery may result in
excessive sodium retention. Use the patient’s circulatory system status as a guide.
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
Reference ID: 3623377
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19635/S-035
Page 6
from normal concentrations may require tailoring of the electrolyte pattern, in these or alternative
solutions.
This solution should be used with care in patients with hypervolemia, renal insufficiency, urinary
tract obstruction, or impending or frank cardiac decompensation.
Extraordinary electrolyte losses such as may occur during protracted nasogastric suction,
vomiting, diarrhea or gastrointestinal fistula drainage may necessitate additional electrolyte
supplementation. Additional essential electrolytes, minerals and vitamins should be supplied as
needed.
Sodium-containing solutions should be administered with caution to patients receiving
corticosteroids or corticotropin, or to other salt-retaining patients. Care should be exercised in
administering solutions containing sodium to patients with renal or cardiovascular insufficiency,
with or without congestive heart failure, particularly if they are postoperative or elderly.
Infusion of more than one liter of isotonic (0.9%) sodium chloride per day may supply more
sodium and chloride than normally found in serum, and can exceed normal tolerance, resulting in
hypernatremia; this may also cause a loss of bicarbonate ions, resulting in an acidifying effect.
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.
Do not use plastic container in series connection.
If administration is controlled by a pumping device, care must be taken to discontinue pumping
action before the container runs dry or air embolism may result.
This solution is intended for intravenous administration using sterile equipment. It is
recommended that intravenous administration apparatus be replaced at least once every 24 hours.
Use only if solution is clear and container and seals are intact.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies with Sodium Chloride Injection USP have not been performed to evaluate carcinogenic
potential, mutagenic potential or effects on fertility.
Pregnancy
Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Sodium
Chloride Injection USP. It is also not known whether Sodium Chloride Injection USP can cause
fetal harm when administered to a pregnant woman or can affect reproduction capacity. Sodium
Chloride Injection USP should be given to a pregnant woman only if clearly needed.
Reference ID: 3623377
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19635/S-035
Page 7
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 Sodium Chloride Injection USP is administered
to a nursing woman.
Pediatric Use
Safety and effectiveness of sodium chloride injections in pediatric patients have not been
established by adequate and well controlled trials, however, the use of electrolyte solutions in the
pediatric population is referenced in the medical literature. The warnings, precautions and
adverse reactions identified in the label copy should be observed in the pediatric population.
Geriatric Use
An evaluation of current literature revealed no clinical experience identifying differences in
response between 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 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
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.
The physician should also be alert to the possibility of adverse reactions to drug additives.
Prescribing information for drug additives to be administered in this manner should be consulted.
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.
Hypernatremia may be associated with edema and exacerbation of congestive heart failure due to
the retention of water, resulting in an expanded extracellular fluid volume.
If infused in large amounts, chloride ions may cause a loss of bicarbonate ions, resulting in an
acidifying effect.
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.
Reference ID: 3623377
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19635/S-035
Page 8
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
This solution is for intravenous use only.
Dosage is to be directed by a physician and is dependent upon age, weight, clinical condition of
the patient and laboratory determinations. Frequent laboratory determinations and clinical
evaluation are essential to monitor changes in blood glucose and electrolyte concentrations, and
fluid and electrolyte balance during prolonged parenteral therapy.
In the average adult, daily requirements of sodium and chloride are met by the infusion of one
liter of 0.9% sodium chloride (154 mEq each of sodium and chloride).
There is no specific pediatric dose. The dose is dependent on weight, clinical condition and
laboratory results. Follow recommendations of appropriate pediatric reference text. (See
PRECAUTIONS, Pediatric Use.)
Fluid administration should be based on calculated maintenance or replacement fluid
requirements for each patient.
0.9% Sodium Chloride Injection USP may also be administered intravascularly as a priming
fluid in hemodialysis procedures.
When Sodium Chloride Injection USP is used as a diluent for infusion of compatible drug
additives, refer to dosage and administration information accompanying additive drugs.
Some additives may be incompatible. Consult with pharmacist. When introducing additives, use
aseptic techniques. Mix thoroughly. Do not store.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit.
HOW SUPPLIED
Sodium Chloride Injection USP is supplied sterile and nonpyrogenic in Plastic Containers
packaged 12 per case.
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.
Directions for Use of Plastic Container
Reference ID: 3623377
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19635/S-035
Page 9
Caution: Do not use plastic container in series connection.
To Open
Check for minute leaks by squeezing solution container firmly. If leaks are found, discard
solution as sterility may be impaired. If supplemental medication is desired, follow directions
below before preparing for administration.
NOTE: Before use, perform the following checks:
Inspect each container. Read the label. Ensure solution is the one ordered and is within the
expiration date.
Invert container and carefully inspect the solution in good light for cloudiness, haze, or
particulate matter. Any container which is suspect should not be used.
Use only if solution is clear and container and seals are intact.
Preparation for Administration
1. Remove plastic protector from sterile set port at bottom of container.
2. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Warning: Some additives may be incompatible.
To Add Medication Before Solution Administration
1. Prepare medication site by removing the additive port closure. Swab the exposed
medication site before puncturing.
2. Using syringe with 18-22 Ga. needle, puncture medication port and inner diaphragm and
inject.
3. Squeeze and tap ports while ports are upright and mix solution and medication
thoroughly.
To Add Medication During Solution Administration
1. Close clamp on the set.
2. Prepare medication site by removing the additive port closure. Swab the exposed
medication site before puncturing.
3. Using syringe with 18-22 Ga. needle of appropriate length (at least 5/8 inch), puncture
resealable medication port and inner diaphragm and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by tapping and squeezing them while container is in the upright
position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
Reference ID: 3623377
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19635/S-035
Page 10
Initiated: January 2014
LD-436-2 Y36-002-859
Package Insert
Rx only
B. Braun Medical Inc.
Irvine, CA 92614-5895 USA
1-800-227-2862
www.bbraun.com
Made in USA
Reference ID: 3623377
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:33.385633
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019635s035lbl.pdf', 'application_number': 19635, 'submission_type': 'SUPPL ', 'submission_number': 35}
|
11,573
|
NDA 19-634/S-021
Page 3
5% Dextrose in Lactated Ringer’s Injection
DESCRIPTION
Rx only
Each 100 mL of 5% Dextrose in Lactated Ringer’s Injection contains:
Hydrous Dextrose USP 5 g; Sodium Chloride USP 0.6 g
Sodium Lactate 0.31 g; Potassium Chloride USP 0.03 g
Calcium Chloride Dihydrate USP 0.02 g
Water for Injection USP qs
pH adjusted with Hydrochloric Acid NF
pH: 4.6 (4.0-6.0)
Calories per liter: 170
Calculated Osmolarity: 530 mOsmol/liter, hypertonic
Concentration of Electrolytes (mEq/liter): Sodium 130 Potassium 4
Calcium 3 Chloride 112 Lactate (CH3CH(OH)COO_) 28
5% Dextrose in Lactated Ringer’s Injection is sterile, nonpyrogenic and contains no bacteriostatic or
antimicrobial agents. This product is intended for intravenous administration.
The formulas of the active ingredients are:
Ingredients
Molecular Formula
Molecular Weight
Sodium Chloride USP
NaCl
58.44
Sodium Lactate
CH3CH(OH)COONa
112.06
Potassium Chloride USP
KCl
74.55
Calcium Chloride Dihydrate USP
CaCl2•2H2O
147.02
Hydrous Dextrose USP
198.17
The EXCEL Container is Latex-free, PVC-free, and DEHP-free.
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.
Addition of medication should be accomplished using complete aseptic technique.
The closure system has two ports; the one for the administration set has a tamper evident plastic
protector and the other is a medication addition site. Refer to the Directions for Use of the container.
CLINICAL PHARMACOLOGY
5% Dextrose in Lactated Ringer’s Injection provides electrolytes and calories, and is a source of water
for hydration. It is capable of inducing diuresis depending on the clinical condition of the patient. This
solution also contains lactate which produces a metabolic alkalinizing effect.
CH2OH
OH
OH
HO
O
OH•H2O
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-634/S-021
Page 4
Sodium, the major cation of the extracellular fluid, functions primarily in the control of water
distribution, fluid balance and osmotic pressure of body fluids. Sodium is also associated with chloride
and bicarbonate in the regulation of the acid-base equilibrium of body fluid.
Potassium, the principal cation of intracellular fluid, participates in carbohydrate utilization and protein
synthesis, and is critical in the regulation of nerve conduction and muscle contraction, particularly in
the heart.
Chloride, the major extracellular anion, closely follows the metabolism of sodium, and changes in the
acid-base balance of the body are reflected by changes in the chloride concentration.
Calcium, an important cation, provides the framework of bones and teeth in the form of calcium
phosphate and calcium carbonate. In the ionized form, calcium is essential for the functional
mechanism of the clotting of blood, normal cardiac function, and regulation of neuromuscular
irritability.
Sodium lactate is a racemic salt containing both the levo form, which is oxidized by the liver to
bicarbonate, and the dextro form, which is converted to glycogen. Lactate is slowly metabolized to
carbon dioxide and water, accepting one hydrogen ion and resulting in the formation of bicarbonate for
the lactate consumed. These reactions depend on oxidative cellular activity.
Dextrose provides a source of calories. Dextrose is readily metabolized, may decrease losses of body
protein and nitrogen, promotes glycogen deposition and decreases or prevents ketosis if sufficient
doses are provided.
INDICATIONS AND USAGE
This solution is indicated for use in adults and pediatric patients as a source of electrolytes, calories
and water for hydration.
CONTRAINDICATIONS
This solution is contraindicated where the administration of sodium, potassium, calcium, chloride or
lactate could be clinically detrimental.
Lactate administration is contraindicated in severe metabolic acidosis or alkalosis, and in severe liver
disease or anoxic states which affect lactate metabolism.
Solutions containing dextrose may be contraindicated in patients with hypersensitivity to corn
products.
WARNINGS
Solutions containing lactate are not for use in the treatment of lactic acidosis. Solutions containing
lactate should be used with great care in patients with metabolic or respiratory alkalosis, and in those
conditions in which there is an increased level or an impaired utilization of lactate, such as severe
hepatic insufficiency.
The administration of intravenous solutions can cause fluid and/or solute overload resulting in dilution
of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of
dilutional states is inversely proportional to the electrolyte concentration. The risk of solute overload
causing congested states with peripheral and pulmonary edema is directly proportional to the
electrolyte concentration.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-634/S-021
Page 5
Solutions containing sodium ions should be used with great care, if at all, in patients with congestive
heart failure, severe renal insufficiency, and in clinical states in which there is sodium retention with
edema.
Solutions containing potassium ions should be used with great care, if at all, in patients with
hyperkalemia, severe renal failure, and in conditions in which potassium ions retention is present.
In patients with diminished renal function, administration of solutions containing sodium or potassium
ions may result in sodium or potassium retention.
Solutions containing calcium ions should not be administered through the same administration set as
blood because of the likelihood of coagulation.
PRECAUTIONS
General
This solution should be used with care in patients with hypervolemia, renal insufficiency, urinary tract
obstruction, or impending or frank cardiac decompensation.
Extraordinary electrolytes losses such as may occur during protracted nasogastric suction, vomiting,
diarrhea or gastrointestinal fistula drainage may necessitate additional electrolyte supplementation.
Additional essential electrolytes, minerals and vitamins should be supplied as needed.
Sodium-containing solutions should be administered with caution to patients receiving corticosteroids
or corticotropin, or to other salt-retaining patients.
Care should be exercised in administering solutions containing sodium or potassium to patients with
renal or cardiovascular insufficiency, with or without congestive heart failure, particularly if they are
postoperative or elderly.
Solutions containing calcium should be used with caution in the presence of cardiac disease,
particularly when accompanied by renal disease. Parenteral calcium should be administered with
extreme caution to patients receiving digitalis preparations.
Solutions containing lactate should be used with caution. Excess administration may result in
metabolic alkalosis.
The conversion of lactate to bicarbonate is markedly delayed in the presence of tissue anoxia and
reduced capacity of the liver to metabolize lactate. This may occur under conditions such as metabolic
acidosis associated with circulatory insufficiency, extracorporeal circulation, hypothermia, glycogen
storage disease, liver dysfunction, respiratory alkalosis, shock or cardiac decompensation.
Solutions containing dextrose should be used with caution in patients with overt or known subclinical
diabetes mellitus, or carbohydrate intolerance for any reason.
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.
Do not use plastic container in series connection.
If administration is controlled by a pumping device, care must be taken to discontinue pumping action
before the container runs dry or air embolism may result.
This solution is intended for intravenous administration using sterile equipment. It is recommended
that intravenous administration apparatus be replaced at least once every 24 hours.
Use only if solution is clear and container and seals are intact.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-634/S-021
Page 6
Laboratory Tests
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 tailoring of the electrolyte pattern, in this or an alternative solution.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies with 5% Dextrose in Lactated Ringer’s Injection have not been performed to evaluate
carcinogenic potential, mutagenic potential or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with 5% Dextrose in
Lactated Ringer’s Injection. It is also not known whether 5% Dextrose in Lactated Ringer’s Injection
can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. 5%
Dextrose in Lactated Ringer’s Injection should be given to a pregnant woman only if clearly needed.
Labor and Delivery
The effects of 5% Dextrose in Lactated Ringer’s Injection on the duration of labor or delivery, on the
possibility that forceps delivery or other intervention or resuscitation of the newborn will be necessary,
and on the later growth, development, and functional maturation of the child are unknown.”
As reported in the literature, 5% Dextrose in Lactated Ringer’s Injection has been administered during
labor and delivery. Caution should be exercised, and the fluid balance, glucose and electrolyte
concentrations, and acid-base balance, of both mother and fetus should be evaluated periodically or
whenever warranted by the condition of the patient or fetus.
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 5% Dextrose in Lactated Ringer’s Injection is
administered to a nursing woman.
Pediatric Use
Safety and effectiveness of 5% Dextrose in Lactated Ringer’s Injection in pediatric patients has not
been established by adequate and well-controlled studies. However, the use of potassium chloride in
pediatric patients to treat potassium deficiency states when oral replacement therapy is not feasible is
referenced in the medical literature.
For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of
serum potassium levels and serial EKGs are recommended.
Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and
Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous
dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight
infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum
glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly
neonates and low birth weight infants.
In neonates or in very small infants even small volumes of fluid may affect fluid and electrolyte
balance. Care must be exercised in treatment of neonates, especially pre-term neonates, whose renal
function may be immature and whose ability to excrete fluid and solute loads may be limited. Fluid
intake, urine output, and serum glucose and electrolytes should be monitored closely.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-634/S-021
Page 7
See WARNINGS and DOSAGE AND ADMINISTRATION.
Geriatric Use
Clinical studies of 5% Dextrose in Lactated Ringer’s Injection, 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 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.
ADVERSE REACTIONS
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.
Too rapid infusion of hypertonic solutions may cause local pain and venous irritation. Rate of
administration should be adjusted according to tolerance. Use of the largest peripheral vein and a small
bore needle is recommended. (See DOSAGE AND ADMINISTRATION.)
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.
Hypernatremia may be associated with edema and exacerbation of congestive heart failure due to the
retention of water, resulting in an expanded extracellular fluid volume.
Reactions reported with the use of potassium-containing solutions include nausea, vomiting,
abdominal pain and diarrhea. The signs and symptoms of potassium intoxication include paresthesias
of the extremities, areflexia, muscular or respiratory paralysis, mental confusion, weakness,
hypotension, cardiac arrhythmias, heart block, electrocardiographic abnormalities and cardiac arrest.
Potassium deficits result in disruption of neuromuscular function, and intestinal ileus and dilatation.
If infused in large amounts, chloride ions may cause a loss of bicarbonate ions, resulting in an
acidifying effect.
Abnormally high plasma levels of calcium can result in depression, amnesia, headaches, drowsiness,
disorientation, syncope, hallucinations, hypotonia of both skeletal and smooth muscles, dysphagia,
arrhythmias and coma. Calcium deficits can result in neuromuscular hyperexcitability, including
cramps and convulsions.
Although the metabolism of lactate to bicarbonate is a relatively slow process, aggressive
administration of sodium lactate may result in metabolic alkalosis. Careful monitoring of blood acid-
base balance is essential during the administration of sodium lactate.
The physician should also be alert to the possibility of adverse reactions to drug additives. Prescribing
information for drug additives to be administered in this manner should be consulted.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-634/S-021
Page 8
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.
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
This solution is for intravenous use only.
Dosage is to be directed by a physician and is dependent upon age, weight, clinical condition of the
patient and laboratory determinations. Frequent laboratory determinations and clinical evaluation are
essential to monitor changes in blood glucose and electrolyte concentrations, and fluid and electrolyte
balance during prolonged parenteral therapy.
When a hypertonic solution is to be administered peripherally, it should be slowly infused through a
small bore needle, placed well within the lumen of a large vein to minimize venous irritation. Carefully
avoid infiltration.
Fluid administration should be based on calculated maintenance or replacement fluid requirements for
each patient.
The presence of calcium ions in this solution should be considered when phosphate is present in
additive solutions, in order to avoid precipitation.
Some additives may be incompatible. Consult with pharmacist. When introducing additives, use
aseptic techniques. Mix thoroughly. Do not store.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration, whenever solution and container permit.
Pediatric Use
There is no specific pediatric dose. The dose is dependent on weight, clinical condition and laboratory
results. See WARNINGS and PRECAUTIONS.
HOW SUPPLIED
5% Dextrose in Lactated Ringer’s Injection is supplied sterile and nonpyrogenic in EXCEL®
Containers. The 1000 mL containers are packaged 12 per case and the 500 mL containers are packaged
24 per case.
NDC
Cat. No.
Size
5% Dextrose in Lactated Ringer’s Injection
(Canada DIN 01931652)
0264-7751-00
L7510
1000 mL
0264-7751-10
L7511
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.
Revised: January 2004
U.S. Patent No. 4,803,102
Made in USA
EXCEL® is a registered trademark of B. Braun Medical Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-634/S-021
Page 9
Directions for Use of EXCEL® Container
Caution: Do not use plastic container in series connection.
To Open
Tear overwrap down at notch and remove solution container. Check for minute leaks by squeezing
solution container firmly. If leaks are found, discard solution as sterility may be impaired. If
supplemental medication is desired, follow directions below before preparing for administration.
NOTE:
Before use, perform the following checks:
Inspect each container. Read the label. Ensure solution is the one ordered and is within the
expiration date.
Invert container and carefully inspect the solution in good light for cloudiness, haze, or
particulate matter. Any container which is suspect should not be used.
Use only if solution is clear and container and seals are intact.
Preparation for Administration
1. Remove plastic protector from sterile set port at bottom of container.
2. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Warning: Some additives may be incompatible.
To Add Medication Before Solution Administration
1. Prepare medication site.
2. Using syringe with 18-22 gauge needle, puncture medication port and inner diaphragm and inject.
3. Squeeze and tap ports while ports are upright and mix solution and medication thoroughly.
To Add Medication During Solution Administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 18-22 gauge needle of appropriate length (at least 5/8 inch), puncture resealable
medication port and inner diaphragm and inject.
4. Remove container from IV pole and/or turn to an upright position.
5. Evacuate both ports by tapping and squeezing them while container is in the upright position.
6. Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
©2004 B. Braun Medical Inc.
B BRAUN
B. BRAUN Medical Inc.
Irvine, CA USA 92614-5895
In Canada, distributed by:
B. Braun Medical Inc.
Scarborough, Ontario M1H 2W4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-634/S-021
Page 10
2.5% Dextrose in Half-Strength Lactated Ringer’s Injection
DESCRIPTION
Rx only
Each 100 mL of 2.5% Dextrose in Half-Strength Lactated Ringer’s Injection contains: Hydrous
Dextrose USP 2.5 g; Sodium Chloride USP 0.3 g
Sodium Lactate 0.16 g; Potassium Chloride USP 0.015 g
Calcium Chloride Dihydrate USP 0.01 g
Water for Injection USP qs
pH adjusted with Hydrochloric Acid NF
pH: 5.0 (4.0-6.0)
Calories per liter: 85
Calculated Osmolarity: 265 mOsmol/liter
Concentration of Electrolytes (mEq/liter): Sodium 65 Potassium 2
Calcium 1.4 Chloride 55 Lactate (CH3CH(OH)COO_) 14
2.5% Dextrose in Half-Strength Lactated Ringer’s Injection is sterile, nonpyrogenic and contains no
bacteriostatic or antimicrobial agents. This product is intended for intravenous administration.
The formulas of the active ingredients are:
Ingredients
Molecular Formula
Molecular Weight
Sodium Chloride USP
NaCl
58.44
Sodium Lactate
CH3CH(OH)COONa
112.06
Potassium Chloride USP
KCl
74.55
Calcium Chloride Dihydrate USP
CaCl2•2H2O
147.02
Hydrous Dextrose USP
198.17
The EXCEL Container is Latex-free, PVC-free, and DEHP-free.
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.
Addition of medication should be accomplished using complete aseptic technique.
The closure system has two ports; the one for the administration set has a tamper evident plastic
protector and the other is a medication addition site. Refer to the Directions for Use of the container.
CLINICAL PHARMACOLOGY
2.5% Dextrose in Half-Strength Lactated Ringer’s Injection provides electrolytes and calories, and is a
source of water for hydration. It is capable of inducing diuresis depending on the clinical condition of
the patient. This solution also contains lactate which produces a metabolic alkalinizing effect.
CH2OH
OH
OH
HO
O
OH•H2O
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-634/S-021
Page 11
Sodium, the major cation of the extracellular fluid, functions primarily in the control of water
distribution, fluid balance and osmotic pressure of body fluids. Sodium is also associated with chloride
and bicarbonate in the regulation of the acid-base equilibrium of body fluid. Potassium, the principal
cation of intracellular fluid, participates in carbohydrate utilization and protein synthesis, and is critical
in the regulation of nerve conduction and muscle contraction, particularly in the heart.
Chloride, the major extracellular anion, closely follows the metabolism of sodium, and changes in the
acid-base balance of the body are reflected by changes in the chloride concentration. Calcium, an
important cation, provides the framework of bones and teeth in the form of calcium phosphate and
calcium carbonate. In the ionized form, calcium is essential for the functional mechanism of the
clotting of blood, normal cardiac function, and regulation of neuromuscular irritability.
Sodium lactate is a racemic salt containing both the levo form, which is oxidized by the liver to
bicarbonate, and the dextro form, which is converted to glycogen. Lactate is slowly metabolized to
carbon dioxide and water, accepting one hydrogen ion and resulting in the formation of bicarbonate for
the lactate consumed. These reactions depend on oxidative cellular activity.
Dextrose provides a source of calories. Dextrose is readily metabolized, may decrease losses of body
protein and nitrogen, promotes glycogen deposition and decreases or prevents ketosis if sufficient
doses are provided.
INDICATIONS AND USAGE
This solution is indicated for use in adults and pediatric patients as a source of electrolytes, calories
and water for hydration.
CONTRAINDICATIONS
This solution is contraindicated where the administration of sodium, potassium, calcium, chloride or
lactate could be clinically detrimental.
Lactate administration is contraindicated in severe metabolic acidosis or alkalosis, and in severe liver
disease or anoxic states which affect lactate metabolism.
Solutions containing dextrose may be contraindicated in patients with hypersensitivity to corn
products.
WARNINGS
Solutions containing lactate are not for use in the treatment of lactic acidosis.
Solutions containing lactate should be used with great care in patients with metabolic or respiratory
alkalosis, and in those conditions in which there is an increased level or an impaired utilization of
lactate, such as severe hepatic insufficiency.
The administration of intravenous solutions can cause fluid and/or solute overload resulting in dilution
of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of
dilutional states is inversely proportional to the electrolyte concentration. The risk of solute overload
causing congested states with peripheral and pulmonary edema is directly proportional to the
electrolyte concentration.
Solutions containing sodium ions should be used with great care, if at all, in patients with congestive
heart failure, severe renal insufficiency, and in clinical states in which there is sodium retention with
edema.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-634/S-021
Page 12
Solutions containing potassium ions should be used with great care, if at all, in patients with
hyperkalemia, severe renal failure, and in conditions in which potassium ions retention is present.
In patients with diminished renal function, administration of solutions containing sodium or potassium
ions may result in sodium or potassium retention.
Solutions containing calcium ions should not be administered through the same administration set as
blood because of the likelihood of coagulation.
PRECAUTIONS
General
This solution should be used with great care in patients with hypervolemia, renal insufficiency, urinary
tract obstruction, or impending or frank cardiac decompensation.
Extraordinary electrolytes losses such as may occur during protracted nasogastric suction, vomiting,
diarrhea or gastrointestinal fistula drainage may necessitate additional electrolyte supplementation.
Additional essential electrolytes, minerals and vitamins should be supplied as needed.
Sodium-containing solutions should be administered with caution to patients receiving corticosteroids
or corticotropin, or to other salt-retaining patients.
Care should be exercised in administering solutions containing sodium or potassium to patients with
renal or cardiovascular insufficiency, with or without congestive heart failure, particularly if they are
postoperative or elderly.
Solutions containing calcium should be used with caution in the presence of cardiac disease,
particularly when accompanied by renal disease. Parenteral calcium should be administered with
extreme caution to patients receiving digitalis preparations.
Solutions containing lactate should be used with caution. Excess administration may result in
metabolic alkalosis.
The conversion of lactate to bicarbonate is markedly delayed in the presence of tissue anoxia and
reduced capacity of the liver to metabolize lactate. This may occur under conditions such as metabolic
acidosis associated with circulatory insufficiency, extracorporeal circulation, hypothermia, glycogen
storage disease, liver dysfunction, respiratory alkalosis, shock or cardiac decompensation.
Solutions containing dextrose should be used with caution in patients with overt or known subclinical
diabetes mellitus, or carbohydrate intolerance for any reason.
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.
Do not use plastic container in series connection.
If administration is controlled by a pumping device, care must be taken to discontinue pumping action
before the container runs dry or air embolism may result.
This solution is intended for intravenous administration using sterile equipment. It is recommended
that intravenous administration apparatus be replaced at least once every 24 hours.
Use only if solution is clear and container and seals are intact.
Laboratory Tests
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-634/S-021
Page 13
whenever the condition of the patient warrants such evaluation. Significant deviations from normal
concentrations may require tailoring of the electrolyte pattern, in this or an alternative solution.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies with 2.5% Dextrose in Half-Strength Lactated Ringer’s Injection have not been performed to
evaluate carcinogenic potential, mutagenic potential or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with 2.5% Dextrose in
Half-Strength Lactated Ringer’s Injection. It is also not known whether 2.5% Dextrose in Half-
Strength Lactated Ringer’s Injection can cause fetal harm when administered to a pregnant woman or
can affect reproduction capacity. 2.5% Dextrose in Half-Strength Lactated Ringer’s Injection should be
given to a pregnant woman only if clearly needed.
Labor and Delivery
The effects of 2.5% Dextrose in Half-Strength Lactated Ringer’s Injection on the duration of labor or
delivery, on the possibility that forceps delivery or other intervention or resuscitation of the newborn
will be necessary, and on the later growth, development, and functional maturation of the child are
unknown.”
As reported in the literature, Dextrose in Lactated Ringer’s Injection has been administered during
labor and delivery. Caution should be exercised, and the fluid balance, glucose and electrolyte
concentrations, and acid-base balance, of both mother and fetus should be evaluated periodically or
whenever warranted by the condition of the patient or fetus.
Nursing Mothers
It is not know whether this drug is excreted in human milk. Because many drugs are excreted in human
milk, caution should be exercised when 2.5% Dextrose in Half-Strength Lactated Ringer’s Injection is
administered to a nursing woman.
Pediatric Use
Safety and effectiveness of 2.5% Dextrose in half-strength Lactated Ringer’s Injection in pediatric
patients has not been established by adequate and well-controlled studies. However, the use of
potassium chloride injection in pediatric patients to treat potassium deficiency states when oral
replacement therapy is not feasible is referenced in the medical literature.
For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of
serum potassium levels and serial EKGs are recommended.
Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and
Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous
dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight
infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum
glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly
neonates and low birth weight infants
In neonates or in very small infants even small volumes of fluid may affect fluid and electrolyte
balance. Care must be exercised in treatment of neonates, especially pre-term neonates, whose renal
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-634/S-021
Page 14
function may be immature and whose ability to excrete fluid and solute loads may be limited. Fluid
intake, urine output, and serum glucose and electrolytes should be monitored closely.
See WARNINGS and DOSAGE AND ADMINISTRATION.
Geriatric Use
Clinical studies of 2.5% Dextrose in half-strength Lactated Ringer’s Injection, 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 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.
ADVERSE REACTIONS
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.
Hypernatremia may be associated with edema and exacerbation of congestive heart failure due to the
retention of water, resulting in an expanded extracellular fluid volume.
If infused in large amounts, chloride ions may cause a loss of bicarbonate ions, resulting in an
acidifying effect.
Although the metabolism of lactate to bicarbonate is a relatively slow process, aggressive
administration of sodium lactate may result in metabolic alkalosis. Careful monitoring of blood acid-
base balance is essential during the administration of sodium lactate.
The physician should also be alert to the possibility of adverse reactions to drug additives. Prescribing
information for drug additives to be administered in this manner should be consulted.
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.
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
This solution is for intravenous use only.
Dosage is to be directed by a physician and is dependent upon age, weight, clinical condition of the
patient and laboratory determinations. Frequent laboratory determinations and clinical evaluation are
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-634/S-021
Page 15
essential to monitor changes in blood glucose and electrolyte concentrations, and fluid and electrolyte
balance during prolonged parenteral therapy.
Fluid administration should be based on calculated maintenance or replacement fluid requirements for
each patient.
The presence of calcium ions in this solution should be considered when phosphate is present in
additive solutions, in order to avoid precipitation.
Some additives may be incompatible. Consult with pharmacist. When introducing additives, use
aseptic techniques. Mix thoroughly. Do not store.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration, whenever solution and container permit.
Pediatric Use
There is no specific pediatric dose. The dose is dependent on weight, clinical condition and laboratory
results. See WARNINGS and PRECAUTIONS.
HOW SUPPLIED
2.5% Dextrose in Half-Strength Lactated Ringer’s Injection is supplied sterile and nonpyrogenic in 250
mL EXCEL® Containers packaged 24 per case.
NDC
Cat. No.
Size
2.5% Dextrose in Half-Strength Lactated Ringer’s Injection
(Canada DIN 01931660)
0264-7759-20
L7592
250 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.
Revised: February 2004
U.S. Patent No. 4,803,102
EXCEL® 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 19-634/S-021
Page 16
Directions for Use of EXCEL® Container
Caution: Do not use plastic container in series connection.
To Open
Tear overwrap down at notch and remove solution container. Check for minute leaks by squeezing
solution container firmly. If leaks are found, discard solution as sterility may be impaired. If
supplemental medication is desired, follow directions below before preparing for administration.
NOTE:
Before use, perform the following checks:
Inspect each container. Read the label. Ensure solution is the one ordered and is within the
expiration date.
Invert container and carefully inspect the solution in good light for cloudiness, haze, or
particulate matter. Any container which is suspect should not be used.
Use only if solution is clear and container and seals are intact.
Preparation for Administration
1. Remove plastic protector from sterile set port at bottom of container.
2. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Warning: Some additives may be incompatible.
To Add Medication Before Solution Administration
1. Prepare medication site.
2. Using syringe with 18-22 gauge needle, puncture medication port and inner diaphragm and inject.
3. Squeeze and tap ports while ports are upright and mix solution and medication thoroughly.
To Add Medication During Solution Administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 18-22 gauge needle of appropriate length (at least 5/8 inch), puncture resealable
medication port and inner diaphragm and inject.
4. Remove container from IV pole and/or turn to an upright position.
5.
Evacuate both ports by tapping and squeezing them while container is in the upright
position.
6.
Mix solution and medication thoroughly.
8. Return container to in use position and continue administration.
©2004 B. Braun Medical Inc.
B BRAUN
B. BRAUN Medical Inc.
Irvine, CA USA 92614-5895
In Canada, distributed by:
B. Braun Medical Inc.
Scarborough, Ontario M1H 2W4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:33.387650
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19634s021lbl.pdf', 'application_number': 19634, 'submission_type': 'SUPPL ', 'submission_number': 21}
|
11,572
|
NDA 19-630/S-023
Page 3
Potassium Chloride in Dextrose and Sodium Chloride Injections USP
DESCRIPTION
Rx only
(See chart below for quantitative information.)
Potassium Chloride in Dextrose and Sodium Chloride Injections USP are sterile, nonpyrogenic and
contain no bacteriostatic or antimicrobial agents. These products are intended for intravenous
administration.
The formulas of the active ingredients are:
Ingredients
Molecular Formula
Molecular Weight
Sodium Chloride USP
NaCl
58.44
Potassium Chloride USP
KCl
74.55
Hydrous Dextrose USP
198.17
The EXCEL Container is Latex-free, PVC-free, and DEHP-free.
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.
Addition of medication should be accomplished using complete aseptic technique.
The closure system has two ports; the one for the administration set has a tamper evident plastic
protector and the other is a medication addition site. Refer to the Directions for Use of the container.
CLINICAL PHARMACOLOGY
These intravenous solutions provide electrolytes and calories, and are a source of water for hydration.
They are capable of inducing diuresis depending on the clinical condition of the patient.
Sodium, the major cation of the extracellular fluid, functions primarily in the control of water
distribution, fluid balance, and osmotic pressure of body fluids. Sodium is also associated with
chloride and bicarbonate in the regulation of the acid-base equilibrium of body fluid.
Potassium, the principal cation of intracellular fluid, participates in carbohydrate utilization and protein
synthesis, and is critical in the regulation of nerve conduction and muscle contraction, particularly in
the heart.
CH2OH
OH
OH
HO
O
OH•H2O
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-630/S-023
Page 4
Composition – Each 100 mL contains:
Concentration of Electrolytes
(mEq/liter)
Solution
Hydrous
Dextrose
USP
Sodium
Chloride
USP
Potassium
Chloride
USP
Sodium
Potassium
Chloride
Calories
per
liter
Calculated
Osmolarity
mOsmol/liter
pH
0.15% Potassium Chloride in 3.3% Dextrose and
0.30% Sodium Chloride Injection USP
3.3 g
0.3 g
0.15 g
51
20
71
110
310
4.4 (3.5-6.5)
0.075% Potassium Chloride in 5% Dextrose and 0.20%
Sodium Chloride Injection USP
5 g
0.2 g
0.075 g
34
10
44
170
340
4.4 (3.5-6.5)
0.15% Potassium Chloride in 5% Dextrose and 0.20%
Sodium Chloride Injection USP
5 g
0.2 g
0.15 g
34
20
54
170
360
4.4 (3.5-6.5)
0.22% Potassium Chloride in 5% Dextrose and 0.20%
Sodium Chloride Injection USP
5 g
0.2 g
0.22 g
34
30
64
170
380
4.4 (3.5-6.5)
0.30% Potassium Chloride in 5% Dextrose and 0.20%
Sodium Chloride Injection USP
5 g
0.2 g
0.3 g
34
40
74
170
400
4.4 (3.5-6.5)
0.15% Potassium Chloride in 5% Dextrose and 0.33%
Sodium Chloride Injection USP
5 g
0.33 g
0.15 g
56
20
76
170
405
4.4 (3.5-6.5)
0.075% Potassium Chloride in 5% Dextrose and 0.45%
Sodium Chloride Injection USP
5 g
0.45 g
0.075 g
77
10
87
170
425
4.4 (3.5-6.5)
0.15% Potassium Chloride in 5% Dextrose and 0.45%
Sodium Chloride Injection USP
5 g
0.45 g
0.15 g
77
20
97
170
445
4.4 (3.5-6.5)
0.22% Potassium Chloride in 5% Dextrose and 0.45%
Sodium Chloride Injection USP
5 g
0.45 g
0.22 g
77
30
107
170
465
4.4 (3.5-6.5)
0.30% Potassium Chloride in 5% Dextrose and 0.45%
Sodium Chloride Injection USP
5 g
0.45 g
0.3 g
77
40
117
170
490
4.4 (3.5-6.5)
0.15% Potassium Chloride in 5% Dextrose and 0.9%
Sodium Chloride Injection USP
5 g
0.9 g
0.15 g
154
20
174
170
600
4.4 (3.5-6.5)
0.15% Potassium Chloride in 10% Dextrose and 0.20%
Sodium Chloride Injection USP
10 g
0.2 g
0.15 g
34
20
54
340
615
4.4 (3.5-6.5)
Water for Injection USP qs
Chloride, the major extracellular anion, closely follows the metabolism of sodium, and changes in the
acid-base balance of the body are reflected by changes in the chloride concentration.
Dextrose provides a source of calories. Dextrose is readily metabolized, may decrease losses of body
protein and nitrogen, promotes glycogen deposition and decreases or prevents ketosis if sufficient
doses are provided.
INDICATIONS AND USAGE
These intravenous solutions are indicated for use in adults and pediatric patients as sources of
electrolytes, calories and water for hydration.
CONTRAINDICATIONS
These solutions are contraindicated where the administration of sodium, potassium or chloride could
be clinically detrimental.
Solutions containing dextrose may be contraindicated in patients with hypersensitivity to corn
products.
WARNINGS
The administration of intravenous solutions can cause fluid and/or solute overload resulting in dilution
of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of
dilutional states is inversely proportional to the electrolyte concentration. The risk of solute overload
causing congested states with peripheral and pulmonary edema is directly proportional to the
electrolyte concentration.
Solutions containing sodium ions should be used with great care, if at all, in patients with congestive
heart failure, severe renal insufficiency, and in clinical states in which there is sodium retention with
edema.
In patients with diminished renal function, administration of solutions containing sodium or potassium
ions may result in sodium or potassium retention.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-630/S-023
Page 5
Solutions containing potassium ions should be used with great care, if at all, in patients with
hyperkalemia, severe renal failure, and in conditions in which potassium retention is present.
PRECAUTIONS
General
These solutions should be used with care in patients with hypervolemia, renal insufficiency, urinary
tract obstruction, or impending or frank cardiac decompensation.
Extraordinary electrolyte losses such as may occur during protracted nasogastric suction, vomiting,
diarrhea or gastrointestinal fistula drainage may necessitate additional electrolyte supplementation.
Additional essential electrolytes, minerals and vitamins should be supplied as needed.
Sodium-containing solutions should be administered with caution to patients receiving corticosteroids
or corticotropin, or to other salt-retaining patients.
Care should be exercised in administering solutions containing sodium or potassium to patients with
renal or cardiovascular insufficiency, with or without congestive heart failure, particularly if they are
postoperative or elderly.
Potassium therapy should be guided primarily by serial electrocardiograms, especially in patients
receiving digitalis. Serum potassium levels are not necessarily indicative of tissue potassium levels.
Solutions containing potassium should be used with caution in the presence of cardiac disease,
particularly when accompanied by renal disease.
Solutions containing dextrose should be used with caution in patients with overt or known subclinical
diabetes mellitus, or carbohydrate intolerance for any reason.
To minimize the risk of possible incompatibilities arising from mixing any of these solutions 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.
Do not use plastic container in series connection.
If administration is controlled by a pumping device, care must be taken to discontinue pumping action
before the container runs dry or air embolism may result.
These solutions are intended for intravenous administration using sterile equipment. It is recommended
that intravenous administration apparatus be replaced at least once every 24 hours.
Use only if solution is clear and container and seals are intact.
Laboratory Tests
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 tailoring of the electrolyte pattern, in these or alternative solutions.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies with Potassium Chloride in Dextrose and Sodium Chloride Injections USP have not been
performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.
Pregnancy: Teratogenic Effects
Pregnancy Category C. Animal reproduction studies have not been conducted with Potassium Chloride
in Dextrose and Sodium Chloride Injections USP. It is also not known whether Potassium Chloride in
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-630/S-023
Page 6
Dextrose and Sodium Chloride Injections USP can cause fetal harm when administered to a pregnant
woman or can affect reproduction capacity. Potassium Chloride in Dextrose and Sodium Chloride
Injections USP should be given to a pregnant woman only if clearly needed.
Labor and Delivery
The effects of Potassium Chloride in Dextrose and Sodium Chloride Injections USP on the duration of
labor or delivery, on the possibility that forceps delivery or other intervention or resuscitation of the
newborn will be necessary, and on the later growth, development, and functional maturation of the
child are unknown.”
As reported in the literature, potassium containing solutions have been administered during labor and
delivery. Caution should be exercised, and the fluid balance, glucose and electrolyte concentrations,
and acid-base balance, of both mother and fetus should be evaluated periodically or whenever
warranted by the condition of the patient or fetus.
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 Potassium Chloride in Dextrose and Sodium Chloride
Injections USP are administered to a nursing woman.
Pediatric Use
Safety and effectiveness of Potassium Chloride in Dextrose and Sodium Chloride Injection, USP in
pediatric patients have not been established by adequate and well-controlled studies. However, the use
of potassium chloride injection in pediatric patients to treat potassium deficiency states when oral
replacement therapy is not feasible is referenced in the medical literature.
For patients receiving potassium supplement at greater than maintenance rates, frequent monitoring of
serum potassium levels and serial EKGs are recommended.
Dextrose is safe and effective for the stated indications in pediatric patients (see Indications and
Usage). As reported in the literature, the dosage selection and constant infusion rate of intravenous
dextrose must be selected with caution in pediatric patients, particularly neonates and low birth weight
infants, because of the increased risk of hyperglycemia/hypoglycemia. Frequent monitoring of serum
glucose concentrations is required when dextrose is prescribed to pediatric patients, particularly
neonates and low birth weight infants See WARNINGS and DOSAGE AND ADMINISTRATION.
In neonates or in very small infants even small volumes of fluid may affect fluid and electrolyte
balance. Care must be exercised in treatment of neonates, especially pre-term neonates, whose renal
function may be immature and whose ability to excrete fluid and solute loads may be limited. Fluid
intake, urine output, and serum electrolytes should be monitored closely.
Geriatric Use: Clinical studies of Potassium Chloride in Dextrose and Sodium Chloride Injection,
USP 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 elderly and younger patients.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-630/S-023
Page 7
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.
These drugs are known to be substantially excreted by the kidney, and the risk of toxic reactions to
these drugs 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.
ADVERSE REACTIONS
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.
Too rapid infusion of hypertonic solutions may cause local pain and venous irritation. Rate of
administration should be adjusted according to tolerance. Use of the largest peripheral vein and a small
bore needle is recommended. (See DOSAGE AND ADMINISTRATION.)
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.
Hypernatremia may be associated with edema and exacerbation of congestive heart failure due to the
retention of water, resulting in an expanded extracellular fluid volume.
Reactions reported with the use of potassium-containing solutions include nausea, vomiting,
abdominal pain and diarrhea. The signs and symptoms of potassium intoxication include paresthesias
of the extremities, areflexia, muscular or respiratory paralysis, mental confusion, weakness,
hypotension, cardiac arrhythmias, heart block, electrocardiographic abnormalities and cardiac arrest.
Potassium deficits result in disruption of neuromuscular function, and intestinal ileus and dilatation.
If infused in large amounts, chloride ions may cause a loss of bicarbonate ions, resulting in an
acidifying effect.
The physician should also be alert to the possibility of adverse reaction to drug additives. Prescribing
information for drug additives to be administered in this manner should be consulted.
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.
OVERDOSAGE
In the event of a fluid or solute overload during parenteral therapy, reevaluate the patient’s condition
and institute appropriate corrective treatment.
In the event of overdosage with potassium-containing solutions, discontinue the infusion immediately
and institute corrective therapy to reduce serum potassium levels.
Treatment of hyperkalemia includes the following:
1.
Dextrose Injection USP, 10% or 25% containing 10 units of crystalline insulin per 20 grams of
dextrose administered intravenously, 300 to 500 mL per hour.
2.
Absorption and exchange of potassium using sodium or ammonium cycle cation exchange
resin, orally and as retention enema.
3.
Hemodialysis and peritoneal dialysis. The use of potassium-containing foods or medications
must be eliminated. However, in cases of digitalization, too rapid a lowering of plasma
potassium concentration can cause digitalis toxicity.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-630/S-023
Page 8
DOSAGE AND ADMINISTRATION
These solutions are for intravenous use only.
Dosage is to be directed by a physician and is dependent upon age, weight, clinical condition of the
patient and laboratory determinations. Frequent laboratory determinations and clinical evaluation are
essential to monitor changes in blood glucose and electrolyte concentrations, and fluid and electrolyte
balance during prolonged parenteral therapy.
When a hypertonic solution is to be administered peripherally, it should be slowly infused through a
small bore needle, placed well within the lumen of a large vein to minimize venous irritation. Carefully
avoid infiltration.
Usually, up to 40 mEq of potassium per liter daily is sufficient to replace normal loss in adults. Typical
infusion rates should not exceed 10 mEq per hour or 120 mEq per day. Pediatric patients may require 2
to 3 mEq per kg of body weight daily. See WARNINGS and PRECAUTIONS for pediatric use.
Fluid administration should be based on calculated maintenance or replacement fluid requirements for
each patient.
Dextrose may be administered to normal individuals at a rate of 0.5 g/kg/hour without producing
glycosuria. At the maximum infusion rate of 0.8 g/kg/hour, approximately 95% of the dextrose is
retained.
Some additives may be incompatible. Consult with pharmacist. When introducing additives, use
aseptic techniques. Mix thoroughly. Do not store.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration, whenever solution and container permit.
HOW SUPPLIED
Potassium Chloride in Dextrose and Sodium Chloride Injections USP are supplied in EXCEL®
Containers. The 1000 mL containers are packaged 12 per case; the 500 mL and 250 mL containers are
packaged 24 per case.
Canada DIN
NDC
Cat. No.
Size
0.15% Potassium Chloride in 3.3% Dextrose and
0.30% Sodium Chloride Injection USP
(20 mEq K+/liter)
01931741
0264-7273-00
L2730
1000 mL
0.075% Potassium Chloride in 5% Dextrose and
0.20% Sodium Chloride Injection USP
(10 mEq K+/liter)
0264-7644-00
L6440
1000 mL
0.15% Potassium Chloride in 5% Dextrose and
0.20% Sodium Chloride Injection USP
(20 mEq K+/liter)
01931598
0264-7645-00
L6450
1000 mL
0264-7645-10
L6451
500 mL
0264-7645-20
L6452
250 mL
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-630/S-023
Page 9
0.22% Potassium Chloride in 5% Dextrose and
0.20% Sodium Chloride Injection USP
(30 mEq K+/liter)
0264-7646-00
L6460
1000 mL
0.30% Potassium Chloride in 5% Dextrose and
0.20% Sodium Chloride Injection USP
(40 mEq K+/liter)
0264-7648-00
L6480
1000 mL
0.15% Potassium Chloride in 5% Dextrose and
0.33% Sodium Chloride Injection USP
(20 mEq K+/liter)
01931601
0264-7655-00
L6550
1000 mL
0.075% Potassium Chloride in 5% Dextrose and
0.45% Sodium Chloride Injection USP
(10 mEq K+/liter)
0264-7634-00
L6340
1000 mL
0.15% Potassium Chloride in 5% Dextrose and
0.45% Sodium Chloride Injection USP
(20 mEq K+/liter)
01931547
0264-7635-00
L6350
1000 mL
0.22% Potassium Chloride in 5% Dextrose and
0.45% Sodium Chloride Injection USP
(30 mEq K+/liter)
0264-7636-00
L6360
1000 mL
0.30% Potassium Chloride in 5% Dextrose and
0.45% Sodium Chloride Injection USP
(40 mEq K+/liter)
01931571
0264-7638-00
L6380
1000 mL
0.15% Potassium Chloride in 5% Dextrose and
0.9% Sodium Chloride Injection USP
(20 mEq K+/liter)
01931644
0264-7652-00
L6520
1000 mL
0.15% Potassium Chloride in 10% Dextrose and
0.20% Sodium Chloride Injection USP
(20 mEq K+/liter)
0264-7663-20
L6632
250 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).
Revised: January 2004
U.S. Patent No. 4,803,102
EXCEL® 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 19-630/S-023
Page 10
Directions for Use of EXCEL® Container
Caution: Do not use plastic container in series connection.
To Open
Tear overwrap down at notch and remove solution container. Check for minute leaks by squeezing
solution container firmly. If leaks are found, discard solution as sterility may be impaired. If
supplemental medication is desired, follow directions below before preparing for administration.
NOTE:
Before use, perform the following checks:
Inspect each container. Read the label. Ensure solution is the one ordered and is within the
expiration date.
Invert container and carefully inspect the solution in good light for cloudiness, haze, or
particulate matter. Any container which is suspect should not be used.
Use only if solution is clear and container and seals are intact.
Preparation for Administration
1. Remove plastic protector from sterile set port at bottom of container.
2. Attach administration set. Refer to complete directions accompanying set.
To Add Medication
Warning: Some additives may be incompatible.
To Add Medication Before Solution Administration
1. Prepare medication site.
2. Using syringe with 18-22 gauge needle, puncture medication port and inner diaphragm and inject.
3. Squeeze and tap ports while ports are upright and mix solution and medication thoroughly.
To Add Medication During Solution Administration
1. Close clamp on the set.
2. Prepare medication site.
3. Using syringe with 18-22 gauge needle of appropriate length (at least 5/8 inch), puncture resealable
medication port and inner diaphragm and inject.
4. Remove container from IV pole and/or turn to an upright position.
5.
Evacuate both ports by tapping and squeezing them while container is in the upright position.
6.
Mix solution and medication thoroughly.
7. Return container to in use position and continue administration.
©2004 B. Braun Medical Inc.
B BRAUN
B. BRAUN Medical Inc.
Irvine, CA USA 92614-5895
In Canada, distributed by:
B. Braun Medical Inc.
Scarborough, Ontario M1H 2W4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:33.400797
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19630s023lbl.pdf', 'application_number': 19630, 'submission_type': 'SUPPL ', 'submission_number': 23}
|
11,576
|
S-045 10.12.2005
1
IDENTIFIER
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
HUMATROPE®
SOMATROPIN (rDNA ORIGIN) FOR INJECTION
VIALS
and
CARTRIDGES FOR USE WITH THE
HumatroPen™ INJECTION DEVICE
DESCRIPTION
Humatrope® (Somatropin, rDNA Origin, for Injection) is a polypeptide hormone of
recombinant DNA origin. Humatrope has 191 amino acid residues and a molecular weight of
about 22,125 daltons. The amino acid sequence of the product is identical to that of human
growth hormone of pituitary origin. Humatrope is synthesized in a strain of Escherichia coli that
has been modified by the addition of the gene for human growth hormone.
Humatrope is a sterile, white, lyophilized powder intended for subcutaneous or intramuscular
administration after reconstitution. Humatrope is a highly purified preparation. Phosphoric acid
and/or sodium hydroxide may have been added to adjust the pH. Reconstituted solutions have a
pH of approximately 7.5. This product is oxygen sensitive.
VIAL — Each vial of Humatrope contains 5 mg somatropin (15 IU or 225 nanomoles); 25 mg
mannitol; 5 mg glycine; and 1.13 mg dibasic sodium phosphate. Each vial is supplied in a
combination package with an accompanying 5-mL vial of diluting solution. The diluent contains
Water for Injection with 0.3% Metacresol as a preservative and 1.7% glycerin.
CARTRIDGE — The cartridges of somatropin contain either 6 mg (18 IU), 12 mg (36 IU), or
24 mg (72 IU) of somatropin. The 6, 12, and 24 mg cartridges contain respectively: mannitol 18,
36, and 72 mg; glycine 6, 12, and 24 mg; dibasic sodium phosphate 1.36, 2.72, and 5.43 mg.
Each cartridge is supplied in a combination package with an accompanying syringe containing
approximately 3 mL of diluting solution. The diluent contains Water for Injection;
0.3% Metacresol as a preservative; and 1.7%, 0.29%, and 0.29% glycerin in the 6, 12, and 24 mg
cartridges, respectively.
CLINICAL PHARMACOLOGY
General
Linear Growth — Humatrope stimulates linear growth in pediatric patients who lack adequate
normal endogenous growth hormone. In vitro, preclinical, and clinical testing have demonstrated
that Humatrope is therapeutically equivalent to human growth hormone of pituitary origin and
achieves equivalent pharmacokinetic profiles in normal adults. Treatment of growth
hormone-deficient pediatric patients and patients with Turner syndrome with Humatrope
produces increased growth rate and IGF-I (Insulin-like Growth Factor-I/Somatomedin-C)
concentrations similar to those seen after therapy with human growth hormone of pituitary
origin.
In addition, the following actions have been demonstrated for Humatrope and/or human
growth hormone of pituitary origin.
A. Tissue Growth — 1. Skeletal Growth: Humatrope stimulates skeletal growth in pediatric
patients with growth hormone deficiency. The measurable increase in body length after
administration of either Humatrope or human growth hormone of pituitary origin results from an
effect on the growth plates of long bones. Concentrations of IGF-I, which may play a role in
skeletal growth, are low in the serum of growth hormone-deficient pediatric patients but increase
during treatment with Humatrope. Elevations in mean serum alkaline phosphatase concentrations
are also seen. 2. Cell Growth: It has been shown that there are fewer skeletal muscle cells in
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
S-045 10.12.2005
2
short-statured pediatric patients who lack endogenous growth hormone as compared with normal
pediatric populations. Treatment with human growth hormone of pituitary origin results in an
increase in both the number and size of muscle cells.
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
B. Protein Metabolism — Linear growth is facilitated in part by increased cellular protein
synthesis. Nitrogen retention, as demonstrated by decreased urinary nitrogen excretion and
serum urea nitrogen, follows the initiation of therapy with human growth hormone of pituitary
origin. Treatment with Humatrope results in a similar decrease in serum urea nitrogen.
C. Carbohydrate Metabolism — Pediatric patients with hypopituitarism sometimes experience
fasting hypoglycemia that is improved by treatment with Humatrope. Large doses of human
growth hormone may impair glucose tolerance. Untreated patients with Turner syndrome have
an increased incidence of glucose intolerance. Administration of human growth hormone to
normal adults or patients with Turner syndrome resulted in increases in mean serum fasting and
postprandial insulin levels although mean values remained in the normal range. In addition,
mean fasting and postprandial glucose and hemoglobin A1c levels remained in the normal range.
D. Lipid Metabolism — In growth hormone-deficient patients, administration of human growth
hormone of pituitary origin has resulted in lipid mobilization, reduction in body fat stores, and
increased plasma fatty acids.
E. Mineral Metabolism — Retention of sodium, potassium, and phosphorus is induced by
human growth hormone of pituitary origin. Serum concentrations of inorganic phosphate
increased in patients with growth hormone deficiency after therapy with Humatrope or human
growth hormone of pituitary origin. Serum calcium is not significantly altered in patients treated
with either human growth hormone of pituitary origin or Humatrope.
Pharmacokinetics
Absorption — Humatrope has been studied following intramuscular, subcutaneous, and
intravenous administration in adult volunteers. The absolute bioavailability of somatropin is 75%
and 63% after subcutaneous and intramuscular administration, respectively.
Distribution — The volume of distribution of somatropin after intravenous injection is about
0.07 L/kg.
Metabolism — Extensive metabolism studies have not been conducted. The metabolic fate of
somatropin involves classical protein catabolism in both the liver and kidneys. In renal cells, at
least a portion of the breakdown products of growth hormone is returned to the systemic
circulation. In normal volunteers, mean clearance is 0.14 L/hr/kg. The mean half-life of
intravenous somatropin is 0.36 hours, whereas subcutaneously and intramuscularly administered
somatropin have mean half-lives of 3.8 and 4.9 hours, respectively. The longer half-life observed
after subcutaneous or intramuscular administration is due to slow absorption from the injection
site.
Excretion — Urinary excretion of intact Humatrope has not been measured. Small amounts of
somatropin have been detected in the urine of pediatric patients following replacement therapy.
Special Populations
Geriatric — The pharmacokinetics of Humatrope has not been studied in patients greater than
65 years of age.
Pediatric — The pharmacokinetics of Humatrope in pediatric patients is similar to adults.
Gender — No studies have been performed with Humatrope. The available literature indicates
that the pharmacokinetics of growth hormone is similar in both men and women.
Race — No data are available.
Renal, Hepatic insufficiency — No studies have been performed with Humatrope.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
S-045 10.12.2005
3
Table 1
Summary of Somatropin Parameters in the Normal Population
Cmax
(ng/mL)
t1/2
(hr)
AUC0-∞
(ng•hr/mL)
Cls
(L/kg•hr)
Vβ
(L/kg)
0.02 mg (0.05 IU*)/kg
iv
MEAN
415
0.363
156
0.135
0.0703
SD
75
0.053
33
0.029
0.0173
0.1 mg (0.27 IU*)/kg
im
MEAN
53.2
4.93
495
0.215
1.55
SD
25.9
2.66
106
0.047
0.91
0.1 mg (0.27 IU*)/kg
sc
MEAN
63.3
3.81
585
0.179
0.957
SD
18.2
1.40
90
0.028
0.301
95
96
97
98
99
100
101
102
103
104
105
106
107
Abbreviations: Cmax=maximum concentration; t1/2=half-life; AUC0-∞=area under the curve; Cls=systemic
clearance; Vβ=volume distribution; iv=intravenous; SD=standard deviation; im=intramuscular; sc=subcutaneous.
* Based on previous International Standard of 2.7 IU=1 mg.
Figure 1
1
10
100
1000
Plasma Concentration (ng/mL)
0
6
12
18
Time (hours)
0.02 mg/kg intravenous injection
0.10 mg/kg intramuscular injection
0.1 mg/kg subcutaneous injection
Single Dose Average Plasma Concentrations
vs Time in Normal Adult Volunteers
Mean +/- SE (n=8)
CLINICAL TRIALS
Effects of Humatrope Treatment in Adults with Growth Hormone Deficiency
Two multicenter trials in adult-onset growth hormone deficiency (n=98) and two studies in
childhood-onset growth hormone deficiency (n=67) were designed to assess the effects of
replacement therapy with Humatrope. The primary efficacy measures were body composition
(lean body mass and fat mass), lipid parameters, and the Nottingham Health Profile. The
Nottingham Health Profile is a general health-related quality of life questionnaire. These
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
S-045 10.12.2005
4
four studies each included a 6-month randomized, blinded, placebo-controlled phase followed by
12 months of open-label therapy for all patients. The Humatrope dosages for all studies were
identical: 1 month of therapy at 0.00625 mg/kg/day followed by the proposed maintenance dose
of 0.0125 mg/kg/day. Adult-onset patients and childhood-onset patients differed by diagnosis
(organic vs. idiopathic pituitary disease), body size (normal vs. small for mean height and
weight), and age (mean=44 vs. 29 years). Lean body mass was determined by bioelectrical
impedance analysis (BIA), validated with potassium 40. Body fat was assessed by BIA and sum
of skinfold thickness. Lipid subfractions were analyzed by standard assay methods in a central
laboratory.
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
Humatrope-treated adult-onset patients, as compared to placebo, experienced an increase in
lean body mass (2.59 vs. -0.22 kg, p<0.001) and a decrease in body fat (-3.27 vs. 0.56 kg,
p<0.001). Similar changes were seen in childhood-onset growth hormone-deficient patients.
These significant changes in lean body mass persisted throughout the 18-month period as
compared to baseline for both groups, and for fat mass in the childhood-onset group. Total
cholesterol decreased short-term (first 3 months) although the changes did not persist. However,
the low HDL cholesterol levels observed at baseline (mean=30.1 mg/mL and 33.9 mg/mL in
adult-onset and childhood-onset patients) normalized by the end of 18 months of therapy (a
change of 13.7 and 11.1 mg/dL for the adult-onset and childhood-onset groups, p<0.001).
Adult-onset patients reported significant improvements as compared to placebo in the following
two of six possible health-related domains: physical mobility and social isolation (Table 2).
Patients with childhood-onset disease failed to demonstrate improvements in Nottingham Health
Profile outcomes.
Two additional studies on the effect of Humatrope on exercise capacity were also conducted.
Improved physical function was documented by increased exercise capacity (VO2 max, p<0.005)
and work performance (Watts, p<0.01) (J Clin Endocrinol Metab 1995; 80:552-557).
Two studies evaluating the effect of Humatrope on bone mineralization were subsequently
conducted. In a 2-year, randomized, double-blind, placebo-controlled trial, 67 patients with
previously untreated adult-onset growth hormone (GH) deficiency received placebo or
Humatrope treatment titrated to maintain serum IGF-I within the age-adjusted normal range. In
men, but not women, lumbar spine bone mineral density (BMD) increased with Humatrope
treatment compared to placebo with a treatment difference of approximately 4% (p=0.001).
There was no significant change in hip BMD with Humatrope treatment in men or women, when
compared to placebo. In a 2-year, open-label, randomized trial, 149 patients with
childhood-onset GH deficiency, who had completed pediatric GH therapy, had attained final
height (height velocity < 1 cm/yr) and were confirmed to be GH-deficient as young adults
(commonly referred to as transition patients), received Humatrope 12.5 µg/kg/day, Humatrope
25 µg/kg/day, or were followed with no therapy. Patients who were randomized to treatment
with Humatrope at 12.5 µg/kg/day achieved a 2.9% greater increase from baseline than control
in total body bone mineral content (BMC) (8.1 ± 9.0% vs. 5.2 ± 8.2%, p=0.02), whereas patients
treated with Humatrope at 25 µg/kg/day had no significant change in BMC. These results include
data from patients who received less than 2 years of treatment. A greater treatment effect was
observed for patients who completed 2 years of treatment. Increases in lumbar spine BMD and
BMC were also statistically significant compared to control with the 12.5 µg/kg/day dose but not
the 25 µg/kg/day dose. Hip BMD and BMC did not change significantly compared to control
with either dose. The effect of GH treatment on BMC and BMD in transition patients at doses
lower than 12.5 µg/kg/day was not studied. The effect of Humatrope on the occurrence of
osteoporotic fractures has not been studied.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
S-045 10.12.2005
5
Table 2
Changesa in Nottingham Health Profile Scoresb in Adult-Onset Growth Hormone-Deficient
Patients
Outcome
Measure
Placebo
(6 Months)
Humatrope Therapy
(6 Months)
Significance
Energy level
-11.4
-15.5
NS
Physical mobility
-3.1
-10.5
p<0.01
Social isolation
0.5
-4.7
p<0.01
Emotional reactions
-4.5
-5.4
NS
Sleep
-6.4
-3.7
NS
Pain
-2.8
-2.9
NS
a An improvement in score is indicated by a more negative change in the score.
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
b To account for multiple analyses, appropriate statistical methods were applied and the required level of
significance is 0.01.
NS=not significant.
Effects of Growth Hormone Treatment in Patients with Turner Syndrome
One long-term, randomized, open-label multicenter concurrently controlled study,
two long-term, open-label multicenter, historically controlled studies and one long-term,
randomized, dose-response study were conducted to evaluate the efficacy of growth hormone for
the treatment of patients with short stature due to Turner syndrome.
In the randomized study, GDCT, comparing growth hormone-treated patients to a concurrent
control group who received no growth hormone, the growth hormone-treated patients who
received a dose of 0.3 mg/kg/wk given 6 times per week from a mean age of 11.7 years for a
mean duration of 4.7 years attained a mean near final height of 146.0 ± 6.2 cm (n=27,
mean ± SD) as compared to the control group who attained a near final height of 142.1 ± 4.8 cm
(n=19). By analysis of covariance∗, the effect of growth hormone therapy was a mean height
increase of 5.4 cm (p=0.001).
In two of the studies (85-023 and 85-044), the effect of long-term growth hormone treatment
(0.375 mg/kg/wk given either 3 times per week or daily) on adult height was determined by
comparing adult heights in the treated patients with those of age-matched historical controls with
Turner syndrome who never received any growth-promoting therapy. The greatest improvement
in adult height was observed in patients who received early growth hormone treatment and
estrogen after age 14 years. In Study 85-023, this resulted in a mean adult height gain of 7.4 cm
(mean duration of GH therapy of 7.6 years) vs. matched historical controls by analysis of
covariance.
In Study 85-044, patients treated with early growth hormone therapy were randomized to
receive estrogen replacement therapy (conjugated estrogens, 0.3 mg escalating to 0.625 mg
daily) at either age 12 or 15 years. Compared with matched historical controls, early GH therapy
(mean duration of GH therapy 5.6 years) combined with estrogen replacement at age 12 years
resulted in an adult height gain of 5.9 cm (n=26), whereas patients who initiated estrogen at age
15 years (mean duration of GH therapy 6.1 years) had a mean adult height gain of 8.3 cm (n=29).
Patients who initiated GH therapy after age 11 (mean age 12.7 years; mean duration of
GH therapy 3.8 years) had a mean adult height gain of 5.0 cm (n=51).
In a randomized blinded dose-response study, GDCI, patients were treated from a mean age of
11.1 years for a mean duration of 5.3 years with a weekly dose of either 0.27 mg/kg or
∗ Analysis of covariance includes adjustments for baseline height relative to age and for
mid-parental height.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
S-045 10.12.2005
6
0.36 mg/kg administered 3 or 6 times weekly. The mean near final height of patients receiving
growth hormone was 148.7 ± 6.5 cm (n=31). When compared to historical control data, the mean
gain in adult height was approximately 5 cm.
191
192
193
194
195
196
In some studies, Turner syndrome patients (n=181) treated to final adult height achieved
statistically significant average height gains ranging from 5.0 to 8.3 cm.
Table 3
Summary Table of Efficacy Results
Study/
Group
Study
Designa
N at Adult
Height
GH
Age (yr)
Estrogen
Age (yr)
GH
Duration (yr)
Adult Height
Gain (cm)b
GDCT
RCT
27
11.7
13
4.7
5.4
85-023
MHT
17
9.1
15.2
7.6
7.4
85-044:
A*
MHT
29
9.4
15
6.1
8.3
B*
26
9.6
12.3
5.6
5.9
C*
51
12.7
13.7
3.8
5
GDCI
RDT
31
11.1
8-13.5
5.3
~5c
a RCT: randomized controlled trial; MHT: matched historical controlled trial; RDT: randomized dose-response trial.
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
b Analysis of covariance vs. controls.
c Compared with historical data.
* A: GH age <11 yr, estrogen age 15 yr.
B: GH age <11 yr, estrogen age 12 yr.
C: GH age >11 yr, estrogen at month 12.
Effect of Humatrope Treatment in Pediatric Patients with Idiopathic Short Stature
Two randomized, multicenter trials, 1 placebo-controlled and 1 dose-response, were conducted
in pediatric patients with idiopathic short stature, also called non-growth hormone-deficient short
stature. The diagnosis of idiopathic short stature was made after excluding other known causes of
short stature, as well as growth hormone deficiency. Limited safety and efficacy data are
available below the age of 7 years. No specific studies have been conducted in pediatric patients
with familial short stature or who were born small for gestational age (SGA).
The placebo-controlled study enrolled 71 pediatric patients (55 males, 16 females) 9 to
15 years old (mean age 12.38 ± 1.51 years), with short stature, 68 of whom received study drug.
Patients were predominately Tanner I (45.1%) and Tanner II (46.5%) at baseline.
In this double-blind trial, patients received subcutaneous injections of either Humatrope
0.222 mg/kg/wk or placebo. Study drug was given in divided doses 3 times per week until height
velocity decreased to ≤1.5 cm/year (“final height”). Thirty-three subjects (22 Humatrope,
11 placebo) had final height measurements after a mean treatment duration of 4.4 years (range
0.11-9.08 years).
The Humatrope group achieved a mean final height Standard Deviation Score (SDS) of
-1.8 (Table 4). Placebo-treated patients had a mean final height SDS of -2.3 (mean treatment
difference = 0.51, p=0.017). Height gain across the duration of the study and final height SDS
minus baseline predicted height SDS were also significantly greater in Humatrope-treated
patients than in placebo-treated patients (Table 4 and 5). In addition, the number of patients who
achieved a final height above the 5th percentile of the general population for age and sex was
significantly greater in the Humatrope group than the placebo group (41% vs. 0%, p<0.05), as
was the number of patients who gained at least 1 SDS unit in height across the duration of the
study (50% vs. 0%, p<0.05).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
S-045 10.12.2005
7
Table 4
Baseline Height Characteristics and Effect of Humatrope on Final Heighta
Humatrope
(n=22)
Mean (SD)
Placebo
(n=11)
Mean (SD)
Treatment Effect
Mean
(95% CI)
p-value
Baseline height SDS
-2.7 (0.6)
-2.75 (0.6)
0.77
BPH SDS
-2.1 (0.7)
-2.3 (0.8)
0.53
Final height SDSb
-1.8 (0.8)
-2.3 (0.6)
0.51 (0.10, 0.92)
0.017
FH SDS - baseline height SDS
0.9 (0.7)
0.4 (0.2)
0.51 (0.04, 0.97)
0.034
FH SDS - BPH SDS
0.3 (0.6)
-0.1 (0.6)
0.46 (0.02, 0.89)
0.043
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
a For final height population.
b Between-group comparison was performed using analysis of covariance with baseline predicted height SDS as the
covariant. Treatment effect is expressed as least squares mean (95% CI).
Abbreviations: FH=final height; SDS=standard deviation score; BPH=baseline predicted height; CI=confidence
interval.
The dose-response study included 239 pediatric patients (158 males, 81 females), 5 to 15 years
old, (mean age 9.8 ± 2.3 years). Mean baseline characteristics included: a height SDS of
-3.21 (±0.70), a predicted adult height SDS of -2.63 (±1.08), and a height velocity SDS of
-1.09 (±1.15). All but 3 patients were Tanner I. Patients were randomized to one of
three Humatrope treatment groups: 0.24 mg/kg/wk; 0.24 mg/kg/wk for 1 year, followed by
0.37 mg/kg/wk; and 0.37 mg/kg/wk.
The primary hypothesis of this study was that treatment with Humatrope would increase height
velocity during the first 2 years of therapy in a dose-dependent manner. Additionally, after
completing the initial 2-year dose-response phase of the study, 50 patients were followed to final
height.
Patients receiving 0.37 mg/kg/wk had a significantly greater increase in mean height velocity
after 2 years of treatment than patients receiving 0.24 mg/kg/wk (4.04 vs. 3.27 cm/year,
p=0.003). The mean difference between final height and baseline predicted height was 7.2 cm for
patients receiving 0.37 mg/kg/wk and 5.4 cm for patients receiving 0.24 mg/kg/wk (Table 5).
While no patient had height above the 5th percentile in any dose group at baseline, 82% of the
patients receiving 0.37 mg/kg/wk and 47% of the patients receiving 0.24 mg/kg/wk achieved a
final height above the 5th percentile of the general population height standards (p=NS).
Table 5
Final Height Minus Baseline Predicted Height: Idiopathic Short Stature Trials
Placebo-controlled Trial
3x per week dosing
Dose Response Trial
6x per week dosing
Placebo
(n=10)
Humatrope
0.22 mg/kg
(n=22)
Humatrope
0.24 mg/kg
(n=13)
Humatrope
0.24/0.37 mg/kg
(n=13)
Humatrope
0.37 mg/kg
(n=13)
FH – Baseline PH
Mean cm
(95% CI)
Mean inches
(95% CI)
-0.7
(-3.6, 2.3)
-0.3
(-1.4, 0.9)
+2.2
(0.4, 3.9)
+0.8
(0.2, 1.5)
+5.4
(2.8, 7.9)
+2.1
(1.1, 3.1)
+6.7
(4.1, 9.2)
+2.6
(1.6, 3.6)
+7.2
(4.6, 9.8)
+2.8
(1.8, 3.9)
253
254
Abbreviations: PH=predicted height; FH=final height; CI=confidence interval.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
S-045 10.12.2005
8
INDICATIONS AND USAGE
255
256
257
258
259
260
261
262
263
264
265
266
Pediatric Patients — Humatrope is indicated for the long-term treatment of pediatric patients
who have growth failure due to an inadequate secretion of normal endogenous growth hormone.
Humatrope is indicated for the treatment of short stature associated with Turner syndrome in
patients whose epiphyses are not closed.
Humatrope is indicated for the long-term treatment of idiopathic short stature, also called
non-growth hormone-deficient short stature, defined by height SDS ≤-2.25, and associated with
growth rates unlikely to permit attainment of adult height in the normal range, in pediatric
patients whose epiphyses are not closed and for whom diagnostic evaluation excludes other
causes associated with short stature that should be observed or treated by other means.
Adult Patients — Humatrope is indicated for replacement of endogenous growth hormone in
adults with growth hormone deficiency who meet either of the following two criteria:
1. Adult Onset: Patients who have growth hormone deficiency either alone, or with multiple
hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease,
surgery, radiation therapy, or trauma;
267
268
269
270
or
2. Childhood Onset: Patients who were growth hormone-deficient during childhood who have
growth hormone deficiency confirmed as an adult before replacement therapy with Humatrope is
started.
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
303
CONTRAINDICATIONS
Humatrope should not be used for growth promotion in pediatric patients with closed
epiphyses.
Humatrope should not be used or should be discontinued when there is any evidence of active
malignancy. Anti-malignancy treatment must be complete with evidence of remission prior to
the institution of therapy.
Humatrope should not be reconstituted with the supplied Diluent for Humatrope for use by
patients with a known sensitivity to either Metacresol or glycerin.
Growth hormone should not be initiated to treat patients with acute critical illness due to
complications following open heart or abdominal surgery, multiple accidental trauma or to
patients having acute respiratory failure. Two placebo-controlled clinical trials in non-growth
hormone-deficient adult patients (n=522) with these conditions revealed a significant increase in
mortality (41.9% vs. 19.3%) among somatropin-treated patients (doses 5.3 to 8 mg/day)
compared to those receiving placebo (see WARNINGS).
Growth hormone is contraindicated in patients with Prader-Willi syndrome who are severely
obese or have severe respiratory impairment (see WARNINGS). Unless patients with
Prader-Willi syndrome also have a diagnosis of growth hormone deficiency, Humatrope is not
indicated for the long term treatment of pediatric patients who have growth failure due to
genetically confirmed Prader-Willi syndrome.
WARNINGS
If sensitivity to the diluent should occur, the vials may be reconstituted with Bacteriostatic
Water for Injection, USP or, Sterile Water for Injection, USP. When Humatrope is used with
Bacteriostatic Water (Benzyl Alcohol preserved), the solution should be kept refrigerated at
2° to 8°C (36° to 46°F) and used within 14 days. Benzyl alcohol as a preservative in
Bacteriostatic Water for Injection, USP has been associated with toxicity in newborns.
When administering Humatrope to newborns, use the Humatrope diluent provided or if the
patient is sensitive to the diluent, use Sterile Water for Injection, USP. When Humatrope is
reconstituted with Sterile Water for Injection, USP in this manner, use only one dose per
Humatrope vial and discard the unused portion. If the solution is not used immediately, it must
be refrigerated [2° to 8°C (36° to 46°F)] and used within 24 hours.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
S-045 10.12.2005
9
Cartridges should be reconstituted only with the supplied diluent. Cartridges should not
be reconstituted with the Diluent for Humatrope provided with Humatrope Vials, or with
any other solution. Cartridges should not be used if the patient is allergic to Metacresol or
glycerin.
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
330
331
332
333
334
335
336
337
338
339
340
341
342
343
344
345
346
347
348
349
350
351
See CONTRAINDICATIONS for information on increased mortality in patients with acute
critical illnesses in intensive care units due to complications following open heart or abdominal
surgery, multiple accidental trauma or with acute respiratory failure. The safety of continuing
growth hormone treatment in patients receiving replacement doses for approved indications who
concurrently develop these illnesses has not been established. Therefore, the potential benefit of
treatment continuation with growth hormone in patients having acute critical illnesses should be
weighed against the potential risk.
There have been reports of fatalities after initiating therapy with growth hormone in pediatric
patients with Prader-Willi syndrome who had one or more of the following risk factors: severe
obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection.
Male patients with one or more of these factors may be at greater risk than females. Patients with
Prader-Willi syndrome should be evaluated for signs of upper airway obstruction and sleep
apnea before initiation of treatment with growth hormone. If, during treatment with growth
hormone, patients show signs of upper airway obstruction (including onset of or increased
snoring) and/or new onset sleep apnea, treatment should be interrupted. All patients with
Prader-Willi syndrome treated with growth hormone should also have effective weight control
and be monitored for signs of respiratory infection, which should be diagnosed as early as
possible and treated aggressively (see CONTRAINDICATIONS). Unless patients with
Prader-Willi syndrome also have a diagnosis of growth hormone deficiency, Humatrope is not
indicated for the long term treatment of pediatric patients who have growth failure due to
genetically confirmed Prader-Willi syndrome.
PRECAUTIONS
General — Therapy with Humatrope should be directed by physicians who are experienced in
the diagnosis and management of patients with growth hormone deficiency, Turner syndrome,
idiopathic short stature, or adult patients with either childhood-onset or adult-onset growth
hormone deficiency.
Patients with preexisting tumors or with growth hormone deficiency secondary to an
intracranial lesion should be examined routinely for progression or recurrence of the underlying
disease process. In pediatric patients, clinical literature has demonstrated no relationship between
somatropin replacement therapy and CNS tumor recurrence. In adults, it is unknown whether
there is any relationship between somatropin replacement therapy and CNS tumor recurrence.
Patients should be monitored carefully for any malignant transformation of skin lesions.
For patients with diabetes mellitus, the insulin dose may require adjustment when somatropin
therapy is instituted. Because human growth hormone may induce a state of insulin resistance,
patients should be observed for evidence of glucose intolerance. Patients with diabetes or glucose
intolerance should be monitored closely during somatropin therapy.
In patients with hypopituitarism (multiple hormonal deficiencies) standard hormonal
replacement therapy should be monitored closely when somatropin therapy is administered.
Hypothyroidism may develop during treatment with somatropin and inadequate treatment of
hypothyroidism may prevent optimal response to somatropin.
Pediatric Patients (see General Precautions) — Pediatric patients with endocrine disorders,
including growth hormone deficiency, may develop slipped capital epiphyses more frequently.
Any pediatric patient with the onset of a limp during growth hormone therapy should be
evaluated.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
S-045 10.12.2005
10
Growth hormone has not been shown to increase the incidence of scoliosis. Progression of
scoliosis can occur in children who experience rapid growth. Because growth hormone increases
growth rate, patients with a history of scoliosis who are treated with growth hormone should be
monitored for progression of scoliosis. Skeletal abnormalities including scoliosis are commonly
seen in untreated Turner syndrome patients.
352
353
354
355
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
376
377
378
379
380
381
382
383
384
385
386
387
388
389
390
391
392
393
394
395
396
397
398
399
Patients with Turner syndrome should be evaluated carefully for otitis media and other ear
disorders since these patients have an increased risk of ear or hearing disorders (see Adverse
Reactions). Patients with Turner syndrome are at risk for cardiovascular disorders (e.g., stroke,
aortic aneurysm, hypertension) and these conditions should be monitored closely.
Patients with Turner syndrome have an inherently increased risk of developing autoimmune
thyroid disease. Therefore, patients should have periodic thyroid function tests and be treated as
indicated (see General Precautions).
Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea and/or
vomiting has been reported in a small number of pediatric patients treated with growth hormone
products. Symptoms usually occurred within the first 8 weeks of the initiation of growth
hormone therapy. In all reported cases, IH-associated signs and symptoms resolved after
termination of therapy or a reduction of the growth hormone dose. Funduscopic examination of
patients is recommended at the initiation and periodically during the course of growth hormone
therapy. Patients with Turner syndrome may be at increased risk for development of IH.
Adult Patients (see General Precautions) — Patients with epiphyseal closure who were treated
with growth hormone replacement therapy in childhood should be re-evaluated according to the
criteria in INDICATIONS AND USAGE before continuation of somatropin therapy at the
reduced dose level recommended for growth hormone-deficient adults.
Experience with prolonged treatment in adults is limited.
Geriatric Use — The safety and effectiveness of Humatrope in patients aged 65 and over has
not been evaluated in clinical studies. Elderly patients may be more sensitive to the action of
Humatrope and may be more prone to develop adverse reactions.
Drug Interactions — Excessive glucocorticoid therapy may prevent optimal response to
somatropin. If glucocorticoid replacement therapy is required, the glucocorticoid dosage and
compliance should be monitored carefully to avoid either adrenal insufficiency or inhibition of
growth promoting effects.
Limited published data indicate that growth hormone (GH) treatment increases
cytochrome P450 (CP450) mediated antipyrine clearance in man. These data suggest that
GH administration may alter the clearance of compounds known to be metabolized by
CP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporin). Careful
monitoring is advisable when GH is administered in combination with other drugs known to be
metabolized by CP450 liver enzymes.
Carcinogenesis, Mutagenesis, Impairment of Fertility — Long-term animal studies for
carcinogenicity and impairment of fertility with this human growth hormone (Humatrope) have
not been performed. There has been no evidence to date of Humatrope-induced mutagenicity.
Pregnancy — Pregnancy Category C — Animal reproduction studies have not been conducted
with Humatrope. It is not known whether Humatrope can cause fetal harm when administered to
a pregnant woman or can affect reproductive capacity. Humatrope should be given to a pregnant
woman only if clearly needed.
Nursing Mothers — There have been no studies conducted with Humatrope in 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 Humatrope is administered to a
nursing woman.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
S-045 10.12.2005
11
Information for Patients — Patients being treated with growth hormone and/or their parents
should be informed of the potential risks and benefits associated with treatment. Instructions on
appropriate use should be given, including a review of the contents of the patient information
insert. This information is intended to aid in the safe and effective administration of the
medication. It is not a disclosure of all possible adverse or intended effects.
400
401
402
403
404
405
406
407
408
409
410
411
412
413
414
415
416
417
418
419
420
421
422
423
424
425
426
427
428
429
430
431
432
433
434
435
436
Patients and/or parents should be thoroughly instructed in the importance of proper needle
disposal. A puncture resistant container should be used for the disposal of used needles and/or
syringes (consistent with applicable state requirements). Needles and syringes must not be reused
(see Information for the Patient insert).
ADVERSE REACTIONS
Growth Hormone-Deficient Pediatric Patients
As with all protein pharmaceuticals, a small percentage of patients may develop antibodies to
the protein. During the first 6 months of Humatrope therapy in 314 naive patients, only 1.6%
developed specific antibodies to Humatrope (binding capacity ≥0.02 mg/L). None had antibody
concentrations which exceeded 2 mg/L. Throughout 8 years of this same study, two patients
(0.6%) had binding capacity >2 mg/L. Neither patient demonstrated a decrease in growth
velocity at or near the time of increased antibody production. It has been reported that growth
attenuation from pituitary-derived growth hormone may occur when antibody concentrations are
>1.5 mg/L.
In addition to an evaluation of compliance with the treatment program and of thyroid status,
testing for antibodies to human growth hormone should be carried out in any patient who fails to
respond to therapy.
In studies with growth hormone-deficient pediatric patients, injection site pain was reported
infrequently. A mild and transient edema, which appeared in 2.5% of patients, was observed
early during the course of treatment.
Leukemia has been reported in a small number of pediatric patients who have been treated with
growth hormone, including growth hormone of pituitary origin as well as of recombinant
DNA origin (somatrem and somatropin). The relationship, if any, between leukemia and growth
hormone therapy is uncertain.
Turner Syndrome Patients
In a randomized, concurrent controlled trial, there was a statistically significant increase in the
occurrence of otitis media (43% vs. 26%), ear disorders (18% vs. 5%) and surgical procedures
(45% vs. 27%) in patients receiving Humatrope compared with untreated control patients
(Table 6). Other adverse events of special interest to Turner syndrome patients were not
significantly different between treatment groups (Table 6). A similar increase in otitis media was
observed in an 18-month placebo-controlled trial.
Table 6
Treatment-Emergent Events of Special Interest by Treatment Group in Turner Syndrome
Treatment Group
Adverse Event
Overall
hGH1
Untreated2
Significance
Total Number of Patients
136
74
62
Surgical procedure
50 (36.8%)
33 (44.6%)
17 (27.4%)
p≤0.05
Otitis media
48 (35.3%)
32 (43.2%)
16 (25.8%)
p≤0.05
Ear disorders
16 (11.8%)
13 (17.6%)
3 (4.8%)
p≤0.05
Bone disorder
13 (9.6%)
6 (8.1%)
7 (11.3%)
NS
Edema
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
S-045 10.12.2005
12
Conjunctival
1 (0.7%)
0
1 (1.6%)
NS
Non-specific
3 (2.2%)
2 (2.7%)
1 (1.6%)
NS
Facial
1 (0.7%)
1 (1.4%)
0
NS
Peripheral
6 (4.4%)
5 (6.8%)
1 (1.6%)
NS
Hyperglycemia
0
0
0
NS
Hypothyroidism
15 (11.0%)
10 (13.5%)
5 (8.1%)
NS
Increased nevi3
10 (7.4%)
8 (10.8%)
2 (3.2%)
NS
Lymphedema
0
0
0
NS
1 Dose=0.3 mg/kg/wk.
437
438
439
440
441
442
443
444
445
446
447
448
449
450
451
452
453
454
455
456
457
2 Open-label study.
3 Includes any nevi coded to the following preferred terms: melanosis, skin hypertrophy, or skin benign neoplasm.
NS=not significant.
Patients with Idiopathic Short Stature
In the placebo-controlled study, the adverse events associated with Humatrope therapy were
similar to those observed in other pediatric populations treated with Humatrope (Table 7). Mean
serum glucose level did not change during Humatrope treatment. Mean fasting serum insulin
levels increased 10% in the Humatrope treatment group at the end of treatment relative to
baseline values but remained within the normal reference range. For the same duration of
treatment the mean fasting serum insulin levels decreased by 2% in the placebo group. The
incidence of above-range values for glucose, insulin, and HbA1c were similar in the growth
hormone and placebo-treated groups. No patient developed diabetes mellitus. Consistent with the
known mechanism of growth hormone action, Humatrope-treated patients had greater mean
increases, relative to baseline, in serum insulin-like growth factor-I (IGF-I) than placebo-treated
patients at each study observation. However, there was no significant difference between the
Humatrope and placebo treatment groups in the proportion of patients who had at least
one serum IGF-I concentration more than 2.0 SD above the age- and gender-appropriate mean
(Humatrope: 9 of 35 patients [26%]; placebo: 7 of 28 patients [25%]).
Table 7
Nonserious Clinically Significant Treatment-Emergent Adverse Events by
Treatment Group in Idiopathic Short Stature
Treatment Group
Adverse Event
Humatrope
Placebo
Total Number of Patients
37
31
Scoliosis
7 (18.9%)
4 (12.9%)
Otitis media
6 (16.2%)
2 (6.5%)
Hyperlipidemia
3 (8.1%)
1 (3.2%)
Gynecomastia
2 (5.4%)
1 (3.2%)
Hypothyroidism
0
2 (6.5%)
Aching joints
0
1 (3.2%)
Hip pain
1 (2.7%)
0
Arthralgia
4 (10.8%)
1 (3.2%)
Arthrosis
4 (10.8%)
2 (6.5%)
Myalgia
9 (24.3%)
4 (12.9%)
Hypertension
1 (2.7%)
0
458
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
S-045 10.12.2005
13
The adverse events observed in the dose-response study (239 patients treated for 2 years) did
not indicate a pattern suggestive of a growth hormone dose effect. Among Humatrope dose
groups, mean fasting blood glucose, mean glycosylated hemoglobin, and the incidence of
elevated fasting blood glucose concentrations were similar. One patient developed abnormalities
of carbohydrate metabolism (glucose intolerance and high serum HbA
459
460
461
462
463
464
465
466
467
468
469
470
471
472
473
474
475
476
477
478
479
480
481
482
1c) on treatment.
Adult Patients — In clinical studies in which high doses of Humatrope were administered to
healthy adult volunteers, the following events occurred infrequently: headache, localized muscle
pain, weakness, mild hyperglycemia, and glucosuria.
In the first 6 months of controlled blinded trials during which patients received either
Humatrope or placebo, adult-onset growth hormone-deficient adults who received Humatrope
experienced a statistically significant increase in edema (Humatrope 17.3% vs. placebo 4.4%,
p=0.043) and peripheral edema (11.5% vs. 0%, respectively, p=0.017). In patients with
adult-onset growth hormone deficiency, edema, muscle pain, joint pain, and joint disorder were
reported early in therapy and tended to be transient or responsive to dosage titration.
Two of 113 adult-onset patients developed carpal tunnel syndrome after beginning
maintenance therapy without a low dose (0.00625 mg/kg/day) lead-in phase. Symptoms abated
in these patients after dosage reduction.
All treatment-emergent adverse events with ≥5% overall incidence during 12 or 18 months of
replacement therapy with Humatrope are shown in Table 8 (adult-onset patients) and in Table 9
(childhood-onset patients).
Adult patients treated with Humatrope who had been diagnosed with growth hormone
deficiency in childhood reported side effects less frequently than those with adult-onset growth
hormone deficiency.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
S-045 10.12.2005
14
Table 8
Treatment-Emergent Adverse Events with ≥5% Overall Incidence in Adult-Onset Growth
Hormone-Deficient Patients Treated with Humatrope for 18 Months as Compared with
6-Month Placebo and 12-Month Humatrope Exposure
18 Months Exposure
[Placebo (6 Months)/hGH (12 Months)]
(N=46)
18 Months hGH Exposure
(N=52)
Adverse Event
n
%
n
%
Edemaa
7
15.2
11
21.2
Arthralgia
7
15.2
9
17.3
Paresthesia
6
13.0
9
17.3
Myalgia
6
13.0
7
13.5
Pain
6
13.0
7
13.5
Rhinitis
5
10.9
7
13.5
Peripheral edemab
8
17.4
6
11.5
Back pain
5
10.9
5
9.6
Headache
5
10.9
4
7.7
Hypertension
2
4.3
4
7.7
Acne
0
0
3
5.8
Joint disorder
1
2.2
3
5.8
Surgical procedure
1
2.2
3
5.8
Flu syndrome
3
6.5
2
3.9
Abbreviations: hGH=Humatrope; N=number of patients receiving treatment in the period stated; n=number of
patients reporting each treatment-emergent adverse event.
483
484
485
486
487
a p=0.04 as compared to placebo (6 months).
b p=0.02 as compared to placebo (6 months).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
S-045 10.12.2005
15
Table 9
Treatment-Emergent Adverse Events with ≥5% Overall Incidence in Childhood-Onset
Growth Hormone-Deficient Patients Treated with Humatrope for 18 Months as Compared
with 6-Month Placebo and 12-Month Humatrope Exposure
18 Months Exposure
[Placebo (6 Months)/hGH (12 Months)]
(N=35)
18 Months hGH Exposure
(N=32)
Adverse Event
n
%
n
%
Flu syndrome
8
22.9
5
15.6
AST increaseda
2
5.7
4
12.5
Headache
4
11.4
3
9.4
Asthenia
1
2.9
2
6.3
Cough increased
0
0
2
6.3
Edema
3
8.6
2
6.3
Hypesthesia
0
0
2
6.3
Myalgia
2
5.7
2
6.3
Pain
3
8.6
2
6.3
Rhinitis
2
5.7
2
6.3
ALT increased
2
5.7
2
6.3
Respiratory disorder
2
5.7
1
3.1
Gastritis
2
5.7
0
0
Pharyngitis
5
14.3
1
3.1
Abbreviations: hGH=Humatrope; N=number of patients receiving treatment in the period stated; n=number of
patients reporting each treatment-emergent adverse event; ALT=alanine amino transferase, formerly SGPT;
AST=aspartate amino transferase, formerly SGOT.
488
489
490
491
492
493
494
495
496
497
498
499
500
501
502
503
504
505
506
507
508
509
510
511
512
513
a p=0.03 as compared to placebo (6 months).
Other adverse drug events that have been reported in growth hormone-treated patients include
the following:
1) Metabolic: Infrequent, mild and transient peripheral or generalized edema.
2) Musculoskeletal: Rare carpal tunnel syndrome.
3) Skin: Rare increased growth of pre-existing nevi. Patients should be monitored carefully
for malignant transformation.
4) Endocrine: Rare gynecomastia. Rare pancreatitis.
OVERDOSAGE
Acute overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia.
Long-term overdosage could result in signs and symptoms of gigantism/acromegaly consistent
with the known effects of excess human growth hormone. (See recommended and maximal
dosage instructions given below.)
DOSAGE AND ADMINISTRATION
Pediatric Patients
The Humatrope dosage and administration schedule should be individualized for each patient.
Therapy should not be continued if epiphyseal fusion has occurred. Response to growth hormone
therapy tends to decrease with time. However, failure to increase growth rate, particularly during
the first year of therapy, should prompt close assessment of compliance and evaluation of other
causes of growth failure such as hypothyroidism, under-nutrition and advanced bone age.
Growth hormone-deficient pediatric patients — The recommended weekly dosage is
0.18 mg/kg (0.54 IU/kg) of body weight. The maximal replacement weekly dosage is
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
S-045 10.12.2005
16
0.3 mg/kg (0.90 IU/kg) of body weight. It should be divided into equal doses given either on
3 alternate days, 6 times per week or daily. The subcutaneous route of administration is
preferable; intramuscular injection is also acceptable. The dosage and administration schedule
for Humatrope should be individualized for each patient.
514
515
516
517
518
519
520
521
522
523
524
525
526
527
528
529
530
531
532
533
534
535
536
537
538
539
540
541
542
543
544
545
546
547
548
549
550
551
552
553
554
555
Turner Syndrome — A weekly dosage of up to 0.375 mg/kg (1.125 IU/kg) of body weight
administered by subcutaneous injection is recommended. It should be divided into equal doses
given either daily or on 3 alternate days.
Patients with idiopathic short stature — A weekly dosage of up to 0.37 mg/kg of body weight
administered by subcutaneous injection is recommended. It should be divided into equal doses
given 6 to 7 times per week.
Adult Patients
Growth hormone-deficient adult patients — The recommended dosage at the start of therapy is
not more than 0.006 mg/kg/day (0.018 IU/kg/day) given as a daily subcutaneous injection. The
dose may be increased according to individual patient requirements to a maximum of
0.0125 mg/kg/day (0.0375 IU/kg/day).
During therapy, dosage should be titrated if required by the occurrence of side effects or to
maintain the IGF-I response below the upper limit of normal IGF-I levels, matched for age and
sex. To minimize the occurrence of adverse events in patients with increasing age or excessive
body weight, dose reductions may be necessary.
Reconstitution
Vial — Each 5-mg vial of Humatrope should be reconstituted with 1.5 to 5 mL of Diluent for
Humatrope. The diluent should be injected into the vial of Humatrope by aiming the stream of
liquid against the glass wall. Following reconstitution, the vial should be swirled with a
GENTLE rotary motion until the contents are completely dissolved. DO NOT SHAKE. The
resulting solution should be inspected for clarity. It should be clear. If the solution is cloudy or
contains particulate matter, the contents MUST NOT be injected.
Before and after injection, the septum of the vial should be wiped with rubbing alcohol or an
alcoholic antiseptic solution to prevent contamination of the contents by repeated needle
insertions. Sterile disposable syringes and needles should be used for administration of
Humatrope. The volume of the syringe should be small enough so that the prescribed dose can be
withdrawn from the vial with reasonable accuracy.
Cartridge — Each cartridge of Humatrope should only be reconstituted using the diluent
syringe and the diluent connector which accompany the cartridge and should not be
reconstituted with the Diluent for Humatrope provided with Humatrope Vials. (See
WARNINGS section.) See the HumatroPen™ User Guide for comprehensive directions on
Humatrope cartridge reconstitution.
The reconstituted solution should be inspected for clarity. It should be clear. If the solution is
cloudy or contains particulate matter, the contents MUST NOT be injected.
The HumatroPen allows the somatropin dosage volume to be dialed in increments of 0.048 mL
per click of dosage knob, and the maximum dosage volume that can be injected is 0.576 mL
(based on a 12-click maximum). (See Table 10 for additional information.)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
S-045 10.12.2005
17
Table 10
Concentration of Reconstituted Humatrope Solutions, Incremental Dosage and
Maximum Injectable Dose for Each Cartridge
Cartridge
Somatropin
Concentration
Dose Per Click of
Dosage Knob
Maximum Injectable
Dose
6 mg
2.08 mg/mL
0.1 mg
1.2 mg
12 mg
4.17 mg/mL
0.2 mg
2.4 mg
24 mg
8.33 mg/mL
0.4 mg
4.8 mg
556
557
558
559
560
561
562
563
564
565
566
567
568
569
570
571
572
573
574
575
576
577
578
579
580
581
582
583
584
585
586
587
588
589
590
591
This cartridge has been designed for use only with the HumatroPen. A sterile disposable needle
should be used for each administration of Humatrope.
STABILITY AND STORAGE
Vials
Before Reconstitution — Vials of Humatrope and Diluent for Humatrope are stable when
refrigerated [2° to 8°C (36° to 46°F)]. Avoid freezing Diluent for Humatrope. Expiration dates
are stated on the labels.
After Reconstitution — Vials of Humatrope are stable for up to 14 days when reconstituted
with Diluent for Humatrope or Bacteriostatic Water for Injection, USP and stored in a
refrigerator at 2° to 8°C (36° to 46°F). Avoid freezing the reconstituted vial of Humatrope.
After Reconstitution with Sterile Water, USP — Use only one dose per Humatrope vial and
discard the unused portion. If the solution is not used immediately, it must be refrigerated
[2° to 8°C (36° to 46°F)] and used within 24 hours.
Cartridges
Before Reconstitution — Cartridges of Humatrope and Diluent for Humatrope are stable when
refrigerated [2° to 8°C (36° to 46°F)]. Avoid freezing Diluent for Humatrope. Expiration dates
are stated on the labels.
After Reconstitution — Cartridges of Humatrope are stable for up to 28 days when
reconstituted with Diluent for Humatrope and stored in a refrigerator at 2° to 8°C (36° to 46°F).
Store the HumatroPen without the needle attached. Avoid freezing the reconstituted cartridge of
Humatrope.
HOW SUPPLIED
Vials
5 mg (No. 7335) — (6s) NDC 0002-7335-16, and 5-mL vials of Diluent for Humatrope
(No. 7336)
Cartridges
Cartridge Kit (MS8089) NDC 0002-8089-01
6 mg cartridge (VL7554), and prefilled syringe of Diluent for Humatrope (VL7557)
Cartridge Kit (MS8090) NDC 0002-8090-01
12 mg cartridge (VL7555), and prefilled syringe of Diluent for Humatrope (VL7558)
Cartridge Kit (MS8091) NDC 0002-8091-01
24 mg cartridge (VL7556), and prefilled syringe of Diluent for Humatrope (VL7558)
Literature revised October 12, 2005
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
S-045 10.12.2005
18
Eli Lilly and Company, Indianapolis, IN 46285, USA
592
593
594
www.lilly.com
IDENTIFIER
PRINTED IN USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:34.216467
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/019640s045lbl.pdf', 'application_number': 19640, 'submission_type': 'SUPPL ', 'submission_number': 45}
|
11,575
|
1
PA 1643 AMP
1
HUMATROPE®
2
SOMATROPIN (rDNA ORIGIN) FOR INJECTION
3
VIALS
4
and
5
CARTRIDGES FOR USE WITH THE
6
HumatroPen™ INJECTION DEVICE
7
DESCRIPTION
8
Humatrope® (Somatropin, rDNA Origin, for Injection) is a polypeptide hormone of
9
recombinant DNA origin. Humatrope has 191 amino acid residues and a molecular weight of
10
about 22,125 daltons. The amino acid sequence of the product is identical to that of human
11
growth hormone of pituitary origin. Humatrope is synthesized in a strain of Escherichia coli that
12
has been modified by the addition of the gene for human growth hormone.
13
Humatrope is a sterile, white, lyophilized powder intended for subcutaneous or intramuscular
14
administration after reconstitution. Humatrope is a highly purified preparation. Phosphoric acid
15
and/or sodium hydroxide may have been added to adjust the pH. Reconstituted solutions have a
16
pH of approximately 7.5. This product is oxygen sensitive.
17
VIAL — Each vial of Humatrope contains 5 mg somatropin (15 IU or 225 nanomoles); 25 mg
18
mannitol; 5 mg glycine; and 1.13 mg dibasic sodium phosphate. Each vial is supplied in a
19
combination package with an accompanying 5-mL vial of diluting solution. The diluent contains
20
Water for Injection with 0.3% Metacresol as a preservative and 1.7% glycerin.
21
CARTRIDGE — The cartridges of somatropin contain either 6 mg (18 IU), 12 mg (36 IU), or
22
24 mg (72 IU) of somatropin. The 6, 12, and 24 mg cartridges contain respectively: mannitol 18,
23
36, and 72 mg; glycine 6, 12, and 24 mg; dibasic sodium phosphate 1.36, 2.72, and 5.43 mg.
24
Each cartridge is supplied in a combination package with an accompanying syringe containing
25
approximately 3 mL of diluting solution. The diluent contains Water for Injection;
26
0.3% Metacresol as a preservative; and 1.7%, 0.29%, and 0.29% glycerin in the 6, 12, and 24 mg
27
cartridges, respectively.
28
CLINICAL PHARMACOLOGY
29
General
30
Linear Growth — Humatrope stimulates linear growth in pediatric patients who lack adequate
31
normal endogenous growth hormone. In vitro, preclinical, and clinical testing have demonstrated
32
that Humatrope is therapeutically equivalent to human growth hormone of pituitary origin and
33
achieves equivalent pharmacokinetic profiles in normal adults. Treatment of growth
34
hormone-deficient pediatric patients and patients with Turner syndrome with Humatrope
35
produces increased growth rate and IGF-I (Insulin-like Growth Factor-I/Somatomedin-C)
36
concentrations similar to those seen after therapy with human growth hormone of pituitary
37
origin.
38
In addition, the following actions have been demonstrated for Humatrope and/or human
39
growth hormone of pituitary origin.
40
A. Tissue Growth — 1. Skeletal Growth: Humatrope stimulates skeletal growth in pediatric
41
patients with growth hormone deficiency. The measurable increase in body length after
42
administration of either Humatrope or human growth hormone of pituitary origin results from an
43
effect on the growth plates of long bones. Concentrations of IGF-I, which may play a role in
44
skeletal growth, are low in the serum of growth hormone-deficient pediatric patients but increase
45
during treatment with Humatrope. Elevations in mean serum alkaline phosphatase concentrations
46
are also seen. 2. Cell Growth: It has been shown that there are fewer skeletal muscle cells in
47
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
short-statured pediatric patients who lack endogenous growth hormone as compared with normal
48
pediatric populations. Treatment with human growth hormone of pituitary origin results in an
49
increase in both the number and size of muscle cells.
50
B. Protein Metabolism — Linear growth is facilitated in part by increased cellular protein
51
synthesis. Nitrogen retention, as demonstrated by decreased urinary nitrogen excretion and
52
serum urea nitrogen, follows the initiation of therapy with human growth hormone of pituitary
53
origin. Treatment with Humatrope results in a similar decrease in serum urea nitrogen.
54
C. Carbohydrate Metabolism — Pediatric patients with hypopituitarism sometimes experience
55
fasting hypoglycemia that is improved by treatment with Humatrope. Large doses of human
56
growth hormone may impair glucose tolerance. Untreated patients with Turner syndrome have
57
an increased incidence of glucose intolerance. Administration of human growth hormone to
58
normal adults or patients with Turner syndrome resulted in increases in mean serum fasting and
59
postprandial insulin levels although mean values remained in the normal range. In addition,
60
mean fasting and postprandial glucose and hemoglobin A1c levels remained in the normal range.
61
D. Lipid Metabolism — In growth hormone-deficient patients, administration of human growth
62
hormone of pituitary origin has resulted in lipid mobilization, reduction in body fat stores, and
63
increased plasma fatty acids.
64
E. Mineral Metabolism — Retention of sodium, potassium, and phosphorus is induced by
65
human growth hormone of pituitary origin. Serum concentrations of inorganic phosphate
66
increased in patients with growth hormone deficiency after therapy with Humatrope or human
67
growth hormone of pituitary origin. Serum calcium is not significantly altered in patients treated
68
with either human growth hormone of pituitary origin or Humatrope.
69
Pharmacokinetics
70
Absorption — Humatrope has been studied following intramuscular, subcutaneous, and
71
intravenous administration in adult volunteers. The absolute bioavailability of somatropin is 75%
72
and 63% after subcutaneous and intramuscular administration, respectively.
73
Distribution — The volume of distribution of somatropin after intravenous injection is about
74
0.07 L/kg.
75
Metabolism — Extensive metabolism studies have not been conducted. The metabolic fate of
76
somatropin involves classical protein catabolism in both the liver and kidneys. In renal cells, at
77
least a portion of the breakdown products of growth hormone is returned to the systemic
78
circulation. In normal volunteers, mean clearance is 0.14 L/hr/kg. The mean half-life of
79
intravenous somatropin is 0.36 hours, whereas subcutaneously and intramuscularly administered
80
somatropin have mean half-lives of 3.8 and 4.9 hours, respectively. The longer half-life observed
81
after subcutaneous or intramuscular administration is due to slow absorption from the injection
82
site.
83
Excretion — Urinary excretion of intact Humatrope has not been measured. Small amounts of
84
somatropin have been detected in the urine of pediatric patients following replacement therapy.
85
Special Populations
86
Geriatric — The pharmacokinetics of Humatrope has not been studied in patients greater than
87
65 years of age.
88
Pediatric — The pharmacokinetics of Humatrope in pediatric patients is similar to adults.
89
Gender — No studies have been performed with Humatrope. The available literature indicates
90
that the pharmacokinetics of growth hormone is similar in both men and women.
91
Race — No data are available.
92
Renal, Hepatic insufficiency — No studies have been performed with Humatrope.
93
94
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Table 1
Summary of Somatropin Parameters in the Normal Population
Cmax
(ng/mL)
t1/2
(hr)
AUC0-∞∞∞∞
(ng•hr/mL)
Cls
(L/kg•hr)
Vββββ
(L/kg)
0.02 mg (0.05 IU*)/kg
iv
MEAN
415
0.363
156
0.135
0.0703
SD
75
0.053
33
0.029
0.0173
0.1 mg (0.27 IU*)/kg
im
MEAN
53.2
4.93
495
0.215
1.55
SD
25.9
2.66
106
0.047
0.91
0.1 mg (0.27 IU*)/kg
sc
MEAN
63.3
3.81
585
0.179
0.957
SD
18.2
1.40
90
0.028
0.301
Abbreviations: Cmax=maximum concentration; t1/2=half-life; AUC0-∞=area under the curve; Cls=systemic
95
clearance; Vβ=volume distribution; iv=intravenous; SD=standard deviation; im=intramuscular; sc=subcutaneous.
96
* Based on previous International Standard of 2.7 IU=1 mg.
97
98
Figure 1
99
100
CLINICAL TRIALS
101
Effects of Humatrope Treatment in Adults with Growth Hormone Deficiency
102
Two multicenter trials in adult-onset growth hormone deficiency (n=98) and two studies in
103
childhood-onset growth hormone deficiency (n=67) were designed to assess the effects of
104
replacement therapy with Humatrope. The primary efficacy measures were body composition
105
(lean body mass and fat mass), lipid parameters, and the Nottingham Health Profile. The
106
Nottingham Health Profile is a general health-related quality of life questionnaire. These
107
1
10
100
1000
Plasma Concentration (ng/mL)
0
6
12
18
Time (hours)
0.02 mg/kg intravenous injection
0.10 mg/kg intramuscular injection
0.1 mg/kg subcutaneous injection
Single Dose Average Plasma Concentrations
vs Time in Normal Adult Volunteers
Mean +/- SE (n=8)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
four studies each included a 6-month randomized, blinded, placebo-controlled phase followed by
108
12 months of open-label therapy for all patients. The Humatrope dosages for all studies were
109
identical: 1 month of therapy at 0.00625 mg/kg/day followed by the proposed maintenance dose
110
of 0.0125 mg/kg/day. Adult-onset patients and childhood-onset patients differed by diagnosis
111
(organic vs. idiopathic pituitary disease), body size (normal vs. small for mean height and
112
weight), and age (mean=44 vs. 29 years). Lean body mass was determined by bioelectrical
113
impedance analysis (BIA), validated with potassium 40. Body fat was assessed by BIA and sum
114
of skinfold thickness. Lipid subfractions were analyzed by standard assay methods in a central
115
laboratory.
116
Humatrope-treated adult-onset patients, as compared to placebo, experienced an increase in
117
lean body mass (2.59 vs. -0.22 kg, p<0.001) and a decrease in body fat (-3.27 vs. 0.56 kg,
118
p<0.001). Similar changes were seen in childhood-onset growth hormone-deficient patients.
119
These significant changes in lean body mass persisted throughout the 18-month period as
120
compared to baseline for both groups, and for fat mass in the childhood-onset group. Total
121
cholesterol decreased short-term (first 3 months) although the changes did not persist. However,
122
the low HDL cholesterol levels observed at baseline (mean=30.1 mg/mL and 33.9 mg/mL in
123
adult-onset and childhood-onset patients) normalized by the end of 18 months of therapy (a
124
change of 13.7 and 11.1 mg/dL for the adult-onset and childhood-onset groups, p<0.001).
125
Adult-onset patients reported significant improvements as compared to placebo in the following
126
two of six possible health-related domains: physical mobility and social isolation (Table 2).
127
Patients with childhood-onset disease failed to demonstrate improvements in Nottingham Health
128
Profile outcomes.
129
Two additional studies on the effect of Humatrope on exercise capacity were also conducted.
130
Improved physical function was documented by increased exercise capacity (VO2 max, p<0.005)
131
and work performance (Watts, p<0.01) (J Clin Endocrinol Metab 1995; 80:552-557).
132
133
Table 2
Changesa in Nottingham Health Profile Scoresb in Adult-Onset Growth Hormone-Deficient
Patients
Outcome
Measure
Placebo
(6 Months)
Humatrope Therapy
(6 Months)
Significance
Energy level
-11.4
-15.5
NS
Physical mobility
-3.1
-10.5
p<0.01
Social isolation
0.5
-4.7
p<0.01
Emotional reactions
-4.5
-5.4
NS
Sleep
-6.4
-3.7
NS
Pain
-2.8
-2.9
NS
a An improvement in score is indicated by a more negative change in the score.
134
b To account for multiple analyses, appropriate statistical methods were applied and the required level of
135
significance is 0.01.
136
NS=not significant.
137
138
Effects of Growth Hormone Treatment in Patients with Turner Syndrome
139
One long-term, randomized, open-label multicenter concurrently controlled study,
140
two long-term, open-label multicenter, historically controlled studies and one long-term,
141
randomized, dose-response study were conducted to evaluate the efficacy of growth hormone for
142
the treatment of patients with short stature due to Turner syndrome.
143
In the randomized study, GDCT, comparing growth hormone-treated patients to a concurrent
144
control group who received no growth hormone, the growth hormone-treated patients who
145
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
received a dose of 0.3 mg/kg/wk given 6 times per week from a mean age of 11.7 years for a
146
mean duration of 4.7 years attained a mean near final height of 146.0 ± 6.2 cm (n=27,
147
mean ± SD) as compared to the control group who attained a near final height of 142.1 ± 4.8 cm
148
(n=19). By analysis of covariance∗, the effect of growth hormone therapy was a mean height
149
increase of 5.4 cm (p=0.001).
150
In two of the studies (85-023 and 85-044), the effect of long-term growth hormone treatment
151
(0.375 mg/kg/wk given either 3 times per week or daily) on adult height was determined by
152
comparing adult heights in the treated patients with those of age-matched historical controls with
153
Turner syndrome who never received any growth-promoting therapy. The greatest improvement
154
in adult height was observed in patients who received early growth hormone treatment and
155
estrogen after age 14 years. In Study 85-023, this resulted in a mean adult height gain of 7.4 cm
156
(mean duration of GH therapy of 7.6 years) vs. matched historical controls by analysis of
157
covariance.
158
In Study 85-044, patients treated with early growth hormone therapy were randomized to
159
receive estrogen replacement therapy (conjugated estrogens, 0.3 mg escalating to 0.625 mg
160
daily) at either age 12 or 15 years. Compared with matched historical controls, early GH therapy
161
(mean duration of GH therapy 5.6 years) combined with estrogen replacement at age 12 years
162
resulted in an adult height gain of 5.9 cm (n=26), whereas patients who initiated estrogen at age
163
15 years (mean duration of GH therapy 6.1 years) had a mean adult height gain of 8.3 cm (n=29).
164
Patients who initiated GH therapy after age 11 (mean age 12.7 years; mean duration of
165
GH therapy 3.8 years) had a mean adult height gain of 5.0 cm (n=51).
166
In a randomized blinded dose-response study, GDCI, patients were treated from a mean age of
167
11.1 years for a mean duration of 5.3 years with a weekly dose of either 0.27 mg/kg or
168
0.36 mg/kg administered 3 or 6 times weekly. The mean near final height of patients receiving
169
growth hormone was 148.7 ± 6.5 cm (n=31). When compared to historical control data, the mean
170
gain in adult height was approximately 5 cm.
171
In some studies, Turner syndrome patients (n=181) treated to final adult height achieved
172
statistically significant average height gains ranging from 5.0 to 8.3 cm.
173
174
Table 3
Summary Table of Efficacy Results
Study/
Group
Study
Designa
N at Adult
Height
GH
Age (yr)
Estrogen
Age (yr)
GH
Duration (yr)
Adult Height
Gain (cm)b
GDCT
RCT
27
11.7
13
4.7
5.4
85-023
MHT
17
9.1
15.2
7.6
7.4
85-044:
A*
MHT
29
9.4
15
6.1
8.3
B*
26
9.6
12.3
5.6
5.9
C*
51
12.7
13.7
3.8
5
GDCI
RDT
31
11.1
8-13.5
5.3
~5c
a RCT: randomized controlled trial; MHT: matched historical controlled trial; RDT: randomized dose-response trial.
175
b Analysis of covariance vs. controls.
176
c Compared with historical data.
177
* A: GH age <11 yr, estrogen age 15 yr.
178
B: GH age <11 yr, estrogen age 12 yr.
179
C: GH age >11 yr, estrogen at month 12.
180
181
∗ Analysis of covariance includes adjustments for baseline height relative to age and for
mid-parental height.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
Effect of Humatrope Treatment in Pediatric Patients with Idiopathic Short Stature
182
Two randomized, multicenter trials, 1 placebo-controlled and 1 dose-response, were conducted
183
in pediatric patients with idiopathic short stature, also called non-growth hormone-deficient short
184
stature. The diagnosis of idiopathic short stature was made after excluding other known causes of
185
short stature, as well as growth hormone deficiency. Limited safety and efficacy data are
186
available below the age of 7 years. No specific studies have been conducted in pediatric patients
187
with familial short stature or who were born small for gestational age (SGA).
188
The placebo-controlled study enrolled 71 pediatric patients (55 males, 16 females) 9 to
189
15 years old (mean age 12.38 ± 1.51 years), with short stature, 68 of whom received study drug.
190
Patients were predominately Tanner I (45.1%) and Tanner II (46.5%) at baseline.
191
In this double-blind trial, patients received subcutaneous injections of either Humatrope
192
0.222 mg/kg/wk or placebo. Study drug was given in divided doses 3 times per week until height
193
velocity decreased to ≤1.5 cm/year (“final height”). Thirty-three subjects (22 Humatrope,
194
11 placebo) had final height measurements after a mean treatment duration of 4.4 years (range
195
0.11-9.08 years).
196
The Humatrope group achieved a mean final height Standard Deviation Score (SDS) of
197
-1.8 (Table 4). Placebo-treated patients had a mean final height SDS of -2.3 (mean treatment
198
difference = 0.51, p=0.017). Height gain across the duration of the study and final height SDS
199
minus baseline predicted height SDS were also significantly greater in Humatrope-treated
200
patients than in placebo-treated patients (Table 4 and 5). In addition, the number of patients who
201
achieved a final height above the 5th percentile of the general population for age and sex was
202
significantly greater in the Humatrope group than the placebo group (41% vs. 0%, p<0.05), as
203
was the number of patients who gained at least 1 SDS unit in height across the duration of the
204
study (50% vs. 0%, p<0.05).
205
206
Table 4
Baseline Height Characteristics and Effect of Humatrope on Final Heighta
Humatrope
(n=22)
Mean (SD)
Placebo
(n=11)
Mean (SD)
Treatment Effect
Mean
(95% CI)
p-value
Baseline height SDS
-2.7 (0.6)
-2.75 (0.6)
0.77
BPH SDS
-2.1 (0.7)
-2.3 (0.8)
0.53
Final height SDSb
-1.8 (0.8)
-2.3 (0.6)
0.51 (0.10, 0.92)
0.017
FH SDS - baseline height SDS
0.9 (0.7)
0.4 (0.2)
0.51 (0.04, 0.97)
0.034
FH SDS - BPH SDS
0.3 (0.6)
-0.1 (0.6)
0.46 (0.02, 0.89)
0.043
a For final height population.
207
b Between-group comparison was performed using analysis of covariance with baseline predicted height SDS as the
208
covariant. Treatment effect is expressed as least squares mean (95% CI).
209
Abbreviations: FH=final height; SDS=standard deviation score; BPH=baseline predicted height; CI=confidence
210
interval.
211
212
The dose-response study included 239 pediatric patients (158 males, 81 females), 5 to 15 years
213
old, (mean age 9.8 ± 2.3 years). Mean baseline characteristics included: a height SDS of
214
-3.21 (±0.70), a predicted adult height SDS of -2.63 (±1.08), and a height velocity SDS of
215
-1.09 (±1.15). All but 3 patients were Tanner I. Patients were randomized to one of
216
three Humatrope treatment groups: 0.24 mg/kg/wk; 0.24 mg/kg/wk for 1 year, followed by
217
0.37 mg/kg/wk; and 0.37 mg/kg/wk.
218
The primary hypothesis of this study was that treatment with Humatrope would increase height
219
velocity during the first 2 years of therapy in a dose-dependent manner. Additionally, after
220
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
completing the initial 2-year dose-response phase of the study, 50 patients were followed to final
221
height.
222
Patients receiving 0.37 mg/kg/wk had a significantly greater increase in mean height velocity
223
after 2 years of treatment than patients receiving 0.24 mg/kg/wk (4.04 vs. 3.27 cm/year,
224
p=0.003). The mean difference between final height and baseline predicted height was 7.2 cm for
225
patients receiving 0.37 mg/kg/wk and 5.4 cm for patients receiving 0.24 mg/kg/wk (Table 5).
226
While no patient had height above the 5th percentile in any dose group at baseline, 82% of the
227
patients receiving 0.37 mg/kg/wk and 47% of the patients receiving 0.24 mg/kg/wk achieved a
228
final height above the 5th percentile of the general population height standards (p=NS).
229
230
Table 5
Final Height Minus Baseline Predicted Height: Idiopathic Short Stature Trials
Placebo-controlled Trial
3x per week dosing
Dose Response Trial
6x per week dosing
Placebo
(n=10)
Humatrope
0.22 mg/kg
(n=22)
Humatrope
0.24 mg/kg
(n=13)
Humatrope
0.24/0.37 mg/kg
(n=13)
Humatrope
0.37 mg/kg
(n=13)
FH – Baseline PH
Mean cm
(95% CI)
Mean inches
(95% CI)
-0.7
(-3.6, 2.3)
-0.3
(-1.4, 0.9)
+2.2
(0.4, 3.9)
+0.8
(0.2, 1.5)
+5.4
(2.8, 7.9)
+2.1
(1.1, 3.1)
+6.7
(4.1, 9.2)
+2.6
(1.6, 3.6)
+7.2
(4.6, 9.8)
+2.8
(1.8, 3.9)
Abbreviations: PH=predicted height; FH=final height; CI=confidence interval.
231
232
INDICATIONS AND USAGE
233
Pediatric Patients — Humatrope is indicated for the long-term treatment of pediatric patients
234
who have growth failure due to an inadequate secretion of normal endogenous growth hormone.
235
Humatrope is indicated for the treatment of short stature associated with Turner syndrome in
236
patients whose epiphyses are not closed.
237
Humatrope is indicated for the long-term treatment of idiopathic short stature, also called
238
non-growth hormone-deficient short stature, defined by height SDS ≤-2.25, and associated with
239
growth rates unlikely to permit attainment of adult height in the normal range, in pediatric
240
patients whose epiphyses are not closed and for whom diagnostic evaluation excludes other
241
causes associated with short stature that should be observed or treated by other means.
242
Adult Patients — Humatrope is indicated for replacement of endogenous growth hormone in
243
adults with growth hormone deficiency who meet either of the following two criteria:
244
1. Adult Onset: Patients who have growth hormone deficiency either alone, or with multiple
245
hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease,
246
surgery, radiation therapy, or trauma;
247
or
248
2. Childhood Onset: Patients who were growth hormone-deficient during childhood who have
249
growth hormone deficiency confirmed as an adult before replacement therapy with Humatrope is
250
started.
251
CONTRAINDICATIONS
252
Humatrope should not be used for growth promotion in pediatric patients with closed
253
epiphyses.
254
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
Humatrope should not be used or should be discontinued when there is any evidence of active
255
malignancy. Anti-malignancy treatment must be complete with evidence of remission prior to
256
the institution of therapy.
257
Humatrope should not be reconstituted with the supplied Diluent for Humatrope for use by
258
patients with a known sensitivity to either Metacresol or glycerin.
259
Growth hormone should not be initiated to treat patients with acute critical illness due to
260
complications following open heart or abdominal surgery, multiple accidental trauma or to
261
patients having acute respiratory failure. Two placebo-controlled clinical trials in non-growth
262
hormone-deficient adult patients (n=522) with these conditions revealed a significant increase in
263
mortality (41.9% vs. 19.3%) among somatropin-treated patients (doses 5.3 to 8 mg/day)
264
compared to those receiving placebo (see WARNINGS).
265
Growth hormone is contraindicated in patients with Prader-Willi syndrome who are severely
266
obese or have severe respiratory impairment (see WARNINGS). Unless patients with
267
Prader-Willi syndrome also have a diagnosis of growth hormone deficiency, Humatrope is not
268
indicated for the long term treatment of pediatric patients who have growth failure due to
269
genetically confirmed Prader-Willi syndrome.
270
WARNINGS
271
If sensitivity to the diluent should occur, the vials may be reconstituted with Bacteriostatic
272
Water for Injection, USP or, Sterile Water for Injection, USP. When Humatrope is used with
273
Bacteriostatic Water (Benzyl Alcohol preserved), the solution should be kept refrigerated at
274
2° to 8°C (36° to 46°F) and used within 14 days. Benzyl alcohol as a preservative in
275
Bacteriostatic Water for Injection, USP has been associated with toxicity in newborns.
276
When administering Humatrope to newborns, use the Humatrope diluent provided or if the
277
patient is sensitive to the diluent, use Sterile Water for Injection, USP. When Humatrope is
278
reconstituted with Sterile Water for Injection, USP in this manner, use only one dose per
279
Humatrope vial and discard the unused portion. If the solution is not used immediately, it must
280
be refrigerated [2° to 8°C (36° to 46°F)] and used within 24 hours.
281
Cartridges should be reconstituted only with the supplied diluent. Cartridges should not
282
be reconstituted with the Diluent for Humatrope provided with Humatrope Vials, or with
283
any other solution. Cartridges should not be used if the patient is allergic to Metacresol or
284
glycerin.
285
See CONTRAINDICATIONS for information on increased mortality in patients with acute
286
critical illnesses in intensive care units due to complications following open heart or abdominal
287
surgery, multiple accidental trauma or with acute respiratory failure. The safety of continuing
288
growth hormone treatment in patients receiving replacement doses for approved indications who
289
concurrently develop these illnesses has not been established. Therefore, the potential benefit of
290
treatment continuation with growth hormone in patients having acute critical illnesses should be
291
weighed against the potential risk.
292
There have been reports of fatalities after initiating therapy with growth hormone in pediatric
293
patients with Prader-Willi syndrome who had one or more of the following risk factors: severe
294
obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection.
295
Male patients with one or more of these factors may be at greater risk than females. Patients with
296
Prader-Willi syndrome should be evaluated for signs of upper airway obstruction and sleep
297
apnea before initiation of treatment with growth hormone. If, during treatment with growth
298
hormone, patients show signs of upper airway obstruction (including onset of or increased
299
snoring) and/or new onset sleep apnea, treatment should be interrupted. All patients with
300
Prader-Willi syndrome treated with growth hormone should also have effective weight control
301
and be monitored for signs of respiratory infection, which should be diagnosed as early as
302
possible and treated aggressively (see CONTRAINDICATIONS). Unless patients with
303
Prader-Willi syndrome also have a diagnosis of growth hormone deficiency, Humatrope is not
304
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
indicated for the long term treatment of pediatric patients who have growth failure due to
305
genetically confirmed Prader-Willi syndrome.
306
PRECAUTIONS
307
General — Therapy with Humatrope should be directed by physicians who are experienced in
308
the diagnosis and management of patients with growth hormone deficiency, Turner syndrome,
309
idiopathic short stature, or adult patients with either childhood-onset or adult-onset growth
310
hormone deficiency.
311
Patients with preexisting tumors or with growth hormone deficiency secondary to an
312
intracranial lesion should be examined routinely for progression or recurrence of the underlying
313
disease process. In pediatric patients, clinical literature has demonstrated no relationship between
314
somatropin replacement therapy and CNS tumor recurrence. In adults, it is unknown whether
315
there is any relationship between somatropin replacement therapy and CNS tumor recurrence.
316
Patients should be monitored carefully for any malignant transformation of skin lesions.
317
For patients with diabetes mellitus, the insulin dose may require adjustment when somatropin
318
therapy is instituted. Because human growth hormone may induce a state of insulin resistance,
319
patients should be observed for evidence of glucose intolerance. Patients with diabetes or glucose
320
intolerance should be monitored closely during somatropin therapy.
321
In patients with hypopituitarism (multiple hormonal deficiencies) standard hormonal
322
replacement therapy should be monitored closely when somatropin therapy is administered.
323
Hypothyroidism may develop during treatment with somatropin and inadequate treatment of
324
hypothyroidism may prevent optimal response to somatropin.
325
Pediatric Patients (see General Precautions) — Pediatric patients with endocrine disorders,
326
including growth hormone deficiency, may develop slipped capital epiphyses more frequently.
327
Any pediatric patient with the onset of a limp during growth hormone therapy should be
328
evaluated.
329
Growth hormone has not been shown to increase the incidence of scoliosis. Progression of
330
scoliosis can occur in children who experience rapid growth. Because growth hormone increases
331
growth rate, patients with a history of scoliosis who are treated with growth hormone should be
332
monitored for progression of scoliosis. Skeletal abnormalities including scoliosis are commonly
333
seen in untreated Turner syndrome patients.
334
Patients with Turner syndrome should be evaluated carefully for otitis media and other ear
335
disorders since these patients have an increased risk of ear or hearing disorders (see Adverse
336
Reactions). Patients with Turner syndrome are at risk for cardiovascular disorders (e.g., stroke,
337
aortic aneurysm, hypertension) and these conditions should be monitored closely.
338
Patients with Turner syndrome have an inherently increased risk of developing autoimmune
339
thyroid disease. Therefore, patients should have periodic thyroid function tests and be treated as
340
indicated (see General Precautions).
341
Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea and/or
342
vomiting has been reported in a small number of pediatric patients treated with growth hormone
343
products. Symptoms usually occurred within the first 8 weeks of the initiation of growth
344
hormone therapy. In all reported cases, IH-associated signs and symptoms resolved after
345
termination of therapy or a reduction of the growth hormone dose. Funduscopic examination of
346
patients is recommended at the initiation and periodically during the course of growth hormone
347
therapy. Patients with Turner syndrome may be at increased risk for development of IH.
348
Adult Patients (see General Precautions) — Patients with epiphyseal closure who were treated
349
with growth hormone replacement therapy in childhood should be re-evaluated according to the
350
criteria in INDICATIONS AND USAGE before continuation of somatropin therapy at the
351
reduced dose level recommended for growth hormone-deficient adults.
352
Experience with prolonged treatment in adults is limited.
353
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
Geriatric Use — The safety and effectiveness of Humatrope in patients aged 65 and over has
354
not been evaluated in clinical studies. Elderly patients may be more sensitive to the action of
355
Humatrope and may be more prone to develop adverse reactions.
356
Drug Interactions — Excessive glucocorticoid therapy may prevent optimal response to
357
somatropin. If glucocorticoid replacement therapy is required, the glucocorticoid dosage and
358
compliance should be monitored carefully to avoid either adrenal insufficiency or inhibition of
359
growth promoting effects.
360
Limited published data indicate that growth hormone (GH) treatment increases
361
cytochrome P450 (CP450) mediated antipyrine clearance in man. These data suggest that
362
GH administration may alter the clearance of compounds known to be metabolized by
363
CP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporin). Careful
364
monitoring is advisable when GH is administered in combination with other drugs known to be
365
metabolized by CP450 liver enzymes.
366
Carcinogenesis, Mutagenesis, Impairment of Fertility — Long-term animal studies for
367
carcinogenicity and impairment of fertility with this human growth hormone (Humatrope) have
368
not been performed. There has been no evidence to date of Humatrope-induced mutagenicity.
369
Pregnancy — Pregnancy Category C — Animal reproduction studies have not been conducted
370
with Humatrope. It is not known whether Humatrope can cause fetal harm when administered to
371
a pregnant woman or can affect reproductive capacity. Humatrope should be given to a pregnant
372
woman only if clearly needed.
373
Nursing Mothers — There have been no studies conducted with Humatrope in nursing
374
mothers. It is not known whether this drug is excreted in human milk. Because many drugs are
375
excreted in human milk, caution should be exercised when Humatrope is administered to a
376
nursing woman.
377
Information for Patients — Patients being treated with growth hormone and/or their parents
378
should be informed of the potential risks and benefits associated with treatment. Instructions on
379
appropriate use should be given, including a review of the contents of the patient information
380
insert. This information is intended to aid in the safe and effective administration of the
381
medication. It is not a disclosure of all possible adverse or intended effects.
382
Patients and/or parents should be thoroughly instructed in the importance of proper needle
383
disposal. A puncture resistant container should be used for the disposal of used needles and/or
384
syringes (consistent with applicable state requirements). Needles and syringes must not be reused
385
(see Information for the Patient insert).
386
ADVERSE REACTIONS
387
Growth Hormone-Deficient Pediatric Patients
388
As with all protein pharmaceuticals, a small percentage of patients may develop antibodies to
389
the protein. During the first 6 months of Humatrope therapy in 314 naive patients, only 1.6%
390
developed specific antibodies to Humatrope (binding capacity ≥0.02 mg/L). None had antibody
391
concentrations which exceeded 2 mg/L. Throughout 8 years of this same study, two patients
392
(0.6%) had binding capacity >2 mg/L. Neither patient demonstrated a decrease in growth
393
velocity at or near the time of increased antibody production. It has been reported that growth
394
attenuation from pituitary-derived growth hormone may occur when antibody concentrations are
395
>1.5 mg/L.
396
In addition to an evaluation of compliance with the treatment program and of thyroid status,
397
testing for antibodies to human growth hormone should be carried out in any patient who fails to
398
respond to therapy.
399
In studies with growth hormone-deficient pediatric patients, injection site pain was reported
400
infrequently. A mild and transient edema, which appeared in 2.5% of patients, was observed
401
early during the course of treatment.
402
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
Leukemia has been reported in a small number of pediatric patients who have been treated with
403
growth hormone, including growth hormone of pituitary origin as well as of recombinant
404
DNA origin (somatrem and somatropin). The relationship, if any, between leukemia and growth
405
hormone therapy is uncertain.
406
Turner Syndrome Patients
407
In a randomized, concurrent controlled trial, there was a statistically significant increase in the
408
occurrence of otitis media (43% vs. 26%), ear disorders (18% vs. 5%) and surgical procedures
409
(45% vs. 27%) in patients receiving Humatrope compared with untreated control patients
410
(Table 6). Other adverse events of special interest to Turner syndrome patients were not
411
significantly different between treatment groups (Table 6). A similar increase in otitis media was
412
observed in an 18-month placebo-controlled trial.
413
414
Table 6
Treatment-Emergent Events of Special Interest by Treatment Group in Turner Syndrome
Treatment Group
Adverse Event
Overall
hGH1
Untreated2
Significance
Total Number of Patients
136
74
62
Surgical procedure
50 (36.8%)
33 (44.6%)
17 (27.4%)
p≤0.05
Otitis media
48 (35.3%)
32 (43.2%)
16 (25.8%)
p≤0.05
Ear disorders
16 (11.8%)
13 (17.6%)
3 (4.8%)
p≤0.05
Bone disorder
13 (9.6%)
6 (8.1%)
7 (11.3%)
NS
Edema
Conjunctival
1 (0.7%)
0
1 (1.6%)
NS
Non-specific
3 (2.2%)
2 (2.7%)
1 (1.6%)
NS
Facial
1 (0.7%)
1 (1.4%)
0
NS
Peripheral
6 (4.4%)
5 (6.8%)
1 (1.6%)
NS
Hyperglycemia
0
0
0
NS
Hypothyroidism
15 (11.0%)
10 (13.5%)
5 (8.1%)
NS
Increased nevi3
10 (7.4%)
8 (10.8%)
2 (3.2%)
NS
Lymphedema
0
0
0
NS
1 Dose=0.3 mg/kg/wk.
415
2 Open-label study.
416
3 Includes any nevi coded to the following preferred terms: melanosis, skin hypertrophy, or skin benign neoplasm.
417
NS=not significant.
418
419
Patients with Idiopathic Short Stature
420
In the placebo-controlled study, the adverse events associated with Humatrope therapy were
421
similar to those observed in other pediatric populations treated with Humatrope (Table 7). Mean
422
serum glucose level did not change during Humatrope treatment. Mean fasting serum insulin
423
levels increased 10% in the Humatrope treatment group at the end of treatment relative to
424
baseline values but remained within the normal reference range. For the same duration of
425
treatment the mean fasting serum insulin levels decreased by 2% in the placebo group. The
426
incidence of above-range values for glucose, insulin, and HbA1c were similar in the growth
427
hormone and placebo-treated groups. No patient developed diabetes mellitus. Consistent with the
428
known mechanism of growth hormone action, Humatrope-treated patients had greater mean
429
increases, relative to baseline, in serum insulin-like growth factor-I (IGF-I) than placebo-treated
430
patients at each study observation. However, there was no significant difference between the
431
Humatrope and placebo treatment groups in the proportion of patients who had at least
432
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
one serum IGF-I concentration more than 2.0 SD above the age- and gender-appropriate mean
433
(Humatrope: 9 of 35 patients [26%]; placebo: 7 of 28 patients [25%]).
434
435
Table 7
Nonserious Clinically Significant Treatment-Emergent Adverse Events by
Treatment Group in Idiopathic Short Stature
Treatment Group
Adverse Event
Humatrope
Placebo
Total Number of Patients
37
31
Scoliosis
7 (18.9%)
4 (12.9%)
Otitis media
6 (16.2%)
2 (6.5%)
Hyperlipidemia
3 (8.1%)
1 (3.2%)
Gynecomastia
2 (5.4%)
1 (3.2%)
Hypothyroidism
0
2 (6.5%)
Aching joints
0
1 (3.2%)
Hip pain
1 (2.7%)
0
Arthralgia
4 (10.8%)
1 (3.2%)
Arthrosis
4 (10.8%)
2 (6.5%)
Myalgia
9 (24.3%)
4 (12.9%)
Hypertension
1 (2.7%)
0
436
The adverse events observed in the dose-response study (239 patients treated for 2 years) did
437
not indicate a pattern suggestive of a growth hormone dose effect. Among Humatrope dose
438
groups, mean fasting blood glucose, mean glycosylated hemoglobin, and the incidence of
439
elevated fasting blood glucose concentrations were similar. One patient developed abnormalities
440
of carbohydrate metabolism (glucose intolerance and high serum HbA1c) on treatment.
441
Adult Patients — In clinical studies in which high doses of Humatrope were administered to
442
healthy adult volunteers, the following events occurred infrequently: headache, localized muscle
443
pain, weakness, mild hyperglycemia, and glucosuria.
444
In the first 6 months of controlled blinded trials during which patients received either
445
Humatrope or placebo, adult-onset growth hormone-deficient adults who received Humatrope
446
experienced a statistically significant increase in edema (Humatrope 17.3% vs. placebo 4.4%,
447
p=0.043) and peripheral edema (11.5% vs. 0%, respectively, p=0.017). In patients with
448
adult-onset growth hormone deficiency, edema, muscle pain, joint pain, and joint disorder were
449
reported early in therapy and tended to be transient or responsive to dosage titration.
450
Two of 113 adult-onset patients developed carpal tunnel syndrome after beginning
451
maintenance therapy without a low dose (0.00625 mg/kg/day) lead-in phase. Symptoms abated
452
in these patients after dosage reduction.
453
All treatment-emergent adverse events with ≥5% overall incidence during 12 or 18 months of
454
replacement therapy with Humatrope are shown in Table 8 (adult-onset patients) and in Table 9
455
(childhood-onset patients).
456
Adult patients treated with Humatrope who had been diagnosed with growth hormone
457
deficiency in childhood reported side effects less frequently than those with adult-onset growth
458
hormone deficiency.
459
460
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
Table 8
Treatment-Emergent Adverse Events with ≥≥≥≥5% Overall Incidence in Adult-Onset Growth
Hormone-Deficient Patients Treated with Humatrope for 18 Months as Compared with
6-Month Placebo and 12-Month Humatrope Exposure
18 Months Exposure
[Placebo (6 Months)/hGH (12 Months)]
(N=46)
18 Months hGH Exposure
(N=52)
Adverse Event
n
%
n
%
Edemaa
7
15.2
11
21.2
Arthralgia
7
15.2
9
17.3
Paresthesia
6
13.0
9
17.3
Myalgia
6
13.0
7
13.5
Pain
6
13.0
7
13.5
Rhinitis
5
10.9
7
13.5
Peripheral edemab
8
17.4
6
11.5
Back pain
5
10.9
5
9.6
Headache
5
10.9
4
7.7
Hypertension
2
4.3
4
7.7
Acne
0
0
3
5.8
Joint disorder
1
2.2
3
5.8
Surgical procedure
1
2.2
3
5.8
Flu syndrome
3
6.5
2
3.9
Abbreviations: hGH=Humatrope; N=number of patients receiving treatment in the period stated; n=number of
461
patients reporting each treatment-emergent adverse event.
462
a p=0.04 as compared to placebo (6 months).
463
b p=0.02 as compared to placebo (6 months).
464
465
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
Table 9
Treatment-Emergent Adverse Events with ≥≥≥≥5% Overall Incidence in Childhood-Onset
Growth Hormone-Deficient Patients Treated with Humatrope for 18 Months as Compared
with 6-Month Placebo and 12-Month Humatrope Exposure
18 Months Exposure
[Placebo (6 Months)/hGH (12 Months)]
(N=35)
18 Months hGH Exposure
(N=32)
Adverse Event
n
%
n
%
Flu syndrome
8
22.9
5
15.6
AST increaseda
2
5.7
4
12.5
Headache
4
11.4
3
9.4
Asthenia
1
2.9
2
6.3
Cough increased
0
0
2
6.3
Edema
3
8.6
2
6.3
Hypesthesia
0
0
2
6.3
Myalgia
2
5.7
2
6.3
Pain
3
8.6
2
6.3
Rhinitis
2
5.7
2
6.3
ALT increased
2
5.7
2
6.3
Respiratory disorder
2
5.7
1
3.1
Gastritis
2
5.7
0
0
Pharyngitis
5
14.3
1
3.1
Abbreviations: hGH=Humatrope; N=number of patients receiving treatment in the period stated; n=number of
466
patients reporting each treatment-emergent adverse event; ALT=alanine amino transferase, formerly SGPT;
467
AST=aspartate amino transferase, formerly SGOT.
468
a p=0.03 as compared to placebo (6 months).
469
470
Other adverse drug events that have been reported in growth hormone-treated patients include
471
the following:
472
1) Metabolic: Infrequent, mild and transient peripheral or generalized edema.
473
2) Musculoskeletal: Rare carpal tunnel syndrome.
474
3) Skin: Rare increased growth of pre-existing nevi. Patients should be monitored carefully
475
for malignant transformation.
476
4) Endocrine: Rare gynecomastia. Rare pancreatitis.
477
OVERDOSAGE
478
Acute overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia.
479
Long-term overdosage could result in signs and symptoms of gigantism/acromegaly consistent
480
with the known effects of excess human growth hormone. (See recommended and maximal
481
dosage instructions given below.)
482
DOSAGE AND ADMINISTRATION
483
Pediatric Patients
484
The Humatrope dosage and administration schedule should be individualized for each patient.
485
Therapy should not be continued if epiphyseal fusion has occurred. Response to growth hormone
486
therapy tends to decrease with time. However, failure to increase growth rate, particularly during
487
the first year of therapy, should prompt close assessment of compliance and evaluation of other
488
causes of growth failure such as hypothyroidism, under-nutrition and advanced bone age.
489
Growth hormone-deficient pediatric patients — The recommended weekly dosage is
490
0.18 mg/kg (0.54 IU/kg) of body weight. The maximal replacement weekly dosage is
491
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
0.3 mg/kg (0.90 IU/kg) of body weight. It should be divided into equal doses given either on
492
3 alternate days, 6 times per week or daily. The subcutaneous route of administration is
493
preferable; intramuscular injection is also acceptable. The dosage and administration schedule
494
for Humatrope should be individualized for each patient.
495
Turner Syndrome — A weekly dosage of up to 0.375 mg/kg (1.125 IU/kg) of body weight
496
administered by subcutaneous injection is recommended. It should be divided into equal doses
497
given either daily or on 3 alternate days.
498
Patients with idiopathic short stature — A weekly dosage of up to 0.37 mg/kg of body weight
499
administered by subcutaneous injection is recommended. It should be divided into equal doses
500
given 6 to 7 times per week.
501
Adult Patients
502
Growth hormone-deficient adult patients — The recommended dosage at the start of therapy is
503
not more than 0.006 mg/kg/day (0.018 IU/kg/day) given as a daily subcutaneous injection. The
504
dose may be increased according to individual patient requirements to a maximum of
505
0.0125 mg/kg/day (0.0375 IU/kg/day).
506
During therapy, dosage should be titrated if required by the occurrence of side effects or to
507
maintain the IGF-I response below the upper limit of normal IGF-I levels, matched for age and
508
sex. To minimize the occurrence of adverse events in patients with increasing age or excessive
509
body weight, dose reductions may be necessary.
510
Reconstitution
511
Vial — Each 5-mg vial of Humatrope should be reconstituted with 1.5 to 5 mL of Diluent for
512
Humatrope. The diluent should be injected into the vial of Humatrope by aiming the stream of
513
liquid against the glass wall. Following reconstitution, the vial should be swirled with a
514
GENTLE rotary motion until the contents are completely dissolved. DO NOT SHAKE. The
515
resulting solution should be inspected for clarity. It should be clear. If the solution is cloudy or
516
contains particulate matter, the contents MUST NOT be injected.
517
Before and after injection, the septum of the vial should be wiped with rubbing alcohol or an
518
alcoholic antiseptic solution to prevent contamination of the contents by repeated needle
519
insertions. Sterile disposable syringes and needles should be used for administration of
520
Humatrope. The volume of the syringe should be small enough so that the prescribed dose can be
521
withdrawn from the vial with reasonable accuracy.
522
Cartridge — Each cartridge of Humatrope should only be reconstituted using the diluent
523
syringe and the diluent connector which accompany the cartridge and should not be
524
reconstituted with the Diluent for Humatrope provided with Humatrope Vials. (See
525
WARNINGS section.) See the HumatroPen™ User Guide for comprehensive directions on
526
Humatrope cartridge reconstitution.
527
The reconstituted solution should be inspected for clarity. It should be clear. If the solution is
528
cloudy or contains particulate matter, the contents MUST NOT be injected.
529
The HumatroPen allows the somatropin dosage volume to be dialed in increments of 0.048 mL
530
per click of dosage knob, and the maximum dosage volume that can be injected is 0.576 mL
531
(based on a 12-click maximum). (See Table 10 for additional information.)
532
533
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
Table 10
Concentration of Reconstituted Humatrope Solutions, Incremental Dosage and
Maximum Injectable Dose for Each Cartridge
Cartridge
Somatropin
Concentration
Dose Per Click of
Dosage Knob
Maximum Injectable
Dose
6 mg
2.08 mg/mL
0.1 mg
1.2 mg
12 mg
4.17 mg/mL
0.2 mg
2.4 mg
24 mg
8.33 mg/mL
0.4 mg
4.8 mg
534
This cartridge has been designed for use only with the HumatroPen. A sterile disposable needle
535
should be used for each administration of Humatrope.
536
STABILITY AND STORAGE
537
Vials
538
Before Reconstitution — Vials of Humatrope and Diluent for Humatrope are stable when
539
refrigerated [2° to 8°C (36° to 46°F)]. Avoid freezing Diluent for Humatrope. Expiration dates
540
are stated on the labels.
541
After Reconstitution — Vials of Humatrope are stable for up to 14 days when reconstituted
542
with Diluent for Humatrope or Bacteriostatic Water for Injection, USP and stored in a
543
refrigerator at 2° to 8°C (36° to 46°F). Avoid freezing the reconstituted vial of Humatrope.
544
After Reconstitution with Sterile Water, USP — Use only one dose per Humatrope vial and
545
discard the unused portion. If the solution is not used immediately, it must be refrigerated
546
[2° to 8°C (36° to 46°F)] and used within 24 hours.
547
Cartridges
548
Before Reconstitution — Cartridges of Humatrope and Diluent for Humatrope are stable when
549
refrigerated [2° to 8°C (36° to 46°F)]. Avoid freezing Diluent for Humatrope. Expiration dates
550
are stated on the labels.
551
After Reconstitution — Cartridges of Humatrope are stable for up to 28 days when
552
reconstituted with Diluent for Humatrope and stored in a refrigerator at 2° to 8°C (36° to 46°F).
553
Store the HumatroPen without the needle attached. Avoid freezing the reconstituted cartridge of
554
Humatrope.
555
HOW SUPPLIED
556
Vials
557
5 mg (No. 7335) — (6s) NDC 0002-7335-16, and 5-mL vials of Diluent for Humatrope
558
(No. 7336)
559
Cartridges
560
Cartridge Kit (MS8089) NDC 0002-8089-01
561
6 mg cartridge (VL7554), and prefilled syringe of Diluent for Humatrope (VL7557)
562
563
Cartridge Kit (MS8090) NDC 0002-8090-01
564
12 mg cartridge (VL7555), and prefilled syringe of Diluent for Humatrope (VL7558)
565
566
Cartridge Kit (MS8091) NDC 0002-8091-01
567
24 mg cartridge (VL7556), and prefilled syringe of Diluent for Humatrope (VL7558)
568
Literature revised March 17, 2004
569
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
Eli Lilly and Company, Indianapolis, IN 46285, USA
570
www.lilly.com
571
PA 1643 AMP
PRINTED IN USA
572
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:34.310253
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19640s040lbl.pdf', 'application_number': 19640, 'submission_type': 'SUPPL ', 'submission_number': 40}
|
11,578
|
1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
HUMATROPE safely and effectively. See full prescribing information for
HUMATROPE.
HUMATROPE® [somatropin (rDNA ORIGIN)] for injection, for
Subcutaneous Use
Initial U.S. Approval: 1987
----------------------RECENT MAJOR CHANGES-------------------------------
Indications and Usage, Small for Gestational Age (1.1)
xx/2009
Dosage and Administration, Small for Gestational Age (2.3)
xx/2009
----------------------INDICATIONS AND USAGE--------------------------------
Humatrope® is a recombinant human growth hormone (somatropin) indicated
for:
• Pediatric Patients: Treatment of children with short stature or
growth failure associated with growth hormone (GH) deficiency,
Turner syndrome, idiopathic short stature, SHOX deficiency, and
failure to catch up in height after small for gestational age birth.
(1.1)
• Adult Patients: Treatment of adults with either childhood-onset
or adult-onset GH deficiency. (1.2)
-------------------DOSAGE AND ADMINISTRATION--------------------------
Humatrope should be administered subcutaneously. (2.2)
Injection sites should always be rotated regularly to avoid lipoatrophy. (2.2)
For pediatric patients, the recommended weekly dosages in milligrams (mg)
per kilogram (kg) of body weight (given in divided doses 6 to 7 times per
week) are:
• Pediatric GH deficiency: 0.18 to 0.30 mg/kg/week (2.3)
• Turner syndrome: Up to 0.375 mg/kg/week (2.3)
• Idiopathic short stature: Up to 0.37 mg/kg/week (2.3)
• SHOX deficiency: 0.35 mg/kg/week (2.3)
• Small for gestational age: Up to 0.47 mg/kg/week (2.3)
• Adult GH deficiency: Either a non-weight based or a weight-
based dosing regimen may be followed, with doses adjusted based
on treatment response and IGF-I concentrations. (2.4)
• Non-weight based dosing: A starting dose of approximately 0.2
mg/day (range, 0.15-0.30 mg/day) may be used without
consideration of body weight, and increased gradually every 1-2
months by increments of approximately 0.1-0.2 mg/day. (2.4)
• Weight-based dosing: The recommended initial daily dose is not
more than 0.006 mg/kg (6 μg/kg); the dose may be increased to a
maximum of 0.0125 mg/kg (12.5 μg/kg) daily. (2.4)
-------------------DOSAGE FORMS AND STRENGTHS------------------------
• 5 mg vial and 5-mL vial of Diluent for Humatrope (3)
• 6 mg (gold), 12 mg (teal) and 24 mg (purple) cartridge, and
prefilled syringe of Diluent for Humatrope (3)
• Humatrope cartridges should be used only with the appropriate
corresponding pen device
-----------------------------CONTRAINDICATIONS--------------------------------
• Acute critical illness. (4.1, 5.1)
• Children with Prader-Willi syndrome who are severely obese or
have severe respiratory impairment – reports of sudden death.
(4.2, 5.2)
• Active malignancy. (4.3)
• Active proliferative or severe non-proliferative diabetic
retinopathy. (4.4)
• Children with closed epiphyses. (4.5)
• Hypersensitivity to somatropin or diluent. (4.6)
------------------------WARNINGS AND PRECAUTIONS---------------------
• Acute Critical Illness: Evaluate potential benefit of treatment
continuation against potential risk. (5.1)
• Prader-Willi Syndrome: Evaluate for signs of upper airway
obstruction and sleep apnea before initiation of treatment for GH
deficiency. Discontinue treatment if these signs occur. (5.2)
• Neoplasm: Monitor patients with preexisting tumors for
progression or recurrence. Increased risk of a second neoplasm in
childhood cancer survivors treated with somatropin - in particular
meningiomas in patients treated with radiation to the head for
their first neoplasm. (5.3)
• Impaired Glucose Tolerance (IGT) and Diabetes Mellitus (DM):
Periodically monitor glucose levels in all patients, as IGT or DM
may be unmasked. Doses of concurrent antihyperglycemic drugs
in patients with DM may require adjustment. (5.4)
• Intracranial Hypertension (IH): Exclude preexisting papilledema.
IH may develop, but is usually reversible after discontinuation or
dose reduction. (5.5)
• Fluid Retention (e.g., edema, arthralgia, carpal tunnel syndrome –
especially in adults): Reduce dose as necessary if such signs
develop. (5.6)
• Hypothyroidism: Monitor thyroid function periodically as
hypothyroidism may first become evident or worsen after
initiation of somatropin. (5.8)
• Slipped Capital Femoral Epiphysis (SCFE): Evaluate any child
with onset of a limp or hip/knee pain for possible SCFE. (5.9)
• Progression of Preexisting Scoliosis: Monitor any child with
scoliosis for progression of the curve. (5.10)
-----------------------------ADVERSE REACTIONS--------------------------------
Common adverse reactions reported in adult and pediatric patients receiving
somatropin include injection site reactions, hypersensitivity to the diluent, and
hypothyroidism (6.1). Additional common adverse reactions in adults include
edema, arthralgia, myalgia, carpal tunnel syndrome, paraesthesias, and
hyperglycemia (6.1, 6.2).
To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and
Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088
or www.fda.gov/medwatch.
-----------------------------DRUG INTERACTIONS--------------------------------
• Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1: May
require the initiation of glucocorticoid replacement therapy.
Patients treated with glucocorticoid replacement for previously
diagnosed hypoadrenalism may require an increase in their
maintenance doses. (7.1, 7.2)
• Glucocorticoid Replacement: Should be carefully adjusted. (7.2)
• Cytochrome P450-Metabolized Drugs: Monitor carefully if used
with somatropin. (7.3)
• Oral Estrogen: Larger doses of somatropin may be required in
women. (7.4)
• Insulin and/or Other Hypoglycemic Agents: May require
adjustment (7.5)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling
Revised: 00/0000
FULL PRESCRIBING INFORMATION: CONTENTS*
2.3
Dosing for Pediatric Patients
2.4
Dosing for Patients with Adult Growth Hormone Deficiency
1
INDICATIONS AND USAGE
3
DOSAGE FORMS AND STRENGTHS
1.1
Pediatric Patients
1.2
Adult Patients
4
CONTRAINDICATIONS
4.1
Acute Critical Illness
2
DOSAGE AND ADMINISTRATION
4.2
Prader-Willi Syndrome in Children
2.1
Reconstitution
4.3
Active Malignancy
2.2
General Administration Guidelines
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
4.4
Diabetic Retinopathy
4.5
Closed Epiphyses
4.6
Hypersensitivity
5
WARNINGS AND PRECAUTIONS
5.1
Acute Critical Illness
5.2
Prader-Willi Syndrome in Children
5.3
Neoplasms
5.4
Glucose Intolerance
5.5
Intracranial Hypertension
5.6
Fluid Retention
5.7
Hypopituitarism
5.8
Hypothyroidism
5.9
Slipped Capital Femoral Epiphysis in Pediatric Patients
5.10
Progression of Preexisting Scoliosis in Pediatric Patients
5.11
Otitis Media and Cardiovascular Disorders in Patients with
Turner Syndrome
5.12
Local and Systemic Reactions
5.13
Laboratory Tests
6
ADVERSE REACTIONS
6.1
Most Serious and/or Most Frequently Observed Adverse
Reactions
6.2
Clinical Trials Experience
6.3
Post-Marketing Experience
7
DRUG INTERACTIONS
7.1
11β-Hydroxysteroid Dehydrogenase Type 1
7.2
Pharmacologic Glucocorticoid Therapy and Supraphysiologic
Glucocorticoid Treatment
7.3
Cytochrome P450-Metabolized Drugs
7.4
Oral Estrogen
7.5
Insulin and/or Other Hypoglycemic Agents
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.5
Geriatric Use
9
DRUG ABUSE AND DEPENDENCE
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
14.1
Adult Patients with Growth Hormone Deficiency
14.2
Pediatric Patients with Turner Syndrome
14.3
Pediatric Patients with Idiopathic Short Stature
14.4
Pediatric Patients with SHOX Deficiency
14.5
Pediatric Patients Born Small for Gestational Age (SGA) Who
Fail to Demonstrate Catch-up Growth by Age 2 - 4 Years
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
16.2
Storage and Handling
17
PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information
are not listed.
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Pediatric Patients
Growth Hormone Deficiency — Humatrope is indicated for the treatment of pediatric patients who have growth failure due to
inadequate secretion of endogenous growth hormone (GH).
Short Stature Associated with Turner Syndrome — Humatrope is indicated for the treatment of short stature associated with
Turner syndrome [see Clinical Studies (14.2)].
Idiopathic Short Stature — Humatrope is indicated for the treatment of idiopathic short stature, also called non-GH-deficient
short stature, defined by height SDS ≤-2.25 and associated with growth rates unlikely to permit attainment of adult height in the
normal range, in pediatric patients for whom diagnostic evaluation excludes other causes of short stature that should be observed or
treated by other means [see Clinical Studies (14.3)]; SDS = standard deviation scores.
SHOX Deficiency — Humatrope is indicated for the treatment of short stature or growth failure in children with short stature
homeobox-containing gene (SHOX) deficiency [see Clinical Studies (14.4)].
Small for Gestational Age — Humatrope is indicated for the treatment of growth failure in children born small for gestational
age (SGA) who fail to demonstrate catch-up growth by age two to four years [see Clinical Studies (14.5)].
1.2
Adult Patients
Humatrope is indicated for the replacement of endogenous GH in adults with GH deficiency who meet either of the following
two criteria [see Clinical Studies (14.1)]:
Adult-Onset (AO): Patients who have GH deficiency, either alone or associated with multiple hormone deficiencies
(hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or
Childhood-Onset (CO): Patients who were GH deficient during childhood as a result of congenital, genetic, acquired, or
idiopathic causes.
Patients who were treated with somatropin for GH deficiency in childhood and whose epiphyses are closed should be
reevaluated before continuation of somatropin therapy at the reduced dose level recommended for GH deficient adults. According to
current standards, confirmation of the diagnosis of adult GH deficiency in both groups involves an appropriate GH provocative test
with two exceptions: (1) patients with multiple other pituitary hormone deficiencies due to organic disease; and (2) patients with
congenital/genetic GH deficiency.
2
DOSAGE AND ADMINISTRATION
For subcutaneous injection.
Therapy with Humatrope should be supervised by a physician who is experienced in the diagnosis and management of
pediatric patients with short stature associated with GH deficiency, Turner syndrome, idiopathic short stature, SHOX deficiency, small
for gestational age birth, or adult patients with either childhood-onset or adult-onset GH deficiency.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
2.1
Reconstitution
Vial — Each 5-mg vial of Humatrope should be reconstituted with 1.5 to 5 mL of Diluent for Humatrope. The diluent should
be injected into the vial of Humatrope by aiming the stream of liquid gently against the vial wall. Following reconstitution, the vial
should be swirled with a GENTLE rotary motion until the contents are completely dissolved. DO NOT SHAKE. The resulting
solution should be clear. If the solution is cloudy or contains particulate matter, the contents MUST NOT be injected.
If sensitivity to the diluent should occur, the vials may be reconstituted with Bacteriostatic Water for Injection (Benzyl
Alcohol preserved), USP or Sterile Water for Injection, USP. When Humatrope is reconstituted with Bacteriostatic Water for
Injection, USP, the solution should be kept refrigerated at 36° to 46°F (2° to 8°C) and used within 14 days. It is important to note that
benzyl alcohol used as a preservative in Bacteriostatic Water has been associated with toxicity in newborns. Therefore, Bacteriostatic
Water for Injection must not be used to reconstitute Humatrope for use in a newborn infant. When Humatrope is to be administered to
a newborn infant it should be reconstituted with the diluent provided or, if the infant is sensitive to the diluent, Sterile Water for
Injection, USP. When reconstituted with Sterile Water for Injection the solution should be kept refrigerated at 36° to 46°F (2° to 8°C)
and used within 24 hours.
Cartridge — The Humatrope cartridge has been designed for use only with the Humatrope injection device. Each cartridge of
Humatrope should be reconstituted using only the diluent syringe that accompanies the cartridge and should not be reconstituted with
the Diluent for Humatrope provided with Humatrope vials. The reconstituted solution should be clear. If the solution is cloudy or
contains particulate matter, the contents MUST NOT be injected. Humatrope cartridges should not be used if the patient is allergic to
metacresol or glycerin.
The somatropin concentrations for the reconstituted Humatrope cartridges are as follows:
6 mg cartridge (gold)
2.08 mg/mL
12 mg cartridge (teal)
4.17 mg/mL
24 mg cartridge (purple)
8.33 mg/mL
[See How Supplied (16.2) and Information for the Patient for comprehensive directions on Humatrope cartridge
reconstitution].
2.2
General Administration Guidelines
For all indications, the following general principles for administration should be followed:
• When using the Humatrope vial the septum of the vial should be wiped with an alcoholic antiseptic solution before and after
each injection to prevent contamination of the contents by repeated needle insertions. Sterile disposable syringes and needles
should be used. The volume of the syringe should be small enough so that the prescribed dose can be withdrawn from the
vial with reasonable accuracy.
• When using the Humatrope cartridge a sterile disposable needle should be used for each injection.
• Humatrope should be administered by subcutaneous injection with regular rotation of injection sites to avoid lipoatrophy.
• For pediatric patients the calculated weekly Humatrope dosage should be divided into equal doses given either 6 or 7 days
per week.
• For adult patients the prescribed dose should be administered daily.
2.3
Dosing for Pediatric Patients
The Humatrope dosage and administration schedule should be individualized for each patient based on the growth response.
Failure to increase height velocity, particularly during the first year of treatment, should prompt close assessment of compliance and
evaluation of other causes of poor growth, such as hypothyroidism, under–nutrition, advanced bone age and antibodies to recombinant
human growth hormone. Response to somatropin treatment tends to decrease with time. Somatropin treatment for stimulation of linear
growth should be discontinued once epiphyseal fusion has occurred.
The recommended weekly dosages in milligrams (mg) per kilogram (kg) of body weight for pediatric patients are:
Growth hormone deficiency
0.026 to 0.043 mg/kg/day (0.18 to 0.30 mg/kg/week)
Turner syndrome
up to 0.054 mg/kg/day (0.375 mg/kg/week)
Idiopathic short stature
up to 0.053 mg/kg/day (0.37 mg/kg/week)
SHOX deficiency
0.050 mg/kg/day (0.35 mg/kg/week)
Small for gestational age
up to 0.067 mg/kg/day (0.47 mg/kg/week) a
a Recent literature has recommended initial treatment with larger doses of somatropin (e.g., 0.067 mg/kg/day), especially in very short
children (i.e., height SDS <–3), and/or older/ pubertal children, and that a reduction in dosage (e.g., gradually towards 0.033
mg/kg/day) should be considered if substantial catch-up growth is observed during the first few years of therapy. On the other hand,
in younger SGA children (e.g., approximately <4 years) (who respond the best in general) with less severe short stature (i.e.,
baseline height SDS values between -2 and -3), consideration should be given to initiating treatment at a lower dose (e.g., 0.033
mg/kg/day), and titrating the dose as needed over time. In all children, clinicians should carefully monitor the growth response, and
adjust the somatropin dose as necessary.
2.4
Dosing for Patients with Adult Growth Hormone Deficiency
Either of two approaches to Humatrope dosing may be followed: a non-weight-based regimen or a weight-based regimen.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Non-weight based — based on published consensus guidelines, a starting dose of approximately 0.2 mg/day (range, 0.15
0.30 mg/day) may be used without consideration of body weight. This dose can be increased gradually every 1-2 months by
increments of approximately 0.1-0.2 mg/day, according to individual patient requirements based on the clinical response and serum
insulin-like growth factor I (IGF-I) concentrations. The dose should be decreased as necessary on the basis of adverse events and/or
serum IGF-I concentrations above the age- and gender-specific normal range. Maintenance dosages vary considerably from person to
person, and between male and female patients.
Weight-based —based on the dosing regimen used in the original adult GH deficiency registration trials, the recommended
dosage at the start of treatment is not more than 0.006 mg/kg (6 μg/kg) daily. The dose may be increased according to individual
patient requirements to a maximum of 0.0125 mg/kg (12.5 μg/kg) daily. Clinical response, side effects, and determination of age- and
gender-adjusted serum IGF-I concentrations should be used as guidance in dose titration.
A lower starting dose and smaller dose increments should be considered for older patients, who are more prone to the adverse
effects of somatropin than younger individuals. In addition, obese individuals are more likely to manifest adverse effects when treated
with a weight-based regimen. Estrogen-replete women may need higher doses than men. Oral estrogen administration may increase
the dose requirements in women.
3
DOSAGE FORMS AND STRENGTHS
Humatrope is a sterile, white lyophilized powder available in the following vial and cartridge sizes:
• 5 mg vial and a 5-mL vial of Diluent for Humatrope
• 6 mg cartridge (gold) and a prefilled syringe of Diluent for Humatrope
• 12 mg cartridge (teal) and a prefilled syringe of Diluent for Humatrope
• 24 mg cartridge (purple) and a prefilled syringe of Diluent for Humatrope
Humatrope cartridges should be used only with the appropriate corresponding pen device.
4
CONTRAINDICATIONS
4.1
Acute Critical Illness
Treatment with pharmacologic amounts of somatropin is contraindicated in patients with acute critical illness due to
complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure.
Two placebo-controlled clinical trials in non-GH deficient adult patients (n=522) with these conditions in intensive care units revealed
a significant increase in mortality (41.9% vs. 19.3%) among somatropin-treated patients (doses 5.3-8.0 mg/day) compared to those
receiving placebo [see Warnings and Precautions (5.1)].
4.2
Prader-Willi Syndrome in Children
Somatropin is contraindicated in patients with Prader-Willi syndrome who are severely obese, have a history of upper airway
obstruction or sleep apnea, or have severe respiratory impairment. There have been reports of sudden death when somatropin was used
in such patients. Humatrope is not indicated for the treatment of pediatric patients who have growth failure due to genetically
confirmed Prader-Willi syndrome. [See Warnings and Precautions (5.2)].
4.3
Active Malignancy
In general, somatropin is contraindicated in the presence of active malignancy. Any preexisting malignancy should be inactive
and its treatment complete prior to instituting therapy with somatropin. Somatropin should be discontinued if there is evidence of
recurrent activity. Since GH deficiency may be an early sign of the presence of a pituitary tumor (or, rarely, other brain tumors), the
presence of such tumors should be ruled out prior to initiation of treatment. Somatropin should not be used in patients with any
evidence of progression or recurrence of an underlying intracranial tumor.
4.4
Diabetic Retinopathy
Somatropin is contraindicated in patients with active proliferative or severe non-proliferative diabetic retinopathy.
4.5
Closed Epiphyses
Somatropin should not be used for growth promotion in pediatric patients with closed epiphyses.
4.6
Hypersensitivity
Humatrope is contraindicated in patients with a known hypersensitivity to somatropin or diluent. Localized reactions are the
most common hypersensitivity reactions.
5
WARNINGS AND PRECAUTIONS
5.1
Acute Critical Illness
Increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery
or multiple accidental trauma, or those with acute respiratory failure has been reported after treatment with pharmacologic dosesof
somatropin [see Contraindications (4.1)]. The safety of continuing somatropin treatment in patients receiving replacement doses for
approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment
continuation with somatropin in patients experiencing acute critical illnesses should be weighed against the potential risk.
5.2
Prader-Willi Syndrome in Children
There have been reports of fatalities after initiating therapy with somatropin in pediatric patients with Prader-Willi syndrome
who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified
respiratory infection. Male patients with one or more of these factors may be at greater risk than females. Patients with Prader-Willi
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
syndrome should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of treatment with somatropin.
If, during treatment with somatropin, patients show signs of upper airway obstruction (including onset of, or increased, snoring) and/or
new onset sleep apnea, treatment should be interrupted. All patients with Prader-Willi syndrome treated with somatropin should also
have effective weight control and be monitored for signs of respiratory infection, which should be diagnosed as early as possible and
treated aggressively [see Contraindications (4.2)]. Humatrope is not indicated for the treatment of pediatric patients who have growth
failure due to genetically confirmed Prader-Willi syndrome.
5.3
Neoplasms
Patients with preexisting tumors or GH deficiency secondary to an intracranial lesion should be examined routinely for
progression or recurrence of the underlying disease process. In pediatric patients, clinical literature has revealed no relationship
between somatropin replacement therapy and central nervous system (CNS) tumor recurrence or new extracranial tumors. However, in
childhood cancer survivors, an increased risk of a second neoplasm has been reported in patients treated with somatropin after their
first neoplasm. Intracranial tumors, in particular meningiomas, in patients treated with radiation to the head for their first neoplasm,
were the most common of these second neoplasms. In adults, it is unknown whether there is any relationship between somatropin
replacement therapy and CNS tumor recurrence.
Patients should be monitored carefully for any malignant transformation of skin lesions (e.g., changes in pre-existing
cutaneous nevi).
5.4
Glucose Intolerance
Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses in susceptible patients. As a result,
previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked during somatropin treatment.
Therefore, glucose levels should be monitored periodically in all patients treated with somatropin, especially in those with risk factors
for diabetes mellitus, such as obesity, Turner syndrome, or a family history of diabetes mellitus. Patients with preexisting type 1 or
type 2 diabetes mellitus or impaired glucose tolerance should be monitored closely during somatropin therapy. The doses of
antihyperglycemic drugs (e.g., insulin or oral agents) may require adjustment when somatropin therapy is instituted in these patients.
5.5
Intracranial Hypertension
Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in a
small number of patients treated with somatropin products. Symptoms usually occurred within the first eight (8) weeks after the
initiation of somatropin therapy. In all reported cases, IH-associated signs and symptoms rapidly resolved after cessation of therapy or
a reduction of the somatropin dose. Funduscopic examination should be performed routinely before initiating treatment with
somatropin to exclude preexisting papilledema, and periodically during the course of somatropin therapy. If papilledema is observed
by funduscopy during somatropin treatment, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with
somatropin can be restarted at a lower dose after IH-associated signs and symptoms have resolved. Patients with Turner syndrome
may be at increased risk for the development of IH.
5.6
Fluid Retention
Fluid retention during somatropin replacement therapy in adults may frequently occur. Clinical manifestations of fluid
retention are usually transient and dose dependent.
5.7
Hypopituitarism
Patients with hypopituitarism (multiple pituitary hormone deficiencies) should have their other hormonal replacement
treatments closely monitored during somatropin treatment.
5.8
Hypothyroidism
Undiagnosed/untreated hypothyroidism may prevent an optimal response to somatropin, in particular, the growth response in
children. Patients with Turner syndrome have an inherently increased risk of developing autoimmune thyroid disease and primary
hypothyroidism. In patients with GH deficiency, central (secondary) hypothyroidism may first become evident or worsen during
somatropin treatment. Therefore, patients treated with somatropin should have periodic thyroid function tests performed, and thyroid
hormone replacement therapy should be initiated or appropriately adjusted when indicated.
5.9
Slipped Capital Femoral Epiphysis in Pediatric Patients
Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders (including pediatric GH
deficiency and Turner syndrome) or in patients undergoing rapid growth. Any pediatric patient with the onset of a limp or complaints
of hip or knee pain during somatropin therapy should be carefully evaluated.
5.10
Progression of Preexisting Scoliosis in Pediatric Patients
Progression of scoliosis can occur in patients who experience rapid growth. Because somatropin increases growth rate,
patients with a history of scoliosis who are treated with somatropin should be monitored for progression of scoliosis. However,
somatropin has not been shown to increase the occurrence of scoliosis. Skeletal abnormalities including scoliosis are commonly seen
in untreated patients with Turner syndrome. Scoliosis is also commonly seen in untreated patients with Prader-Willi syndrome.
Physicians should be alert to these abnormalities, which may manifest during somatropin therapy.
5.11
Otitis Media and Cardiovascular Disorders in Patients with Turner Syndrome
Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders, as these patients have an
increased risk of ear and hearing disorders. Somatropin treatment may increase the occurrence of otitis media in patients with Turner
syndrome. In addition, patients with Turner syndrome should be monitored closely for cardiovascular disorders (e.g., hypertension,
aortic aneurysm or dissection, stroke) as patients with Turner syndrome are also at increased risk for these conditions.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
5.12
Local and Systemic Reactions
When somatropin is administered subcutaneously at the same site over a long period of time, tissue atrophy may result. This
can be avoided by rotating the injection site [see Dosage and Administration (2.2)]. As with any protein, local or systemic allergic
reactions may occur. Parents/patients should be informed that such reactions are possible and that prompt medical attention should be
sought if allergic reactions occur.
5.13
Laboratory Tests
Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone and IGF-I may increase after somatropin
therapy.
6
ADVERSE REACTIONS
6.1
Most Serious and/or Most Frequently Observed Adverse Reactions
This list presents the most seriousa and/or most frequently observedb adverse reactions during treatment with somatropin
(including events observed in patients who received brands of somatropin other than Humatrope):
• aSudden death in pediatric patients with Prader-Willi syndrome who had risk factors including severe obesity,
history of upper airway obstruction or sleep apnea and unidentified respiratory infection [see Contraindications
(4.2) and Warnings and Precautions (5.2)]
• aIntracranial tumors, in particular meningiomas, in teenagers/young adults treated with radiation to the head for a
first neoplasm who subsequently receive somatropin [see Contraindications (4.3) and Warnings and Precautions
(5.3)]
• a,bGlucose intolerance including impaired glucose tolerance/impaired fasting glucose as well as overt diabetes
mellitus [see Warnings and Precautions (5.4)]
• aIntracranial hypertension [see Warnings and Precautions (5.5)]
• aSignificant diabetic retinopathy [see Contraindications (4.4)]
• aSlipped capital femoral epiphysis in pediatric patients [see Warnings and Precautions (5.9)]
• aProgression of preexisting scoliosis in pediatric patients [see Warnings and Precautions (5.10)]
• bFluid retention manifested by edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel
syndrome/paraesthesias [see Warnings and Precautions (5.6)]
• aUnmasking of latent central hypothyroidism [see Warnings and Precautions (5.8)]
• aInjection site reactions/rashes and lipoatrophy (as well as rare generalized hypersensitivity reactions) [see Warnings
and Precautions (5.12)]
6.2
Clinical Trials Experience
Because clinical trials are conducted under varying conditions, adverse reaction rates observed during the clinical trials
performed with one somatropin formulation cannot always be directly compared to the rates observed during the clinical trials
performed with a second somatropin formulation, and may not reflect the adverse reaction rates observed in practice.
Pediatric Patients
GH Deficiency
As with all protein pharmaceuticals, a small percentage of patients may develop antibodies to the protein. During the first
6 months of Humatrope therapy in 314 naive patients, only 1.6% developed specific antibodies to Humatrope (binding capacity
≥0.02 mg/L). None had antibody concentrations which exceeded 2 mg/L. Throughout 8 years of this same study, two patients (0.6%)
had binding capacity >2 mg/L. Neither patient demonstrated a decrease in growth velocity at or near the time of increased antibody
production. It has been reported that growth attenuation from pituitary-derived GH may occur when antibody concentrations are
>1.5 mg/L.
In addition to an evaluation of compliance with the treatment program and of thyroid status, testing for antibodies to
somatropin should be carried out in any patient who fails to respond to therapy.
In studies with GH deficient pediatric patients, injection site pain was reported infrequently. A mild and transient edema,
which appeared in 2.5% of patients, was observed early during the course of treatment.
Turner Syndrome
In a randomized, concurrent-controlled, open-label trial, there was a statistically significant increase in the occurrence of otitis
media (43% vs. 26%), ear disorders (18% vs. 5%) and surgical procedures (45% vs. 27%) in patients receiving Humatrope compared
with untreated control patients (Table 1). A similar increase in otitis media was observed in an 18-month placebo-controlled trial.
Table 1: Treatment-Emergent Adverse Reactions of Special Interest by Treatment Group in Turner Syndrome
Treatment Groupa
Adverse Reaction
Untreated
Humatropeb
Significance
Total Number of Patients
62
74
Surgical procedure
17 (27.4%)
33 (44.6%)
p≤0.05
16 (25.8%)
32 (43.2%)
p≤0.05
3 (4.8%)
13 (17.6%)
p≤0.05
Otitis media
Ear disorders
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
a Open-label study.
b Dose=0.3 mg/kg/wk.
Idiopathic Short Stature
In a randomized, placebo-controlled study of Humatrope treatment (0.22 mg/kg/week) to adult height in patients with
idiopathic short stature, the adverse events reported in Humatrope-treated patients (Table 2) were similar to those observed in other
pediatric populations treated with Humatrope. Mean serum glucose concentration did not change during Humatrope treatment. Mean
fasting serum insulin concentration increased 10% in the Humatrope treatment group at the end of treatment relative to baseline, but
remained within the normal reference range. For the same duration of treatment, the mean fasting serum insulin concentration
decreased by 2% in the placebo group. The occurrence rates of above-range values for glucose, insulin, and HbA1c were similar in the
Humatrope (somatropin)- and placebo-treated groups. No patient developed diabetes mellitus. Consistent with the known mechanism
of growth hormone action, Humatrope-treated patients had greater mean increases, relative to baseline, in serum insulin-like growth
factor-I (IGF-I) than placebo-treated patients at each study observation. However, there was no significant difference between the
Humatrope and placebo treatment groups in the proportion of patients who had at least one serum IGF-I concentration more than
2.0 SD above the age- and gender-appropriate mean (Humatrope: 9 of 35 patients [26%]; placebo: 7 of 28 patients [25%]).
Table 2: Non-serious Clinically Significant Treatment-Emergent Adverse Reactions by Treatment Group in Idiopathic Short
Stature
Treatment Group
Adverse Reaction
Placebo
Humatrope
Total Number of Patients
31
37
Scoliosis
4 (12.9%)
2 (6.5%)
1 (3.2%)
1 (3.2%)
0
1 (3.2%)
2 (6.5%)
4 (12.9%)
0
7 (18.9%)
6 (16.2%)
3 (8.1%)
2 (5.4%)
1 (2.7%)
4 (10.8%)
4 (10.8%)
9 (24.3%)
1 (2.7%)
Otitis media
Hyperlipidemia
Gynecomastia
Hip pain
Arthralgia
Arthrosis
Myalgia
Hypertension
The adverse events observed in the dose-response study (239 patients treated for 2 years) did not indicate a pattern suggestive
of a somatropin dose effect. Among Humatrope dose groups, mean fasting blood glucose, mean glycosylated hemoglobin, and the
incidence of elevated fasting blood glucose concentrations were similar. One patient developed abnormalities of carbohydrate
metabolism (glucose intolerance and high serum HbA1c) on treatment.
SHOX Deficiency
Clinically significant adverse events (adverse events previously observed in association with growth hormone treatment in
general) were assessed prospectively during the 2-year randomized, open-label study; those observed are presented in Table 3. In both
treatment groups, the mean fasting plasma glucose concentration at the end of the first year was similar to the baseline value and
remained in the normal range. No patient developed diabetes mellitus or had an above normal value for fasting plasma glucose at the
end of one-year of treatment. During the 2 year study period, the proportion of patients who had at least one IGF-I concentration
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
greater than 2.0 SD above the age- and gender-appropriate mean was 10 of 27 [37.0%] for the Humatrope-treated group vs. 0 of 24
patients [0.0%] for the untreated group. The proportion of patients who had at least one IGFBP-3 concentration greater than 2.0 SD
above the age and gender appropriate mean was 16 of 27 [59.3%] for the Humatrope treated group vs. 7 of 24 [29.2%] for the
untreated group.
Table 3: Clinically Significant Treatment-Emergent Adverse Reactionsa,b by Treatment Group in Patients with SHOX
Deficiency
Adverse Reaction
Treatment Group
Untreated
Humatrope
Total Number of Patients
25
27
Patients with at least one event
2
2 (8.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
5
3 (11.1%)
1 (8.3%)
2 (7.4%)
1 (3.7%)
Arthralgia
Gynecomastiac
Excessive number of cutaneous nevi
Scoliosis
a All events were non-serious.
b Events are included only if reported for a greater number of Humatrope-treated than Untreated patients.
c Percentage calculated for males only (1/12).
Small for Gestational Age
Study 1 — In a 2-year, multicenter, randomized study, 193 non-GH deficient children with short stature born SGA who failed
to demonstrate catch-up growth were treated with 2 different Humatrope treatment regimens: a fixed dose of 0.067 mg/kg/day (FHD
group) or an individually adjusted dose regimen (IAD group; starting dose 0.035 mg/kg/day which could be increased as early as
Month 3 to 0.067 mg/kg/day based on a validated growth prediction model). The most frequently reported adverse events were
common childhood infectious diseases. Adverse events possibly/probably related to Humatrope were otitis media and headaches
(where there was a suggestion of a modest dose response), and slipped capital femoral epiphysis (1 child) [see Warnings and
Precautions (5.9) and Adverse Reactions (6.1)]. There were no clear cut cases of new-onset diabetes mellitus, no children treated for
hyperglycemia, and no children whose fasting blood glucose exceeded 126 mg/dL at any time during the study. However, 6 children
(4 in the FHD group and 2 in the IAD group whose dose was increased from 0.035 mg/kg/day to 0.067 mg/kg/day [one at Month 3
and one at Year 1]) manifested impaired fasting glucose at Year 2. Two of these six children displayed impaired fasting glucose
during the study as well, and one of them was required to discontinue Humatrope at Month 15 as a consequence [see Warnings and
Precautions (5.4) and Adverse Reactions (6.1)]. A modestly dose-dependent increase in mean serum IGF-I SDS concentrations within
the reference range was observed; of note, at study completion, 20-25% of these children had serum IGF-I SDS values > +2.
Study 2 — A 2-year, open-label, single-arm study of Humatrope at a dosage of 0.067 mg/kg/day in 35 non-GH deficient
children with short stature born SGA who failed to demonstrate catch-up growth did not reveal further safety data of note.
Study 3 — Additional safety information was obtained from 340 short children born SGA followed in an observational study
who received an average Humatrope dosage of 0.041 mg/kg/day (maximum dose: 0.084 mg/kg/day) for an average of 3.0 years. Type
2 diabetes mellitus apparently precipitated by Humatrope therapy was reported in a single patient, but appeared to resolve after
discontinuation of Humatrope treatment, as the child had a normal oral glucose tolerance test and was receiving no antihyperglycemic
medications 9 months after the drug was discontinued. One patient manifested carpal tunnel syndrome [see Adverse Reactions (6.1)]
and another developed an exacerbation of preexisting scoliosis [see Warnings and Precautions (5.10) and Adverse Reactions (6.1)]
which may have been related to Humatrope treatment.
In both Study 1 and Study 2, after treatment with Humatrope, bone maturation did not accelerate excessively, and the timing
of puberty was age-appropriate in boys and girls.
Therefore, it can be concluded that no novel adverse events potentially related to treatment with Humatrope were reported in
either short-term study or were apparent after a review of the post-marketing, observational, safety database.
Adult Patients
In clinical studies in which high doses of Humatrope were administered to healthy adult volunteers, the following events
occurred infrequently: headache, localized muscle pain, weakness, mild hyperglycemia, and glucosuria.
Adult-Onset GH Deficiency
In the first 6 months of controlled blinded trials during which patients received either Humatrope or placebo, adult-onset GH
deficient adults who received Humatrope experienced a statistically significant increase in edema (Humatrope 17.3% vs.
placebo 4.4%, p=0.043) and peripheral edema (11.5% vs. 0%, respectively, p=0.017). In patients with adult-onset GH deficiency,
edema, muscle pain, joint pain, and joint disorder were reported early in therapy and tended to be transient or responsive to dosage
titration.
Two of 113 adult-onset patients developed carpal tunnel syndrome after beginning maintenance therapy without a low dose
(0.00625 mg/kg/day) lead-in phase. Symptoms abated in these patients after dosage reduction.
All treatment-emergent adverse events with ≥5% overall occurrence rate during 12 or 18 months of replacement therapy with
Humatrope are shown in Table 4 (adult-onset patients) and in Table 5 (childhood-onset patients).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
Adult patients treated with Humatrope who had been diagnosed with GH deficiency in childhood reported side effects less
frequently than those with adult-onset GH deficiency.
Table 4: Treatment-Emergent Adverse Reactions with ≥5% Overall Occurrence in Adult-Onset Growth Hormone-Deficient
Patients Treated with Humatrope for 18 Months as Compared with 6-Month Placebo and 12-Month Humatrope Exposurea
Adverse Reaction
18 Months Exposure
[Placebo (6 Months)/GH (12 Months)]
(N=46)
18 Months GH Exposure
(N=52)
n
%
n
%
Edemab
7
15.2
7
15.2
6
13.0
6
13.0
6
13.0
5
10.9
8
17.4
5
10.9
5
10.9
2
4.3
0
0
1
2.2
1
2.2
3
6.5
11
21.2
9
17.3
9
17.3
7
13.5
7
13.5
7
13.5
6
11.5
5
9.6
4
7.7
4
7.7
3
5.8
3
5.8
3
5.8
2
3.9
Arthralgia
Paresthesia
Myalgia
Pain
Rhinitis
Peripheral edemac
Back pain
Headache
Hypertension
Acne
Joint disorder
Surgical procedure
Flu syndrome
a Abbreviations: GH=Humatrope; N=number of patients receiving treatment in the period stated; n=number of patients reporting each
treatment-emergent adverse event.
b p=0.04 as compared to placebo (6 months).
c p=0.02 as compared to placebo (6 months).
Childhood-Onset GH Deficiency
Two double-blind, placebo-controlled trials were conducted in 67 adult patients with childhood-onset GH deficiency who had
received previous somatropin treatment during childhood. Patients were randomized to receive either placebo injections or Humatrope
(0.00625 mg/kg/day [6.25 µg/kg/day] for the first 4 weeks, then 0.0125 mg/kg/day [12.5 µg/kg/day] thereafter) for the first 6 months,
followed by open-label Humatrope for the next 12 months for all patients. The patients in these studies reported side effects less
frequently than those with adult-onset GH deficiency. During the placebo-controlled phase (first 6 months) of the study, elevations of
serum glutamic oxaloacetic transferase were reported significantly more often for Humatrope-treated (12.5%) than placebo-treated
patients (0.0%, p=0.031). No other events were reported significantly more often for Humatrope-treated patients during the placebo-
controlled phase. The following events were reported for at least 5% of patients in either of the 2 treatment groups over the 18-month
duration of the study, listed in descending order of maximum frequency for either group: aspartate aminotransferase increased 13%,
headache 11%, edema 9%, pain 9%, alanine aminotransferase increased 6%, asthenia 6%, myalgia 6%, respiratory disorder 6%.
Table 5: Treatment-Emergent Adverse Reactions with ≥5% Overall Occurrence in Childhood-Onset Growth
Hormone-Deficient Patients Treated with Humatrope for 18 Months as Compared with 6-Month Placebo and 12-Month
Humatrope Exposurea
Adverse Reactions
18 Months Exposure
[Placebo (6 Months)/GH (12 Months)]
(N=35)
18 Months GH Exposure
(N=32)
n
%
n
%
Flu syndrome
8
22.9
2
5.7
4
11.4
1
2.9
0
0
3
8.6
0
0
2
5.7
3
8.6
2
5.7
2
5.7
5
15.6
4
12.5
3
9.4
2
6.3
2
6.3
2
6.3
2
6.3
2
6.3
2
6.3
2
6.3
2
6.3
AST increasedb
Headache
Asthenia
Cough increased
Edema
Hypesthesia
Myalgia
Pain
Rhinitis
ALT increased
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
Respiratory disorder
2
2
5
5.7
1
5.7
0
14.3
1
3.1
0
3.1
Gastritis
Pharyngitis
a Abbreviations: GH=Humatrope; N=number of patients receiving treatment in the period stated; n=number of patients reporting each
treatment-emergent adverse event; ALT=alanine aminotransferase, formerly SGPT; AST=aspartate aminotransferase, formerly
SGOT.
b p=0.03 as compared to placebo (6 months).
6.3
Post-Marketing Experience
Because these adverse events 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. The adverse events reported during post-marketing
surveillance do not differ from those listed/discussed above in Sections 6.1 and 6.2 in children and adults.
Other adverse events that have been reported in somatropin-treated patients include the following:
Neurologic — Headaches (common in children and occasional in adults).
Skin — Increase in size or number of cutaneous nevi, especially in patients with Turner syndrome and those with SHOX
deficiency [see Warnings and Precautions (5.3)].
Endocrine — Gynecomastia.
Gastrointestinal — Pancreatitis.
Neoplasia — Leukemia has been reported in a small number of GH deficient children treated with somatropin, somatrem
(methionylated rhGH), and GH of pituitary origin. It is uncertain whether these cases of leukemia are related to GH therapy, the
pathology of GH deficiency itself, or other associated treatments such as radiation therapy. On the basis of current evidence, experts
have not been able to conclude that GH therapy per se was responsible for these cases of leukemia. The risk for children with GH
deficiency, if any, remains to be established [see Contraindications (4.3) and Warnings and Precautions (5.3)].
7
DRUG INTERACTIONS
7.1
11β-Hydroxysteroid Dehydrogenase Type 1
The microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) is required for conversion of cortisone to its
active metabolite, cortisol, in hepatic and adipose tissue. GH and somatropin inhibit 11βHSD-1. Consequently, individuals with
untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol. Introduction of somatropin treatment may result in
inhibition of 11βHSD-1 and reduced serum cortisol concentrations. As a consequence, previously undiagnosed central (secondary)
hypoadrenalism may be unmasked and glucocorticoid replacement may be required in patients treated with somatropin. In addition,
patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their
maintenance or stress doses following initiation of somatropin treatment; this may be especially true for patients treated with cortisone
acetate and prednisone since conversion of these drugs to their biologically active metabolites is dependent on the activity of
11βHSD-1.
7.2
Phyarmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment
Pharmacologic glucocorticoid therapy and supraphysiologic glucocorticoid treatment may attenuate the growth promoting
effects of somatropin in children. Therefore, glucocorticoid replacement dosing should be carefully adjusted in children receiving
concomitant somatropin and glucocorticoid treatments to avoid both hypoadrenalism and an inhibitory effect on growth.
7.3
Cytochrome P450-Metabolized Drugs
Limited published data indicate that somatropin treatment increases cytochrome P450 (CP450)-mediated antipyrine clearance
in man. These data suggest that somatropin administration may alter the clearance of compounds metabolized by CP450 liver enzymes
(e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine). Therefore, careful monitoring is advised when somatropin is
administered in combination with drugs metabolized by CP450 liver enzymes. However, formal drug interaction studies have not been
conducted.
7. 4
Oral Estrogen
Because oral estrogens may reduce the serum IGF-I response to somatropin treatment, girls and women receiving oral
estrogen replacement may require greater somatropin dosages [see Dosage and Administration (2.4)].
7. 5
Insulin and/or Other Hypoglycemic Agents
Patients with diabetes mellitus who receive concomitant treatment with somatropin may require adjustment of their doses of
insulin and/or other hypoglycemic agents [see Warnings and Precautions (5.4)].
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category C — Animal reproduction studies have not been conducted with Humatrope. It is not known whether
Humatrope can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Humatrope should be
given to a pregnant woman only if clearly needed.
8.3
Nursing Mothers
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
There have been no studies conducted with Humatrope in 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 Humatrope is administered to a
nursing woman.
8.5
Geriatric Use
The safety and effectiveness of Humatrope in patients aged 65 years and over has not been evaluated in clinical studies.
Elderly patients may be more sensitive to the action of somatropin, and therefore may be more prone to development of adverse
reactions. A lower starting dose and smaller dose increments should be considered for older patients [see Dosage and Administration
(2.4)].
9
DRUG ABUSE AND DEPENDENCE
Inappropriate use of somatropin by individuals who do not have indications for which somatropin is approved, may result in
significant negative health consequences. Somatropin is not a drug of dependence.
10
OVERDOSAGE
Short-term — Acute overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia.
Long-term — Long-term overdosage could result in signs and symptoms of gigantism or acromegaly consistent with the
known effects of excess endogenous human GH.
11
DESCRIPTION
Humatrope (somatropin, rDNA origin, for injection) is a polypeptide hormone of recombinant DNA origin. Humatrope is
synthesized in a strain of Escherichia coli that has been modified by the addition of the gene for human GH. The peptide is comprised
of 191 amino acid residues and has a molecular weight of about 22,125 daltons. The amino acid sequence of the peptide is identical to
that of human GH of pituitary origin.
Humatrope is a sterile, white, lyophilized powder intended for subcutaneous or intramuscular administration after
reconstitution to its liquid form. Humatrope is a highly purified preparation. Phosphoric acid and/or sodium hydroxide may have been
added to adjust the pH. Reconstituted solutions have a pH of approximately 7.5. This product is oxygen sensitive.
Vial — Each vial of Humatrope contains 5 mg somatropin (15 IU or 225 nanomoles); 25 mg mannitol; 5 mg glycine; and
1.13 mg dibasic sodium phosphate. Each vial is supplied in a combination package with an accompanying 5-mL vial of diluting
solution (diluent). The diluent contains Water for Injection with 0.3% metacresol as a preservative and 1.7% glycerin.
Cartridge — Cartridges of Humatrope contain either 6 mg (18 IU), 12 mg (36 IU), or 24 mg (72 IU) of somatropin. Each
Humatrope cartridge contains the following:
Cartridge
6 mg
(gold)
12 mg
(teal)
24 mg
(purple)
Component
Somatropin
6 mg
12 mg
24 mg
Mannitol
18 mg
36 mg
72 mg
Glycine
6 mg
12 mg
24 mg
Dibasic sodium phosphate
1.36 mg
2.72 mg
5.43 mg
Each cartridge is supplied in a combination package with an accompanying syringe containing approximately 3 mL of diluting
solution (diluent). The diluent contains Water for Injection; 0.3% metacresol as a preservative; and 1.7%, 0.29%, and 0.29% glycerin
in the 6, 12, and 24 mg cartridges, respectively.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
GH binds to dimeric GH receptors located within the cell membranes of target tissue cells. This interaction results in
intracellular signal transduction and subsequent induction of transcription and translation of GH-dependent proteins including IGF-I,
IGF BP-3 and acid-labile subunit. GH has direct tissue and metabolic effects, including stimulation of chondrocyte differentiation,
stimulation of lipolysis and stimulation of hepatic glucose output. In addition, some effects of somatropin are mediated indirectly by
IGF-I, including stimulation of protein synthesis and chondrocyte proliferation.
12.2
Pharmacodynamics
In vitro, preclinical, and clinical testing have demonstrated that Humatrope is therapeutically equivalent to human GH of
pituitary origin and achieves equivalent pharmacokinetic profiles in healthy adults. The following effects have been reported for
human GH of pituitary origin, and/or somatropin.
Cell Growth — Total numbers of muscle cells are reduced in GH deficient children. Somatropin increases the number and
size of muscle cells in such children.
Skeletal Growth — Somatropin stimulates skeletal growth in children with GH deficiency as a result of effects on the growth
plates (epiphyses) of long bones. Concentrations of IGF-I, which play a role in skeletal growth, are low in the serum of GH deficient
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
children but increase during somatropin treatment in most patients. The stimulation of skeletal growth increases linear growth rate
(height velocity) in most somatropin-treated children.
Protein Metabolism — Linear growth is facilitated in part by increased cellular protein synthesis as reflected by nitrogen
retention, which can be demonstrated by decreased urinary nitrogen excretion and serum urea nitrogen.
Connective Tissue Metabolism — Somatropin stimulates the synthesis of chondroitin sulfate and collagen, and increases the
urinary excretion of hydroxyproline.
Carbohydrate Metabolism — GH has a physiological role in the maintenance of normoglycemia during times of substrate
restriction (e.g., fasting), via mechanisms such as stimulation of hepatic gluconeogenesis and suppression of insulin-stimulated
glucose uptake by peripheral tissues. Because of these actions GH is considered an insulin antagonist with respect to carbohydrate
metabolism. Consequently, the fasting hypoglycemia that may occur in some children with hypopituitarism may be improved by
somatropin treatment. As an extension of its physiological actions, supraphysiological GH concentrations may increase glucose
production sufficiently to stimulate insulin secretion to maintain normoglycemia. Large doses of somatropin may impair glucose
tolerance if compensatory insulin secretion is inadequate. Administration of somatropin to healthy adults and patients with
Turner syndrome resulted in increases in mean serum fasting and postprandial insulin concentrations, although mean values remained
in the normal range. In addition, mean HbA1c concentrations and mean fasting and postprandial glucose concentrations remained in
the normal range.
Lipid Metabolism — Somatropin stimulates intracellular lipolysis, and administration of somatropin leads to an increase in
plasma free fatty acids and triglycerides. Untreated GH deficiency is associated with increased body fat stores, including increased
abdominal visceral and subcutaneous adipose tissue. Treatment of GH deficient patients with somatropin results in a general
reduction of fat stores, and decreased serum concentrations of low density lipoprotein (LDL) cholesterol.
Mineral Metabolism — Administration of somatropin results in an increase in total body potassium and phosphorus and to a
lesser extent sodium, probably as the result of cell growth. Serum concentrations of inorganic phosphate increase in somatropin-
treated GH deficient children because of the metabolic activities associated with bone growth. Although urinary calcium excretion is
increased, there is a simultaneous increase in calcium absorption from the intestine. Consequently, serum calcium concentrations
generally are not altered, although negative calcium balance may occur occasionally during somatropin treatment. Associated with the
changes in mineral metabolism, parathyroid hormone may increase during somatropin treatment.
12.3
Pharmacokinetics
Absorption — Humatrope has been studied following intramuscular, subcutaneous, and intravenous administration in adult
volunteers (see Figure 1). The absolute bioavailability of somatropin is 75% and 63% after subcutaneous and intramuscular
administration, respectively.
Distribution — The volume of distribution of somatropin after intravenous injection is about 0.07 L/kg (Table 6).
Metabolism — Extensive metabolism studies have not been conducted. The metabolic fate of somatropin involves classical
protein catabolism in both the liver and kidneys. In renal cells, at least a portion of the breakdown products of somatropin is returned
to the systemic circulation. In healthy volunteers, mean somatropin clearance is 0.14 L/hr/kg. The mean half-life of intravenous
somatropin is 0.36 hours, whereas subcutaneously and intramuscularly administered somatropin have mean half-lives of 3.8 and
4.9 hours, respectively. The longer half-life observed after subcutaneous or intramuscular administration is due to slow absorption
from the injection site.
Excretion — Urinary excretion of intact Humatrope has not been measured. Small amounts of somatropin have been detected
in the urine of pediatric patients following replacement therapy.
Geriatric patients — The pharmacokinetics of Humatrope have not been studied in patients greater than 65 years of age.
Pediatric patients — The pharmacokinetics of Humatrope in pediatric patients are similar to those of adults.
Gender — No gender-specific pharmacokinetic studies have been performed with Humatrope. The available literature
indicates that the pharmacokinetics of somatropin are similar in men and women.
Race — No data are available.
Renal, hepatic insufficiency — No studies have been performed with Humatrope.
Table 6: Summary of Somatropin Parameters in Healthy Adult Volunteersa
Cmax
(ng/mL)
t1/2
(hr)
AUC0-∞
(ngyhr/mL)
Cls
(L/kgyhr)
Vβ
(L/kg)
0.02 mg (0.05 IUb)/kg, iv
Mean (SD)
415 (75)
0.363 (0.053)
156 (33)
0.135 (0.029)
0.0703 (0.0173)
0.1 mg (0.27 IUb)/kg, im
Mean (SD)
53.2 (25.9)
4.93 (2.66)
495 (106)
0.215 (0.047)
1.55 (0.91)
0.1 mg (0.27 IUb)/kg, sc
Mean (SD)
63.3 (18.2)
3.81 (1.40)
585 (90)
0.179 (0.028)
0.957 (0.301)
a Abbreviations: Cmax=maximum concentration; t1/2=half-life; AUC0-∞=area under the curve; Cls=systemic clearance; Vβ=volume
distribution; iv=intravenous; SD=standard deviation; im=intramuscular; sc=subcutaneous.
b Based on previous International Standard of 2.7 IU=1 mg.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13 Graph
Figure 1
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
There has been no evidence to date of Humatrope-induced mutagenicity. No long-term animal studies for carcinogenicity or
impairment of fertility with somatropin have been performed.
14
CLINICAL STUDIES
14.1
Adult Patients with Growth Hormone Deficiency
Two multicenter trials in patients with adult-onset GH deficiency (n=98) and two studies in patients with childhood-onset
GH deficiency (n=67) were designed to assess the effects of replacement therapy with Humatrope. These four studies each included a
6-month randomized, blinded, placebo-controlled phase, during which approximately half of the patients received placebo injections,
while the other half received Humatrope injections. The Humatrope dosages for all studies were identical: 1 month of treatment at
0.00625 mg/kg/day (6.25µg/kg/day) followed by 0.0125 mg/kg/day (12.5 µg/kg/day) for the next 5 months. The 6-month, double-
blind phase was followed by 12 months of open-label Humatrope treatment for all patients. The primary efficacy measures were body
composition (lean body mass and fat mass), lipid parameters, and quality of life, as measured by the Nottingham Health Profile (a
general health-related quality of life questionnaire). Lean body mass was determined by bioelectrical impedance analysis (BIA),
validated with potassium 40. Body fat was assessed by BIA and sum of skinfold thickness. Lipid subfractions were analyzed by
standard assay methods in a central laboratory. Adult-onset patients and childhood-onset patients differed by diagnosis (organic vs.
idiopathic pituitary disease), body size (average vs. small [mean height and weight]), and age (mean 44 vs. 29 years).
In patients with adult-onset GH deficiency, Humatrope treatment (vs. placebo) resulted in an increase in mean lean body
mass (2.59 vs. -0.22 kg, p<0.001) and a decrease in body fat (-3.27 vs. 0.56 kg, p<0.001). Similar changes were seen in
childhood-onset GH deficient patients. These significant changes in lean body mass persisted throughout the 18-month period for
both the adult-onset and childhood-onset groups; the changes in fat mass persisted in the childhood-onset group. Serum concentrations
of high-density lipoprotein (HDL) cholesterol which were low at baseline (mean, 30.1 mg/mL and 33.9 mg/mL in adult-onset and
childhood-onset patients, respectively) had normalized by the end of 18 months of Humatrope treatment (mean change of 13.7 and
11.1 mg/dL for the adult-onset and childhood-onset groups, respectively p<0.001). After 6 months, the physical mobility and social
isolation domains on the Nottingham Health Profile were significantly improved in Humatrope-treated vs. placebo-treated patients
with adult-onset GH deficiency (p<0.01) (Table 7). There were no significant between-group differences (Humatrope vs. placebo) for
the other Nottingham Health Profile domains (energy level, emotional reactions, sleep, pain) in patients with adult-onset GH
deficiency, and no significant between-group differences in any of the domains were demonstrated for patients with childhood-onset
GH deficiency.
Two additional studies on the effect of Humatrope on exercise capacity were conducted. Improved physical function was
documented by increased exercise capacity (VO2 max, p<0.005) and work performance (Watts, p<0.01).
Table 7: Changesa in Nottingham Health Profile Scoresb in Adult-Onset Growth Hormone-Deficient Patients
Outcome Measure
Placebo
(6 Months)
Humatrope Therapy
(6 Months)
Significance
Energy level
-11.4
-15.5
NS
Physical mobility
-3.1
-10.5
p<0.01
Social isolation
0.5
-4.7
p<0.01
Emotional reactions
-4.5
-5.4
NSc
Sleep
-6.4
-3.7
NSc
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
Pain
-2.8
-2.9
NSc
a An improvement in score is indicated by a more negative change in the score.
b To account for multiple analyses, appropriate statistical methods were applied and the required level of significance is 0.01.
c NS=not significant.
Two studies evaluating the effect of Humatrope on bone mineralization were conducted subsequently. In a 2-year,
randomized, double-blind, placebo-controlled trial, 67 patients with previously untreated adult-onset GH deficiency received placebo
or Humatrope injections titrated to maintain serum IGF-I within the age-adjusted normal range. In men, but not women, lumbar spine
bone mineral density (BMD) increased with Humatrope treatment compared to placebo, with a treatment difference of
approximately 4% (p=0.001). There was no significant change in hip BMD with Humatrope treatment in men or women, when
compared to placebo.
In a 2-year, open-label, randomized trial, 149 patients with childhood-onset GH deficiency who had completed pediatric
somatropin therapy, had attained final height (height velocity <1 cm/yr) and were confirmed to be GH-deficient as young adults
(commonly referred to as transition patients), were randomized to receive Humatrope 0.0125 mg/kg/day (12.5 µg/kg/day), Humatrope
0.025 mg/kg/day (25 µg/kg/day), or no injections (control). Patients who were randomized to treatment with Humatrope at
12.5 µg/kg/day achieved a 2.9% greater increase from baseline than control patients in total body bone mineral content (BMC)
(8.1 ± 9.0% vs. 5.2 ± 8.2%, p=0.02), whereas patients treated with Humatrope at 25 µg/kg/day had no significant change in BMC.
These results include data from patients who received less than 2 years of treatment. A greater treatment effect was observed for
patients who completed 2 years of treatment. Increases in lumbar spine BMD and BMC were also statistically significant compared to
control with the 12.5 µg/kg/day dose but not the 25 µg/kg/day dose. Hip BMD and BMC did not change significantly compared to
control with either dose. The effect of GH treatment on BMC and BMD in transition patients at doses lower than12.5 µg/kg/day was
not studied. The effect of Humatrope on the occurrence of osteoporotic fractures has not been studied.
14.2
Pediatric Patients with Turner Syndrome
One long-term, randomized, open-label, Canadian multicenter, concurrently controlled study, two long-term, open-label
multicenter, historically controlled US studies and one long-term, randomized, US dose-response study were conducted to evaluate the
efficacy of somatropin treatment of short stature due to Turner syndrome.
The Canadian randomized study compared near-adult height outcomes for Humatrope-treated patients to those of a concurrent
control group who received no injections. The Humatrope-treated patients received a dosage of 0.3 mg/kg/week given in divided doses
6 times per week from a mean age of 11.7 years for a mean duration of 4.7 years. Puberty was induced with a standardized estrogen
regimen initiated at 13 years of age for both treatment groups. The Humatrope-treated group (n=27) attained a mean (± SD) near-final
height of 146.0 ± 6.2 cm; the untreated control group (n=19) attained a near-final height of 142.1 ± 4.8 cm. By analysis of covariance
(with adjustments for baseline height and mid-parental height), the effect of somatropin treatment was a mean height increase of
5.4 cm (p=0.001).
In two of the US studies, the effect of long-term somatropin treatment (0.375 mg/kg/week given in divided doses either
3 times per week or daily) on adult height was determined by comparing adult heights in the treated patients with those of
age-matched historical controls with Turner syndrome who received no growth-promoting therapy. Puberty was induced with a
standardized estrogen regimen initiated after 14 years of age in one study; in the second study patients treated with early somatropin
(before 11 years of age) were randomized to begin pubertal induction at either age 12 (n=26) or 15 (n=29) years (conjugated
estrogens, 0.3 mg escalating to 0.625 mg daily); those whose somatropin was initiated after 11 years of age began estrogen
replacement after 1 year of somatropin. Mean height gains from baseline to adult (or near-adult) height ranged from 5.0 to 8.3 cm,
depending on age at initiation of somatropin treatment and estrogen replacement (Table 8).
In the third US study, a randomized, blinded dose-response study, patients were treated from a mean age of 11.1 years for a
mean duration of 5.3 years with a weekly Humatrope dosage of either 0.27 mg/kg or 0.36 mg/kg administered in divided doses 3 or
6 times weekly. The mean near-final height of Humatrope-treated patients was 148.7 ± 6.5 cm (n=31). When compared to historical
control data, the mean gain in adult height was approximately 5 cm.
In summary, patients with Turner syndrome (total n=181 from the 4 studies above) treated to adult height achieved
statistically significant average height gains ranging from 5.0 to 8.3 cm.
Table 8: Summary Table of Efficacy Resultsa
Study
Group
Study
Designb
Number at Adult
Height
GH
Age (yr)
Estrogen
Age (yr)
GH
Duration (yr)
Adult Height
Gain (cm)c
Canadian
RCT
27
11.7
13
4.7
5.4
US 1
MHT
17
9.1
15.2
7.6
7.4
US 2
Ae
MHT
29
9.4
15
6.1
8.3
Bf
26
9.6
12.3
5.6
5.9
Cg
51
12.7
13.7
3.8
5
US 3
RDT
31
11.1
8-13.5
5.3
~5d
a Data shown are mean values.
b RCT: randomized controlled trial; MHT: matched historical controlled trial; RDT: randomized dose-response trial.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
c Analysis of covariance vs. controls.
d Compared with historical data.
e GH age <11 yr, estrogen age 15 yr.
f GH age <11 yr, estrogen age 12 yr.
g GH age >11 yr, estrogen at month 12.
14.3
Pediatric Patients with Idiopathic Short Stature
Two randomized, multicenter trials, 1 placebo-controlled and 1 dose-response, were conducted in pediatric patients with
idiopathic short stature, also called non-GH-deficient short stature. The diagnosis of idiopathic short stature was made after excluding
other known causes of short stature, as well as GH deficiency. Limited safety and efficacy data are available below the age of 7 years.
No specific studies have been conducted in pediatric patients with familial short stature. The placebo-controlled study enrolled
71 pediatric patients (55 males, 16 females) 9 to 15 years old (mean age 12.4 ± 1.5 years), with short stature, 68 of whom received
Humatrope. Patients were predominately prepubertal (Tanner I, 45%) or in early puberty (Tanner II, 47%) at baseline. In this
double-blind trial, patients received subcutaneous injections of either Humatrope 0.222 mg/kg/week (equivalent to 32 µg/kg/day), or
placebo given in divided doses 3 times per week until height velocity decreased to ≤1.5 cm/year (“final height”). Final height
measurements were available for 33 subjects (22 Humatrope, 11 placebo) after a mean treatment duration of 4.4 years (range 0.1-9.1
years).
The Humatrope-treated group achieved a mean final height SDS of -1.8 (Table 9), whereas placebo-treated patients had a
mean final height SDS of -2.3 (mean treatment difference, 0.51 SDS, p=0.017). Height gain across the duration of the study and final
height SDS minus baseline predicted height SDS were also significantly greater in Humatrope-treated patients than in placebo-treated
patients (Tables 9 and 10). In addition, the number of patients whose final height was above the 5th percentile of the general
population height standard for age and sex was significantly greater in the Humatrope group than the placebo group (41% vs. 0%,
p<0.05), as was the number of patients who gained at least 1 SDS unit in height across the duration of the study (50% vs. 0%, p<0.05).
Table 9: Baseline Height Characteristics and Effect of Humatrope on Final Height in Placebo-Controlled Studya,b
Placebo
(n=11)
Mean (SD)
Humatrope
(n=22)
Mean (SD)
Treatment Effect
Mean
(95%CI)
p-value
Baseline height SDS
-2.75 (0.6)
-2.7 (0.6)
NA
0.77
BPH SDS
-2.3 (0.8)
-2.1 (0.7)
NA
0.53
Final height SDSc
-2.3 (0.6)
-1.8 (0.8)
0.51 (0.10, 0.92)
0.017
FH SDS - baseline height SDS
0.4 (0.2)
0.9 (0.7)
0.51 (0.04, 0.97)
0.034
FH SDS - BPH SDS
-0.1 (0.6)
0.3 (0.6)
0.46 (0.02, 0.89)
0.043
a Abbreviations: BPH=baseline predicted height; CI=confidence interval; FH=final height; NA=not applicable; SDS=standard
deviation score.
b For final height population.
c Between-group comparison was performed using analysis of covariance with baseline predicted height SDS as the covariate.
Treatment effect is expressed as least squares mean (95% CI).
The dose-response study included 239 pediatric patients (158 males, 81 females), 5 to 15 years old, (mean age
9.8 ± 2.3 years). Mean ± SD baseline characteristics included: height SDS -3.21 ± 0.70, predicted adult height SDS -2.63 ± 1.08, and
height velocity SDS -1.09 ± 1.15. All but 3 patients were prepubertal. Patients were randomized to one of three Humatrope treatment
groups: 0.24 mg/kg/week (equivalent to 34 µg/kg/day); 0.24 mg/kg/week for 1 year, followed by 0.37 mg/kg/week (equivalent to
53 µg/kg/day); and 0.37 mg/kg/week. The primary hypothesis of this study was that treatment with Humatrope would increase height
velocity during the first 2 years of therapy in a dose-dependent manner. Additionally, after completing the initial 2-year dose-response
phase of the study, 50 patients were followed to final height.
Patients who received the Humatrope dosage of 0.37 mg/kg/week had a significantly greater increase in mean height velocity
after 2 years of treatment than patients who received 0.24 mg/kg/week (4.04 vs. 3.27 cm/year, p=0.003). The mean difference between
final height and baseline predicted height was 7.2 cm for patients who received Humatrope 0.37 mg/kg/week and 5.4 cm for patients
who received 0.24 mg/kg/week (Table 10). While no patient had height above the 5th percentile in any dosage group at baseline,
82% of the patients who received 0.37 mg/kg/week and 47% of the patients who received 0.24 mg/kg/week achieved final heights
above the 5th percentile of the general population height standards (p=NS).
Table 10: Idiopathic Short Stature Trials: Final Height Minus Baseline Predicted Heighta
Placebo-controlled Trial
3x per week dosing
Dose Response Trial
6x per week dosing
Placebo
Humatrope
0.22 mg/kg
Humatrope
0.24 mg/kg
Humatrope
0.24/0.37 mg/kg
Humatrope
0.37 mg/kg
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
(n=10)
(n=22)
(n=13)
(n=13)
(n=13)
FH - Baseline PH
Mean (95% CI), cm
-0.7 (-3.6, 2.3)
+2.2 (0.4, 3.9)
+5.4 (2.8, 7.9)
+6.7 (4.1, 9.2)
+7.2 (4.6, 9.8)
a Abbreviations: FH=final height; PH=predicted height; CI=confidence interval; cm=centimeters.
14.4
Pediatric Patients with SHOX Deficiency
SHOX deficiency may result either from a deletion of one copy of the short stature homeobox-containing (SHOX) gene or
from a mutation within or outside one copy of the SHOX gene that impairs the production or function of SHOX protein.
A randomized, controlled, two-year, three-arm, open-label study was conducted to evaluate the efficacy of Humatrope
treatment of short stature in pediatric patients with SHOX deficiency who were not GH–deficient. 52 patients (24 male, 28 female)
with SHOX deficiency, 3.0 to 12.3 years of age, were randomized to either a Humatrope-treated arm (27 patients; mean age
7.3 ± 2.1 years) or an untreated control arm (25 patients; mean age 7.5 ± 2.7 years). To determine the comparability of treatment effect
between patients with SHOX deficiency and patients with Turner syndrome, the third study arm enrolled 26 patients with Turner
syndrome, 4.5 to 11.8 years of age (mean age 7.5 ± 1.9 years), to Humatrope treatment. All patients were prepubertal at study entry.
Patients in the Humatrope-treated group(s) received daily subcutaneous injections of 0.05 mg/kg (50 µg/kg) of Humatrope, equivalent
to 0.35 mg/kg/week. Patients in the untreated group received no injections.
Patients with SHOX deficiency who received Humatrope had significantly greater first-year height velocity than untreated
patients (8.7 cm/year vs. 5.2 cm/year, p<0.001, primary efficacy analysis) and similar first-year height velocity to Humatrope-treated
patients with Turner syndrome (8.7 cm/year vs. 8.9 cm/year). In addition, patients who received Humatrope had significantly greater
second year height velocity, and first- and second-year height gain (cm and SDS) than untreated patients (Table 11).
Table 11: Summary of Efficacy Results in Patients with SHOX deficiency and Turner Syndrome
SHOX Deficiency
Turner Syndrome
Untreated
(n=24)
Mean (SD)
Humatrope
(n=27)
Mean (SD)
Treatment
Differencea
Mean (95% CI)
Humatrope
(n=26)
Mean (SD)
Height Velocity (cm/yr)
1st Year
2nd Year
5.2 (1.1)
5.4 (1.2)
8.7 (1.6)b
7.3 (1.1)b
+3.5 (2.8, 4.2)
+2.0 (1.3, 2.6)
8.9 (2.0)
7.0 (1.1)
Height Gain (cm)
Baseline to 1st Year
Baseline to 2nd Year
+5.4 (1.2)
+10.5 (1.9)
+9.1 (1.5)b
+16.4 (2.0)b
+3.7 (2.9, 4.5)
+5.8 (4.6, 7.1)
+8.9 (1.9)
+15.7 (2.7)
Height SDS Gain
Baseline to 1st Year
Baseline to 2nd Year
+0.1 (0.5)
+0.2 (0.5)
+0.7 (0.5)b
+1.2 (0.7)b
+0.5 (0.3, 0.8)
+1.0 (0.7, 1.3)
+0.8 (0.5)
+1.2 (0.7)
Patients with height SDS > -2.0 at 2 years
1 (4%)
11 (41%)c
--
8 (31%)
a Positive values favor Humatrope
b Statistically significantly different from untreated, p<0.001.
c Statistically significantly different from untreated, p<0.05.
14.5
Pediatric Patients Born Small for Gestational Age (SGA) Who Fail to Demonstrate Catch-up Growth by
Age 2 - 4 Years
Data from 2 clinical trials demonstrate the effectiveness of Humatrope in promoting linear growth in short children born SGA
who fail to demonstrate catch-up growth.
The primary objective of Study 1 was to demonstrate that the increase from baseline in height SDS after 1 year of treatment
would be similar when Humatrope is administered according to an individually adjusted dose (IAD) regimen or a fixed high dose
(FHD) regimen. The height increases would be considered similar if the lower bound of the 95% confidence interval (CI) for the mean
difference between the groups (IAD – FHD) was greater than -0.5 height SDS. This 2-year, open-label, multicenter, European study
enrolled 193 prepubertal, non-GH deficient children with mean chronological age 6.8 ± 2.4 years (range: 3.0 to 12.3). Additional
study entry criteria included birth weight <10th percentile and/or birth length SDS <-2 for gestational age, and height SDS for
chronological age ≤-3. Exclusion criteria included syndromal conditions (e.g., Turner syndrome), chronic disease (e.g., diabetes
mellitus), and tumor activity. Children were randomized to either a FHD (0.067 mg/kg/day [0.47 mg/kg/week]; n=99) or an IAD
treatment group (n=94). The initial Humatrope dosage in the IAD treatment group was 0.035 mg/kg/day (0.25 mg/kg/week). The
dosage was increased to 0.067 mg/kg/day in those patients in the IAD group whose 1-year height gain predicted at Month 3 was <0.75
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
height SDS (n=40) or whose actual height gain measured at Year 1 was <0.75 height SDS (n=11). Approximately 85% of the
randomized patients completed 2 years of therapy.
At baseline, the FHD and IAD treatment groups had comparable height SDS (mean -3.9; Table 12). Although the mean 1-year
height increase in the IAD group was statistically significantly lower than that observed in the FHD group, the study achieved its
primary objective by demonstrating that the increase from baseline in height SDS in the IAD group was clinically similar (non
inferior) to that in the FHD group (mean between-group difference = -0.3 SDS [95% CI: -0.4, -0.2 SDS]). The mean changes from
baseline in height SDS at the end of the 2-year study were 1.4 and 1.6 SDS in the IAD and FHD groups, respectively. The results were
similar when children who entered puberty during the study were removed from the analysis.
Table 12: Study 1 – Results for Height SDS and Change from Baseline in Height SDS at Year 1 and Year 2 After Humatrope
Treatment of Short Children Born SGA Who Fail to Demonstrate Catch-up Growtha
IAD Group
0.035 to 0.067 mg/kg/day
Mean (SD)
FHD Group
0.067 mg/kg/day
Mean (SD)
Between-Group
Difference
IAD – FHDb
Baseline
(n=86)
-3.9 (0.6)
(n=93)
-3.9 (0.7)
-0.0 ± 0.1
(-0.2, 0.2)
p-value = 0.95
Year 1
Height SDS
Change from baseline
(n=86)c
-3.0 (0.7)
0.9 (0.4)
(n=93)c
-2.7 (0.7)
1.1 (0.4)
-0.3 ± 0.1
(-0.4, -0.2)
p-value <0.001
Year 2
Height SDS
Change from baseline
(n=82)c
-2.5 (0.8)
1.4 (0.5)
(n=88)c
-2.2 (0.7)
1.6 (0.5)
-0.3 ± 0.1
(-0.4, -0.1)
p-value = 0.003
a Abbreviations: IAD=individually adjusted dose; FHD=fixed high dose; SD=standard deviation; SDS=standard deviation score
b Least squares mean difference ± standard error and 95% confidence interval based on ANCOVA model with treatment and gender as
fixed effects, and baseline height SDS, baseline chronological age, baseline bone age, and mid-parental target height SDS as
covariates.
c Only children with actual height measurements were included in the Year 1 and Year 2 analyses.
Study 2 was an open-label, multicenter, single arm study conducted in France, during which 35 prepubertal, non-GH deficient
children were treated for 2 years with Humatrope 0.067 mg/kg/day (0.47 mg/kg/week). Mean chronological age at baseline was
9.3 ± 0.9 years (range: 6.7 to 10.8). Additional study entry criteria included birth length SDS <-2 or <3rd percentile for gestational
age, and height SDS for chronological age <-2. Exclusion criteria included syndromal conditions (e.g., Turner syndrome), chronic
disease (e.g., diabetes mellitus), and any active disease. All 35 patients completed the study. Mean height SDS increased from a
baseline value of -2.7 (SD 0.5) to -1.5 (SD 0.6) after 2 years of Humatrope treatment.
16
16.1
HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
Vials
Vial Kit — (6s) NDC 0002-7335-16
5 mg vial (no. 7335) and 5-mL vial of Diluent for Humatrope (No. 7336)
Cartridges
Cartridge Kit (MS8147) NDC 0002-8147-01 (gold)
6 mg cartridge (gold) (VL7554), and prefilled syringe of Diluent for Humatrope (VL7618)
Cartridge Kit (MS8148) NDC 0002-8148-01 (teal)
12 mg cartridge (teal) (VL7555), and prefilled syringe of Diluent for Humatrope (VL7619)
16.2
Vials
Cartridge Kit (MS8149) NDC 0002-8149-01 (purple)
24 mg cartridge (purple) (VL7556), and prefilled syringe of Diluent for Humatrope (VL7619)
Storage and Handling
Before Reconstitution — Vials of Humatrope and Diluent for Humatrope are stable when refrigerated at 2° to 8°C
(36° to 46°F). Avoid freezing Diluent for Humatrope. Expiration dates are stated on the labels.
After Reconstitution — Vials of Humatrope are stable for up to 14 days when reconstituted with Diluent for Humatrope or
Bacteriostatic Water for Injection, USP and refrigerated at 2° to 8°C (36° to 46°F). Avoid freezing the reconstituted vial of
Humatrope.
After Reconstitution with Sterile Water, USP — Use only one dose per Humatrope vial and discard the unused portion. If the
solution is not used immediately, it must be refrigerated at 2° to 8°C (36° to 46°F) and used within 24 hours.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18
17
Cartridges
Before Reconstitution — Cartridges of Humatrope and Diluent for Humatrope are stable when refrigerated at 2° to 8°C
(36° to 46°F). Avoid freezing Diluent for Humatrope. Expiration dates are stated on the labels.
After Reconstitution — Cartridges of Humatrope are stable for up to 28 days when reconstituted with Diluent for Humatrope
and refrigerated at 2° to 8°C (36° to 46°F). Store the Humatrope injection device without the needle attached. Avoid freezing the
reconstituted cartridge of Humatrope. Cartridges should be reconstituted only with the supplied diluent. Cartridges should not be
reconstituted with the Diluent for Humatrope provided with Humatrope vials, or with any other solution.
PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling.
Patients being treated with Humatrope (and/or their parents) should be informed about the potential benefits and risks
associated with Humatrope treatment, and the contents of the Patient Information Insert should be reviewed. This information is
intended to educate patients (and caregivers); it is not a disclosure of all possible intended or adverse effects.
Patients and caregivers who will administer Humatrope should receive appropriate training and instruction on the proper use
of Humatrope from the physician or other suitably qualified health care professional. A puncture-resistant container for the disposal of
used needles and syringes should be strongly recommended. Patients and/or parents should be thoroughly instructed in the importance
of proper disposal, and cautioned against any reuse of needles and syringes. This information is intended to aid in the safe and
effective administration of the medication.
Literature revised mm/dd/yyyy
Manufactured by Lilly France
F-67640 Fegersheim, France
for Eli Lilly and Company
Indianapolis, IN 46285, USA
Copyright © XXXX, Eli Lilly and Company. All rights reserved.
0.10 ANL 9325 FSAMP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:34.494792
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019640s068lbl.pdf', 'application_number': 19640, 'submission_type': 'SUPPL ', 'submission_number': 68}
|
11,577
|
1
PA 1646 AMP
HUMATROPE®
SOMATROPIN (rDNA ORIGIN) FOR INJECTION
VIALS and CARTRIDGES
DESCRIPTION
Humatrope® (Somatropin, rDNA Origin, for Injection) is a polypeptide hormone of
recombinant DNA origin. Humatrope has 191 amino acid residues and a molecular weight of
about 22,125 daltons. The amino acid sequence of the product is identical to that of human
growth hormone of pituitary origin. Humatrope is synthesized in a strain of Escherichia coli that
has been modified by the addition of the gene for human growth hormone.
Humatrope is a sterile, white, lyophilized powder intended for subcutaneous or intramuscular
administration after reconstitution. Humatrope is a highly purified preparation. Phosphoric acid
and/or sodium hydroxide may have been added to adjust the pH. Reconstituted solutions have a
pH of approximately 7.5. This product is oxygen sensitive.
VIAL — Each vial of Humatrope contains 5 mg somatropin (15 IU or 225 nanomoles); 25 mg
mannitol; 5 mg glycine; and 1.13 mg dibasic sodium phosphate. Each vial is supplied in a
combination package with an accompanying 5-mL vial of diluting solution. The diluent contains
Water for Injection with 0.3% Metacresol as a preservative and 1.7% glycerin.
CARTRIDGE — The cartridges of somatropin contain either 6 mg (18 IU), 12 mg (36 IU), or
24 mg (72 IU) of somatropin. The 6, 12, and 24 mg cartridges contain respectively: mannitol 18,
36, and 72 mg; glycine 6, 12, and 24 mg; dibasic sodium phosphate 1.36, 2.72, and 5.43 mg.
Each cartridge is supplied in a combination package with an accompanying syringe containing
approximately 3 mL of diluting solution. The diluent contains Water for Injection;
0.3% Metacresol as a preservative; and 1.7%, 0.29%, and 0.29% glycerin in the 6, 12, and 24 mg
cartridges, respectively.
CLINICAL PHARMACOLOGY
General
Linear Growth — Humatrope stimulates linear growth in pediatric patients who lack adequate
normal endogenous growth hormone. In vitro, preclinical, and clinical testing have demonstrated
that Humatrope is therapeutically equivalent to human growth hormone of pituitary origin and
achieves equivalent pharmacokinetic profiles in normal adults. Treatment of growth
hormone-deficient pediatric patients and patients with Turner syndrome with Humatrope
produces increased growth rate and IGF-I (Insulin-like Growth Factor-I/Somatomedin-C)
concentrations similar to those seen after therapy with human growth hormone of pituitary
origin.
In addition, the following actions have been demonstrated for Humatrope and/or human
growth hormone of pituitary origin.
A. Tissue Growth — 1. Skeletal Growth: Humatrope stimulates skeletal growth in pediatric
patients with growth hormone deficiency. The measurable increase in body length after
administration of either Humatrope or human growth hormone of pituitary origin results from an
effect on the growth plates of long bones. Concentrations of IGF-I, which may play a role in
skeletal growth, are low in the serum of growth hormone-deficient pediatric patients but increase
during treatment with Humatrope. Elevations in mean serum alkaline phosphatase concentrations
are also seen. 2. Cell Growth: It has been shown that there are fewer skeletal muscle cells in
short-statured pediatric patients who lack endogenous growth hormone as compared with normal
pediatric populations. Treatment with human growth hormone of pituitary origin results in an
increase in both the number and size of muscle cells.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
B. Protein Metabolism — Linear growth is facilitated in part by increased cellular protein
synthesis. Nitrogen retention, as demonstrated by decreased urinary nitrogen excretion and
serum urea nitrogen, follows the initiation of therapy with human growth hormone of pituitary
origin. Treatment with Humatrope results in a similar decrease in serum urea nitrogen.
C. Carbohydrate Metabolism — Pediatric patients with hypopituitarism sometimes experience
fasting hypoglycemia that is improved by treatment with Humatrope. Large doses of human
growth hormone may impair glucose tolerance. Untreated patients with Turner syndrome have
an increased incidence of glucose intolerance. Administration of human growth hormone to
normal adults or patients with Turner syndrome resulted in increases in mean serum fasting and
postprandial insulin levels although mean values remained in the normal range. In addition,
mean fasting and postprandial glucose and hemoglobin A1c levels remained in the normal range.
D. Lipid Metabolism — In growth hormone-deficient patients, administration of human growth
hormone of pituitary origin has resulted in lipid mobilization, reduction in body fat stores, and
increased plasma fatty acids.
E. Mineral Metabolism — Retention of sodium, potassium, and phosphorus is induced by
human growth hormone of pituitary origin. Serum concentrations of inorganic phosphate
increased in patients with growth hormone deficiency after therapy with Humatrope or human
growth hormone of pituitary origin. Serum calcium is not significantly altered in patients treated
with either human growth hormone of pituitary origin or Humatrope.
Pharmacokinetics
Absorption — Humatrope has been studied following intramuscular, subcutaneous, and
intravenous administration in adult volunteers. The absolute bioavailability of somatropin is 75%
and 63% after subcutaneous and intramuscular administration, respectively.
Distribution — The volume of distribution of somatropin after intravenous injection is about
0.07 L/kg.
Metabolism — Extensive metabolism studies have not been conducted. The metabolic fate of
somatropin involves classical protein catabolism in both the liver and kidneys. In renal cells, at
least a portion of the breakdown products of growth hormone is returned to the systemic
circulation. In normal volunteers, mean clearance is 0.14 L/hr/kg. The mean half-life of
intravenous somatropin is 0.36 hours, whereas subcutaneously and intramuscularly administered
somatropin have mean half-lives of 3.8 and 4.9 hours, respectively. The longer half-life observed
after subcutaneous or intramuscular administration is due to slow absorption from the injection
site.
Excretion — Urinary excretion of intact Humatrope has not been measured. Small amounts of
somatropin have been detected in the urine of pediatric patients following replacement therapy.
Special Populations
Geriatric — The pharmacokinetics of Humatrope has not been studied in patients greater than
65 years of age.
Pediatric — The pharmacokinetics of Humatrope in pediatric patients is similar to adults.
Gender — No studies have been performed with Humatrope. The available literature indicates
that the pharmacokinetics of growth hormone is similar in both men and women.
Race — No data are available.
Renal, Hepatic insufficiency — No studies have been performed with Humatrope.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Table 1
Summary of Somatropin Parameters in the Normal Population
Cmax
(ng/mL)
t1/2
(hr)
AUC0-∞
(ng•hr/mL)
Cls
(L/kg•hr)
Vβ
(L/kg)
0.02 mg (0.05 IU*)/kg
iv
MEAN
415
0.363
156
0.135
0.0703
SD
75
0.053
33
0.029
0.0173
0.1 mg (0.27 IU*)/kg
im
MEAN
53.2
4.93
495
0.215
1.55
SD
25.9
2.66
106
0.047
0.91
0.1 mg (0.27 IU*)/kg
sc
MEAN
63.3
3.81
585
0.179
0.957
SD
18.2
1.40
90
0.028
0.301
Abbreviations: Cmax=maximum concentration; t1/2=half-life; AUC0-∞=area under the curve; Cls=systemic
clearance; Vβ=volume distribution; iv=intravenous; SD=standard deviation; im=intramuscular; sc=subcutaneous.
* Based on previous International Standard of 2.7 IU=1 mg.
Figure 1
1
10
100
1000
Plasma Concentration (ng/mL)
0
6
12
18
Time (hours)
0.02 mg/kg intravenous injection
0.10 mg/kg intramuscular injection
0.1 mg/kg subcutaneous injection
Single Dose Average Plasma Concentrations
vs Time in Normal Adult Volunteers
Mean +/- SE (n=8)
CLINICAL TRIALS
Effects of Humatrope Treatment in Adults with Growth Hormone Deficiency
Two multicenter trials in adult-onset growth hormone deficiency (n=98) and two studies in
childhood-onset growth hormone deficiency (n=67) were designed to assess the effects of
replacement therapy with Humatrope. The primary efficacy measures were body composition
(lean body mass and fat mass), lipid parameters, and the Nottingham Health Profile. The
Nottingham Health Profile is a general health-related quality of life questionnaire. These
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
four studies each included a 6-month randomized, blinded, placebo-controlled phase followed by
12 months of open-label therapy for all patients. The Humatrope dosages for all studies were
identical: 1 month of therapy at 0.00625 mg/kg/day followed by the proposed maintenance dose
of 0.0125 mg/kg/day. Adult-onset patients and childhood-onset patients differed by diagnosis
(organic vs. idiopathic pituitary disease), body size (normal vs. small for mean height and
weight), and age (mean=44 vs. 29 years). Lean body mass was determined by bioelectrical
impedance analysis (BIA), validated with potassium 40. Body fat was assessed by BIA and sum
of skinfold thickness. Lipid subfractions were analyzed by standard assay methods in a central
laboratory.
Humatrope-treated adult-onset patients, as compared to placebo, experienced an increase in
lean body mass (2.59 vs. -0.22 kg, p<0.001) and a decrease in body fat (-3.27 vs. 0.56 kg,
p<0.001). Similar changes were seen in childhood-onset growth hormone-deficient patients.
These significant changes in lean body mass persisted throughout the 18-month period as
compared to baseline for both groups, and for fat mass in the childhood-onset group. Total
cholesterol decreased short-term (first 3 months) although the changes did not persist. However,
the low HDL cholesterol levels observed at baseline (mean=30.1 mg/mL and 33.9 mg/mL in
adult-onset and childhood-onset patients) normalized by the end of 18 months of therapy (a
change of 13.7 and 11.1 mg/dL for the adult-onset and childhood-onset groups, p<0.001).
Adult-onset patients reported significant improvements as compared to placebo in the following
two of six possible health-related domains: physical mobility and social isolation (Table 2).
Patients with childhood-onset disease failed to demonstrate improvements in Nottingham Health
Profile outcomes.
Two additional studies on the effect of Humatrope on exercise capacity were also conducted.
Improved physical function was documented by increased exercise capacity (VO2 max, p<0.005)
and work performance (Watts, p<0.01) (J Clin Endocrinol Metab 1995; 80:552-557).
Two studies evaluating the effect of Humatrope on bone mineralization were subsequently
conducted. In a 2-year, randomized, double-blind, placebo-controlled trial, 67 patients with
previously untreated adult-onset growth hormone (GH) deficiency received placebo or
Humatrope treatment titrated to maintain serum IGF-I within the age-adjusted normal range. In
men, but not women, lumbar spine bone mineral density (BMD) increased with Humatrope
treatment compared to placebo with a treatment difference of approximately 4% (p=0.001).
There was no significant change in hip BMD with Humatrope treatment in men or women, when
compared to placebo. In a 2-year, open-label, randomized trial, 149 patients with
childhood-onset GH deficiency, who had completed pediatric GH therapy, had attained final
height (height velocity <1 cm/yr) and were confirmed to be GH-deficient as young adults
(commonly referred to as transition patients), received Humatrope 12.5 µg/kg/day, Humatrope
25 µg/kg/day, or were followed with no therapy. Patients who were randomized to treatment
with Humatrope at 12.5 µg/kg/day achieved a 2.9% greater increase from baseline than control
in total body bone mineral content (BMC) (8.1 ± 9.0% vs. 5.2 ± 8.2%, p=0.02), whereas patients
treated with Humatrope at 25 µg/kg/day had no significant change in BMC. These results include
data from patients who received less than 2 years of treatment. A greater treatment effect was
observed for patients who completed 2 years of treatment. Increases in lumbar spine BMD and
BMC were also statistically significant compared to control with the 12.5 µg/kg/day dose but not
the 25 µg/kg/day dose. Hip BMD and BMC did not change significantly compared to control
with either dose. The effect of GH treatment on BMC and BMD in transition patients at doses
lower than 12.5 µg/kg/day was not studied. The effect of Humatrope on the occurrence of
osteoporotic fractures has not been studied.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Table 2
Changesa in Nottingham Health Profile Scoresb in Adult-Onset Growth Hormone-Deficient Patients
Outcome
Measure
Placebo
(6 Months)
Humatrope Therapy
(6 Months)
Significance
Energy level
-11.4
-15.5
NS
Physical mobility
-3.1
-10.5
p<0.01
Social isolation
0.5
-4.7
p<0.01
Emotional reactions
-4.5
-5.4
NS
Sleep
-6.4
-3.7
NS
Pain
-2.8
-2.9
NS
a An improvement in score is indicated by a more negative change in the score.
b To account for multiple analyses, appropriate statistical methods were applied and the required level of
significance is 0.01.
NS=not significant.
Effects of Growth Hormone Treatment in Patients with Turner Syndrome
One long-term, randomized, open-label multicenter concurrently controlled study,
two long-term, open-label multicenter, historically controlled studies and one long-term,
randomized, dose-response study were conducted to evaluate the efficacy of growth hormone for
the treatment of patients with short stature due to Turner syndrome.
In the randomized study, GDCT, comparing growth hormone-treated patients to a concurrent
control group who received no growth hormone, the growth hormone-treated patients who
received a dose of 0.3 mg/kg/wk given 6 times per week from a mean age of 11.7 years for a
mean duration of 4.7 years attained a mean near final height of 146.0 ± 6.2 cm (n=27,
mean ± SD) as compared to the control group who attained a near final height of 142.1 ± 4.8 cm
(n=19). By analysis of covariance∗, the effect of growth hormone therapy was a mean height
increase of 5.4 cm (p=0.001).
In two of the studies (85-023 and 85-044), the effect of long-term growth hormone treatment
(0.375 mg/kg/wk given either 3 times per week or daily) on adult height was determined by
comparing adult heights in the treated patients with those of age-matched historical controls with
Turner syndrome who never received any growth-promoting therapy. The greatest improvement
in adult height was observed in patients who received early growth hormone treatment and
estrogen after age 14 years. In Study 85-023, this resulted in a mean adult height gain of 7.4 cm
(mean duration of GH therapy of 7.6 years) vs. matched historical controls by analysis of
covariance.
In Study 85-044, patients treated with early growth hormone therapy were randomized to
receive estrogen replacement therapy (conjugated estrogens, 0.3 mg escalating to 0.625 mg
daily) at either age 12 or 15 years. Compared with matched historical controls, early GH therapy
(mean duration of GH therapy 5.6 years) combined with estrogen replacement at age 12 years
resulted in an adult height gain of 5.9 cm (n=26), whereas patients who initiated estrogen at age
15 years (mean duration of GH therapy 6.1 years) had a mean adult height gain of 8.3 cm (n=29).
Patients who initiated GH therapy after age 11 (mean age 12.7 years; mean duration of
GH therapy 3.8 years) had a mean adult height gain of 5.0 cm (n=51).
In a randomized blinded dose-response study, GDCI, patients were treated from a mean age of
11.1 years for a mean duration of 5.3 years with a weekly dose of either 0.27 mg/kg or
0.36 mg/kg administered 3 or 6 times weekly. The mean near final height of patients receiving
* Analysis of covariance includes adjustments for baseline height relative to age and for
mid-parental height.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
growth hormone was 148.7 ± 6.5 cm (n=31). When compared to historical control data, the mean
gain in adult height was approximately 5 cm.
In some studies, Turner syndrome patients (n=181) treated to final adult height achieved
statistically significant average height gains ranging from 5.0 to 8.3 cm.
Table 3
Summary Table of Efficacy Results
Study/
Group
Study
Designa
N at Adult
Height
GH
Age (yr)
Estrogen
Age (yr)
GH
Duration (yr)
Adult Height
Gain (cm)b
GDCT
RCT
27
11.7
13
4.7
5.4
85-023
MHT
17
9.1
15.2
7.6
7.4
85-044:
A*
MHT
29
9.4
15
6.1
8.3
B*
26
9.6
12.3
5.6
5.9
C*
51
12.7
13.7
3.8
5
GDCI
RDT
31
11.1
8-13.5
5.3
~5c
a RCT: randomized controlled trial; MHT: matched historical controlled trial; RDT: randomized dose-response trial.
b Analysis of covariance vs. controls.
c Compared with historical data.
* A: GH age <11 yr, estrogen age 15 yr.
B: GH age <11 yr, estrogen age 12 yr.
C: GH age >11 yr, estrogen at month 12.
Effect of Humatrope Treatment in Pediatric Patients with Idiopathic Short Stature
Two randomized, multicenter trials, 1 placebo-controlled and 1 dose-response, were conducted
in pediatric patients with idiopathic short stature, also called non-growth hormone-deficient short
stature. The diagnosis of idiopathic short stature was made after excluding other known causes of
short stature, as well as growth hormone deficiency. Limited safety and efficacy data are
available below the age of 7 years. No specific studies have been conducted in pediatric patients
with familial short stature or who were born small for gestational age (SGA).
The placebo-controlled study enrolled 71 pediatric patients (55 males, 16 females) 9 to
15 years old (mean age 12.38 ± 1.51 years), with short stature, 68 of whom received study drug.
Patients were predominately Tanner I (45.1%) and Tanner II (46.5%) at baseline.
In this double-blind trial, patients received subcutaneous injections of either Humatrope
0.222 mg/kg/wk or placebo. Study drug was given in divided doses 3 times per week until height
velocity decreased to ≤1.5 cm/year (“final height”). Thirty-three subjects (22 Humatrope,
11 placebo) had final height measurements after a mean treatment duration of 4.4 years (range
0.11-9.08 years).
The Humatrope group achieved a mean final height Standard Deviation Score (SDS) of
-1.8 (Table 4). Placebo-treated patients had a mean final height SDS of -2.3 (mean treatment
difference = 0.51, p=0.017). Height gain across the duration of the study and final height SDS
minus baseline predicted height SDS were also significantly greater in Humatrope-treated
patients than in placebo-treated patients (Table 4 and 5). In addition, the number of patients who
achieved a final height above the 5th percentile of the general population for age and sex was
significantly greater in the Humatrope group than the placebo group (41% vs. 0%, p<0.05), as
was the number of patients who gained at least 1 SDS unit in height across the duration of the
study (50% vs. 0%, p<0.05).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
Table 4
Baseline Height Characteristics and Effect of Humatrope on Final Heighta
Humatrope
(n=22)
Mean (SD)
Placebo
(n=11)
Mean (SD)
Treatment Effect
Mean
(95% CI)
p-value
Baseline height SDS
-2.7 (0.6)
-2.75 (0.6)
0.77
BPH SDS
-2.1 (0.7)
-2.3 (0.8)
0.53
Final height SDSb
-1.8 (0.8)
-2.3 (0.6)
0.51 (0.10, 0.92)
0.017
FH SDS - baseline height SDS
0.9 (0.7)
0.4 (0.2)
0.51 (0.04, 0.97)
0.034
FH SDS - BPH SDS
0.3 (0.6)
-0.1 (0.6)
0.46 (0.02, 0.89)
0.043
a For final height population.
b Between-group comparison was performed using analysis of covariance with baseline predicted height SDS as the
covariant. Treatment effect is expressed as least squares mean (95% CI).
Abbreviations: FH=final height; SDS=standard deviation score; BPH=baseline predicted height; CI=confidence
interval.
The dose-response study included 239 pediatric patients (158 males, 81 females), 5 to 15 years
old, (mean age 9.8 ± 2.3 years). Mean baseline characteristics included: a height SDS of
-3.21 (±0.70), a predicted adult height SDS of -2.63 (±1.08), and a height velocity SDS of
-1.09 (±1.15). All but 3 patients were Tanner I. Patients were randomized to one of
three Humatrope treatment groups: 0.24 mg/kg/wk; 0.24 mg/kg/wk for 1 year, followed by
0.37 mg/kg/wk; and 0.37 mg/kg/wk.
The primary hypothesis of this study was that treatment with Humatrope would increase height
velocity during the first 2 years of therapy in a dose-dependent manner. Additionally, after
completing the initial 2-year dose-response phase of the study, 50 patients were followed to final
height.
Patients receiving 0.37 mg/kg/wk had a significantly greater increase in mean height velocity
after 2 years of treatment than patients receiving 0.24 mg/kg/wk (4.04 vs. 3.27 cm/year,
p=0.003). The mean difference between final height and baseline predicted height was 7.2 cm for
patients receiving 0.37 mg/kg/wk and 5.4 cm for patients receiving 0.24 mg/kg/wk (Table 5).
While no patient had height above the 5th percentile in any dose group at baseline, 82% of the
patients receiving 0.37 mg/kg/wk and 47% of the patients receiving 0.24 mg/kg/wk achieved a
final height above the 5th percentile of the general population height standards (p=NS).
Table 5
Final Height Minus Baseline Predicted Height: Idiopathic Short Stature Trials
Placebo-controlled Trial
3x per week dosing
Dose Response Trial
6x per week dosing
Placebo
(n=10)
Humatrope
0.22 mg/kg
(n=22)
Humatrope
0.24 mg/kg
(n=13)
Humatrope
0.24/0.37 mg/kg
(n=13)
Humatrope
0.37 mg/kg
(n=13)
FH – Baseline PH
Mean cm
(95% CI)
Mean inches
(95% CI)
-0.7
(-3.6, 2.3)
-0.3
(-1.4, 0.9)
+2.2
(0.4, 3.9)
+0.8
(0.2, 1.5)
+5.4
(2.8, 7.9)
+2.1
(1.1, 3.1)
+6.7
(4.1, 9.2)
+2.6
(1.6, 3.6)
+7.2
(4.6, 9.8)
+2.8
(1.8, 3.9)
Abbreviations: PH=predicted height; FH=final height; CI=confidence interval.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
INDICATIONS AND USAGE
Pediatric Patients — Humatrope is indicated for the long-term treatment of pediatric patients
who have growth failure due to an inadequate secretion of normal endogenous growth hormone.
Humatrope is indicated for the treatment of short stature associated with Turner syndrome in
patients whose epiphyses are not closed.
Humatrope is indicated for the long-term treatment of idiopathic short stature, also called
non-growth hormone-deficient short stature, defined by height SDS ≤-2.25, and associated with
growth rates unlikely to permit attainment of adult height in the normal range, in pediatric
patients whose epiphyses are not closed and for whom diagnostic evaluation excludes other
causes associated with short stature that should be observed or treated by other means.
Adult Patients — Humatrope is indicated for replacement of endogenous growth hormone in
adults with growth hormone deficiency who meet either of the following two criteria:
1. Adult Onset: Patients who have growth hormone deficiency either alone, or with multiple
hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease,
surgery, radiation therapy, or trauma;
or
2. Childhood Onset: Patients who were growth hormone-deficient during childhood who have
growth hormone deficiency confirmed as an adult before replacement therapy with Humatrope is
started.
CONTRAINDICATIONS
Humatrope should not be used for growth promotion in pediatric patients with closed
epiphyses.
Humatrope should not be used or should be discontinued when there is any evidence of active
malignancy. Anti-malignancy treatment must be complete with evidence of remission prior to
the institution of therapy.
Humatrope should not be reconstituted with the supplied Diluent for Humatrope for use by
patients with a known sensitivity to either Metacresol or glycerin.
Growth hormone should not be initiated to treat patients with acute critical illness due to
complications following open heart or abdominal surgery, multiple accidental trauma or to
patients having acute respiratory failure. Two placebo-controlled clinical trials in non-growth
hormone-deficient adult patients (n=522) with these conditions revealed a significant increase in
mortality (41.9% vs. 19.3%) among somatropin-treated patients (doses 5.3 to 8 mg/day)
compared to those receiving placebo (see WARNINGS).
Growth hormone is contraindicated in patients with Prader-Willi syndrome who are severely
obese or have severe respiratory impairment (see WARNINGS). Unless patients with
Prader-Willi syndrome also have a diagnosis of growth hormone deficiency, Humatrope is not
indicated for the long term treatment of pediatric patients who have growth failure due to
genetically confirmed Prader-Willi syndrome.
WARNINGS
If sensitivity to the diluent should occur, the vials may be reconstituted with Bacteriostatic
Water for Injection, USP or, Sterile Water for Injection, USP. When Humatrope is used with
Bacteriostatic Water (Benzyl Alcohol preserved), the solution should be kept refrigerated at
2° to 8°C (36° to 46°F) and used within 14 days. Benzyl alcohol as a preservative in
Bacteriostatic Water for Injection, USP has been associated with toxicity in newborns.
When administering Humatrope to newborns, use the Humatrope diluent provided or if the
patient is sensitive to the diluent, use Sterile Water for Injection, USP. When Humatrope is
reconstituted with Sterile Water for Injection, USP in this manner, use only one dose per
Humatrope vial and discard the unused portion. If the solution is not used immediately, it must
be refrigerated [2° to 8°C (36° to 46°F)] and used within 24 hours.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
Cartridges should be reconstituted only with the supplied diluent. Cartridges should not
be reconstituted with the Diluent for Humatrope provided with Humatrope Vials, or with
any other solution. Cartridges should not be used if the patient is allergic to Metacresol or
glycerin.
See CONTRAINDICATIONS for information on increased mortality in patients with acute
critical illnesses in intensive care units due to complications following open heart or abdominal
surgery, multiple accidental trauma or with acute respiratory failure. The safety of continuing
growth hormone treatment in patients receiving replacement doses for approved indications who
concurrently develop these illnesses has not been established. Therefore, the potential benefit of
treatment continuation with growth hormone in patients having acute critical illnesses should be
weighed against the potential risk.
There have been reports of fatalities after initiating therapy with growth hormone in pediatric
patients with Prader-Willi syndrome who had one or more of the following risk factors: severe
obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection.
Male patients with one or more of these factors may be at greater risk than females. Patients with
Prader-Willi syndrome should be evaluated for signs of upper airway obstruction and sleep
apnea before initiation of treatment with growth hormone. If, during treatment with growth
hormone, patients show signs of upper airway obstruction (including onset of or increased
snoring) and/or new onset sleep apnea, treatment should be interrupted. All patients with
Prader-Willi syndrome treated with growth hormone should also have effective weight control
and be monitored for signs of respiratory infection, which should be diagnosed as early as
possible and treated aggressively (see CONTRAINDICATIONS). Unless patients with
Prader-Willi syndrome also have a diagnosis of growth hormone deficiency, Humatrope is not
indicated for the long term treatment of pediatric patients who have growth failure due to
genetically confirmed Prader-Willi syndrome.
PRECAUTIONS
General — Therapy with Humatrope should be directed by physicians who are experienced in
the diagnosis and management of patients with growth hormone deficiency, Turner syndrome,
idiopathic short stature, or adult patients with either childhood-onset or adult-onset growth
hormone deficiency.
Patients with preexisting tumors or with growth hormone deficiency secondary to an
intracranial lesion should be examined routinely for progression or recurrence of the underlying
disease process. In pediatric patients, clinical literature has demonstrated no relationship between
somatropin replacement therapy and CNS tumor recurrence. In adults, it is unknown whether
there is any relationship between somatropin replacement therapy and CNS tumor recurrence.
Patients should be monitored carefully for any malignant transformation of skin lesions.
For patients with diabetes mellitus, the insulin dose may require adjustment when somatropin
therapy is instituted. Because human growth hormone may induce a state of insulin resistance,
patients should be observed for evidence of glucose intolerance. Patients with diabetes or glucose
intolerance should be monitored closely during somatropin therapy.
In patients with hypopituitarism (multiple hormonal deficiencies) standard hormonal
replacement therapy should be monitored closely when somatropin therapy is administered.
Hypothyroidism may develop during treatment with somatropin and inadequate treatment of
hypothyroidism may prevent optimal response to somatropin.
Pediatric Patients (see General Precautions) — Pediatric patients with endocrine disorders,
including growth hormone deficiency, may develop slipped capital epiphyses more frequently.
Any pediatric patient with the onset of a limp during growth hormone therapy should be
evaluated.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
Growth hormone has not been shown to increase the incidence of scoliosis. Progression of
scoliosis can occur in children who experience rapid growth. Because growth hormone increases
growth rate, patients with a history of scoliosis who are treated with growth hormone should be
monitored for progression of scoliosis. Skeletal abnormalities including scoliosis are commonly
seen in untreated Turner syndrome patients.
Patients with Turner syndrome should be evaluated carefully for otitis media and other ear
disorders since these patients have an increased risk of ear or hearing disorders (see Adverse
Reactions). Patients with Turner syndrome are at risk for cardiovascular disorders (e.g., stroke,
aortic aneurysm, hypertension) and these conditions should be monitored closely.
Patients with Turner syndrome have an inherently increased risk of developing autoimmune
thyroid disease. Therefore, patients should have periodic thyroid function tests and be treated as
indicated (see General Precautions).
Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea and/or
vomiting has been reported in a small number of pediatric patients treated with growth hormone
products. Symptoms usually occurred within the first 8 weeks of the initiation of growth
hormone therapy. In all reported cases, IH-associated signs and symptoms resolved after
termination of therapy or a reduction of the growth hormone dose. Funduscopic examination of
patients is recommended at the initiation and periodically during the course of growth hormone
therapy. Patients with Turner syndrome may be at increased risk for development of IH.
Adult Patients (see General Precautions) — Patients with epiphyseal closure who were treated
with growth hormone replacement therapy in childhood should be re-evaluated according to the
criteria in INDICATIONS AND USAGE before continuation of somatropin therapy at the
reduced dose level recommended for growth hormone-deficient adults.
Experience with prolonged treatment in adults is limited.
Geriatric Use — The safety and effectiveness of Humatrope in patients aged 65 and over has
not been evaluated in clinical studies. Elderly patients may be more sensitive to the action of
Humatrope and may be more prone to develop adverse reactions.
Drug Interactions — Excessive glucocorticoid therapy may prevent optimal response to
somatropin. If glucocorticoid replacement therapy is required, the glucocorticoid dosage and
compliance should be monitored carefully to avoid either adrenal insufficiency or inhibition of
growth promoting effects.
Limited published data indicate that growth hormone (GH) treatment increases
cytochrome P450 (CP450) mediated antipyrine clearance in man. These data suggest that
GH administration may alter the clearance of compounds known to be metabolized by
CP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporin). Careful
monitoring is advisable when GH is administered in combination with other drugs known to be
metabolized by CP450 liver enzymes.
Carcinogenesis, Mutagenesis, Impairment of Fertility — Long-term animal studies for
carcinogenicity and impairment of fertility with this human growth hormone (Humatrope) have
not been performed. There has been no evidence to date of Humatrope-induced mutagenicity.
Pregnancy — Pregnancy Category C — Animal reproduction studies have not been conducted
with Humatrope. It is not known whether Humatrope can cause fetal harm when administered to
a pregnant woman or can affect reproductive capacity. Humatrope should be given to a pregnant
woman only if clearly needed.
Nursing Mothers — There have been no studies conducted with Humatrope in 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 Humatrope is administered to a
nursing woman.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
Information for Patients — Patients being treated with growth hormone and/or their parents
should be informed of the potential risks and benefits associated with treatment. Instructions on
appropriate use should be given, including a review of the contents of the patient information
insert. This information is intended to aid in the safe and effective administration of the
medication. It is not a disclosure of all possible adverse or intended effects.
Patients and/or parents should be thoroughly instructed in the importance of proper needle
disposal. A puncture-resistant container should be used for the disposal of used needles and/or
syringes (consistent with applicable state requirements). Needles and syringes must not be reused
(see Information for the Patient insert).
ADVERSE REACTIONS
Growth Hormone-Deficient Pediatric Patients
As with all protein pharmaceuticals, a small percentage of patients may develop antibodies to
the protein. During the first 6 months of Humatrope therapy in 314 naive patients, only 1.6%
developed specific antibodies to Humatrope (binding capacity ≥0.02 mg/L). None had antibody
concentrations which exceeded 2 mg/L. Throughout 8 years of this same study, two patients
(0.6%) had binding capacity >2 mg/L. Neither patient demonstrated a decrease in growth
velocity at or near the time of increased antibody production. It has been reported that growth
attenuation from pituitary-derived growth hormone may occur when antibody concentrations are
>1.5 mg/L.
In addition to an evaluation of compliance with the treatment program and of thyroid status,
testing for antibodies to human growth hormone should be carried out in any patient who fails to
respond to therapy.
In studies with growth hormone-deficient pediatric patients, injection site pain was reported
infrequently. A mild and transient edema, which appeared in 2.5% of patients, was observed
early during the course of treatment.
Leukemia has been reported in a small number of pediatric patients who have been treated with
growth hormone, including growth hormone of pituitary origin as well as of recombinant
DNA origin (somatrem and somatropin). The relationship, if any, between leukemia and growth
hormone therapy is uncertain.
Turner Syndrome Patients
In a randomized, concurrent controlled trial, there was a statistically significant increase in the
occurrence of otitis media (43% vs. 26%), ear disorders (18% vs. 5%) and surgical procedures
(45% vs. 27%) in patients receiving Humatrope compared with untreated control patients
(Table 6). Other adverse events of special interest to Turner syndrome patients were not
significantly different between treatment groups (Table 6). A similar increase in otitis media was
observed in an 18-month placebo-controlled trial.
Table 6
Treatment-Emergent Events of Special Interest by Treatment Group in Turner Syndrome
Treatment Group
Adverse Event
Overall
hGH1
Untreated2
Significance
Total Number of Patients
136
74
62
Surgical procedure
50 (36.8%)
33 (44.6%)
17 (27.4%)
p≤0.05
Otitis media
48 (35.3%)
32 (43.2%)
16 (25.8%)
p≤0.05
Ear disorders
16 (11.8%)
13 (17.6%)
3 (4.8%)
p≤0.05
Bone disorder
13 (9.6%)
6 (8.1%)
7 (11.3%)
NS
Edema
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
Conjunctival
1 (0.7%)
0
1 (1.6%)
NS
Non-specific
3 (2.2%)
2 (2.7%)
1 (1.6%)
NS
Facial
1 (0.7%)
1 (1.4%)
0
NS
Peripheral
6 (4.4%)
5 (6.8%)
1 (1.6%)
NS
Hyperglycemia
0
0
0
NS
Hypothyroidism
15 (11.0%)
10 (13.5%)
5 (8.1%)
NS
Increased nevi3
10 (7.4%)
8 (10.8%)
2 (3.2%)
NS
Lymphedema
0
0
0
NS
1 Dose=0.3 mg/kg/wk.
2 Open-label study.
3 Includes any nevi coded to the following preferred terms: melanosis, skin hypertrophy, or skin benign neoplasm.
NS=not significant.
Patients with Idiopathic Short Stature
In the placebo-controlled study, the adverse events associated with Humatrope therapy were
similar to those observed in other pediatric populations treated with Humatrope (Table 7). Mean
serum glucose level did not change during Humatrope treatment. Mean fasting serum insulin
levels increased 10% in the Humatrope treatment group at the end of treatment relative to
baseline values but remained within the normal reference range. For the same duration of
treatment the mean fasting serum insulin levels decreased by 2% in the placebo group. The
incidence of above-range values for glucose, insulin, and HbA1c were similar in the growth
hormone and placebo-treated groups. No patient developed diabetes mellitus. Consistent with the
known mechanism of growth hormone action, Humatrope-treated patients had greater mean
increases, relative to baseline, in serum insulin-like growth factor-I (IGF-I) than placebo-treated
patients at each study observation. However, there was no significant difference between the
Humatrope and placebo treatment groups in the proportion of patients who had at least
one serum IGF-I concentration more than 2.0 SD above the age- and gender-appropriate mean
(Humatrope: 9 of 35 patients [26%]; placebo: 7 of 28 patients [25%]).
Table 7
Nonserious Clinically Significant Treatment-Emergent Adverse Events by Treatment
Group in Idiopathic Short Stature
Treatment Group
Adverse Event
Humatrope
Placebo
Total Number of Patients
37
31
Scoliosis
7 (18.9%)
4 (12.9%)
Otitis media
6 (16.2%)
2 (6.5%)
Hyperlipidemia
3 (8.1%)
1 (3.2%)
Gynecomastia
2 (5.4%)
1 (3.2%)
Hypothyroidism
0
2 (6.5%)
Aching joints
0
1 (3.2%)
Hip pain
1 (2.7%)
0
Arthralgia
4 (10.8%)
1 (3.2%)
Arthrosis
4 (10.8%)
2 (6.5%)
Myalgia
9 (24.3%)
4 (12.9%)
Hypertension
1 (2.7%)
0
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
The adverse events observed in the dose-response study (239 patients treated for 2 years) did
not indicate a pattern suggestive of a growth hormone dose effect. Among Humatrope dose
groups, mean fasting blood glucose, mean glycosylated hemoglobin, and the incidence of
elevated fasting blood glucose concentrations were similar. One patient developed abnormalities
of carbohydrate metabolism (glucose intolerance and high serum HbA1c) on treatment.
Adult Patients — In clinical studies in which high doses of Humatrope were administered to
healthy adult volunteers, the following events occurred infrequently: headache, localized muscle
pain, weakness, mild hyperglycemia, and glucosuria.
In the first 6 months of controlled blinded trials during which patients received either
Humatrope or placebo, adult-onset growth hormone-deficient adults who received Humatrope
experienced a statistically significant increase in edema (Humatrope 17.3% vs. placebo 4.4%,
p=0.043) and peripheral edema (11.5% vs. 0%, respectively, p=0.017). In patients with
adult-onset growth hormone deficiency, edema, muscle pain, joint pain, and joint disorder were
reported early in therapy and tended to be transient or responsive to dosage titration.
Two of 113 adult-onset patients developed carpal tunnel syndrome after beginning
maintenance therapy without a low dose (0.00625 mg/kg/day) lead-in phase. Symptoms abated
in these patients after dosage reduction.
All treatment-emergent adverse events with ≥5% overall incidence during 12 or 18 months of
replacement therapy with Humatrope are shown in Table 8 (adult-onset patients) and in Table 9
(childhood-onset patients).
Adult patients treated with Humatrope who had been diagnosed with growth hormone
deficiency in childhood reported side effects less frequently than those with adult-onset growth
hormone deficiency.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
Table 8
Treatment-Emergent Adverse Events with ≥5% Overall Incidence in Adult-Onset Growth
Hormone-Deficient Patients Treated with Humatrope for 18 Months as Compared with 6-Month
Placebo and 12-Month Humatrope Exposure
18 Months Exposure
[Placebo (6 Months)/hGH (12 Months)]
(N=46)
18 Months hGH Exposure
(N=52)
Adverse Event
n
%
n
%
Edemaa
7
15.2
11
21.2
Arthralgia
7
15.2
9
17.3
Paresthesia
6
13.0
9
17.3
Myalgia
6
13.0
7
13.5
Pain
6
13.0
7
13.5
Rhinitis
5
10.9
7
13.5
Peripheral edemab
8
17.4
6
11.5
Back pain
5
10.9
5
9.6
Headache
5
10.9
4
7.7
Hypertension
2
4.3
4
7.7
Acne
0
0
3
5.8
Joint disorder
1
2.2
3
5.8
Surgical procedure
1
2.2
3
5.8
Flu syndrome
3
6.5
2
3.9
Abbreviations: hGH=Humatrope; N=number of patients receiving treatment in the period stated; n=number of
patients reporting each treatment-emergent adverse event.
a p=0.04 as compared to placebo (6 months).
b p=0.02 as compared to placebo (6 months).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
Table 9
Treatment-Emergent Adverse Events with ≥5% Overall Incidence in Childhood-Onset Growth
Hormone-Deficient Patients Treated with Humatrope for 18 Months as Compared with 6-Month
Placebo and 12-Month Humatrope Exposure
18 Months Exposure
[Placebo (6 Months)/hGH (12 Months)]
(N=35)
18 Months hGH Exposure
(N=32)
Adverse Event
n
%
n
%
Flu syndrome
8
22.9
5
15.6
AST increaseda
2
5.7
4
12.5
Headache
4
11.4
3
9.4
Asthenia
1
2.9
2
6.3
Cough increased
0
0
2
6.3
Edema
3
8.6
2
6.3
Hypesthesia
0
0
2
6.3
Myalgia
2
5.7
2
6.3
Pain
3
8.6
2
6.3
Rhinitis
2
5.7
2
6.3
ALT increased
2
5.7
2
6.3
Respiratory disorder
2
5.7
1
3.1
Gastritis
2
5.7
0
0
Pharyngitis
5
14.3
1
3.1
Abbreviations: hGH=Humatrope; N=number of patients receiving treatment in the period stated; n=number of
patients reporting each treatment-emergent adverse event; ALT=alanine amino transferase, formerly SGPT;
AST=aspartate amino transferase, formerly SGOT.
a p=0.03 as compared to placebo (6 months).
Other adverse drug events that have been reported in growth hormone-treated patients include
the following:
1) Metabolic: Infrequent, mild and transient peripheral or generalized edema.
2) Musculoskeletal: Rare carpal tunnel syndrome.
3) Skin: Rare increased growth of pre-existing nevi. Patients should be monitored carefully
for malignant transformation.
4) Endocrine: Rare gynecomastia. Rare pancreatitis.
OVERDOSAGE
Acute overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia.
Long-term overdosage could result in signs and symptoms of gigantism/acromegaly consistent
with the known effects of excess human growth hormone. (See recommended and maximal
dosage instructions given below.)
DOSAGE AND ADMINISTRATION
Pediatric Patients
The Humatrope dosage and administration schedule should be individualized for each patient.
Therapy should not be continued if epiphyseal fusion has occurred. Response to growth hormone
therapy tends to decrease with time. However, failure to increase growth rate, particularly during
the first year of therapy, should prompt close assessment of compliance and evaluation of other
causes of growth failure such as hypothyroidism, under-nutrition and advanced bone age.
Growth hormone-deficient pediatric patients — The recommended weekly dosage is
0.18 mg/kg (0.54 IU/kg) of body weight. The maximal replacement weekly dosage is
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
0.3 mg/kg (0.90 IU/kg) of body weight. It should be divided into equal doses given either on
3 alternate days, 6 times per week or daily. The subcutaneous route of administration is
preferable; intramuscular injection is also acceptable. The dosage and administration schedule
for Humatrope should be individualized for each patient.
Turner Syndrome — A weekly dosage of up to 0.375 mg/kg (1.125 IU/kg) of body weight
administered by subcutaneous injection is recommended. It should be divided into equal doses
given either daily or on 3 alternate days.
Patients with idiopathic short stature — A weekly dosage of up to 0.37 mg/kg of body weight
administered by subcutaneous injection is recommended. It should be divided into equal doses
given 6 to 7 times per week.
Adult Patients
Growth hormone-deficient adult patients — The recommended dosage at the start of therapy is
not more than 0.006 mg/kg/day (0.018 IU/kg/day) given as a daily subcutaneous injection. The
dose may be increased according to individual patient requirements to a maximum of
0.0125 mg/kg/day (0.0375 IU/kg/day).
During therapy, dosage should be titrated if required by the occurrence of side effects or to
maintain the IGF-I response below the upper limit of normal IGF-I levels, matched for age and
sex. To minimize the occurrence of adverse events in patients with increasing age or excessive
body weight, dose reductions may be necessary.
Reconstitution
Vial — Each 5-mg vial of Humatrope should be reconstituted with 1.5 to 5 mL of Diluent for
Humatrope. The diluent should be injected into the vial of Humatrope by aiming the stream of
liquid against the glass wall. Following reconstitution, the vial should be swirled with a
GENTLE rotary motion until the contents are completely dissolved. DO NOT SHAKE. The
resulting solution should be inspected for clarity. It should be clear. If the solution is cloudy or
contains particulate matter, the contents MUST NOT be injected.
Before and after injection, the septum of the vial should be wiped with rubbing alcohol or an
alcoholic antiseptic solution to prevent contamination of the contents by repeated needle
insertions. Sterile disposable syringes and needles should be used for administration of
Humatrope. The volume of the syringe should be small enough so that the prescribed dose can be
withdrawn from the vial with reasonable accuracy.
Cartridge — Each cartridge of Humatrope should only be reconstituted using the diluent
syringe that accompanies the cartridge and should not be reconstituted with the Diluent for
Humatrope provided with Humatrope Vials. (See WARNINGS section.) See Information for
the Patient for comprehensive directions on Humatrope cartridge reconstitution.
The reconstituted solution should be inspected for clarity. It should be clear. If the solution is
cloudy or contains particulate matter, the contents MUST NOT be injected.
The somatropin concentrations for the reconstituted Humatrope cartridges are as follows:
2.08 mg/mL for the 6 mg cartridge; 4.17 mg/mL for the 12 mg cartridge; and 8.33 mg/mL for the
24 mg cartridge.
This cartridge has been designed for use only with the Humatrope injection device. A sterile
disposable needle should be used for each injection of Humatrope.
STABILITY AND STORAGE
Vials
Before Reconstitution — Vials of Humatrope and Diluent for Humatrope are stable when
refrigerated [2° to 8°C (36° to 46°F)]. Avoid freezing Diluent for Humatrope. Expiration dates
are stated on the labels.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
After Reconstitution — Vials of Humatrope are stable for up to 14 days when reconstituted
with Diluent for Humatrope or Bacteriostatic Water for Injection, USP and stored in a
refrigerator at 2° to 8°C (36° to 46°F). Avoid freezing the reconstituted vial of Humatrope.
After Reconstitution with Sterile Water, USP — Use only one dose per Humatrope vial and
discard the unused portion. If the solution is not used immediately, it must be refrigerated
[2° to 8°C (36° to 46°F)] and used within 24 hours.
Cartridges
Before Reconstitution — Cartridges of Humatrope and Diluent for Humatrope are stable when
refrigerated [2° to 8°C (36° to 46°F)]. Avoid freezing Diluent for Humatrope. Expiration dates
are stated on the labels.
After Reconstitution — Cartridges of Humatrope are stable for up to 28 days when
reconstituted with Diluent for Humatrope and stored in a refrigerator at 2° to 8°C (36° to 46°F).
Store the Humatrope injection device without the needle attached. Avoid freezing the
reconstituted cartridge of Humatrope.
HOW SUPPLIED
Vials
5 mg (No. 7335) — (6s) NDC 0002-7335-16, and 5-mL vials of Diluent for Humatrope
(No. 7336)
Cartridges
Cartridge Kit (MS8147) NDC 0002-8147-01
6 mg cartridge (VL7554), and prefilled syringe of Diluent for Humatrope (VL7618)
Cartridge Kit (MS8148) NDC 0002-8148-01
12 mg cartridge (VL7555), and prefilled syringe of Diluent for Humatrope (VL7619)
Cartridge Kit (MS8149) NDC 0002-8149-01
24 mg cartridge (VL7556), and prefilled syringe of Diluent for Humatrope (VL7619)
Literature revised October 13, 2005
Eli Lilly and Company, Indianapolis, IN 46285, USA
www.humatrope.com
PA 1646 AMP
PRINTED IN USA
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
1
PA 1646 AMP
HUMATROPE®
SOMATROPIN (rDNA ORIGIN) FOR INJECTION
VIALS and CARTRIDGES
DESCRIPTION
Humatrope® (Somatropin, rDNA Origin, for Injection) is a polypeptide hormone of
recombinant DNA origin. Humatrope has 191 amino acid residues and a molecular weight of
about 22,125 daltons. The amino acid sequence of the product is identical to that of human
growth hormone of pituitary origin. Humatrope is synthesized in a strain of Escherichia coli that
has been modified by the addition of the gene for human growth hormone.
Humatrope is a sterile, white, lyophilized powder intended for subcutaneous or intramuscular
administration after reconstitution. Humatrope is a highly purified preparation. Phosphoric acid
and/or sodium hydroxide may have been added to adjust the pH. Reconstituted solutions have a
pH of approximately 7.5. This product is oxygen sensitive.
VIAL — Each vial of Humatrope contains 5 mg somatropin (15 IU or 225 nanomoles); 25 mg
mannitol; 5 mg glycine; and 1.13 mg dibasic sodium phosphate. Each vial is supplied in a
combination package with an accompanying 5-mL vial of diluting solution. The diluent contains
Water for Injection with 0.3% Metacresol as a preservative and 1.7% glycerin.
CARTRIDGE — The cartridges of somatropin contain either 6 mg (18 IU), 12 mg (36 IU), or
24 mg (72 IU) of somatropin. The 6, 12, and 24 mg cartridges contain respectively: mannitol 18,
36, and 72 mg; glycine 6, 12, and 24 mg; dibasic sodium phosphate 1.36, 2.72, and 5.43 mg.
Each cartridge is supplied in a combination package with an accompanying syringe containing
approximately 3 mL of diluting solution. The diluent contains Water for Injection;
0.3% Metacresol as a preservative; and 1.7%, 0.29%, and 0.29% glycerin in the 6, 12, and 24 mg
cartridges, respectively.
CLINICAL PHARMACOLOGY
General
Linear Growth — Humatrope stimulates linear growth in pediatric patients who lack adequate
normal endogenous growth hormone. In vitro, preclinical, and clinical testing have demonstrated
that Humatrope is therapeutically equivalent to human growth hormone of pituitary origin and
achieves equivalent pharmacokinetic profiles in normal adults. Treatment of growth
hormone-deficient pediatric patients and patients with Turner syndrome with Humatrope
produces increased growth rate and IGF-I (Insulin-like Growth Factor-I/Somatomedin-C)
concentrations similar to those seen after therapy with human growth hormone of pituitary
origin.
In addition, the following actions have been demonstrated for Humatrope and/or human
growth hormone of pituitary origin.
A. Tissue Growth — 1. Skeletal Growth: Humatrope stimulates skeletal growth in pediatric
patients with growth hormone deficiency. The measurable increase in body length after
administration of either Humatrope or human growth hormone of pituitary origin results from an
effect on the growth plates of long bones. Concentrations of IGF-I, which may play a role in
skeletal growth, are low in the serum of growth hormone-deficient pediatric patients but increase
during treatment with Humatrope. Elevations in mean serum alkaline phosphatase concentrations
are also seen. 2. Cell Growth: It has been shown that there are fewer skeletal muscle cells in
short-statured pediatric patients who lack endogenous growth hormone as compared with normal
pediatric populations. Treatment with human growth hormone of pituitary origin results in an
increase in both the number and size of muscle cells.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
B. Protein Metabolism — Linear growth is facilitated in part by increased cellular protein
synthesis. Nitrogen retention, as demonstrated by decreased urinary nitrogen excretion and
serum urea nitrogen, follows the initiation of therapy with human growth hormone of pituitary
origin. Treatment with Humatrope results in a similar decrease in serum urea nitrogen.
C. Carbohydrate Metabolism — Pediatric patients with hypopituitarism sometimes experience
fasting hypoglycemia that is improved by treatment with Humatrope. Large doses of human
growth hormone may impair glucose tolerance. Untreated patients with Turner syndrome have
an increased incidence of glucose intolerance. Administration of human growth hormone to
normal adults or patients with Turner syndrome resulted in increases in mean serum fasting and
postprandial insulin levels although mean values remained in the normal range. In addition,
mean fasting and postprandial glucose and hemoglobin A1c levels remained in the normal range.
D. Lipid Metabolism — In growth hormone-deficient patients, administration of human growth
hormone of pituitary origin has resulted in lipid mobilization, reduction in body fat stores, and
increased plasma fatty acids.
E. Mineral Metabolism — Retention of sodium, potassium, and phosphorus is induced by
human growth hormone of pituitary origin. Serum concentrations of inorganic phosphate
increased in patients with growth hormone deficiency after therapy with Humatrope or human
growth hormone of pituitary origin. Serum calcium is not significantly altered in patients treated
with either human growth hormone of pituitary origin or Humatrope.
Pharmacokinetics
Absorption — Humatrope has been studied following intramuscular, subcutaneous, and
intravenous administration in adult volunteers. The absolute bioavailability of somatropin is 75%
and 63% after subcutaneous and intramuscular administration, respectively.
Distribution — The volume of distribution of somatropin after intravenous injection is about
0.07 L/kg.
Metabolism — Extensive metabolism studies have not been conducted. The metabolic fate of
somatropin involves classical protein catabolism in both the liver and kidneys. In renal cells, at
least a portion of the breakdown products of growth hormone is returned to the systemic
circulation. In normal volunteers, mean clearance is 0.14 L/hr/kg. The mean half-life of
intravenous somatropin is 0.36 hours, whereas subcutaneously and intramuscularly administered
somatropin have mean half-lives of 3.8 and 4.9 hours, respectively. The longer half-life observed
after subcutaneous or intramuscular administration is due to slow absorption from the injection
site.
Excretion — Urinary excretion of intact Humatrope has not been measured. Small amounts of
somatropin have been detected in the urine of pediatric patients following replacement therapy.
Special Populations
Geriatric — The pharmacokinetics of Humatrope has not been studied in patients greater than
65 years of age.
Pediatric — The pharmacokinetics of Humatrope in pediatric patients is similar to adults.
Gender — No studies have been performed with Humatrope. The available literature indicates
that the pharmacokinetics of growth hormone is similar in both men and women.
Race — No data are available.
Renal, Hepatic insufficiency — No studies have been performed with Humatrope.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Table 1
Summary of Somatropin Parameters in the Normal Population
Cmax
(ng/mL)
t1/2
(hr)
AUC0-∞
(ng•hr/mL)
Cls
(L/kg•hr)
Vβ
(L/kg)
0.02 mg (0.05 IU*)/kg
iv
MEAN
415
0.363
156
0.135
0.0703
SD
75
0.053
33
0.029
0.0173
0.1 mg (0.27 IU*)/kg
im
MEAN
53.2
4.93
495
0.215
1.55
SD
25.9
2.66
106
0.047
0.91
0.1 mg (0.27 IU*)/kg
sc
MEAN
63.3
3.81
585
0.179
0.957
SD
18.2
1.40
90
0.028
0.301
Abbreviations: Cmax=maximum concentration; t1/2=half-life; AUC0-∞=area under the curve; Cls=systemic
clearance; Vβ=volume distribution; iv=intravenous; SD=standard deviation; im=intramuscular; sc=subcutaneous.
* Based on previous International Standard of 2.7 IU=1 mg.
Figure 1
1
10
100
1000
Plasma Concentration (ng/mL)
0
6
12
18
Time (hours)
0.02 mg/kg intravenous injection
0.10 mg/kg intramuscular injection
0.1 mg/kg subcutaneous injection
Single Dose Average Plasma Concentrations
vs Time in Normal Adult Volunteers
Mean +/- SE (n=8)
CLINICAL TRIALS
Effects of Humatrope Treatment in Adults with Growth Hormone Deficiency
Two multicenter trials in adult-onset growth hormone deficiency (n=98) and two studies in
childhood-onset growth hormone deficiency (n=67) were designed to assess the effects of
replacement therapy with Humatrope. The primary efficacy measures were body composition
(lean body mass and fat mass), lipid parameters, and the Nottingham Health Profile. The
Nottingham Health Profile is a general health-related quality of life questionnaire. These
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
four studies each included a 6-month randomized, blinded, placebo-controlled phase followed by
12 months of open-label therapy for all patients. The Humatrope dosages for all studies were
identical: 1 month of therapy at 0.00625 mg/kg/day followed by the proposed maintenance dose
of 0.0125 mg/kg/day. Adult-onset patients and childhood-onset patients differed by diagnosis
(organic vs. idiopathic pituitary disease), body size (normal vs. small for mean height and
weight), and age (mean=44 vs. 29 years). Lean body mass was determined by bioelectrical
impedance analysis (BIA), validated with potassium 40. Body fat was assessed by BIA and sum
of skinfold thickness. Lipid subfractions were analyzed by standard assay methods in a central
laboratory.
Humatrope-treated adult-onset patients, as compared to placebo, experienced an increase in
lean body mass (2.59 vs. -0.22 kg, p<0.001) and a decrease in body fat (-3.27 vs. 0.56 kg,
p<0.001). Similar changes were seen in childhood-onset growth hormone-deficient patients.
These significant changes in lean body mass persisted throughout the 18-month period as
compared to baseline for both groups, and for fat mass in the childhood-onset group. Total
cholesterol decreased short-term (first 3 months) although the changes did not persist. However,
the low HDL cholesterol levels observed at baseline (mean=30.1 mg/mL and 33.9 mg/mL in
adult-onset and childhood-onset patients) normalized by the end of 18 months of therapy (a
change of 13.7 and 11.1 mg/dL for the adult-onset and childhood-onset groups, p<0.001).
Adult-onset patients reported significant improvements as compared to placebo in the following
two of six possible health-related domains: physical mobility and social isolation (Table 2).
Patients with childhood-onset disease failed to demonstrate improvements in Nottingham Health
Profile outcomes.
Two additional studies on the effect of Humatrope on exercise capacity were also conducted.
Improved physical function was documented by increased exercise capacity (VO2 max, p<0.005)
and work performance (Watts, p<0.01) (J Clin Endocrinol Metab 1995; 80:552-557).
Two studies evaluating the effect of Humatrope on bone mineralization were subsequently
conducted. In a 2-year, randomized, double-blind, placebo-controlled trial, 67 patients with
previously untreated adult-onset growth hormone (GH) deficiency received placebo or
Humatrope treatment titrated to maintain serum IGF-I within the age-adjusted normal range. In
men, but not women, lumbar spine bone mineral density (BMD) increased with Humatrope
treatment compared to placebo with a treatment difference of approximately 4% (p=0.001).
There was no significant change in hip BMD with Humatrope treatment in men or women, when
compared to placebo. In a 2-year, open-label, randomized trial, 149 patients with
childhood-onset GH deficiency, who had completed pediatric GH therapy, had attained final
height (height velocity <1 cm/yr) and were confirmed to be GH-deficient as young adults
(commonly referred to as transition patients), received Humatrope 12.5 µg/kg/day, Humatrope
25 µg/kg/day, or were followed with no therapy. Patients who were randomized to treatment
with Humatrope at 12.5 µg/kg/day achieved a 2.9% greater increase from baseline than control
in total body bone mineral content (BMC) (8.1 ± 9.0% vs. 5.2 ± 8.2%, p=0.02), whereas patients
treated with Humatrope at 25 µg/kg/day had no significant change in BMC. These results include
data from patients who received less than 2 years of treatment. A greater treatment effect was
observed for patients who completed 2 years of treatment. Increases in lumbar spine BMD and
BMC were also statistically significant compared to control with the 12.5 µg/kg/day dose but not
the 25 µg/kg/day dose. Hip BMD and BMC did not change significantly compared to control
with either dose. The effect of GH treatment on BMC and BMD in transition patients at doses
lower than 12.5 µg/kg/day was not studied. The effect of Humatrope on the occurrence of
osteoporotic fractures has not been studied.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Table 2
Changesa in Nottingham Health Profile Scoresb in Adult-Onset Growth Hormone-Deficient Patients
Outcome
Measure
Placebo
(6 Months)
Humatrope Therapy
(6 Months)
Significance
Energy level
-11.4
-15.5
NS
Physical mobility
-3.1
-10.5
p<0.01
Social isolation
0.5
-4.7
p<0.01
Emotional reactions
-4.5
-5.4
NS
Sleep
-6.4
-3.7
NS
Pain
-2.8
-2.9
NS
a An improvement in score is indicated by a more negative change in the score.
b To account for multiple analyses, appropriate statistical methods were applied and the required level of
significance is 0.01.
NS=not significant.
Effects of Growth Hormone Treatment in Patients with Turner Syndrome
One long-term, randomized, open-label multicenter concurrently controlled study,
two long-term, open-label multicenter, historically controlled studies and one long-term,
randomized, dose-response study were conducted to evaluate the efficacy of growth hormone for
the treatment of patients with short stature due to Turner syndrome.
In the randomized study, GDCT, comparing growth hormone-treated patients to a concurrent
control group who received no growth hormone, the growth hormone-treated patients who
received a dose of 0.3 mg/kg/wk given 6 times per week from a mean age of 11.7 years for a
mean duration of 4.7 years attained a mean near final height of 146.0 ± 6.2 cm (n=27,
mean ± SD) as compared to the control group who attained a near final height of 142.1 ± 4.8 cm
(n=19). By analysis of covariance∗, the effect of growth hormone therapy was a mean height
increase of 5.4 cm (p=0.001).
In two of the studies (85-023 and 85-044), the effect of long-term growth hormone treatment
(0.375 mg/kg/wk given either 3 times per week or daily) on adult height was determined by
comparing adult heights in the treated patients with those of age-matched historical controls with
Turner syndrome who never received any growth-promoting therapy. The greatest improvement
in adult height was observed in patients who received early growth hormone treatment and
estrogen after age 14 years. In Study 85-023, this resulted in a mean adult height gain of 7.4 cm
(mean duration of GH therapy of 7.6 years) vs. matched historical controls by analysis of
covariance.
In Study 85-044, patients treated with early growth hormone therapy were randomized to
receive estrogen replacement therapy (conjugated estrogens, 0.3 mg escalating to 0.625 mg
daily) at either age 12 or 15 years. Compared with matched historical controls, early GH therapy
(mean duration of GH therapy 5.6 years) combined with estrogen replacement at age 12 years
resulted in an adult height gain of 5.9 cm (n=26), whereas patients who initiated estrogen at age
15 years (mean duration of GH therapy 6.1 years) had a mean adult height gain of 8.3 cm (n=29).
Patients who initiated GH therapy after age 11 (mean age 12.7 years; mean duration of
GH therapy 3.8 years) had a mean adult height gain of 5.0 cm (n=51).
In a randomized blinded dose-response study, GDCI, patients were treated from a mean age of
11.1 years for a mean duration of 5.3 years with a weekly dose of either 0.27 mg/kg or
0.36 mg/kg administered 3 or 6 times weekly. The mean near final height of patients receiving
* Analysis of covariance includes adjustments for baseline height relative to age and for
mid-parental height.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
growth hormone was 148.7 ± 6.5 cm (n=31). When compared to historical control data, the mean
gain in adult height was approximately 5 cm.
In some studies, Turner syndrome patients (n=181) treated to final adult height achieved
statistically significant average height gains ranging from 5.0 to 8.3 cm.
Table 3
Summary Table of Efficacy Results
Study/
Group
Study
Designa
N at Adult
Height
GH
Age (yr)
Estrogen
Age (yr)
GH
Duration (yr)
Adult Height
Gain (cm)b
GDCT
RCT
27
11.7
13
4.7
5.4
85-023
MHT
17
9.1
15.2
7.6
7.4
85-044:
A*
MHT
29
9.4
15
6.1
8.3
B*
26
9.6
12.3
5.6
5.9
C*
51
12.7
13.7
3.8
5
GDCI
RDT
31
11.1
8-13.5
5.3
~5c
a RCT: randomized controlled trial; MHT: matched historical controlled trial; RDT: randomized dose-response trial.
b Analysis of covariance vs. controls.
c Compared with historical data.
* A: GH age <11 yr, estrogen age 15 yr.
B: GH age <11 yr, estrogen age 12 yr.
C: GH age >11 yr, estrogen at month 12.
Effect of Humatrope Treatment in Pediatric Patients with Idiopathic Short Stature
Two randomized, multicenter trials, 1 placebo-controlled and 1 dose-response, were conducted
in pediatric patients with idiopathic short stature, also called non-growth hormone-deficient short
stature. The diagnosis of idiopathic short stature was made after excluding other known causes of
short stature, as well as growth hormone deficiency. Limited safety and efficacy data are
available below the age of 7 years. No specific studies have been conducted in pediatric patients
with familial short stature or who were born small for gestational age (SGA).
The placebo-controlled study enrolled 71 pediatric patients (55 males, 16 females) 9 to
15 years old (mean age 12.38 ± 1.51 years), with short stature, 68 of whom received study drug.
Patients were predominately Tanner I (45.1%) and Tanner II (46.5%) at baseline.
In this double-blind trial, patients received subcutaneous injections of either Humatrope
0.222 mg/kg/wk or placebo. Study drug was given in divided doses 3 times per week until height
velocity decreased to ≤1.5 cm/year (“final height”). Thirty-three subjects (22 Humatrope,
11 placebo) had final height measurements after a mean treatment duration of 4.4 years (range
0.11-9.08 years).
The Humatrope group achieved a mean final height Standard Deviation Score (SDS) of
-1.8 (Table 4). Placebo-treated patients had a mean final height SDS of -2.3 (mean treatment
difference = 0.51, p=0.017). Height gain across the duration of the study and final height SDS
minus baseline predicted height SDS were also significantly greater in Humatrope-treated
patients than in placebo-treated patients (Table 4 and 5). In addition, the number of patients who
achieved a final height above the 5th percentile of the general population for age and sex was
significantly greater in the Humatrope group than the placebo group (41% vs. 0%, p<0.05), as
was the number of patients who gained at least 1 SDS unit in height across the duration of the
study (50% vs. 0%, p<0.05).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
Table 4
Baseline Height Characteristics and Effect of Humatrope on Final Heighta
Humatrope
(n=22)
Mean (SD)
Placebo
(n=11)
Mean (SD)
Treatment Effect
Mean
(95% CI)
p-value
Baseline height SDS
-2.7 (0.6)
-2.75 (0.6)
0.77
BPH SDS
-2.1 (0.7)
-2.3 (0.8)
0.53
Final height SDSb
-1.8 (0.8)
-2.3 (0.6)
0.51 (0.10, 0.92)
0.017
FH SDS - baseline height SDS
0.9 (0.7)
0.4 (0.2)
0.51 (0.04, 0.97)
0.034
FH SDS - BPH SDS
0.3 (0.6)
-0.1 (0.6)
0.46 (0.02, 0.89)
0.043
a For final height population.
b Between-group comparison was performed using analysis of covariance with baseline predicted height SDS as the
covariant. Treatment effect is expressed as least squares mean (95% CI).
Abbreviations: FH=final height; SDS=standard deviation score; BPH=baseline predicted height; CI=confidence
interval.
The dose-response study included 239 pediatric patients (158 males, 81 females), 5 to 15 years
old, (mean age 9.8 ± 2.3 years). Mean baseline characteristics included: a height SDS of
-3.21 (±0.70), a predicted adult height SDS of -2.63 (±1.08), and a height velocity SDS of
-1.09 (±1.15). All but 3 patients were Tanner I. Patients were randomized to one of
three Humatrope treatment groups: 0.24 mg/kg/wk; 0.24 mg/kg/wk for 1 year, followed by
0.37 mg/kg/wk; and 0.37 mg/kg/wk.
The primary hypothesis of this study was that treatment with Humatrope would increase height
velocity during the first 2 years of therapy in a dose-dependent manner. Additionally, after
completing the initial 2-year dose-response phase of the study, 50 patients were followed to final
height.
Patients receiving 0.37 mg/kg/wk had a significantly greater increase in mean height velocity
after 2 years of treatment than patients receiving 0.24 mg/kg/wk (4.04 vs. 3.27 cm/year,
p=0.003). The mean difference between final height and baseline predicted height was 7.2 cm for
patients receiving 0.37 mg/kg/wk and 5.4 cm for patients receiving 0.24 mg/kg/wk (Table 5).
While no patient had height above the 5th percentile in any dose group at baseline, 82% of the
patients receiving 0.37 mg/kg/wk and 47% of the patients receiving 0.24 mg/kg/wk achieved a
final height above the 5th percentile of the general population height standards (p=NS).
Table 5
Final Height Minus Baseline Predicted Height: Idiopathic Short Stature Trials
Placebo-controlled Trial
3x per week dosing
Dose Response Trial
6x per week dosing
Placebo
(n=10)
Humatrope
0.22 mg/kg
(n=22)
Humatrope
0.24 mg/kg
(n=13)
Humatrope
0.24/0.37 mg/kg
(n=13)
Humatrope
0.37 mg/kg
(n=13)
FH – Baseline PH
Mean cm
(95% CI)
Mean inches
(95% CI)
-0.7
(-3.6, 2.3)
-0.3
(-1.4, 0.9)
+2.2
(0.4, 3.9)
+0.8
(0.2, 1.5)
+5.4
(2.8, 7.9)
+2.1
(1.1, 3.1)
+6.7
(4.1, 9.2)
+2.6
(1.6, 3.6)
+7.2
(4.6, 9.8)
+2.8
(1.8, 3.9)
Abbreviations: PH=predicted height; FH=final height; CI=confidence interval.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
INDICATIONS AND USAGE
Pediatric Patients — Humatrope is indicated for the long-term treatment of pediatric patients
who have growth failure due to an inadequate secretion of normal endogenous growth hormone.
Humatrope is indicated for the treatment of short stature associated with Turner syndrome in
patients whose epiphyses are not closed.
Humatrope is indicated for the long-term treatment of idiopathic short stature, also called
non-growth hormone-deficient short stature, defined by height SDS ≤-2.25, and associated with
growth rates unlikely to permit attainment of adult height in the normal range, in pediatric
patients whose epiphyses are not closed and for whom diagnostic evaluation excludes other
causes associated with short stature that should be observed or treated by other means.
Adult Patients — Humatrope is indicated for replacement of endogenous growth hormone in
adults with growth hormone deficiency who meet either of the following two criteria:
1. Adult Onset: Patients who have growth hormone deficiency either alone, or with multiple
hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease,
surgery, radiation therapy, or trauma;
or
2. Childhood Onset: Patients who were growth hormone-deficient during childhood who have
growth hormone deficiency confirmed as an adult before replacement therapy with Humatrope is
started.
CONTRAINDICATIONS
Humatrope should not be used for growth promotion in pediatric patients with closed
epiphyses.
Humatrope should not be used or should be discontinued when there is any evidence of active
malignancy. Anti-malignancy treatment must be complete with evidence of remission prior to
the institution of therapy.
Humatrope should not be reconstituted with the supplied Diluent for Humatrope for use by
patients with a known sensitivity to either Metacresol or glycerin.
Growth hormone should not be initiated to treat patients with acute critical illness due to
complications following open heart or abdominal surgery, multiple accidental trauma or to
patients having acute respiratory failure. Two placebo-controlled clinical trials in non-growth
hormone-deficient adult patients (n=522) with these conditions revealed a significant increase in
mortality (41.9% vs. 19.3%) among somatropin-treated patients (doses 5.3 to 8 mg/day)
compared to those receiving placebo (see WARNINGS).
Growth hormone is contraindicated in patients with Prader-Willi syndrome who are severely
obese or have severe respiratory impairment (see WARNINGS). Unless patients with
Prader-Willi syndrome also have a diagnosis of growth hormone deficiency, Humatrope is not
indicated for the long term treatment of pediatric patients who have growth failure due to
genetically confirmed Prader-Willi syndrome.
WARNINGS
If sensitivity to the diluent should occur, the vials may be reconstituted with Bacteriostatic
Water for Injection, USP or, Sterile Water for Injection, USP. When Humatrope is used with
Bacteriostatic Water (Benzyl Alcohol preserved), the solution should be kept refrigerated at
2° to 8°C (36° to 46°F) and used within 14 days. Benzyl alcohol as a preservative in
Bacteriostatic Water for Injection, USP has been associated with toxicity in newborns.
When administering Humatrope to newborns, use the Humatrope diluent provided or if the
patient is sensitive to the diluent, use Sterile Water for Injection, USP. When Humatrope is
reconstituted with Sterile Water for Injection, USP in this manner, use only one dose per
Humatrope vial and discard the unused portion. If the solution is not used immediately, it must
be refrigerated [2° to 8°C (36° to 46°F)] and used within 24 hours.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
Cartridges should be reconstituted only with the supplied diluent. Cartridges should not
be reconstituted with the Diluent for Humatrope provided with Humatrope Vials, or with
any other solution. Cartridges should not be used if the patient is allergic to Metacresol or
glycerin.
See CONTRAINDICATIONS for information on increased mortality in patients with acute
critical illnesses in intensive care units due to complications following open heart or abdominal
surgery, multiple accidental trauma or with acute respiratory failure. The safety of continuing
growth hormone treatment in patients receiving replacement doses for approved indications who
concurrently develop these illnesses has not been established. Therefore, the potential benefit of
treatment continuation with growth hormone in patients having acute critical illnesses should be
weighed against the potential risk.
There have been reports of fatalities after initiating therapy with growth hormone in pediatric
patients with Prader-Willi syndrome who had one or more of the following risk factors: severe
obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection.
Male patients with one or more of these factors may be at greater risk than females. Patients with
Prader-Willi syndrome should be evaluated for signs of upper airway obstruction and sleep
apnea before initiation of treatment with growth hormone. If, during treatment with growth
hormone, patients show signs of upper airway obstruction (including onset of or increased
snoring) and/or new onset sleep apnea, treatment should be interrupted. All patients with
Prader-Willi syndrome treated with growth hormone should also have effective weight control
and be monitored for signs of respiratory infection, which should be diagnosed as early as
possible and treated aggressively (see CONTRAINDICATIONS). Unless patients with
Prader-Willi syndrome also have a diagnosis of growth hormone deficiency, Humatrope is not
indicated for the long term treatment of pediatric patients who have growth failure due to
genetically confirmed Prader-Willi syndrome.
PRECAUTIONS
General — Therapy with Humatrope should be directed by physicians who are experienced in
the diagnosis and management of patients with growth hormone deficiency, Turner syndrome,
idiopathic short stature, or adult patients with either childhood-onset or adult-onset growth
hormone deficiency.
Patients with preexisting tumors or with growth hormone deficiency secondary to an
intracranial lesion should be examined routinely for progression or recurrence of the underlying
disease process. In pediatric patients, clinical literature has demonstrated no relationship between
somatropin replacement therapy and CNS tumor recurrence. In adults, it is unknown whether
there is any relationship between somatropin replacement therapy and CNS tumor recurrence.
Patients should be monitored carefully for any malignant transformation of skin lesions.
For patients with diabetes mellitus, the insulin dose may require adjustment when somatropin
therapy is instituted. Because human growth hormone may induce a state of insulin resistance,
patients should be observed for evidence of glucose intolerance. Patients with diabetes or glucose
intolerance should be monitored closely during somatropin therapy.
In patients with hypopituitarism (multiple hormonal deficiencies) standard hormonal
replacement therapy should be monitored closely when somatropin therapy is administered.
Hypothyroidism may develop during treatment with somatropin and inadequate treatment of
hypothyroidism may prevent optimal response to somatropin.
Pediatric Patients (see General Precautions) — Pediatric patients with endocrine disorders,
including growth hormone deficiency, may develop slipped capital epiphyses more frequently.
Any pediatric patient with the onset of a limp during growth hormone therapy should be
evaluated.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
Growth hormone has not been shown to increase the incidence of scoliosis. Progression of
scoliosis can occur in children who experience rapid growth. Because growth hormone increases
growth rate, patients with a history of scoliosis who are treated with growth hormone should be
monitored for progression of scoliosis. Skeletal abnormalities including scoliosis are commonly
seen in untreated Turner syndrome patients.
Patients with Turner syndrome should be evaluated carefully for otitis media and other ear
disorders since these patients have an increased risk of ear or hearing disorders (see Adverse
Reactions). Patients with Turner syndrome are at risk for cardiovascular disorders (e.g., stroke,
aortic aneurysm, hypertension) and these conditions should be monitored closely.
Patients with Turner syndrome have an inherently increased risk of developing autoimmune
thyroid disease. Therefore, patients should have periodic thyroid function tests and be treated as
indicated (see General Precautions).
Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea and/or
vomiting has been reported in a small number of pediatric patients treated with growth hormone
products. Symptoms usually occurred within the first 8 weeks of the initiation of growth
hormone therapy. In all reported cases, IH-associated signs and symptoms resolved after
termination of therapy or a reduction of the growth hormone dose. Funduscopic examination of
patients is recommended at the initiation and periodically during the course of growth hormone
therapy. Patients with Turner syndrome may be at increased risk for development of IH.
Adult Patients (see General Precautions) — Patients with epiphyseal closure who were treated
with growth hormone replacement therapy in childhood should be re-evaluated according to the
criteria in INDICATIONS AND USAGE before continuation of somatropin therapy at the
reduced dose level recommended for growth hormone-deficient adults.
Experience with prolonged treatment in adults is limited.
Geriatric Use — The safety and effectiveness of Humatrope in patients aged 65 and over has
not been evaluated in clinical studies. Elderly patients may be more sensitive to the action of
Humatrope and may be more prone to develop adverse reactions.
Drug Interactions — Excessive glucocorticoid therapy may prevent optimal response to
somatropin. If glucocorticoid replacement therapy is required, the glucocorticoid dosage and
compliance should be monitored carefully to avoid either adrenal insufficiency or inhibition of
growth promoting effects.
Limited published data indicate that growth hormone (GH) treatment increases
cytochrome P450 (CP450) mediated antipyrine clearance in man. These data suggest that
GH administration may alter the clearance of compounds known to be metabolized by
CP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporin). Careful
monitoring is advisable when GH is administered in combination with other drugs known to be
metabolized by CP450 liver enzymes.
Carcinogenesis, Mutagenesis, Impairment of Fertility — Long-term animal studies for
carcinogenicity and impairment of fertility with this human growth hormone (Humatrope) have
not been performed. There has been no evidence to date of Humatrope-induced mutagenicity.
Pregnancy — Pregnancy Category C — Animal reproduction studies have not been conducted
with Humatrope. It is not known whether Humatrope can cause fetal harm when administered to
a pregnant woman or can affect reproductive capacity. Humatrope should be given to a pregnant
woman only if clearly needed.
Nursing Mothers — There have been no studies conducted with Humatrope in 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 Humatrope is administered to a
nursing woman.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
Information for Patients — Patients being treated with growth hormone and/or their parents
should be informed of the potential risks and benefits associated with treatment. Instructions on
appropriate use should be given, including a review of the contents of the patient information
insert. This information is intended to aid in the safe and effective administration of the
medication. It is not a disclosure of all possible adverse or intended effects.
Patients and/or parents should be thoroughly instructed in the importance of proper needle
disposal. A puncture-resistant container should be used for the disposal of used needles and/or
syringes (consistent with applicable state requirements). Needles and syringes must not be reused
(see Information for the Patient insert).
ADVERSE REACTIONS
Growth Hormone-Deficient Pediatric Patients
As with all protein pharmaceuticals, a small percentage of patients may develop antibodies to
the protein. During the first 6 months of Humatrope therapy in 314 naive patients, only 1.6%
developed specific antibodies to Humatrope (binding capacity ≥0.02 mg/L). None had antibody
concentrations which exceeded 2 mg/L. Throughout 8 years of this same study, two patients
(0.6%) had binding capacity >2 mg/L. Neither patient demonstrated a decrease in growth
velocity at or near the time of increased antibody production. It has been reported that growth
attenuation from pituitary-derived growth hormone may occur when antibody concentrations are
>1.5 mg/L.
In addition to an evaluation of compliance with the treatment program and of thyroid status,
testing for antibodies to human growth hormone should be carried out in any patient who fails to
respond to therapy.
In studies with growth hormone-deficient pediatric patients, injection site pain was reported
infrequently. A mild and transient edema, which appeared in 2.5% of patients, was observed
early during the course of treatment.
Leukemia has been reported in a small number of pediatric patients who have been treated with
growth hormone, including growth hormone of pituitary origin as well as of recombinant
DNA origin (somatrem and somatropin). The relationship, if any, between leukemia and growth
hormone therapy is uncertain.
Turner Syndrome Patients
In a randomized, concurrent controlled trial, there was a statistically significant increase in the
occurrence of otitis media (43% vs. 26%), ear disorders (18% vs. 5%) and surgical procedures
(45% vs. 27%) in patients receiving Humatrope compared with untreated control patients
(Table 6). Other adverse events of special interest to Turner syndrome patients were not
significantly different between treatment groups (Table 6). A similar increase in otitis media was
observed in an 18-month placebo-controlled trial.
Table 6
Treatment-Emergent Events of Special Interest by Treatment Group in Turner Syndrome
Treatment Group
Adverse Event
Overall
hGH1
Untreated2
Significance
Total Number of Patients
136
74
62
Surgical procedure
50 (36.8%)
33 (44.6%)
17 (27.4%)
p≤0.05
Otitis media
48 (35.3%)
32 (43.2%)
16 (25.8%)
p≤0.05
Ear disorders
16 (11.8%)
13 (17.6%)
3 (4.8%)
p≤0.05
Bone disorder
13 (9.6%)
6 (8.1%)
7 (11.3%)
NS
Edema
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
Conjunctival
1 (0.7%)
0
1 (1.6%)
NS
Non-specific
3 (2.2%)
2 (2.7%)
1 (1.6%)
NS
Facial
1 (0.7%)
1 (1.4%)
0
NS
Peripheral
6 (4.4%)
5 (6.8%)
1 (1.6%)
NS
Hyperglycemia
0
0
0
NS
Hypothyroidism
15 (11.0%)
10 (13.5%)
5 (8.1%)
NS
Increased nevi3
10 (7.4%)
8 (10.8%)
2 (3.2%)
NS
Lymphedema
0
0
0
NS
1 Dose=0.3 mg/kg/wk.
2 Open-label study.
3 Includes any nevi coded to the following preferred terms: melanosis, skin hypertrophy, or skin benign neoplasm.
NS=not significant.
Patients with Idiopathic Short Stature
In the placebo-controlled study, the adverse events associated with Humatrope therapy were
similar to those observed in other pediatric populations treated with Humatrope (Table 7). Mean
serum glucose level did not change during Humatrope treatment. Mean fasting serum insulin
levels increased 10% in the Humatrope treatment group at the end of treatment relative to
baseline values but remained within the normal reference range. For the same duration of
treatment the mean fasting serum insulin levels decreased by 2% in the placebo group. The
incidence of above-range values for glucose, insulin, and HbA1c were similar in the growth
hormone and placebo-treated groups. No patient developed diabetes mellitus. Consistent with the
known mechanism of growth hormone action, Humatrope-treated patients had greater mean
increases, relative to baseline, in serum insulin-like growth factor-I (IGF-I) than placebo-treated
patients at each study observation. However, there was no significant difference between the
Humatrope and placebo treatment groups in the proportion of patients who had at least
one serum IGF-I concentration more than 2.0 SD above the age- and gender-appropriate mean
(Humatrope: 9 of 35 patients [26%]; placebo: 7 of 28 patients [25%]).
Table 7
Nonserious Clinically Significant Treatment-Emergent Adverse Events by Treatment
Group in Idiopathic Short Stature
Treatment Group
Adverse Event
Humatrope
Placebo
Total Number of Patients
37
31
Scoliosis
7 (18.9%)
4 (12.9%)
Otitis media
6 (16.2%)
2 (6.5%)
Hyperlipidemia
3 (8.1%)
1 (3.2%)
Gynecomastia
2 (5.4%)
1 (3.2%)
Hypothyroidism
0
2 (6.5%)
Aching joints
0
1 (3.2%)
Hip pain
1 (2.7%)
0
Arthralgia
4 (10.8%)
1 (3.2%)
Arthrosis
4 (10.8%)
2 (6.5%)
Myalgia
9 (24.3%)
4 (12.9%)
Hypertension
1 (2.7%)
0
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
The adverse events observed in the dose-response study (239 patients treated for 2 years) did
not indicate a pattern suggestive of a growth hormone dose effect. Among Humatrope dose
groups, mean fasting blood glucose, mean glycosylated hemoglobin, and the incidence of
elevated fasting blood glucose concentrations were similar. One patient developed abnormalities
of carbohydrate metabolism (glucose intolerance and high serum HbA1c) on treatment.
Adult Patients — In clinical studies in which high doses of Humatrope were administered to
healthy adult volunteers, the following events occurred infrequently: headache, localized muscle
pain, weakness, mild hyperglycemia, and glucosuria.
In the first 6 months of controlled blinded trials during which patients received either
Humatrope or placebo, adult-onset growth hormone-deficient adults who received Humatrope
experienced a statistically significant increase in edema (Humatrope 17.3% vs. placebo 4.4%,
p=0.043) and peripheral edema (11.5% vs. 0%, respectively, p=0.017). In patients with
adult-onset growth hormone deficiency, edema, muscle pain, joint pain, and joint disorder were
reported early in therapy and tended to be transient or responsive to dosage titration.
Two of 113 adult-onset patients developed carpal tunnel syndrome after beginning
maintenance therapy without a low dose (0.00625 mg/kg/day) lead-in phase. Symptoms abated
in these patients after dosage reduction.
All treatment-emergent adverse events with ≥5% overall incidence during 12 or 18 months of
replacement therapy with Humatrope are shown in Table 8 (adult-onset patients) and in Table 9
(childhood-onset patients).
Adult patients treated with Humatrope who had been diagnosed with growth hormone
deficiency in childhood reported side effects less frequently than those with adult-onset growth
hormone deficiency.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
Table 8
Treatment-Emergent Adverse Events with ≥5% Overall Incidence in Adult-Onset Growth
Hormone-Deficient Patients Treated with Humatrope for 18 Months as Compared with 6-Month
Placebo and 12-Month Humatrope Exposure
18 Months Exposure
[Placebo (6 Months)/hGH (12 Months)]
(N=46)
18 Months hGH Exposure
(N=52)
Adverse Event
n
%
n
%
Edemaa
7
15.2
11
21.2
Arthralgia
7
15.2
9
17.3
Paresthesia
6
13.0
9
17.3
Myalgia
6
13.0
7
13.5
Pain
6
13.0
7
13.5
Rhinitis
5
10.9
7
13.5
Peripheral edemab
8
17.4
6
11.5
Back pain
5
10.9
5
9.6
Headache
5
10.9
4
7.7
Hypertension
2
4.3
4
7.7
Acne
0
0
3
5.8
Joint disorder
1
2.2
3
5.8
Surgical procedure
1
2.2
3
5.8
Flu syndrome
3
6.5
2
3.9
Abbreviations: hGH=Humatrope; N=number of patients receiving treatment in the period stated; n=number of
patients reporting each treatment-emergent adverse event.
a p=0.04 as compared to placebo (6 months).
b p=0.02 as compared to placebo (6 months).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
Table 9
Treatment-Emergent Adverse Events with ≥5% Overall Incidence in Childhood-Onset Growth
Hormone-Deficient Patients Treated with Humatrope for 18 Months as Compared with 6-Month
Placebo and 12-Month Humatrope Exposure
18 Months Exposure
[Placebo (6 Months)/hGH (12 Months)]
(N=35)
18 Months hGH Exposure
(N=32)
Adverse Event
n
%
n
%
Flu syndrome
8
22.9
5
15.6
AST increaseda
2
5.7
4
12.5
Headache
4
11.4
3
9.4
Asthenia
1
2.9
2
6.3
Cough increased
0
0
2
6.3
Edema
3
8.6
2
6.3
Hypesthesia
0
0
2
6.3
Myalgia
2
5.7
2
6.3
Pain
3
8.6
2
6.3
Rhinitis
2
5.7
2
6.3
ALT increased
2
5.7
2
6.3
Respiratory disorder
2
5.7
1
3.1
Gastritis
2
5.7
0
0
Pharyngitis
5
14.3
1
3.1
Abbreviations: hGH=Humatrope; N=number of patients receiving treatment in the period stated; n=number of
patients reporting each treatment-emergent adverse event; ALT=alanine amino transferase, formerly SGPT;
AST=aspartate amino transferase, formerly SGOT.
a p=0.03 as compared to placebo (6 months).
Other adverse drug events that have been reported in growth hormone-treated patients include
the following:
1) Metabolic: Infrequent, mild and transient peripheral or generalized edema.
2) Musculoskeletal: Rare carpal tunnel syndrome.
3) Skin: Rare increased growth of pre-existing nevi. Patients should be monitored carefully
for malignant transformation.
4) Endocrine: Rare gynecomastia. Rare pancreatitis.
OVERDOSAGE
Acute overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia.
Long-term overdosage could result in signs and symptoms of gigantism/acromegaly consistent
with the known effects of excess human growth hormone. (See recommended and maximal
dosage instructions given below.)
DOSAGE AND ADMINISTRATION
Pediatric Patients
The Humatrope dosage and administration schedule should be individualized for each patient.
Therapy should not be continued if epiphyseal fusion has occurred. Response to growth hormone
therapy tends to decrease with time. However, failure to increase growth rate, particularly during
the first year of therapy, should prompt close assessment of compliance and evaluation of other
causes of growth failure such as hypothyroidism, under-nutrition and advanced bone age.
Growth hormone-deficient pediatric patients — The recommended weekly dosage is
0.18 mg/kg (0.54 IU/kg) of body weight. The maximal replacement weekly dosage is
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
0.3 mg/kg (0.90 IU/kg) of body weight. It should be divided into equal doses given either on
3 alternate days, 6 times per week or daily. The subcutaneous route of administration is
preferable; intramuscular injection is also acceptable. The dosage and administration schedule
for Humatrope should be individualized for each patient.
Turner Syndrome — A weekly dosage of up to 0.375 mg/kg (1.125 IU/kg) of body weight
administered by subcutaneous injection is recommended. It should be divided into equal doses
given either daily or on 3 alternate days.
Patients with idiopathic short stature — A weekly dosage of up to 0.37 mg/kg of body weight
administered by subcutaneous injection is recommended. It should be divided into equal doses
given 6 to 7 times per week.
Adult Patients
Growth hormone-deficient adult patients — The recommended dosage at the start of therapy is
not more than 0.006 mg/kg/day (0.018 IU/kg/day) given as a daily subcutaneous injection. The
dose may be increased according to individual patient requirements to a maximum of
0.0125 mg/kg/day (0.0375 IU/kg/day).
During therapy, dosage should be titrated if required by the occurrence of side effects or to
maintain the IGF-I response below the upper limit of normal IGF-I levels, matched for age and
sex. To minimize the occurrence of adverse events in patients with increasing age or excessive
body weight, dose reductions may be necessary.
Reconstitution
Vial — Each 5-mg vial of Humatrope should be reconstituted with 1.5 to 5 mL of Diluent for
Humatrope. The diluent should be injected into the vial of Humatrope by aiming the stream of
liquid against the glass wall. Following reconstitution, the vial should be swirled with a
GENTLE rotary motion until the contents are completely dissolved. DO NOT SHAKE. The
resulting solution should be inspected for clarity. It should be clear. If the solution is cloudy or
contains particulate matter, the contents MUST NOT be injected.
Before and after injection, the septum of the vial should be wiped with rubbing alcohol or an
alcoholic antiseptic solution to prevent contamination of the contents by repeated needle
insertions. Sterile disposable syringes and needles should be used for administration of
Humatrope. The volume of the syringe should be small enough so that the prescribed dose can be
withdrawn from the vial with reasonable accuracy.
Cartridge — Each cartridge of Humatrope should only be reconstituted using the diluent
syringe that accompanies the cartridge and should not be reconstituted with the Diluent for
Humatrope provided with Humatrope Vials. (See WARNINGS section.) See Information for
the Patient for comprehensive directions on Humatrope cartridge reconstitution.
The reconstituted solution should be inspected for clarity. It should be clear. If the solution is
cloudy or contains particulate matter, the contents MUST NOT be injected.
The somatropin concentrations for the reconstituted Humatrope cartridges are as follows:
2.08 mg/mL for the 6 mg cartridge; 4.17 mg/mL for the 12 mg cartridge; and 8.33 mg/mL for the
24 mg cartridge.
This cartridge has been designed for use only with the Humatrope injection device. A sterile
disposable needle should be used for each injection of Humatrope.
STABILITY AND STORAGE
Vials
Before Reconstitution — Vials of Humatrope and Diluent for Humatrope are stable when
refrigerated [2° to 8°C (36° to 46°F)]. Avoid freezing Diluent for Humatrope. Expiration dates
are stated on the labels.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
After Reconstitution — Vials of Humatrope are stable for up to 14 days when reconstituted
with Diluent for Humatrope or Bacteriostatic Water for Injection, USP and stored in a
refrigerator at 2° to 8°C (36° to 46°F). Avoid freezing the reconstituted vial of Humatrope.
After Reconstitution with Sterile Water, USP — Use only one dose per Humatrope vial and
discard the unused portion. If the solution is not used immediately, it must be refrigerated
[2° to 8°C (36° to 46°F)] and used within 24 hours.
Cartridges
Before Reconstitution — Cartridges of Humatrope and Diluent for Humatrope are stable when
refrigerated [2° to 8°C (36° to 46°F)]. Avoid freezing Diluent for Humatrope. Expiration dates
are stated on the labels.
After Reconstitution — Cartridges of Humatrope are stable for up to 28 days when
reconstituted with Diluent for Humatrope and stored in a refrigerator at 2° to 8°C (36° to 46°F).
Store the Humatrope injection device without the needle attached. Avoid freezing the
reconstituted cartridge of Humatrope.
HOW SUPPLIED
Vials
5 mg (No. 7335) — (6s) NDC 0002-7335-16, and 5-mL vials of Diluent for Humatrope
(No. 7336)
Cartridges
Cartridge Kit (MS8147) NDC 0002-8147-01
6 mg cartridge (VL7554), and prefilled syringe of Diluent for Humatrope (VL7618)
Cartridge Kit (MS8148) NDC 0002-8148-01
12 mg cartridge (VL7555), and prefilled syringe of Diluent for Humatrope (VL7619)
Cartridge Kit (MS8149) NDC 0002-8149-01
24 mg cartridge (VL7556), and prefilled syringe of Diluent for Humatrope (VL7619)
Literature revised October 13, 2005
Eli Lilly and Company, Indianapolis, IN 46285, USA
www.humatrope.com
PA 1646 AMP
PRINTED IN USA
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ENGINEER'S APPROVAL
D-1290-LE02
Finishing Line No.:
Approved by:
Date:
Baxter Pharmaceuticals
Tonjalee Miller
09-05-03
D-1290-LBO2
Approved by:
Date:
BKGD ID
Roger W. Wetzel
3-7-05
Item Code:
Colors:
COLOR ID
WG 4140 AMX
For use with
6 mg
cartridge only
Sterile Diluent
for
Humatrope®
somatropin (rDNA origin)
for injection
Rx only
MAY REFRIGERATE OR
STORE AT ROOM TEMPERATURE
Do Not Freeze
NDC 0002-7618-01
VL 7618
Exp. Date/Control No.
WG 4140 AMX
• For injection with the Humatrope® (somatropin
[rDNA origin] for injection) pen injection device.
• Contains: Water for Injection with 0.3% Metacresol
as a preservative and 1.7% Glycerin.
Mfg. by Baxter Pharmaceutical Solutions LLC
Bloomington, IN 47403, USA for
Eli Lilly and Company, Indianapolis, IN 46285, USA
BLACK
1055 WHITE
COATING
WG 4140 AMX
D-1290-LB02
D-1290-LE02
(01)10300027618019
Die No.:
KC Drawing No:
View:
D-1290
N/A
Printed Side Up
DIE ID
Proofreader:
Label Editor
or Label Editor Asst:
Printing
Quality Control:
Date:
Date:
Date:
Graphics Operator:
Date:
LILLY APPROVALS
VENDOR APPROVALS
Production Order Number:
Scanner
Code:
Item Number:
Production Engineering:
Date:
FINAL OK
OK FOR
PRODUCTION(copy only)
Client Services:
Date:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
(b)(4)
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
1
Humatrope®
Model MS8050
somatropin (rDNA origin)
for injection
HumatroPen
Injection Device For Use With Humatrope® Cartridges
If you have questions, call 1-800-847-6988
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
HumatroPen
Package
(When first opened)
Blue protective storage case
HumatroPen Injection Device and storage case
HumatroPen User Guide
a
Please fold out to reference the diagrams for the HumatroPen
Injection Device.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
b
† Sold separately by prescription as part of the Humatrope® Cartridge Kit.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Accessories Sold Separately
Additional supplies you will need before using the HumatroPen (all sold separately) are:
Humatrope Cartridge Kit
(6, 12, or 24 mg quantity) as
prescribed by your healthcare
professional.
Alcohol swab
c
Becton, Dickinson and Company pen needles are suitable for use with the
HumatroPen
.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
If you have questions, call 1-800-847-6988
Contents
PA 9184 FSAMP
Introduction
! HumatroPen Package
X
! HumatroPen and Cartridge Elements
X
! Accessories Sold Separately
X
! Introducing the HumatroPen Injection Device
X
! Introduction
X
Important Notes
! Maintenance and Care of the HumatroPen
X
! Storage of the HumatroPen
X
! Terms and Definitions
X
! Features
X
Step-by-Step Instructions
! Steps for Using the HumatroPen Injection Device
XX
Helpful Information
! Replacing a Cartridge
XX
! Injection Site Chart
XX
! Determining the Humatrope Dose
XX
! Conversion Chart
XX
! Commonly Asked Questions
XX
! Troubleshooting Tips
XX
Replacement of the HumatroPen
XX
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
Humatrope®
somatropin (rDNA origin)
for injection
Introducing the HumatroPen
Injection Device
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
If you have questions, call 1-800-847-6988
Introduction
This booklet is the User Guide for the HumatroPen Injection Device. Before using the
HumatroPen, please read this User Guide thoroughly. Keep this important guide for
future reference. Your healthcare professional has told you the Humatrope® dose that you
or your child should receive. DO NOT change this dose unless directed by your
healthcare professional. If you have any questions about the HumatroPen Injection
Device, please call Eli Lilly and Company at 1-800-847-6988 or visit
www.humatrope.com.
WARNING: DO NOT USE THE HUMATROPEN INJECTION DEVICE AND
HUMATROPE CARTRIDGES IF YOU ARE ALLERGIC TO METACRESOL OR
GLYCERIN.
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
Humatrope®
somatropin (rDNA origin)
for injection
Important Notes
The HumatroPen is not recommended for use by blind or visually impaired individuals
without the assistance of a sighted individual trained in its use.
Maintenance and Care of the HumatroPen
! The pen requires no maintenance.
! Soiled parts can be cleaned with a damp cloth. Do not use alcohol or other
cleaning agents.
! Protect the pen and case from moisture especially when transporting in a cooler.
! For the cleaning of the HumatroPen Injection Device, the body of the HumatroPen
may be wiped with a cloth slightly dampened with water. DO NOT IMMERSE
THE HUMATROPEN IN WATER.
! The case is not watertight and will not protect the pen if immersed.
! Do not soak or immerse the pen in liquid.
! Do not apply oil or other lubricant.
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
If you have questions, call 1-800-847-6988
Storage of the HumatroPen
! All Humatrope cartridges and diluent must be refrigerated at temperatures
between +2° and +8°C (36° and 46°F). DO NOT FREEZE. A prepared cartridge
can be left on a pen for 28 days in the refrigerator. If any reconstituted product
remains after 28 days, it should be discarded.
! While traveling, daily room temperature exposure should not exceed 30 minutes.
! Use a new needle for each injection. Do not store the pen with needle attached.
This could cause liquid to leak, air bubbles to form, or growth hormone crystals to
clog the needle.
! Pen should be stored with dosage knob in locked position.
! Discomfort may be noticed at the injection site if Humatrope is given cold. Let
Humatrope stand at room temperature for 10 minutes before injecting.
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
Humatrope®
somatropin (rDNA origin)
for injection
Terms and Definitions
It may be helpful to refer to the fold-out diagrams on the inside front cover of this
booklet, page X, as you review these terms.
Dosage knob - The cylindrical knob extending from the end of the HumatroPen that
turns to dial the dosage setting of Humatrope. The arrow marked on the flat end of
the dosage knob indicates the direction in which the knob is turned to dial the dose.
Dosage knob click - The slight sharp noise that is heard and the snap felt when the
dosage knob is turned.
Dosage setting - The numbers that appear in the digital display window and
correspond to the number of dosage knob clicks. The dosage setting you dial should
be calculated by your healthcare professional to correspond to the prescribed
Humatrope dose. The chart on page XX illustrates the relationship between the
Humatrope dose and the HumatroPen dosage setting.
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
If you have questions, call 1-800-847-6988
Humatrope cartridge - A sealed container of Humatrope powder that attaches to
the HumatroPen. Humatrope is mixed directly in the cartridge and stored there.
Cartridges are available in three (3) Humatrope quantities: 6 mg, 12 mg, and 24 mg.
Reconstitution - The mixing of diluent (liquid) with the Humatrope powder in
order to make it injectable. Reconstituted Humatrope must be refrigerated and used
within 28 days.
Release button - The white button on the opposite side of the HumatroPen from the
digital display window. Pressing the white release button unlocks the dosage knob.
Reset button - The blue ridged button on the slanted area near the digital display
window. The blue reset button allows you to dial the dosage knob backward. Note
that when the dosage knob is turned backward, no clicking sound is heard.
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
Humatrope®
somatropin (rDNA origin)
for injection
† Humatrope Cartridges sold separately by prescription as part of the Humatrope
Cartridge Kit.
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
If you have questions, call 1-800-847-6988
Features
The HumatroPen Injection Device system is:
! Convenient - One (1) injection device that can be used with any one of three (3)
Humatrope cartridges (6 mg, 12 mg, and 24 mg).
! Versatile - Your healthcare professional can adjust the dose in either 0.1, 0.2, or
0.4 mg increments depending on the strength of reconstituted Humatrope in the
cartridge.
! Stable - Once reconstituted, refrigerated Humatrope in cartridges can be used for
up to 28 days.
! “Sense”-able - See, Hear, and Feel, as you dial the dosage setting that
corresponds to the prescribed Humatrope dose.
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
Humatrope®
somatropin (rDNA origin)
for injection
Steps for Using the HumatroPen Injection Device
Follow these steps for using the HumatroPen. Refer to the
fold-out diagrams on the inside front cover, page X, as
you go through these steps.
1. Getting Started
! Wash your hands before you start.
! Before first-time use, remove the pen cap and
unscrew the white shipping cartridge from the
HumatroPen. Dispose of the white shipping cartridge.
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
If you have questions, call 1-800-847-6988
! Firmly press the white release button on the HumatroPen
to unlock the dosage knob. The numbers "00" will
appear in the digital display window.
! Press and hold in the blue reset button and turn the
dosage knob counterclockwise (in the direction opposite
to the arrow on the end of the dosage knob) until the
metal rod is fully retracted and stops.
NOTE: Do not use excessive force while turning the
dosage knob. If the dosage knob does not turn, it is
already in the correct position.
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
Humatrope®
somatropin (rDNA origin)
for injection
! You will see either "00" or "--" in the digital display
window.
! If the display shows “00” in the digital display window,
then proceed to the next page.
! If the display shows “--” in the digital display window,
then press down the dosage knob until it locks in place.
Press the white release button. The dosage knob will
unlock, and the numbers “00” will reappear in the digital
display window.
NOTE: The digital display will automatically shut off in
two (2) minutes. The display can be reactivated by
pressing down the dosage knob until it locks in place.
Then press the white release button, and “00” will
reappear.
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
If you have questions, call 1-800-847-6988
Follow the mixing (reconstitution) directions as described in your Humatrope Cartridge
Kit.
! If a
cartridge is
already
attached to
your pen:
go to
“Attaching
the Pen
Needle” on
page X.
OR
! If a cartridge is not already
attached to your pen: place a
reconstituted cartridge on the
pen by screwing the cartridge
counterclockwise (in the
direction opposite the arrow on
the end of the dose knob) into
the pen. Go to “Attaching the
Pen Needle” on page X.
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18
Humatrope®
somatropin (rDNA origin)
for injection
2. Attaching the Pen Needle
! Wipe the rubber seal on the Humatrope cartridge
with an alcohol swab.
! Remove the tab from the needle outer shield but do
not remove the needle. Holding the HumatroPen
upright and away from your face, screw the needle
shield onto the Humatrope cartridge until snug.
! Remove the needle outer shield but do not discard.
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19
If you have questions, call 1-800-847-6988
3. Priming the HumatroPen Injection Device
The HumatroPen must be primed before setting or
injecting the first dose from each new cartridge. After
priming the HumatroPen with a new cartridge, it is not
necessary to prime the HumatroPen again between
doses. This is only necessary when you remove or
replace the cartridge.
! Hold the HumatroPen with the pen needle pointing
upright and away from your face. Pull off and
discard the needle inner shield.
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
20
Humatrope®
somatropin (rDNA origin)
for injection
! Push in the dosage knob at the end of the
HumatroPen until it locks in place. A small stream of
solution and air bubbles may come out of the tip of
the pen needle.
! Continuing to hold the HumatroPen with the pen
needle upright, unlock the dosage knob by firmly
pressing the white release button. You should see,
hear, and feel the dosage knob unlock.
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
21
If you have questions, call 1-800-847-6988
! Turn the dosage knob clockwise, in the direction of
the arrow marked on its end, until "01" appears in the
digital display window and a click is heard as the
number locks in place. Holding the HumatroPen
upright, push the dosage knob in until it locks in
place. “01” will remain in the digital display window
until the white release button is pressed. Then press
the white release button. Repeat this procedure until
Humatrope solution appears at the pen needle tip.
Once the solution appears at the pen needle tip—the
injection device is primed.
NOTE: It is normal for a small air bubble to remain
in the cartridge.
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
22
Humatrope®
somatropin (rDNA origin)
for injection
4. Dialing the Prescribed Dose
! With your healthcare professional, determine the
HumatroPen dosage setting (number of dosage knob
clicks) that corresponds to the prescribed dose of
Humatrope.
! To dial the dose, press the white release button. The
numbers "00" should reappear in the digital display
window. The dosage knob is now unlocked. Do not
depress the dosage knob while setting the dose. This
will cause the solution to be released from the
HumatroPen prior to injection, making the dose
inaccurate.
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
If you have questions, call 1-800-847-6988
! Turn the dosage knob in the direction of the arrow
until the dosage setting corresponding to the
prescribed dose appears in the digital display
window. You will hear and feel a click as the
numbers are dialed.
NOTE: The HumatroPen will dial to a maximum
dosage setting of 12 (twelve clicks of the dosage
knob).
! If the dosage knob will not dial the prescribed dosage
setting, the cartridge may be nearly empty and may
not contain enough Humatrope solution for a
complete dose. Talk with your healthcare
professional at the start of therapy about how to deal
with this.
NOTE: If you turn the dosage knob past the correct
number of clicks, press and hold in the blue reset
button and dial the dosage knob counterclockwise
(in the direction opposite to the arrow) until the
correct number appears in the digital display
window. If you dial back past "00", refer to
Troubleshooting Tip #7.
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
24
Humatrope®
somatropin (rDNA origin)
for injection
5. Preparing the Injection Site
! Choose an appropriate site for injection as instructed
by your healthcare professional. Using an alcohol
swab, apply firm pressure to the injection site and
rub outward in increasingly larger circles. Do not
retrace your steps. Let the alcohol dry a few seconds
before injecting.
NOTE: Humatrope should be injected
subcutaneously (under the skin). Rotate injection
sites daily. See the Injection Site Chart on pages XX-
XX and talk to your healthcare professional about
injection site rotation.
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
25
If you have questions, call 1-800-847-6988
6. Injecting the Humatrope Dose
! Gently pinch up a large area of skin. Quickly push
the pen needle into the skin, as instructed by your
healthcare professional.
! Inject the dose of Humatrope by slowly pushing the
dosage knob in until it locks in place, then slowly
count to five (5). Let go of the pinched-up area of
skin. Then pull the pen needle straight out.
! After injection, the dosage setting will stay in the
digital display window. The display will turn off
after two (2) minutes.
NOTE: It is normal for a small drop of Humatrope
solution to form on the pen needle tip after removing
it from the skin. It is also quite common to see a
small drop of Humatrope solution or blood on the
skin at the injection site. Simply apply pressure to
the site.
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
26
Humatrope®
somatropin (rDNA origin)
for injection
! Carefully replace the needle outer
shield as instructed by your
healthcare professional.
! Remove the capped needle by turning
counterclockwise and throw it away
as instructed by your healthcare
professional.
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
27
If you have questions, call 1-800-847-6988
! Recap the HumatroPen, leaving the cartridge in
place. Make sure the dosage knob is locked in place.
If it is not, push the dosage knob in until you feel it
lock in place.
23
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
28
Humatrope®
somatropin (rDNA origin)
for injection
! Store the HumatroPen with attached Humatrope
cartridge in the blue protective storage case in the
refrigerator until the time of the next injection. DO
NOT FREEZE.
! At the time of the next injection from the same
cartridge, reinspect the solution for clarity as
described in your Humatrope Cartridge Kit. Making
sure the cartridge remains snug, attach a new (sterile)
pen needle as described in Step 2, on page XX. To
dial and inject the dose, proceed from Step 4, on
page XX.
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
29
If you have questions, call 1-800-847-6988
Replacing a Cartridge
When a Humatrope cartridge needs to be replaced:
! Wash your hands.
! Remove the pen cap.
! Unscrew the empty cartridge from the HumatroPen.
! Dispose of the cartridge as directed by your
healthcare professional.
! Check that the threaded metal rod is completely
wound back into the HumatroPen. To rewind the
threaded metal rod, press and hold in the blue reset
button, and turn the dosage knob counterclockwise
(in the direction opposite to the arrow on the end of
the dosage knob) until it stops.
NOTE: Do not use excessive force when turning the
dosage knob. If the dosage knob does not turn, it is
already in the correct position.
! Return to the top of page XX, and follow all of the
remaining Steps for Using the HumatroPen Injection
Device.
25
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
30
Humatrope®
somatropin (rDNA origin)
for injection
Cleaning the HumatroPen Injection Device
The body of the HumatroPen may be wiped with a cloth slightly dampened with water
only. DO NOT IMMERSE THE HUMATROPEN IN WATER.
Injection Site Chart
Injections can be given in the following areas:
! Abdomen (above, below, or either side of the navel)
! Front of the upper thighs
! Upper, outer buttocks
! Back of the arms above the elbow and below the shoulder
Discuss the appropriate injection sites and site rotation with your healthcare
professional.
26
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
31
If you have questions, call 1-800-847-6988
27
Discuss the appropriate injection sites and
site rotation with your healthcare
professional.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
32
Humatrope®
somatropin (rDNA origin)
for injection
Determining the Humatrope Dose
Your healthcare professional should discuss the prescribed dose and the appropriate
dosage setting with you. The following conversion chart illustrates the relationship
between the prescribed dose and the dosage setting (number of clicks) on your
HumatroPen. If you have any questions, ask your healthcare professional.
28
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
33
If you have questions, call 1-800-847-6988
Conversion Chart
After Reconstitution
Clicks
Volume
(mL)
6 mg
Cartridge
Dose (mg)
12 mg
Cartridge
Dose (mg)
24 mg
Cartridge
Dose (mg)
1
0.05
0.1
0.2
0.4
2
0.10
0.2
0.4
0.8
3
0.15
0.3
0.6
1.2
4
0.20
0.4
0.8
1.6
5
0.25
0.5
1.0
2.0
6
0.30
0.6
1.2
2.4
7
0.35
0.7
1.4
2.8
8
0.40
0.8
1.6
3.2
9
0.45
0.9
1.8
3.6
10
0.50
1.0
2.0
4.0
11
0.55
1.1
2.2
4.4
12
0.60
1.2
2.4
4.8
29
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
34
Humatrope®
somatropin (rDNA origin)
for injection
Commonly Asked Questions
How should I store the Humatrope cartridges and the HumatroPen?
Cartridges-Humatrope must be kept refrigerated (36° to 46°F or 2° to 8°C) before and
after reconstitution. DO NOT FREEZE. Store the HumatroPen with the Humatrope
cartridge attached in the refrigerator until time of the next injection. Reconstituted
Humatrope must be used within 28 days. Discard any remaining Humatrope after 28 days.
Check the date on the cartridge. Do not use the cartridge if it has expired.
HumatroPen-Store the HumatroPen with the dosage knob locked in the depressed
position. Store the HumatroPen with the Humatrope cartridge attached in the blue
protective storage case in the refrigerator until the time of the next injection. Do not store
the HumatroPen with the pen needle attached because this could cause a safety
hazard. DO NOT FREEZE.
30
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
35
If you have questions, call 1-800-847-6988
When should I attach a new pen needle to the HumatroPen?
Use a new pen needle for each injection. Do not attach a pen needle until you are
ready to use the HumatroPen. Pen needles are to be used one (1) time only and
then discarded properly.
What is the lifetime of the HumatroPen?
The HumatroPen should last approximately two (2) years from the first use.
However, the lifetime may vary by a few months. When the pen is about to expire,
"≡" will appear in the digital display window. Please call Eli Lilly and Company at
1-800-847-6988 for assistance. The digital display window will show "≡ ≡" when
the pen has expired and should no longer be used.
31
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
36
Humatrope®
somatropin (rDNA origin)
for injection
How will I know if my HumatroPen battery is low?
When "bt" (see adjacent photo) appears in the digital
display window, this indicates that the HumatroPen has
a low battery. It is time to replace the injection device
immediately. Call Eli Lilly and Company at
1-800-847-6988 for assistance.
32
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
37
If you have questions, call 1-800-847-6988
Troubleshooting Tips
It may be helpful to refer to the fold-out diagrams on the inside front cover, page X, as
you review these tips.
1. Problem: The Humatrope cartridge and HumatroPen injection device will not screw
together.
Action: The threaded metal rod in the injection device may not be completely wound
back.
! Check to make sure the dosage knob is unlocked by pressing the white release button.
! Turn the injection device so the dosage knob on the end is facing you.
! Press and hold down the blue reset button and turn the dosage knob counterclockwise
(in the direction opposite the arrow on the end of the dosage knob).
! Make sure you turn the dosage knob until it stops. This will retract the threaded
metal rod in the injection device.
! Screw the white-tipped end of the cartridge onto the HumatroPen, as described on
page XX.
33
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
38
Humatrope®
somatropin (rDNA origin)
for injection
2. Problem: Humatrope solution is not clear after mixing.
Action: Gently invert the HumatroPen up and down ten (10) times. DO NOT SHAKE.
Then let the HumatroPen sit for at least three (3) minutes. If the Humatrope solution
remains cloudy or contains particles, then gently invert the HumatroPen up and down ten
(10) more times. Let the HumatroPen sit for five (5) more minutes. The Humatrope
solution should then be clear. If the solution remains cloudy or contains particles,
the contents MUST NOT be injected. Call your healthcare professional or Humatrope
provider.
3. Problem: The small white plastic piece in the end of the cartridge moves when the
dosage knob is unlocked.
Action: This is normal. The white plastic piece may move freely inside the cartridge.
34
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
39
If you have questions, call 1-800-847-6988
4. Problem: Dosage knob is unlocked and display turns off before dose is dialed.
Action: The display will turn off after two (2) minutes to save battery life. The display
can be reactivated by pressing down the dosage knob until it locks in place. Press the
white release button. The dosage knob will be unlocked, and the numbers "00" will
appear in the digital display window.
5. Problem: Dosage knob is unlocked and display turns off after dose is dialed.
Action: The display will turn off after two (2) minutes to save battery life. If you are
unsure of the dosage setting, press and hold in the blue reset button and slowly turn the
dosage knob counterclockwise (in the direction opposite to the arrow on the end of the
dosage knob) until the digital display turns back on. Then release the reset button and turn
the dosage knob clockwise, in the same direction of the arrow, until you reach the
prescribed dose. Proceed with the injection.
35
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
40
Humatrope®
somatropin (rDNA origin)
for injection
6. Problem: You have over-dialed the dose.
Action: Press and hold in the blue reset button and turn the dosage knob
counterclockwise (in the direction opposite to the arrow on the end of the dosage knob)
until the correct dosage setting appears in the digital display window.
7. Problem: You have dialed back past "00".
Action: DO NOT PUSH IN THE DOSAGE KNOB. Two dashes "--" will appear in the
digital display window. Dial the dosage knob forward again in the direction of the arrow.
The "00" should reappear in the digital display window. Follow the steps to dial the
number of dosage knob clicks that corresponds to the prescribed dose as described on
pages XX-XX.
36
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
41
If you have questions, call 1-800-847-6988
8. Problem: Full dose cannot be dialed.
Action: The Humatrope cartridge does not contain a full dose. Follow the procedure
recommended by your healthcare professional at the start of therapy.
9. Problem: After the Humatrope cartridge is changed, the dosage knob is stuck and will
not turn.
Action: Please call Eli Lilly and Company at 1-800-847-6988 for instructions on
replacing the HumatroPen.
37
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
42
Humatrope®
somatropin (rDNA origin)
for injection
10. Problem: Dosage knob is dialed beyond the maximum dose — dosage setting of 12
(twelve).
Action: The dose is still accurate up to the dosage setting of 12. However, the additional
drug dose beyond the maximum dose of 12 will be wasted. (Humatrope solution will flow
out from the pen needle tip as you dial past 12.) To dial back, see Troubleshooting
Tip #6, on page XX.
11. Problem: After insertion of the needle through the skin, the dosage knob will not
depress.
Action: First withdraw the needle from the skin. Check to make sure the pen needle is
screwed on tightly. If the needle is tight, then the problem could be a clogged pen needle.
Replace the pen needle.
38
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
43
If you have questions, call 1-800-847-6988
12. Problem: Following an injection, Humatrope solution continues to drip out of the
pen needle.
Action: Air bubbles may be present in the cartridge. Before dialing the next dose, follow
Step 3, Priming the HumatroPen Injection Device, on pages XX-XX. See also Step 6,
Injecting the Humatrope Dose, on page XX.
13. Problem: A click sound is not heard when the dosage knob is depressed.
Action: The sound level of the HumatroPen dosage knob varies depending on dose size,
speed of pressing dosage knob, and the injection device itself. As long as the knob locks
in place, the HumatroPen is working properly.
39
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
44
Humatrope®
somatropin (rDNA origin)
for injection
14. Problem: Display shows "≡" instead of "00".
Action: The expected life of the HumatroPen is about to expire. The display will work
for approximately another four (4) weeks before it shuts off automatically. The
mechanical parts of the pen will remain functional. Please call Eli Lilly and Company at
1-800-847-6988 for instructions on replacing the HumatroPen.
15. Problem: Flashing "--" or "00" appears in the digital display window.
Action: You may have dialed too quickly or slowly. A flashing "--" or "00" indicates that
a counting error may have occurred. DO NOT INJECT. Point the pen away from your
face, depress the dosage knob until a click is heard as the number locks in place, and
continue preparing your dose by following Step 4, Dialing the Prescribed Dose, on pages
XX-XX.
40
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
45
If you have questions, call 1-800-847-6988
16. Problem: With a Humatrope cartridge attached to the HumatroPen, the dosage knob
does not fully extend when the white release button is pressed.
Action: Loosen the cartridge by turning the cartridge ¼ turn in a clockwise direction (in
the same direction as the arrow on the end of the dosage knob). The dosage knob should
now fully extend. Retighten the cartridge. Turn the dosage knob in the direction of the
arrow marked on its end until “01” appears in the digital display window. Push in the
dosage knob until it locks in place. Press the white release button. Before dialing the next
dose, follow Step 3, Priming the HumatroPen Injection Device, on pages XX-XX. If the
dosage knob still does not fully extend, please call Eli Lilly and Company at
1-800-847-6988 for instructions on replacing the HumatroPen.
41
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
46
Humatrope®
somatropin (rDNA origin)
for injection
17. Problem: How can I check that the medication comes out of my pen when I push
the dosage knob?
Action: If you suspect that your pen may have been damaged, you can check that your
pen is delivering the medication by performing the steps below.
1. Hold pen with needle pointing upright and away from your face.
2. Remove needle container and needle cap.
3. Depress the dosage knob until it locks in place.
4. You should hear or feel a click when the dosage knob is fully depressed.
5. A drop of liquid may appear at the tip of the needle.
6. Unlock the dosage knob by pressing the white release button.
7. Turn the dosage knob as indicated by direction of the arrow on the end of the
dosage knob until "01" appears in the digital display window and a click is heard
or felt.
8. Depress the dosage knob until it locks in place.
9. The check is complete when liquid is seen at the tip of the needle.
10. If liquid does not appear repeat Steps 6, 7, and 8 above until at least a drop of
liquid is seen.
11. If liquid does not appear after repeating the procedure several times, please call
Eli Lilly and Company at 1-800-847-6988 for instructions on replacing the
HumatroPen.
42
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
47
If you have questions, call 1-800-847-6988
Replacement of the HumatroPen
Eli Lilly and Company (“Lilly”) will replace this HumatroPen for the HumatroPen
user without charge at any time, if the pen is damaged or stops working properly, or
if the low battery indicator (“bt”) or the expiration indicator ("≡") is displayed in the
digital display window of the pen.
To return the HumatroPen for replacement, please call 1-800-847-6988 toll-free for
instructions.
If you are concerned that the HumatroPen may not be working properly, please call
1-800-847-6988 toll-free for assistance.
Lilly’s replacement of the HumatroPen for the HumatroPen user without charge is
the user’s only remedy for any claim relating to the HumatroPen. Lilly is not liable
for incidental or consequential damages.
43
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
48
Humatrope®
somatropin (rDNA origin)
for injection
Manufactured for Eli Lilly and Company
Pharmaceutical Delivery Systems
Indianapolis, IN 46285, USA
Packaged by Lilly France S.A.S.
F-67640 Fegersheim, France
Made in Switzerland
www.lilly.com
1-800-847-6988
www.humatrope.com
June 2005
Copyright 1999, 2005, Eli Lilly and Company. ALL RIGHTS RESERVED.
HumatroPen and Humatrope are trademarks of Eli Lilly and Company.
US Patent Nos. 5,334,162; 5,383,865; and 5,454,786.
PA 9184 FSAMP
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
|
custom-source
|
2025-02-12T13:45:34.582734
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/019640s047,019640s052lbl.pdf', 'application_number': 19640, 'submission_type': 'SUPPL ', 'submission_number': 52}
|
11,582
|
TERAZOL
7(terconazole) Vaginal Cream 0.4%
TERAZOL
3(terconazole) Vaginal Cream 0.8%
TERAZOL® 3 (terconazole) Vaginal Suppositories 80 mg
DESCRIPTION
TERAZOL® 7(terconazole) Vaginal Cream 0.4% is a white to off-white, water washable
cream for intravaginal administration containing 0.4% of the antifungal agent
terconazole, cis-1-[p-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-
dioxolan-4-yl]methoxy]phenyl]-4-isopropylpiperazine, compounded in a cream base
consisting of butylated hydroxyanisole, cetyl alcohol, isopropyl myristate, polysorbate
60, polysorbate 80, propylene glycol, stearyl alcohol, and purified water.
TERAZOL® 3 (terconazole) Vaginal Cream 0.8% is a white to off-white, water washable
cream for intravaginal administration containing 0.8% of the antifungal agent
terconazole, cis-1-[p-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-
dioxolan-4-yl]methoxy]phenyl]-4-isopropylpiperazine, compounded in a cream base
consisting of butylated hydroxyanisole, cetyl alcohol, isopropyl myristate, polysorbate
60, polysorbate 80, propylene glycol, stearyl alcohol, and purified water.
TERAZOL® 3 (terconazole) Vaginal Suppositories are white to off-white suppositories
for intravaginal administration containing 80 mg of the antifungal agent terconazole, cis-
1-[p-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-
yl]methoxy]phenyl]-4-isopropylpiperazine, in triglycerides derived from coconut and/or
palm kernel oil (a base of hydrogenated vegetable oils) and butylated hydroxyanisole.
The structural formula of terconazole is as follows:
TERCONAZOLE
C26H31Cl2N5O3
[INSERT STRUCTURE HERE]
Terconazole, a triazole derivative, is a white to almost white powder with a molecular
weight of 532.47. It is insoluble in water; sparingly soluble in ethanol; and soluble in
butanol.
CLINICAL PHARMACOLOGY
Following intravaginal administration of terconazole in humans, absorption ranged from
5-8% in three hysterectomized subjects and 12-16% in two non-hysterectomized subjects
with tubal ligations.
Following daily intravaginal administration of 0.8% terconazole 40 mg
(0.8% cream x 5 g) for seven days to normal humans, plasma concentrations were low
and gradually rose to a daily peak (mean of 5.9 ng/mL or 0.006 mcg/mL) at 6.6 hours.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Results from similar studies in patients with vulvovaginal candidiasis indicate that the
slow rate of absorption, the lack of accumulation, and the mean peak plasma
concentration of terconazole was not different from that observed in healthy women. The
absorption characteristics of terconazole 0.8% in pregnant or non-pregnant patients with
vulvovaginal candidiasis were also similar to those found in normal volunteers.
Following oral (30 mg) administration of 14C-labelled terconazole, the harmonic half-life
of elimination from the blood for the parent terconazole was 6.9 hours (range 4.0-11.3).
Terconazole is extensively metabolized; the plasma AUC for terconazole compared to the
AUC for total radioactivity was 0.6%. Total radioactivity was eliminated from the blood
with a harmonic half-life of 52.2 hours (range 44-60). Excretion of radioactivity was both
by renal (32-56%) and fecal (47-52%) routes.
In vitro, terconazole is highly protein bound (94.9%) and the degree of binding is
independent of drug concentration.
Photosensitivity reactions were observed in some normal volunteers following repeated
dermal application of terconazole 2.0% and 0.8% creams under conditions of filtered
artificial ultraviolet light.
Photosensitivity reactions have not been observed in U.S. and foreign clinical trials in
patients who were treated with terconazole suppositories or vaginal cream (0.4% and
0.8%).
Microbiology: Terconazole exhibits fungicidal activity in vitro against Candida
albicans. Antifungal activity has also been demonstrated against other fungi. The MIC
values of terconazole against most Lactobacillus spp. typically found in the human
vagina were ≥128 mcg/mL; therefore these beneficial bacteria were not affected by drug
treatment.
The exact pharmacologic mode of action of terconazole is uncertain; however, it may
exert its antifungal activity by the disruption of normal fungal cell membrane
permeability. No resistance to terconazole has developed during successive passages of
C. albicans.
INDICATIONS AND USAGE
TERAZOL 7 Vaginal Cream 0.4%, TERAZOL 3 Vaginal Cream 0.8% and TERAZOL 3
Vaginal Suppositories 80 mg are indicated for the local treatment of vulvovaginal
candidiasis (moniliasis). As these products are effective only for vulvovaginitis caused by
the genus Candida, the diagnosis should be confirmed by KOH smears and/or cultures.
CONTRAINDICATIONS
Patients known to be hypersensitive to terconazole or to any of the components of the
cream or suppositories.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WARNINGS
None.
PRECAUTIONS
General: Discontinue use and do not retreat with terconazole if sensitization, irritation,
fever, chills or flu-like symptoms are reported during use.
The base contained in the suppository formulation may interact with certain rubber or
latex products, such as those used in vaginal contraceptive diaphragms, therefore
concurrent use is not recommended.
Laboratory Tests: If there is lack of response to terconazole, appropriate microbiologic
studies (standard KOH smear and/or cultures) should be repeated to confirm the
diagnosis and rule out other pathogens.
Drug Interactions:
TERAZOL 7 Vaginal Cream 0.4% and TERAZOL 3 Vaginal Suppositories80mg:
The therapeutic effect of these products is not affected by oral contraceptive usage.
TERAZOL 3 Vaginal Cream 0.8%:
The levels of estradiol (E2) and progesterone did not differ significantly when 0.8%
terconazole vaginal cream was administered to healthy female volunteers established on a
low dose oral contraceptive.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Carcinogenesis: Studies to determine the carcinogenic potential of terconazole have not
been performed.
Mutagenicity: Terconazole was not mutagenic when tested in vitro for induction of
microbial point mutations (Ames test), or for inducing cellular transformation, or in vivo
for chromosome breaks (micronucleus test) or dominant lethal mutations in mouse germ
cells.
Impairment of Fertility: No impairment of fertility occurred when female rats were
administered terconazole orally up to 40 mg/kg/day for a three month period.
Pregnancy:
Teratogenic Effects:
Pregnancy Category C.
There was no evidence of teratogenicity when terconazole was administered orally up to
40 mg/kg/day (25x the recommended intravaginal human dose of the suppository
formulation, 50x the recommended intravaginal human dose of the 0.8% vaginal cream
formulation, and 100x the intravaginal human dose of the 0.4% vaginal cream
formulation) in rats, or 20 mg/kg/day in rabbits, or subcutaneously up to 20 mg/kg/day in
rats.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Dosages at or below 10 mg/kg/day produced no embryotoxicity; however, there was a
delay in fetal ossification at 10 mg/kg/day in rats. There was some evidence of
embryotoxicity in rabbits and rats at 20-40 mg/kg. In rats, this was reflected as a decrease
in litter size and number of viable young and reduced fetal weight. There was also delay
in ossification and an increased incidence of skeletal variants.
The no-effect dose of 10 mg/kg/day resulted in a mean peak plasma level of terconazole
in pregnant rats of 0.176 mcg/mL which exceeds by 44 times the mean peak plasma level
(0.004 mcg/mL) seen in normal subjects after intravaginal administration of terconazole
0.4% vaginal cream, by 30 times the mean peak plasma level (0.006 mcg/mL) seen in
normal subjects after intravaginal administration of terconazole 0.8% vaginal cream, and
by 17 times the mean peak plasma level (0.010 mcg/mL) seen in normal subjects after
intravaginal administration of terconazole 80 mg vaginal suppository. This safety
assessment does not account for possible exposure of the fetus through direct transfer to
terconazole from the irritated vagina by diffusion across amniotic membranes.
Since terconazole is absorbed from the human vagina, it should not be used in the first
trimester of pregnancy unless the physician considers it essential to the welfare of the
patient.
Nursing Mothers:
It is not known whether this drug is excreted in human milk. Animal studies have shown
that rat offspring exposed via the milk of treated (40 mg/kg/orally) dams showed
decreased survival during the first few post-partum days, but overall pup weight and
weight gain were comparable to or greater than controls throughout lactation. Because
many drugs are excreted in human milk, and because of the potential for adverse reaction
in nursing infants from terconazole, 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 efficacy in children have not been established.
Geriatric Use:
Clinical studies of TERAZOL 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.
ADVERSE REACTIONS
TERAZOL 7 Vaginal Cream 0.4%:
During controlled clinical studies conducted in the United States, 521 patients with
vulvovaginal candidiasis were treated with terconazole 0.4% vaginal cream. Based on
comparative analyses with placebo, the adverse experiences considered most likely
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
related to terconazole 0.4% vaginal cream were headache (26% vs. 17% with placebo)
and body pain (2.1% vs. 0% with placebo). Vulvovaginal burning (5.2%), itching (2.3%)
or irritation (3.1%) occurred less frequently with terconazole 0.4% vaginal cream than
with the vehicle placebo. Fever (1.7% vs. 0.5% with placebo) and chills (0.4% vs. 0.0%
with placebo) have also been reported. The therapy-related dropout rate was 1.9%. The
adverse drug experience on terconazole most frequently causing discontinuation was
vulvovaginal itching (0.6%), which was lower than the incidence for placebo (0.9%).
TERAZOL 3 Vaginal Cream 0.8%:
During controlled clinical studies conducted in the United States, patients with
vulvovaginal candidiasis were treated with terconazole 0.8% vaginal cream for three
days. Based on comparative analyses with placebo and a standard agent, the adverse
experiences considered most likely related to terconazole 0.8% vaginal cream were
headache (21% vs. 16% with placebo) and dysmenorrhea (6% vs. 2% with placebo).
Genital complaints in general, and burning and itching in particular, occurred less
frequently in the terconazole 0.8% vaginal cream 3 day regimen (5% vs. 6%-9% with
placebo). Other adverse experiences reported with terconazole 0.8% vaginal cream were
abdominal pain (3.4% vs. 1% with placebo) and fever (1% vs. 0.3% with placebo). The
therapy-related dropout rate was 2.0% for the terconazole 0.8% vaginal cream. The
adverse drug experience most frequently causing discontinuation of therapy was
vulvovaginal itching, 0.7% with the terconazole 0.8% vaginal cream group and 0.3%
with the placebo group.
TERAZOL 3 Vaginal Suppositories 80 mg:
During controlled clinical studies conducted in the United States, 284 patients with
vulvovaginal candidiasis were treated with terconazole 80 mg vaginal suppositories.
Based on comparative analyses with placebo (295 patients), the adverse experiences
considered adverse reactions most likely related to terconazole 80 mg vaginal
suppositories were headache (30.3% vs. 20.7% with placebo) and pain of the female
genitalia (4.2% vs. 0.7% with placebo). Adverse reactions that were reported but were
not statistically significantly different from placebo were burning (15.2% vs. 11.2% with
placebo) and body pain (3.9% vs. 1.7% with placebo). Fever (2.8% v. 1.4% with placebo)
and chills (1.8% vs. 0.7% with placebo) have also been reported. The therapy-related
dropout rate was 3.5% and the placebo therapy-related dropout rate was 2.7%. The
adverse drug experience on terconazole most frequently causing discontinuation was
burning (2.5% vs. 1.4% with placebo) and pruritus (1.8% vs. 1.4% with placebo).
OVERDOSAGE
Overdose of terconazole in humans has not been reported to date. In the rat, the oral LD
50 values were found to be 1741 and 849 mg/kg for the male and female, respectively.
The oral LD 50 values for the male and female dog were ~1280 and ≥640 mg/kg,
respectively.
DOSAGE AND ADMINISTRATION
TERAZOL 7 Vaginal Cream 0.4%:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
One full applicator (5 g) of TERAZOL 7 Vaginal Cream (20 mg terconazole) should be
administered intravaginally once daily at bedtime for seven consecutive days.
TERAZOL 3 Vaginal Cream 0.8%:
One full applicator (5 g) of TERAZOL 3 Vaginal Cream (40 mg terconazole) should be
administered intravaginally once daily at bedtime for three consecutive days.
TERAZOL 3 Vaginal Suppositories 80 mg
One TERAZOL 3 Vaginal Suppository (80 mg terconazole) should be administered
intravaginally once daily at bedtime for three consecutive days.
Before prescribing another course of therapy, the diagnosis should be reconfirmed by
smears and/or cultures and other pathogens commonly associated with vulvovaginitis
ruled out. The therapeutic effect of these products is not affected by menstruation.
HOW SUPPLIED
TERAZOL® 7 (terconazole) Vaginal Cream 0.4% is available in 45 g
(NDC 0062-5350-01) tubes with an ORTHO* Measured-Dose Applicator. Store at
Controlled Room Temperature 15 - 30° C (59 - 86° F).
TERAZOL® 3 (terconazole) Vaginal Cream 0.8% is available in 20 g
(NDC 0062-5356-01) tubes with an ORTHO* Measured-Dose Applicator. Store at
Controlled Room Temperature 15 - 30° C (59 - 86° F).
TERAZOL® 3 (terconazole) Vaginal Suppositories 80 mg are available as 2.5 g,
elliptically shaped white to off-white suppositories in packages of three
(NDC 0062-5351-01) with a vaginal applicator. Store at controlled room temperature 15 -
30° C (59 - 86° F).
Rx only *Trademark
ORTHO McNEIL
ORTHO McNEIL PHARMACEUTICAL, INC.
Raritan, New Jersey 08869
OMP 1998 Printed in U.S.A.
Issued March 2001
642-10-300-1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
TERAZOL
7 (terconazole) Vaginal Cream 0.4%
TERAZOL
3 (terconazole) Vaginal Cream 0.8%
PATIENT INSTRUCTIONS
Filling the applicator:
1. Remove the cap from the tube.
2. Use the pointed tip on the top of the cap to puncture the seal on the tube.
3. Screw the applicator onto the tube.
4. Squeeze the tube from the bottom and fill the applicator until the plunger stops.
5. Unscrew the applicator from the tube.
Illustration of cap puncturing tube
Illustration of applicator screwed onto tube
Using the applicator:
1. Lie on your back with your knees drawn up toward your chest.
Illustration of lower extremities.
2. Holding the applicator by the ribbed end of the barrel, insert the filled applicator into
the vagina as far as it will comfortably go.
3. Slowly press the plunger of the applicator to release the cream into the vagina.
4. Remove the applicator from the vagina.
5. Apply one applicatorful each night for as many days at bedtime, as directed by your
doctor.
Cleaning the applicator: (Does not apply to sample applicators, which are for one
time use only)
After each use, you should thoroughly clean the applicator by following the procedure
below:
1. Pull the plunger out of the barrel.
2. Wash the pieces with lukewarm, soapy water, and dry them thoroughly.
3. Put the applicator back together by gently pushing the plunger into the barrel as far as
it will go.
Illustration – separate plunger from barrel
NOTE: Store the cream at Controlled Room Temperature 15-30oC (59-86oF). See end
flap for lot number and expiration date.
U.S. Patent No. D-279,504
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
TERAZOL
3 (terconazole) Vaginal Suppositories 80 mg
Three oval suppositories, for use inside the vagina only.
Designed to be inserted into the vagina.
HOW TO USE:
Place one suppository into the vagina each night at bedtime, for 3 nights, as directed by
your doctor. The TERAZOL Suppository is self-lubricating and may be inserted with or
without the applicator.
A. Insertion with the applicator
1. Filling the applicator
• Break off suppository from the plastic strip.
• Pull the plastic completely apart at the notched end.
• Place the flat end of the suppository into the open end of the applicator
as shown. You are now ready to insert the suppository into the vagina.
Illustration 1
Illustration 2
2. Using the applicator
• Lie on your back with your knees drawn up toward your chest.
• Holding the applicator by the ribbed end of the barrel, gently insert it
into the vagina as far as it will comfortably go.
• Press the plunger to release the suppository into the vagina.
• Remove the applicator from the vagina.
Illustration of lower extremities
3. Cleaning the applicator (Does not apply to sample applicators, which
are for one time use only)
After each use, you should thoroughly clean the applicator by following
the procedure below:
• Pull the plunger out of the barrel.
• Wash both pieces with lukewarm, soapy water, and dry them
thoroughly.
• Put the applicator back together by gently pushing the plunger into the
barrel as far as it will go.
B. Insertion without the applicator
• Lie on your back with your knees drawn up toward your chest.
• Place the suppository on the tip of your finger as shown.
• Insert the suppository gently into the vagina as far as it will comfortably go.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NOTE: Store the suppositories at Controlled Room Temperature 15-30°C (59-86°F). See
end flap for lot number and expiration date.
U.S. Patent No. D-279,504
A WORD ABOUT YEAST INFECTIONS
Why do yeast infections occur?
Yeast infections are caused by an organism called Candida (KAN di duh). It may be
present in small and harmless amounts in the mouth, digestive tract, and vagina.
Sometimes the natural balance of the vagina becomes upset. This may lead to rapid
growth of Candida, which results in a yeast infection. Symptoms of a yeast infection
include itching, burning, redness, and an abnormal discharge.
Your doctor can make the diagnosis of a yeast infection by evaluating your symptoms
and looking at a sample of the discharge under the microscope.
How can I prevent yeast infections?
Certain factors may increase your chance of developing a yeast infection. These factors
don’t actually cause the problem, but they may create a situation that allows the yeast to
grow rapidly.
• Clothing: Tight jeans, nylon underwear, pantyhose, and wet bathing suits can hold in
heat and moisture (two conditions in which yeast organisms thrive). Looser pants or
skirts, 100% cotton underwear, and stockings may help avoid this problem.
• Diet: Cutting down on sweets, milk products, and artificial sweeteners may reduce
the risk of yeast infections.
• Antibiotics: Antibiotics work by eliminating disease-causing organisms. While
they are helpful in curing other problems, antibiotics may lead to an overgrowth of
Candida in the vagina.
• Pregnancy: Hormonal changes in the body during pregnancy encourage the growth
of yeast. This is a very common time for an infection to occur. Until the baby is
born, it may be hard to completely eliminate yeast infections. If you believe you are
pregnant, tell your doctor.
• Menstruation: Sometimes monthly changes in hormone levels may lead to yeast
infections.
• Diabetes: In addition to heat and moisture, yeast thrives on sugar. Because diabetics
often have sugar in their urine, their vaginas are rich in this substance. Careful
control of diabetes may help prevent yeast infection.
Controlling these factors can help eliminate yeast infections and may prevent them from
coming back.
Some other helpful tips:
1. For best results, be sure to use the medication as prescribed by your doctor, even if
you feel better quickly.
2. Avoid sexual intercourse, if your doctor advises you to do so. The suppository
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
formulation (not the cream) may damage the diaphragm. Therefore, use of the
diaphragm during therapy with the suppository is not recommended. Consult your
physician.
3. If your partner has any penile itching, redness, or discomfort, he should consult his
physician and mention that you are being treated for a yeast infection.
4. You can use the medication even if you are having your menstrual period. However,
you should not use tampons because they may absorb the medication. Instead, use
external pads or napkins until you have finished your medication. You may also wish
to wear a sanitary napkin if the vaginal medication leaks.
5. Dry the genital area thoroughly after showering, bathing, or swimming. Change out
of a wet bathing suit or damp exercise clothes as soon as possible. A dry
environment is less likely to encourage the growth of yeast.
6. Wipe from front to rear (away from the vagina) after a bowel movement.
7. Don’t douche unless your doctor specifically tells you to do so. Douching may
disturb the vaginal balance.
8. Don’t scratch if you can help it. Scratching can cause more irritation and spread the
infection.
9. Discuss with your physician any medication you are already taking. Certain types of
medication can make your vagina more susceptible to infection.
10. Eat nutritious meals to promote your general health.
ORTHO McNEIL
ORTHO McNEIL PHARMACEUTICAL, INC.
Raritan, New Jersey 08869
OMP 1998 Printed in U.S.A.
Issued March 2001
642-10-300-1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:34.834477
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/019641s016lbl.pdf', 'application_number': 19641, 'submission_type': 'SUPPL ', 'submission_number': 16}
|
11,583
|
TERAZOL 7(terconazole) Vaginal Cream 0.4%
TERAZOL 3(terconazole) Vaginal Cream 0.8%
TERAZOL® 3 (terconazole) Vaginal Suppositories 80 mg
DESCRIPTION
TERAZOL® 7(terconazole) Vaginal Cream 0.4% is a white to off-white, water washable
cream for intravaginal administration containing 0.4% of the antifungal agent
terconazole, cis-1-[p-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-
dioxolan-4-yl]methoxy]phenyl]-4-isopropylpiperazine, compounded in a cream base
consisting of butylated hydroxyanisole, cetyl alcohol, isopropyl myristate, polysorbate
60, polysorbate 80, propylene glycol, stearyl alcohol, and purified water.
TERAZOL® 3 (terconazole) Vaginal Cream 0.8% is a white to off-white, water washable
cream for intravaginal administration containing 0.8% of the antifungal agent
terconazole, cis-1-[p-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-
dioxolan-4-yl]methoxy]phenyl]-4-isopropylpiperazine, compounded in a cream base
consisting of butylated hydroxyanisole, cetyl alcohol, isopropyl myristate, polysorbate
60, polysorbate 80, propylene glycol, stearyl alcohol, and purified water.
TERAZOL® 3 (terconazole) Vaginal Suppositories are white to off-white suppositories
for intravaginal administration containing 80 mg of the antifungal agent terconazole, cis-
1-[p-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-
yl]methoxy]phenyl]-4-isopropylpiperazine, in triglycerides derived from coconut and/or
palm kernel oil (a base of hydrogenated vegetable oils) and butylated hydroxyanisole.
The structural formula of terconazole is as follows:
TERCONAZOLE
C26H31Cl2N5O3
[INSERT STRUCTURE HERE]
Terconazole, a triazole derivative, is a white to almost white powder with a molecular
weight of 532.47. It is insoluble in water; sparingly soluble in ethanol; and soluble in
butanol.
CLINICAL PHARMACOLOGY
Following intravaginal administration of terconazole in humans, absorption ranged from
5-8% in three hysterectomized subjects and 12-16% in two non-hysterectomized subjects
with tubal ligations.
Following daily intravaginal administration of 0.8% terconazole 40 mg
(0.8% cream x 5 g) for seven days to normal humans, plasma concentrations were low
and gradually rose to a daily peak (mean of 5.9 ng/mL or 0.006 mcg/mL) at 6.6 hours.
Results from similar studies in patients with vulvovaginal candidiasis indicate that the
slow rate of absorption, the lack of accumulation, and the mean peak plasma
concentration of terconazole was not different from that observed in healthy women. The
absorption characteristics of terconazole 0.8% in pregnant or non-pregnant patients with
vulvovaginal candidiasis were also similar to those found in normal volunteers.
Following oral (30 mg) administration of 14C-labelled terconazole, the harmonic half-life
of elimination from the blood for the parent terconazole was 6.9 hours (range 4.0-11.3).
Terconazole is extensively metabolized; the plasma AUC for terconazole compared to the
AUC for total radioactivity was 0.6%. Total radioactivity was eliminated from the blood
with a harmonic half-life of 52.2 hours (range 44-60). Excretion of radioactivity was both
by renal (32-56%) and fecal (47-52%) routes.
In vitro, terconazole is highly protein bound (94.9%) and the degree of binding is
independent of drug concentration.
Photosensitivity reactions were observed in some normal volunteers following repeated
dermal application of terconazole 2.0% and 0.8% creams under conditions of filtered
artificial ultraviolet light.
Photosensitivity reactions have not been observed in U.S. and foreign clinical trials in
patients who were treated with terconazole suppositories or vaginal cream (0.4% and
0.8%).
Microbiology: Terconazole exhibits fungicidal activity in vitro against Candida
albicans. Antifungal activity has also been demonstrated against other fungi. The MIC
values of terconazole against most Lactobacillus spp. typically found in the human
vagina were ≥128 mcg/mL; therefore these beneficial bacteria were not affected by drug
treatment.
The exact pharmacologic mode of action of terconazole is uncertain; however, it may
exert its antifungal activity by the disruption of normal fungal cell membrane
permeability. No resistance to terconazole has developed during successive passages of
C. albicans.
INDICATIONS AND USAGE
TERAZOL 7 Vaginal Cream 0.4%, TERAZOL 3 Vaginal Cream 0.8% and TERAZOL 3
Vaginal Suppositories 80 mg are indicated for the local treatment of vulvovaginal
candidiasis (moniliasis). As these products are effective only for vulvovaginitis caused by
the genus Candida, the diagnosis should be confirmed by KOH smears and/or cultures.
CONTRAINDICATIONS
Patients known to be hypersensitive to terconazole or to any of the components of the
cream or suppositories.
WARNINGS
None.
PRECAUTIONS
General: Discontinue use and do not retreat with terconazole if sensitization, irritation,
fever, chills or flu-like symptoms are reported during use.
The base contained in the suppository formulation may interact with certain rubber or
latex products, such as those used in vaginal contraceptive diaphragms, therefore
concurrent use is not recommended.
Laboratory Tests: If there is lack of response to terconazole, appropriate microbiologic
studies (standard KOH smear and/or cultures) should be repeated to confirm the
diagnosis and rule out other pathogens.
Drug Interactions:
TERAZOL 7 Vaginal Cream 0.4% and TERAZOL 3 Vaginal Suppositories 80mg:
The therapeutic effect of these products is not affected by oral contraceptive usage.
TERAZOL 3 Vaginal Cream 0.8%:
The levels of estradiol (E2) and progesterone did not differ significantly when 0.8%
terconazole vaginal cream was administered to healthy female volunteers established on a
low dose oral contraceptive.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Carcinogenesis: Studies to determine the carcinogenic potential of terconazole have not
been performed.
Mutagenicity: Terconazole was not mutagenic when tested in vitro for induction of
microbial point mutations (Ames test), or for inducing cellular transformation, or in vivo
for chromosome breaks (micronucleus test) or dominant lethal mutations in mouse germ
cells.
Impairment of Fertility: No impairment of fertility occurred when female rats were
administered terconazole orally up to 40 mg/kg/day for a three month period.
Pregnancy:
Teratogenic Effects:
Pregnancy Category C.
There was no evidence of teratogenicity when terconazole was administered orally up to
40 mg/kg/day (25x the recommended intravaginal human dose of the suppository
formulation, 50x the recommended intravaginal human dose of the 0.8% vaginal cream
formulation, and 100x the intravaginal human dose of the 0.4% vaginal cream
formulation) in rats, or 20 mg/kg/day in rabbits, or subcutaneously up to 20 mg/kg/day in
rats.
Dosages at or below 10 mg/kg/day produced no embryotoxicity; however, there was a
delay in fetal ossification at 10 mg/kg/day in rats. There was some evidence of
embryotoxicity in rabbits and rats at 20-40 mg/kg. In rats, this was reflected as a decrease
in litter size and number of viable young and reduced fetal weight. There was also delay
in ossification and an increased incidence of skeletal variants.
The no-effect dose of 10 mg/kg/day resulted in a mean peak plasma level of terconazole
in pregnant rats of 0.176 mcg/mL which exceeds by 44 times the mean peak plasma level
(0.004 mcg/mL) seen in normal subjects after intravaginal administration of terconazole
0.4% vaginal cream, by 30 times the mean peak plasma level (0.006 mcg/mL) seen in
normal subjects after intravaginal administration of terconazole 0.8% vaginal cream, and
by 17 times the mean peak plasma level (0.010 mcg/mL) seen in normal subjects after
intravaginal administration of terconazole 80 mg vaginal suppository. This safety
assessment does not account for possible exposure of the fetus through direct transfer to
terconazole from the irritated vagina by diffusion across amniotic membranes.
Since terconazole is absorbed from the human vagina, it should not be used in the first
trimester of pregnancy unless the physician considers it essential to the welfare of the
patient.
Nursing Mothers:
It is not known whether this drug is excreted in human milk. Animal studies have shown
that rat offspring exposed via the milk of treated (40 mg/kg/orally) dams showed
decreased survival during the first few post-partum days, but overall pup weight and
weight gain were comparable to or greater than controls throughout lactation. Because
many drugs are excreted in human milk, and because of the potential for adverse reaction
in nursing infants from terconazole, 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 efficacy in children have not been established.
Geriatric Use:
Clinical studies of TERAZOL 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.
ADVERSE REACTIONS
TERAZOL 7 Vaginal Cream 0.4%:
During controlled clinical studies conducted in the United States, 521 patients with
vulvovaginal candidiasis were treated with terconazole 0.4% vaginal cream. Based on
comparative analyses with placebo, the adverse experiences considered most likely
related to terconazole 0.4% vaginal cream were headache (26% vs. 17% with placebo)
and body pain (2.1% vs. 0% with placebo). Vulvovaginal burning (5.2%), itching (2.3%)
or irritation (3.1%) occurred less frequently with terconazole 0.4% vaginal cream than
with the vehicle placebo. Fever (1.7% vs. 0.5% with placebo) and chills (0.4% vs. 0.0%
with placebo) have also been reported. The therapy-related dropout rate was 1.9%. The
adverse drug experience on terconazole most frequently causing discontinuation was
vulvovaginal itching (0.6%), which was lower than the incidence for placebo (0.9%).
TERAZOL 3 Vaginal Cream 0.8%:
During controlled clinical studies conducted in the United States, patients with
vulvovaginal candidiasis were treated with terconazole 0.8% vaginal cream for three
days. Based on comparative analyses with placebo and a standard agent, the adverse
experiences considered most likely related to terconazole 0.8% vaginal cream were
headache (21% vs. 16% with placebo) and dysmenorrhea (6% vs. 2% with placebo).
Genital complaints in general, and burning and itching in particular, occurred less
frequently in the terconazole 0.8% vaginal cream 3 day regimen (5% vs. 6%-9% with
placebo). Other adverse experiences reported with terconazole 0.8% vaginal cream were
abdominal pain (3.4% vs. 1% with placebo) and fever (1% vs. 0.3% with placebo). The
therapy-related dropout rate was 2.0% for the terconazole 0.8% vaginal cream. The
adverse drug experience most frequently causing discontinuation of therapy was
vulvovaginal itching, 0.7% with the terconazole 0.8% vaginal cream group and 0.3%
with the placebo group.
TERAZOL 3 Vaginal Suppositories 80 mg:
During controlled clinical studies conducted in the United States, 284 patients with
vulvovaginal candidiasis were treated with terconazole 80 mg vaginal suppositories.
Based on comparative analyses with placebo (295 patients), the adverse experiences
considered adverse reactions most likely related to terconazole 80 mg vaginal
suppositories were headache (30.3% vs. 20.7% with placebo) and pain of the female
genitalia (4.2% vs. 0.7% with placebo). Adverse reactions that were reported but were
not statistically significantly different from placebo were burning (15.2% vs. 11.2% with
placebo) and body pain (3.9% vs. 1.7% with placebo). Fever (2.8% v. 1.4% with placebo)
and chills (1.8% vs. 0.7% with placebo) have also been reported. The therapy-related
dropout rate was 3.5% and the placebo therapy-related dropout rate was 2.7%. The
adverse drug experience on terconazole most frequently causing discontinuation was
burning (2.5% vs. 1.4% with placebo) and pruritus (1.8% vs. 1.4% with placebo).
OVERDOSAGE
Overdose of terconazole in humans has not been reported to date. In the rat, the oral LD
50 values were found to be 1741 and 849 mg/kg for the male and female, respectively.
The oral LD 50 values for the male and female dog were ~1280 and ≥640 mg/kg,
respectively.
DOSAGE AND ADMINISTRATION
TERAZOL 7 Vaginal Cream 0.4%:
One full applicator (5 g) of TERAZOL 7 Vaginal Cream (20 mg terconazole) should be
administered intravaginally once daily at bedtime for seven consecutive days.
TERAZOL 3 Vaginal Cream 0.8%:
One full applicator (5 g) of TERAZOL 3 Vaginal Cream (40 mg terconazole) should be
administered intravaginally once daily at bedtime for three consecutive days.
TERAZOL 3 Vaginal Suppositories 80 mg
One TERAZOL 3 Vaginal Suppository (80 mg terconazole) should be administered
intravaginally once daily at bedtime for three consecutive days.
Before prescribing another course of therapy, the diagnosis should be reconfirmed by
smears and/or cultures and other pathogens commonly associated with vulvovaginitis
ruled out. The therapeutic effect of these products is not affected by menstruation.
HOW SUPPLIED
TERAZOL® 7 (terconazole) Vaginal Cream 0.4% is available in 45 g
(NDC 0062-5350-01) tubes with an ORTHO* Measured-Dose Applicator. Store at
Controlled Room Temperature 15 - 30° C (59 - 86° F).
TERAZOL® 3 (terconazole) Vaginal Cream 0.8% is available in 20 g
(NDC 0062-5356-01) tubes with an ORTHO* Measured-Dose Applicator. Store at
Controlled Room Temperature 15 - 30° C (59 - 86° F).
TERAZOL® 3 (terconazole) Vaginal Suppositories 80 mg are available as 2.5 g,
elliptically shaped white to off-white suppositories in packages of three
(NDC 0062-5351-01) with a vaginal applicator. Store at controlled room temperature 15 -
30° C (59 - 86° F).
Rx only *Trademark
ORTHO McNEIL
ORTHO McNEIL PHARMACEUTICAL, INC.
Raritan, New Jersey 08869
OMP 1998 Printed in U.S.A.
Issued March 2001
642-10-300-1
TERAZOL 7 (terconazole) Vaginal Cream 0.4%
TERAZOL 3 (terconazole) Vaginal Cream 0.8%
PATIENT INSTRUCTIONS
Filling the applicator:
1. Remove the cap from the tube.
2. Use the pointed tip on the top of the cap to puncture the seal on the tube.
3. Screw the applicator onto the tube.
4. Squeeze the tube from the bottom and fill the applicator until the plunger stops.
5. Unscrew the applicator from the tube.
Illustration of cap puncturing tube
Illustration of applicator screwed onto tube
Using the applicator:
1. Lie on your back with your knees drawn up toward your chest.
Illustration of lower extremities.
2. Holding the applicator by the ribbed end of the barrel, insert the filled applicator into
the vagina as far as it will comfortably go.
3. Slowly press the plunger of the applicator to release the cream into the vagina.
4. Remove the applicator from the vagina.
5. Apply one applicatorful each night for as many days at bedtime, as directed by your
doctor.
Cleaning the applicator: (Does not apply to sample applicators, which are for one
time use only)
After each use, you should thoroughly clean the applicator by following the procedure
below:
1. Pull the plunger out of the barrel.
2. Wash the pieces with lukewarm, soapy water, and dry them thoroughly.
3. Put the applicator back together by gently pushing the plunger into the barrel as far as
it will go.
Illustration – separate plunger from barrel
NOTE: Store the cream at Controlled Room Temperature 15-30oC (59-86oF). See end
flap for lot number and expiration date.
U.S. Patent No. D-279,504
TERAZOL 3 (terconazole) Vaginal Suppositories 80 mg
Three oval suppositories, for use inside the vagina only.
Designed to be inserted into the vagina.
HOW TO USE:
Place one suppository into the vagina each night at bedtime, for 3 nights, as directed by
your doctor. The TERAZOL Suppository is self-lubricating and may be inserted with or
without the applicator.
A. Insertion with the applicator
1. Filling the applicator
• Break off suppository from the plastic strip.
• Pull the plastic completely apart at the notched end.
• Place the flat end of the suppository into the open end of the applicator
as shown. You are now ready to insert the suppository into the vagina.
Illustration 1
Illustration 2
2. Using the applicator
• Lie on your back with your knees drawn up toward your chest.
• Holding the applicator by the ribbed end of the barrel, gently insert it
into the vagina as far as it will comfortably go.
• Press the plunger to release the suppository into the vagina.
• Remove the applicator from the vagina.
Illustration of lower extremities
3. Cleaning the applicator (Does not apply to sample applicators, which
are for one time use only)
After each use, you should thoroughly clean the applicator by following
the procedure below:
• Pull the plunger out of the barrel.
• Wash both pieces with lukewarm, soapy water, and dry them
thoroughly.
• Put the applicator back together by gently pushing the plunger into the
barrel as far as it will go.
B. Insertion without the applicator
• Lie on your back with your knees drawn up toward your chest.
• Place the suppository on the tip of your finger as shown.
• Insert the suppository gently into the vagina as far as it will comfortably go.
NOTE: Store the suppositories at Controlled Room Temperature 15-30°C (59-86°F). See
end flap for lot number and expiration date.
U.S. Patent No. D-279,504
A WORD ABOUT YEAST INFECTIONS
Why do yeast infections occur?
Yeast infections are caused by an organism called Candida (KAN di duh). It may be
present in small and harmless amounts in the mouth, digestive tract, and vagina.
Sometimes the natural balance of the vagina becomes upset. This may lead to rapid
growth of Candida, which results in a yeast infection. Symptoms of a yeast infection
include itching, burning, redness, and an abnormal discharge.
Your doctor can make the diagnosis of a yeast infection by evaluating your symptoms
and looking at a sample of the discharge under the microscope.
How can I prevent yeast infections?
Certain factors may increase your chance of developing a yeast infection. These factors
don’t actually cause the problem, but they may create a situation that allows the yeast to
grow rapidly.
• Clothing: Tight jeans, nylon underwear, pantyhose, and wet bathing suits can hold in
heat and moisture (two conditions in which yeast organisms thrive). Looser pants or
skirts, 100% cotton underwear, and stockings may help avoid this problem.
• Diet: Cutting down on sweets, milk products, and artificial sweeteners may reduce
the risk of yeast infections.
• Antibiotics: Antibiotics work by eliminating disease-causing organisms. While
they are helpful in curing other problems, antibiotics may lead to an overgrowth of
Candida in the vagina.
• Pregnancy: Hormonal changes in the body during pregnancy encourage the growth
of yeast. This is a very common time for an infection to occur. Until the baby is
born, it may be hard to completely eliminate yeast infections. If you believe you are
pregnant, tell your doctor.
• Menstruation: Sometimes monthly changes in hormone levels may lead to yeast
infections.
• Diabetes: In addition to heat and moisture, yeast thrives on sugar. Because diabetics
often have sugar in their urine, their vaginas are rich in this substance. Careful
control of diabetes may help prevent yeast infection.
Controlling these factors can help eliminate yeast infections and may prevent them from
coming back.
Some other helpful tips:
1. For best results, be sure to use the medication as prescribed by your doctor, even if
you feel better quickly.
2. Avoid sexual intercourse, if your doctor advises you to do so. The suppository
formulation (not the cream) may damage the diaphragm. Therefore, use of the
diaphragm during therapy with the suppository is not recommended. Consult your
physician.
3. If your partner has any penile itching, redness, or discomfort, he should consult his
physician and mention that you are being treated for a yeast infection.
4. You can use the medication even if you are having your menstrual period. However,
you should not use tampons because they may absorb the medication. Instead, use
external pads or napkins until you have finished your medication. You may also wish
to wear a sanitary napkin if the vaginal medication leaks.
5. Dry the genital area thoroughly after showering, bathing, or swimming. Change out
of a wet bathing suit or damp exercise clothes as soon as possible. A dry
environment is less likely to encourage the growth of yeast.
6. Wipe from front to rear (away from the vagina) after a bowel movement.
7. Don’t douche unless your doctor specifically tells you to do so. Douching may
disturb the vaginal balance.
8. Don’t scratch if you can help it. Scratching can cause more irritation and spread the
infection.
9. Discuss with your physician any medication you are already taking. Certain types of
medication can make your vagina more susceptible to infection.
10. Eat nutritious meals to promote your general health.
ORTHO McNEIL
ORTHO McNEIL PHARMACEUTICAL, INC.
Raritan, New Jersey 08869
OMP 1998 Printed in U.S.A.
Issued March 2001
642-10-300-1
|
custom-source
|
2025-02-12T13:45:34.866950
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19579slr026,19641slr022,19964slr021_terazol_lbl.pdf', 'application_number': 19641, 'submission_type': 'SUPPL ', 'submission_number': 22}
|
11,579
|
1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
HUMATROPE safely and effectively. See full prescribing information for
HUMATROPE.
HUMATROPE® [somatropin (rDNA ORIGIN)] for injection, for
Subcutaneous Use
Initial U.S. Approval: 1987
----------------------RECENT MAJOR CHANGES-------------------------------
Warnings and Precautions, Pancreatitis (5.12)
MM/YYYY
----------------------INDICATIONS AND USAGE--------------------------------
Humatrope® is a recombinant human growth hormone (somatropin) indicated
for:
•
Pediatric Patients: Treatment of children with short stature or
growth failure associated with growth hormone (GH) deficiency,
Turner syndrome, idiopathic short stature, SHOX deficiency, and
failure to catch up in height after small for gestational age birth.
(1.1)
•
Adult Patients: Treatment of adults with either childhood-onset or
adult-onset GH deficiency. (1.2)
-------------------DOSAGE AND ADMINISTRATION--------------------------
Humatrope should be administered subcutaneously. (2.2)
Injection sites should always be rotated regularly to avoid lipoatrophy. (2.2)
For pediatric patients, the recommended weekly dosages in milligrams (mg)
per kilogram (kg) of body weight (given in divided doses 6 to 7 times per
week) are:
•
Pediatric GH deficiency: 0.18 to 0.30 mg/kg/week (2.3)
•
Turner syndrome: Up to 0.375 mg/kg/week (2.3)
•
Idiopathic short stature: Up to 0.37 mg/kg/week (2.3)
•
SHOX deficiency: 0.35 mg/kg/week (2.3)
•
Small for gestational age: Up to 0.47 mg/kg/week (2.3)
•
Adult GH deficiency: Either a non-weight based or a weight-based
dosing regimen may be followed, with doses adjusted based on
treatment response and IGF-I concentrations. (2.4)
•
Non-weight based dosing: A starting dose of approximately 0.2
mg/day (range, 0.15-0.30 mg/day) may be used without
consideration of body weight, and increased gradually every 1-2
months by increments of approximately 0.1-0.2 mg/day. (2.4)
•
Weight-based dosing: The recommended initial daily dose is not
more than 0.006 mg/kg (6 μg/kg); the dose may be increased to a
maximum of 0.0125 mg/kg (12.5 μg/kg) daily. (2.4)
-------------------DOSAGE FORMS AND STRENGTHS------------------------
•
5 mg vial and 5-mL vial of Diluent for Humatrope (3)
•
6 mg (gold), 12 mg (teal) and 24 mg (purple) cartridge, and
prefilled syringe of Diluent for Humatrope (3)
•
Humatrope cartridges should be used only with the appropriate
corresponding pen device
-----------------------------CONTRAINDICATIONS--------------------------------
•
Acute critical illness. (4.1, 5.1)
•
Children with Prader-Willi syndrome who are severely obese or
have severe respiratory impairment – reports of sudden death. (4.2,
5.2)
•
Active malignancy. (4.3)
•
Active proliferative or severe non-proliferative diabetic
retinopathy. (4.4)
•
Children with closed epiphyses. (4.5)
•
Hypersensitivity to somatropin or diluent. (4.6)
------------------------WARNINGS AND PRECAUTIONS-------------
•
Acute Critical Illness: Evaluate potential benefit of treatment
continuation against potential risk. (5.1)
•
Prader-Willi Syndrome: Evaluate for signs of upper airway
obstruction and sleep apnea before initiation of treatment for GH
deficiency. Discontinue treatment if these signs occur. (5.2)
•
Neoplasm: Monitor patients with preexisting tumors for
progression or recurrence. Increased risk of a second neoplasm in
childhood cancer survivors treated with somatropin - in particular
meningiomas in patients treated with radiation to the head for their
first neoplasm. (5.3)
•
Impaired Glucose Tolerance (IGT) and Diabetes Mellitus (DM):
Periodically monitor glucose levels in all patients, as IGT or DM
may be unmasked. Doses of concurrent antihyperglycemic drugs in
patients with DM may require adjustment. (5.4)
•
Intracranial Hypertension (IH): Exclude preexisting papilledema.
IH may develop, but is usually reversible after discontinuation or
dose reduction. (5.5)
•
Fluid Retention (e.g., edema, arthralgia, carpal tunnel syndrome –
especially in adults): Reduce dose as necessary if such signs
develop. (5.6)
•
Hypothyroidism: Monitor thyroid function periodically as
hypothyroidism may first become evident or worsen after initiation
of somatropin. (5.8)
•
Slipped Capital Femoral Epiphysis (SCFE): Evaluate any child
with onset of a limp or hip/knee pain for possible SCFE. (5.9)
•
Progression of Preexisting Scoliosis: Monitor any child with
scoliosis for progression of the curve. (5.10)
•
Pancreatitis: Consider pancreatitis in patients with abdominal pain,
especially children. (5.12)
-----------------------------ADVERSE REACTIONS--------------------------------
Common adverse reactions reported in adult and pediatric patients receiving
somatropin include injection site reactions, hypersensitivity to the diluent, and
hypothyroidism (6.1). Additional common adverse reactions in adults include
edema, arthralgia, myalgia, carpal tunnel syndrome, paraesthesias, and
hyperglycemia (6.1, 6.2).
To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and
Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088
or www.fda.gov/medwatch.
-----------------------------DRUG INTERACTIONS--------------------------------
•
Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1: May
require the initiation of glucocorticoid replacement therapy.
Patients treated with glucocorticoid replacement for previously
diagnosed hypoadrenalism may require an increase in their
maintenance doses. (7.1, 7.2)
•
Glucocorticoid Replacement: Should be carefully adjusted. (7.2)
•
Cytochrome P450-Metabolized Drugs: Monitor carefully if used
with somatropin. (7.3)
•
Oral Estrogen: Larger doses of somatropin may be required in
women. (7.4)
•
Insulin and/or Other Hypoglycemic Agents: May require
adjustment (7.5)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling
Revised: MM/YYYY
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1
Pediatric Patients
1.2
Adult Patients
2
DOSAGE AND ADMINISTRATION
2.1
Reconstitution
2.2
General Administration Guidelines
2.3
Dosing for Pediatric Patients
2.4
Dosing for Patients with Adult Growth Hormone Deficiency
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
4.1
Acute Critical Illness
4.2
Prader-Willi Syndrome in Children
4.3
Active Malignancy
4.4
Diabetic Retinopathy
4.5
Closed Epiphyses
4.6
Hypersensitivity
5
WARNINGS AND PRECAUTIONS
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
5.1
Acute Critical Illness
5.2
Prader-Willi Syndrome in Children
5.3
Neoplasms
5.4
Glucose Intolerance
5.5
Intracranial Hypertension
5.6
Fluid Retention
5.7
Hypopituitarism
5.8
Hypothyroidism
5.9
Slipped Capital Femoral Epiphysis in Pediatric Patients
5.10
Progression of Preexisting Scoliosis in Pediatric Patients
5.11
Otitis Media and Cardiovascular Disorders in Patients with
Turner Syndrome
5.12
Pancreatitis
5.13
Local and Systemic Reactions
5.14
Laboratory Tests
6
ADVERSE REACTIONS
6.1
Most Serious and/or Most Frequently Observed Adverse
Reactions
6.2
Clinical Trials Experience
6.3
Post-Marketing Experience
7
DRUG INTERACTIONS
7.1
11β-Hydroxysteroid Dehydrogenase Type 1
7.2
Pharmacologic Glucocorticoid Therapy and Supraphysiologic
Glucocorticoid Treatment
7.3
Cytochrome P450-Metabolized Drugs
7.4
Oral Estrogen
7.5
Insulin and/or Other Hypoglycemic Agents
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.5
Geriatric Use
9
DRUG ABUSE AND DEPENDENCE
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
14
CLINICAL STUDIES
14.1
Adult Patients with Growth Hormone Deficiency
14.2
Pediatric Patients with Turner Syndrome
14.3
Pediatric Patients with Idiopathic Short Stature
14.4
Pediatric Patients with SHOX Deficiency
14.5
Pediatric Patients Born Small for Gestational Age (SGA) Who
Fail to Demonstrate Catch-up Growth by Age 2 - 4 Years
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
16.2
Storage and Handling
17
PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information
are not listed.
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1
Pediatric Patients
Growth Hormone Deficiency — Humatrope is indicated for the treatment of pediatric patients who have growth failure due to
inadequate secretion of endogenous growth hormone (GH).
Short Stature Associated with Turner Syndrome — Humatrope is indicated for the treatment of short stature associated with
Turner syndrome [see Clinical Studies (14.2)].
Idiopathic Short Stature — Humatrope is indicated for the treatment of idiopathic short stature, also called non-GH-deficient
short stature, defined by height SDS ≤-2.25 and associated with growth rates unlikely to permit attainment of adult height in the
normal range, in pediatric patients for whom diagnostic evaluation excludes other causes of short stature that should be observed or
treated by other means [see Clinical Studies (14.3)]; SDS = standard deviation scores.
SHOX Deficiency — Humatrope is indicated for the treatment of short stature or growth failure in children with short stature
homeobox-containing gene (SHOX) deficiency [see Clinical Studies (14.4)].
Small for Gestational Age — Humatrope is indicated for the treatment of growth failure in children born small for gestational
age (SGA) who fail to demonstrate catch-up growth by age two to four years [see Clinical Studies (14.5)].
1.2
Adult Patients
Humatrope is indicated for the replacement of endogenous GH in adults with GH deficiency who meet either of the following
two criteria [see Clinical Studies (14.1)]:
Adult-Onset (AO): Patients who have GH deficiency, either alone or associated with multiple hormone deficiencies
(hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or
Childhood-Onset (CO): Patients who were GH deficient during childhood as a result of congenital, genetic, acquired, or
idiopathic causes.
Patients who were treated with somatropin for GH deficiency in childhood and whose epiphyses are closed should be
reevaluated before continuation of somatropin therapy at the reduced dose level recommended for GH deficient adults. According to
current standards, confirmation of the diagnosis of adult GH deficiency in both groups involves an appropriate GH provocative test
with two exceptions: (1) patients with multiple other pituitary hormone deficiencies due to organic disease; and (2) patients with
congenital/genetic GH deficiency.
2
DOSAGE AND ADMINISTRATION
For subcutaneous injection.
Therapy with Humatrope should be supervised by a physician who is experienced in the diagnosis and management of
pediatric patients with short stature associated with GH deficiency, Turner syndrome, idiopathic short stature, SHOX deficiency, small
for gestational age birth, or adult patients with either childhood-onset or adult-onset GH deficiency.
2.1
Reconstitution
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Vial — Each 5-mg vial of Humatrope should be reconstituted with 1.5 to 5 mL of Diluent for Humatrope. The diluent should
be injected into the vial of Humatrope by aiming the stream of liquid gently against the vial wall. Following reconstitution, the vial
should be swirled with a GENTLE rotary motion until the contents are completely dissolved. DO NOT SHAKE. The resulting
solution should be clear. If the solution is cloudy or contains particulate matter, the contents MUST NOT be injected.
If sensitivity to the diluent should occur, the vials may be reconstituted with Bacteriostatic Water for Injection (Benzyl
Alcohol preserved), USP or Sterile Water for Injection, USP. When Humatrope is reconstituted with Bacteriostatic Water for
Injection, USP, the solution should be kept refrigerated at 36° to 46°F (2° to 8°C) and used within 14 days. It is important to note that
benzyl alcohol used as a preservative in Bacteriostatic Water has been associated with toxicity in newborns. Therefore, Bacteriostatic
Water for Injection must not be used to reconstitute Humatrope for use in a newborn infant. When Humatrope is to be administered to
a newborn infant it should be reconstituted with the diluent provided or, if the infant is sensitive to the diluent, Sterile Water for
Injection, USP. When reconstituted with Sterile Water for Injection the solution should be kept refrigerated at 36° to 46°F (2° to 8°C)
and used within 24 hours.
Cartridge — The Humatrope cartridge has been designed for use only with the Humatrope injection device. Each cartridge of
Humatrope should be reconstituted using only the diluent syringe that accompanies the cartridge and should not be reconstituted with
the Diluent for Humatrope provided with Humatrope vials. The reconstituted solution should be clear. If the solution is cloudy or
contains particulate matter, the contents MUST NOT be injected. Humatrope cartridges should not be used if the patient is allergic to
metacresol or glycerin.
The somatropin concentrations for the reconstituted Humatrope cartridges are as follows:
6 mg cartridge (gold)
2.08 mg/mL
12 mg cartridge (teal)
4.17 mg/mL
24 mg cartridge (purple)
8.33 mg/mL
[See How Supplied (16.2) and Information for the Patient for comprehensive directions on Humatrope cartridge
reconstitution].
2.2
General Administration Guidelines
For all indications, the following general principles for administration should be followed:
•
When using the Humatrope vial the septum of the vial should be wiped with an alcoholic antiseptic solution before
and after each injection to prevent contamination of the contents by repeated needle insertions. Sterile disposable
syringes and needles should be used. The volume of the syringe should be small enough so that the prescribed dose
can be withdrawn from the vial with reasonable accuracy.
•
When using the Humatrope cartridge a sterile disposable needle should be used for each injection.
•
Humatrope should be administered by subcutaneous injection with regular rotation of injection sites to avoid
lipoatrophy.
•
For pediatric patients the calculated weekly Humatrope dosage should be divided into equal doses given either 6 or 7
days per week.
•
For adult patients the prescribed dose should be administered daily.
2.3
Dosing for Pediatric Patients
The Humatrope dosage and administration schedule should be individualized for each patient based on the growth response.
Failure to increase height velocity, particularly during the first year of treatment, should prompt close assessment of compliance and
evaluation of other causes of poor growth, such as hypothyroidism, under–nutrition, advanced bone age and antibodies to recombinant
human growth hormone. Response to somatropin treatment tends to decrease with time. Somatropin treatment for stimulation of linear
growth should be discontinued once epiphyseal fusion has occurred.
The recommended weekly dosages in milligrams (mg) per kilogram (kg) of body weight for pediatric patients are:
Growth hormone deficiency
0.026 to 0.043 mg/kg/day (0.18 to 0.30 mg/kg/week)
Turner syndrome
up to 0.054 mg/kg/day (0.375 mg/kg/week)
Idiopathic short stature
up to 0.053 mg/kg/day (0.37 mg/kg/week)
SHOX deficiency
0.050 mg/kg/day (0.35 mg/kg/week)
Small for gestational age
up to 0.067 mg/kg/day (0.47 mg/kg/week)a
a Recent literature has recommended initial treatment with larger doses of somatropin (e.g., 0.067 mg/kg/day), especially in very short
children (i.e., height SDS <–3), and/or older pubertal children, and that a reduction in dosage (e.g., gradually towards 0.033
mg/kg/day) should be considered if substantial catch-up growth is observed during the first few years of therapy. On the other hand,
in younger SGA children (e.g., approximately <4 years) (who respond the best in general) with less severe short stature (i.e.,
baseline height SDS values between -2 and -3), consideration should be given to initiating treatment at a lower dose (e.g., 0.033
mg/kg/day), and titrating the dose as needed over time. In all children, clinicians should carefully monitor the growth response, and
adjust the somatropin dose as necessary.
2.4
Dosing for Patients with Adult Growth Hormone Deficiency
Either of two approaches to Humatrope dosing may be followed: a non-weight-based regimen or a weight-based regimen.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Non-weight based — based on published consensus guidelines, a starting dose of approximately 0.2 mg/day (range, 0.15-
0.30 mg/day) may be used without consideration of body weight. This dose can be increased gradually every 1-2 months by
increments of approximately 0.1-0.2 mg/day, according to individual patient requirements based on the clinical response and serum
insulin-like growth factor I (IGF-I) concentrations. The dose should be decreased as necessary on the basis of adverse events and/or
serum IGF-I concentrations above the age- and gender-specific normal range. Maintenance dosages vary considerably from person to
person, and between male and female patients.
Weight-based —based on the dosing regimen used in the original adult GH deficiency registration trials, the recommended
dosage at the start of treatment is not more than 0.006 mg/kg (6 μg/kg) daily. The dose may be increased according to individual
patient requirements to a maximum of 0.0125 mg/kg (12.5 μg/kg) daily. Clinical response, side effects, and determination of age- and
gender-adjusted serum IGF-I concentrations should be used as guidance in dose titration.
A lower starting dose and smaller dose increments should be considered for older patients, who are more prone to the adverse
effects of somatropin than younger individuals. In addition, obese individuals are more likely to manifest adverse effects when treated
with a weight-based regimen. Estrogen-replete women may need higher doses than men. Oral estrogen administration may increase
the dose requirements in women.
3
DOSAGE FORMS AND STRENGTHS
Humatrope is a sterile, white lyophilized powder available in the following vial and cartridge sizes:
• 5 mg vial and a 5-mL vial of Diluent for Humatrope
• 6 mg cartridge (gold) and a prefilled syringe of Diluent for Humatrope
• 12 mg cartridge (teal) and a prefilled syringe of Diluent for Humatrope
• 24 mg cartridge (purple) and a prefilled syringe of Diluent for Humatrope
Humatrope cartridges should be used only with the appropriate corresponding pen device.
4
CONTRAINDICATIONS
4.1
Acute Critical Illness
Treatment with pharmacologic amounts of somatropin is contraindicated in patients with acute critical illness due to
complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure.
Two placebo-controlled clinical trials in non-GH deficient adult patients (n=522) with these conditions in intensive care units revealed
a significant increase in mortality (41.9% vs. 19.3%) among somatropin-treated patients (doses 5.3-8.0 mg/day) compared to those
receiving placebo [see Warnings and Precautions (5.1)].
4.2
Prader-Willi Syndrome in Children
Somatropin is contraindicated in patients with Prader-Willi syndrome who are severely obese, have a history of upper airway
obstruction or sleep apnea, or have severe respiratory impairment. There have been reports of sudden death when somatropin was used
in such patients. Humatrope is not indicated for the treatment of pediatric patients who have growth failure due to genetically
confirmed Prader-Willi syndrome. [See Warnings and Precautions (5.2)].
4.3
Active Malignancy
In general, somatropin is contraindicated in the presence of active malignancy. Any preexisting malignancy should be inactive
and its treatment complete prior to instituting therapy with somatropin. Somatropin should be discontinued if there is evidence of
recurrent activity. Since GH deficiency may be an early sign of the presence of a pituitary tumor (or, rarely, other brain tumors), the
presence of such tumors should be ruled out prior to initiation of treatment. Somatropin should not be used in patients with any
evidence of progression or recurrence of an underlying intracranial tumor.
4.4
Diabetic Retinopathy
Somatropin is contraindicated in patients with active proliferative or severe non-proliferative diabetic retinopathy.
4.5
Closed Epiphyses
Somatropin should not be used for growth promotion in pediatric patients with closed epiphyses.
4.6
Hypersensitivity
Humatrope is contraindicated in patients with a known hypersensitivity to somatropin or diluent. Localized reactions are the
most common hypersensitivity reactions.
5
WARNINGS AND PRECAUTIONS
5.1
Acute Critical Illness
Increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery
or multiple accidental trauma, or those with acute respiratory failure has been reported after treatment with pharmacologic doses of
somatropin [see Contraindications (4.1)]. The safety of continuing somatropin treatment in patients receiving replacement doses for
approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment
continuation with somatropin in patients experiencing acute critical illnesses should be weighed against the potential risk.
5.2
Prader-Willi Syndrome in Children
There have been reports of fatalities after initiating therapy with somatropin in pediatric patients with Prader-Willi syndrome
who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified
respiratory infection. Male patients with one or more of these factors may be at greater risk than females. Patients with Prader-Willi
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
syndrome should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of treatment with somatropin.
If, during treatment with somatropin, patients show signs of upper airway obstruction (including onset of, or increased, snoring) and/or
new onset sleep apnea, treatment should be interrupted. All patients with Prader-Willi syndrome treated with somatropin should also
have effective weight control and be monitored for signs of respiratory infection, which should be diagnosed as early as possible and
treated aggressively [see Contraindications (4.2)]. Humatrope is not indicated for the treatment of pediatric patients who have growth
failure due to genetically confirmed Prader-Willi syndrome.
5.3
Neoplasms
Patients with preexisting tumors or GH deficiency secondary to an intracranial lesion should be examined routinely for
progression or recurrence of the underlying disease process. In pediatric patients, clinical literature has revealed no relationship
between somatropin replacement therapy and central nervous system (CNS) tumor recurrence or new extracranial tumors. However, in
childhood cancer survivors, an increased risk of a second neoplasm has been reported in patients treated with somatropin after their
first neoplasm. Intracranial tumors, in particular meningiomas, in patients treated with radiation to the head for their first neoplasm,
were the most common of these second neoplasms. In adults, it is unknown whether there is any relationship between somatropin
replacement therapy and CNS tumor recurrence.
Patients should be monitored carefully for any malignant transformation of skin lesions (e.g., changes in pre-existing
cutaneous nevi).
5.4
Glucose Intolerance
Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses in susceptible patients. As a result,
previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked during somatropin treatment.
Therefore, glucose levels should be monitored periodically in all patients treated with somatropin, especially in those with risk factors
for diabetes mellitus, such as obesity, Turner syndrome, or a family history of diabetes mellitus. Patients with preexisting type 1 or
type 2 diabetes mellitus or impaired glucose tolerance should be monitored closely during somatropin therapy. The doses of
antihyperglycemic drugs (e.g., insulin or oral agents) may require adjustment when somatropin therapy is instituted in these patients.
5.5
Intracranial Hypertension
Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in a
small number of patients treated with somatropin products. Symptoms usually occurred within the first eight (8) weeks after the
initiation of somatropin therapy. In all reported cases, IH-associated signs and symptoms rapidly resolved after cessation of therapy or
a reduction of the somatropin dose. Funduscopic examination should be performed routinely before initiating treatment with
somatropin to exclude preexisting papilledema, and periodically during the course of somatropin therapy. If papilledema is observed
by funduscopy during somatropin treatment, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with
somatropin can be restarted at a lower dose after IH-associated signs and symptoms have resolved. Patients with Turner syndrome
may be at increased risk for the development of IH.
5.6
Fluid Retention
Fluid retention during somatropin replacement therapy in adults may frequently occur. Clinical manifestations of fluid
retention are usually transient and dose dependent.
5.7
Hypopituitarism
Patients with hypopituitarism (multiple pituitary hormone deficiencies) should have their other hormonal replacement
treatments closely monitored during somatropin treatment.
5.8
Hypothyroidism
Undiagnosed/untreated hypothyroidism may prevent an optimal response to somatropin, in particular, the growth response in
children. Patients with Turner syndrome have an inherently increased risk of developing autoimmune thyroid disease and primary
hypothyroidism. In patients with GH deficiency, central (secondary) hypothyroidism may first become evident or worsen during
somatropin treatment. Therefore, patients treated with somatropin should have periodic thyroid function tests performed, and thyroid
hormone replacement therapy should be initiated or appropriately adjusted when indicated.
5.9
Slipped Capital Femoral Epiphysis in Pediatric Patients
Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders (including pediatric GH
deficiency and Turner syndrome) or in patients undergoing rapid growth. Any pediatric patient with the onset of a limp or complaints
of hip or knee pain during somatropin therapy should be carefully evaluated.
5.10
Progression of Preexisting Scoliosis in Pediatric Patients
Progression of scoliosis can occur in patients who experience rapid growth. Because somatropin increases growth rate,
patients with a history of scoliosis who are treated with somatropin should be monitored for progression of scoliosis. However,
somatropin has not been shown to increase the occurrence of scoliosis. Skeletal abnormalities including scoliosis are commonly seen
in untreated patients with Turner syndrome. Scoliosis is also commonly seen in untreated patients with Prader-Willi syndrome.
Physicians should be alert to these abnormalities, which may manifest during somatropin therapy.
5.11
Otitis Media and Cardiovascular Disorders in Patients with Turner Syndrome
Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders, as these patients have an
increased risk of ear and hearing disorders. Somatropin treatment may increase the occurrence of otitis media in patients with Turner
syndrome. In addition, patients with Turner syndrome should be monitored closely for cardiovascular disorders (e.g., hypertension,
aortic aneurysm or dissection, stroke) as patients with Turner syndrome are also at increased risk for these conditions.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
5.12
Pancreatitis
Cases of pancreatitis have been reported rarely in children and adults receiving somatropin treatment, with some evidence
supporting a greater risk in children compared with adults. Published literature indicates that girls who have Turner syndrome may be
at greater risk than other somatropin-treated children. Pancreatitis should be considered in any somatropin-treated patient, especially a
child, who develops abdominal pain.
5.13
Local and Systemic Reactions
When somatropin is administered subcutaneously at the same site over a long period of time, tissue atrophy may result. This
can be avoided by rotating the injection site [see Dosage and Administration (2.2)]. As with any protein, local or systemic allergic
reactions may occur. Parents/patients should be informed that such reactions are possible and that prompt medical attention should be
sought if allergic reactions occur.
5.14
Laboratory Tests
Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone and IGF-I may increase after somatropin
therapy.
6
ADVERSE REACTIONS
6.1
Most Serious and/or Most Frequently Observed Adverse Reactions
This list presents the most seriousa and/or most frequently observedb adverse reactions during treatment with somatropin
(including events observed in patients who received brands of somatropin other than Humatrope):
• aSudden death in pediatric patients with Prader-Willi syndrome who had risk factors including severe obesity,
history of upper airway obstruction or sleep apnea and unidentified respiratory infection [see Contraindications
(4.2) and Warnings and Precautions (5.2)]
• aIntracranial tumors, in particular meningiomas, in teenagers/young adults treated with radiation to the head for a
first neoplasm who subsequently receive somatropin [see Contraindications (4.3) and Warnings and Precautions
(5.3)]
• aPancreatitis [see Warnings and Precautions (5.12)]
• a,bGlucose intolerance including impaired glucose tolerance/impaired fasting glucose as well as overt diabetes
mellitus [see Warnings and Precautions (5.4)]
• aIntracranial hypertension [see Warnings and Precautions (5.5)]
• aSignificant diabetic retinopathy [see Contraindications (4.4)]
• aSlipped capital femoral epiphysis in pediatric patients [see Warnings and Precautions (5.9)]
• aProgression of preexisting scoliosis in pediatric patients [see Warnings and Precautions (5.10)]
• bFluid retention manifested by edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel
syndrome/paraesthesias [see Warnings and Precautions (5.6)]
• aUnmasking of latent central hypothyroidism [see Warnings and Precautions (5.8)]
• aInjection site reactions/rashes and lipoatrophy (as well as rare generalized hypersensitivity reactions) [see Warnings
and Precautions (5.13)]
6.2
Clinical Trials Experience
Because clinical trials are conducted under varying conditions, adverse reaction rates observed during the clinical trials
performed with one somatropin formulation cannot always be directly compared to the rates observed during the clinical trials
performed with a second somatropin formulation, and may not reflect the adverse reaction rates observed in practice.
Pediatric Patients
GH Deficiency
As with all protein pharmaceuticals, a small percentage of patients may develop antibodies to the protein. During the first
6 months of Humatrope therapy in 314 naive patients, only 1.6% developed specific antibodies to Humatrope (binding capacity
≥0.02 mg/L). None had antibody concentrations which exceeded 2 mg/L. Throughout 8 years of this same study, two patients (0.6%)
had binding capacity >2 mg/L. Neither patient demonstrated a decrease in growth velocity at or near the time of increased antibody
production. It has been reported that growth attenuation from pituitary-derived GH may occur when antibody concentrations are
>1.5 mg/L.
In addition to an evaluation of compliance with the treatment program and of thyroid status, testing for antibodies to
somatropin should be carried out in any patient who fails to respond to therapy.
In studies with GH deficient pediatric patients, injection site pain was reported infrequently. A mild and transient edema,
which appeared in 2.5% of patients, was observed early during the course of treatment.
Turner Syndrome
In a randomized, concurrent-controlled, open-label trial, there was a statistically significant increase in the occurrence of otitis
media (43% vs. 26%), ear disorders (18% vs. 5%) and surgical procedures (45% vs. 27%) in patients receiving Humatrope compared
with untreated control patients (Table 1). A similar increase in otitis media was observed in an 18-month placebo-controlled trial.
Table 1: Treatment-Emergent Adverse Reactions of Special Interest by Treatment Group in Turner Syndrome
Treatment Groupa
Adverse Reaction
Untreated
Humatropeb
Significance
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
Total Number of Patients
62
74
Surgical procedure
17 (27.4%)
33 (44.6%)
p≤0.05
Otitis media
16 (25.8%)
32 (43.2%)
p≤0.05
Ear disorders
3 (4.8%)
13 (17.6%)
p≤0.05
a Open-label study.
b Dose=0.3 mg/kg/wk.
Idiopathic Short Stature
In a randomized, placebo-controlled study of Humatrope treatment (0.22 mg/kg/week) to adult height in patients with
idiopathic short stature, the adverse events reported in Humatrope-treated patients (Table 2) were similar to those observed in other
pediatric populations treated with Humatrope. Mean serum glucose concentration did not change during Humatrope treatment. Mean
fasting serum insulin concentration increased 10% in the Humatrope treatment group at the end of treatment relative to baseline, but
remained within the normal reference range. For the same duration of treatment, the mean fasting serum insulin concentration
decreased by 2% in the placebo group. The occurrence rates of above-range values for glucose, insulin, and HbA1c were similar in the
Humatrope (somatropin)- and placebo-treated groups. No patient developed diabetes mellitus. Consistent with the known mechanism
of growth hormone action, Humatrope-treated patients had greater mean increases, relative to baseline, in serum insulin-like growth
factor-I (IGF-I) than placebo-treated patients at each study observation. However, there was no significant difference between the
Humatrope and placebo treatment groups in the proportion of patients who had at least one serum IGF-I concentration more than
2.0 SD above the age- and gender-appropriate mean (Humatrope: 9 of 35 patients [26%]; placebo: 7 of 28 patients [25%]).
Table 2: Non-serious Clinically Significant Treatment-Emergent Adverse Reactions by Treatment Group in Idiopathic Short
Stature
Treatment Group
Adverse Reaction
Placebo
Humatrope
Total Number of Patients
31
37
Scoliosis
4 (12.9%)
7 (18.9%)
Otitis media
2 (6.5%)
6 (16.2%)
Hyperlipidemia
1 (3.2%)
3 (8.1%)
Gynecomastia
1 (3.2%)
2 (5.4%)
Hip pain
0
1 (2.7%)
Arthralgia
1 (3.2%)
4 (10.8%)
Arthrosis
2 (6.5%)
4 (10.8%)
Myalgia
4 (12.9%)
9 (24.3%)
Hypertension
0
1 (2.7%)
The adverse events observed in the dose-response study (239 patients treated for 2 years) did not indicate a pattern suggestive
of a somatropin dose effect. Among Humatrope dose groups, mean fasting blood glucose, mean glycosylated hemoglobin, and the
incidence of elevated fasting blood glucose concentrations were similar. One patient developed abnormalities of carbohydrate
metabolism (glucose intolerance and high serum HbA1c) on treatment.
SHOX Deficiency
Clinically significant adverse events (adverse events previously observed in association with growth hormone treatment in
general) were assessed prospectively during the 2-year randomized, open-label study; those observed are presented in Table 3. In both
treatment groups, the mean fasting plasma glucose concentration at the end of the first year was similar to the baseline value and
remained in the normal range. No patient developed diabetes mellitus or had an above normal value for fasting plasma glucose at the
end of one-year of treatment. During the 2 year study period, the proportion of patients who had at least one IGF-I concentration
greater than 2.0 SD above the age- and gender-appropriate mean was 10 of 27 [37.0%] for the Humatrope-treated group vs. 0 of 24
patients [0.0%] for the untreated group. The proportion of patients who had at least one IGFBP-3 concentration greater than 2.0 SD
above the age and gender appropriate mean was 16 of 27 [59.3%] for the Humatrope treated group vs. 7 of 24 [29.2%] for the
untreated group.
Table 3: Clinically Significant Treatment-Emergent Adverse Reactionsa,b by Treatment Group in Patients with SHOX
Deficiency
Treatment Group
Adverse Reaction
Untreated
Humatrope
Total Number of Patients
25
27
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
Patients with at least one event
2
5
Arthralgia
2 (8.0%)
3 (11.1%)
Gynecomastiac
0 (0.0%)
1 (8.3%)
Excessive number of cutaneous nevi
0 (0.0%)
2 (7.4%)
Scoliosis
0 (0.0%)
1 (3.7%)
a All events were non-serious.
b Events are included only if reported for a greater number of Humatrope-treated than Untreated patients.
c Percentage calculated for males only (1/12).
Small for Gestational Age
Study 1 — In a 2-year, multicenter, randomized study, 193 non-GH deficient children with short stature born SGA who failed
to demonstrate catch-up growth were treated with 2 different Humatrope treatment regimens: a fixed dose of 0.067 mg/kg/day (FHD
group) or an individually adjusted dose regimen (IAD group; starting dose 0.035 mg/kg/day which could be increased as early as
Month 3 to 0.067 mg/kg/day based on a validated growth prediction model). The most frequently reported adverse events were
common childhood infectious diseases. Adverse events possibly/probably related to Humatrope were otitis media and headaches
(where there was a suggestion of a modest dose response), and slipped capital femoral epiphysis (1 child) [see Warnings and
Precautions (5.9) and Adverse Reactions (6.1)]. There were no clear cut cases of new-onset diabetes mellitus, no children treated for
hyperglycemia, and no children whose fasting blood glucose exceeded 126 mg/dL at any time during the study. However, 6 children
(4 in the FHD group and 2 in the IAD group whose dose was increased from 0.035 mg/kg/day to 0.067 mg/kg/day [one at Month 3
and one at Year 1]) manifested impaired fasting glucose at Year 2. Two of these six children displayed impaired fasting glucose
during the study as well, and one of them was required to discontinue Humatrope at Month 15 as a consequence [see Warnings and
Precautions (5.4) and Adverse Reactions (6.1)]. A modestly dose-dependent increase in mean serum IGF-I SDS concentrations within
the reference range was observed; of note, at study completion, 20-25% of these children had serum IGF-I SDS values > +2.
Study 2 — A 2-year, open-label, single-arm study of Humatrope at a dosage of 0.067 mg/kg/day in 35 non-GH deficient
children with short stature born SGA who failed to demonstrate catch-up growth did not reveal further safety data of note.
Study 3 — Additional safety information was obtained from 340 short children born SGA followed in an observational study
who received an average Humatrope dosage of 0.041 mg/kg/day (maximum dose: 0.084 mg/kg/day) for an average of 3.0 years. Type
2 diabetes mellitus apparently precipitated by Humatrope therapy was reported in a single patient, but appeared to resolve after
discontinuation of Humatrope treatment, as the child had a normal oral glucose tolerance test and was receiving no antihyperglycemic
medications 9 months after the drug was discontinued. One patient manifested carpal tunnel syndrome [see Adverse Reactions (6.1)]
and another developed an exacerbation of preexisting scoliosis [see Warnings and Precautions (5.10) and Adverse Reactions (6.1)]
which may have been related to Humatrope treatment.
In both Study 1 and Study 2, after treatment with Humatrope, bone maturation did not accelerate excessively, and the timing
of puberty was age-appropriate in boys and girls.
Therefore, it can be concluded that no novel adverse events potentially related to treatment with Humatrope were reported in
either short-term study or were apparent after a review of the post-marketing, observational, safety database.
Adult Patients
In clinical studies in which high doses of Humatrope were administered to healthy adult volunteers, the following events
occurred infrequently: headache, localized muscle pain, weakness, mild hyperglycemia, and glucosuria.
Adult-Onset GH Deficiency
In the first 6 months of controlled blinded trials during which patients received either Humatrope or placebo, adult-onset GH
deficient adults who received Humatrope experienced a statistically significant increase in edema (Humatrope 17.3% vs.
placebo 4.4%, p=0.043) and peripheral edema (11.5% vs. 0%, respectively, p=0.017). In patients with adult-onset GH deficiency,
edema, muscle pain, joint pain, and joint disorder were reported early in therapy and tended to be transient or responsive to dosage
titration.
Two of 113 adult-onset patients developed carpal tunnel syndrome after beginning maintenance therapy without a low dose
(0.00625 mg/kg/day) lead-in phase. Symptoms abated in these patients after dosage reduction.
All treatment-emergent adverse events with ≥5% overall occurrence rate during 12 or 18 months of replacement therapy with
Humatrope are shown in Table 4 (adult-onset patients) and in Table 5 (childhood-onset patients).
Adult patients treated with Humatrope who had been diagnosed with GH deficiency in childhood reported side effects less
frequently than those with adult-onset GH deficiency.
Table 4: Treatment-Emergent Adverse Reactions with ≥5% Overall Occurrence in Adult-Onset Growth Hormone-Deficient
Patients Treated with Humatrope for 18 Months as Compared with 6-Month Placebo and 12-Month Humatrope Exposurea
18 Months Exposure
[Placebo (6 Months)/GH (12 Months)]
(N=46)
18 Months GH Exposure
(N=52)
Adverse Reaction
n
%
n
%
Edemab
7
15.2
11
21.2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
Arthralgia
7
15.2
9
17.3
Paresthesia
6
13.0
9
17.3
Myalgia
6
13.0
7
13.5
Pain
6
13.0
7
13.5
Rhinitis
5
10.9
7
13.5
Peripheral edemac
8
17.4
6
11.5
Back pain
5
10.9
5
9.6
Headache
5
10.9
4
7.7
Hypertension
2
4.3
4
7.7
Acne
0
0
3
5.8
Joint disorder
1
2.2
3
5.8
Surgical procedure
1
2.2
3
5.8
Flu syndrome
3
6.5
2
3.9
a Abbreviations: GH=Humatrope; N=number of patients receiving treatment in the period stated; n=number of patients reporting each
treatment-emergent adverse event.
b p=0.04 as compared to placebo (6 months).
c p=0.02 as compared to placebo (6 months).
Childhood-Onset GH Deficiency
Two double-blind, placebo-controlled trials were conducted in 67 adult patients with childhood-onset GH deficiency who had
received previous somatropin treatment during childhood. Patients were randomized to receive either placebo injections or Humatrope
(0.00625 mg/kg/day [6.25 µg/kg/day] for the first 4 weeks, then 0.0125 mg/kg/day [12.5 µg/kg/day] thereafter) for the first 6 months,
followed by open-label Humatrope for the next 12 months for all patients. The patients in these studies reported side effects less
frequently than those with adult-onset GH deficiency. During the placebo-controlled phase (first 6 months) of the study, elevations of
serum glutamic oxaloacetic transferase were reported significantly more often for Humatrope-treated (12.5%) than placebo-treated
patients (0.0%, p=0.031). No other events were reported significantly more often for Humatrope-treated patients during the placebo-
controlled phase. The following events were reported for at least 5% of patients in either of the 2 treatment groups over the 18-month
duration of the study, listed in descending order of maximum frequency for either group: aspartate aminotransferase increased 13%,
headache 11%, edema 9%, pain 9%, alanine aminotransferase increased 6%, asthenia 6%, myalgia 6%, respiratory disorder 6%.
Table 5: Treatment-Emergent Adverse Reactions with ≥5% Overall Occurrence in Childhood-Onset Growth
Hormone-Deficient Patients Treated with Humatrope for 18 Months as Compared with 6-Month Placebo and 12-Month
Humatrope Exposurea
18 Months Exposure
[Placebo (6 Months)/GH (12 Months)]
(N=35)
18 Months GH Exposure
(N=32)
Adverse Reaction
n
%
n
%
Flu syndrome
8
22.9
5
15.6
AST increasedb
2
5.7
4
12.5
Headache
4
11.4
3
9.4
Asthenia
1
2.9
2
6.3
Cough increased
0
0
2
6.3
Edema
3
8.6
2
6.3
Hypesthesia
0
0
2
6.3
Myalgia
2
5.7
2
6.3
Pain
3
8.6
2
6.3
Rhinitis
2
5.7
2
6.3
ALT increased
2
5.7
2
6.3
Respiratory disorder
2
5.7
1
3.1
Gastritis
2
5.7
0
0
Pharyngitis
5
14.3
1
3.1
a Abbreviations: GH=Humatrope; N=number of patients receiving treatment in the period stated; n=number of patients reporting each
treatment-emergent adverse event; ALT=alanine aminotransferase, formerly SGPT; AST=aspartate aminotransferase, formerly
SGOT.
b p=0.03 as compared to placebo (6 months).
6.3
Post-Marketing Experience
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
Because these adverse events 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. The adverse events reported during post-
marketing surveillance do not differ from those listed/discussed above in Sections 6.1 and 6.2 in children and adults.
Other adverse events that have been reported in somatropin-treated patients include the following:
Neurologic — Headaches (common in children and occasional in adults).
Skin — Increase in size or number of cutaneous nevi, especially in patients with Turner syndrome and those with SHOX
deficiency [see Warnings and Precautions (5.3)].
Endocrine — Gynecomastia.
Gastrointestinal — Pancreatitis. Cases of pancreatitis have been reported rarely in children and adults receiving somatropin
treatment, with some evidence supporting a greater risk in children compared with adults. Published literature indicates that girls who
have Turner syndrome may be at greater risk than other somatropin-treated children. Pancreatitis should be considered in any
somatropin-treated patient, especially a child, who develops abdominal pain [see Warnings and Precautions (5.12)].
Neoplasia — Leukemia has been reported in a small number of GH deficient children treated with somatropin, somatrem
(methionylated rhGH), and GH of pituitary origin. It is uncertain whether these cases of leukemia are related to GH therapy, the
pathology of GH deficiency itself, or other associated treatments such as radiation therapy. On the basis of current evidence, experts
have not been able to conclude that GH therapy per se was responsible for these cases of leukemia. The risk for children with GH
deficiency, if any, remains to be established [see Contraindications (4.3) and Warnings and Precautions (5.3)].
In an ongoing post-marketing observational study of somatropin treatment in 3,102 GH-deficient adults, hypertension,
dyspnea, and sleep apnea were reported by 1% to less than 10% of patients after various durations of treatment.
7
DRUG INTERACTIONS
7.1
11β-Hydroxysteroid Dehydrogenase Type 1
The microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) is required for conversion of cortisone to its
active metabolite, cortisol, in hepatic and adipose tissue. GH and somatropin inhibit 11βHSD-1. Consequently, individuals with
untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol. Introduction of somatropin treatment may result in
inhibition of 11βHSD-1 and reduced serum cortisol concentrations. As a consequence, previously undiagnosed central (secondary)
hypoadrenalism may be unmasked and glucocorticoid replacement may be required in patients treated with somatropin. In addition,
patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their
maintenance or stress doses following initiation of somatropin treatment; this may be especially true for patients treated with cortisone
acetate and prednisone since conversion of these drugs to their biologically active metabolites is dependent on the activity of
11βHSD-1.
7.2
Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment
Pharmacologic glucocorticoid therapy and supraphysiologic glucocorticoid treatment may attenuate the growth promoting
effects of somatropin in children. Therefore, glucocorticoid replacement dosing should be carefully adjusted in children receiving
concomitant somatropin and glucocorticoid treatments to avoid both hypoadrenalism and an inhibitory effect on growth.
7.3
Cytochrome P450-Metabolized Drugs
Limited published data indicate that somatropin treatment increases cytochrome P450 (CP450)-mediated antipyrine clearance
in man. These data suggest that somatropin administration may alter the clearance of compounds metabolized by CP450 liver enzymes
(e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine). Therefore, careful monitoring is advised when somatropin is
administered in combination with drugs metabolized by CP450 liver enzymes. However, formal drug interaction studies have not been
conducted.
7.4
Oral Estrogen
Because oral estrogens may reduce the serum IGF-I response to somatropin treatment, girls and women receiving oral
estrogen replacement may require greater somatropin dosages [see Dosage and Administration (2.4)].
7.5
Insulin and/or Other Hypoglycemic Agents
Patients with diabetes mellitus who receive concomitant treatment with somatropin may require adjustment of their doses of
insulin and/or other hypoglycemic agents [see Warnings and Precautions (5.4)].
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category C — Animal reproduction studies have not been conducted with Humatrope. It is not known whether
Humatrope can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Humatrope should be
given to a pregnant woman only if clearly needed.
8.3
Nursing Mothers
There have been no studies conducted with Humatrope in 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 Humatrope is administered to a
nursing woman.
8.5
Geriatric Use
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
The safety and effectiveness of Humatrope in patients aged 65 years and over has not been evaluated in clinical studies.
Elderly patients may be more sensitive to the action of somatropin, and therefore may be more prone to development of adverse
reactions. A lower starting dose and smaller dose increments should be considered for older patients [see Dosage and Administration
(2.4)].
9
DRUG ABUSE AND DEPENDENCE
Inappropriate use of somatropin by individuals who do not have indications for which somatropin is approved, may result in
significant negative health consequences. Somatropin is not a drug of dependence.
10
OVERDOSAGE
Short-term — Acute overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia.
Long-term — Long-term overdosage could result in signs and symptoms of gigantism or acromegaly consistent with the
known effects of excess endogenous human GH.
11
DESCRIPTION
Humatrope (somatropin, rDNA origin, for injection) is a polypeptide hormone of recombinant DNA origin. Humatrope is
synthesized in a strain of Escherichia coli that has been modified by the addition of the gene for human GH. The peptide is comprised
of 191 amino acid residues and has a molecular weight of about 22,125 daltons. The amino acid sequence of the peptide is identical to
that of human GH of pituitary origin.
Humatrope is a sterile, white, lyophilized powder intended for subcutaneous or intramuscular administration after
reconstitution to its liquid form. Humatrope is a highly purified preparation. Phosphoric acid and/or sodium hydroxide may have been
added to adjust the pH. Reconstituted solutions have a pH of approximately 7.5. This product is oxygen sensitive.
Vial — Each vial of Humatrope contains 5 mg somatropin (15 IU or 225 nanomoles); 25 mg mannitol; 5 mg glycine; and
1.13 mg dibasic sodium phosphate. Each vial is supplied in a combination package with an accompanying 5-mL vial of diluting
solution (diluent). The diluent contains Water for Injection with 0.3% metacresol as a preservative and 1.7% glycerin.
Cartridge — Cartridges of Humatrope contain either 6 mg (18 IU), 12 mg (36 IU), or 24 mg (72 IU) of somatropin. Each
Humatrope cartridge contains the following:
Cartridge
6 mg
(gold)
12 mg
(teal)
24 mg
(purple)
Component
Somatropin
6 mg
12 mg
24 mg
Mannitol
18 mg
36 mg
72 mg
Glycine
6 mg
12 mg
24 mg
Dibasic sodium phosphate
1.36 mg
2.72 mg
5.43 mg
Each cartridge is supplied in a combination package with an accompanying syringe containing approximately 3 mL of diluting
solution (diluent). The diluent contains Water for Injection; 0.3% metacresol as a preservative; and 1.7%, 0.29%, and 0.29% glycerin
in the 6, 12, and 24 mg cartridges, respectively.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
GH binds to dimeric GH receptors located within the cell membranes of target tissue cells. This interaction results in
intracellular signal transduction and subsequent induction of transcription and translation of GH-dependent proteins including IGF-I,
IGF BP-3 and acid-labile subunit. GH has direct tissue and metabolic effects, including stimulation of chondrocyte differentiation,
stimulation of lipolysis and stimulation of hepatic glucose output. In addition, some effects of somatropin are mediated indirectly by
IGF-I, including stimulation of protein synthesis and chondrocyte proliferation.
12.2
Pharmacodynamics
In vitro, preclinical, and clinical testing have demonstrated that Humatrope is therapeutically equivalent to human GH of
pituitary origin and achieves equivalent pharmacokinetic profiles in healthy adults. The following effects have been reported for
human GH of pituitary origin, and/or somatropin.
Cell Growth — Total numbers of muscle cells are reduced in GH deficient children. Somatropin increases the number and
size of muscle cells in such children.
Skeletal Growth — Somatropin stimulates skeletal growth in children with GH deficiency as a result of effects on the growth
plates (epiphyses) of long bones. Concentrations of IGF-I, which play a role in skeletal growth, are low in the serum of GH deficient
children but increase during somatropin treatment in most patients. The stimulation of skeletal growth increases linear growth rate
(height velocity) in most somatropin-treated children.
Protein Metabolism — Linear growth is facilitated in part by increased cellular protein synthesis as reflected by nitrogen
retention, which can be demonstrated by decreased urinary nitrogen excretion and serum urea nitrogen.
Connective Tissue Metabolism — Somatropin stimulates the synthesis of chondroitin sulfate and collagen, and increases the
urinary excretion of hydroxyproline.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
Carbohydrate Metabolism — GH has a physiological role in the maintenance of normoglycemia during times of substrate
restriction (e.g., fasting), via mechanisms such as stimulation of hepatic gluconeogenesis and suppression of insulin-stimulated
glucose uptake by peripheral tissues. Because of these actions GH is considered an insulin antagonist with respect to carbohydrate
metabolism. Consequently, the fasting hypoglycemia that may occur in some children with hypopituitarism may be improved by
somatropin treatment. As an extension of its physiological actions, supraphysiological GH concentrations may increase glucose
production sufficiently to stimulate insulin secretion to maintain normoglycemia. Large doses of somatropin may impair glucose
tolerance if compensatory insulin secretion is inadequate. Administration of somatropin to healthy adults and patients with
Turner syndrome resulted in increases in mean serum fasting and postprandial insulin concentrations, although mean values remained
in the normal range. In addition, mean HbA1c concentrations and mean fasting and postprandial glucose concentrations remained in
the normal range.
Lipid Metabolism — Somatropin stimulates intracellular lipolysis, and administration of somatropin leads to an increase in
plasma free fatty acids and triglycerides. Untreated GH deficiency is associated with increased body fat stores, including increased
abdominal visceral and subcutaneous adipose tissue. Treatment of GH deficient patients with somatropin results in a general reduction
of fat stores, and decreased serum concentrations of low density lipoprotein (LDL) cholesterol.
Mineral Metabolism — Administration of somatropin results in an increase in total body potassium and phosphorus and to a
lesser extent sodium, probably as the result of cell growth. Serum concentrations of inorganic phosphate increase in somatropin-
treated GH deficient children because of the metabolic activities associated with bone growth. Although urinary calcium excretion is
increased, there is a simultaneous increase in calcium absorption from the intestine. Consequently, serum calcium concentrations
generally are not altered, although negative calcium balance may occur occasionally during somatropin treatment. Associated with the
changes in mineral metabolism, parathyroid hormone may increase during somatropin treatment.
12.3
Pharmacokinetics
Absorption — Humatrope has been studied following intramuscular, subcutaneous, and intravenous administration in adult
volunteers (see Figure 1). The absolute bioavailability of somatropin is 75% and 63% after subcutaneous and intramuscular
administration, respectively.
Distribution — The volume of distribution of somatropin after intravenous injection is about 0.07 L/kg (Table 6).
Metabolism — Extensive metabolism studies have not been conducted. The metabolic fate of somatropin involves classical
protein catabolism in both the liver and kidneys. In renal cells, at least a portion of the breakdown products of somatropin is returned
to the systemic circulation. In healthy volunteers, mean somatropin clearance is 0.14 L/hr/kg. The mean half-life of intravenous
somatropin is 0.36 hours, whereas subcutaneously and intramuscularly administered somatropin have mean half-lives of 3.8 and
4.9 hours, respectively. The longer half-life observed after subcutaneous or intramuscular administration is due to slow absorption
from the injection site.
Excretion — Urinary excretion of intact Humatrope has not been measured. Small amounts of somatropin have been detected
in the urine of pediatric patients following replacement therapy.
Geriatric patients — The pharmacokinetics of Humatrope have not been studied in patients greater than 65 years of age.
Pediatric patients — The pharmacokinetics of Humatrope in pediatric patients are similar to those of adults.
Gender — No gender-specific pharmacokinetic studies have been performed with Humatrope. The available literature
indicates that the pharmacokinetics of somatropin are similar in men and women.
Race — No data are available.
Renal, hepatic insufficiency — No studies have been performed with Humatrope.
Table 6: Summary of Somatropin Parameters in Healthy Adult Volunteersa
Cmax
(ng/mL)
t1/2
(hr)
AUC0-∞
(ngyhr/mL)
Cls
(L/kgyhr)
Vβ
(L/kg)
0.02 mg (0.05 IUb)/kg, iv
Mean (SD)
415 (75)
0.363 (0.053)
156 (33)
0.135 (0.029)
0.0703 (0.0173)
0.1 mg (0.27 IUb)/kg, im
Mean (SD)
53.2 (25.9)
4.93 (2.66)
495 (106)
0.215 (0.047)
1.55 (0.91)
0.1 mg (0.27 IUb)/kg, sc
Mean (SD)
63.3 (18.2)
3.81 (1.40)
585 (90)
0.179 (0.028)
0.957 (0.301)
a Abbreviations: Cmax=maximum concentration; t1/2=half-life; AUC0-∞=area under the curve; Cls=systemic clearance; Vβ=volume
distribution; iv=intravenous; SD=standard deviation; im=intramuscular; sc=subcutaneous.
b Based on previous International Standard of 2.7 IU=1 mg.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
Figure 1
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
There has been no evidence to date of Humatrope-induced mutagenicity. No long-term animal studies for carcinogenicity or
impairment of fertility with somatropin have been performed.
14
CLINICAL STUDIES
14.1
Adult Patients with Growth Hormone Deficiency
Two multicenter trials in patients with adult-onset GH deficiency (n=98) and two studies in patients with childhood-onset
GH deficiency (n=67) were designed to assess the effects of replacement therapy with Humatrope. These four studies each included a
6-month randomized, blinded, placebo-controlled phase, during which approximately half of the patients received placebo injections,
while the other half received Humatrope injections. The Humatrope dosages for all studies were identical: 1 month of treatment at
0.00625 mg/kg/day (6.25µg/kg/day) followed by 0.0125 mg/kg/day (12.5 µg/kg/day) for the next 5 months. The 6-month, double-
blind phase was followed by 12 months of open-label Humatrope treatment for all patients. The primary efficacy measures were body
composition (lean body mass and fat mass), lipid parameters, and quality of life, as measured by the Nottingham Health Profile (a
general health-related quality of life questionnaire). Lean body mass was determined by bioelectrical impedance analysis (BIA),
validated with potassium 40. Body fat was assessed by BIA and sum of skinfold thickness. Lipid subfractions were analyzed by
standard assay methods in a central laboratory. Adult-onset patients and childhood-onset patients differed by diagnosis (organic vs.
idiopathic pituitary disease), body size (average vs. small [mean height and weight]), and age (mean 44 vs. 29 years).
In patients with adult-onset GH deficiency, Humatrope treatment (vs. placebo) resulted in an increase in mean lean body
mass (2.59 vs. -0.22 kg, p<0.001) and a decrease in body fat (-3.27 vs. 0.56 kg, p<0.001). Similar changes were seen in
childhood-onset GH deficient patients. These significant changes in lean body mass persisted throughout the 18-month period for both
the adult-onset and childhood-onset groups; the changes in fat mass persisted in the childhood-onset group. Serum concentrations of
high-density lipoprotein (HDL) cholesterol which were low at baseline (mean, 30.1 mg/mL and 33.9 mg/mL in adult-onset and
childhood-onset patients, respectively) had normalized by the end of 18 months of Humatrope treatment (mean change of 13.7 and
11.1 mg/dL for the adult-onset and childhood-onset groups, respectively p<0.001). After 6 months, the physical mobility and social
isolation domains on the Nottingham Health Profile were significantly improved in Humatrope-treated vs. placebo-treated patients
with adult-onset GH deficiency (p<0.01) (Table 7). There were no significant between-group differences (Humatrope vs. placebo) for
the other Nottingham Health Profile domains (energy level, emotional reactions, sleep, pain) in patients with adult-onset GH
deficiency, and no significant between-group differences in any of the domains were demonstrated for patients with childhood-onset
GH deficiency.
Two additional studies on the effect of Humatrope on exercise capacity were conducted. Improved physical function was
documented by increased exercise capacity (VO2 max, p<0.005) and work performance (Watts, p<0.01).
Table 7: Changesa in Nottingham Health Profile Scoresb in Adult-Onset Growth Hormone-Deficient Patients
Outcome Measure
Placebo
(6 Months)
Humatrope Therapy
(6 Months)
Significance
Energy level
-11.4
-15.5
NS
Physical mobility
-3.1
-10.5
p<0.01
Social isolation
0.5
-4.7
p<0.01
Emotional reactions
-4.5
-5.4
NSc
Sleep
-6.4
-3.7
NSc
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
Pain
-2.8
-2.9
NSc
a An improvement in score is indicated by a more negative change in the score.
b To account for multiple analyses, appropriate statistical methods were applied and the required level of significance is 0.01.
c NS=not significant.
Two studies evaluating the effect of Humatrope on bone mineralization were conducted subsequently. In a 2-year,
randomized, double-blind, placebo-controlled trial, 67 patients with previously untreated adult-onset GH deficiency received placebo
or Humatrope injections titrated to maintain serum IGF-I within the age-adjusted normal range. In men, but not women, lumbar spine
bone mineral density (BMD) increased with Humatrope treatment compared to placebo, with a treatment difference of
approximately 4% (p=0.001). There was no significant change in hip BMD with Humatrope treatment in men or women, when
compared to placebo.
In a 2-year, open-label, randomized trial, 149 patients with childhood-onset GH deficiency who had completed pediatric
somatropin therapy, had attained final height (height velocity <1 cm/yr) and were confirmed to be GH-deficient as young adults
(commonly referred to as transition patients), were randomized to receive Humatrope 0.0125 mg/kg/day (12.5 µg/kg/day), Humatrope
0.025 mg/kg/day (25 µg/kg/day), or no injections (control). Patients who were randomized to treatment with Humatrope at
12.5 µg/kg/day achieved a 2.9% greater increase from baseline than control patients in total body bone mineral content (BMC)
(8.1 ± 9.0% vs. 5.2 ± 8.2%, p=0.02), whereas patients treated with Humatrope at 25 µg/kg/day had no significant change in BMC.
These results include data from patients who received less than 2 years of treatment. A greater treatment effect was observed for
patients who completed 2 years of treatment. Increases in lumbar spine BMD and BMC were also statistically significant compared to
control with the 12.5 µg/kg/day dose but not the 25 µg/kg/day dose. Hip BMD and BMC did not change significantly compared to
control with either dose. The effect of GH treatment on BMC and BMD in transition patients at doses lower than12.5 µg/kg/day was
not studied. The effect of Humatrope on the occurrence of osteoporotic fractures has not been studied.
14.2
Pediatric Patients with Turner Syndrome
One long-term, randomized, open-label, Canadian multicenter, concurrently controlled study, two long-term, open-label
multicenter, historically controlled US studies and one long-term, randomized, US dose-response study were conducted to evaluate the
efficacy of somatropin treatment of short stature due to Turner syndrome.
The Canadian randomized study compared near-adult height outcomes for Humatrope-treated patients to those of a concurrent
control group who received no injections. The Humatrope-treated patients received a dosage of 0.3 mg/kg/week given in divided doses
6 times per week from a mean age of 11.7 years for a mean duration of 4.7 years. Puberty was induced with a standardized estrogen
regimen initiated at 13 years of age for both treatment groups. The Humatrope-treated group (n=27) attained a mean (± SD) near-final
height of 146.0 ± 6.2 cm; the untreated control group (n=19) attained a near-final height of 142.1 ± 4.8 cm. By analysis of covariance
(with adjustments for baseline height and mid-parental height), the effect of somatropin treatment was a mean height increase of
5.4 cm (p=0.001).
In two of the US studies, the effect of long-term somatropin treatment (0.375 mg/kg/week given in divided doses either
3 times per week or daily) on adult height was determined by comparing adult heights in the treated patients with those of
age-matched historical controls with Turner syndrome who received no growth-promoting therapy. Puberty was induced with a
standardized estrogen regimen initiated after 14 years of age in one study; in the second study patients treated with early somatropin
(before 11 years of age) were randomized to begin pubertal induction at either age 12 (n=26) or 15 (n=29) years (conjugated
estrogens, 0.3 mg escalating to 0.625 mg daily); those whose somatropin was initiated after 11 years of age began estrogen
replacement after 1 year of somatropin. Mean height gains from baseline to adult (or near-adult) height ranged from 5.0 to 8.3 cm,
depending on age at initiation of somatropin treatment and estrogen replacement (Table 8).
In the third US study, a randomized, blinded dose-response study, patients were treated from a mean age of 11.1 years for a
mean duration of 5.3 years with a weekly Humatrope dosage of either 0.27 mg/kg or 0.36 mg/kg administered in divided doses 3 or
6 times weekly. The mean near-final height of Humatrope-treated patients was 148.7 ± 6.5 cm (n=31). When compared to historical
control data, the mean gain in adult height was approximately 5 cm.
In summary, patients with Turner syndrome (total n=181 from the 4 studies above) treated to adult height achieved
statistically significant average height gains ranging from 5.0 to 8.3 cm.
Table 8: Summary Table of Efficacy Resultsa
Study
Group
Study
Designb
Number at Adult
Height
GH
Age (yr)
Estrogen
Age (yr)
GH
Duration (yr)
Adult Height
Gain (cm)c
Canadian
RCT
27
11.7
13
4.7
5.4
US 1
MHT
17
9.1
15.2
7.6
7.4
Ae
MHT
29
9.4
15
6.1
8.3
Bf
26
9.6
12.3
5.6
5.9
US 2
Cg
51
12.7
13.7
3.8
5
US 3
RDT
31
11.1
8-13.5
5.3
~5d
a Data shown are mean values.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
b RCT: randomized controlled trial; MHT: matched historical controlled trial; RDT: randomized dose-response trial.
c Analysis of covariance vs. controls.
d Compared with historical data.
e GH age <11 yr, estrogen age 15 yr.
f GH age <11 yr, estrogen age 12 yr.
g GH age >11 yr, estrogen at month 12.
14.3
Pediatric Patients with Idiopathic Short Stature
Two randomized, multicenter trials, 1 placebo-controlled and 1 dose-response, were conducted in pediatric patients with
idiopathic short stature, also called non-GH-deficient short stature. The diagnosis of idiopathic short stature was made after excluding
other known causes of short stature, as well as GH deficiency. Limited safety and efficacy data are available below the age of 7 years.
No specific studies have been conducted in pediatric patients with familial short stature. The placebo-controlled study enrolled
71 pediatric patients (55 males, 16 females) 9 to 15 years old (mean age 12.4 ± 1.5 years), with short stature, 68 of whom received
Humatrope. Patients were predominately prepubertal (Tanner I, 45%) or in early puberty (Tanner II, 47%) at baseline. In this
double-blind trial, patients received subcutaneous injections of either Humatrope 0.222 mg/kg/week (equivalent to 32 µg/kg/day), or
placebo given in divided doses 3 times per week until height velocity decreased to ≤1.5 cm/year (“final height”). Final height
measurements were available for 33 subjects (22 Humatrope, 11 placebo) after a mean treatment duration of 4.4 years (range 0.1-9.1
years).
The Humatrope-treated group achieved a mean final height SDS of -1.8 (Table 9), whereas placebo-treated patients had a
mean final height SDS of -2.3 (mean treatment difference, 0.51 SDS, p=0.017). Height gain across the duration of the study and final
height SDS minus baseline predicted height SDS were also significantly greater in Humatrope-treated patients than in placebo-treated
patients (Tables 9 and 10). In addition, the number of patients whose final height was above the 5th percentile of the general
population height standard for age and sex was significantly greater in the Humatrope group than the placebo group (41% vs. 0%,
p<0.05), as was the number of patients who gained at least 1 SDS unit in height across the duration of the study (50% vs. 0%, p<0.05).
Table 9: Baseline Height Characteristics and Effect of Humatrope on Final Height in Placebo-Controlled Studya,b
Placebo
(n=11)
Mean (SD)
Humatrope
(n=22)
Mean (SD)
Treatment Effect
Mean
(95%CI)
p-value
Baseline height SDS
-2.75 (0.6)
-2.7 (0.6)
NA
0.77
BPH SDS
-2.3 (0.8)
-2.1 (0.7)
NA
0.53
Final height SDSc
-2.3 (0.6)
-1.8 (0.8)
0.51 (0.10, 0.92)
0.017
FH SDS - baseline height SDS
0.4 (0.2)
0.9 (0.7)
0.51 (0.04, 0.97)
0.034
FH SDS - BPH SDS
-0.1 (0.6)
0.3 (0.6)
0.46 (0.02, 0.89)
0.043
a Abbreviations: BPH=baseline predicted height; CI=confidence interval; FH=final height; NA=not applicable; SDS=standard
deviation score.
b For final height population.
c Between-group comparison was performed using analysis of covariance with baseline predicted height SDS as the covariate.
Treatment effect is expressed as least squares mean (95% CI).
The dose-response study included 239 pediatric patients (158 males, 81 females), 5 to 15 years old, (mean age
9.8 ± 2.3 years). Mean ± SD baseline characteristics included: height SDS -3.21 ± 0.70, predicted adult height SDS -2.63 ± 1.08, and
height velocity SDS -1.09 ± 1.15. All but 3 patients were prepubertal. Patients were randomized to one of three Humatrope treatment
groups: 0.24 mg/kg/week (equivalent to 34 µg/kg/day); 0.24 mg/kg/week for 1 year, followed by 0.37 mg/kg/week (equivalent to
53 µg/kg/day); and 0.37 mg/kg/week. The primary hypothesis of this study was that treatment with Humatrope would increase height
velocity during the first 2 years of therapy in a dose-dependent manner. Additionally, after completing the initial 2-year dose-response
phase of the study, 50 patients were followed to final height.
Patients who received the Humatrope dosage of 0.37 mg/kg/week had a significantly greater increase in mean height velocity
after 2 years of treatment than patients who received 0.24 mg/kg/week (4.04 vs. 3.27 cm/year, p=0.003). The mean difference between
final height and baseline predicted height was 7.2 cm for patients who received Humatrope 0.37 mg/kg/week and 5.4 cm for patients
who received 0.24 mg/kg/week (Table 10). While no patient had height above the 5th percentile in any dosage group at baseline,
82% of the patients who received 0.37 mg/kg/week and 47% of the patients who received 0.24 mg/kg/week achieved final heights
above the 5th percentile of the general population height standards (p=NS).
Table 10: Idiopathic Short Stature Trials: Final Height Minus Baseline Predicted Heighta
Placebo-controlled Trial
3x per week dosing
Dose Response Trial
6x per week dosing
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
Placebo
(n=10)
Humatrope
0.22 mg/kg
(n=22)
Humatrope
0.24 mg/kg
(n=13)
Humatrope
0.24/0.37 mg/kg
(n=13)
Humatrope
0.37 mg/kg
(n=13)
FH - Baseline PH
Mean (95% CI), cm
-0.7 (-3.6, 2.3)
+2.2 (0.4, 3.9)
+5.4 (2.8, 7.9)
+6.7 (4.1, 9.2)
+7.2 (4.6, 9.8)
a Abbreviations: FH=final height; PH=predicted height; CI=confidence interval; cm=centimeters.
14.4
Pediatric Patients with SHOX Deficiency
SHOX deficiency may result either from a deletion of one copy of the short stature homeobox-containing (SHOX) gene or
from a mutation within or outside one copy of the SHOX gene that impairs the production or function of SHOX protein.
A randomized, controlled, two-year, three-arm, open-label study was conducted to evaluate the efficacy of Humatrope
treatment of short stature in pediatric patients with SHOX deficiency who were not GH–deficient. 52 patients (24 male, 28 female)
with SHOX deficiency, 3.0 to 12.3 years of age, were randomized to either a Humatrope-treated arm (27 patients; mean age
7.3 ± 2.1 years) or an untreated control arm (25 patients; mean age 7.5 ± 2.7 years). To determine the comparability of treatment effect
between patients with SHOX deficiency and patients with Turner syndrome, the third study arm enrolled 26 patients with Turner
syndrome, 4.5 to 11.8 years of age (mean age 7.5 ± 1.9 years), to Humatrope treatment. All patients were prepubertal at study entry.
Patients in the Humatrope-treated group(s) received daily subcutaneous injections of 0.05 mg/kg (50 µg/kg) of Humatrope, equivalent
to 0.35 mg/kg/week. Patients in the untreated group received no injections.
Patients with SHOX deficiency who received Humatrope had significantly greater first-year height velocity than untreated
patients (8.7 cm/year vs. 5.2 cm/year, p<0.001, primary efficacy analysis) and similar first-year height velocity to Humatrope-treated
patients with Turner syndrome (8.7 cm/year vs. 8.9 cm/year). In addition, patients who received Humatrope had significantly greater
second year height velocity, and first- and second-year height gain (cm and SDS) than untreated patients (Table 11).
Table 11: Summary of Efficacy Results in Patients with SHOX deficiency and Turner Syndrome
SHOX Deficiency
Turner Syndrome
Untreated
(n=24)
Mean (SD)
Humatrope
(n=27)
Mean (SD)
Treatment
Differencea
Mean (95% CI)
Humatrope
(n=26)
Mean (SD)
Height Velocity (cm/yr)
1st Year
5.2 (1.1)
8.7 (1.6)b
+3.5 (2.8, 4.2)
8.9 (2.0)
2nd Year
5.4 (1.2)
7.3 (1.1)b
+2.0 (1.3, 2.6)
7.0 (1.1)
Height Gain (cm)
Baseline to 1st Year
+5.4 (1.2)
+9.1 (1.5)b
+3.7 (2.9, 4.5)
+8.9 (1.9)
Baseline to 2nd Year
+10.5 (1.9)
+16.4 (2.0)b
+5.8 (4.6, 7.1)
+15.7 (2.7)
Height SDS Gain
Baseline to 1st Year
+0.1 (0.5)
+0.7 (0.5)b
+0.5 (0.3, 0.8)
+0.8 (0.5)
Baseline to 2nd Year
+0.2 (0.5)
+1.2 (0.7)b
+1.0 (0.7, 1.3)
+1.2 (0.7)
Patients with height SDS > -2.0 at 2 years
1 (4%)
11 (41%)c
--
8 (31%)
a Positive values favor Humatrope
b Statistically significantly different from untreated, p<0.001.
c Statistically significantly different from untreated, p<0.05.
14.5
Pediatric Patients Born Small for Gestational Age (SGA) Who Fail to Demonstrate Catch-up Growth by Age 2 -
4 Years
Data from 2 clinical trials demonstrate the effectiveness of Humatrope in promoting linear growth in short children born SGA
who fail to demonstrate catch-up growth.
The primary objective of Study 1 was to demonstrate that the increase from baseline in height SDS after 1 year of treatment
would be similar when Humatrope is administered according to an individually adjusted dose (IAD) regimen or a fixed high dose
(FHD) regimen. The height increases would be considered similar if the lower bound of the 95% confidence interval (CI) for the mean
difference between the groups (IAD – FHD) was greater than -0.5 height SDS. This 2-year, open-label, multicenter, European study
enrolled 193 prepubertal, non-GH deficient children with mean chronological age 6.8 ± 2.4 years (range: 3.0 to 12.3). Additional
study entry criteria included birth weight <10th percentile and/or birth length SDS <-2 for gestational age, and height SDS for
chronological age ≤-3. Exclusion criteria included syndromal conditions (e.g., Turner syndrome), chronic disease (e.g., diabetes
mellitus), and tumor activity. Children were randomized to either a FHD (0.067 mg/kg/day [0.47 mg/kg/week]; n=99) or an IAD
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
treatment group (n=94). The initial Humatrope dosage in the IAD treatment group was 0.035 mg/kg/day (0.25 mg/kg/week). The
dosage was increased to 0.067 mg/kg/day in those patients in the IAD group whose 1-year height gain predicted at Month 3 was <0.75
height SDS (n=40) or whose actual height gain measured at Year 1 was <0.75 height SDS (n=11). Approximately 85% of the
randomized patients completed 2 years of therapy.
At baseline, the FHD and IAD treatment groups had comparable height SDS (mean -3.9; Table 12). Although the mean 1-year
height increase in the IAD group was statistically significantly lower than that observed in the FHD group, the study achieved its
primary objective by demonstrating that the increase from baseline in height SDS in the IAD group was clinically similar (non-
inferior) to that in the FHD group (mean between-group difference = -0.3 SDS [95% CI: -0.4, -0.2 SDS]). The mean changes from
baseline in height SDS at the end of the 2-year study were 1.4 and 1.6 SDS in the IAD and FHD groups, respectively. The results were
similar when children who entered puberty during the study were removed from the analysis.
Table 12: Study 1 – Results for Height SDS and Change from Baseline in Height SDS at Year 1 and Year 2 After Humatrope
Treatment of Short Children Born SGA Who Fail to Demonstrate Catch-up Growtha
IAD Group
0.035 to 0.067 mg/kg/day
Mean (SD)
FHD Group
0.067 mg/kg/day
Mean (SD)
Between-Group
Difference
IAD – FHDb
Baseline
(n=86)
-3.9 (0.6)
(n=93)
-3.9 (0.7)
-0.0 ± 0.1
(-0.2, 0.2)
p-value = 0.95
Year 1
Height SDS
Change from baseline
(n=86)c
-3.0 (0.7)
0.9 (0.4)
(n=93)c
-2.7 (0.7)
1.1 (0.4)
-0.3 ± 0.1
(-0.4, -0.2)
p-value <0.001
Year 2
Height SDS
Change from baseline
(n=82)c
-2.5 (0.8)
1.4 (0.5)
(n=88)c
-2.2 (0.7)
1.6 (0.5)
-0.3 ± 0.1
(-0.4, -0.1)
p-value = 0.003
a Abbreviations: IAD=individually adjusted dose; FHD=fixed high dose; SD=standard deviation; SDS=standard deviation score
b Least squares mean difference ± standard error and 95% confidence interval based on ANCOVA model with treatment and gender as
fixed effects, and baseline height SDS, baseline chronological age, baseline bone age, and mid-parental target height SDS as
covariates.
c Only children with actual height measurements were included in the Year 1 and Year 2 analyses.
Study 2 was an open-label, multicenter, single arm study conducted in France, during which 35 prepubertal, non-GH deficient
children were treated for 2 years with Humatrope 0.067 mg/kg/day (0.47 mg/kg/week). Mean chronological age at baseline was
9.3 ± 0.9 years (range: 6.7 to 10.8). Additional study entry criteria included birth length SDS <-2 or <3rd percentile for gestational
age, and height SDS for chronological age <-2. Exclusion criteria included syndromal conditions (e.g., Turner syndrome), chronic
disease (e.g., diabetes mellitus), and any active disease. All 35 patients completed the study. Mean height SDS increased from a
baseline value of -2.7 (SD 0.5) to -1.5 (SD 0.6) after 2 years of Humatrope treatment.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
Vials
Vial Kit — (6s) NDC 0002-7335-16
5 mg vial (no. 7335) and 5-mL vial of Diluent for Humatrope (No. 7336)
Cartridges
Cartridge Kit (MS8147) NDC 0002-8147-01 (gold)
6 mg cartridge (gold) (VL7554), and prefilled syringe of Diluent for Humatrope (VL7618)
Cartridge Kit (MS8148) NDC 0002-8148-01 (teal)
12 mg cartridge (teal) (VL7555), and prefilled syringe of Diluent for Humatrope (VL7619)
Cartridge Kit (MS8149) NDC 0002-8149-01 (purple)
24 mg cartridge (purple) (VL7556), and prefilled syringe of Diluent for Humatrope (VL7619)
16.2
Storage and Handling
Vials
Before Reconstitution — Vials of Humatrope and Diluent for Humatrope are stable when refrigerated at 2° to 8°C
(36° to 46°F). Avoid freezing Diluent for Humatrope. Expiration dates are stated on the labels.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18
After Reconstitution — Vials of Humatrope are stable for up to 14 days when reconstituted with Diluent for Humatrope or
Bacteriostatic Water for Injection, USP and refrigerated at 2° to 8°C (36° to 46°F). Avoid freezing the reconstituted vial of
Humatrope.
After Reconstitution with Sterile Water, USP — Use only one dose per Humatrope vial and discard the unused portion. If the
solution is not used immediately, it must be refrigerated at 2° to 8°C (36° to 46°F) and used within 24 hours.
Cartridges
Before Reconstitution — Cartridges of Humatrope and Diluent for Humatrope are stable when refrigerated at 2° to 8°C
(36° to 46°F). Avoid freezing Diluent for Humatrope. Expiration dates are stated on the labels.
After Reconstitution — Cartridges of Humatrope are stable for up to 28 days when reconstituted with Diluent for Humatrope
and refrigerated at 2° to 8°C (36° to 46°F). Store the Humatrope injection device without the needle attached. Avoid freezing the
reconstituted cartridge of Humatrope. Cartridges should be reconstituted only with the supplied diluent. Cartridges should not be
reconstituted with the Diluent for Humatrope provided with Humatrope vials, or with any other solution.
17
PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling.
Patients being treated with Humatrope (and/or their parents) should be informed about the potential benefits and risks
associated with Humatrope treatment, and the contents of the Patient Information Insert should be reviewed. This information is
intended to educate patients (and caregivers); it is not a disclosure of all possible intended or adverse effects.
Patients and caregivers who will administer Humatrope should receive appropriate training and instruction on the proper use
of Humatrope from the physician or other suitably qualified health care professional. A puncture-resistant container for the disposal of
used needles and syringes should be strongly recommended. Patients and/or parents should be thoroughly instructed in the importance
of proper disposal, and cautioned against any reuse of needles and syringes. This information is intended to aid in the safe and
effective administration of the medication.
Literature revised MMM DD, YYYY
Manufactured by Lilly France
F-67640 Fegersheim, France
for Eli Lilly and Company
Indianapolis, IN 46285, USA
Copyright © YYYY, Eli Lilly and Company. All rights reserved.
B 0.01 NL 9327 FSAMP
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:35.256719
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019640s078_2lbl.pdf', 'application_number': 19640, 'submission_type': 'SUPPL ', 'submission_number': 78}
|
11,581
|
1
[H
Block
graphic]
PV 6501 AMP
Humatrope®
somatropin (rDNA origin)
for injection
HumatroPen® 6 mg
Growth Hormone Delivery
System
Injection Device for Use
with Humatrope®
[somatropin (rDNA origin)
for injection] Cartridges
PEN USER MANUAL
6
mg Lilly
SECTION 1 Read this section completely before you begin.
Then, move on to Section 2.
WHAT YOU NEED TO KNOW ABOUT THE HUMATROPEN® 6 MG
Read these instructions carefully BEFORE using the HumatroPen® 6 mg. You need to use the Pen
correctly in order to get the most benefit from the Humatrope® treatment. Failure to follow these
instructions completely may result in too much or too little Humatrope being injected.
INTRODUCTION
The HumatroPen 6 mg is an injection device intended for use with Humatrope 6 mg Cartridges. Your
healthcare professional has prescribed the Humatrope dose and Pen that you or your child should
receive.
DO NOT CHANGE the dose or Pen unless directed by your healthcare
professional.
If your healthcare professional changes the prescribed cartridge size from the 6 mg Humatrope
Cartridge to the 12 mg or 24 mg Humatrope Cartridge, you must get a new HumatroPen to match the
new cartridge size.
Before using the HumatroPen 6 mg, make sure that you thoroughly read this user manual. It explains
the Pen operations and has a troubleshooting guide, should questions arise.
These instructions do not take the place of talking with your healthcare professional about your
or your child’s medical condition, or its treatment. If you are having problems using the
HumatroPen 6 mg, call 1-800-545-5979.
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
IMPORTANT INFORMATION ABOUT THE HUMATROPEN 6 MG
•
Where you see
in this manual, please pay special attention.
•
DO NOT USE the Pen if any part of the Pen or Cartridge appears broken or damaged. Contact your
healthcare professional.
•
Confirm that you have a 6 mg Humatrope Cartridge to match the HumatroPen 6 mg. If it does not
match DO NOT USE and contact your healthcare professional. This is important to ensure the
correct dose of Humatrope is given.
•
DO NOT use the Humatrope Cartridge past the expiration date.
•
Follow Section 2 ONLY to set up a new Cartridge before first use.
•
Section 3 of this manual should be used for every injection.
•
DO NOT transfer the contents of the Humatrope Cartridge to a syringe.
•
DO NOT share your HumatroPen 6 mg or needles with anyone else. You may give an infection to
them, or get an infection from them.
•
The HumatroPen 6 mg is not recommended for use by blind or visually impaired individuals without
the assistance of a sighted individual trained in its use.
ABOUT PEN NEEDLES
What kinds of Needles can be used with the HumatroPen 6 mg?
•
Pen Needles are not included. You may need a prescription to get the Needles from your pharmacist.
•
Becton, Dickinson and Company Pen Needles are suitable for use with the HumatroPen 6 mg.
•
Ask your healthcare professional what Needle gauge and length is best to use.
•
Follow your healthcare professional's instructions on safe handling of needles.
Must a new Needle be used for each injection?
•
Yes, a new Needle must be used for each injection.
•
Remove the Needle immediately after each injection. Use a new Needle for each injection. This will
help minimize the risk of infection, prevent leakage of Humatrope, keep out air bubbles, and reduce
Needle clogs.
How do I throw away used Needles?
•
Throw away used Needles in a puncture-proof container. Follow your healthcare professional’s
instructions on how to do this safely.
CARE AND STORAGE FOR THE HUMATROPEN 6 MG
Care
•
Soiled parts can be cleaned with a damp cloth. DO NOT USE alcohol or other cleaning agents.
•
DO NOT SOAK or immerse the Pen in liquid.
•
DO NOT APPLY oil or any other lubricant.
Storage
•
Store the HumatroPen 6 mg with attached Humatrope Cartridge in the storage case in the refrigerator
until the time of the next injection. DO NOT FREEZE.
•
All Humatrope Cartridges and diluent must be refrigerated at temperatures between 36°F to 46°F
(+2°C and +8°C). DO NOT FREEZE. A prepared Cartridge can be left on a Pen for 28 days in the
refrigerator. DO NOT USE any prepared Cartridge after 28 days.
•
Let the HumatroPen 6 mg with attached Humatrope Cartridge stand at room temperature for 10
minutes before injecting. Discomfort may be noticed at the injection site if Humatrope is injected cold.
•
Daily room temperature exposure should not exceed 30 minutes.
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
•
DO NOT STORE the Pen with the Needle attached.
REPLACEMENT
The HumatroPen 6 mg has been designed to be used for up to 3 years after first use. Record the date the
Pen was first used here: __ / __ / __. Contact your healthcare professional if a new HumatroPen 6 mg is
needed, or when the Pen has been used for 3 years.
Please see the accompanying complete Humatrope Patient Information Sheet. For additional
information, call 1-800-545-5979 or visit www.humatrope.com
HUMATROPEN 6 MG PARTS
Humatrope
6 mg Cartridge
6 mg
Injection
(sold separately) Screw
Pen Body
Button Humatropen parts
Pen
Rubber
White
Front
Dose
Dose
Cap
Seal
Tip
Housing
Window
Knob
PEN NEEDLE PARTS (PEN NEEDLES NOT INCLUDED) pen needle parts
Outer Cap
Inner Cap
Needle
Paper Tab
SECTION 2 Read and follow the directions in this section only after you have
read Section 1.
GETTING STARTED
Be sure to follow the reconstitution (mixing) directions as described in the Humatrope Cartridge
Kit. Perform the New Cartridge Setup only once at the beginning of each new Cartridge. For
daily use, DO NOT REPEAT this one-time-only New Cartridge Setup. If you do, you may run
out of Humatrope early.
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
NEW CARTRIDGE SETUP
STEP A - CHECK THE PEN AND CARTRIDGE check the pen and cartridge
Be sure to check the Cartridge:
• For 6 mg Cartridge label
• For expiration date
• Contents should be clear and
free of particles
Pull off the Pen Cap.
NOTE
DO NOT USE the Cartridge past
the expiration date.
DO NOT USE the Pen if any part
of the Pen or Cartridge appears
broken or damaged. Contact
your healthcare professional.
STEP B - ATTACH THE CARTRIDGE check the pen and cartridge
Look at the Injection Button and
the Front Housing to confirm it is a
6 mg Pen.
CHECK
Check that the number on the
Front Housing matches the
Cartridge strength on the
Cartridge label. If the Pen and
Cartridge do not match, contact
your healthcare professional. attach the cartridge
Use the White Tip of the Cartridge
Push the White Tip of a
to push the Screw back.
reconstituted Cartridge into the Pen
CHECK
Body. Screw the 6 mg Pen Body
Look at the Injection Button and
onto the Cartridge until it is secure.
the Front Housing to confirm it
is a 6 mg Pen.
NOTE
NOTE
The Screw may not be out when
If the Cartridge is not completely
you get the Pen.
attached, the Screw may not
move and an incorrect dose may
be given.
STEP C - ATTACH THE NEEDLE attach the needleattach the needle
Remove the Paper Tab from the
end of the Outer Cap.
Push the Needle straight onto the
• Pull off the Outer Cap and the
6 mg Cartridge and screw on
Inner Cap.
clockwise until secure.
• Keep the Outer Cap to remove
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
the Needle after the injection.
STEP D – REMOVE AIR FROM NEW CARTRIDGE remove air from new cartridge
Dial 1.25 mg.
• Point the Needle straight up.
• Push the Injection Button and hold for five seconds.
• Dial 0.05 mg and repeat these steps until you see a stream of
liquid.
NOTE
• The Pen must be set up before injecting the first dose from each new 6 mg Cartridge.
• Setting up the new Cartridge is important to remove large air bubbles that may be present after reconstitution
(mixing).
• If a stream is not seen after several attempts, contact your healthcare professional or Lilly.
STEP E – CONTINUE ON TO DAILY USE
• DO NOT REPEAT Cartridge Setup before each dose.
• Leave the Cartridge attached and DO NOT REMOVE until the Cartridge is empty.
• Go to Section 3, Step 3, for instructions on how to inject the first dose.
Now that you have done the one-time-only New Cartridge Setup,
SECTION 3 follow Section 3 for all of the injections.
DAILY USE
STEP 1 – CHECK THE PEN check the pen
Pull off the Pen Cap.
Be sure to check the Cartridge:
Look at the Injection Button and
• For 6 mg Cartridge label
the Front Housing to confirm it is a
• For expiration date
6 mg Pen.
• Contents should be clear and
free of particles
NOTE
NOTE
DO NOT USE the Pen if any part
DO NOT USE the Cartridge past
CHECK
of the Pen or Cartridge appears
the expiration date.
Check that the number on the
broken or damaged. Contact
Front Housing matches the
your healthcare professional.
Cartridge strength on the
Cartridge label. If the Pen and
Cartridge do not match, contact
your healthcare professional.
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
STEP 2 – ATTACH THE NEEDLE attach the needleattach the needle
Remove the Paper Tab from the
end of the Outer Cap.
Push the Needle straight onto the
6 mg Cartridge and screw on
clockwise until secure.
• Pull off the Outer Cap and the
Inner Cap.
• Keep the Outer Cap to remove
the Needle after the injection.
NOTE
Hidden Needle Cover is available separately from the HumatroPen 6 mg Cartridge Kit. Refer to the Hidden
Needle Cover user manual for instructions.
STEP 3 – DIAL AND INJECT THE DOSE dial and inject the dose
Turn the Dose Knob to desired
dose.
EXAMPLE
0.25 mg shown in the drawing
above.
If you dial past the desired dose,
you can correct the dose by dialing
backwards.
Insert the Needle as directed by
your healthcare professional.
Place your thumb on the Injection
Button, then slowly and firmly push
the Injection Button until it stops
moving.
Continue to hold the Injection
Button for five seconds, then
remove the Needle from the skin.
Check to make sure you see a
0.00 in the Dose Window to
confirm the complete dose was
received.
NOTE
It is possible to set a dose larger
than the amount of Humatrope left
in the Cartridge.
At the end of the injection, the number
in the Dose Window should be 0.00.
If it is not, this is the amount of
Humatrope that WAS NOT
delivered.
Consult with your healthcare
professional on how to handle a
partial dose. Remove the Needle
and empty Cartridge.
For the next daily use attach a new
Cartridge as shown in Section 2,
Step A, and continue with New
Cartridge Setup (Section 2).
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
STEP 4 – REMOVE AND DISPOSE OF THE NEEDLE remove and dispose of the needle
Carefully replace the Outer Cap as
Remove the capped Needle by
Replace the Pen Cap.
instructed by your healthcare
turning counter-clockwise. Throw
professional.
away as directed by your
healthcare professional.
NOTE
• DO NOT STORE the Pen with a Needle attached to prevent air from entering the Cartridge.
• DO NOT REMOVE this Cartridge from the Pen until the Cartridge is empty or needs to be replaced to avoid
the possibility of an inaccurate dose.
STEP 5 – STORE PEN AND CARTRIDGE FOR NEXT USE
Store the HumatroPen 6 mg properly. (See “Care and Storage for the HumatroPen 6 mg” in Section 1 of this
user manual for more information.)
When it is time for the next routine dose, go to Section 3, and repeat Steps 1-5.
SECTION 4
COMMONLY ASKED QUESTIONS
1. Do I need to perform the New Cartridge Setup before every dose?
• No. The New Cartridge Setup is performed only once for each Cartridge, just before a
new Cartridge is used for the first time.
• The purpose of the setup is to make sure the HumatroPen 6 mg and 6 mg Cartridge are
ready to use.
• If you repeat the New Cartridge Setup before each routine dose, you may run out of
Humatrope early. The small amount of product used in the New Cartridge Setup will not
affect the supply of Humatrope.
2. What should I do if the Cartridge Label and Pen do not match?
• DO NOT USE the Pen if the Cartridge strength on the Humatrope Cartridge label does
not match the number on the Pen’s Front Housing. This is important to ensure the
correct dose of Humatrope is given.
• Contact your healthcare professional for assistance or to obtain a replacement.
3. What should I do if the Humatrope is not clear after mixing?
• Be sure to gently invert the Pen up and down 10 times. DO NOT SHAKE. Then, let the
Pen sit for at least three minutes. If the solution remains cloudy or has particles, gently
invert the Pen up and down 10 more times. Let the Pen sit for five more minutes.
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
• If the solution remains cloudy or contains particles after reconstitution (mixing), DO NOT
USE. Contact your healthcare professional for assistance.
4. Why are there air bubbles in the Cartridge?
• Air bubbles may remain in the Cartridge after reconstitution (mixing).
• If the Pen is stored with a Needle attached, air bubbles may form in the Cartridge.
DO NOT STORE the Pen with a Needle attached.
• Perform the New Cartridge Setup to remove air bubbles from the Cartridge.
• A small air bubble is normal. It will not cause any harm nor affect the dose.
5. Why doesn’t the Screw move out when there is no Cartridge attached to the Pen?
• The Screw may not move out when you push the Injection Button unless there is a
Cartridge in the Pen. This feature allows you to easily push the Screw into the Pen Body
when replacing a Cartridge.
• Once a Cartridge is attached, the Screw will move out when the Injection Button is
pushed.
6. What should I do if I can’t attach the Cartridge to the Pen Body?
• Check that the Cartridge is not damaged or broken.
• Carefully line up the Cartridge with the Pen Body and screw together until secure. If the
Cartridge and Pen cannot be screwed together contact your healthcare professional.
7. Why is it difficult to push the Injection Button when I try to inject the dose?
• The Needle may be clogged. Try attaching a new Needle.
• Pushing the Injection Button down quickly may make the Injection Button harder to
push. Pushing the Injection Button more slowly may make it easier.
• Using a larger diameter Needle will make it easier to push the Injection Button during
injection. Ask your healthcare professional which Needle is best for you.
• The Injection Button may become harder to push if the inside of the Pen gets dirty with
Humatrope, food, drink, or other materials.
8. Why doesn’t the Dose Knob go to zero when I inject the dose?
• This can happen if the Humatrope Cartridge does not have enough Humatrope left in it
for the full dose. It is possible to set a dose larger than the amount of Humatrope left in
the Cartridge. At the end of the injection, the number in the Dose Window should be
0.00. If it is not, this is the amount of Humatrope that WAS NOT delivered. Consult
with your healthcare professional on how to handle a partial dose. Remove the Needle
and empty Cartridge. For the next daily use attach a new Cartridge as shown in
Section 2, Step A, and continue with New Cartridge Setup (Section 2).
9. Why do I see Humatrope leaking from the Needle after I have finished the injection?
• It is normal for a single drop to remain on the tip of the Needle after the injection is
complete. If you see more than one drop:
- The full dose may not have been delivered. DO NOT INJECT another dose. Consult
with your healthcare professional for assistance.
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
- To prevent this, for the next dose, firmly push and hold the Injection Button in and
slowly count to five (see Section 3, Step 3).
10. How can I tell when the injection is complete?
•
The injection is complete when:
- You have slowly counted to five while you are still holding the Injection Button in and
before you remove the Needle from the skin.
AND
- 0.00 is in the center of the Dose Window.
Made for Eli Lilly and Company
Pharmaceutical Delivery Systems
Lilly Corporate Center
Indianapolis, IN 46285, USA
Authorized Representative in the EU:
Eli Lilly and Company Ltd.
Erl Wood Manor, Windlesham, Surrey
GU20 6PH, UK
CE 0344
Humatrope®, HumatroPen® 6 mg and the H Block design are registered trademarks of Eli Lilly
and Company.
The HumatroPen 6 mg is for use with Humatrope 6 mg Cartridges only.
© 2009, 2011, Eli Lilly and Company. All rights reserved.
Literature revised July 26, 2011
PV 6501 AMP
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
[H
Block
graphic]
PV 6511 AMP
Humatrope®
somatropin (rDNA origin)
for injection
HumatroPen® 12 mg
Growth Hormone Delivery
System
Injection Device for Use
with Humatrope®
[somatropin (rDNA origin)
for injection] Cartridges
PEN USER MANUAL
12
mg Lilly
SECTION 1 Read this section completely before you begin.
Then, move on to Section 2.
WHAT YOU NEED TO KNOW ABOUT THE HUMATROPEN® 12 MG
Read these instructions carefully BEFORE using the HumatroPen® 12 mg. You need to use the Pen
correctly in order to get the most benefit from the Humatrope® treatment. Failure to follow these
instructions completely may result in too much or too little Humatrope being injected.
INTRODUCTION
The HumatroPen 12 mg is an injection device intended for use with Humatrope 12 mg Cartridges. Your
healthcare professional has prescribed the Humatrope dose and Pen that you or your child should
receive.
DO NOT CHANGE the dose or Pen unless directed by your healthcare
professional.
If your healthcare professional changes the prescribed cartridge size from the 12 mg Humatrope
Cartridge to the 6 mg or 24 mg Humatrope Cartridge, you must get a new HumatroPen to match the
new cartridge size.
Before using the HumatroPen 12 mg, make sure that you thoroughly read this user manual. It explains
the Pen operations and has a troubleshooting guide, should questions arise.
These instructions do not take the place of talking with your healthcare professional about your
or your child’s medical condition, or its treatment. If you are having problems using the
HumatroPen 12 mg, call 1-800-545-5979.
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
IMPORTANT INFORMATION ABOUT THE HUMATROPEN 12 MG
•
Where you see
in this manual, please pay special attention.
•
DO NOT USE the Pen if any part of the Pen or Cartridge appears broken or damaged. Contact your
healthcare professional.
•
Confirm that you have a 12 mg Humatrope Cartridge to match the HumatroPen 12 mg. If it does not
match DO NOT USE and contact your healthcare professional. This is important to ensure the correct
dose of Humatrope is given.
•
DO NOT use the Humatrope Cartridge past the expiration date.
•
Follow Section 2 ONLY to set up a new Cartridge before first use.
•
Section 3 of this manual should be used for every injection.
•
DO NOT transfer the contents of the Humatrope Cartridge to a syringe.
•
DO NOT share your HumatroPen 12 mg or needles with anyone else. You may give an infection to
them, or get an infection from them,
•
The HumatroPen 12 mg is not recommended for use by blind or visually impaired individuals without
the assistance of a sighted individual trained in its use.
ABOUT PEN NEEDLES
What kinds of Needles can be used with the HumatroPen 12 mg?
•
Pen Needles are not included. You may need a prescription to get the Needles from your pharmacist.
•
Becton, Dickinson and Company Pen Needles are suitable for use with the HumatroPen 12 mg.
•
Ask your healthcare professional what Needle gauge and length is best to use.
•
Follow your healthcare professional's instructions on safe handling of needles.
Must a new Needle be used for each injection?
•
Yes, a new Needle must be used for each injection.
•
Remove the Needle immediately after each injection. Use a new Needle for each injection. This will
help minimize the risk of infection, prevent leakage of Humatrope, keep out air bubbles, and reduce
Needle clogs.
How do I throw away used Needles?
•
Throw away used Needles in a puncture-proof container. Follow your healthcare professional’s
instructions on how to do this safely.
CARE AND STORAGE FOR THE HUMATROPEN 12 MG
Care
•
Soiled parts can be cleaned with a damp cloth. DO NOT USE alcohol or other cleaning agents.
•
DO NOT SOAK or immerse the Pen in liquid.
•
DO NOT APPLY oil or any other lubricant.
Storage
•
Store the HumatroPen 12 mg with attached Humatrope Cartridge in the storage case in the
refrigerator until the time of the next injection. DO NOT FREEZE.
•
All Humatrope Cartridges and diluent must be refrigerated at temperatures between 36°F to 46°F
(+2°C and +8°C). DO NOT FREEZE. A prepared Cartridge can be left on a Pen for 28 days in the
refrigerator. DO NOT USE any prepared Cartridge after 28 days.
•
Let the HumatroPen 12 mg with attached Humatrope Cartridge stand at room temperature for 10
minutes before injecting. Discomfort may be noticed at the injection site if Humatrope is injected cold.
•
Daily room temperature exposure should not exceed 30 minutes.
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
•
DO NOT STORE the Pen with the Needle attached.
REPLACEMENT
The HumatroPen 12 mg has been designed to be used for up to 3 years after first use. Record the date
the Pen was first used here: __ / __ / __. Contact your healthcare professional if a new HumatroPen 12
mg is needed, or when the Pen has been used for 3 years.
Please see the accompanying complete Humatrope Patient Information Sheet. For additional
information, call 1-800-545-5979 or visit www.humatrope.com
HUMATROPEN 12 MG PARTS
Humatrope
12 mg Cartridge
12 mg
Injection
(sold separately) Screw
Pen Body
Button parts
Pen
Rubber
White
Front
Dose
Dose
Cap
Seal
Tip
Housing
Window
Knob
PEN NEEDLE PARTS (PEN NEEDLES NOT INCLUDED) parts
Outer Cap
Inner Cap
Needle
Paper Tab
SECTION 2 Read and follow the directions in this section only after you have
read Section 1.
GETTING STARTED
Be sure to follow the reconstitution (mixing) directions as described in the Humatrope Cartridge
Kit. Perform the New Cartridge Setup only once at the beginning of each new Cartridge. For
daily use, DO NOT REPEAT this one-time-only New Cartridge Setup. If you do, you may run
out of Humatrope early.
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
NEW CARTRIDGE SETUP
STEP A - CHECK THE PEN AND CARTRIDGE check the pen and cartridge
Be sure to check the Cartridge:
• For 12 mg Cartridge label
• For expiration date
• Contents should be clear and
free of particles
Pull off the Pen Cap.
NOTE
DO NOT USE the Cartridge past
the expiration date.
DO NOT USE the Pen if any part
of the Pen or Cartridge appears
broken or damaged. Contact
your healthcare professional.
STEP B - ATTACH THE CARTRIDGE check the pen
Look at the Injection Button and
the Front Housing to confirm it is a
12 mg Pen.
CHECK
Check that the number on the
Front Housing matches the
Cartridge strength on the
Cartridge label. If the Pen and
Cartridge do not match, contact
your healthcare professional. attach the cartridge
Use the White Tip of the Cartridge
Push the White Tip of a
to push the Screw back.
reconstituted Cartridge into the Pen
Body. Screw the 12 mg Pen Body
CHECK
onto the Cartridge until it is secure.
Look at the Injection Button
and the Front Housing to
confirm it is a 12 mg Pen.
NOTE
NOTE
The Screw may not be out when
If the Cartridge is not completely
you get the Pen.
attached, the Screw may not
move and an incorrect dose may
be given.
STEP C - ATTACH THE NEEDLE attach the needleattach the needle
Remove the Paper Tab from the
end of the Outer Cap.
Push the Needle straight onto the
• Pull off the Outer Cap and the
12 mg Cartridge and screw on
Inner Cap.
clockwise until secure.
• Keep the Outer Cap to remove
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
the Needle after the injection.
STEP D – REMOVE AIR FROM NEW CARTRIDGE remove air from new cartridge
Dial 2.50 mg.
• Point the Needle straight up.
• Push the Injection Button and hold for five seconds.
• Dial 0.10 mg and repeat these steps until you see a stream of
liquid.
NOTE
• The Pen must be set up before injecting the first dose from each new 12 mg Cartridge.
• Setting up the new Cartridge is important to remove large air bubbles that may be present after reconstitution
(mixing).
• If a stream is not seen after several attempts, contact your healthcare professional or Lilly.
STEP E – CONTINUE ON TO DAILY USE
•
DO NOT REPEAT Cartridge Setup before each dose.
•
Leave the Cartridge attached and DO NOT REMOVE until the Cartridge is empty.
•
Go to Section 3, Step 3, for instructions on how to inject the first dose.
SECTION 3 Now that you have done the one-time-only New Cartridge Setup,
follow Section 3 for all of the injections.
DAILY USE
STEP 1 – CHECK THE PEN check the pencheck the pen
Pull off the Pen Cap.
Be sure to check the Cartridge:
• For 12 mg Cartridge label
• For expiration date
• Contents should be clear and
free of particles
NOTE
NOTE
DO NOT USE the Pen if any part
DO NOT USE the Cartridge past
CHECK
of the Pen or Cartridge appears
the expiration date.
Check that the number on the
broken or damaged. Contact
Front Housing matches the
your healthcare professional.
Cartridge strength on the
Cartridge label. If the Pen and
Cartridge do not match, contact
your healthcare professional.
Look at the Injection Button and
the Front Housing to confirm it is a
12 mg Pen.
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
STEP 2 – ATTACH THE NEEDLE attach the needle
Remove the Paper Tab from the
end of the Outer Cap.
Push the Needle straight onto the
12 mg Cartridge and screw on
• Pull off the Outer Cap and the
Inner Cap.
clockwise until secure.
• Keep the Outer Cap to remove
the Needle after the injection.
NOTE
Hidden Needle Cover is available separately from the HumatroPen 12 mg Cartridge Kit. Refer to the Hidden
Needle Cover user manual for instructions.
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
STEP 3 – DIAL AND INJECT THE DOSE dial and inject the dose
Turn the Dose Knob to desired
dose.
EXAMPLE
0.50 mg shown in the drawing
above.
If you dial past the desired dose,
you can correct the dose by dialing
backwards.
Insert the Needle as directed by
your healthcare professional.
Place your thumb on the Injection
Button, then slowly and firmly push
the Injection Button until it stops
moving.
Continue to hold the Injection
Button for five seconds, then
remove the Needle from the skin.
Check to make sure you see a
0.00 in the Dose Window to
confirm the complete dose was
received.
STEP 4 – REMOVE AND DISPOSE OF THE NEEDLE
NOTE
It is possible to set a dose larger
than the amount of Humatrope left
in the Cartridge.
At the end of the injection, the number
in the Dose Window should be 0.00.
If it is not, this is the amount of
Humatrope that WAS NOT
delivered.
Consult with your healthcare
professional on how to handle a
partial dose. Remove the Needle
and empty Cartridge.
For the next daily use attach a new
Cartridge as shown in Section 2,
Step A, and continue with New
Cartridge Setup (Section 2). remove and dispose of the needle
Carefully replace the Outer Cap as
instructed by your healthcare
professional. remove and dispose of the needle
Remove the capped Needle by
turning counter-clockwise. Throw
away as directed by your
healthcare professional. remove and dispose of the needle
Replace the Pen Cap.
NOTE
•
DO NOT STORE the Pen with a Needle attached to prevent air from entering the Cartridge.
•
DO NOT REMOVE this Cartridge from the Pen until the Cartridge is empty or needs to be replaced to
avoid the possibility of an inaccurate dose.
STEP 5 – STORE PEN AND CARTRIDGE FOR NEXT USE
Store the HumatroPen 12 mg properly. (See “Care and Storage for the HumatroPen 12 mg” in Section 1 of this
user manual for more information.)
When it is time for the next routine dose, go to Section 3, and repeat Steps 1-5.
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
SECTION 4
COMMONLY ASKED QUESTIONS
1. Do I need to perform the New Cartridge Setup before every dose?
• No. The New Cartridge Setup is performed only once for each Cartridge, just before a
new Cartridge is used for the first time.
• The purpose of the setup is to make sure the HumatroPen 12 mg and 12 mg Cartridge
are ready to use.
• If you repeat the New Cartridge Setup before each routine dose, you may run out of
Humatrope early. The small amount of product used in the New Cartridge Setup will not
affect the supply of Humatrope.
2. What should I do if the Cartridge Label and Pen do not match?
• DO NOT USE the Pen if the Cartridge strength on the Humatrope Cartridge label does
not match the number on the Pen’s Front Housing. This is important to ensure the
correct dose of Humatrope is given.
• Contact your healthcare professional for assistance or to obtain a replacement.
3. What should I do if the Humatrope is not clear after mixing?
• Be sure to gently invert the Pen up and down 10 times. DO NOT SHAKE. Then, let the
Pen sit for at least three minutes. If the solution remains cloudy or has particles, gently
invert the Pen up and down 10 more times. Let the Pen sit for five more minutes.
• If the solution remains cloudy or contains particles after reconstitution (mixing), DO NOT
USE. Contact your healthcare professional for assistance.
4. Why are there air bubbles in the Cartridge?
• Air bubbles may remain in the Cartridge after reconstitution (mixing).
• If the Pen is stored with a Needle attached, air bubbles may form in the Cartridge.
DO NOT STORE the Pen with a Needle attached.
• Perform the New Cartridge Setup to remove air bubbles from the Cartridge.
• A small air bubble is normal. It will not cause any harm nor affect the dose.
5. Why doesn’t the Screw move out when there is no Cartridge attached to the Pen?
• The Screw may not move out when you push the Injection Button unless there is a
Cartridge in the Pen. This feature allows you to easily push the Screw into the Pen
Body when replacing a Cartridge.
• Once a Cartridge is attached, the Screw will move out when the Injection Button is
pushed.
6. What should I do if I can’t attach the Cartridge to the Pen Body?
• Check that the Cartridge is not damaged or broken.
• Carefully line up the Cartridge with the Pen Body and screw together until secure. If the
Cartridge and Pen cannot be screwed together contact your healthcare professional.
7. Why is it difficult to push the Injection Button when I try to inject the dose?
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
• The Needle may be clogged. Try attaching a new Needle.
• Pushing the Injection Button down quickly may make the Injection Button harder to
push. Pushing the Injection Button more slowly may make it easier.
• Using a larger diameter Needle will make it easier to push the Injection Button during
injection. Ask your healthcare professional which Needle is best for you.
• The Injection Button may become harder to push if the inside of the Pen gets dirty with
Humatrope, food, drink, or other materials.
8. Why doesn’t the Dose Knob go to zero when I inject the dose?
• This can happen if the Humatrope Cartridge does not have enough Humatrope left in it
for the full dose. It is possible to set a dose larger than the amount of Humatrope left
in the Cartridge. At the end of the injection, the number in the Dose Window should be
0.00. If it is not, this is the amount of Humatrope that WAS NOT delivered. Consult
with your healthcare professional on how to handle a partial dose. Remove the
Needle and empty Cartridge. For the next daily use attach a new Cartridge as shown
in Section 2, Step A, and continue with New Cartridge Setup (Section 2).
9. Why do I see Humatrope leaking from the Needle after I have finished the injection?
• It is normal for a single drop to remain on the tip of the Needle after the injection is
complete. If you see more than one drop:
- The full dose may not have been delivered. DO NOT INJECT another dose. Consult
with your healthcare professional for assistance.
- To prevent this, for the next dose, firmly push and hold the Injection Button in and
slowly count to five (see Section 3, Step 3).
10. How can I tell when the injection is complete?
• The injection is complete when:
- You have slowly counted to five while you are still holding the Injection Button in and
before you remove the Needle from the skin.
AND
- 0.00 is in the center of the Dose Window.
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
Made for Eli Lilly and Company
Pharmaceutical Delivery Systems
Lilly Corporate Center
Indianapolis, IN 46285, USA
Authorized Representative in the EU:
Eli Lilly and Company Ltd.
Erl Wood Manor, Windlesham, Surrey
GU20 6PH, UK
CE 0344
Humatrope®, HumatroPen® 12 mg and the H Block design are registered trademarks of Eli Lilly
and Company.
The HumatroPen 12 mg is for use with Humatrope 12 mg Cartridges only.
© 2009, 2011, Eli Lilly and Company. All rights reserved.
Literature revised July 26, 2011
PV 6511 AMP
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
[H
Block
graphic]
PV 6521 AMP
Humatrope®
somatropin (rDNA origin)
for injection
HumatroPen® 24 mg
Growth Hormone Delivery
System
mg
Injection Device for Use
with Humatrope®
[somatropin (rDNA origin)
for injection] Cartridges
PEN USER MANUAL
pen instructionsLilly
SECTION 1 Read this section completely before you begin.
Then, move on to Section 2.
WHAT YOU NEED TO KNOW ABOUT THE HUMATROPEN® 24 MG
Read these instructions carefully BEFORE using the HumatroPen® 24 mg. You need to use the Pen
correctly in order to get the most benefit from the Humatrope® treatment. Failure to follow these
instructions completely may result in too much or too little Humatrope being injected.
INTRODUCTION
The HumatroPen 24 mg is an injection device intended for use with Humatrope 24 mg Cartridges. Your
healthcare professional has prescribed the Humatrope dose and Pen that you or your child should
receive.
DO NOT CHANGE the dose or Pen unless directed by your healthcare
professional.
If your healthcare professional changes the prescribed cartridge size from the 24 mg Humatrope
Cartridge to the 6 mg or 12 mg Humatrope Cartridge, you must get a new HumatroPen to match the
new cartridge size.
Before using the HumatroPen 24 mg, make sure that you thoroughly read this user manual. It explains
the Pen operations and has a troubleshooting guide, should questions arise.
These instructions do not take the place of talking with your healthcare professional about your
or your child’s medical condition, or its treatment. If you are having problems using the
HumatroPen 24 mg, call 1-800-545-5979.
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
IMPORTANT INFORMATION ABOUT THE HUMATROPEN 24 MG
•
Where you see
in this manual, please pay special attention.
•
DO NOT USE the Pen if any part of the Pen or Cartridge appears broken or damaged. Contact your
healthcare professional.
•
Confirm that you have a 24 mg Humatrope Cartridge to match the HumatroPen 24 mg. If it does not
match DO NOT USE and contact your healthcare professional. This is important to ensure the correct
dose of Humatrope is given.
•
DO NOT use the Humatrope Cartridge past the expiration date.
•
Follow Section 2 ONLY to set up a new Cartridge before first use.
•
Section 3 of this manual should be used for every injection.
•
DO NOT transfer the contents of the Humatrope Cartridge to a syringe.
•
DO NOT share your HumatroPen 24 mg or needles with anyone else. You may give an infection to
them, or get an infection from them,
•
The HumatroPen 24 mg is not recommended for use by blind or visually impaired individuals without
the assistance of a sighted individual trained in its use.
ABOUT PEN NEEDLES
What kinds of Needles can be used with the HumatroPen 24 mg?
•
Pen Needles are not included. You may need a prescription to get the Needles from your pharmacist.
•
Becton, Dickinson and Company Pen Needles are suitable for use with the HumatroPen 24 mg.
•
Ask your healthcare professional what Needle gauge and length is best to use.
•
Follow your healthcare professional's instructions on safe handling of needles.
Must a new Needle be used for each injection?
•
Yes, a new Needle must be used for each injection.
•
Remove the Needle immediately after each injection. Use a new Needle for each injection. This will
help minimize the risk of infection, prevent leakage of Humatrope, keep out air bubbles, and reduce
Needle clogs.
How do I throw away used Needles?
•
Throw away used Needles in a puncture-proof container. Follow your healthcare professional’s
instructions on how to do this safely.
CARE AND STORAGE FOR THE HUMATROPEN 24 MG
Care
•
Soiled parts can be cleaned with a damp cloth. DO NOT USE alcohol or other cleaning agents.
•
DO NOT SOAK or immerse the Pen in liquid.
•
DO NOT APPLY oil or any other lubricant.
Storage
•
Store the HumatroPen 24 mg with attached Humatrope Cartridge in the storage case in the
refrigerator until the time of the next injection. DO NOT FREEZE.
•
All Humatrope Cartridges and diluent must be refrigerated at temperatures between 36°F to 46°F
(+2°C and +8°C). DO NOT FREEZE. A prepared Cartridge can be left on a Pen for 28 days in the
refrigerator. DO NOT USE any prepared Cartridge after 28 days.
•
Let the HumatroPen 24 mg with attached Humatrope Cartridge stand at room temperature for 10
minutes before injecting. Discomfort may be noticed at the injection site if Humatrope is injected cold.
•
Daily room temperature exposure should not exceed 30 minutes.
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
•
DO NOT STORE the Pen with the Needle attached.
REPLACEMENT
The HumatroPen 24 mg has been designed to be used for up to 3 years after first use. Record the date
the Pen was first used here: __ / __ / __. Contact your healthcare professional if a new HumatroPen 24
mg is needed, or when the Pen has been used for 3 years.
Please see the accompanying complete Humatrope Patient Information Sheet. For additional
information, call 1-800-545-5979 or visit www.humatrope.com
HUMATROPEN 24 MG PARTS
Humatrope
24 mg Cartridge
24 mg
Injection
(sold separately)
Screw
Pen Body
Button parts
Pen
Rubber
White
Front
Dose
Dose
Cap
Seal
Tip
Housing
Window
Knob
PEN NEEDLE PARTS (PEN NEEDLES NOT INCLUDED) parts
Outer Cap
Inner Cap
Needle
Paper Tab
SECTION 2 Read and follow the directions in this section only after you have
read Section 1.
GETTING STARTED
Be sure to follow the reconstitution (mixing) directions as described in the Humatrope Cartridge
Kit. Perform the New Cartridge Setup only once at the beginning of each new Cartridge. For
daily use, DO NOT REPEAT this one-time-only New Cartridge Setup. If you do, you may run
out of Humatrope early.
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
NEW CARTRIDGE SETUP
STEP A - CHECK THE PEN AND CARTRIDGE check pen and cartridge
Be sure to check the Cartridge:
Pull off the Pen Cap.
• For 24 mg Cartridge label
• For expiration date
• Contents should be clear and
free of particles
NOTE
DO NOT USE the Cartridge past
the expiration date.
DO NOT USE the Pen if any part
of the Pen or Cartridge appears
broken or damaged. Contact
your healthcare professional.
STEP B - ATTACH THE CARTRIDGE
Look at the Injection Button and
the Front Housing to confirm it is a
24 mg Pen.
CHECK
Check that the number on the
Front Housing matches the
Cartridge strength on the
Cartridge label. If the Pen and
Cartridge do not match, contact
your healthcare professional. attach the cartridge
Use the White Tip of the Cartridge
Push the White Tip of a
to push the Screw back.
reconstituted Cartridge into the Pen
CHECK
Body. Screw the 24 mg Pen Body
Look at the Injection Button
onto the Cartridge until it is secure.
and the Front Housing to
confirm it is a 24 mg Pen.
NOTE
NOTE
The Screw may not be out when
If the Cartridge is not completely
you get the Pen.
attached, the Screw may not
move and an incorrect dose may
be given.
STEP C - ATTACH THE NEEDLE attach the needleattach the needle
Remove the Paper Tab from the
end of the Outer Cap.
Push the Needle straight onto the
• Pull off the Outer Cap and the
24 mg Cartridge and screw on
Inner Cap.
clockwise until secure.
• Keep the Outer Cap to remove
the Needle after the injection.
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
STEP D – REMOVE AIR FROM NEW CARTRIDGE remove air from new cartridge
Dial 5.00 mg.
• Point the Needle straight up.
• Push the Injection Button and hold for five seconds.
• Dial 0.20 mg and repeat these steps until you see a stream of
liquid.
NOTE
• The Pen must be set up before injecting the first dose from each new 24 mg Cartridge.
• Setting up the new Cartridge is important to remove large air bubbles that may be present after reconstitution
(mixing).
• If a stream is not seen after several attempts, contact your healthcare professional or Lilly.
STEP E – CONTINUE ON TO DAILY USE
• DO NOT REPEAT Cartridge Setup before each dose.
• Leave the Cartridge attached and DO NOT REMOVE until the Cartridge is empty.
• Go to Section 3, Step 3, for instructions on how to inject the first dose.
SECTION 3 Now that you have done the one-time-only New Cartridge Setup,
follow Section 3 for all of the injections.
DAILY USE
STEP 1 – CHECK THE PEN check the pen
Pull off the Pen Cap.
Be sure to check the Cartridge:
Look at the Injection Button and
• For 24 mg Cartridge label
the Front Housing to confirm it is a
• For expiration date
24 mg Pen.
• Contents should be clear and
free of particles
NOTE
NOTE
DO NOT USE the Pen if any part
DO NOT USE the Cartridge past
CHECK
of the Pen or Cartridge appears
the expiration date.
Check that the number on the
broken or damaged. Contact
Front Housing matches the
your healthcare professional.
Cartridge strength on the
Cartridge label. If the Pen and
Cartridge do not match, contact
your healthcare professional.
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
STEP 2 – ATTACH THE NEEDLE attach the needle
Remove the Paper Tab from the
end of the Outer Cap.
Push the Needle straight onto the
24 mg Cartridge and screw on
• Pull off the Outer Cap and the
Inner Cap.
clockwise until secure.
• Keep the Outer Cap to remove
the Needle after the injection.
NOTE
Hidden Needle Cover is available separately from the HumatroPen 24 mg Cartridge Kit. Refer to the Hidden
Needle Cover user manual for instructions.
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
STEP 3 – DIAL AND INJECT THE DOSE dial and inject the dose
Turn the Dose Knob to desired
dose.
EXAMPLE
1.00 mg shown in the drawing
above.
If you dial past the desired dose,
you can correct the dose by dialing
backwards.
Insert the Needle as directed by
your healthcare professional.
Place your thumb on the Injection
Button, then slowly and firmly push
the Injection Button until it stops
moving.
Continue to hold the Injection
Button for five seconds, then
remove the Needle from the skin.
Check to make sure you see a
0.00 in the Dose Window to
confirm the complete dose was
received.
NOTE
It is possible to set a dose larger
than the amount of Humatrope left
in the Cartridge.
At the end of the injection, the number
in the Dose Window should be 0.00.
If it is not, this is the amount of
Humatrope that WAS NOT
delivered.
Consult with your healthcare
professional on how to handle a
partial dose. Remove the Needle
and empty Cartridge.
For the next daily use attach a new
Cartridge as shown in Section 2,
Step A, and continue with New
Cartridge Setup (Section 2).
STEP 4 – REMOVE AND DISPOSE OF THE NEEDLE remove and dispose of the needle
Carefully replace the Outer Cap as
Remove the capped Needle by
Replace the Pen Cap.
instructed by your healthcare
turning counter-clockwise. Throw
professional.
away as directed by your
healthcare professional.
NOTE
• DO NOT STORE the Pen with a Needle attached to prevent air from entering the Cartridge.
• DO NOT REMOVE this Cartridge from the Pen until the Cartridge is empty or needs to be replaced to avoid
the possibility of an inaccurate dose.
STEP 5 – STORE PEN AND CARTRIDGE FOR NEXT USE
Store the HumatroPen 24 mg properly. (See “Care and Storage for the HumatroPen 24 mg” in Section 1 of this
user manual for more information.)
When it is time for the next routine dose, go to Section 3, and repeat Steps 1-5.
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
SECTION 4
COMMONLY ASKED QUESTIONS
1. Do I need to perform the New Cartridge Setup before every dose?
• No. The New Cartridge Setup is performed only once for each Cartridge, just before a
new Cartridge is used for the first time.
• The purpose of the setup is to make sure the HumatroPen 24 mg and 24 mg Cartridge
are ready to use.
• If you repeat the New Cartridge Setup before each routine dose, you may run out of
Humatrope early. The small amount of product used in the New Cartridge Setup will not
affect the supply of Humatrope.
2. What should I do if the Cartridge Label and Pen do not match?
• DO NOT USE the Pen if the Cartridge strength on the Humatrope Cartridge label does
not match the number on the Pen’s Front Housing. This is important to ensure the
correct dose of Humatrope is given.
• Contact your healthcare professional for assistance or to obtain a replacement.
3. What should I do if the Humatrope is not clear after mixing?
• Be sure to gently invert the Pen up and down 10 times. DO NOT SHAKE. Then, let the
Pen sit for at least three minutes. If the solution remains cloudy or has particles, gently
invert the Pen up and down 10 more times. Let the Pen sit for five more minutes.
• If the solution remains cloudy or contains particles after reconstitution (mixing), DO NOT
USE. Contact your healthcare professional for assistance.
4. Why are there air bubbles in the Cartridge?
• Air bubbles may remain in the Cartridge after reconstitution (mixing).
• If the Pen is stored with a Needle attached, air bubbles may form in the Cartridge.
DO NOT STORE the Pen with a Needle attached.
• Perform the New Cartridge Setup to remove air bubbles from the Cartridge.
• A small air bubble is normal. It will not cause any harm nor affect the dose.
5. Why doesn’t the Screw move out when there is no Cartridge attached to the Pen?
• The Screw may not move out when you push the Injection Button unless there is a
Cartridge in the Pen. This feature allows you to easily push the Screw into the Pen Body
when replacing a Cartridge.
• Once a Cartridge is attached, the Screw will move out when the Injection Button is
pushed.
6. What should I do if I can’t attach the Cartridge to the Pen Body?
• Check that the Cartridge is not damaged or broken.
• Carefully line up the Cartridge with the Pen Body and screw together until secure. If the
Cartridge and Pen cannot be screwed together contact your healthcare professional.
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
7. Why is it difficult to push the Injection Button when I try to inject the dose?
• The Needle may be clogged. Try attaching a new Needle.
• Pushing the Injection Button down quickly may make the Injection Button harder to
push. Pushing the Injection Button more slowly may make it easier.
• Using a larger diameter Needle will make it easier to push the Injection Button during
injection. Ask your healthcare professional which Needle is best for you.
• The Injection Button may become harder to push if the inside of the Pen gets dirty with
Humatrope, food, drink, or other materials.
8. Why doesn’t the Dose Knob go to zero when I inject the dose?
• This can happen if the Humatrope Cartridge does not have enough Humatrope left in it
for the full dose. It is possible to set a dose larger than the amount of Humatrope left in
the Cartridge. At the end of the injection, the number in the Dose Window should be
0.00. If it is not, this is the amount of Humatrope that WAS NOT delivered. Consult
with your healthcare professional on how to handle a partial dose. Remove the Needle
and empty Cartridge. For the next daily use attach a new Cartridge as shown in
Section 2, Step A, and continue with New Cartridge Setup (Section 2).
9. Why do I see Humatrope leaking from the Needle after I have finished the injection?
• It is normal for a single drop to remain on the tip of the Needle after the injection is
complete. If you see more than one drop:
- The full dose may not have been delivered. DO NOT INJECT another dose. Consult
with your healthcare professional for assistance.
- To prevent this, for the next dose, firmly push and hold the Injection Button in and
slowly count to five (see Section 3, Step 3).
10. How can I tell when the injection is complete?
• The injection is complete when:
- You have slowly counted to five while you are still holding the Injection Button in and
before you remove the Needle from the skin.
AND
- 0.00 is in the center of the Dose Window.
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
Made for Eli Lilly and Company
Pharmaceutical Delivery Systems
Lilly Corporate Center
Indianapolis, IN 46285, USA
Authorized Representative in the EU:
Eli Lilly and Company Ltd.
Erl Wood Manor, Windlesham, Surrey
GU20 6PH, UK
CE 0344
Humatrope®, HumatroPen® 24 mg and the H Block design are registered trademarks of Eli Lilly
and Company.
The HumatroPen 24 mg is for use with Humatrope 24 mg Cartridges only.
© 2009, 2011, Eli Lilly and Company. All rights reserved.
Literature revised July 26, 2011
PV 6521 AMP
Reference ID: 3004202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:35.274905
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019640s086lbl.pdf', 'application_number': 19640, 'submission_type': 'SUPPL ', 'submission_number': 86}
|
11,584
|
NDA 019579/S-035
NDA 019641/S-028
NDA 019964/S-030
Page 4
TERAZOL® 7 VAGINAL CREAM 0.4%
(terconazole)
TERAZOL® 3 VAGINAL CREAM 0.8%
(terconazole)
TERAZOL® 3 VAGINAL SUPPOSITORIES 80mg
(terconazole)
DESCRIPTION
TERAZOL® 7 (terconazole) Vaginal Cream 0.4% is a white to off-white, water washable cream
for intravaginal administration containing 0.4% of the antifungal agent terconazole, cis-1-[p-[[2
(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4
isopropylpiperazine, compounded in a cream base consisting of butylated hydroxyanisole, cetyl
alcohol, isopropyl myristate, polysorbate 60, polysorbate 80, propylene glycol, stearyl alcohol,
and purified water.
TERAZOL® 3 (terconazole) Vaginal Cream 0.8% is a white to off-white, water washable cream
for intravaginal administration containing 0.8% of the antifungal agent terconazole, cis-1-[p-[[2
(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4
isopropylpiperazine, compounded in a cream base consisting of butylated hydroxyanisole, cetyl
alcohol, isopropyl myristate, polysorbate 60, polysorbate 80, propylene glycol, stearyl alcohol,
and purified water.
TERAZOL® 3 (terconazole) Vaginal Suppositories are white to off-white suppositories for
intravaginal administration containing 80 mg of the antifungal agent terconazole, cis-1-[p-[[2
(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4
isopropylpiperazine, in triglycerides derived from coconut and/or palm kernel oil (a base of
hydrogenated vegetable oils) and butylated hydroxyanisole.
Reference ID: 3379688
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 019579/S-035
NDA 019641/S-028
NDA 019964/S-030
Page 5
The structural formula of terconazole is as follows: structural formula
Terconazole, a triazole derivative, is a white to almost white powder with a molecular weight of
532.47. It is insoluble in water; sparingly soluble in ethanol; and soluble in butanol.
CLINICAL PHARMACOLOGY
Following intravaginal administration of terconazole in humans, absorption ranged from 5–8% in
three hysterectomized subjects and 12–16% in two non-hysterectomized subjects with tubal
ligations.
Following daily intravaginal administration of 0.8% terconazole 40 mg (0.8% cream x 5 g) for
seven days to normal humans, plasma concentrations were low and gradually rose to a daily peak
(mean of 5.9 ng/mL or 0.006 mcg/mL) at 6.6 hours.
Results from similar studies in patients with vulvovaginal candidiasis indicate that the slow rate
of absorption, the lack of accumulation, and the mean peak plasma concentration of terconazole
was not different from that observed in healthy women. The absorption characteristics of
terconazole 0.8% in pregnant or non-pregnant patients with vulvovaginal candidiasis were also
similar to those found in normal volunteers.
Following oral (30 mg) administration of 14C-labelled terconazole, the harmonic half-life of
elimination from the blood for the parent terconazole was 6.9 hours (range 4.0–11.3).
Terconazole is extensively metabolized; the plasma AUC for terconazole compared to the AUC
for total radioactivity was 0.6%. Total radioactivity was eliminated from the blood with a
harmonic half-life of 52.2 hours (range 44–60). Excretion of radioactivity was both by renal (32–
56%) and fecal (47–52%) routes.
In vitro, terconazole is highly protein bound (94.9%) and the degree of binding is independent of
drug concentration.
Reference ID: 3379688
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 019579/S-035
NDA 019641/S-028
NDA 019964/S-030
Page 6
Photosensitivity reactions were observed in some normal volunteers following repeated dermal
application of terconazole 2.0% and 0.8% creams under conditions of filtered artificial ultraviolet
light.
Photosensitivity reactions have not been observed in U.S. and foreign clinical trials in patients
who were treated with terconazole suppositories or vaginal cream (0.4% and 0.8%).
Microbiology: Terconazole exhibits fungicidal activity in vitro against Candida albicans.
Antifungal activity has also been demonstrated against other fungi. The MIC values of
terconazole against most Lactobacillus spp. typically found in the human vagina were ≥128
mcg/mL; therefore these beneficial bacteria are not affected by drug treatment.
The exact pharmacologic mode of action of terconazole is uncertain; however, it may exert its
antifungal activity by the disruption of normal fungal cell membrane permeability. No resistance
to terconazole has developed during successive passages of C. albicans.
INDICATIONS AND USAGE
TERAZOL® 7 (terconazole) Vaginal Cream 0.4%, TERAZOL® 3 (terconazole) Vaginal Cream
0.8% and TERAZOL® 3 (terconazole) Vaginal Suppositories 80 mg are indicated for the local
treatment of vulvovaginal candidiasis (moniliasis). As these products are effective only for
vulvovaginitis caused by the genus Candida, the diagnosis should be confirmed by KOH smears
and/or cultures.
CONTRAINDICATIONS
Patients known to be hypersensitive to terconazole or to any of the components of the cream or
suppositories.
WARNINGS
Anaphylaxis and toxic epidermal necrolysis have been reported during terconazole therapy.
TERAZOL® therapy should be discontinued if anaphylaxis or toxic epidermal necrolysis
develops.
PRECAUTIONS
General: Discontinue use and do not retreat with terconazole if sensitization, irritation, fever,
chills or flu-like symptoms are reported during use.
Reference ID: 3379688
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 019579/S-035
NDA 019641/S-028
NDA 019964/S-030
Page 7
The base contained in the suppository formulation may interact with certain rubber or latex
products, such as those used in vaginal contraceptive diaphragms; therefore concurrent use is not
recommended.
Laboratory Tests: If there is lack of response to terconazole, appropriate microbiologic
studies (standard KOH smear and/or cultures) should be repeated to confirm the diagnosis and
rule out other pathogens.
Drug Interactions:
TERAZOL® 7 (terconazole) Vaginal Cream 0.4% and TERAZOL® 3 (terconazole) Vaginal
Suppositories 80 mg:
The therapeutic effect of these products is not affected by oral contraceptive usage.
TERAZOL® 3 (terconazole) Vaginal Cream 0.8%:
The levels of estradiol (E2) and progesterone did not differ significantly when 0.8% terconazole
vaginal cream was administered to healthy female volunteers established on a low dose oral
contraceptive.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Carcinogenesis: Studies to determine the carcinogenic potential of terconazole have not been
performed.
Mutagenicity: Terconazole was not mutagenic when tested in vitro for induction of microbial
point mutations (Ames test), or for inducing cellular transformation, or in vivo for chromosome
breaks (micronucleus test) or dominant lethal mutations in mouse germ cells.
Impairment of Fertility: No impairment of fertility occurred when female rats were
administered terconazole orally up to 40 mg/kg/day for a three month period.
Pregnancy:
Teratogenic Effects:
Pregnancy Category C.
There was no evidence of teratogenicity when terconazole was administered orally up to 40
mg/kg/day (25x the recommended intravaginal human dose of the suppository formulation, 50x
the recommended intravaginal human dose of the 0.8% vaginal cream formulation, and 100x the
intravaginal human dose of the 0.4% vaginal cream formulation) in rats, or 20 mg/kg/day in
rabbits, or subcutaneously up to 20 mg/kg/day in rats.
Reference ID: 3379688
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 019579/S-035
NDA 019641/S-028
NDA 019964/S-030
Page 8
Dosages at or below 10 mg/kg/day produced no embryotoxicity; however, there was a delay in
fetal ossification at 10 mg/kg/day in rats. There was some evidence of embryotoxicity in rabbits
and rats at 20-40 mg/kg. In rats, this was reflected as a decrease in litter size and number of
viable young and reduced fetal weight. There was also delay in ossification and an increased
incidence of skeletal variants.
The no-effect dose of 10 mg/kg/day resulted in a mean peak plasma level of terconazole in
pregnant rats of 0.176 mcg/mL which exceeds by 44 times the mean peak plasma level (0.004
mcg/mL) seen in normal subjects after intravaginal administration of terconazole 0.4% vaginal
cream, by 30 times the mean peak plasma level (0.006 mcg/mL) seen in normal subjects after
intravaginal administration of terconazole 0.8% vaginal cream, and by 17 times the mean peak
plasma level (0.010 mcg/mL) seen in normal subjects after intravaginal administration of
terconazole 80 mg vaginal suppository. This safety assessment does not account for possible
exposure of the fetus through direct transfer to terconazole from the irritated vagina by diffusion
across amniotic membranes.
Since terconazole is absorbed from the human vagina, it should not be used in the first trimester
of pregnancy unless the physician considers it essential to the welfare of the patient.
Nursing Mothers:
It is not known whether this drug is excreted in human milk. Animal studies have shown that rat
offspring exposed via the milk of treated (40 mg/kg/orally) dams showed decreased survival
during the first few post-partum days, but overall pup weight and weight gain were comparable
to or greater than controls throughout lactation. Because many drugs are excreted in human milk,
and because of the potential for adverse reaction in nursing infants from terconazole, 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 efficacy in children have not been established.
Geriatric Use:
Clinical studies of TERAZOL® 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.
Reference ID: 3379688
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 019579/S-035
NDA 019641/S-028
NDA 019964/S-030
Page 9
ADVERSE REACTIONS
Clinical Trials
TERAZOL® 7 (terconazole) Vaginal Cream 0.4%:
During controlled clinical studies conducted in the United States, 521 patients with vulvovaginal
candidiasis were treated with terconazole 0.4% vaginal cream. Based on comparative analyses
with placebo, the adverse experiences considered most likely related to terconazole 0.4% vaginal
cream were headache (26% vs. 17% with placebo) and body pain (2.1% vs. 0% with placebo).
Vulvovaginal burning (5.2%), itching (2.3%) or irritation (3.1%) occurred less frequently with
terconazole 0.4% vaginal cream than with the vehicle placebo. Fever (1.7% vs. 0.5% with
placebo) and chills (0.4% vs. 0.0% with placebo) have also been reported. The therapy-related
dropout rate was 1.9%. The adverse drug experience on terconazole most frequently causing
discontinuation was vulvovaginal itching (0.6%), which was lower than the incidence for
placebo (0.9%).
TERAZOL® 3 (terconazole) Vaginal Cream 0.8%:
During controlled clinical studies conducted in the United States, patients with vulvovaginal
candidiasis were treated with terconazole 0.8% vaginal cream for three days. Based on
comparative analyses with placebo and a standard agent, the adverse experiences considered
most likely related to terconazole 0.8% vaginal cream were headache (21% vs. 16% with
placebo) and dysmenorrhea (6% vs. 2% with placebo). Genital complaints in general, and
burning and itching in particular, occurred less frequently in the terconazole 0.8% vaginal cream
3 day regimen (5% vs. 6%-9% with placebo). Other adverse experiences reported with
terconazole 0.8% vaginal cream were abdominal pain (3.4% vs. 1% with placebo) and fever (1%
vs. 0.3% with placebo). The therapy-related dropout rate was 2.0% for the terconazole 0.8%
vaginal cream. The adverse drug experience most frequently causing discontinuation of therapy
was vulvovaginal itching, 0.7% with the terconazole 0.8% vaginal cream group and 0.3% with
the placebo group.
TERAZOL® 3 (terconazole) Vaginal Suppositories 80 mg:
During controlled clinical studies conducted in the United States, 284 patients with vulvovaginal
candidiasis were treated with terconazole 80 mg vaginal suppositories. Based on comparative
analyses with placebo (295 patients), the adverse experiences considered adverse reactions most
likely related to terconazole 80 mg vaginal suppositories were headache (30.3% vs. 20.7% with
placebo) and pain of the female genitalia (4.2% vs. 0.7% with placebo). Adverse reactions that
were reported but were not statistically significantly different from placebo were burning (15.2%
vs. 11.2% with placebo) and body pain (3.9% vs. 1.7% with placebo). Fever (2.8% vs. 1.4% with
Reference ID: 3379688
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 019579/S-035
NDA 019641/S-028
NDA 019964/S-030
Page 10
placebo) and chills (1.8% vs. 0.7% with placebo) have also been reported. The therapy-related
dropout rate was 3.5% and the placebo therapy-related dropout rate was 2.7%. The adverse drug
experience on terconazole most frequently causing discontinuation was burning (2.5% vs. 1.4%
with placebo) and pruritus (1.8% vs. 1.4% with placebo).
Post-marketing Experience
The following adverse drug reactions have been first identified during post-marketing experience
with TERAZOL® . 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.
General: Asthenia, Influenza-Like Illness consisting of multiple listed reactions including fever
and chills, nausea, vomiting, myalgia, arthralgia, malaise
Immune: Hypersensitivity, Anaphylaxis, Face Edema
Nervous: Dizziness
Respiratory: Bronchospasm
Skin: Rash, Toxic Epidermal Necrolysis, Urticaria
OVERDOSAGE
Overdose of terconazole in humans has not been reported to date. In the rat, the oral LD 50
values were found to be 1741 and 849 mg/kg for the male and female, respectively. The oral LD
50 values for the male and female dog were ≅1280 and ≥640 mg/kg, respectively.
DOSAGE AND ADMINISTRATION
TERAZOL® 7 (terconazole) Vaginal Cream 0.4%:
One full applicator (5 g) of TERAZOL® 7 Vaginal Cream (20 mg terconazole) should be
administered intravaginally once daily at bedtime for seven consecutive days.
TERAZOL® 3 (terconazole) Vaginal Cream 0.8%:
One full applicator (5 g) of TERAZOL® 3 Vaginal Cream (40 mg terconazole) should be
administered intravaginally once daily at bedtime for three consecutive days.
TERAZOL® 3 (terconazole) Vaginal Suppositories 80 mg:
One TERAZOL® 3 Vaginal Suppository (80 mg terconazole) should be administered
intravaginally once daily at bedtime for three consecutive days.
Reference ID: 3379688
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 019579/S-035
NDA 019641/S-028
NDA 019964/S-030
Page 11
Before prescribing another course of therapy, the diagnosis should be reconfirmed by smears
and/or cultures and other pathogens commonly associated with vulvovaginitis ruled out. The
therapeutic effect of these products is not affected by menstruation.
HOW SUPPLIED
TERAZOL® 7 (terconazole) Vaginal Cream 0.4% is available in 45g (NDC 50458-535-01) tubes
with an ORTHO* Measured-Dose Applicator. Store at Controlled Room Temperature 15–30°C
(59–86°F).
TERAZOL® 3 (terconazole) Vaginal Cream 0.8% is available in 20g (NDC 50458-536-01) tubes
with an ORTHO* Measured-Dose Applicator. Store at Controlled Room Temperature 15–30°C
(59–86°F).
TERAZOL® 3 (terconazole) Vaginal Suppositories 80 mg are available as 2.5g, elliptically-
shaped white to off-white suppositories in packages of three (NDC 50458-531-01) with a vaginal
applicator. Store at Controlled Room Temperature 15–30°C (59–86°F).
*Trademark
Manufactured by:
Janssen Ortho, LLC, Manati, Puerto Rico 00674 (for the Vaginal Cream)
Jubilant HollisterStier General Partnership, Kirkland, Quebec, Canada H9H 4J4 (for the Vaginal
Cream and Vaginal Suppositories)
Manufactured for:
(logo)
Janssen Pharmaceuticals, Inc. Titusville, New Jersey 08560
© Janssen Pharmaceuticals, Inc. 1998
Revised MONTH YEAR
TERAZOL® 7 VAGINAL CREAM 0.4%
(terconazole)
TERAZOL® 3 VAGINAL CREAM 0.8%
(terconazole)
PATIENT INSTRUCTIONS
Reference ID: 3379688
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 019579/S-035
NDA 019641/S-028
NDA 019964/S-030
Page 12
Filling the applicator:
Remove the cap from the tube. usage illustration
Use the pointed tip on the top of the cap to puncture the seal on the tube.
Screw the applicator onto the tube. usage illustration
Squeeze the tube from the bottom and fill the applicator until the plunger stops.
Unscrew the applicator from the tube.
Using the applicator:
1. Lie on your back with your knees drawn up toward your chest.
Holding the applicator by the ribbed end of the barrel, insert the filled applicator into the
vagina as far as it will comfortably go.
Slowly press the plunger of the applicator to release the cream into the vagina.
Reference ID: 3379688
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 019579/S-035
NDA 019641/S-028
NDA 019964/S-030
Page 13 usage illustration
Remove the applicator from the vagina.
Apply one applicatorful each night for as many days at bedtime, as directed by your doctor.
Cleaning the applicator: (Does not apply to sample applicators, which are for one time use
only)
After each use, you should thoroughly clean the applicator by following the procedure below:
1. Pull the plunger out of the barrel. usage illustration
Wash the pieces with lukewarm, soapy water, and dry them thoroughly.
Put the applicator back together by gently pushing the plunger into the barrel as far as it will
go.
NOTE: Store the cream at Controlled Room Temperature 15–30°C (59–86°F). See end flap for
lot number and expiration date.
TERAZOL® 3 VAGINAL SUPPOSITORIES 80mg
(terconazole)
Three oval suppositories, for use inside the vagina only.
Designed to be inserted into the vagina.
Reference ID: 3379688
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 019579/S-035
NDA 019641/S-028
NDA 019964/S-030
Page 14
HOW TO USE:
Place one suppository into the vagina each night at bedtime, for 3 nights, as directed by your
doctor. The TERAZOL Suppository is self-lubricating and may be inserted with or without the
applicator.
A. Insertion with the applicator
1. Filling the applicator
Break off suppository from the plastic strip.
Pull the plastic completely apart at the notched end. usage illustration
Place the flat end of the suppository into the open end of the applicator as
shown. You are now ready to insert the suppository into the vagina. usage illustration
2. Using the applicator
Lie on your back with your knees drawn up toward your chest.
Holding the applicator by the ribbed end of the barrel, gently insert it into
the vagina as far as it will comfortably go.
Press the plunger to release the suppository into the vagina.
Reference ID: 3379688
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 019579/S-035
NDA 019641/S-028
NDA 019964/S-030
Page 15 usage illustration
Remove the applicator from the vagina.
3. Cleaning the applicator (Does not apply to sample applicators, which are
for one time use only)
After each use, you should thoroughly clean the applicator by following the
procedure below:
Pull the plunger out of the barrel.
Wash both pieces with lukewarm, soapy water, and dry them thoroughly.
Put the applicator back together by gently pushing the plunger into the barrel
as far as it will go.
B. Insertion without the applicator
Lie on your back with your knees drawn up toward your chest.
Place the suppository on the tip of your finger as shown. usage illustration
Insert the suppository gently into the vagina as far as it will comfortably go.
NOTE: Store the suppositories at Controlled Room Temperature 15–30°C (59–86°F). See end
flap for lot number and expiration date.
Reference ID: 3379688
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 019579/S-035
NDA 019641/S-028
NDA 019964/S-030
Page 16
A WORD ABOUT YEAST INFECTIONS
Why do yeast infections occur?
Yeast infections are caused by an organism called Candida (KAN di duh). It may be present in
small and harmless amounts in the mouth, digestive tract, and vagina. Sometimes the natural
balance of the vagina becomes upset. This may lead to rapid growth of Candida, which results in
a yeast infection. Symptoms of a yeast infection include itching, burning, redness, and an
abnormal discharge.
Your doctor can make the diagnosis of a yeast infection by evaluating your symptoms and
looking at a sample of the discharge under the microscope.
How can I prevent yeast infections?
Certain factors may increase your chance of developing a yeast infection. These factors don’t
actually cause the problem, but they may create a situation that allows the yeast to grow rapidly.
Clothing: Tight jeans, nylon underwear, pantyhose, and wet bathing suits can hold in heat
and moisture (two conditions in which yeast organisms thrive). Looser pants or skirts,
100% cotton underwear, and stockings may help avoid this problem.
Diet: Cutting down on sweets, milk products, and artificial sweeteners may reduce the risk of
yeast infections.
Antibiotics: Antibiotics work by eliminating disease-causing organisms. While they are
helpful in curing other problems, antibiotics may lead to an overgrowth of Candida in the
vagina.
Pregnancy: Hormonal changes in the body during pregnancy encourage the growth of yeast.
This is a very common time for an infection to occur. Until the baby is born, it may be
hard to completely eliminate yeast infections. If you believe you are pregnant, tell your
doctor.
Menstruation: Sometimes monthly changes in hormone levels may lead to yeast infections.
Diabetes: In addition to heat and moisture, yeast thrives on sugar. Because diabetics often
have sugar in their urine, their vaginas are rich in this substance. Careful control of
diabetes may help prevent yeast infection.
Controlling these factors can help eliminate yeast infections and may prevent them from coming
back.
Reference ID: 3379688
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 019579/S-035
NDA 019641/S-028
NDA 019964/S-030
Page 17
Some other helpful tips:
1. For best results, be sure to use the medication as prescribed by your doctor, even if you
feel better quickly.
Avoid sexual intercourse, if your doctor advises you to do so. The suppository formulation
(not the cream) may damage the diaphragm. Therefore, use of the diaphragm during
therapy with the suppository is not recommended. Consult your physician.
If your partner has any penile itching, redness, or discomfort, he should consult his physician
and mention that you are being treated for a yeast infection.
You can use the medication even if you are having your menstrual period. However, you
should not use tampons because they may absorb the medication. Instead, use external
pads or napkins until you have finished your medication. You may also wish to wear a
sanitary napkin if the vaginal medication leaks.
Dry the genital area thoroughly after showering, bathing, or swimming. Change out of a wet
bathing suit or damp exercise clothes as soon as possible. A dry environment is less likely
to encourage the growth of yeast.
Wipe from front to rear (away from the vagina) after a bowel movement.
Don’t douche unless your doctor specifically tells you to do so. Douching may disturb the
vaginal balance.
Don’t scratch if you can help it. Scratching can cause more irritation and spread the infection.
Discuss with your physician any medication you are already taking. Certain types of
medication can make your vagina more susceptible to infection.
Eat nutritious meals to promote your general health.
Manufactured by:
Janssen Ortho, LLC, Manati, Puerto Rico 00674 (for the Vaginal Cream)
Jubilant HollisterStier General Partnership, Kirkland, Quebec, Canada H9H 4J4 (for the
Vaginal Cream and Vaginal Suppositories)
Manufactured for:
(logo)
Reference ID: 3379688
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 019579/S-035
NDA 019641/S-028
NDA 019964/S-030
Page 18
Janssen Pharmaceuticals, Inc. Titusville, New Jersey 08560
© Janssen Pharmaceuticals, Inc. 1998
Revised MONTH YEAR
Reference ID: 3379688
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:35.445659
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019579s035,019641s028,019964s030lbl.pdf', 'application_number': 19641, 'submission_type': 'SUPPL ', 'submission_number': 28}
|
11,586
|
TABLETS
MEVACOR®
(LOVASTATIN)
DESCRIPTION
MEVACOR* (Lovastatin) is a cholesterol lowering agent isolated from a strain of Aspergillus terreus.
After oral ingestion, lovastatin, which is an inactive lactone, is hydrolyzed to the corresponding β-
hydroxyacid form. This is a principal metabolite and an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A
(HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an
early and rate limiting step in the biosynthesis of cholesterol.
Lovastatin
is
[1S-[1α(R*),3α,7β,8β(2S*,4S*),
8aβ]]-1,2,3,7,
8,8a-hexahydro-3,7-dimethyl-8-[2-
(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl 2-methylbutanoate. The empirical formula
of lovastatin is C24H36O5 and its molecular weight is 404.55. Its structural formula is:
Lovastatin is a white, nonhygroscopic crystalline powder that is insoluble in water and sparingly soluble
in ethanol, methanol, and acetonitrile.
Tablets MEVACOR are supplied as 10 mg, 20 mg and 40 mg tablets for oral administration. In addition
to the active ingredient lovastatin, each tablet contains the following inactive ingredients: cellulose, lactose,
magnesium stearate, and starch. Butylated hydroxyanisole (BHA) is added as a preservative. Tablets
MEVACOR 10 mg also contain red ferric oxide and yellow ferric oxide. Tablets MEVACOR 20 mg also
contain FD&C Blue 2. Tablets MEVACOR 40 mg also contain D&C Yellow 10 and FD&C Blue 2.
CLINICAL PHARMACOLOGY
The involvement of low-density lipoprotein cholesterol (LDL-C) in atherogenesis has been well-
documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological
and clinical studies have established that high LDL-C and low high-density lipoprotein cholesterol (HDL-C)
are both associated with coronary heart disease. However, the risk of developing coronary heart disease
is continuous and graded over the range of cholesterol levels and many coronary events do occur in
patients with total cholesterol (total-C) and LDL-C in the lower end of this range.
MEVACOR has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed
from very low-density lipoprotein (VLDL) and is catabolized predominantly by the high affinity LDL
receptor. The mechanism of the LDL-lowering effect of MEVACOR may involve both reduction of VLDL-C
concentration, and induction of the LDL receptor, leading to reduced production and/or increased
catabolism of LDL-C. Apolipoprotein B also falls substantially during treatment with MEVACOR. Since
each LDL particle contains one molecule of apolipoprotein B, and since little apolipoprotein B is found in
other lipoproteins, this strongly suggests that MEVACOR does not merely cause cholesterol to be lost
from LDL, but also reduces the concentration of circulating LDL particles. In addition, MEVACOR can
produce increases of variable magnitude in HDL-C, and modestly reduces VLDL-C and plasma
triglycerides (TG) (see Tables I-III under Clinical Studies). The effects of MEVACOR on Lp(a), fibrinogen,
and certain other independent biochemical risk markers for coronary heart disease are unknown.
MEVACOR is a specific inhibitor of HMG-CoA reductase, the enzyme which catalyzes the conversion
of HMG-CoA to mevalonate. The conversion of HMG-CoA to mevalonate is an early step in the
biosynthetic pathway for cholesterol.
*Registered trademark of MERCK & CO., Inc.
COPYRIGHT © MERCK & CO., Inc., 1987,1989,1991
All rights reserved
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
Pharmacokinetics
Lovastatin is a lactone which is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent
inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in
pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis,
active plus latent inhibitors (total inhibitors) in plasma following administration of lovastatin.
Following an oral dose of 14C-labeled lovastatin in man, 10% of the dose was excreted in urine and
83% in feces. The latter represents absorbed drug equivalents excreted in bile, as well as any unabsorbed
drug. Plasma concentrations of total radioactivity (lovastatin plus 14C-metabolites) peaked at 2 hours and
declined rapidly to about 10% of peak by 24 hours postdose. Absorption of lovastatin, estimated relative to
an intravenous reference dose, in each of four animal species tested, averaged about 30% of an oral
dose. In animal studies, after oral dosing, lovastatin had high selectivity for the liver, where it achieved
substantially higher concentrations than in non-target tissues. Lovastatin undergoes extensive first-pass
extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile.
As a consequence of extensive hepatic extraction of lovastatin, the availability of drug to the general
circulation is low and variable. In a single dose study in four hypercholesterolemic patients, it was
estimated that less than 5% of an oral dose of lovastatin reaches the general circulation as active
inhibitors. Following administration of lovastatin tablets the coefficient of variation, based on between-
subject variability, was approximately 40% for the area under the curve (AUC) of total inhibitory activity in
the general circulation.
Both lovastatin and its β-hydroxyacid metabolite are highly bound (>95%) to human plasma proteins.
Animal studies demonstrated that lovastatin crosses the blood-brain and placental barriers.
The major active metabolites present in human plasma are the β-hydroxyacid of lovastatin, its
6′-hydroxy derivative, and two additional metabolites. Peak plasma concentrations of both active and total
inhibitors were attained within 2 to 4 hours of dose administration. While the recommended therapeutic
dose range is 10 to 80 mg/day, linearity of inhibitory activity in the general circulation was established by a
single dose study employing lovastatin tablet dosages from 60 to as high as 120 mg. With a once-a-day
dosing regimen, plasma concentrations of total inhibitors over a dosing interval achieved a steady state
between the second and third days of therapy and were about 1.5 times those following a single dose.
When lovastatin was given under fasting conditions, plasma concentrations of total inhibitors were on
average about two-thirds those found when lovastatin was administered immediately after a standard test
meal.
In a study of patients with severe renal insufficiency (creatinine clearance 10-30 mL/min), the plasma
concentrations of total inhibitors after a single dose of lovastatin were approximately two-fold higher than
those in healthy volunteers.
In a study including 16 elderly patients between 70-78 years of age who received MEVACOR
80 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately
45% compared with 18 patients between 18-30 years of age (see PRECAUTIONS, Geriatric Use).
Lovastatin is a substrate for cytochrome P450 isoform 3A4 (CYP3A4) (see PRECAUTIONS, Drug
Interactions). Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the
plasma concentrations of drugs metabolized by CYP3A4. In one study
**, 10 subjects consumed 200 mL of
double-strength grapefruit juice (one can of frozen concentrate diluted with one rather than 3 cans of
water) three times daily for 2 days and an additional 200 mL double-strength grapefruit juice together with
and 30 and 90 minutes following a single dose of 80 mg lovastatin on the third day. This regimen of
grapefruit juice resulted in a mean increase in the serum concentration of lovastatin and its β-hydroxyacid
metabolite (as measured by the area under the concentration-time curve) of 15-fold and 5-fold,
respectively [as measured using a chemical assay — high performance liquid chromatography]. In a
second study, 15 subjects consumed one 8 oz glass of single-strength grapefruit juice (one can of frozen
concentrate diluted with 3 cans of water) with breakfast for 3 consecutive days and a single dose of 40 mg
lovastatin in the evening of the third day. This regimen of grapefruit juice resulted in a mean increase in
the plasma concentration (as measured by the area under the concentration-time curve) of active and
total HMG-CoA reductase inhibitory activity [using an enzyme inhibition assay both before (for active
inhibitors) and after (for total inhibitors) base hydrolysis] of 1.34-fold and 1.36-fold, respectively, and of
lovastatin
and
its
β-hydroxyacid
metabolite
[measured
using
a
chemical
assay —
liquid
chromatography/tandem mass spectrometry — different from that used in the first** study] of 1.94-fold
and 1.57-fold, respectively. The effect of amounts of grapefruit juice between those used in these two
studies on lovastatin pharmacokinetics has not been studied.
** Kantola, T, et al., Clin Pharmacol Ther 1998; 63(4):397-402.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
Clinical Studies
MEVACOR has been shown to be highly effective in reducing total-C and LDL-C in heterozygous
familial and non-familial forms of primary hypercholesterolemia and in mixed hyperlipidemia. A marked
response was seen within 2 weeks, and the maximum therapeutic response occurred within 4-6 weeks.
The response was maintained during continuation of therapy. Single daily doses given in the evening were
more effective than the same dose given in the morning, perhaps because cholesterol is synthesized
mainly at night.
In multicenter, double-blind studies in patients with familial or non-familial hypercholesterolemia,
MEVACOR, administered in doses ranging from 10 mg q.p.m. to 40 mg b.i.d., was compared to placebo.
MEVACOR consistently and significantly decreased plasma total-C, LDL-C, total-C/HDL-C ratio and LDL-
C/HDL-C ratio. In addition, MEVACOR produced increases of variable magnitude in HDL-C, and modestly
decreased VLDL-C and plasma TG (see Tables I through III for dose response results).
The results of a study in patients with primary hypercholesterolemia are presented in Table I.
TABLE I
MEVACOR vs. Placebo
(Mean Percent Change from Baseline After 6 Weeks)
DOSAGE
N
TOTAL-C
LDL-C
HDL-C
LDL-C/
HDL-C
TOTAL-C/
HDL-C
TG.
Placebo
33
–2
–1
–1
0
+1
+9
MEVACOR
10 mg q.p.m.
20 mg q.p.m.
10 mg b.i.d.
40 mg q.p.m.
20 mg b.i.d.
33
33
32
33
36
–16
–19
–19
–22
–24
–21
–27
–28
–31
–32
+5
+6
+8
+5
+2
–24
–30
–33
–33
–32
–19
–23
–25
–25
–24
–10
+9
–7
–8
–6
MEVACOR was compared to cholestyramine in a randomized open parallel study. The study was
performed with patients with hypercholesterolemia who were at high risk of myocardial infarction.
Summary results are presented in Table II.
TABLE II
MEVACOR vs. Cholestyramine
(Percent Change from Baseline After 12 Weeks)
TREATMENT
N
TOTAL-C
(mean)
LDL-C
(mean)
HDL-C
(mean)
LDL-C/
HDL-C
(mean)
TOTAL-C/
HDL-C
(mean)
VLDL-C
(median)
TG.
(mean)
MEVACOR
20 mg b.i.d.
40 mg b.i.d.
85
88
–27
–34
–32
–42
+9
+8
–36
–44
–31
–37
–34
–31
–21
–27
Cholestyramine
12 g b.i.d.
88
–17
–23
+8
–27
–21
+2
+11
MEVACOR was studied in controlled trials in hypercholesterolemic patients with well-controlled non-
insulin dependent diabetes mellitus with normal renal function. The effect of MEVACOR on lipids and
lipoproteins and the safety profile of MEVACOR were similar to that demonstrated in studies in
nondiabetics. MEVACOR had no clinically important effect on glycemic control or on the dose requirement
of oral hypoglycemic agents.
Expanded Clinical Evaluation of Lovastatin (EXCEL) Study
MEVACOR was compared to placebo in 8,245 patients with hypercholesterolemia (total-C 240-300
mg/dL [6.2 mmol/L - 7.6 mmol/L], LDL-C >160 mg/dL [4.1 mmol/L]) in the randomized, double-blind,
parallel, 48-week EXCEL study. All changes in the lipid measurements (Table III) in MEVACOR treated
patients were dose-related and significantly different from placebo (p≤0.001). These results were
sustained throughout the study.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
TABLE III
MEVACOR vs. Placebo
(Percent Change from Baseline —
Average Values Between Weeks 12 and 48)
DOSAGE
N**
TOTAL-C
(mean)
LDL-C
(mean)
HDL-C
(mean)
LDL-C/
HDL-C
(mean)
TOTAL-C/
HDL-C
(mean)
TG.
(median)
Placebo
1663
+0.7
+0.4
+2.0
+0.2
+0.6
+4
MEVACOR
20 mg q.p.m.
40 mg q.p.m.
20 mg b.i.d.
40 mg b.i.d.
1642
1645
1646
1649
–17
–22
–24
–29
–24
–30
–34
–40
+6.6
+7.2
+8.6
+9.5
–27
–34
–38
–44
–21
–26
–29
–34
–10
–14
–16
–19
**Patients enrolled
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), a double-blind,
randomized, placebo-controlled, primary prevention study, demonstrated that treatment with MEVACOR
decreased the rate of acute major coronary events (composite endpoint of myocardial infarction, unstable
angina, and sudden cardiac death) compared with placebo during a median of 5.1 years of follow-up.
Participants were middle-aged and elderly men (ages 45-73) and women (ages 55-73) without
symptomatic cardiovascular disease with average to moderately elevated total-C and LDL-C, below
average HDL-C, and who were at high risk based on elevated total-C/HDL-C. In addition to age, 63% of
the participants had at least one other risk factor (baseline HDL-C <35 mg/dL, hypertension, family history,
smoking and diabetes).
AFCAPS/TexCAPS enrolled 6,605 participants (5,608 men, 997 women) based on the following lipid
entry criteria: total-C range of 180-264 mg/dL, LDL-C range of 130-190 mg/dL, HDL-C of ≤45 mg/dL for
men and ≤47 mg/dL for women, and TG of ≤400 mg/dL. Participants were treated with standard care,
including diet, and either MEVACOR 20-40 mg daily (n= 3,304) or placebo (n= 3,301). Approximately 50%
of the participants treated with MEVACOR were titrated to 40 mg daily when their LDL-C remained >110
mg/dL at the 20-mg starting dose.
MEVACOR reduced the risk of a first acute major coronary event, the primary efficacy endpoint, by
37% (MEVACOR 3.5%, placebo 5.5%; p<0.001; Figure 1). A first acute major coronary event was defined
as myocardial infarction (54 participants on MEVACOR, 94 on placebo) or unstable angina (54 vs. 80)
or
sudden cardiac death (8 vs. 9). Furthermore, among the secondary endpoints, MEVACOR reduced the
risk of unstable angina by 32% (1.8 vs. 2.6%; p=0.023), of myocardial infarction by 40% (1.7 vs. 2.9%;
p=0.002), and of undergoing coronary revascularization procedures (e.g., coronary artery bypass grafting
or percutaneous transluminal coronary angioplasty) by 33% (3.2 vs. 4.8%; p=0.001). Trends in risk
reduction associated with treatment with MEVACOR were consistent across men and women, smokers
and non-smokers, hypertensives and non-hypertensives, and older and younger participants. Participants
with ≥2 risk factors had risk reductions (RR) in both acute major coronary events (RR 43%) and coronary
revascularization procedures (RR 37%). Because there were too few events among those participants
with age as their only risk factor in this study, the effect of MEVACOR on outcomes could not be
adequately assessed in this subgroup.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
Atherosclerosis
In the Canadian Coronary Atherosclerosis Intervention Trial (CCAIT), the effect of therapy with
lovastatin on coronary atherosclerosis was assessed by coronary angiography in hyperlipidemic patients.
In the randomized, double-blind, controlled clinical trial, patients were treated with conventional measures
(usually diet and 325 mg of aspirin every other day) and either lovastatin 20-80 mg daily or placebo.
Angiograms were evaluated at baseline and at two years by computerized quantitative coronary
angiography (QCA). Lovastatin significantly slowed the progression of lesions as measured by the mean
change per-patient in minimum lumen diameter (the primary endpoint) and percent diameter stenosis, and
decreased the proportions of patients categorized with disease progression (33% vs. 50%) and with new
lesions (16% vs. 32%).
In a similarly designed trial, the Monitored Atherosclerosis Regression Study (MARS), patients were
treated with diet and either lovastatin 80 mg daily or placebo. No statistically significant difference between
lovastatin and placebo was seen for the primary endpoint (mean change per patient in percent diameter
stenosis of all lesions), or for most secondary QCA endpoints. Visual assessment by angiographers who
formed a consensus opinion of overall angiographic change (Global Change Score) was also a secondary
endpoint. By this endpoint, significant slowing of disease was seen, with regression in 23% of patients
treated with lovastatin compared to 11% of placebo patients.
In the Familial Atherosclerosis Treatment Study (FATS), either lovastatin or niacin in combination with
a bile acid sequestrant for 2.5 years in hyperlipidemic subjects significantly reduced the frequency of
progression and increased the frequency of regression of coronary atherosclerotic lesions by QCA
compared to diet and, in some cases, low-dose resin.
The effect of lovastatin on the progression of atherosclerosis in the coronary arteries has been
corroborated by similar findings in another vasculature. In the Asymptomatic Carotid Artery Progression
Study (ACAPS), the effect of therapy with lovastatin on carotid atherosclerosis was assessed by B-mode
ultrasonography in hyperlipidemic patients with early carotid lesions and without known coronary heart
disease at baseline. In this double-blind, controlled clinical trial, 919 patients were randomized in a 2 x 2
factorial design to placebo, lovastatin 10-40 mg daily and/or warfarin. Ultrasonograms of the carotid walls
were used to determine the change per patient from baseline to three years in mean maximum intimal-
medial thickness (IMT) of 12 measured segments. There was a significant regression of carotid lesions in
patients receiving lovastatin alone compared to those receiving placebo alone (p=0.001). The predictive
value of changes in IMT for stroke has not yet been established. In the lovastatin group there was a
significant reduction in the number of patients with major cardiovascular events relative to the placebo
group (5 vs. 14) and a significant reduction in all-cause mortality (1 vs. 8).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
Eye
There was a high prevalence of baseline lenticular opacities in the patient population included in the
early clinical trials with lovastatin. During these trials the appearance of new opacities was noted in both
the lovastatin and placebo groups. There was no clinically significant change in visual acuity in the patients
who had new opacities reported nor was any patient, including those with opacities noted at baseline,
discontinued from therapy because of a decrease in visual acuity.
A three-year, double-blind, placebo-controlled study in hypercholesterolemic patients to assess the
effect of lovastatin on the human lens demonstrated that there were no clinically or statistically significant
differences between the lovastatin and placebo groups in the incidence, type or progression of lenticular
opacities. There are no controlled clinical data assessing the lens available for treatment beyond three
years.
INDICATIONS AND USAGE
Therapy with MEVACOR should be a component of multiple risk factor intervention in those individuals
with dyslipidemia at risk for atherosclerotic vascular disease. MEVACOR should be used in addition to a
diet restricted in saturated fat and cholesterol as part of a treatment strategy to lower total-C and LDL-C to
target levels when the response to diet and other nonpharmacological measures alone has been
inadequate to reduce risk.
Primary Prevention of Coronary Heart Disease
In individuals without symptomatic cardiovascular disease, average to moderately elevated total-C and
LDL-C, and below average HDL-C, MEVACOR is indicated to reduce the risk of:
- Myocardial infarction
- Unstable angina
- Coronary revascularization procedures
(See CLINICAL PHARMACOLOGY, Clinical Studies.)
Coronary Heart Disease
MEVACOR is indicated to slow the progression of coronary atherosclerosis in patients with coronary
heart disease as part of a treatment strategy to lower total-C and LDL-C to target levels.
Hypercholesterolemia
Therapy with lipid-altering agents should be a component of multiple risk factor intervention in those
individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia.
MEVACOR is indicated as an adjunct to diet for the reduction of elevated total-C and LDL-C levels in
patients with primary hypercholesterolemia (Types IIa and IIb
***), when the response to diet restricted in
saturated fat and cholesterol and to other nonpharmacological measures alone has been inadequate.
General Recommendations
Prior to initiating therapy with lovastatin, secondary causes for hypercholesterolemia (e.g., poorly
controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver
disease, other drug therapy, alcoholism) should be excluded, and a lipid profile performed to measure
total-C, HDL-C, and TG. For patients with TG less than 400 mg/dL (<4.5 mmol/L), LDL-C can be
estimated using the following equation:
LDL-C = total-C – [0.2 × (TG) + HDL-C]
For TG levels >400 mg/dL (>4.5 mmol/L), this equation is less accurate and LDL-C concentrations
should be determined by ultracentrifugation. In hypertriglyceridemic patients, LDL-C may be low or normal
despite elevated total-C. In such cases, MEVACOR is not indicated.
The National Cholesterol Education Program (NCEP) Treatment Guidelines are summarized below:
*** Classification of Hyperlipoproteinemias
Lipid
Lipoproteins
Elevations
Type
elevated
major
minor
I
chylomicrons
TG
↑→C
IIa
LDL
C
—
IIb
LDL, VLDL
C
TG
III (rare)
IDL
C/TG
—
IV
VLDL
TG
↑→C
V (rare)
chylomicrons, VLDL
TG
↑→C
IDL = intermediate-density lipoprotein.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
LDL-Cholesterol
mg/dL (mmol/L)
Definite
Atherosclerotic
Disease†
Two or More
Other Risk
Factors††
Initiation
Level
Goal
NO
NO
≥190
<160
(≥4.9)
(<4.1)
NO
YES
≥160
<130
(≥4.1)
(<3.4)
YES
YES or NO
≥130†††
≤100
(≥3.4)
(≤2.6)
†
Coronary heart disease or peripheral vascular disease (including symptomatic carotid artery disease).
††
Other risk factors for coronary heart disease (CHD) include: age (males: ≥45 years; females: ≥55 years or premature
menopause without estrogen replacement therapy); family history of premature CHD; current cigarette smoking;
hypertension; confirmed HDL-C <35 mg/dL (<0.91 mmol/L); and diabetes mellitus. Subtract one risk factor if HDL-C is
≥60 mg/dL (≥1.6 mmol/L).
†††
In CHD patients with LDL-C levels 100-129 mg/dL, the physician should exercise clinical judgment in deciding whether to
initiate drug treatment.
At the time of hospitalization for an acute coronary event, consideration can be given to initiating drug
therapy at discharge if the LDL-C is ≥130 mg/dL (see NCEP Guidelines above).
Since the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C levels be used to
initiate and assess treatment response. Only if LDL-C levels are not available, should the total-C be used
to monitor therapy.
Although MEVACOR may be useful to reduce elevated LDL-C levels in patients with combined
hypercholesterolemia and hypertriglyceridemia where hypercholesterolemia is the major abnormality
(Type IIb hyperlipoproteinemia), it has not been studied in conditions where the major abnormality is
elevation of chylomicrons, VLDL or IDL (i.e., hyperlipoproteinemia types I, III, IV, or V).***
CONTRAINDICATIONS
Hypersensitivity to any component of this medication.
Active liver disease or unexplained persistent elevations of serum transaminases (see WARNINGS).
Pregnancy and lactation. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering
drugs during pregnancy should have little impact on the outcome of long-term therapy of primary
hypercholesterolemia. Moreover, cholesterol and other products of the cholesterol biosynthesis pathway
are essential components for fetal development, including synthesis of steroids and cell membranes.
Because of the ability of inhibitors of HMG-CoA reductase such as MEVACOR to decrease the synthesis
of cholesterol and possibly other products of the cholesterol biosynthesis pathway, MEVACOR is
contraindicated during pregnancy and in nursing mothers. MEVACOR should be administered to
women of childbearing age only when such patients are highly unlikely to conceive. If the patient
becomes pregnant while taking this drug, MEVACOR should be discontinued immediately and the patient
should be apprised of the potential hazard to the fetus (see PRECAUTIONS, Pregnancy).
WARNINGS
Skeletal Muscle
Lovastatin and other inhibitors of HMG-CoA reductase occasionally cause myopathy, which is
manifested as muscle pain or weakness associated with grossly elevated creatine kinase (> 10X the
upper limit of normal [ULN]). Rhabdomyolysis, with or without acute renal failure secondary to
myoglobinuria, has been reported rarely and can occur at any time. In the EXCEL study, there was
one case of myopathy among 4933 patients randomized to lovastatin 20-40 mg daily for 48 weeks, and 4
among 1649 patients randomized to 80 mg daily. When drug treatment was interrupted or discontinued in
these patients, muscle symptoms and creatine kinase (CK) increases promptly resolved. The risk of
myopathy is increased by concomitant therapy with certain drugs, some of which were excluded by the
EXCEL study design.
Myopathy caused by drug interactions.
The incidence and severity of myopathy are increased by concomitant administration of HMG-CoA
reductase inhibitors with drugs that can cause myopathy when given alone, such as gemfibrozil and other
fibrates, and lipid-lowering doses (≥ 1 g/day) of niacin (nicotinic acid).
In addition, the risk of myopathy may be increased by high levels of HMG-CoA reductase inhibitory
activity in plasma. Lovastatin is metabolized by the cytochrome P450 isoform 3A4 (CYP3A4). Potent
inhibitors of this metabolic pathway can raise the plasma level of HMG-CoA reductase inhibitory activity
and may increase the risk of myopathy. These include cyclosporine; the azole antifungals, itraconazole
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
and ketoconazole; the macrolide antibiotics, erythromycin and clarithromycin; HIV protease inhibitors; the
antidepressant nefazodone; and large quantities of grapefruit juice (> 1 quart daily) (see below; CLINICAL
PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions; and DOSAGE AND
ADMINISTRATION).
Although the data are insufficient for lovastatin, the risk of myopathy appears to be increased when
verapamil is used concomitantly with a closely related HMG-CoA reductase inhibitor (see PRECAUTIONS,
Drug Interactions).
Reducing the risk of myopathy.
1. General measures. Patients starting therapy with lovastatin should be advised of the risk of
myopathy, and told to report promptly unexplained muscle pain, tenderness or weakness. A
creatine kinase (CK) level above 10X ULN in a patient with unexplained muscle symptoms indicates
myopathy. Lovastatin therapy should be discontinued if myopathy is diagnosed or suspected. In
most cases, when patients were promptly discontinued from treatment, muscle symptoms and CK
increases resolved.
Of the patients with rhabdomyolysis, many had complicated medical histories. Some had preexisting
renal insufficiency, usually as a consequence of long-standing diabetes. In such patients, dose escalation
requires caution. Also, as there are no known adverse consequences of brief interruption of therapy,
treatment with lovastatin should be stopped a few days before elective major surgery and when any major
acute medical or surgical condition supervenes.
2. Measures to reduce the risk of myopathy caused by drug interactions (see above and
PRECAUTIONS, Drug Interactions). Physicians contemplating combined therapy with lovastatin
and any of the interacting drugs should weigh the potential benefits and risks, and should
carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness,
particularly during the initial months of therapy and during any periods of upward dosage titration
of either drug. Periodic CK determinations may be considered in such situations, but there is no
assurance that such monitoring will prevent myopathy.
The combined use of lovastatin with fibrates or niacin should be avoided unless the benefit of further
alteration in lipid levels is likely to outweigh the increased risk of this drug combination. Combinations of
fibrates or niacin with low doses of lovastatin have been used without myopathy in small, short-term
clinical trials with careful monitoring. Addition of these drugs to lovastatin typically provides little additional
reduction in LDL cholesterol, but further reductions of triglycerides and further increases in HDL
cholesterol may be obtained. If one of these drugs must be used with lovastatin, clinical experience
suggests that the risk of myopathy is less with niacin than with the fibrates.
In patients taking concomitant cyclosporine, fibrates or niacin, the dose of lovastatin should
generally not exceed 20 mg/day (see DOSAGE AND ADMINISTRATION and DOSAGE AND
ADMINISTRATION, Concomitant Lipid-Lowering Therapy), as the risk of myopathy increases substantially
at higher doses. Concomitant use of lovastatin with itraconazole, ketoconazole, erythromycin,
clarithromycin, HIV protease inhibitors, nefazodone, or large quantities of grapefruit juice (> 1 quart daily)
is not recommended. If no alternative to a short course of treatment with itraconazole, ketoconazole,
erythromycin, or clarithromycin is available, a brief suspension of lovastatin therapy during such treatment
can be considered as there are no known adverse consequences to brief interruptions of long-term
cholesterol-lowering therapy.
Liver Dysfunction
Persistent increases (to more than 3 times the upper limit of normal) in serum transaminases
occurred in 1.9% of adult patients who received lovastatin for at least one year in early clinical
trials (see ADVERSE REACTIONS). When the drug was interrupted or discontinued in these patients, the
transaminase levels usually fell slowly to pretreatment levels. The increases usually appeared 3 to 12
months after the start of therapy with lovastatin, and were not associated with jaundice or other clinical
signs or symptoms. There was no evidence of hypersensitivity. In the EXCEL study (see CLINICAL
PHARMACOLOGY, Clinical Studies), the incidence of persistent increases in serum transaminases over
48 weeks was 0.1% for placebo, 0.1% at 20 mg/day, 0.9% at 40 mg/day, and 1.5% at 80 mg/day in
patients on lovastatin. However, in post-marketing experience with MEVACOR, symptomatic liver disease
has been reported rarely at all dosages (see ADVERSE REACTIONS).
In AFCAPS/TexCAPS, the number of participants with consecutive elevations of either alanine
aminotransferase (ALT) or aspartate aminotransferase (AST) (> 3 times the upper limit of normal), over a
median of 5.1 years of follow-up, was not significantly different between the MEVACOR and placebo
groups (18 [0.6%] vs. 11 [0.3%]). The starting dose of MEVACOR was 20 mg/day; 50% of the MEVACOR
treated participants were titrated to 40 mg/day at Week 18. Of the 18 participants on MEVACOR with
consecutive elevations of either ALT or AST, 11 (0.7%) elevations occurred in participants taking 20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
mg/day, while 7 (0.4%) elevations occurred in participants titrated to 40 mg/day. Elevated transaminases
resulted in discontinuation of 6 (0.2%) participants from therapy in the MEVACOR group (n=3,304) and 4
(0.1%) in the placebo group (n=3,301).
It is recommended that liver function tests be performed before the initiation of treatment, at 6
and 12 weeks after initiation of therapy or elevation in dose, and periodically thereafter (e.g.,
semiannually). Patients who develop increased transaminase levels should be monitored with a second
liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests
until the abnormality(ies) returns to normal. Should an increase in AST or ALT of three times the upper
limit of normal or greater persist, withdrawal of therapy with MEVACOR is recommended.
The drug should be used with caution in patients who consume substantial quantities of alcohol and/or
have a past history of liver disease. Active liver disease or unexplained transaminase elevations are
contraindications to the use of lovastatin.
As with other lipid-lowering agents, moderate (less than three times the upper limit of normal)
elevations of serum transaminases have been reported following therapy with MEVACOR (see ADVERSE
REACTIONS). These changes appeared soon after initiation of therapy with MEVACOR, were often
transient, were not accompanied by any symptoms and interruption of treatment was not required.
PRECAUTIONS
General
Lovastatin may elevate creatine phosphokinase and transaminase levels (see WARNINGS and
ADVERSE REACTIONS). This should be considered in the differential diagnosis of chest pain in a patient
on therapy with lovastatin.
Homozygous Familial Hypercholesterolemia
MEVACOR is less effective in patients with the rare homozygous familial hypercholesterolemia,
possibly because these patients have no functional LDL receptors. MEVACOR appears to be more likely
to raise serum transaminases (see ADVERSE REACTIONS) in these homozygous patients.
Information for Patients
Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness (see
WARNINGS, Skeletal Muscle).
Drug Interactions
Gemfibrozil and other fibrates, lipid-lowering doses (≥ 1 g/day) of niacin (nicotinic acid): These drugs
increase the risk of myopathy when given concomitantly with lovastatin, probably because they can
produce myopathy when given alone (see WARNINGS, Skeletal Muscle). There is no evidence to suggest
that these agents affect the pharmacokinetics of lovastatin.
CYP3A4 Interactions: Lovastatin has no CYP3A4 inhibitory activity; therefore, it is not expected to
affect the plasma concentrations of other drugs metabolized by CYP3A4. However, lovastatin itself is a
substrate for CYP3A4. Potent inhibitors of CYP3A4 may increase the risk of myopathy by increasing the
plasma concentration of HMG-CoA reductase inhibitory activity during lovastatin therapy. These inhibitors
include cyclosporine, itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors,
nefazodone, and large quantities of grapefruit juice (> 1 quart daily) (see CLINICAL PHARMACOLOGY,
Pharmacokinetics and WARNINGS, Skeletal Muscle).
Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the plasma
concentrations of drugs metabolized by CYP3A4. Large quantities of grapefruit juice (> 1 quart daily)
significantly increase the serum concentrations of lovastatin and its β-hydroxyacid metabolite during
lovastatin therapy and should be avoided (see CLINICAL PHARMACOLOGY, Pharmacokinetics and
WARNINGS, Skeletal Muscle).
Although the data are insufficient for lovastatin, the risk of myopathy appears to be increased when
verapamil is used concomitantly with a closely related HMG-CoA reductase inhibitor (see WARNINGS,
Skeletal Muscle).
Coumarin Anticoagulants: In a small clinical trial in which lovastatin was administered to warfarin
treated patients, no effect on prothrombin time was detected. However, another HMG-CoA reductase
inhibitor has been found to produce a less than two-second increase in prothrombin time in healthy
volunteers receiving low doses of warfarin. Also, bleeding and/or increased prothrombin time have been
reported in a few patients taking coumarin anticoagulants concomitantly with lovastatin. It is recommended
that in patients taking anticoagulants, prothrombin time be determined before starting lovastatin and
frequently enough during early therapy to insure that no significant alteration of prothrombin time occurs.
Once a stable prothrombin time has been documented, prothrombin times can be monitored at the
intervals usually recommended for patients on coumarin anticoagulants. If the dose of lovastatin is
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
changed, the same procedure should be repeated. Lovastatin therapy has not been associated with
bleeding or with changes in prothrombin time in patients not taking anticoagulants.
Propranolol: In normal volunteers, there was no clinically significant pharmacokinetic or
pharmacodynamic interaction with concomitant administration of single doses of lovastatin and
propranolol.
Digoxin: In patients with hypercholesterolemia, concomitant administration of lovastatin and digoxin
resulted in no effect on digoxin plasma concentrations.
Oral Hypoglycemic Agents: In pharmacokinetic studies of MEVACOR in hypercholesterolemic non-
insulin dependent diabetic patients, there was no drug interaction with glipizide or with chlorpropamide
(see CLINICAL PHARMACOLOGY, Clinical Studies).
Endocrine Function
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically blunt
adrenal and/or gonadal steroid production. Results of clinical trials with drugs in this class have been
inconsistent with regard to drug effects on basal and reserve steroid levels. However, clinical studies have
shown that lovastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve, and
does not reduce basal plasma testosterone concentration. Another HMG-CoA reductase inhibitor has
been shown to reduce the plasma testosterone response to HCG. In the same study, the mean
testosterone response to HCG was slightly but not significantly reduced after treatment with lovastatin
40 mg daily for 16 weeks in 21 men. The effects of HMG-CoA reductase inhibitors on male fertility have
not been studied in adequate numbers of male patients. The effects, if any, on the pituitary-gonadal axis in
pre-menopausal women are unknown. Patients treated with lovastatin who develop clinical evidence of
endocrine dysfunction should be evaluated appropriately. Caution should also be exercised if an
HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients
also receiving other drugs (e.g., ketoconazole, spironolactone, cimetidine) that may decrease the levels or
activity of endogenous steroid hormones.
CNS Toxicity
Lovastatin produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in
clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean
plasma drug levels about 30 times higher than the mean drug level in humans taking the highest
recommended dose (as measured by total enzyme inhibitory activity). Vestibulocochlear Wallerian-like
degeneration and retinal ganglion cell 4chromatolysis were also seen in dogs treated for 14 weeks at 180
mg/kg/day, a dose which resulted in a mean plasma drug level (Cmax) similar to that seen with the 60
mg/kg/day dose.
CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell
infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels, were seen in
dogs treated with lovastatin at a dose of 180 mg/kg/day, a dose which produced plasma drug levels (Cmax)
which were about 30 times higher than the mean values in humans taking 80 mg/day.
Similar optic nerve and CNS vascular lesions have been observed with other drugs of this class.
Cataracts were seen in dogs treated for 11 and 28 weeks at 180 mg/kg/day and 1 year at
60 mg/kg/day.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 21-month carcinogenic study in mice, there was a statistically significant increase in the incidence
of hepatocellular carcinomas and adenomas in both males and females at 500 mg/kg/day. This dose
produced a total plasma drug exposure 3 to 4 times that of humans given the highest recommended dose
of lovastatin (drug exposure was measured as total HMG-CoA reductase inhibitory activity in extracted
plasma). Tumor increases were not seen at 20 and 100 mg/kg/day, doses that produced drug exposures
of 0.3 to 2 times that of humans at the 80 mg/day dose. A statistically significant increase in pulmonary
adenomas was seen in female mice at approximately 4 times the human drug exposure. (Although mice
were given 300 times the human dose [HD] on a mg/kg body weight basis, plasma levels of total inhibitory
activity were only 4 times higher in mice than in humans given 80 mg of MEVACOR.)
There was an increase in incidence of papilloma in the non-glandular mucosa of the stomach of mice
beginning at exposures of 1 to 2 times that of humans. The glandular mucosa was not affected. The
human stomach contains only glandular mucosa.
In a 24-month carcinogenicity study in rats, there was a positive dose response relationship for
hepatocellular carcinogenicity in males at drug exposures between 2-7 times that of human exposure at
80 mg/day (doses in rats were 5, 30 and 180 mg/kg/day).
An increased incidence of thyroid neoplasms in rats appears to be a response that has been seen with
other HMG-CoA reductase inhibitors.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
A chemically similar drug in this class was administered to mice for 72 weeks at 25, 100, and
400 mg/kg body weight, which resulted in mean serum drug levels approximately 3, 15, and 33 times
higher than the mean human serum drug concentration (as total inhibitory activity) after a 40 mg oral dose.
Liver carcinomas were significantly increased in high dose females and mid- and high dose males, with a
maximum incidence of 90 percent in males. The incidence of adenomas of the liver was significantly
increased in mid- and high dose females. Drug treatment also significantly increased the incidence of lung
adenomas in mid- and high dose males and females. Adenomas of the Harderian gland (a gland of the
eye of rodents) were significantly higher in high dose mice than in controls.
No evidence of mutagenicity was observed in a microbial mutagen test using mutant strains of
Salmonella typhimurium with or without rat or mouse liver metabolic activation. In addition, no evidence of
damage to genetic material was noted in an in vitro alkaline elution assay using rat or mouse hepatocytes,
a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or
an in vivo chromosomal aberration assay in mouse bone marrow.
Drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell
formation were seen in dogs starting at 20 mg/kg/day. Similar findings were seen with another drug in this
class. No drug-related effects on fertility were found in studies with lovastatin in rats. However, in studies
with a similar drug in this class, there was decreased fertility in male rats treated for 34 weeks at 25 mg/kg
body weight, although this effect was not observed in a subsequent fertility study when this same dose
was administered for 11 weeks (the entire cycle of spermatogenesis, including epididymal maturation). In
rats treated with this same reductase inhibitor at 180 mg/kg/day, seminiferous tubule degeneration
(necrosis and loss of spermatogenic epithelium) was observed. No microscopic changes were observed
in the testes from rats of either study. The clinical significance of these findings is unclear.
Pregnancy
Pregnancy Category X
See CONTRAINDICATIONS.
Safety in pregnant women has not been established.
Lovastatin has been shown to produce skeletal malformations at plasma levels 40 times the human
exposure (for mouse fetus) and 80 times the human exposure (for rat fetus) based on mg/m2 surface area
(doses were 800 mg/kg/day). No drug-induced changes were seen in either species at multiples of 8 times
(rat) or 4 times (mouse) based on surface area. No evidence of malformations was noted in rabbits at
exposures up to 3 times the human exposure (dose of 15 mg/kg/day, highest tolerated dose).
Rare reports of congenital anomalies have been received following intrauterine exposure to HMG-CoA
reductase inhibitors. In a review† of approximately 100 prospectively followed pregnancies in women
exposed to MEVACOR or another structurally related HMG-CoA reductase inhibitor, the incidences of
congenital anomalies, spontaneous abortions and fetal deaths/stillbirths did not exceed what would be
expected in the general population. The number of cases is adequate only to exclude a 3 to 4-fold
increase in congenital anomalies over the background incidence. In 89% of the prospectively followed
pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the
first trimester when pregnancy was identified. As safety in pregnant women has not been established and
there is no apparent benefit to therapy with MEVACOR during pregnancy (see CONTRAINDICATIONS),
treatment should be immediately discontinued as soon as pregnancy is recognized. MEVACOR should be
administered to women of child-bearing potential only when such patients are highly unlikely to conceive
and have been informed of the potential hazards.
Nursing Mothers
It is not known whether lovastatin is excreted in human milk. Because a small amount of another drug
in this class is excreted in human breast milk and because of the potential for serious adverse reactions in
nursing infants, women taking MEVACOR should not nurse their infants (see CONTRAINDICATIONS).
Pediatric Use
Safety and effectiveness in pediatric patients have not been established. Because pediatric patients
are not likely to benefit from cholesterol lowering for at least a decade and because experience with this
drug is limited (no studies in subjects below the age of 20 years), treatment of pediatric patients with
lovastatin is not recommended at this time.
Geriatric Use
A pharmacokinetic study with lovastatin showed the mean plasma level of HMG-CoA reductase
inhibitory activity to be approximately 45% higher in elderly patients between 70-78 years of age compared
with patients between 18-30 years of age; however, clinical study experience in the elderly indicates that
dosage adjustment based on this age-related pharmacokinetic difference is not needed. In the two large
† Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During
Pregnancy. Reproductive Toxicology. 10(6):439-446. 1996.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
clinical studies conducted with lovastatin (EXCEL and AFCAPS/TexCAPS), 21% (3094/14850) of patients
were ≥65 years of age. Lipid-lowering efficacy with lovastatin was at least as great in elderly patients
compared with younger patients, and there were no overall differences in safety over the 20 to 80 mg/day
dosage range (see CLINICAL PHARMACOLOGY).
ADVERSE REACTIONS
MEVACOR is generally well tolerated; adverse reactions usually have been mild and transient.
Phase III Clinical Studies
In Phase III controlled clinical studies involving 613 patients treated with MEVACOR, the adverse
experience profile was similar to that shown below for the 8,245-patient EXCEL study (see Expanded
Clinical Evaluation of Lovastatin [EXCEL] Study).
Persistent increases of serum transaminases have been noted (see WARNINGS, Liver Dysfunction).
About 11% of patients had elevations of CK levels of at least twice the normal value on one or more
occasions. The corresponding values for the control agent cholestyramine was 9 percent. This was
attributable to the noncardiac fraction of CK. Large increases in CK have sometimes been reported (see
WARNINGS, Skeletal Muscle).
Expanded Clinical Evaluation of Lovastatin (EXCEL) Study
MEVACOR was compared to placebo in 8,245 patients with hypercholesterolemia (total-C 240-300
mg/dL [6.2-7.8 mmol/L]) in the randomized, double-blind, parallel, 48-week EXCEL study. Clinical adverse
experiences reported as possibly, probably or definitely drug-related in ≥1% in any treatment group are
shown in the table below. For no event was the incidence on drug and placebo statistically different.
Placebo
(N = 1663)
%
MEVACOR
20 mg q.p.m.
(N = 1642)
%
MEVACOR
40 mg q.p.m.
(N = 1645)
%
MEVACOR
20 mg b.i.d.
(N = 1646)
%
MEVACOR
40 mg b.i.d.
(N = 1649)
%
Body As a Whole
Asthenia
1.4
1.7
1.4
1.5
1.2
Gastrointestinal
Abdominal pain
Constipation
Diarrhea
Dyspepsia
Flatulence
Nausea
1.6
1.9
2.3
1.9
4.2
2.5
2.0
2.0
2.6
1.3
3.7
1.9
2.0
3.2
2.4
1.3
4.3
2.5
2.2
3.2
2.2
1.0
3.9
2.2
2.5
3.5
2.6
1.6
4.5
2.2
Musculoskeletal
Muscle cramps
Myalgia
0.5
1.7
0.6
2.6
0.8
1.8
1.1
2.2
1.0
3.0
Nervous System/
Psychiatric
Dizziness
Headache
0.7
2.7
0.7
2.6
1.2
2.8
0.5
2.1
0.5
3.2
Skin
Rash
0.7
0.8
1.0
1.2
1.3
Special Senses
Blurred vision
0.8
1.1
0.9
0.9
1.2
Other clinical adverse experiences reported as possibly, probably or definitely drug-related in 0.5 to 1.0
percent of patients in any drug-treated group are listed below. In all these cases the incidence on drug and
placebo was not statistically different. Body as a Whole: chest pain; Gastrointestinal: acid regurgitation,
dry mouth, vomiting; Musculoskeletal: leg pain, shoulder pain, arthralgia; Nervous System/Psychiatric:
insomnia, paresthesia; Skin: alopecia, pruritus; Special Senses: eye irritation.
In the EXCEL study (see CLINICAL PHARMACOLOGY, Clinical Studies), 4.6% of the patients treated
up to 48 weeks were discontinued due to clinical or laboratory adverse experiences which were rated by
the investigator as possibly, probably or definitely related to therapy with MEVACOR. The value for the
placebo group was 2.5%.
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
In AFCAPS/TexCAPS (see CLINICAL PHARMACOLOGY, Clinical Studies) involving 6,605
participants treated with 20-40 mg/day of MEVACOR (n=3,304) or placebo (n=3,301), the safety and
tolerability profile of the group treated with MEVACOR was comparable to that of the group treated with
placebo during a median of 5.1 years of follow-up. The adverse experiences reported in
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
AFCAPS/TexCAPS were similar to those reported in EXCEL (see ADVERSE REACTIONS, Expanded
Clinical Evaluation of Lovastatin (EXCEL) Study).
Concomitant Therapy
In controlled clinical studies in which lovastatin was administered concomitantly with cholestyramine,
no adverse reactions peculiar to this concomitant treatment were observed. The adverse reactions that
occurred were limited to those reported previously with lovastatin or cholestyramine. Other lipid-lowering
agents were not administered concomitantly with lovastatin during controlled clinical studies. Preliminary
data suggests that the addition of gemfibrozil to therapy with lovastatin is not associated with greater
reduction in LDL-C than that achieved with lovastatin alone. In uncontrolled clinical studies, most of the
patients who have developed myopathy were receiving concomitant therapy with cyclosporine, gemfibrozil
or niacin (nicotinic acid) (see WARNINGS, Skeletal Muscle).
The following effects have been reported with drugs in this class. Not all the effects listed below have
necessarily been associated with lovastatin therapy.
Skeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias.
Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-
ocular movement, facial paresis), tremor, dizziness, vertigo, memory loss, paresthesia, peripheral
neuropathy, peripheral nerve palsy, psychic disturbances, anxiety, insomnia, depression.
Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which has
included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like
syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia,
hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia,
photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme,
including Stevens-Johnson syndrome.
Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty
change in liver; and rarely, cirrhosis, fulminant hepatic necrosis, and hepatoma; anorexia, vomiting.
Skin: alopecia, pruritus. A variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous
membranes, changes to hair/nails) have been reported.
Reproductive: gynecomastia, loss of libido, erectile dysfunction.
Eye: progression of cataracts (lens opacities), ophthalmoplegia.
Laboratory Abnormalities: elevated transaminases, alkaline phosphatase, γ-glutamyl transpeptidase,
and bilirubin; thyroid function abnormalities.
OVERDOSAGE
After oral administration of MEVACOR to mice, the median lethal dose observed was >15 g/m2.
Five healthy human volunteers have received up to 200 mg of lovastatin as a single dose without
clinically significant adverse experiences. A few cases of accidental overdosage have been reported; no
patients had any specific symptoms, and all patients recovered without sequelae. The maximum dose
taken was 5-6 g.
Until further experience is obtained, no specific treatment of overdosage with MEVACOR can be
recommended.
The dialyzability of lovastatin and its metabolites in man is not known at present.
DOSAGE AND ADMINISTRATION
The patient should be placed on a standard cholesterol-lowering diet before receiving MEVACOR and
should continue on this diet during treatment with MEVACOR (see NCEP Treatment Guidelines for details
on dietary therapy). MEVACOR should be given with meals.
The usual recommended starting dose is 20 mg once a day given with the evening meal. The
recommended dosing range is 10-80 mg/day in single or two divided doses; the maximum recommended
dose is 80 mg/day. Doses should be individualized according to the recommended goal of therapy (see
NCEP Guidelines and CLINICAL PHARMACOLOGY). Patients requiring reductions in LDL-C of 20% or
more to achieve their goal (see INDICATIONS AND USAGE) should be started on 20 mg/day of
MEVACOR. A starting dose of 10 mg may be considered for patients requiring smaller reductions.
Adjustments should be made at intervals of 4 weeks or more.
In patients taking cyclosporine concomitantly with lovastatin (see WARNINGS, Skeletal Muscle),
therapy should begin with 10 mg of MEVACOR and should not exceed 20 mg/day.
Cholesterol levels should be monitored periodically and consideration should be given to reducing the
dosage of MEVACOR if cholesterol levels fall significantly below the targeted range.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
Concomitant Lipid-Lowering Therapy
MEVACOR is effective alone or when used concomitantly with bile-acid sequestrants. Use of
MEVACOR with fibrates or niacin should generally be avoided. However, if MEVACOR is used in
combination with fibrates or niacin, the dose of MEVACOR should generally not exceed 20 mg/day (see
WARNINGS, Skeletal Muscle and PRECAUTIONS, Drug Interactions).
Dosage in Patients with Renal Insufficiency
In patients with severe renal insufficiency (creatinine clearance <30 mL/min), dosage increases above
20 mg/day should be carefully considered and, if deemed necessary, implemented cautiously (see
CLINICAL PHARMACOLOGY and WARNINGS, Skeletal Muscle).
HOW SUPPLIED
No. 3560 — Tablets MEVACOR 10 mg are peach, octagonal tablets, coded MSD 730 on one side and
MEVACOR on the other. They are supplied as follows:
NDC 0006-0730-61 unit of use bottles of 60.
No. 3561 — Tablets MEVACOR 20 mg are light blue, octagonal tablets, coded MSD 731 on one side
and MEVACOR on the other. They are supplied as follows:
NDC 0006-0731-61 unit of use bottles of 60
NDC 0006-0731-94 unit of use bottles of 90
NDC 0006-0731-28 unit dose packages of 100
NDC 0006-0731-82 bottles of 1,000
NDC 0006-0731-87 bottles of 10,000.
No. 3562 — Tablets MEVACOR 40 mg are green, octagonal tablets, coded MSD 732 on one side and
MEVACOR on the other. They are supplied as follows:
NDC 0006-0732-61 unit of use bottles of 60
NDC 0006-0732-94 unit of use bottles of 90
NDC 0006-0732-82 bottles of 1,000
NDC 0006-0732-87 bottles of 10,000.
Storage
Store between 5-30°C (41-86°F). Tablets MEVACOR must be protected from light and stored in a well-
closed, light-resistant container.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:35.820564
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/19643s64lbl.pdf', 'application_number': 19643, 'submission_type': 'SUPPL ', 'submission_number': 64}
|
11,587
|
78253XX
TABLETS
MEVACOR®
(LOVASTATIN)
DESCRIPTION
MEVACOR* (Lovastatin) is a cholesterol lowering agent isolated from a strain of Aspergillus terreus.
After oral ingestion, lovastatin, which is an inactive lactone, is hydrolyzed to the corresponding β-
hydroxyacid form. This is a principal metabolite and an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A
(HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an
early and rate limiting step in the biosynthesis of cholesterol.
Lovastatin
is
[1S-[1α(R*),3α,7β,8β(2S*,4S*),
8aβ]]-1,2,3,7,
8,8a-hexahydro-3,7-dimethyl-8-[2-
(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl 2-methylbutanoate. The empirical formula
of lovastatin is C24H36O5 and its molecular weight is 404.55. Its structural formula is:
Lovastatin is a white, nonhygroscopic crystalline powder that is insoluble in water and sparingly soluble
in ethanol, methanol, and acetonitrile.
Tablets MEVACOR are supplied as 10 mg, 20 mg and 40 mg tablets for oral administration. In addition
to the active ingredient lovastatin, each tablet contains the following inactive ingredients: cellulose, lactose,
magnesium stearate, and starch. Butylated hydroxyanisole (BHA) is added as a preservative. Tablets
MEVACOR 10 mg also contain red ferric oxide and yellow ferric oxide. Tablets MEVACOR 20 mg also
contain FD&C Blue 2. Tablets MEVACOR 40 mg also contain D&C Yellow 10 and FD&C Blue 2.
CLINICAL PHARMACOLOGY
The involvement of low-density lipoprotein cholesterol (LDL-C) in atherogenesis has been well-
documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological
and clinical studies have established that high LDL-C and low high-density lipoprotein cholesterol (HDL-C)
are both associated with coronary heart disease. However, the risk of developing coronary heart disease
is continuous and graded over the range of cholesterol levels and many coronary events do occur in
patients with total cholesterol (total-C) and LDL-C in the lower end of this range.
MEVACOR has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed
from very low-density lipoprotein (VLDL) and is catabolized predominantly by the high affinity LDL
receptor. The mechanism of the LDL-lowering effect of MEVACOR may involve both reduction of VLDL-C
concentration, and induction of the LDL receptor, leading to reduced production and/or increased
catabolism of LDL-C. Apolipoprotein B also falls substantially during treatment with MEVACOR. Since
each LDL particle contains one molecule of apolipoprotein B, and since little apolipoprotein B is found in
other lipoproteins, this strongly suggests that MEVACOR does not merely cause cholesterol to be lost
from LDL, but also reduces the concentration of circulating LDL particles. In addition, MEVACOR can
produce increases of variable magnitude in HDL-C, and modestly reduces VLDL-C and plasma
triglycerides (TG) (see Tables I-III under Clinical Studies). The effects of MEVACOR on Lp(a), fibrinogen,
and certain other independent biochemical risk markers for coronary heart disease are unknown.
MEVACOR is a specific inhibitor of HMG-CoA reductase, the enzyme which catalyzes the conversion
of HMG-CoA to mevalonate. The conversion of HMG-CoA to mevalonate is an early step in the
biosynthetic pathway for cholesterol.
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT © MERCK & CO., Inc., 1987, 1989, 1991, 2002
All rights reserved
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
78253XX
2
Pharmacokinetics
Lovastatin is a lactone which is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent
inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in
pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis,
active plus latent inhibitors (total inhibitors) in plasma following administration of lovastatin.
Following an oral dose of 14C-labeled lovastatin in man, 10% of the dose was excreted in urine and
83% in feces. The latter represents absorbed drug equivalents excreted in bile, as well as any unabsorbed
drug. Plasma concentrations of total radioactivity (lovastatin plus 14C-metabolites) peaked at 2 hours and
declined rapidly to about 10% of peak by 24 hours postdose. Absorption of lovastatin, estimated relative to
an intravenous reference dose, in each of four animal species tested, averaged about 30% of an oral
dose. In animal studies, after oral dosing, lovastatin had high selectivity for the liver, where it achieved
substantially higher concentrations than in non-target tissues. Lovastatin undergoes extensive first-pass
extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile.
As a consequence of extensive hepatic extraction of lovastatin, the availability of drug to the general
circulation is low and variable. In a single dose study in four hypercholesterolemic patients, it was
estimated that less than 5% of an oral dose of lovastatin reaches the general circulation as active
inhibitors. Following administration of lovastatin tablets the coefficient of variation, based on between-
subject variability, was approximately 40% for the area under the curve (AUC) of total inhibitory activity in
the general circulation.
Both lovastatin and its β-hydroxyacid metabolite are highly bound (>95%) to human plasma proteins.
Animal studies demonstrated that lovastatin crosses the blood-brain and placental barriers.
The major active metabolites present in human plasma are the β-hydroxyacid of lovastatin, its
6′-hydroxy derivative, and two additional metabolites. Peak plasma concentrations of both active and total
inhibitors were attained within 2 to 4 hours of dose administration. While the recommended therapeutic
dose range is 10 to 80 mg/day, linearity of inhibitory activity in the general circulation was established by a
single dose study employing lovastatin tablet dosages from 60 to as high as 120 mg. With a once-a-day
dosing regimen, plasma concentrations of total inhibitors over a dosing interval achieved a steady state
between the second and third days of therapy and were about 1.5 times those following a single dose.
When lovastatin was given under fasting conditions, plasma concentrations of total inhibitors were on
average about two-thirds those found when lovastatin was administered immediately after a standard test
meal.
In a study of patients with severe renal insufficiency (creatinine clearance 10-30 mL/min), the plasma
concentrations of total inhibitors after a single dose of lovastatin were approximately two-fold higher than
those in healthy volunteers.
In a study including 16 elderly patients between 70-78 years of age who received MEVACOR
80 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately
45% compared with 18 patients between 18-30 years of age (see PRECAUTIONS, Geriatric Use).
The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.
Potent inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and
increase the risk of myopathy (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug
Interactions).
Lovastatin is a substrate for cytochrome P450 isoform 3A4 (CYP3A4) (see PRECAUTIONS, Drug
Interactions). Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the
plasma concentrations of drugs metabolized by CYP3A4. In one study**, 10 subjects consumed 200 mL of
double-strength grapefruit juice (one can of frozen concentrate diluted with one rather than 3 cans of
water) three times daily for 2 days and an additional 200 mL double-strength grapefruit juice together with
and 30 and 90 minutes following a single dose of 80 mg lovastatin on the third day. This regimen of
grapefruit juice resulted in a mean increase in the serum concentration of lovastatin and its β-hydroxyacid
metabolite (as measured by the area under the concentration-time curve) of 15-fold and 5-fold,
respectively [as measured using a chemical assay — high performance liquid chromatography]. In a
second study, 15 subjects consumed one 8 oz glass of single-strength grapefruit juice (one can of frozen
concentrate diluted with 3 cans of water) with breakfast for 3 consecutive days and a single dose of 40 mg
lovastatin in the evening of the third day. This regimen of grapefruit juice resulted in a mean increase in
the plasma concentration (as measured by the area under the concentration-time curve) of active and
total HMG-CoA reductase inhibitory activity [using an enzyme inhibition assay both before (for active
** Kantola, T, et al., Clin Pharmacol Ther 1998; 63(4):397-402.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
78253XX
3
inhibitors) and after (for total inhibitors) base hydrolysis] of 1.34-fold and 1.36-fold, respectively, and of
lovastatin
and
its
β-hydroxyacid
metabolite
[measured
using
a
chemical
assay —
liquid
chromatography/tandem mass spectrometry — different from that used in the first** study] of 1.94-fold
and 1.57-fold, respectively. The effect of amounts of grapefruit juice between those used in these two
studies on lovastatin pharmacokinetics has not been studied.
Clinical Studies in Adults
MEVACOR has been shown to be highly effective in reducing total-C and LDL-C in heterozygous
familial and non-familial forms of primary hypercholesterolemia and in mixed hyperlipidemia. A marked
response was seen within 2 weeks, and the maximum therapeutic response occurred within 4-6 weeks.
The response was maintained during continuation of therapy. Single daily doses given in the evening were
more effective than the same dose given in the morning, perhaps because cholesterol is synthesized
mainly at night.
In multicenter, double-blind studies in patients with familial or non-familial hypercholesterolemia,
MEVACOR, administered in doses ranging from 10 mg q.p.m. to 40 mg b.i.d., was compared to placebo.
MEVACOR consistently and significantly decreased plasma total-C, LDL-C, total-C/HDL-C ratio and LDL-
C/HDL-C ratio. In addition, MEVACOR produced increases of variable magnitude in HDL-C, and modestly
decreased VLDL-C and plasma TG (see Tables I through III for dose response results).
The results of a study in patients with primary hypercholesterolemia are presented in Table I.
TABLE I
MEVACOR vs. Placebo
(Mean Percent Change from Baseline After 6 Weeks)
DOSAGE
N
TOTAL-C
LDL-C
HDL-C
LDL-C/
HDL-C
TOTAL-C/
HDL-C
TG.
Placebo
33
–2
–1
–1
0
+1
+9
MEVACOR
10 mg q.p.m.
20 mg q.p.m.
10 mg b.i.d.
40 mg q.p.m.
20 mg b.i.d.
33
33
32
33
36
–16
–19
–19
–22
–24
–21
–27
–28
–31
–32
+5
+6
+8
+5
+2
–24
–30
–33
–33
–32
–19
–23
–25
–25
–24
–10
+9
–7
–8
–6
MEVACOR was compared to cholestyramine in a randomized open parallel study. The study was
performed with patients with hypercholesterolemia who were at high risk of myocardial infarction.
Summary results are presented in Table II.
TABLE II
MEVACOR vs. Cholestyramine
(Percent Change from Baseline After 12 Weeks)
TREATMENT
N
TOTAL-C
(mean)
LDL-C
(mean)
HDL-C
(mean)
LDL-C/
HDL-C
(mean)
TOTAL-C/
HDL-C
(mean)
VLDL-C
(median)
TG.
(mean)
MEVACOR
20 mg b.i.d.
40 mg b.i.d.
85
88
–27
–34
–32
–42
+9
+8
–36
–44
–31
–37
–34
–31
–21
–27
Cholestyramine
12 g b.i.d.
88
–17
–23
+8
–27
–21
+2
+11
MEVACOR was studied in controlled trials in hypercholesterolemic patients with well-controlled non-
insulin dependent diabetes mellitus with normal renal function. The effect of MEVACOR on lipids and
lipoproteins and the safety profile of MEVACOR were similar to that demonstrated in studies in
nondiabetics. MEVACOR had no clinically important effect on glycemic control or on the dose requirement
of oral hypoglycemic agents.
Expanded Clinical Evaluation of Lovastatin (EXCEL) Study
MEVACOR was compared to placebo in 8,245 patients with hypercholesterolemia (total-C 240-300
mg/dL [6.2 mmol/L - 7.6 mmol/L], LDL-C >160 mg/dL [4.1 mmol/L]) in the randomized, double-blind,
parallel, 48-week EXCEL study. All changes in the lipid measurements (Table III) in MEVACOR treated
patients were dose-related and significantly different from placebo (p≤0.001). These results were
sustained throughout the study.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
78253XX
4
TABLE III
MEVACOR vs. Placebo
(Percent Change from Baseline —
Average Values Between Weeks 12 and 48)
DOSAGE
N**
TOTAL-C
(mean)
LDL-C
(mean)
HDL-C
(mean)
LDL-C/
HDL-C
(mean)
TOTAL-C/
HDL-C
(mean)
TG.
(median)
Placebo
1663
+0.7
+0.4
+2.0
+0.2
+0.6
+4
MEVACOR
20 mg q.p.m.
40 mg q.p.m.
20 mg b.i.d.
40 mg b.i.d.
1642
1645
1646
1649
–17
–22
–24
–29
–24
–30
–34
–40
+6.6
+7.2
+8.6
+9.5
–27
–34
–38
–44
–21
–26
–29
–34
–10
–14
–16
–19
**Patients enrolled
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), a double-blind,
randomized, placebo-controlled, primary prevention study, demonstrated that treatment with MEVACOR
decreased the rate of acute major coronary events (composite endpoint of myocardial infarction, unstable
angina, and sudden cardiac death) compared with placebo during a median of 5.1 years of follow-up.
Participants were middle-aged and elderly men (ages 45-73) and women (ages 55-73) without
symptomatic cardiovascular disease with average to moderately elevated total-C and LDL-C, below
average HDL-C, and who were at high risk based on elevated total-C/HDL-C. In addition to age, 63% of
the participants had at least one other risk factor (baseline HDL-C <35 mg/dL, hypertension, family history,
smoking and diabetes).
AFCAPS/TexCAPS enrolled 6,605 participants (5,608 men, 997 women) based on the following lipid
entry criteria: total-C range of 180-264 mg/dL, LDL-C range of 130-190 mg/dL, HDL-C of ≤45 mg/dL for
men and ≤47 mg/dL for women, and TG of ≤400 mg/dL. Participants were treated with standard care,
including diet, and either MEVACOR 20-40 mg daily (n= 3,304) or placebo (n= 3,301). Approximately 50%
of the participants treated with MEVACOR were titrated to 40 mg daily when their LDL-C remained >110
mg/dL at the 20-mg starting dose.
MEVACOR reduced the risk of a first acute major coronary event, the primary efficacy endpoint, by
37% (MEVACOR 3.5%, placebo 5.5%; p<0.001; Figure 1). A first acute major coronary event was defined
as myocardial infarction (54 participants on MEVACOR, 94 on placebo) or unstable angina (54 vs. 80) or
sudden cardiac death (8 vs. 9). Furthermore, among the secondary endpoints, MEVACOR reduced the
risk of unstable angina by 32% (1.8 vs. 2.6%; p=0.023), of myocardial infarction by 40% (1.7 vs. 2.9%;
p=0.002), and of undergoing coronary revascularization procedures (e.g., coronary artery bypass grafting
or percutaneous transluminal coronary angioplasty) by 33% (3.2 vs. 4.8%; p=0.001). Trends in risk
reduction associated with treatment with MEVACOR were consistent across men and women, smokers
and non-smokers, hypertensives and non-hypertensives, and older and younger participants. Participants
with ≥2 risk factors had risk reductions (RR) in both acute major coronary events (RR 43%) and coronary
revascularization procedures (RR 37%). Because there were too few events among those participants
with age as their only risk factor in this study, the effect of MEVACOR on outcomes could not be
adequately assessed in this subgroup.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
78253XX
5
Atherosclerosis
In the Canadian Coronary Atherosclerosis Intervention Trial (CCAIT), the effect of therapy with
lovastatin on coronary atherosclerosis was assessed by coronary angiography in hyperlipidemic patients.
In the randomized, double-blind, controlled clinical trial, patients were treated with conventional measures
(usually diet and 325 mg of aspirin every other day) and either lovastatin 20-80 mg daily or placebo.
Angiograms were evaluated at baseline and at two years by computerized quantitative coronary
angiography (QCA). Lovastatin significantly slowed the progression of lesions as measured by the mean
change per-patient in minimum lumen diameter (the primary endpoint) and percent diameter stenosis, and
decreased the proportions of patients categorized with disease progression (33% vs. 50%) and with new
lesions (16% vs. 32%).
In a similarly designed trial, the Monitored Atherosclerosis Regression Study (MARS), patients were
treated with diet and either lovastatin 80 mg daily or placebo. No statistically significant difference between
lovastatin and placebo was seen for the primary endpoint (mean change per patient in percent diameter
stenosis of all lesions), or for most secondary QCA endpoints. Visual assessment by angiographers who
formed a consensus opinion of overall angiographic change (Global Change Score) was also a secondary
endpoint. By this endpoint, significant slowing of disease was seen, with regression in 23% of patients
treated with lovastatin compared to 11% of placebo patients.
In the Familial Atherosclerosis Treatment Study (FATS), either lovastatin or niacin in combination with
a bile acid sequestrant for 2.5 years in hyperlipidemic subjects significantly reduced the frequency of
progression and increased the frequency of regression of coronary atherosclerotic lesions by QCA
compared to diet and, in some cases, low-dose resin.
The effect of lovastatin on the progression of atherosclerosis in the coronary arteries has been
corroborated by similar findings in another vasculature. In the Asymptomatic Carotid Artery Progression
Study (ACAPS), the effect of therapy with lovastatin on carotid atherosclerosis was assessed by B-mode
ultrasonography in hyperlipidemic patients with early carotid lesions and without known coronary heart
disease at baseline. In this double-blind, controlled clinical trial, 919 patients were randomized in a 2 x 2
factorial design to placebo, lovastatin 10-40 mg daily and/or warfarin. Ultrasonograms of the carotid walls
were used to determine the change per patient from baseline to three years in mean maximum intimal-
medial thickness (IMT) of 12 measured segments. There was a significant regression of carotid lesions in
patients receiving lovastatin alone compared to those receiving placebo alone (p=0.001). The predictive
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
78253XX
6
value of changes in IMT for stroke has not yet been established. In the lovastatin group there was a
significant reduction in the number of patients with major cardiovascular events relative to the placebo
group (5 vs. 14) and a significant reduction in all-cause mortality (1 vs. 8).
Eye
There was a high prevalence of baseline lenticular opacities in the patient population included in the
early clinical trials with lovastatin. During these trials the appearance of new opacities was noted in both
the lovastatin and placebo groups. There was no clinically significant change in visual acuity in the patients
who had new opacities reported nor was any patient, including those with opacities noted at baseline,
discontinued from therapy because of a decrease in visual acuity.
A three-year, double-blind, placebo-controlled study in hypercholesterolemic patients to assess the
effect of lovastatin on the human lens demonstrated that there were no clinically or statistically significant
differences between the lovastatin and placebo groups in the incidence, type or progression of lenticular
opacities. There are no controlled clinical data assessing the lens available for treatment beyond three
years.
Clinical Studies in Adolescent Patients
Efficacy of Lovastatin in Adolescent Boys with Heterozygous Familial Hypercholesterolemia
In a double-blind, placebo-controlled study, 132 boys 10-17 years of age (mean age 12.7 yrs) with
heterozygous familial hypercholesterolemia (heFH) were randomized to lovastatin (n=67) or placebo
(n=65) for 48 weeks. Inclusion in the study required a baseline LDL-C level between 189 and 500 mg/dL
and at least one parent with an LDL-C level >189 mg/dL. The mean baseline LDL-C value was
253.1 mg/dL (range: 171-379 mg/dL) in the MEVACOR group compared to 248.2 mg/dL (range:
158.5-413.5 mg/dL) in the placebo group. The dosage of lovastatin (once daily in the evening) was 10 mg
for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter.
MEVACOR significantly decreased plasma levels of total-C, LDL-C and apolipoprotein B (see
Table IV).
TABLE IV
Lipid-lowering Effects of Lovastatin in Adolescent Boys with Heterozygous Familial Hypercholesterolemia
(Mean Percent Change from Baseline at week 48 in Intention-to-Treat Population)
DOSAGE
N
TOTAL-C
LDL-C
HDL-C
TG.*
Apolipoprotein B
Placebo
61
-1.1
-1.4
-2.2
-1.4
-4.4
MEVACOR
64
-19.3
-24.2
+1.1
-1.9
-21
*data presented as median percent changes
The mean achieved LDL-C value was 190.9 mg/dL (range: 108-336 mg/dL) in the MEVACOR group
compared to 244.8 mg/dL (range: 135-404 mg/dL) in the placebo group.
Efficacy of Lovastatin in Post-menarchal Girls with Heterozygous Familial Hypercholesterolemia
In a double-blind, placebo-controlled study, 54 girls 10-17 years of age who were at least 1 year
post-menarche with heFH were randomized to lovastatin (n=35) or placebo (n=19) for 24 weeks. Inclusion
in the study required a baseline LDL-C level of 160-400 mg/dL and a parental history of familial
hypercholesterolemia. The mean baseline LDL-C value was 218.3 mg/dL (range: 136.3-363.7 mg/dL) in
the MEVACOR group compared to 198.8 mg/dL (range: 151.1-283.1 mg/dL) in the placebo group. The
dosage of lovastatin (once daily in the evening) was 20 mg for the first 4 weeks, and 40 mg thereafter.
MEVACOR significantly decreased plasma levels of total-C, LDL-C, and apolipoprotein B (see
Table V).
TABLE V
Lipid-lowering Effects of Lovastatin in Post-menarchal Girls with Heterozygous Familial Hypercholesterolemia
(Mean Percent Change from Baseline at Week 24 in Intention-to-Treat Population)
DOSAGE
N
TOTAL-C
LDL-C
HDL-C
TG.*
Apolipoprotein B
Placebo
18
+3.6
+2.5
+4.8
-3.0
+6.4
MEVACOR
35
-22.4
-29.2
+2.4
-22.7
-24.4
*data presented as median percent changes
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
78253XX
7
The mean achieved LDL-C value was 154.5 mg/dL (range: 82-286 mg/dL) in the MEVACOR group
compared to 203.5 mg/dL (range: 135-304 mg/dL) in the placebo group.
The safety and efficacy of doses above 40 mg daily have not been studied in children. The long-term
efficacy of lovastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been
established.
INDICATIONS AND USAGE
Therapy with MEVACOR should be a component of multiple risk factor intervention in those individuals
with dyslipidemia at risk for atherosclerotic vascular disease. MEVACOR should be used in addition to a
diet restricted in saturated fat and cholesterol as part of a treatment strategy to lower total-C and LDL-C to
target levels when the response to diet and other nonpharmacological measures alone has been
inadequate to reduce risk.
Primary Prevention of Coronary Heart Disease
In individuals without symptomatic cardiovascular disease, average to moderately elevated total-C and
LDL-C, and below average HDL-C, MEVACOR is indicated to reduce the risk of:
- Myocardial infarction
- Unstable angina
- Coronary revascularization procedures
(See CLINICAL PHARMACOLOGY, Clinical Studies.)
Coronary Heart Disease
MEVACOR is indicated to slow the progression of coronary atherosclerosis in patients with coronary
heart disease as part of a treatment strategy to lower total-C and LDL-C to target levels.
Hypercholesterolemia
Therapy with lipid-altering agents should be a component of multiple risk factor intervention in those
individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia.
MEVACOR is indicated as an adjunct to diet for the reduction of elevated total-C and LDL-C levels in
patients with primary hypercholesterolemia (Types IIa and IIb***), when the response to diet restricted in
saturated fat and cholesterol and to other nonpharmacological measures alone has been inadequate.
Adolescent Patients with Heterozygous Familial Hypercholesterolemia
MEVACOR is indicated as an adjunct to diet to reduce total-C, LDL-C and apolipoprotein B levels in
adolescent boys and girls who are at least one year post-menarche, 10-17 years of age, with heFH if after
an adequate trial of diet therapy the following findings are present:
1. LDL-C remains >189 mg/dL or
2. LDL-C remains >160 mg/dL and:
•
there is a positive family history of premature cardiovascular disease or
•
two or more other CVD risk factors are present in the adolescent patient
General Recommendations
Prior to initiating therapy with lovastatin, secondary causes for hypercholesterolemia (e.g., poorly
controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver
disease, other drug therapy, alcoholism) should be excluded, and a lipid profile performed to measure
total-C, HDL-C, and TG. For patients with TG less than 400 mg/dL (<4.5 mmol/L), LDL-C can be
estimated using the following equation:
LDL-C = total-C – [0.2 × (TG) + HDL-C]
*** Classification of Hyperlipoproteinemias
Lipid
Lipoproteins
Elevations
Type
elevated
major
minor
I
chylomicrons
TG
↑→C
IIa
LDL
C
—
IIb
LDL, VLDL
C
TG
III (rare)
IDL
C/TG
—
IV
VLDL
TG
↑→C
V (rare)
chylomicrons, VLDL
TG
↑→C
IDL = intermediate-density lipoprotein.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
78253XX
8
For TG levels >400 mg/dL (>4.5 mmol/L), this equation is less accurate and LDL-C concentrations
should be determined by ultracentrifugation. In hypertriglyceridemic patients, LDL-C may be low or normal
despite elevated total-C. In such cases, MEVACOR is not indicated.
The National Cholesterol Education Program (NCEP) Treatment Guidelines are summarized below:
NCEP Treatment Guidelines:
LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes
and Drug Therapy in Different Risk Categories
Risk Category
LDL Goal
(mg/dL)
LDL Level at Which to
Initiate Therapeutic Lifestyle Changes
(mg/dL)
LDL Level at Which to
Consider Drug Therapy
(mg/dL)
CHD† or CHD risk equivalents
(10-year risk >20%)
2+ Risk factors
(10- year risk ≤20%)
0-1 Risk factor†††
<100
<130
<160
≥100
≥130
≥160
≥130
(100-129: drug optional)††
10-year risk 10-20%: ≥130
10-year risk <10%: ≥160
≥190
(160-189: LDL-lowering drug
optional)
†
CHD, coronary heart disease
††
Some authorities recommend use of LDL-lowering drugs in this category if an LDL-C level of <100 mg/dL cannot be achieved by therapeutic
lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL-C, e.g., nicotinic acid or fibrate. Clinical judgment also may
call for deferring drug therapy in this subcategory.
†††
Almost all people with 0-1 risk factor have a 10-year risk <10%; thus, 10-year risk assessment in people with 0-1 risk factor is not necessary.
After the LDL-C goal has been achieved, if the TG is still ≥200 mg/dL, non-HDL-C (total-C minus HDL-
C) becomes a secondary target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals
for each risk category.
At the time of hospitalization for an acute coronary event, consideration can be given to initiating drug
therapy at discharge if the LDL-C is ≥130 mg/dL (see NCEP Guidelines above).
Since the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C levels be used to
initiate and assess treatment response. Only if LDL-C levels are not available, should the total-C be used
to monitor therapy.
Although MEVACOR may be useful to reduce elevated LDL-C levels in patients with combined
hypercholesterolemia and hypertriglyceridemia where hypercholesterolemia is the major abnormality
(Type IIb hyperlipoproteinemia), it has not been studied in conditions where the major abnormality is
elevation of chylomicrons, VLDL or IDL (i.e., hyperlipoproteinemia types I, III, IV, or V).***
The NCEP classification of cholesterol levels in pediatric patients with a familial history of
hypercholesterolemia or premature cardiovascular disease is summarized below:
Category
Total-C (mg/dL)
LDL-C (mg/dL)
Acceptable
Borderline
High
<170
170-199
≥200
<110
110-129
≥130
Children treated with lovastatin in adolescence should be re-evaluated in adulthood and appropriate
changes made to their cholesterol-lowering regimen to achieve adult goals for LDL-C.
CONTRAINDICATIONS
Hypersensitivity to any component of this medication.
Active liver disease or unexplained persistent elevations of serum transaminases (see WARNINGS).
Pregnancy and lactation. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering
drugs during pregnancy should have little impact on the outcome of long-term therapy of primary
hypercholesterolemia. Moreover, cholesterol and other products of the cholesterol biosynthesis pathway
are essential components for fetal development, including synthesis of steroids and cell membranes.
Because of the ability of inhibitors of HMG-CoA reductase such as MEVACOR to decrease the synthesis
of cholesterol and possibly other products of the cholesterol biosynthesis pathway, MEVACOR is
contraindicated during pregnancy and in nursing mothers. MEVACOR should be administered to
women of childbearing age only when such patients are highly unlikely to conceive. If the patient
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
78253XX
9
becomes pregnant while taking this drug, MEVACOR should be discontinued immediately and the patient
should be apprised of the potential hazard to the fetus (see PRECAUTIONS, Pregnancy).
WARNINGS
Myopathy/Rhabdomyolysis
Lovastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as
muscle pain, tenderness or weakness with creatine kinase (CK) above 10X the upper limit of normal
(ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure
secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high
levels of HMG-CoA reductase inhibitory activity in plasma.
•
The risk of myopathy/rhabdomyolysis is increased by concomitant use of lovastatin with the
following:
Potent inhibitors of CYP3A4: Cyclosporine, itraconazole, ketoconazole, erythromycin,
clarithromycin, HIV protease inhibitors, nefazodone, or large quantities of grapefruit juice
(>1 quart daily), particularly with higher doses of lovastatin (see below; CLINICAL
PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions, CYP3A4 Interactions).
Lipid-lowering drugs that can cause myopathy when given alone: Gemfibrozil, other fibrates,
or lipid-lowering doses (≥1 g/day) of niacin, particularly with higher doses of lovastatin (see
below; CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions,
Interactions with lipid-lowering drugs that can cause myopathy when given alone).
Other drugs: The risk of myopathy/rhabdomyolysis is increased when either amiodarone or
verapamil is used concomitantly with higher doses of a closely related member of the HMG-CoA
reductase inhibitor class (see PRECAUTIONS, Drug Interactions, Other drug interactions).
•
The risk of myopathy/rhabdomyolysis is dose related. In a clinical study (EXCEL) in which
patients were carefully monitored and some interacting drugs were excluded, there was one case of
myopathy among 4933 patients randomized to lovastatin 20-40 mg daily for 48 weeks, and 4 among 1649
patients randomized to 80 mg daily.
CONSEQUENTLY:
1. Use of lovastatin concomitantly with itraconazole, ketoconazole, erythromycin, clarithromycin,
HIV protease inhibitors, nefazodone, or large quantities of grapefruit juice (>1 quart daily) should
be avoided. If treatment with itraconazole, ketoconazole, erythromycin, or clarithromycin is unavoidable,
therapy with lovastatin should be suspended during the course of treatment. Concomitant use with other
medicines labeled as having a potent inhibitory effect on CYP3A4 at therapeutic doses should be avoided
unless the benefits of combined therapy outweigh the increased risk.
2. The dose of lovastatin should not exceed 20 mg daily in patients receiving concomitant
medication with cyclosporine, gemfibrozil, other fibrates or lipid-lowering doses (≥1 g/day) of
niacin. The combined use of lovastatin with fibrates or niacin should be avoided unless the benefit
of further alteration in lipid levels is likely to outweigh the increased risk of this drug combination.
Addition of these drugs to lovastatin typically provides little additional reduction in LDL-C, but further
reductions of TG and further increases in HDL-C may be obtained.
3. The dose of lovastatin should not exceed 40 mg daily in patients receiving concomitant
medication with amiodarone or verapamil. The combined use of lovastatin at doses higher than 40
mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to
outweigh the increased risk of myopathy.
4. All patients starting therapy with lovastatin, or whose dose of lovastatin is being increased,
should be advised of the risk of myopathy and told to report promptly any unexplained muscle
pain, tenderness or weakness. Lovastatin therapy should be discontinued immediately if
myopathy is diagnosed or suspected. The presence of these symptoms, and/or a CK level >10 times
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
78253XX
10
the ULN indicates myopathy. In most cases, when patients were promptly discontinued from treatment,
muscle symptoms and CK increases resolved. Periodic CK determinations may be considered in patients
starting therapy with lovastatin or whose dose is being increased, but there is no assurance that such
monitoring will prevent myopathy.
5. Many of the patients who have developed rhabdomyolysis on therapy with lovastatin have had
complicated medical histories, including renal insufficiency usually as a consequence of long-standing
diabetes mellitus. Such patients merit closer monitoring. Therapy with lovastatin should be temporarily
stopped a few days prior to elective major surgery and when any major medical or surgical condition
supervenes.
Liver Dysfunction
Persistent increases (to more than 3 times the upper limit of normal) in serum transaminases
occurred in 1.9% of adult patients who received lovastatin for at least one year in early clinical
trials (see ADVERSE REACTIONS). When the drug was interrupted or discontinued in these patients, the
transaminase levels usually fell slowly to pretreatment levels. The increases usually appeared 3 to 12
months after the start of therapy with lovastatin, and were not associated with jaundice or other clinical
signs or symptoms. There was no evidence of hypersensitivity. In the EXCEL study (see CLINICAL
PHARMACOLOGY, Clinical Studies), the incidence of persistent increases in serum transaminases over
48 weeks was 0.1% for placebo, 0.1% at 20 mg/day, 0.9% at 40 mg/day, and 1.5% at 80 mg/day in
patients on lovastatin. However, in post-marketing experience with MEVACOR, symptomatic liver disease
has been reported rarely at all dosages (see ADVERSE REACTIONS).
In AFCAPS/TexCAPS, the number of participants with consecutive elevations of either alanine
aminotransferase (ALT) or aspartate aminotransferase (AST) (>3 times the upper limit of normal), over a
median of 5.1 years of follow-up, was not significantly different between the MEVACOR and placebo
groups (18 [0.6%] vs. 11 [0.3%]). The starting dose of MEVACOR was 20 mg/day; 50% of the MEVACOR
treated participants were titrated to 40 mg/day at Week 18. Of the 18 participants on MEVACOR with
consecutive elevations of either ALT or AST, 11 (0.7%) elevations occurred in participants taking 20
mg/day, while 7 (0.4%) elevations occurred in participants titrated to 40 mg/day. Elevated transaminases
resulted in discontinuation of 6 (0.2%) participants from therapy in the MEVACOR group (n=3,304) and 4
(0.1%) in the placebo group (n=3,301).
It is recommended that liver function tests be performed prior to initiation of therapy in patients with a
history of liver disease, or when otherwise clinically indicated. It is recommended that liver function tests
be performed in all patients prior to use of 40 mg or more daily and thereafter when clinically indicated.
Patients who develop increased transaminase levels should be monitored with a second liver function
evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the
abnormality(ies) returns to normal. Should an increase in AST or ALT of three times the upper limit of
normal or greater persist, withdrawal of therapy with MEVACOR is recommended.
The drug should be used with caution in patients who consume substantial quantities of alcohol and/or
have a past history of liver disease. Active liver disease or unexplained transaminase elevations are
contraindications to the use of lovastatin.
As with other lipid-lowering agents, moderate (less than three times the upper limit of normal)
elevations of serum transaminases have been reported following therapy with MEVACOR (see ADVERSE
REACTIONS). These changes appeared soon after initiation of therapy with MEVACOR, were often
transient, were not accompanied by any symptoms and interruption of treatment was not required.
PRECAUTIONS
General
Lovastatin may elevate creatine phosphokinase and transaminase levels (see WARNINGS and
ADVERSE REACTIONS). This should be considered in the differential diagnosis of chest pain in a patient
on therapy with lovastatin.
Homozygous Familial Hypercholesterolemia
MEVACOR is less effective in patients with the rare homozygous familial hypercholesterolemia,
possibly because these patients have no functional LDL receptors. MEVACOR appears to be more likely
to raise serum transaminases (see ADVERSE REACTIONS) in these homozygous patients.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
78253XX
11
Information for Patients
Patients should be advised about substances they should not take concomitantly with
lovastatin and be advised to report promptly unexplained muscle pain, tenderness, or weakness
(see list below and WARNINGS, Myopathy/Rhabdomyolysis). Patients should also be advised to
inform other physicians prescribing a new medication that they are taking MEVACOR.
Drug Interactions
CYP3A4 Interactions
Lovastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected
to affect the plasma concentrations of other drugs metabolized by CYP3A4. Potent inhibitors of CYP3A4
(below) increase the risk of myopathy by reducing the elimination of lovastatin.
See
WARNINGS,
Myopathy/Rhabdomyolysis,
and
CLINICAL
PHARMACOLOGY,
Pharmacokinetics.
Itraconazole
Ketoconazole
Erythromycin
Clarithromycin
HIV protease inhibitors
Nefazodone
Cyclosporine
Large quantities of grapefruit juice (>1 quart daily)
Interactions with lipid-lowering drugs that can cause myopathy when given alone
The risk of myopathy is also increased by the following lipid-lowering drugs that are not potent CYP3A4
inhibitors, but which can cause myopathy when given alone.
See WARNINGS, Myopathy/Rhabdomyolysis.
Gemfibrozil
Other fibrates
Niacin (nicotinic acid) (≥1 g/day)
Other drug interactions
Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased when either amiodarone
or verapamil is used concomitantly with a closely related member of the HMG-CoA reductase inhibitor
class (see WARNINGS, Myopathy/Rhabdomyolysis).
Coumarin Anticoagulants: In a small clinical trial in which lovastatin was administered to warfarin
treated patients, no effect on prothrombin time was detected. However, another HMG-CoA reductase
inhibitor has been found to produce a less than two-second increase in prothrombin time in healthy
volunteers receiving low doses of warfarin. Also, bleeding and/or increased prothrombin time have been
reported in a few patients taking coumarin anticoagulants concomitantly with lovastatin. It is recommended
that in patients taking anticoagulants, prothrombin time be determined before starting lovastatin and
frequently enough during early therapy to insure that no significant alteration of prothrombin time occurs.
Once a stable prothrombin time has been documented, prothrombin times can be monitored at the
intervals usually recommended for patients on coumarin anticoagulants. If the dose of lovastatin is
changed, the same procedure should be repeated. Lovastatin therapy has not been associated with
bleeding or with changes in prothrombin time in patients not taking anticoagulants.
Propranolol: In normal volunteers, there was no clinically significant pharmacokinetic or
pharmacodynamic interaction with concomitant administration of single doses of lovastatin and
propranolol.
Digoxin: In patients with hypercholesterolemia, concomitant administration of lovastatin and digoxin
resulted in no effect on digoxin plasma concentrations.
Oral Hypoglycemic Agents: In pharmacokinetic studies of MEVACOR in hypercholesterolemic non-
insulin dependent diabetic patients, there was no drug interaction with glipizide or with chlorpropamide
(see CLINICAL PHARMACOLOGY, Clinical Studies).
Endocrine Function
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically blunt
adrenal and/or gonadal steroid production. Results of clinical trials with drugs in this class have been
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
78253XX
12
inconsistent with regard to drug effects on basal and reserve steroid levels. However, clinical studies have
shown that lovastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve, and
does not reduce basal plasma testosterone concentration. Another HMG-CoA reductase inhibitor has
been shown to reduce the plasma testosterone response to HCG. In the same study, the mean
testosterone response to HCG was slightly but not significantly reduced after treatment with lovastatin
40 mg daily for 16 weeks in 21 men. The effects of HMG-CoA reductase inhibitors on male fertility have
not been studied in adequate numbers of male patients. The effects, if any, on the pituitary-gonadal axis in
pre-menopausal women are unknown. Patients treated with lovastatin who develop clinical evidence of
endocrine dysfunction should be evaluated appropriately. Caution should also be exercised if an
HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients
also receiving other drugs (e.g., ketoconazole, spironolactone, cimetidine) that may decrease the levels or
activity of endogenous steroid hormones.
CNS Toxicity
Lovastatin produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in
clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean
plasma drug levels about 30 times higher than the mean drug level in humans taking the highest
recommended dose (as measured by total enzyme inhibitory activity). Vestibulocochlear Wallerian-like
degeneration and retinal ganglion cell chromatolysis were also seen in dogs treated for 14 weeks at 180
mg/kg/day, a dose which resulted in a mean plasma drug level (Cmax) similar to that seen with the 60
mg/kg/day dose.
CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell
infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels, were seen in
dogs treated with lovastatin at a dose of 180 mg/kg/day, a dose which produced plasma drug levels (Cmax)
which were about 30 times higher than the mean values in humans taking 80 mg/day.
Similar optic nerve and CNS vascular lesions have been observed with other drugs of this class.
Cataracts were seen in dogs treated for 11 and 28 weeks at 180 mg/kg/day and 1 year at
60 mg/kg/day.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 21-month carcinogenic study in mice, there was a statistically significant increase in the incidence
of hepatocellular carcinomas and adenomas in both males and females at 500 mg/kg/day. This dose
produced a total plasma drug exposure 3 to 4 times that of humans given the highest recommended dose
of lovastatin (drug exposure was measured as total HMG-CoA reductase inhibitory activity in extracted
plasma). Tumor increases were not seen at 20 and 100 mg/kg/day, doses that produced drug exposures
of 0.3 to 2 times that of humans at the 80 mg/day dose. A statistically significant increase in pulmonary
adenomas was seen in female mice at approximately 4 times the human drug exposure. (Although mice
were given 300 times the human dose [HD] on a mg/kg body weight basis, plasma levels of total inhibitory
activity were only 4 times higher in mice than in humans given 80 mg of MEVACOR.)
There was an increase in incidence of papilloma in the non-glandular mucosa of the stomach of mice
beginning at exposures of 1 to 2 times that of humans. The glandular mucosa was not affected. The
human stomach contains only glandular mucosa.
In a 24-month carcinogenicity study in rats, there was a positive dose response relationship for
hepatocellular carcinogenicity in males at drug exposures between 2-7 times that of human exposure at
80 mg/day (doses in rats were 5, 30 and 180 mg/kg/day).
An increased incidence of thyroid neoplasms in rats appears to be a response that has been seen with
other HMG-CoA reductase inhibitors.
A chemically similar drug in this class was administered to mice for 72 weeks at 25, 100, and
400 mg/kg body weight, which resulted in mean serum drug levels approximately 3, 15, and 33 times
higher than the mean human serum drug concentration (as total inhibitory activity) after a 40 mg oral dose.
Liver carcinomas were significantly increased in high-dose females and mid- and high-dose males, with a
maximum incidence of 90 percent in males. The incidence of adenomas of the liver was significantly
increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of lung
adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of the
eye of rodents) were significantly higher in high-dose mice than in controls.
No evidence of mutagenicity was observed in a microbial mutagen test using mutant strains of
Salmonella typhimurium with or without rat or mouse liver metabolic activation. In addition, no evidence of
damage to genetic material was noted in an in vitro alkaline elution assay using rat or mouse hepatocytes,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
78253XX
13
a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or
an in vivo chromosomal aberration assay in mouse bone marrow.
Drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell
formation were seen in dogs starting at 20 mg/kg/day. Similar findings were seen with another drug in this
class. No drug-related effects on fertility were found in studies with lovastatin in rats. However, in studies
with a similar drug in this class, there was decreased fertility in male rats treated for 34 weeks at 25 mg/kg
body weight, although this effect was not observed in a subsequent fertility study when this same dose
was administered for 11 weeks (the entire cycle of spermatogenesis, including epididymal maturation). In
rats treated with this same reductase inhibitor at 180 mg/kg/day, seminiferous tubule degeneration
(necrosis and loss of spermatogenic epithelium) was observed. No microscopic changes were observed
in the testes from rats of either study. The clinical significance of these findings is unclear.
Pregnancy
Pregnancy Category X
See CONTRAINDICATIONS.
Safety in pregnant women has not been established.
Lovastatin has been shown to produce skeletal malformations at plasma levels 40 times the human
exposure (for mouse fetus) and 80 times the human exposure (for rat fetus) based on mg/m2 surface area
(doses were 800 mg/kg/day). No drug-induced changes were seen in either species at multiples of 8 times
(rat) or 4 times (mouse) based on surface area. No evidence of malformations was noted in rabbits at
exposures up to 3 times the human exposure (dose of 15 mg/kg/day, highest tolerated dose).
Rare reports of congenital anomalies have been received following intrauterine exposure to HMG-CoA
reductase inhibitors. In a review† of approximately 100 prospectively followed pregnancies in women
exposed to MEVACOR or another structurally related HMG-CoA reductase inhibitor, the incidences of
congenital anomalies, spontaneous abortions and fetal deaths/stillbirths did not exceed what would be
expected in the general population. The number of cases is adequate only to exclude a 3- to 4-fold
increase in congenital anomalies over the background incidence. In 89% of the prospectively followed
pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the
first trimester when pregnancy was identified. As safety in pregnant women has not been established and
there is no apparent benefit to therapy with MEVACOR during pregnancy (see CONTRAINDICATIONS),
treatment should be immediately discontinued as soon as pregnancy is recognized. MEVACOR should be
administered to women of child-bearing potential only when such patients are highly unlikely to conceive
and have been informed of the potential hazards.
Nursing Mothers
It is not known whether lovastatin is excreted in human milk. Because a small amount of another drug
in this class is excreted in human breast milk and because of the potential for serious adverse reactions in
nursing infants, women taking MEVACOR should not nurse their infants (see CONTRAINDICATIONS).
Pediatric Use
Safety and effectiveness in patients 10-17 years of age with heFH have been evaluated in controlled
clinical trials of 48 weeks duration in adolescent boys and controlled clinical trials of 24 weeks duration in
girls who were at least 1 year post-menarche. Patients treated with lovastatin had an adverse experience
profile generally similar to that of patients treated with placebo. Doses greater than 40 mg have not
been studied in this population. In these limited controlled studies, there was no detectable effect on
growth or sexual maturation in the adolescent boys or on menstrual cycle length in girls. See CLINICAL
PHARMACOLOGY, Clinical Studies in Adolescent Patients; ADVERSE REACTIONS, Adolescent
Patients; and DOSAGE AND ADMINISTRATION, Adolescent Patients (10-17 years of age) with
Heterozygous Familial Hypercholesterolemia. Adolescent females should be counseled on appropriate
contraceptive methods while on lovastatin therapy (see CONTRAINDICATIONS and PRECAUTIONS,
Pregnancy). Lovastatin has not been studied in pre-pubertal patients or patients younger than
10 years of age.
Geriatric Use
A pharmacokinetic study with lovastatin showed the mean plasma level of HMG-CoA reductase
inhibitory activity to be approximately 45% higher in elderly patients between 70-78 years of age compared
with patients between 18-30 years of age; however, clinical study experience in the elderly indicates that
dosage adjustment based on this age-related pharmacokinetic difference is not needed. In the two large
† Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During
Pregnancy. Reproductive Toxicology. 10(6):439-446. 1996.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
78253XX
14
clinical studies conducted with lovastatin (EXCEL and AFCAPS/TexCAPS), 21% (3,094/14,850) of
patients were ≥65 years of age. Lipid-lowering efficacy with lovastatin was at least as great in elderly
patients compared with younger patients, and there were no overall differences in safety over the
20 to 80 mg/day dosage range (see CLINICAL PHARMACOLOGY).
ADVERSE REACTIONS
MEVACOR is generally well tolerated; adverse reactions usually have been mild and transient.
Phase III Clinical Studies
In Phase III controlled clinical studies involving 613 patients treated with MEVACOR, the adverse
experience profile was similar to that shown below for the 8,245-patient EXCEL study (see Expanded
Clinical Evaluation of Lovastatin [EXCEL] Study).
Persistent increases of serum transaminases have been noted (see WARNINGS, Liver Dysfunction).
About 11% of patients had elevations of CK levels of at least twice the normal value on one or more
occasions. The corresponding values for the control agent cholestyramine was 9 percent. This was
attributable to the noncardiac fraction of CK. Large increases in CK have sometimes been reported (see
WARNINGS, Myopathy/Rhabdomyolysis).
Expanded Clinical Evaluation of Lovastatin (EXCEL) Study
MEVACOR was compared to placebo in 8,245 patients with hypercholesterolemia (total-C 240-300
mg/dL [6.2-7.8 mmol/L]) in the randomized, double-blind, parallel, 48-week EXCEL study. Clinical adverse
experiences reported as possibly, probably or definitely drug-related in ≥1% in any treatment group are
shown in the table below. For no event was the incidence on drug and placebo statistically different.
Placebo
(N = 1663)
%
MEVACOR
20 mg q.p.m.
(N = 1642)
%
MEVACOR
40 mg q.p.m.
(N = 1645)
%
MEVACOR
20 mg b.i.d.
(N = 1646)
%
MEVACOR
40 mg b.i.d.
(N = 1649)
%
Body As a Whole
Asthenia
1.4
1.7
1.4
1.5
1.2
Gastrointestinal
Abdominal pain
Constipation
Diarrhea
Dyspepsia
Flatulence
Nausea
1.6
1.9
2.3
1.9
4.2
2.5
2.0
2.0
2.6
1.3
3.7
1.9
2.0
3.2
2.4
1.3
4.3
2.5
2.2
3.2
2.2
1.0
3.9
2.2
2.5
3.5
2.6
1.6
4.5
2.2
Musculoskeletal
Muscle cramps
Myalgia
0.5
1.7
0.6
2.6
0.8
1.8
1.1
2.2
1.0
3.0
Nervous System/
Psychiatric
Dizziness
Headache
0.7
2.7
0.7
2.6
1.2
2.8
0.5
2.1
0.5
3.2
Skin
Rash
0.7
0.8
1.0
1.2
1.3
Special Senses
Blurred vision
0.8
1.1
0.9
0.9
1.2
Other clinical adverse experiences reported as possibly, probably or definitely drug-related in 0.5 to 1.0
percent of patients in any drug-treated group are listed below. In all these cases the incidence on drug and
placebo was not statistically different. Body as a Whole: chest pain; Gastrointestinal: acid regurgitation,
dry mouth, vomiting; Musculoskeletal: leg pain, shoulder pain, arthralgia; Nervous System/Psychiatric:
insomnia, paresthesia; Skin: alopecia, pruritus; Special Senses: eye irritation.
In the EXCEL study (see CLINICAL PHARMACOLOGY, Clinical Studies), 4.6% of the patients treated
up to 48 weeks were discontinued due to clinical or laboratory adverse experiences which were rated by
the investigator as possibly, probably or definitely related to therapy with MEVACOR. The value for the
placebo group was 2.5%.
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
In AFCAPS/TexCAPS (see CLINICAL PHARMACOLOGY, Clinical Studies) involving 6,605
participants treated with 20-40 mg/day of MEVACOR (n=3,304) or placebo (n=3,301), the safety and
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
78253XX
15
tolerability profile of the group treated with MEVACOR was comparable to that of the group treated with
placebo during a median of 5.1 years of follow-up. The adverse experiences reported in
AFCAPS/TexCAPS were similar to those reported in EXCEL (see ADVERSE REACTIONS, Expanded
Clinical Evaluation of Lovastatin (EXCEL) Study).
Concomitant Therapy
In controlled clinical studies in which lovastatin was administered concomitantly with cholestyramine,
no adverse reactions peculiar to this concomitant treatment were observed. The adverse reactions that
occurred were limited to those reported previously with lovastatin or cholestyramine. Other lipid-lowering
agents were not administered concomitantly with lovastatin during controlled clinical studies. Preliminary
data suggests that the addition of gemfibrozil to therapy with lovastatin is not associated with greater
reduction in LDL-C than that achieved with lovastatin alone. In uncontrolled clinical studies, most of the
patients who have developed myopathy were receiving concomitant therapy with cyclosporine, gemfibrozil
or niacin (nicotinic acid). The combined use of lovastatin at doses exceeding 20 mg/day with cyclosporine,
gemfibrozil, other fibrates or lipid-lowering doses (≥1 g/day) of niacin should be avoided (see WARNINGS,
Myopathy/Rhabdomyolysis).
The following effects have been reported with drugs in this class. Not all the effects listed below have
necessarily been associated with lovastatin therapy.
Skeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias.
Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-
ocular movement, facial paresis), tremor, dizziness, vertigo, memory loss, paresthesia, peripheral
neuropathy, peripheral nerve palsy, psychic disturbances, anxiety, insomnia, depression.
Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which has
included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like
syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia,
hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia,
photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme,
including Stevens-Johnson syndrome.
Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty
change in liver; and rarely, cirrhosis, fulminant hepatic necrosis, and hepatoma; anorexia, vomiting.
Skin: alopecia, pruritus. A variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous
membranes, changes to hair/nails) have been reported.
Reproductive: gynecomastia, loss of libido, erectile dysfunction.
Eye: progression of cataracts (lens opacities), ophthalmoplegia.
Laboratory Abnormalities: elevated transaminases, alkaline phosphatase, γ-glutamyl transpeptidase,
and bilirubin; thyroid function abnormalities.
Adolescent Patients (ages 10-17 years)
In a 48-week controlled study in adolescent boys with heFH (n=132) and a 24-week controlled study in
girls who were at least 1 year post-menarche with heFH (n=54), the safety and tolerability profile of the
groups treated with MEVACOR (10 to 40 mg daily) was generally similar to that of the groups treated with
placebo (see CLINICAL PHARMACOLOGY, Clinical Studies in Adolescent Patients and PRECAUTIONS,
Pediatric Use).
OVERDOSAGE
After oral administration of MEVACOR to mice, the median lethal dose observed was >15 g/m2.
Five healthy human volunteers have received up to 200 mg of lovastatin as a single dose without
clinically significant adverse experiences. A few cases of accidental overdosage have been reported; no
patients had any specific symptoms, and all patients recovered without sequelae. The maximum dose
taken was 5-6 g.
Until further experience is obtained, no specific treatment of overdosage with MEVACOR can be
recommended.
The dialyzability of lovastatin and its metabolites in man is not known at present.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
78253XX
16
DOSAGE AND ADMINISTRATION
The patient should be placed on a standard cholesterol-lowering diet before receiving MEVACOR and
should continue on this diet during treatment with MEVACOR (see NCEP Treatment Guidelines for details
on dietary therapy). MEVACOR should be given with meals.
Adult Patients
The usual recommended starting dose is 20 mg once a day given with the evening meal. The
recommended dosing range is 10-80 mg/day in single or two divided doses; the maximum recommended
dose is 80 mg/day. Doses should be individualized according to the recommended goal of therapy (see
NCEP Guidelines and CLINICAL PHARMACOLOGY). Patients requiring reductions in LDL-C of 20% or
more to achieve their goal (see INDICATIONS AND USAGE) should be started on 20 mg/day of
MEVACOR. A starting dose of 10 mg may be considered for patients requiring smaller reductions.
Adjustments should be made at intervals of 4 weeks or more.
Cholesterol levels should be monitored periodically and consideration should be given to reducing the
dosage of MEVACOR if cholesterol levels fall significantly below the targeted range.
Dosage in Patients taking Cyclosporine
In
patients
taking
cyclosporine
concomitantly
with
lovastatin
(see
WARNINGS,
Myopathy/Rhabdomyolysis), therapy should begin with 10 mg of MEVACOR and should not exceed
20 mg/day.
Dosage in Patients taking Amiodarone or Verapamil
In patients taking amiodarone or verapamil concomitantly with MEVACOR, the dose should not exceed
40 mg/day (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions, Other
drug interactions).
Adolescent Patients (10-17 years of age) with Heterozygous Familial Hypercholesterolemia
The recommended dosing range is 10-40 mg/day; the maximum recommended dose is 40 mg/day.
Doses should be individualized according to the recommended goal of therapy (see NCEP Pediatric Panel
Guidelines††, CLINICAL PHARMACOLOGY, and INDICATIONS AND USAGE). Patients requiring
reductions in LDL-C of 20% or more to achieve their goal should be started on 20 mg/day of MEVACOR.
A starting dose of 10 mg may be considered for patients requiring smaller reductions. Adjustments should
be made at intervals of 4 weeks or more.
Concomitant Lipid-Lowering Therapy
MEVACOR is effective alone or when used concomitantly with bile-acid sequestrants. If MEVACOR is
used in combination with gemfibrozil, other fibrates or lipid-lowering doses (≥1g/day) of niacin, the dose of
MEVACOR should not exceed 20 mg/day (see WARNINGS, Myopathy/Rhabdomyolysis and
PRECAUTIONS, Drug Interactions).
Dosage in Patients with Renal Insufficiency
In patients with severe renal insufficiency (creatinine clearance <30 mL/min), dosage increases above
20 mg/day should be carefully considered and, if deemed necessary, implemented cautiously (see
CLINICAL PHARMACOLOGY and WARNINGS, Myopathy/Rhabdomyolysis).
HOW SUPPLIED
No. 3560 — Tablets MEVACOR 10 mg are peach, octagonal tablets, coded MSD 730 on one side and
MEVACOR on the other. They are supplied as follows:
NDC 0006-0730-61 unit of use bottles of 60.
No. 3561 — Tablets MEVACOR 20 mg are light blue, octagonal tablets, coded MSD 731 on one side
and MEVACOR on the other. They are supplied as follows:
NDC 0006-0731-61 unit of use bottles of 60
NDC 0006-0731-94 unit of use bottles of 90
NDC 0006-0731-28 unit dose packages of 100
NDC 0006-0731-82 bottles of 1,000
NDC 0006-0731-87 bottles of 10,000.
No. 3562 — Tablets MEVACOR 40 mg are green, octagonal tablets, coded MSD 732 on one side and
MEVACOR on the other. They are supplied as follows:
NDC 0006-0732-61 unit of use bottles of 60
†† National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and
Adolescents. Pediatrics. 89(3):495-501. 1992.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
78253XX
17
NDC 0006-0732-94 unit of use bottles of 90
NDC 0006-0732-82 bottles of 1,000
NDC 0006-0732-87 bottles of 10,000.
Storage
Store between 5-30°C (41-86°F). Tablets MEVACOR must be protected from light and stored in a well-
closed, light-resistant container.
Issued June 2002
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(b)(4)
(b)(4)
|
custom-source
|
2025-02-12T13:45:35.972564
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/19643s075lbl.pdf', 'application_number': 19643, 'submission_type': 'SUPPL ', 'submission_number': 75}
|
11,585
|
7825356
TABLETS
MEVACOR®
(LOVASTATIN)
DESCRIPTION
MEVACOR* (Lovastatin) is a cholesterol lowering agent isolated from a strain of Aspergillus terreus.
After oral ingestion, lovastatin, which is an inactive lactone, is hydrolyzed to the corresponding β-
hydroxyacid form. This is a principal metabolite and an inhibitor of 3-hydroxy-3-methylglutaryl-
coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate,
which is an early and rate limiting step in the biosynthesis of cholesterol.
Lovastatin
is
[1S-[1α(R*),3α,7β,8β(2S*,4S*),
8aβ]]-1,2,3,7,
8,8a-hexahydro-3,7-dimethyl-8-[2-
(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl
2-methylbutanoate.
The
empirical
formula of lovastatin is C24H36O5 and its molecular weight is 404.55. Its structural formula is:
Lovastatin is a white, nonhygroscopic crystalline powder that is insoluble in water and sparingly
soluble in ethanol, methanol, and acetonitrile.
Tablets MEVACOR are supplied as 10 mg, 20 mg and 40 mg tablets for oral administration. In
addition to the active ingredient lovastatin, each tablet contains the following inactive ingredients:
cellulose, lactose, magnesium stearate, and starch. Butylated hydroxyanisole (BHA) is added as a
preservative. Tablets MEVACOR 10 mg also contain red ferric oxide and yellow ferric oxide. Tablets
MEVACOR 20 mg also contain FD&C Blue 2 aluminum lake. Tablets MEVACOR 40 mg also contain
D&C Yellow 10 aluminum lake and FD&C Blue 2 aluminum lake.
CLINICAL PHARMACOLOGY
The involvement of low-density lipoprotein cholesterol (LDL-C) in atherogenesis has been well-
documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological
and clinical studies have established that high LDL-C and low high-density lipoprotein cholesterol (HDL-
C) are both associated with coronary heart disease. However, the risk of developing coronary heart
disease is continuous and graded over the range of cholesterol levels and many coronary events do
occur in patients with total cholesterol (total-C) and LDL-C in the lower end of this range.
MEVACOR has been shown to reduce both normal and elevated LDL-C concentrations. LDL is
formed from very low-density lipoprotein (VLDL) and is catabolized predominantly by the high affinity LDL
receptor. The mechanism of the LDL-lowering effect of MEVACOR may involve both reduction of VLDL-C
concentration, and induction of the LDL receptor, leading to reduced production and/or increased
catabolism of LDL-C. Apolipoprotein B also falls substantially during treatment with MEVACOR. Since
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT © 1987-2005 MERCK & CO., 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
MEVACOR (Lovastatin)
7825356
2
each LDL particle contains one molecule of apolipoprotein B, and since little apolipoprotein B is found in
other lipoproteins, this strongly suggests that MEVACOR does not merely cause cholesterol to be lost
from LDL, but also reduces the concentration of circulating LDL particles. In addition, MEVACOR can
produce increases of variable magnitude in HDL-C, and modestly reduces VLDL-C and plasma
triglycerides (TG) (see Tables I-III under Clinical Studies). The effects of MEVACOR on Lp(a), fibrinogen,
and certain other independent biochemical risk markers for coronary heart disease are unknown.
MEVACOR is a specific inhibitor of HMG-CoA reductase, the enzyme which catalyzes the conversion
of HMG-CoA to mevalonate. The conversion of HMG-CoA to mevalonate is an early step in the
biosynthetic pathway for cholesterol.
Pharmacokinetics
Lovastatin is a lactone which is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent
inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in
pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base
hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of lovastatin.
Following an oral dose of 14C-labeled lovastatin in man, 10% of the dose was excreted in urine and
83% in feces. The latter represents absorbed drug equivalents excreted in bile, as well as any
unabsorbed drug. Plasma concentrations of total radioactivity (lovastatin plus 14C-metabolites) peaked at
2 hours and declined rapidly to about 10% of peak by 24 hours postdose. Absorption of lovastatin,
estimated relative to an intravenous reference dose, in each of four animal species tested, averaged
about 30% of an oral dose. In animal studies, after oral dosing, lovastatin had high selectivity for the liver,
where it achieved substantially higher concentrations than in non-target tissues. Lovastatin undergoes
extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug
equivalents in the bile. As a consequence of extensive hepatic extraction of lovastatin, the availability of
drug to the general circulation is low and variable. In a single dose study in four hypercholesterolemic
patients, it was estimated that less than 5% of an oral dose of lovastatin reaches the general circulation
as active inhibitors. Following administration of lovastatin tablets the coefficient of variation, based on
between-subject variability, was approximately 40% for the area under the curve (AUC) of total inhibitory
activity in the general circulation.
Both lovastatin and its β-hydroxyacid metabolite are highly bound (>95%) to human plasma proteins.
Animal studies demonstrated that lovastatin crosses the blood-brain and placental barriers.
The major active metabolites present in human plasma are the β-hydroxyacid of lovastatin, its
6′-hydroxy derivative, and two additional metabolites. Peak plasma concentrations of both active and total
inhibitors were attained within 2 to 4 hours of dose administration. While the recommended therapeutic
dose range is 10 to 80 mg/day, linearity of inhibitory activity in the general circulation was established by
a single dose study employing lovastatin tablet dosages from 60 to as high as 120 mg. With a once-a-day
dosing regimen, plasma concentrations of total inhibitors over a dosing interval achieved a steady state
between the second and third days of therapy and were about 1.5 times those following a single dose.
When lovastatin was given under fasting conditions, plasma concentrations of total inhibitors were on
average about two-thirds those found when lovastatin was administered immediately after a standard test
meal.
In a study of patients with severe renal insufficiency (creatinine clearance 10-30 mL/min), the plasma
concentrations of total inhibitors after a single dose of lovastatin were approximately two-fold higher than
those in healthy volunteers.
In a study including 16 elderly patients between 70-78 years of age who received MEVACOR
80 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately
45% compared with 18 patients between 18-30 years of age (see PRECAUTIONS, Geriatric Use).
Although the mechanism is not fully understood, cyclosporine has been shown to increase the AUC of
HMG-CoA reductase inhibitors. The increase in AUC for lovastatin and lovastatin acid is presumably due,
in part, to inhibition of CYP3A4.
The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.
Potent inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
7825356
3
increase the risk of myopathy (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug
Interactions).
Lovastatin is a substrate for cytochrome P450 isoform 3A4 (CYP3A4) (see PRECAUTIONS, Drug
Interactions). Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase
the plasma concentrations of drugs metabolized by CYP3A4. In one study**, 10 subjects consumed 200
mL of double-strength grapefruit juice (one can of frozen concentrate diluted with one rather than 3 cans
of water) three times daily for 2 days and an additional 200 mL double-strength grapefruit juice together
with and 30 and 90 minutes following a single dose of 80 mg lovastatin on the third day. This regimen of
grapefruit juice resulted in a mean increase in the serum concentration of lovastatin and its β-hydroxyacid
metabolite (as measured by the area under the concentration-time curve) of 15-fold and 5-fold,
respectively [as measured using a chemical assay — high performance liquid chromatography]. In a
second study, 15 subjects consumed one 8 oz glass of single-strength grapefruit juice (one can of frozen
concentrate diluted with 3 cans of water) with breakfast for 3 consecutive days and a single dose of
40 mg lovastatin in the evening of the third day. This regimen of grapefruit juice resulted in a mean
increase in the plasma concentration (as measured by the area under the concentration-time curve) of
active and total HMG-CoA reductase inhibitory activity [using an enzyme inhibition assay both before (for
active inhibitors) and after (for total inhibitors) base hydrolysis] of 1.34-fold and 1.36-fold, respectively,
and of lovastatin and its β-hydroxyacid metabolite [measured using a chemical assay — liquid
chromatography/tandem mass spectrometry — different from that used in the first** study] of 1.94-fold
and 1.57-fold, respectively. The effect of amounts of grapefruit juice between those used in these two
studies on lovastatin pharmacokinetics has not been studied.
Clinical Studies in Adults
MEVACOR has been shown to be highly effective in reducing total-C and LDL-C in heterozygous
familial and non-familial forms of primary hypercholesterolemia and in mixed hyperlipidemia. A marked
response was seen within 2 weeks, and the maximum therapeutic response occurred within 4-6 weeks.
The response was maintained during continuation of therapy. Single daily doses given in the evening
were more effective than the same dose given in the morning, perhaps because cholesterol is
synthesized mainly at night.
In multicenter, double-blind studies in patients with familial or non-familial hypercholesterolemia,
MEVACOR, administered in doses ranging from 10 mg q.p.m. to 40 mg b.i.d., was compared to placebo.
MEVACOR consistently and significantly decreased plasma total-C, LDL-C, total-C/HDL-C ratio and LDL-
C/HDL-C ratio. In addition, MEVACOR produced increases of variable magnitude in HDL-C, and
modestly decreased VLDL-C and plasma TG (see Tables I through III for dose response results).
The results of a study in patients with primary hypercholesterolemia are presented in Table I.
TABLE I
MEVACOR vs. Placebo
(Mean Percent Change from Baseline After 6 Weeks)
DOSAGE
N
TOTAL-C
LDL-C
HDL-C
LDL-C/
HDL-C
TOTAL-C/
HDL-C
TG.
Placebo
33
–2
–1
–1
0
+1
+9
MEVACOR
10 mg q.p.m.
20 mg q.p.m.
10 mg b.i.d.
40 mg q.p.m.
20 mg b.i.d.
33
33
32
33
36
–16
–19
–19
–22
–24
–21
–27
–28
–31
–32
+5
+6
+8
+5
+2
–24
–30
–33
–33
–32
–19
–23
–25
–25
–24
–10
+9
–7
–8
–6
MEVACOR was compared to cholestyramine in a randomized open parallel study. The study was
performed with patients with hypercholesterolemia who were at high risk of myocardial infarction.
Summary results are presented in Table II.
** Kantola, T, et al., Clin Pharmacol Ther 1998; 63(4):397-402.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
7825356
4
TABLE II
MEVACOR vs. Cholestyramine
(Percent Change from Baseline After 12 Weeks)
TREATMENT
N
TOTAL-C
(mean)
LDL-C
(mean)
HDL-C
(mean)
LDL-C/
HDL-C
(mean)
TOTAL-C/
HDL-C
(mean)
VLDL-C
(median)
TG.
(mean)
MEVACOR
20 mg b.i.d.
40 mg b.i.d.
85
88
–27
–34
–32
–42
+9
+8
–36
–44
–31
–37
–34
–31
–21
–27
Cholestyramine
12 g b.i.d.
88
–17
–23
+8
–27
–21
+2
+11
MEVACOR was studied in controlled trials in hypercholesterolemic patients with well-controlled non-
insulin dependent diabetes mellitus with normal renal function. The effect of MEVACOR on lipids and
lipoproteins and the safety profile of MEVACOR were similar to that demonstrated in studies in
nondiabetics. MEVACOR had no clinically important effect on glycemic control or on the dose
requirement of oral hypoglycemic agents.
Expanded Clinical Evaluation of Lovastatin (EXCEL) Study
MEVACOR was compared to placebo in 8,245 patients with hypercholesterolemia (total-C 240-300
mg/dL [6.2 mmol/L - 7.6 mmol/L], LDL-C >160 mg/dL [4.1 mmol/L]) in the randomized, double-blind,
parallel, 48-week EXCEL study. All changes in the lipid measurements (Table III) in MEVACOR treated
patients were dose-related and significantly different from placebo (p≤0.001). These results were
sustained throughout the study.
TABLE III
MEVACOR vs. Placebo
(Percent Change from Baseline —
Average Values Between Weeks 12 and 48)
DOSAGE
N**
TOTAL-C
(mean)
LDL-C
(mean)
HDL-C
(mean)
LDL-C/
HDL-C
(mean)
TOTAL-C/
HDL-C
(mean)
TG.
(median)
Placebo
1663
+0.7
+0.4
+2.0
+0.2
+0.6
+4
MEVACOR
20 mg q.p.m.
40 mg q.p.m.
20 mg b.i.d.
40 mg b.i.d.
1642
1645
1646
1649
–17
–22
–24
–29
–24
–30
–34
–40
+6.6
+7.2
+8.6
+9.5
–27
–34
–38
–44
–21
–26
–29
–34
–10
–14
–16
–19
**Patients enrolled
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), a double-blind,
randomized, placebo-controlled, primary prevention study, demonstrated that treatment with MEVACOR
decreased the rate of acute major coronary events (composite endpoint of myocardial infarction, unstable
angina, and sudden cardiac death) compared with placebo during a median of 5.1 years of follow-up.
Participants were middle-aged and elderly men (ages 45-73) and women (ages 55-73) without
symptomatic cardiovascular disease with average to moderately elevated total-C and LDL-C, below
average HDL-C, and who were at high risk based on elevated total-C/HDL-C. In addition to age, 63% of
the participants had at least one other risk factor (baseline HDL-C <35 mg/dL, hypertension, family
history, smoking and diabetes).
AFCAPS/TexCAPS enrolled 6,605 participants (5,608 men, 997 women) based on the following lipid
entry criteria: total-C range of 180-264 mg/dL, LDL-C range of 130-190 mg/dL, HDL-C of ≤45 mg/dL for
men and ≤47 mg/dL for women, and TG of ≤400 mg/dL. Participants were treated with standard care,
including diet, and either MEVACOR 20-40 mg daily (n= 3,304) or placebo (n= 3,301). Approximately
50% of the participants treated with MEVACOR were titrated to 40 mg daily when their LDL-C remained
>110 mg/dL at the 20-mg starting dose.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
7825356
5
MEVACOR reduced the risk of a first acute major coronary event, the primary efficacy endpoint, by
37% (MEVACOR 3.5%, placebo 5.5%; p<0.001; Figure 1). A first acute major coronary event was defined
as myocardial infarction (54 participants on MEVACOR, 94 on placebo) or unstable angina (54 vs. 80) or
sudden cardiac death (8 vs. 9). Furthermore, among the secondary endpoints, MEVACOR reduced the
risk of unstable angina by 32% (1.8 vs. 2.6%; p=0.023), of myocardial infarction by 40% (1.7 vs. 2.9%;
p=0.002), and of undergoing coronary revascularization procedures (e.g., coronary artery bypass grafting
or percutaneous transluminal coronary angioplasty) by 33% (3.2 vs. 4.8%; p=0.001). Trends in risk
reduction associated with treatment with MEVACOR were consistent across men and women, smokers
and non-smokers, hypertensives and non-hypertensives, and older and younger participants. Participants
with ≥2 risk factors had risk reductions (RR) in both acute major coronary events (RR 43%) and coronary
revascularization procedures (RR 37%). Because there were too few events among those participants
with age as their only risk factor in this study, the effect of MEVACOR on outcomes could not be
adequately assessed in this subgroup.
Atherosclerosis
In the Canadian Coronary Atherosclerosis Intervention Trial (CCAIT), the effect of therapy with
lovastatin on coronary atherosclerosis was assessed by coronary angiography in hyperlipidemic patients.
In the randomized, double-blind, controlled clinical trial, patients were treated with conventional measures
(usually diet and 325 mg of aspirin every other day) and either lovastatin 20-80 mg daily or placebo.
Angiograms were evaluated at baseline and at two years by computerized quantitative coronary
angiography (QCA). Lovastatin significantly slowed the progression of lesions as measured by the mean
change per-patient in minimum lumen diameter (the primary endpoint) and percent diameter stenosis,
and decreased the proportions of patients categorized with disease progression (33% vs. 50%) and with
new lesions (16% vs. 32%).
In a similarly designed trial, the Monitored Atherosclerosis Regression Study (MARS), patients were
treated with diet and either lovastatin 80 mg daily or placebo. No statistically significant difference
between lovastatin and placebo was seen for the primary endpoint (mean change per patient in percent
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
7825356
6
diameter stenosis of all lesions), or for most secondary QCA endpoints. Visual assessment by
angiographers who formed a consensus opinion of overall angiographic change (Global Change Score)
was also a secondary endpoint. By this endpoint, significant slowing of disease was seen, with regression
in 23% of patients treated with lovastatin compared to 11% of placebo patients.
In the Familial Atherosclerosis Treatment Study (FATS), either lovastatin or niacin in combination with
a bile acid sequestrant for 2.5 years in hyperlipidemic subjects significantly reduced the frequency of
progression and increased the frequency of regression of coronary atherosclerotic lesions by QCA
compared to diet and, in some cases, low-dose resin.
The effect of lovastatin on the progression of atherosclerosis in the coronary arteries has been
corroborated by similar findings in another vasculature. In the Asymptomatic Carotid Artery Progression
Study (ACAPS), the effect of therapy with lovastatin on carotid atherosclerosis was assessed by B-mode
ultrasonography in hyperlipidemic patients with early carotid lesions and without known coronary heart
disease at baseline. In this double-blind, controlled clinical trial, 919 patients were randomized in a 2 x 2
factorial design to placebo, lovastatin 10-40 mg daily and/or warfarin. Ultrasonograms of the carotid walls
were used to determine the change per patient from baseline to three years in mean maximum intimal-
medial thickness (IMT) of 12 measured segments. There was a significant regression of carotid lesions in
patients receiving lovastatin alone compared to those receiving placebo alone (p=0.001). The predictive
value of changes in IMT for stroke has not yet been established. In the lovastatin group there was a
significant reduction in the number of patients with major cardiovascular events relative to the placebo
group (5 vs. 14) and a significant reduction in all-cause mortality (1 vs. 8).
Eye
There was a high prevalence of baseline lenticular opacities in the patient population included in the
early clinical trials with lovastatin. During these trials the appearance of new opacities was noted in both
the lovastatin and placebo groups. There was no clinically significant change in visual acuity in the
patients who had new opacities reported nor was any patient, including those with opacities noted at
baseline, discontinued from therapy because of a decrease in visual acuity.
A three-year, double-blind, placebo-controlled study in hypercholesterolemic patients to assess the
effect of lovastatin on the human lens demonstrated that there were no clinically or statistically significant
differences between the lovastatin and placebo groups in the incidence, type or progression of lenticular
opacities. There are no controlled clinical data assessing the lens available for treatment beyond three
years.
Clinical Studies in Adolescent Patients
Efficacy of Lovastatin in Adolescent Boys with Heterozygous Familial Hypercholesterolemia
In a double-blind, placebo-controlled study, 132 boys 10-17 years of age (mean age 12.7 yrs) with
heterozygous familial hypercholesterolemia (heFH) were randomized to lovastatin (n=67) or placebo
(n=65) for 48 weeks. Inclusion in the study required a baseline LDL-C level between 189 and 500 mg/dL
and at least one parent with an LDL-C level >189 mg/dL. The mean baseline LDL-C value was
253.1 mg/dL (range: 171-379 mg/dL) in the MEVACOR group compared to 248.2 mg/dL (range:
158.5-413.5 mg/dL) in the placebo group. The dosage of lovastatin (once daily in the evening) was 10 mg
for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter.
MEVACOR significantly decreased plasma levels of total-C, LDL-C and apolipoprotein B (see
Table IV).
TABLE IV
Lipid-lowering Effects of Lovastatin in Adolescent Boys with Heterozygous Familial Hypercholesterolemia
(Mean Percent Change from Baseline at week 48 in Intention-to-Treat Population)
DOSAGE
N
TOTAL-C
LDL-C
HDL-C
TG.*
Apolipoprotein B
Placebo
61
-1.1
-1.4
-2.2
-1.4
-4.4
MEVACOR
64
-19.3
-24.2
+1.1
-1.9
-21
*data presented as median percent changes
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
7825356
7
The mean achieved LDL-C value was 190.9 mg/dL (range: 108-336 mg/dL) in the MEVACOR group
compared to 244.8 mg/dL (range: 135-404 mg/dL) in the placebo group.
Efficacy of Lovastatin in Post-menarchal Girls with Heterozygous Familial Hypercholesterolemia
In a double-blind, placebo-controlled study, 54 girls 10-17 years of age who were at least 1 year
post-menarche with heFH were randomized to lovastatin (n=35) or placebo (n=19) for 24 weeks.
Inclusion in the study required a baseline LDL-C level of 160-400 mg/dL and a parental history of familial
hypercholesterolemia. The mean baseline LDL-C value was 218.3 mg/dL (range: 136.3-363.7 mg/dL) in
the MEVACOR group compared to 198.8 mg/dL (range: 151.1-283.1 mg/dL) in the placebo group. The
dosage of lovastatin (once daily in the evening) was 20 mg for the first 4 weeks, and 40 mg thereafter.
MEVACOR significantly decreased plasma levels of total-C, LDL-C, and apolipoprotein B (see
Table V).
TABLE V
Lipid-lowering Effects of Lovastatin in Post-menarchal Girls with Heterozygous Familial Hypercholesterolemia
(Mean Percent Change from Baseline at Week 24 in Intention-to-Treat Population)
DOSAGE
N
TOTAL-C
LDL-C
HDL-C
TG.*
Apolipoprotein B
Placebo
18
+3.6
+2.5
+4.8
-3.0
+6.4
MEVACOR
35
-22.4
-29.2
+2.4
-22.7
-24.4
*data presented as median percent changes
The mean achieved LDL-C value was 154.5 mg/dL (range: 82-286 mg/dL) in the MEVACOR group
compared to 203.5 mg/dL (range: 135-304 mg/dL) in the placebo group.
The safety and efficacy of doses above 40 mg daily have not been studied in children. The long-term
efficacy of lovastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been
established.
INDICATIONS AND USAGE
Therapy with MEVACOR should be a component of multiple risk factor intervention in those
individuals with dyslipidemia at risk for atherosclerotic vascular disease. MEVACOR should be used in
addition to a diet restricted in saturated fat and cholesterol as part of a treatment strategy to lower total-C
and LDL-C to target levels when the response to diet and other nonpharmacological measures alone has
been inadequate to reduce risk.
Primary Prevention of Coronary Heart Disease
In individuals without symptomatic cardiovascular disease, average to moderately elevated total-C
and LDL-C, and below average HDL-C, MEVACOR is indicated to reduce the risk of:
- Myocardial infarction
- Unstable angina
- Coronary revascularization procedures
(See CLINICAL PHARMACOLOGY, Clinical Studies.)
Coronary Heart Disease
MEVACOR is indicated to slow the progression of coronary atherosclerosis in patients with coronary
heart disease as part of a treatment strategy to lower total-C and LDL-C to target levels.
Hypercholesterolemia
Therapy with lipid-altering agents should be a component of multiple risk factor intervention in those
individuals
at
significantly
increased
risk
for
atherosclerotic
vascular
disease
due
to
hypercholesterolemia. MEVACOR is indicated as an adjunct to diet for the reduction of elevated total-C
and LDL-C levels in patients with primary hypercholesterolemia (Types IIa and IIb***), when the response
*** Classification of Hyperlipoproteinemias
Lipid
Lipoproteins
Elevations
Type
elevated
major
minor
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
7825356
8
to diet restricted in saturated fat and cholesterol and to other nonpharmacological measures alone has
been inadequate.
Adolescent Patients with Heterozygous Familial Hypercholesterolemia
MEVACOR is indicated as an adjunct to diet to reduce total-C, LDL-C and apolipoprotein B levels in
adolescent boys and girls who are at least one year post-menarche, 10-17 years of age, with heFH if
after an adequate trial of diet therapy the following findings are present:
1. LDL-C remains >189 mg/dL or
2. LDL-C remains >160 mg/dL and:
•
there is a positive family history of premature cardiovascular disease or
•
two or more other CVD risk factors are present in the adolescent patient
General Recommendations
Prior to initiating therapy with lovastatin, secondary causes for hypercholesterolemia (e.g., poorly
controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver
disease, other drug therapy, alcoholism) should be excluded, and a lipid profile performed to measure
total-C, HDL-C, and TG. For patients with TG less than 400 mg/dL (<4.5 mmol/L), LDL-C can be
estimated using the following equation:
LDL-C = total-C – [0.2 × (TG) + HDL-C]
For TG levels >400 mg/dL (>4.5 mmol/L), this equation is less accurate and LDL-C concentrations
should be determined by ultracentrifugation. In hypertriglyceridemic patients, LDL-C may be low or
normal despite elevated total-C. In such cases, MEVACOR is not indicated.
The National Cholesterol Education Program (NCEP) Treatment Guidelines are summarized below:
NCEP Treatment Guidelines:
LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes
and Drug Therapy in Different Risk Categories
Risk Category
LDL Goal
(mg/dL)
LDL Level at Which to
Initiate Therapeutic Lifestyle Changes
(mg/dL)
LDL Level at Which to
Consider Drug Therapy
(mg/dL)
CHD† or CHD risk equivalents
(10-year risk >20%)
2+ Risk factors
(10 year risk ≤20%)
0-1 Risk factor†††
<100
<130
<160
≥100
≥130
≥160
≥130
(100-129: drug optional)††
10-year risk 10-20%: ≥130
10-year risk <10%: ≥ 160
≥190
(160-189: LDL-lowering drug
optional)
†
CHD, coronary heart disease
††
Some authorities recommend use of LDL-lowering drugs in this category if an LDL-C level of <100 mg/dL cannot be achieved by therapeutic
lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL-C, e.g., nicotinic acid or fibrate. Clinical judgment also
may call for deferring drug therapy in this subcategory.
†††
Almost all people with 0-1 risk factor have a 10-year risk <10%; thus, 10-year risk assessment in people with 0-1 risk factor is not necessary.
After the LDL-C goal has been achieved, if the TG is still ≥200 mg/dL, non-HDL-C (total-C minus HDL-
C) becomes a secondary target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals
for each risk category.
At the time of hospitalization for an acute coronary event, consideration can be given to initiating drug
therapy at discharge if the LDL-C is ≥130 mg/dL (see NCEP Guidelines above).
I
chylomicrons
TG
↑→C
IIa
LDL
C
—
IIb
LDL, VLDL
C
TG
III (rare)
IDL
C/TG
—
IV
VLDL
TG
↑→C
V (rare)
chylomicrons, VLDL
TG
↑→C
IDL = intermediate-density lipoprotein.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
7825356
9
Since the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C levels be used to
initiate and assess treatment response. Only if LDL-C levels are not available, should the total-C be used
to monitor therapy.
Although MEVACOR may be useful to reduce elevated LDL-C levels in patients with combined
hypercholesterolemia and hypertriglyceridemia where hypercholesterolemia is the major abnormality
(Type IIb hyperlipoproteinemia), it has not been studied in conditions where the major abnormality is
elevation of chylomicrons, VLDL or IDL (i.e., hyperlipoproteinemia types I, III, IV, or V).***
The NCEP classification of cholesterol levels in pediatric patients with a familial history of
hypercholesterolemia or premature cardiovascular disease is summarized below:
Category
Total-C (mg/dL)
LDL-C (mg/dL)
Acceptable
Borderline
High
<170
170-199
≥200
<110
110-129
≥130
Children treated with lovastatin in adolescence should be re-evaluated in adulthood and appropriate
changes made to their cholesterol-lowering regimen to achieve adult goals for LDL-C.
CONTRAINDICATIONS
Hypersensitivity to any component of this medication.
Active liver disease or unexplained persistent elevations of serum transaminases (see WARNINGS).
Pregnancy and lactation (see PRECAUTIONS, Pregnancy and Nursing Mothers). Atherosclerosis is a
chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact
on the outcome of long-term therapy of primary hypercholesterolemia. Moreover, cholesterol and other
products of the cholesterol biosynthesis pathway are essential components for fetal development,
including synthesis of steroids and cell membranes. Because of the ability of inhibitors of HMG-CoA
reductase such as MEVACOR to decrease the synthesis of cholesterol and possibly other products of the
cholesterol biosynthesis pathway, MEVACOR is contraindicated during pregnancy and in nursing
mothers. MEVACOR should be administered to women of childbearing age only when such
patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug,
MEVACOR should be discontinued immediately and the patient should be apprised of the potential
hazard to the fetus (see PRECAUTIONS, Pregnancy).
WARNINGS
Myopathy/Rhabdomyolysis
Lovastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as
muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal
(ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure
secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high
levels of HMG-CoA reductase inhibitory activity in plasma.
As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose
related. In a clinical study (EXCEL) in which patients were carefully monitored and some interacting
drugs were excluded, there was one case of myopathy among 4933 patients randomized to lovastatin 20-
40 mg daily for 48 weeks, and 4 among 1649 patients randomized to 80 mg daily.
All patients starting therapy with lovastatin, or whose dose of lovastatin is being increased,
should be advised of the risk of myopathy and told to report promptly any unexplained muscle
pain, tenderness or weakness. Lovastatin therapy should be discontinued immediately if
myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved
when treatment was promptly discontinued. Periodic CK determinations may be considered in patients
starting therapy with lovastatin or whose dose is being increased, but there is no assurance that such
monitoring will prevent myopathy.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
7825356
10
Many of the patients who have developed rhabdomyolysis on therapy with lovastatin have had
complicated medical histories, including renal insufficiency usually as a consequence of long-standing
diabetes mellitus. Such patients merit closer monitoring. Therapy with lovastatin should be temporarily
stopped a few days prior to elective major surgery and when any major medical or surgical condition
supervenes.
The risk of myopathy/rhabdomyolysis is increased by concomitant use of lovastatin with the
following:
Potent inhibitors of CYP3A4: Lovastatin, like several other inhibitors of HMG-CoA reductase, is a
substrate of cytochrome P450 3A4 (CYP3A4). When lovastatin is used with a potent inhibitor of
CYP3A4, elevated plasma levels of HMG-CoA reductase inhibitory activity can increase the risk of
myopathy and rhabdomyolysis, particularly with higher doses of lovastatin.
The use of lovastatin concomitantly with the potent CYP3A4 inhibitors itraconazole,
ketoconazole,
erythromycin,
clarithromycin,
telithromycin,
HIV
protease
inhibitors,
nefazodone, or large quantities of grapefruit juice (>1 quart daily) should be avoided.
Concomitant use of other medicines labeled as having a potent inhibitory effect on CYP3A4 should
be avoided unless the benefits of combined therapy outweigh the increased risk. If treatment with
itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with
lovastatin should be suspended during the course of treatment.
Gemfibrozil, particularly with higher doses of lovastatin: The dose of lovastatin should not
exceed 20 mg daily in patients receiving concomitant medication with gemfibrozil. The
combined use of lovastatin with gemfibrozil should be avoided, unless the benefits are likely
to outweigh the increased risks of this drug combination.
Other lipid-lowering drugs (other fibrates or ≥1 g/day of niacin): The dose of lovastatin should
not exceed 20 mg daily in patients receiving concomitant medication with other fibrates or
≥1 g/day of niacin. Caution should be used when prescribing other fibrates or lipid-lowering doses
(≥1 g/day) of niacin with lovastatin, as these agents can cause myopathy when given alone. The
benefit of further alterations in lipid levels by the combined use of lovastatin with other
fibrates or niacin should be carefully weighed against the potential risks of these
combinations.
Cyclosporine or danazol, with higher doses of lovastatin: The dose of lovastatin should not
exceed 20 mg daily in patients receiving concomitant medication with cyclosporine or
danazol. The benefits of the use of lovastatin in patients receiving cyclosporine or danazol should be
carefully weighed against the risks of these combinations.
Amiodarone or verapamil: The dose of lovastatin should not exceed 40 mg daily in patients
receiving concomitant medication with amiodarone or verapamil. The combined use of
lovastatin at doses higher than 40 mg daily with amiodarone or verapamil should be avoided unless
the clinical benefit is likely to outweigh the increased risk of myopathy. The risk of
myopathy/rhabdomyolysis is increased when either amiodarone or verapamil is used concomitantly
with higher doses of a closely related member of the HMG-CoA reductase inhibitor class.
Prescribing recommendations for interacting agents are summarized in Table VI (see also CLINICAL
PHARMACOLOGY,
Pharmacokinetics;
PRECAUTIONS,
Drug
Interactions;
DOSAGE
AND
ADMINISTRATION).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
7825356
11
Table VI
Drug Interactions Associated with Increased
Risk of Myopathy/Rhabdomyolysis
Interacting Agents
Prescribing Recommendations
Itraconazole
Ketoconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors
Nefazodone
Avoid lovastatin
Gemfibrozil
Other fibrates
Lipid-lowering doses (≥1 g/day)
of niacin
Cyclosporine
Danazol
Do not exceed 20 mg lovastatin daily
Amiodarone
Verapamil
Do not exceed 40 mg lovastatin daily
Grapefruit juice
Avoid large quantities of grapefruit juice
(>1 quart daily)
Liver Dysfunction
Persistent increases (to more than 3 times the upper limit of normal) in serum transaminases
occurred in 1.9% of adult patients who received lovastatin for at least one year in early clinical
trials (see ADVERSE REACTIONS). When the drug was interrupted or discontinued in these patients,
the transaminase levels usually fell slowly to pretreatment levels. The increases usually appeared 3 to 12
months after the start of therapy with lovastatin, and were not associated with jaundice or other clinical
signs or symptoms. There was no evidence of hypersensitivity. In the EXCEL study (see CLINICAL
PHARMACOLOGY, Clinical Studies), the incidence of persistent increases in serum transaminases over
48 weeks was 0.1% for placebo, 0.1% at 20 mg/day, 0.9% at 40 mg/day, and 1.5% at 80 mg/day in
patients on lovastatin. However, in post-marketing experience with MEVACOR, symptomatic liver disease
has been reported rarely at all dosages (see ADVERSE REACTIONS).
In AFCAPS/TexCAPS, the number of participants with consecutive elevations of either alanine
aminotransferase (ALT) or aspartate aminotransferase (AST) (> 3 times the upper limit of normal), over a
median of 5.1 years of follow-up, was not significantly different between the MEVACOR and placebo
groups (18 [0.6%] vs. 11 [0.3%]). The starting dose of MEVACOR was 20 mg/day; 50% of the MEVACOR
treated participants were titrated to 40 mg/day at Week 18. Of the 18 participants on MEVACOR with
consecutive elevations of either ALT or AST, 11 (0.7%) elevations occurred in participants taking 20
mg/day, while 7 (0.4%) elevations occurred in participants titrated to 40 mg/day. Elevated transaminases
resulted in discontinuation of 6 (0.2%) participants from therapy in the MEVACOR group (n=3,304) and 4
(0.1%) in the placebo group (n=3,301).
It is recommended that liver function tests be performed prior to initiation of therapy in patients with a
history of liver disease, or when otherwise clinically indicated. It is recommended that liver function tests
be performed in all patients prior to use of 40 mg or more daily and thereafter when clinically indicated.
Patients who develop increased transaminase levels should be monitored with a second liver function
evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the
abnormality(ies) returns to normal. Should an increase in AST or ALT of three times the upper limit of
normal or greater persist, withdrawal of therapy with MEVACOR is recommended.
The drug should be used with caution in patients who consume substantial quantities of alcohol and/or
have a past history of liver disease. Active liver disease or unexplained transaminase elevations are
contraindications to the use of lovastatin.
As with other lipid-lowering agents, moderate (less than three times the upper limit of normal)
elevations of serum transaminases have been reported following therapy with MEVACOR (see
ADVERSE REACTIONS). These changes appeared soon after initiation of therapy with MEVACOR, were
often transient, were not accompanied by any symptoms and interruption of treatment was not required.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
7825356
12
PRECAUTIONS
General
Lovastatin may elevate creatine phosphokinase and transaminase levels (see WARNINGS and
ADVERSE REACTIONS). This should be considered in the differential diagnosis of chest pain in a patient
on therapy with lovastatin.
Homozygous Familial Hypercholesterolemia
MEVACOR is less effective in patients with the rare homozygous familial hypercholesterolemia,
possibly because these patients have no functional LDL receptors. MEVACOR appears to be more likely
to raise serum transaminases (see ADVERSE REACTIONS) in these homozygous patients.
Information for Patients
Patients should be advised about substances they should not take concomitantly with
lovastatin and be advised to report promptly unexplained muscle pain, tenderness, or weakness
(see list below and WARNINGS, Myopathy/Rhabdomyolysis). Patients should also be advised to
inform other physicians prescribing a new medication that they are taking MEVACOR.
Drug Interactions
CYP3A4 Interactions
Lovastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not
expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. Potent inhibitors of
CYP3A4 (below) increase the risk of myopathy by reducing the elimination of lovastatin.
See
WARNINGS,
Myopathy/Rhabdomyolysis,
and
CLINICAL
PHARMACOLOGY,
Pharmacokinetics.
Itraconazole
Ketoconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors
Nefazodone
Large quantities of grapefruit juice (>1 quart daily)
Interactions with lipid-lowering drugs that can cause myopathy when given alone
The risk of myopathy is also increased by the following lipid-lowering drugs that are not potent
CYP3A4 inhibitors, but which can cause myopathy when given alone.
See WARNINGS, Myopathy/Rhabdomyolysis.
Gemfibrozil
Other fibrates
Niacin (nicotinic acid) (≥1 g/day)
Other drug interactions
Cyclosporine or Danazol: The risk of myopathy/rhabdomyolysis is increased by concomitant
administration of cyclosporine or danazol particularly with higher doses of lovastatin (see WARNINGS,
Myopathy/Rhabdomyolysis; CLINICAL PHARMACOLOGY, Pharmacokinetics).
Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased when either amiodarone
or verapamil is used concomitantly with a closely related member of the HMG-CoA reductase inhibitor
class (see WARNINGS, Myopathy/Rhabdomyolysis).
Coumarin Anticoagulants: In a small clinical trial in which lovastatin was administered to warfarin
treated patients, no effect on prothrombin time was detected. However, another HMG-CoA reductase
inhibitor has been found to produce a less than two-second increase in prothrombin time in healthy
volunteers receiving low doses of warfarin. Also, bleeding and/or increased prothrombin time have been
reported in a few patients taking coumarin anticoagulants concomitantly with lovastatin. It is
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
7825356
13
recommended that in patients taking anticoagulants, prothrombin time be determined before starting
lovastatin and frequently enough during early therapy to insure that no significant alteration of
prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can
be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose
of lovastatin is changed, the same procedure should be repeated. Lovastatin therapy has not been
associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
Propranolol: In normal volunteers, there was no clinically significant pharmacokinetic or
pharmacodynamic interaction with concomitant administration of single doses of lovastatin and
propranolol.
Digoxin: In patients with hypercholesterolemia, concomitant administration of lovastatin and digoxin
resulted in no effect on digoxin plasma concentrations.
Oral Hypoglycemic Agents: In pharmacokinetic studies of MEVACOR in hypercholesterolemic non-
insulin dependent diabetic patients, there was no drug interaction with glipizide or with chlorpropamide
(see CLINICAL PHARMACOLOGY, Clinical Studies).
Endocrine Function
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically
blunt adrenal and/or gonadal steroid production. Results of clinical trials with drugs in this class have
been inconsistent with regard to drug effects on basal and reserve steroid levels. However, clinical
studies have shown that lovastatin does not reduce basal plasma cortisol concentration or impair adrenal
reserve, and does not reduce basal plasma testosterone concentration. Another HMG-CoA reductase
inhibitor has been shown to reduce the plasma testosterone response to HCG. In the same study, the
mean testosterone response to HCG was slightly but not significantly reduced after treatment with
lovastatin 40 mg daily for 16 weeks in 21 men. The effects of HMG-CoA reductase inhibitors on male
fertility have not been studied in adequate numbers of male patients. The effects, if any, on the pituitary-
gonadal axis in pre-menopausal women are unknown. Patients treated with lovastatin who develop
clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be
exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is
administered to patients also receiving other drugs (e.g., ketoconazole, spironolactone, cimetidine) that
may decrease the levels or activity of endogenous steroid hormones.
CNS Toxicity
Lovastatin produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in
clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean
plasma drug levels about 30 times higher than the mean drug level in humans taking the highest
recommended dose (as measured by total enzyme inhibitory activity). Vestibulocochlear Wallerian-like
degeneration and retinal ganglion cell chromatolysis were also seen in dogs treated for 14 weeks at 180
mg/kg/day, a dose which resulted in a mean plasma drug level (Cmax) similar to that seen with the 60
mg/kg/day dose.
CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell
infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels, were seen in
dogs treated with lovastatin at a dose of 180 mg/kg/day, a dose which produced plasma drug levels
(Cmax) which were about 30 times higher than the mean values in humans taking 80 mg/day.
Similar optic nerve and CNS vascular lesions have been observed with other drugs of this class.
Cataracts were seen in dogs treated for 11 and 28 weeks at 180 mg/kg/day and 1 year at
60 mg/kg/day.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 21-month carcinogenic study in mice, there was a statistically significant increase in the incidence
of hepatocellular carcinomas and adenomas in both males and females at 500 mg/kg/day. This dose
produced a total plasma drug exposure 3 to 4 times that of humans given the highest recommended dose
of lovastatin (drug exposure was measured as total HMG-CoA reductase inhibitory activity in extracted
plasma). Tumor increases were not seen at 20 and 100 mg/kg/day, doses that produced drug exposures
of 0.3 to 2 times that of humans at the 80 mg/day dose. A statistically significant increase in pulmonary
adenomas was seen in female mice at approximately 4 times the human drug exposure. (Although mice
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
7825356
14
were given 300 times the human dose [HD] on a mg/kg body weight basis, plasma levels of total
inhibitory activity were only 4 times higher in mice than in humans given 80 mg of MEVACOR.)
There was an increase in incidence of papilloma in the non-glandular mucosa of the stomach of mice
beginning at exposures of 1 to 2 times that of humans. The glandular mucosa was not affected. The
human stomach contains only glandular mucosa.
In a 24-month carcinogenicity study in rats, there was a positive dose response relationship for
hepatocellular carcinogenicity in males at drug exposures between 2-7 times that of human exposure at
80 mg/day (doses in rats were 5, 30 and 180 mg/kg/day).
An increased incidence of thyroid neoplasms in rats appears to be a response that has been seen
with other HMG-CoA reductase inhibitors.
A chemically similar drug in this class was administered to mice for 72 weeks at 25, 100, and
400 mg/kg body weight, which resulted in mean serum drug levels approximately 3, 15, and 33 times
higher than the mean human serum drug concentration (as total inhibitory activity) after a 40 mg oral
dose. Liver carcinomas were significantly increased in high dose females and mid- and high dose males,
with a maximum incidence of 90 percent in males. The incidence of adenomas of the liver was
significantly increased in mid- and high dose females. Drug treatment also significantly increased the
incidence of lung adenomas in mid- and high dose males and females. Adenomas of the Harderian gland
(a gland of the eye of rodents) were significantly higher in high dose mice than in controls.
No evidence of mutagenicity was observed in a microbial mutagen test using mutant strains of
Salmonella typhimurium with or without rat or mouse liver metabolic activation. In addition, no evidence of
damage to genetic material was noted in an in vitro alkaline elution assay using rat or mouse
hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in
CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow.
Drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant
cell formation were seen in dogs starting at 20 mg/kg/day. Similar findings were seen with another drug in
this class. No drug-related effects on fertility were found in studies with lovastatin in rats. However, in
studies with a similar drug in this class, there was decreased fertility in male rats treated for 34 weeks at
25 mg/kg body weight, although this effect was not observed in a subsequent fertility study when this
same dose was administered for 11 weeks (the entire cycle of spermatogenesis, including epididymal
maturation). In rats treated with this same reductase inhibitor at 180 mg/kg/day, seminiferous tubule
degeneration (necrosis and loss of spermatogenic epithelium) was observed. No microscopic changes
were observed in the testes from rats of either study. The clinical significance of these findings is unclear.
Pregnancy
Pregnancy Category X
See CONTRAINDICATIONS.
Safety in pregnant women has not been established.
Lovastatin has been shown to produce skeletal malformations in offspring of pregnant mice and rats
dosed during gestation at 80 mg/kg/day (affected mouse fetuses/total: 8/307 compared to 4/289 in the
control group; affected rat fetuses/total: 6/324 compared to 2/308 in the control group). Female rats
dosed before mating through gestation at 80 mg/kg/day also had fetuses with skeletal malformations
(affected fetuses/total: 1/152 compared to 0/171 in the control group). The 80 mg/kg/day dose in mice is 7
times the human dose based on body surface area and in rats results in 5 times the human exposure
based on AUC. In pregnant rats given doses of 2, 20, or 200 mg/kg/day and treated through lactation, the
following effects were observed: neonatal mortality (4.1%, 3.5%, and 46%, respectively, compared to
0.6% in the control group), decreased pup body weights throughout lactation (up to 5%, 8%, and 38%,
respectively, below control), supernumerary ribs in dead pups (affected fetuses/total: 0/7, 1/17, and
11/79, respectively, compared to 0/5 in the control group), delays in ossification in dead pups (affected
fetuses/total: 0/7, 0/17, and 1/79, respectively, compared to 0/5 in the control group) and delays in pup
development (delays in the appearance of an auditory startle response at 200 mg/kg/day and free-fall
righting reflexes at 20 and 200 mg/kg/day).
Direct dosing of neonatal rats by subcutaneous injection with 10 mg/kg/day of the open hydroxyacid
form of lovastatin resulted in delayed passive avoidance learning in female rats (mean of 8.3 trials to
criterion, compared to 7.3 and 6.4 in untreated and vehicle-treated controls; no effects on retention 1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
7825356
15
week later) at exposures 4 times the human systemic exposure at 80 mg/day based on AUC. No effect
was seen in male rats. No evidence of malformations was observed when pregnant rabbits were given 5
mg/kg/day (doses equivalent to a human dose of 80 mg/day based on body surface area) or a maternally
toxic dose of 15 mg/kg/day (3 times the human dose of 80 mg/day based on body surface area).
Rare clinical reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase
inhibitors have been received. However, in an analysis† of greater than 200 prospectively followed
pregnancies exposed during the first trimester to MEVACOR or another closely related HMG-CoA
reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general
population. This number of pregnancies was sufficient to exclude a 3-fold or greater increase in
congenital anomalies over the background incidence.
Maternal treatment with MEVACOR may reduce the fetal levels of mevalonate, which is a precursor of
cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-
lowering drugs during pregnancy should have little impact on the long-term risk associated with primary
hypercholesterolemia. For these reasons, MEVACOR should not be used in women who are pregnant, or
can become pregnant (see CONTRAINDICATIONS). MEVACOR should be administered to women of
child-bearing potential only when such patients are highly unlikely to conceive and have been informed of
the potential hazards. Treatment should be immediately discontinued as soon as pregnancy is
recognized.
Nursing Mothers
It is not known whether lovastatin is excreted in human milk. Because a small amount of another drug
in this class is excreted in human breast milk and because of the potential for serious adverse reactions
in nursing infants, women taking MEVACOR should not nurse their infants (see CONTRAINDICATIONS).
Pediatric Use
Safety and effectiveness in patients 10-17 years of age with heFH have been evaluated in controlled
clinical trials of 48 weeks duration in adolescent boys and controlled clinical trials of 24 weeks duration in
girls who were at least 1 year post-menarche. Patients treated with lovastatin had an adverse experience
profile generally similar to that of patients treated with placebo. Doses greater than 40 mg have not
been studied in this population. In these limited controlled studies, there was no detectable effect on
growth or sexual maturation in the adolescent boys or on menstrual cycle length in girls. See CLINICAL
PHARMACOLOGY, Clinical Studies in Adolescent Patients; ADVERSE REACTIONS, Adolescent
Patients; and DOSAGE AND ADMINISTRATION, Adolescent Patients (10-17 years of age) with
Heterozygous Familial Hypercholesterolemia. Adolescent females should be counseled on appropriate
contraceptive methods while on lovastatin therapy (see CONTRAINDICATIONS and PRECAUTIONS,
Pregnancy). Lovastatin has not been studied in pre-pubertal patients or patients younger than
10 years of age.
Geriatric Use
A pharmacokinetic study with lovastatin showed the mean plasma level of HMG-CoA reductase
inhibitory activity to be approximately 45% higher in elderly patients between 70-78 years of age
compared with patients between 18-30 years of age; however, clinical study experience in the elderly
indicates that dosage adjustment based on this age-related pharmacokinetic difference is not needed. In
the two large clinical studies conducted with lovastatin (EXCEL and AFCAPS/TexCAPS), 21%
(3094/14850) of patients were ≥65 years of age. Lipid-lowering efficacy with lovastatin was at least as
great in elderly patients compared with younger patients, and there were no overall differences in safety
over the 20 to 80 mg/day dosage range (see CLINICAL PHARMACOLOGY).
ADVERSE REACTIONS
MEVACOR is generally well tolerated; adverse reactions usually have been mild and transient.
† Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During
Pregnancy. Reproductive Toxicology. 10(6):439-446. 1996.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
7825356
16
Phase III Clinical Studies
In Phase III controlled clinical studies involving 613 patients treated with MEVACOR, the adverse
experience profile was similar to that shown below for the 8,245-patient EXCEL study (see Expanded
Clinical Evaluation of Lovastatin [EXCEL] Study).
Persistent increases of serum transaminases have been noted (see WARNINGS, Liver Dysfunction).
About 11% of patients had elevations of CK levels of at least twice the normal value on one or more
occasions. The corresponding values for the control agent cholestyramine was 9 percent. This was
attributable to the noncardiac fraction of CK. Large increases in CK have sometimes been reported (see
WARNINGS, Myopathy/Rhabdomyolysis).
Expanded Clinical Evaluation of Lovastatin (EXCEL) Study
MEVACOR was compared to placebo in 8,245 patients with hypercholesterolemia (total-C 240-300
mg/dL [6.2-7.8 mmol/L]) in the randomized, double-blind, parallel, 48-week EXCEL study. Clinical
adverse experiences reported as possibly, probably or definitely drug-related in ≥1% in any treatment
group are shown in the table below. For no event was the incidence on drug and placebo statistically
different.
Placebo
(N = 1663)
%
MEVACOR
20 mg q.p.m.
(N = 1642)
%
MEVACOR
40 mg q.p.m.
(N = 1645)
%
MEVACOR
20 mg b.i.d.
(N = 1646)
%
MEVACOR
40 mg b.i.d.
(N = 1649)
%
Body As a Whole
Asthenia
1.4
1.7
1.4
1.5
1.2
Gastrointestinal
Abdominal pain
Constipation
Diarrhea
Dyspepsia
Flatulence
Nausea
1.6
1.9
2.3
1.9
4.2
2.5
2.0
2.0
2.6
1.3
3.7
1.9
2.0
3.2
2.4
1.3
4.3
2.5
2.2
3.2
2.2
1.0
3.9
2.2
2.5
3.5
2.6
1.6
4.5
2.2
Musculoskeletal
Muscle cramps
Myalgia
0.5
1.7
0.6
2.6
0.8
1.8
1.1
2.2
1.0
3.0
Nervous System/
Psychiatric
Dizziness
Headache
0.7
2.7
0.7
2.6
1.2
2.8
0.5
2.1
0.5
3.2
Skin
Rash
0.7
0.8
1.0
1.2
1.3
Special Senses
Blurred vision
0.8
1.1
0.9
0.9
1.2
Other clinical adverse experiences reported as possibly, probably or definitely drug-related in 0.5 to
1.0 percent of patients in any drug-treated group are listed below. In all these cases the incidence on
drug and placebo was not statistically different. Body as a Whole: chest pain; Gastrointestinal: acid
regurgitation, dry mouth, vomiting; Musculoskeletal: leg pain, shoulder pain, arthralgia; Nervous
System/Psychiatric: insomnia, paresthesia; Skin: alopecia, pruritus; Special Senses: eye irritation.
In the EXCEL study (see CLINICAL PHARMACOLOGY, Clinical Studies), 4.6% of the patients treated
up to 48 weeks were discontinued due to clinical or laboratory adverse experiences which were rated by
the investigator as possibly, probably or definitely related to therapy with MEVACOR. The value for the
placebo group was 2.5%.
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
In AFCAPS/TexCAPS (see CLINICAL PHARMACOLOGY, Clinical Studies) involving 6,605
participants treated with 20-40 mg/day of MEVACOR (n=3,304) or placebo (n=3,301), the safety and
tolerability profile of the group treated with MEVACOR was comparable to that of the group treated with
placebo during a median of 5.1 years of follow-up. The adverse experiences reported in
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
7825356
17
AFCAPS/TexCAPS were similar to those reported in EXCEL (see ADVERSE REACTIONS, Expanded
Clinical Evaluation of Lovastatin (EXCEL) Study).
Concomitant Therapy
In controlled clinical studies in which lovastatin was administered concomitantly with cholestyramine,
no adverse reactions peculiar to this concomitant treatment were observed. The adverse reactions that
occurred were limited to those reported previously with lovastatin or cholestyramine. Other lipid-lowering
agents were not administered concomitantly with lovastatin during controlled clinical studies. Preliminary
data suggests that the addition of gemfibrozil to therapy with lovastatin is not associated with greater
reduction in LDL-C than that achieved with lovastatin alone. In uncontrolled clinical studies, most of the
patients who have developed myopathy were receiving concomitant therapy with cyclosporine,
gemfibrozil or niacin (nicotinic acid). The combined use of lovastatin at doses exceeding 20 mg/day with
cyclosporine, gemfibrozil, other fibrates or lipid-lowering doses (≥1 g/day) of niacin should be avoided
(see WARNINGS, Myopathy/Rhabdomyolysis).
The following effects have been reported with drugs in this class. Not all the effects listed below have
necessarily been associated with lovastatin therapy.
Skeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias.
Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-
ocular movement, facial paresis), tremor, dizziness, vertigo, memory loss, paresthesia, peripheral
neuropathy, peripheral nerve palsy, psychic disturbances, anxiety, insomnia, depression.
Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which
has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like
syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia,
hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia,
photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme,
including Stevens-Johnson syndrome.
Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty
change in liver; and rarely, cirrhosis, fulminant hepatic necrosis, and hepatoma; anorexia, vomiting.
Skin: alopecia, pruritus. A variety of skin changes (e.g., nodules, discoloration, dryness of
skin/mucous membranes, changes to hair/nails) have been reported.
Reproductive: gynecomastia, loss of libido, erectile dysfunction.
Eye: progression of cataracts (lens opacities), ophthalmoplegia.
Laboratory Abnormalities: elevated transaminases, alkaline phosphatase, γ-glutamyl transpeptidase,
and bilirubin; thyroid function abnormalities.
Adolescent Patients (ages 10-17 years)
In a 48-week controlled study in adolescent boys with heFH (n=132) and a 24-week controlled study
in girls who were at least 1 year post-menarche with heFH (n=54), the safety and tolerability profile of the
groups treated with MEVACOR (10 to 40 mg daily) was generally similar to that of the groups treated with
placebo (see CLINICAL PHARMACOLOGY, Clinical Studies in Adolescent Patients and PRECAUTIONS,
Pediatric Use).
OVERDOSAGE
After oral administration of MEVACOR to mice, the median lethal dose observed was >15 g/m2.
Five healthy human volunteers have received up to 200 mg of lovastatin as a single dose without
clinically significant adverse experiences. A few cases of accidental overdosage have been reported; no
patients had any specific symptoms, and all patients recovered without sequelae. The maximum dose
taken was 5-6 g.
Until further experience is obtained, no specific treatment of overdosage with MEVACOR can be
recommended.
The dialyzability of lovastatin and its metabolites in man is not known at present.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
7825356
18
DOSAGE AND ADMINISTRATION
The patient should be placed on a standard cholesterol-lowering diet before receiving MEVACOR and
should continue on this diet during treatment with MEVACOR (see NCEP Treatment Guidelines for
details on dietary therapy). MEVACOR should be given with meals.
Adult Patients
The usual recommended starting dose is 20 mg once a day given with the evening meal. The
recommended dosing range is 10-80 mg/day in single or two divided doses; the maximum recommended
dose is 80 mg/day. Doses should be individualized according to the recommended goal of therapy (see
NCEP Guidelines and CLINICAL PHARMACOLOGY). Patients requiring reductions in LDL-C of 20% or
more to achieve their goal (see INDICATIONS AND USAGE) should be started on 20 mg/day of
MEVACOR. A starting dose of 10 mg may be considered for patients requiring smaller reductions.
Adjustments should be made at intervals of 4 weeks or more.
Cholesterol levels should be monitored periodically and consideration should be given to reducing the
dosage of MEVACOR if cholesterol levels fall significantly below the targeted range.
Dosage in Patients taking Cyclosporine or Danazol
In patients taking cyclosporine or danazol concomitantly with lovastatin (see WARNINGS,
Myopathy/Rhabdomyolysis), therapy should begin with 10 mg of MEVACOR and should not exceed
20 mg/day.
Dosage in Patients taking Amiodarone or Verapamil
In patients taking amiodarone or verapamil concomitantly with MEVACOR, the dose should not
exceed 40 mg/day (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions,
Other drug interactions).
Adolescent Patients (10-17 years of age) with Heterozygous Familial Hypercholesterolemia
The recommended dosing range is 10-40 mg/day; the maximum recommended dose is 40 mg/day.
Doses should be individualized according to the recommended goal of therapy (see NCEP Pediatric
Panel Guidelines††, CLINICAL PHARMACOLOGY, and INDICATIONS AND USAGE). Patients requiring
reductions in LDL-C of 20% or more to achieve their goal should be started on 20 mg/day of MEVACOR.
A starting dose of 10 mg may be considered for patients requiring smaller reductions. Adjustments should
be made at intervals of 4 weeks or more.
Concomitant Lipid-Lowering Therapy
MEVACOR is effective alone or when used concomitantly with bile-acid sequestrants. If MEVACOR is
used in combination with gemfibrozil, other fibrates or lipid-lowering doses (≥ 1g/day) of niacin, the dose
of MEVACOR should not exceed 20 mg/day (see WARNINGS, Myopathy/Rhabdomyolysis and
PRECAUTIONS, Drug Interactions).
Dosage in Patients with Renal Insufficiency
In patients with severe renal insufficiency (creatinine clearance <30 mL/min), dosage increases above
20 mg/day should be carefully considered and, if deemed necessary, implemented cautiously (see
CLINICAL PHARMACOLOGY and WARNINGS, Myopathy/Rhabdomyolysis).
HOW SUPPLIED
No. 3560 — Tablets MEVACOR 10 mg are peach, octagonal tablets, coded MSD 730 on one side and
MEVACOR on the other. They are supplied as follows:
NDC 0006-0730-61 unit of use bottles of 60.
No. 3561 — Tablets MEVACOR 20 mg are light blue, octagonal tablets, coded MSD 731 on one side
and MEVACOR on the other. They are supplied as follows:
NDC 0006-0731-61 unit of use bottles of 60
NDC 0006-0731-94 unit of use bottles of 90
NDC 0006-0731-82 bottles of 1,000.
†† National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and
Adolescents. Pediatrics. 89(3):495-501. 1992.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
7825356
19
No. 3562 — Tablets MEVACOR 40 mg are green, octagonal tablets, coded MSD 732 on one side and
MEVACOR on the other. They are supplied as follows:
NDC 0006-0732-61 unit of use bottles of 60
NDC 0006-0732-94 unit of use bottles of 90
NDC 0006-0732-82 bottles of 1,000.
Storage
Store between 5-30°C (41-86°F). Tablets MEVACOR must be protected from light and stored in a
well-closed, light-resistant container.
Issued April 2007
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:36.006467
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/019643s061lbl.pdf', 'application_number': 19643, 'submission_type': 'SUPPL ', 'submission_number': 61}
|
11,588
|
782535378253XX
TABLETS
MEVACOR®
(LOVASTATIN)
DESCRIPTION
MEVACOR* (Lovastatin) is a cholesterol lowering agent isolated from a strain of Aspergillus terreus.
After oral ingestion, lovastatin, which is an inactive lactone, is hydrolyzed to the corresponding β-
hydroxyacid form. This is a principal metabolite and an inhibitor of 3-hydroxy-3-methylglutaryl-
coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate,
which is an early and rate limiting step in the biosynthesis of cholesterol.
Lovastatin
is
[1S-[1α(R*),3α,7β,8β(2S*,4S*),
8aβ]]-1,2,3,7,
8,8a-hexahydro-3,7-dimethyl-8-[2-
(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl
2-methylbutanoate.
The
empirical
formula of lovastatin is C24H36O5 and its molecular weight is 404.55. Its structural formula is:
Lovastatin is a white, nonhygroscopic crystalline powder that is insoluble in water and sparingly
soluble in ethanol, methanol, and acetonitrile.
Tablets MEVACOR are supplied as 10 mg, 20 mg and 40 mg tablets for oral administration. In
addition to the active ingredient lovastatin, each tablet contains the following inactive ingredients:
cellulose, lactose, magnesium stearate, and starch. Butylated hydroxyanisole (BHA) is added as a
preservative. Tablets MEVACOR 10 mg also contain red ferric oxide and yellow ferric oxide. Tablets
MEVACOR 20 mg also contain FD&C Blue 2. Tablets MEVACOR 40 mg also contain D&C Yellow 10 and
FD&C Blue 2.
CLINICAL PHARMACOLOGY
The involvement of low-density lipoprotein cholesterol (LDL-C) in atherogenesis has been well-
documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological
and clinical studies have established that high LDL-C and low high-density lipoprotein cholesterol (HDL-
C) are both associated with coronary heart disease. However, the risk of developing coronary heart
disease is continuous and graded over the range of cholesterol levels and many coronary events do
occur in patients with total cholesterol (total-C) and LDL-C in the lower end of this range.
MEVACOR has been shown to reduce both normal and elevated LDL-C concentrations. LDL is
formed from very low-density lipoprotein (VLDL) and is catabolized predominantly by the high affinity LDL
receptor. The mechanism of the LDL-lowering effect of MEVACOR may involve both reduction of VLDL-C
concentration, and induction of the LDL receptor, leading to reduced production and/or increased
catabolism of LDL-C. Apolipoprotein B also falls substantially during treatment with MEVACOR. Since
each LDL particle contains one molecule of apolipoprotein B, and since little apolipoprotein B is found in
other lipoproteins, this strongly suggests that MEVACOR does not merely cause cholesterol to be lost
from LDL, but also reduces the concentration of circulating LDL particles. In addition, MEVACOR can
produce increases of variable magnitude in HDL-C, and modestly reduces VLDL-C and plasma
triglycerides (TG) (see Tables I-III under Clinical Studies). The effects of MEVACOR on Lp(a), fibrinogen,
and certain other independent biochemical risk markers for coronary heart disease are unknown.
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT © 1987-XXXX MERCK & CO., 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
MEVACOR (Lovastatin)
782535378253XX
2
MEVACOR is a specific inhibitor of HMG-CoA reductase, the enzyme which catalyzes the conversion
of HMG-CoA to mevalonate. The conversion of HMG-CoA to mevalonate is an early step in the
biosynthetic pathway for cholesterol.
Pharmacokinetics
Lovastatin is a lactone which is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent
inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in
pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base
hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of lovastatin.
Following an oral dose of 14C-labeled lovastatin in man, 10% of the dose was excreted in urine and
83% in feces. The latter represents absorbed drug equivalents excreted in bile, as well as any
unabsorbed drug. Plasma concentrations of total radioactivity (lovastatin plus 14C-metabolites) peaked at
2 hours and declined rapidly to about 10% of peak by 24 hours postdose. Absorption of lovastatin,
estimated relative to an intravenous reference dose, in each of four animal species tested, averaged
about 30% of an oral dose. In animal studies, after oral dosing, lovastatin had high selectivity for the liver,
where it achieved substantially higher concentrations than in non-target tissues. Lovastatin undergoes
extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug
equivalents in the bile. As a consequence of extensive hepatic extraction of lovastatin, the availability of
drug to the general circulation is low and variable. In a single dose study in four hypercholesterolemic
patients, it was estimated that less than 5% of an oral dose of lovastatin reaches the general circulation
as active inhibitors. Following administration of lovastatin tablets the coefficient of variation, based on
between-subject variability, was approximately 40% for the area under the curve (AUC) of total inhibitory
activity in the general circulation.
Both lovastatin and its β-hydroxyacid metabolite are highly bound (>95%) to human plasma proteins.
Animal studies demonstrated that lovastatin crosses the blood-brain and placental barriers.
The major active metabolites present in human plasma are the β-hydroxyacid of lovastatin, its
6′-hydroxy derivative, and two additional metabolites. Peak plasma concentrations of both active and total
inhibitors were attained within 2 to 4 hours of dose administration. While the recommended therapeutic
dose range is 10 to 80 mg/day, linearity of inhibitory activity in the general circulation was established by
a single dose study employing lovastatin tablet dosages from 60 to as high as 120 mg. With a once-a-day
dosing regimen, plasma concentrations of total inhibitors over a dosing interval achieved a steady state
between the second and third days of therapy and were about 1.5 times those following a single dose.
When lovastatin was given under fasting conditions, plasma concentrations of total inhibitors were on
average about two-thirds those found when lovastatin was administered immediately after a standard test
meal.
In a study of patients with severe renal insufficiency (creatinine clearance 10-30 mL/min), the plasma
concentrations of total inhibitors after a single dose of lovastatin were approximately two-fold higher than
those in healthy volunteers.
In a study including 16 elderly patients between 70-78 years of age who received MEVACOR
80 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately
45% compared with 18 patients between 18-30 years of age (see PRECAUTIONS, Geriatric Use).
Although the mechanism is not fully understood, cyclosporine has been shown to increase the AUC of
HMG-CoA reductase inhibitors. The increase in AUC for lovastatin and lovastatin acid is presumably due,
in part, to inhibition of CYP3A4.
The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.
Potent inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and
increase the risk of myopathy (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug
Interactions).
Lovastatin is a substrate for cytochrome P450 isoform 3A4 (CYP3A4) (see PRECAUTIONS, Drug
Interactions). Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase
the plasma concentrations of drugs metabolized by CYP3A4. In one study**, 10 subjects consumed 200
mL of double-strength grapefruit juice (one can of frozen concentrate diluted with one rather than 3 cans
of water) three times daily for 2 days and an additional 200 mL double-strength grapefruit juice together
with and 30 and 90 minutes following a single dose of 80 mg lovastatin on the third day. This regimen of
grapefruit juice resulted in a mean increase in the serum concentration of lovastatin and its β-hydroxyacid
metabolite (as measured by the area under the concentration-time curve) of 15-fold and 5-fold,
respectively [as measured using a chemical assay — high performance liquid chromatography]. In a
second study, 15 subjects consumed one 8 oz glass of single-strength grapefruit juice (one can of frozen
** Kantola, T, et al., Clin Pharmacol Ther 1998; 63(4):397-402.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
782535378253XX
3
concentrate diluted with 3 cans of water) with breakfast for 3 consecutive days and a single dose of
40 mg lovastatin in the evening of the third day. This regimen of grapefruit juice resulted in a mean
increase in the plasma concentration (as measured by the area under the concentration-time curve) of
active and total HMG-CoA reductase inhibitory activity [using an enzyme inhibition assay both before (for
active inhibitors) and after (for total inhibitors) base hydrolysis] of 1.34-fold and 1.36-fold, respectively,
and of lovastatin and its β-hydroxyacid metabolite [measured using a chemical assay — liquid
chromatography/tandem mass spectrometry — different from that used in the first** study] of 1.94-fold
and 1.57-fold, respectively. The effect of amounts of grapefruit juice between those used in these two
studies on lovastatin pharmacokinetics has not been studied.
Clinical Studies in Adults
MEVACOR has been shown to be highly effective in reducing total-C and LDL-C in heterozygous
familial and non-familial forms of primary hypercholesterolemia and in mixed hyperlipidemia. A marked
response was seen within 2 weeks, and the maximum therapeutic response occurred within 4-6 weeks.
The response was maintained during continuation of therapy. Single daily doses given in the evening
were more effective than the same dose given in the morning, perhaps because cholesterol is
synthesized mainly at night.
In multicenter, double-blind studies in patients with familial or non-familial hypercholesterolemia,
MEVACOR, administered in doses ranging from 10 mg q.p.m. to 40 mg b.i.d., was compared to placebo.
MEVACOR consistently and significantly decreased plasma total-C, LDL-C, total-C/HDL-C ratio and LDL-
C/HDL-C ratio. In addition, MEVACOR produced increases of variable magnitude in HDL-C, and
modestly decreased VLDL-C and plasma TG (see Tables I through III for dose response results).
The results of a study in patients with primary hypercholesterolemia are presented in Table I.
TABLE I
MEVACOR vs. Placebo
(Mean Percent Change from Baseline After 6 Weeks)
DOSAGE
N
TOTAL-C
LDL-C
HDL-C
LDL-C/
HDL-C
TOTAL-C/
HDL-C
TG.
Placebo
33
–2
–1
–1
0
+1
+9
MEVACOR
10 mg q.p.m.
20 mg q.p.m.
10 mg b.i.d.
40 mg q.p.m.
20 mg b.i.d.
33
33
32
33
36
–16
–19
–19
–22
–24
–21
–27
–28
–31
–32
+5
+6
+8
+5
+2
–24
–30
–33
–33
–32
–19
–23
–25
–25
–24
–10
+9
–7
–8
–6
MEVACOR was compared to cholestyramine in a randomized open parallel study. The study was
performed with patients with hypercholesterolemia who were at high risk of myocardial infarction.
Summary results are presented in Table II.
TABLE II
MEVACOR vs. Cholestyramine
(Percent Change from Baseline After 12 Weeks)
TREATMENT
N
TOTAL-C
(mean)
LDL-C
(mean)
HDL-C
(mean)
LDL-C/
HDL-C
(mean)
TOTAL-C/
HDL-C
(mean)
VLDL-C
(median)
TG.
(mean)
MEVACOR
20 mg b.i.d.
40 mg b.i.d.
85
88
–27
–34
–32
–42
+9
+8
–36
–44
–31
–37
–34
–31
–21
–27
Cholestyramine
12 g b.i.d.
88
–17
–23
+8
–27
–21
+2
+11
MEVACOR was studied in controlled trials in hypercholesterolemic patients with well-controlled non-
insulin dependent diabetes mellitus with normal renal function. The effect of MEVACOR on lipids and
lipoproteins and the safety profile of MEVACOR were similar to that demonstrated in studies in
nondiabetics. MEVACOR had no clinically important effect on glycemic control or on the dose
requirement of oral hypoglycemic agents.
Expanded Clinical Evaluation of Lovastatin (EXCEL) Study
MEVACOR was compared to placebo in 8,245 patients with hypercholesterolemia (total-C 240-300
mg/dL [6.2 mmol/L - 7.6 mmol/L], LDL-C >160 mg/dL [4.1 mmol/L]) in the randomized, double-blind,
parallel, 48-week EXCEL study. All changes in the lipid measurements (Table III) in MEVACOR treated
patients were dose-related and significantly different from placebo (p≤0.001). These results were
sustained throughout the study.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
782535378253XX
4
TABLE III
MEVACOR vs. Placebo
(Percent Change from Baseline —
Average Values Between Weeks 12 and 48)
DOSAGE
N**
TOTAL-C
(mean)
LDL-C
(mean)
HDL-C
(mean)
LDL-C/
HDL-C
(mean)
TOTAL-C/
HDL-C
(mean)
TG.
(median)
Placebo
1663
+0.7
+0.4
+2.0
+0.2
+0.6
+4
MEVACOR
20 mg q.p.m.
40 mg q.p.m.
20 mg b.i.d.
40 mg b.i.d.
1642
1645
1646
1649
–17
–22
–24
–29
–24
–30
–34
–40
+6.6
+7.2
+8.6
+9.5
–27
–34
–38
–44
–21
–26
–29
–34
–10
–14
–16
–19
**Patients enrolled
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), a double-blind,
randomized, placebo-controlled, primary prevention study, demonstrated that treatment with MEVACOR
decreased the rate of acute major coronary events (composite endpoint of myocardial infarction, unstable
angina, and sudden cardiac death) compared with placebo during a median of 5.1 years of follow-up.
Participants were middle-aged and elderly men (ages 45-73) and women (ages 55-73) without
symptomatic cardiovascular disease with average to moderately elevated total-C and LDL-C, below
average HDL-C, and who were at high risk based on elevated total-C/HDL-C. In addition to age, 63% of
the participants had at least one other risk factor (baseline HDL-C <35 mg/dL, hypertension, family
history, smoking and diabetes).
AFCAPS/TexCAPS enrolled 6,605 participants (5,608 men, 997 women) based on the following lipid
entry criteria: total-C range of 180-264 mg/dL, LDL-C range of 130-190 mg/dL, HDL-C of ≤45 mg/dL for
men and ≤47 mg/dL for women, and TG of ≤400 mg/dL. Participants were treated with standard care,
including diet, and either MEVACOR 20-40 mg daily (n= 3,304) or placebo (n= 3,301). Approximately
50% of the participants treated with MEVACOR were titrated to 40 mg daily when their LDL-C remained
>110 mg/dL at the 20-mg starting dose.
MEVACOR reduced the risk of a first acute major coronary event, the primary efficacy endpoint, by
37% (MEVACOR 3.5%, placebo 5.5%; p<0.001; Figure 1). A first acute major coronary event was defined
as myocardial infarction (54 participants on MEVACOR, 94 on placebo) or unstable angina (54 vs. 80) or
sudden cardiac death (8 vs. 9). Furthermore, among the secondary endpoints, MEVACOR reduced the
risk of unstable angina by 32% (1.8 vs. 2.6%; p=0.023), of myocardial infarction by 40% (1.7 vs. 2.9%;
p=0.002), and of undergoing coronary revascularization procedures (e.g., coronary artery bypass grafting
or percutaneous transluminal coronary angioplasty) by 33% (3.2 vs. 4.8%; p=0.001). Trends in risk
reduction associated with treatment with MEVACOR were consistent across men and women, smokers
and non-smokers, hypertensives and non-hypertensives, and older and younger participants. Participants
with ≥2 risk factors had risk reductions (RR) in both acute major coronary events (RR 43%) and coronary
revascularization procedures (RR 37%). Because there were too few events among those participants
with age as their only risk factor in this study, the effect of MEVACOR on outcomes could not be
adequately assessed in this subgroup.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
782535378253XX
5
Atherosclerosis
In the Canadian Coronary Atherosclerosis Intervention Trial (CCAIT), the effect of therapy with
lovastatin on coronary atherosclerosis was assessed by coronary angiography in hyperlipidemic patients.
In the randomized, double-blind, controlled clinical trial, patients were treated with conventional measures
(usually diet and 325 mg of aspirin every other day) and either lovastatin 20-80 mg daily or placebo.
Angiograms were evaluated at baseline and at two years by computerized quantitative coronary
angiography (QCA). Lovastatin significantly slowed the progression of lesions as measured by the mean
change per-patient in minimum lumen diameter (the primary endpoint) and percent diameter stenosis,
and decreased the proportions of patients categorized with disease progression (33% vs. 50%) and with
new lesions (16% vs. 32%).
In a similarly designed trial, the Monitored Atherosclerosis Regression Study (MARS), patients were
treated with diet and either lovastatin 80 mg daily or placebo. No statistically significant difference
between lovastatin and placebo was seen for the primary endpoint (mean change per patient in percent
diameter stenosis of all lesions), or for most secondary QCA endpoints. Visual assessment by
angiographers who formed a consensus opinion of overall angiographic change (Global Change Score)
was also a secondary endpoint. By this endpoint, significant slowing of disease was seen, with regression
in 23% of patients treated with lovastatin compared to 11% of placebo patients.
In the Familial Atherosclerosis Treatment Study (FATS), either lovastatin or niacin in combination with
a bile acid sequestrant for 2.5 years in hyperlipidemic subjects significantly reduced the frequency of
progression and increased the frequency of regression of coronary atherosclerotic lesions by QCA
compared to diet and, in some cases, low-dose resin.
The effect of lovastatin on the progression of atherosclerosis in the coronary arteries has been
corroborated by similar findings in another vasculature. In the Asymptomatic Carotid Artery Progression
Study (ACAPS), the effect of therapy with lovastatin on carotid atherosclerosis was assessed by B-mode
ultrasonography in hyperlipidemic patients with early carotid lesions and without known coronary heart
disease at baseline. In this double-blind, controlled clinical trial, 919 patients were randomized in a 2 x 2
factorial design to placebo, lovastatin 10-40 mg daily and/or warfarin. Ultrasonograms of the carotid walls
were used to determine the change per patient from baseline to three years in mean maximum intimal-
medial thickness (IMT) of 12 measured segments. There was a significant regression of carotid lesions in
patients receiving lovastatin alone compared to those receiving placebo alone (p=0.001). The predictive
value of changes in IMT for stroke has not yet been established. In the lovastatin group there was a
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
782535378253XX
6
significant reduction in the number of patients with major cardiovascular events relative to the placebo
group (5 vs. 14) and a significant reduction in all-cause mortality (1 vs. 8).
Eye
There was a high prevalence of baseline lenticular opacities in the patient population included in the
early clinical trials with lovastatin. During these trials the appearance of new opacities was noted in both
the lovastatin and placebo groups. There was no clinically significant change in visual acuity in the
patients who had new opacities reported nor was any patient, including those with opacities noted at
baseline, discontinued from therapy because of a decrease in visual acuity.
A three-year, double-blind, placebo-controlled study in hypercholesterolemic patients to assess the
effect of lovastatin on the human lens demonstrated that there were no clinically or statistically significant
differences between the lovastatin and placebo groups in the incidence, type or progression of lenticular
opacities. There are no controlled clinical data assessing the lens available for treatment beyond three
years.
Clinical Studies in Adolescent Patients
Efficacy of Lovastatin in Adolescent Boys with Heterozygous Familial Hypercholesterolemia
In a double-blind, placebo-controlled study, 132 boys 10-17 years of age (mean age 12.7 yrs) with
heterozygous familial hypercholesterolemia (heFH) were randomized to lovastatin (n=67) or placebo
(n=65) for 48 weeks. Inclusion in the study required a baseline LDL-C level between 189 and 500 mg/dL
and at least one parent with an LDL-C level >189 mg/dL. The mean baseline LDL-C value was
253.1 mg/dL (range: 171-379 mg/dL) in the MEVACOR group compared to 248.2 mg/dL (range:
158.5-413.5 mg/dL) in the placebo group. The dosage of lovastatin (once daily in the evening) was 10 mg
for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter.
MEVACOR significantly decreased plasma levels of total-C, LDL-C and apolipoprotein B (see
Table IV).
TABLE IV
Lipid-lowering Effects of Lovastatin in Adolescent Boys with Heterozygous Familial Hypercholesterolemia
(Mean Percent Change from Baseline at week 48 in Intention-to-Treat Population)
DOSAGE
N
TOTAL-C
LDL-C
HDL-C
TG.*
Apolipoprotein B
Placebo
61
-1.1
-1.4
-2.2
-1.4
-4.4
MEVACOR
64
-19.3
-24.2
+1.1
-1.9
-21
*data presented as median percent changes
The mean achieved LDL-C value was 190.9 mg/dL (range: 108-336 mg/dL) in the MEVACOR group
compared to 244.8 mg/dL (range: 135-404 mg/dL) in the placebo group.
Efficacy of Lovastatin in Post-menarchal Girls with Heterozygous Familial Hypercholesterolemia
In a double-blind, placebo-controlled study, 54 girls 10-17 years of age who were at least 1 year
post-menarche with heFH were randomized to lovastatin (n=35) or placebo (n=19) for 24 weeks.
Inclusion in the study required a baseline LDL-C level of 160-400 mg/dL and a parental history of familial
hypercholesterolemia. The mean baseline LDL-C value was 218.3 mg/dL (range: 136.3-363.7 mg/dL) in
the MEVACOR group compared to 198.8 mg/dL (range: 151.1-283.1 mg/dL) in the placebo group. The
dosage of lovastatin (once daily in the evening) was 20 mg for the first 4 weeks, and 40 mg thereafter.
MEVACOR significantly decreased plasma levels of total-C, LDL-C, and apolipoprotein B (see
Table V).
TABLE V
Lipid-lowering Effects of Lovastatin in Post-menarchal Girls with Heterozygous Familial Hypercholesterolemia
(Mean Percent Change from Baseline at Week 24 in Intention-to-Treat Population)
DOSAGE
N
TOTAL-C
LDL-C
HDL-C
TG.*
Apolipoprotein B
Placebo
18
+3.6
+2.5
+4.8
-3.0
+6.4
MEVACOR
35
-22.4
-29.2
+2.4
-22.7
-24.4
*data presented as median percent changes
The mean achieved LDL-C value was 154.5 mg/dL (range: 82-286 mg/dL) in the MEVACOR group
compared to 203.5 mg/dL (range: 135-304 mg/dL) in the placebo group.
The safety and efficacy of doses above 40 mg daily have not been studied in children. The long-term
efficacy of lovastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been
established.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
782535378253XX
7
INDICATIONS AND USAGE
Therapy with MEVACOR should be a component of multiple risk factor intervention in those
individuals with dyslipidemia at risk for atherosclerotic vascular disease. MEVACOR should be used in
addition to a diet restricted in saturated fat and cholesterol as part of a treatment strategy to lower total-C
and LDL-C to target levels when the response to diet and other nonpharmacological measures alone has
been inadequate to reduce risk.
Primary Prevention of Coronary Heart Disease
In individuals without symptomatic cardiovascular disease, average to moderately elevated total-C
and LDL-C, and below average HDL-C, MEVACOR is indicated to reduce the risk of:
- Myocardial infarction
- Unstable angina
- Coronary revascularization procedures
(See CLINICAL PHARMACOLOGY, Clinical Studies.)
Coronary Heart Disease
MEVACOR is indicated to slow the progression of coronary atherosclerosis in patients with coronary
heart disease as part of a treatment strategy to lower total-C and LDL-C to target levels.
Hypercholesterolemia
Therapy with lipid-altering agents should be a component of multiple risk factor intervention in those
individuals
at
significantly
increased
risk
for
atherosclerotic
vascular
disease
due
to
hypercholesterolemia. MEVACOR is indicated as an adjunct to diet for the reduction of elevated total-C
and LDL-C levels in patients with primary hypercholesterolemia (Types IIa and IIb***), when the response
to diet restricted in saturated fat and cholesterol and to other nonpharmacological measures alone has
been inadequate.
Adolescent Patients with Heterozygous Familial Hypercholesterolemia
MEVACOR is indicated as an adjunct to diet to reduce total-C, LDL-C and apolipoprotein B levels in
adolescent boys and girls who are at least one year post-menarche, 10-17 years of age, with heFH if
after an adequate trial of diet therapy the following findings are present:
1. LDL-C remains >189 mg/dL or
2. LDL-C remains >160 mg/dL and:
•
there is a positive family history of premature cardiovascular disease or
•
two or more other CVD risk factors are present in the adolescent patient
General Recommendations
Prior to initiating therapy with lovastatin, secondary causes for hypercholesterolemia (e.g., poorly
controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver
disease, other drug therapy, alcoholism) should be excluded, and a lipid profile performed to measure
total-C, HDL-C, and TG. For patients with TG less than 400 mg/dL (<4.5 mmol/L), LDL-C can be
estimated using the following equation:
LDL-C = total-C – [0.2 × (TG) + HDL-C]
For TG levels >400 mg/dL (>4.5 mmol/L), this equation is less accurate and LDL-C concentrations
should be determined by ultracentrifugation. In hypertriglyceridemic patients, LDL-C may be low or
normal despite elevated total-C. In such cases, MEVACOR is not indicated.
The National Cholesterol Education Program (NCEP) Treatment Guidelines are summarized below:
*** Classification of Hyperlipoproteinemias
Lipid
Lipoproteins
Elevations
Type
elevated
major
minor
I
chylomicrons
TG
↑→C
IIa
LDL
C
—
IIb
LDL, VLDL
C
TG
III (rare)
IDL
C/TG
—
IV
VLDL
TG
↑→C
V (rare)
chylomicrons, VLDL
TG
↑→C
IDL = intermediate-density lipoprotein.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
782535378253XX
8
NCEP Treatment Guidelines:
LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes
and Drug Therapy in Different Risk Categories
Risk Category
LDL Goal
(mg/dL)
LDL Level at Which to
Initiate Therapeutic Lifestyle Changes
(mg/dL)
LDL Level at Which to
Consider Drug Therapy
(mg/dL)
CHD† or CHD risk equivalents
(10-year risk >20%)
2+ Risk factors
(10 year risk ≤20%)
0-1 Risk factor†††
<100
<130
<160
≥100
≥130
≥160
≥130
(100-129: drug optional)††
10-year risk 10-20%: ≥130
10-year risk <10%: ≥ 160
≥190
(160-189: LDL-lowering drug
optional)
†
CHD, coronary heart disease
††
Some authorities recommend use of LDL-lowering drugs in this category if an LDL-C level of <100 mg/dL cannot be achieved by therapeutic
lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL-C, e.g., nicotinic acid or fibrate. Clinical judgment also
may call for deferring drug therapy in this subcategory.
†††
Almost all people with 0-1 risk factor have a 10-year risk <10%; thus, 10-year risk assessment in people with 0-1 risk factor is not necessary.
After the LDL-C goal has been achieved, if the TG is still ≥200 mg/dL, non-HDL-C (total-C minus HDL-
C) becomes a secondary target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals
for each risk category.
At the time of hospitalization for an acute coronary event, consideration can be given to initiating drug
therapy at discharge if the LDL-C is ≥130 mg/dL (see NCEP Guidelines above).
Since the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C levels be used to
initiate and assess treatment response. Only if LDL-C levels are not available, should the total-C be used
to monitor therapy.
Although MEVACOR may be useful to reduce elevated LDL-C levels in patients with combined
hypercholesterolemia and hypertriglyceridemia where hypercholesterolemia is the major abnormality
(Type IIb hyperlipoproteinemia), it has not been studied in conditions where the major abnormality is
elevation of chylomicrons, VLDL or IDL (i.e., hyperlipoproteinemia types I, III, IV, or V).***
The NCEP classification of cholesterol levels in pediatric patients with a familial history of
hypercholesterolemia or premature cardiovascular disease is summarized below:
Category
Total-C (mg/dL)
LDL-C (mg/dL)
Acceptable
Borderline
High
<170
170-199
≥200
<110
110-129
≥130
Children treated with lovastatin in adolescence should be re-evaluated in adulthood and appropriate
changes made to their cholesterol-lowering regimen to achieve adult goals for LDL-C.
CONTRAINDICATIONS
Hypersensitivity to any component of this medication.
Active liver disease or unexplained persistent elevations of serum transaminases (see WARNINGS).
Pregnancy and lactation. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering
drugs during pregnancy should have little impact on the outcome of long-term therapy of primary
hypercholesterolemia. Moreover, cholesterol and other products of the cholesterol biosynthesis pathway
are essential components for fetal development, including synthesis of steroids and cell membranes.
Because of the ability of inhibitors of HMG-CoA reductase such as MEVACOR to decrease the synthesis
of cholesterol and possibly other products of the cholesterol biosynthesis pathway, MEVACOR is
contraindicated during pregnancy and in nursing mothers. MEVACOR should be administered to
women of childbearing age only when such patients are highly unlikely to conceive. If the patient
becomes pregnant while taking this drug, MEVACOR should be discontinued immediately and the patient
should be apprised of the potential hazard to the fetus (see PRECAUTIONS, Pregnancy).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
782535378253XX
9
WARNINGS
Myopathy/Rhabdomyolysis
Lovastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as
muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal
(ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure
secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high
levels of HMG-CoA reductase inhibitory activity in plasma.
As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose
related. In a clinical study (EXCEL) in which patients were carefully monitored and some interacting
drugs were excluded, there was one case of myopathy among 4933 patients randomized to lovastatin 20-
40 mg daily for 48 weeks, and 4 among 1649 patients randomized to 80 mg daily.
All patients starting therapy with lovastatin, or whose dose of lovastatin is being increased,
should be advised of the risk of myopathy and told to report promptly any unexplained muscle
pain, tenderness or weakness. Lovastatin therapy should be discontinued immediately if
myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved
when treatment was promptly discontinued. Periodic CK determinations may be considered in patients
starting therapy with lovastatin or whose dose is being increased, but there is no assurance that such
monitoring will prevent myopathy.
Many of the patients who have developed rhabdomyolysis on therapy with lovastatin have had
complicated medical histories, including renal insufficiency usually as a consequence of long-standing
diabetes mellitus. Such patients merit closer monitoring. Therapy with lovastatin should be temporarily
stopped a few days prior to elective major surgery and when any major medical or surgical condition
supervenes.
The risk of myopathy/rhabdomyolysis is increased by concomitant use of lovastatin with the
following:
Potent inhibitors of CYP3A4: Lovastatin, like several other inhibitors of HMG-CoA reductase, is a
substrate of cytochrome P450 3A4 (CYP3A4). When lovastatin is used with a potent inhibitor of
CYP3A4, elevated plasma levels of HMG-CoA reductase inhibitory activity can increase the risk of
myopathy and rhabdomyolysis, particularly with higher doses of lovastatin.
The use of lovastatin concomitantly with the potent CYP3A4 inhibitors itraconazole,
ketoconazole,
erythromycin,
clarithromycin,
telithromycin,
HIV
protease
inhibitors,
nefazodone, or large quantities of grapefruit juice (>1 quart daily) should be avoided.
Concomitant use of other medicines labeled as having a potent inhibitory effect on CYP3A4 should
be avoided unless the benefits of combined therapy outweigh the increased risk. If treatment with
itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with
lovastatin should be suspended during the course of treatment.
Gemfibrozil, particularly with higher doses of lovastatin: The dose of lovastatin should not
exceed 20 mg daily in patients receiving concomitant medication with gemfibrozil. The
combined use of lovastatin with gemfibrozil should be avoided, unless the benefits are likely
to outweigh the increased risks of this drug combination.
Other lipid-lowering drugs (other fibrates or ≥1 g/day of niacin): The dose of lovastatin should
not exceed 20 mg daily in patients receiving concomitant medication with other fibrates or
≥1 g/day of niacin. Caution should be used when prescribing other fibrates or lipid-lowering doses
(≥1 g/day) of niacin with lovastatin, as these agents can cause myopathy when given alone. The
benefit of further alterations in lipid levels by the combined use of lovastatin with other
fibrates or niacin should be carefully weighed against the potential risks of these
combinations.
Cyclosporine or danazol, with higher doses of lovastatin: The dose of lovastatin should not
exceed 20 mg daily in patients receiving concomitant medication with cyclosporine or
danazol. The benefits of the use of lovastatin in patients receiving cyclosporine or danazol should be
carefully weighed against the risks of these combinations.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
782535378253XX
10
Amiodarone or verapamil: The dose of lovastatin should not exceed 40 mg daily in patients
receiving concomitant medication with amiodarone or verapamil. The combined use of
lovastatin at doses higher than 40 mg daily with amiodarone or verapamil should be avoided unless
the clinical benefit is likely to outweigh the increased risk of myopathy. The risk of
myopathy/rhabdomyolysis is increased when either amiodarone or verapamil is used concomitantly
with higher doses of a closely related member of the HMG-CoA reductase inhibitor class.
Prescribing recommendations for interacting agents are summarized in Table VI (see also CLINICAL
PHARMACOLOGY,
Pharmacokinetics;
PRECAUTIONS,
Drug
Interactions;
DOSAGE
AND
ADMINISTRATION).
Table VI
Drug Interactions Associated with Increased
Risk of Myopathy/Rhabdomyolysis
Interacting Agents
Prescribing Recommendations
Itraconazole
Ketoconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors
Nefazodone
Avoid lovastatin
Gemfibrozil
Other fibrates
Lipid-lowering doses (≥1 g/day)
of niacin
Cyclosporine
Danazol
Do not exceed 20 mg lovastatin daily
Amiodarone
Verapamil
Do not exceed 40 mg lovastatin daily
Grapefruit juice
Avoid large quantities of grapefruit juice
(>1 quart daily)
Liver Dysfunction
Persistent increases (to more than 3 times the upper limit of normal) in serum transaminases
occurred in 1.9% of adult patients who received lovastatin for at least one year in early clinical
trials (see ADVERSE REACTIONS). When the drug was interrupted or discontinued in these patients,
the transaminase levels usually fell slowly to pretreatment levels. The increases usually appeared 3 to 12
months after the start of therapy with lovastatin, and were not associated with jaundice or other clinical
signs or symptoms. There was no evidence of hypersensitivity. In the EXCEL study (see CLINICAL
PHARMACOLOGY, Clinical Studies), the incidence of persistent increases in serum transaminases over
48 weeks was 0.1% for placebo, 0.1% at 20 mg/day, 0.9% at 40 mg/day, and 1.5% at 80 mg/day in
patients on lovastatin. However, in post-marketing experience with MEVACOR, symptomatic liver disease
has been reported rarely at all dosages (see ADVERSE REACTIONS).
In AFCAPS/TexCAPS, the number of participants with consecutive elevations of either alanine
aminotransferase (ALT) or aspartate aminotransferase (AST) (> 3 times the upper limit of normal), over a
median of 5.1 years of follow-up, was not significantly different between the MEVACOR and placebo
groups (18 [0.6%] vs. 11 [0.3%]). The starting dose of MEVACOR was 20 mg/day; 50% of the MEVACOR
treated participants were titrated to 40 mg/day at Week 18. Of the 18 participants on MEVACOR with
consecutive elevations of either ALT or AST, 11 (0.7%) elevations occurred in participants taking 20
mg/day, while 7 (0.4%) elevations occurred in participants titrated to 40 mg/day. Elevated transaminases
resulted in discontinuation of 6 (0.2%) participants from therapy in the MEVACOR group (n=3,304) and 4
(0.1%) in the placebo group (n=3,301).
It is recommended that liver function tests be performed prior to initiation of therapy in patients with a
history of liver disease, or when otherwise clinically indicated. It is recommended that liver function tests
be performed in all patients prior to use of 40 mg or more daily and thereafter when clinically indicated.
Patients who develop increased transaminase levels should be monitored with a second liver function
evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the
abnormality(ies) returns to normal. Should an increase in AST or ALT of three times the upper limit of
normal or greater persist, withdrawal of therapy with MEVACOR is recommended.
The drug should be used with caution in patients who consume substantial quantities of alcohol and/or
have a past history of liver disease. Active liver disease or unexplained transaminase elevations are
contraindications to the use of lovastatin.
As with other lipid-lowering agents, moderate (less than three times the upper limit of normal)
elevations of serum transaminases have been reported following therapy with MEVACOR (see
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
782535378253XX
11
ADVERSE REACTIONS). These changes appeared soon after initiation of therapy with MEVACOR, were
often transient, were not accompanied by any symptoms and interruption of treatment was not required.
PRECAUTIONS
General
Lovastatin may elevate creatine phosphokinase and transaminase levels (see WARNINGS and
ADVERSE REACTIONS). This should be considered in the differential diagnosis of chest pain in a patient
on therapy with lovastatin.
Homozygous Familial Hypercholesterolemia
MEVACOR is less effective in patients with the rare homozygous familial hypercholesterolemia,
possibly because these patients have no functional LDL receptors. MEVACOR appears to be more likely
to raise serum transaminases (see ADVERSE REACTIONS) in these homozygous patients.
Information for Patients
Patients should be advised about substances they should not take concomitantly with
lovastatin and be advised to report promptly unexplained muscle pain, tenderness, or weakness
(see list below and WARNINGS, Myopathy/Rhabdomyolysis). Patients should also be advised to
inform other physicians prescribing a new medication that they are taking MEVACOR.
Drug Interactions
CYP3A4 Interactions
Lovastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not
expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. Potent inhibitors of
CYP3A4 (below) increase the risk of myopathy by reducing the elimination of lovastatin.
See
WARNINGS,
Myopathy/Rhabdomyolysis,
and
CLINICAL
PHARMACOLOGY,
Pharmacokinetics.
Itraconazole
Ketoconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors
Nefazodone
Large quantities of grapefruit juice (>1 quart daily)
Interactions with lipid-lowering drugs that can cause myopathy when given alone
The risk of myopathy is also increased by the following lipid-lowering drugs that are not potent
CYP3A4 inhibitors, but which can cause myopathy when given alone.
See WARNINGS, Myopathy/Rhabdomyolysis.
Gemfibrozil
Other fibrates
Niacin (nicotinic acid) (≥1 g/day)
Other drug interactions
Cyclosporine or Danazol: The risk of myopathy/rhabdomyolysis is increased by concomitant
administration of cyclosporine or danazol particularly with higher doses of lovastatin (see WARNINGS,
Myopathy/Rhabdomyolysis; CLINICAL PHARMACOLOGY, Pharmacokinetics).
Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased when either amiodarone
or verapamil is used concomitantly with a closely related member of the HMG-CoA reductase inhibitor
class (see WARNINGS, Myopathy/Rhabdomyolysis).
Coumarin Anticoagulants: In a small clinical trial in which lovastatin was administered to warfarin
treated patients, no effect on prothrombin time was detected. However, another HMG-CoA reductase
inhibitor has been found to produce a less than two-second increase in prothrombin time in healthy
volunteers receiving low doses of warfarin. Also, bleeding and/or increased prothrombin time have been
reported in a few patients taking coumarin anticoagulants concomitantly with lovastatin. It is
recommended that in patients taking anticoagulants, prothrombin time be determined before starting
lovastatin and frequently enough during early therapy to insure that no significant alteration of
prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
782535378253XX
12
be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose
of lovastatin is changed, the same procedure should be repeated. Lovastatin therapy has not been
associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
Propranolol: In normal volunteers, there was no clinically significant pharmacokinetic or
pharmacodynamic interaction with concomitant administration of single doses of lovastatin and
propranolol.
Digoxin: In patients with hypercholesterolemia, concomitant administration of lovastatin and digoxin
resulted in no effect on digoxin plasma concentrations.
Oral Hypoglycemic Agents: In pharmacokinetic studies of MEVACOR in hypercholesterolemic non-
insulin dependent diabetic patients, there was no drug interaction with glipizide or with chlorpropamide
(see CLINICAL PHARMACOLOGY, Clinical Studies).
Endocrine Function
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically
blunt adrenal and/or gonadal steroid production. Results of clinical trials with drugs in this class have
been inconsistent with regard to drug effects on basal and reserve steroid levels. However, clinical
studies have shown that lovastatin does not reduce basal plasma cortisol concentration or impair adrenal
reserve, and does not reduce basal plasma testosterone concentration. Another HMG-CoA reductase
inhibitor has been shown to reduce the plasma testosterone response to HCG. In the same study, the
mean testosterone response to HCG was slightly but not significantly reduced after treatment with
lovastatin 40 mg daily for 16 weeks in 21 men. The effects of HMG-CoA reductase inhibitors on male
fertility have not been studied in adequate numbers of male patients. The effects, if any, on the pituitary-
gonadal axis in pre-menopausal women are unknown. Patients treated with lovastatin who develop
clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be
exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is
administered to patients also receiving other drugs (e.g., ketoconazole, spironolactone, cimetidine) that
may decrease the levels or activity of endogenous steroid hormones.
CNS Toxicity
Lovastatin produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in
clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean
plasma drug levels about 30 times higher than the mean drug level in humans taking the highest
recommended dose (as measured by total enzyme inhibitory activity). Vestibulocochlear Wallerian-like
degeneration and retinal ganglion cell chromatolysis were also seen in dogs treated for 14 weeks at 180
mg/kg/day, a dose which resulted in a mean plasma drug level (Cmax) similar to that seen with the 60
mg/kg/day dose.
CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell
infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels, were seen in
dogs treated with lovastatin at a dose of 180 mg/kg/day, a dose which produced plasma drug levels
(Cmax) which were about 30 times higher than the mean values in humans taking 80 mg/day.
Similar optic nerve and CNS vascular lesions have been observed with other drugs of this class.
Cataracts were seen in dogs treated for 11 and 28 weeks at 180 mg/kg/day and 1 year at
60 mg/kg/day.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 21-month carcinogenic study in mice, there was a statistically significant increase in the incidence
of hepatocellular carcinomas and adenomas in both males and females at 500 mg/kg/day. This dose
produced a total plasma drug exposure 3 to 4 times that of humans given the highest recommended dose
of lovastatin (drug exposure was measured as total HMG-CoA reductase inhibitory activity in extracted
plasma). Tumor increases were not seen at 20 and 100 mg/kg/day, doses that produced drug exposures
of 0.3 to 2 times that of humans at the 80 mg/day dose. A statistically significant increase in pulmonary
adenomas was seen in female mice at approximately 4 times the human drug exposure. (Although mice
were given 300 times the human dose [HD] on a mg/kg body weight basis, plasma levels of total
inhibitory activity were only 4 times higher in mice than in humans given 80 mg of MEVACOR.)
There was an increase in incidence of papilloma in the non-glandular mucosa of the stomach of mice
beginning at exposures of 1 to 2 times that of humans. The glandular mucosa was not affected. The
human stomach contains only glandular mucosa.
In a 24-month carcinogenicity study in rats, there was a positive dose response relationship for
hepatocellular carcinogenicity in males at drug exposures between 2-7 times that of human exposure at
80 mg/day (doses in rats were 5, 30 and 180 mg/kg/day).
An increased incidence of thyroid neoplasms in rats appears to be a response that has been seen
with other HMG-CoA reductase inhibitors.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
782535378253XX
13
A chemically similar drug in this class was administered to mice for 72 weeks at 25, 100, and
400 mg/kg body weight, which resulted in mean serum drug levels approximately 3, 15, and 33 times
higher than the mean human serum drug concentration (as total inhibitory activity) after a 40 mg oral
dose. Liver carcinomas were significantly increased in high dose females and mid- and high dose males,
with a maximum incidence of 90 percent in males. The incidence of adenomas of the liver was
significantly increased in mid- and high dose females. Drug treatment also significantly increased the
incidence of lung adenomas in mid- and high dose males and females. Adenomas of the Harderian gland
(a gland of the eye of rodents) were significantly higher in high dose mice than in controls.
No evidence of mutagenicity was observed in a microbial mutagen test using mutant strains of
Salmonella typhimurium with or without rat or mouse liver metabolic activation. In addition, no evidence of
damage to genetic material was noted in an in vitro alkaline elution assay using rat or mouse
hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in
CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow.
Drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant
cell formation were seen in dogs starting at 20 mg/kg/day. Similar findings were seen with another drug in
this class. No drug-related effects on fertility were found in studies with lovastatin in rats. However, in
studies with a similar drug in this class, there was decreased fertility in male rats treated for 34 weeks at
25 mg/kg body weight, although this effect was not observed in a subsequent fertility study when this
same dose was administered for 11 weeks (the entire cycle of spermatogenesis, including epididymal
maturation). In rats treated with this same reductase inhibitor at 180 mg/kg/day, seminiferous tubule
degeneration (necrosis and loss of spermatogenic epithelium) was observed. No microscopic changes
were observed in the testes from rats of either study. The clinical significance of these findings is unclear.
Pregnancy
Pregnancy Category X
See CONTRAINDICATIONS.
Safety in pregnant women has not been established.
Lovastatin has been shown to produce skeletal malformations at plasma levels 40 times the human
exposure (for mouse fetus) and 80 times the human exposure (for rat fetus) based on mg/m2 surface
area (doses were 800 mg/kg/day). No drug-induced changes were seen in either species at multiples of 8
times (rat) or 4 times (mouse) based on surface area. No evidence of malformations was noted in rabbits
at exposures up to 3 times the human exposure (dose of 15 mg/kg/day, highest tolerated dose).
Rare reports of congenital anomalies have been received following intrauterine exposure to HMG-CoA
reductase inhibitors. In a review† of approximately 100 prospectively followed pregnancies in women
exposed to MEVACOR or another structurally related HMG-CoA reductase inhibitor, the incidences of
congenital anomalies, spontaneous abortions and fetal deaths/stillbirths did not exceed what would be
expected in the general population. The number of cases is adequate only to exclude a 3 to 4-fold
increase in congenital anomalies over the background incidence. In 89% of the prospectively followed
pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the
first trimester when pregnancy was identified. As safety in pregnant women has not been established and
there is no apparent benefit to therapy with MEVACOR during pregnancy (see CONTRAINDICATIONS),
treatment should be immediately discontinued as soon as pregnancy is recognized. MEVACOR should
be administered to women of child-bearing potential only when such patients are highly unlikely to
conceive and have been informed of the potential hazards.
Nursing Mothers
It is not known whether lovastatin is excreted in human milk. Because a small amount of another drug
in this class is excreted in human breast milk and because of the potential for serious adverse reactions
in nursing infants, women taking MEVACOR should not nurse their infants (see CONTRAINDICATIONS).
Pediatric Use
Safety and effectiveness in patients 10-17 years of age with heFH have been evaluated in controlled
clinical trials of 48 weeks duration in adolescent boys and controlled clinical trials of 24 weeks duration in
girls who were at least 1 year post-menarche. Patients treated with lovastatin had an adverse experience
profile generally similar to that of patients treated with placebo. Doses greater than 40 mg have not
been studied in this population. In these limited controlled studies, there was no detectable effect on
growth or sexual maturation in the adolescent boys or on menstrual cycle length in girls. See CLINICAL
PHARMACOLOGY, Clinical Studies in Adolescent Patients; ADVERSE REACTIONS, Adolescent
Patients; and DOSAGE AND ADMINISTRATION, Adolescent Patients (10-17 years of age) with
† Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During
Pregnancy. Reproductive Toxicology. 10(6):439-446. 1996.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
782535378253XX
14
Heterozygous Familial Hypercholesterolemia. Adolescent females should be counseled on appropriate
contraceptive methods while on lovastatin therapy (see CONTRAINDICATIONS and PRECAUTIONS,
Pregnancy). Lovastatin has not been studied in pre-pubertal patients or patients younger than
10 years of age.
Geriatric Use
A pharmacokinetic study with lovastatin showed the mean plasma level of HMG-CoA reductase
inhibitory activity to be approximately 45% higher in elderly patients between 70-78 years of age
compared with patients between 18-30 years of age; however, clinical study experience in the elderly
indicates that dosage adjustment based on this age-related pharmacokinetic difference is not needed. In
the two large clinical studies conducted with lovastatin (EXCEL and AFCAPS/TexCAPS), 21%
(3094/14850) of patients were ≥65 years of age. Lipid-lowering efficacy with lovastatin was at least as
great in elderly patients compared with younger patients, and there were no overall differences in safety
over the 20 to 80 mg/day dosage range (see CLINICAL PHARMACOLOGY).
ADVERSE REACTIONS
MEVACOR is generally well tolerated; adverse reactions usually have been mild and transient.
Phase III Clinical Studies
In Phase III controlled clinical studies involving 613 patients treated with MEVACOR, the adverse
experience profile was similar to that shown below for the 8,245-patient EXCEL study (see Expanded
Clinical Evaluation of Lovastatin [EXCEL] Study).
Persistent increases of serum transaminases have been noted (see WARNINGS, Liver Dysfunction).
About 11% of patients had elevations of CK levels of at least twice the normal value on one or more
occasions. The corresponding values for the control agent cholestyramine was 9 percent. This was
attributable to the noncardiac fraction of CK. Large increases in CK have sometimes been reported (see
WARNINGS, Myopathy/Rhabdomyolysis).
Expanded Clinical Evaluation of Lovastatin (EXCEL) Study
MEVACOR was compared to placebo in 8,245 patients with hypercholesterolemia (total-C 240-300
mg/dL [6.2-7.8 mmol/L]) in the randomized, double-blind, parallel, 48-week EXCEL study. Clinical
adverse experiences reported as possibly, probably or definitely drug-related in ≥1% in any treatment
group are shown in the table below. For no event was the incidence on drug and placebo statistically
different.
Placebo
(N = 1663)
%
MEVACOR
20 mg q.p.m.
(N = 1642)
%
MEVACOR
40 mg q.p.m.
(N = 1645)
%
MEVACOR
20 mg b.i.d.
(N = 1646)
%
MEVACOR
40 mg b.i.d.
(N = 1649)
%
Body As a Whole
Asthenia
1.4
1.7
1.4
1.5
1.2
Gastrointestinal
Abdominal pain
Constipation
Diarrhea
Dyspepsia
Flatulence
Nausea
1.6
1.9
2.3
1.9
4.2
2.5
2.0
2.0
2.6
1.3
3.7
1.9
2.0
3.2
2.4
1.3
4.3
2.5
2.2
3.2
2.2
1.0
3.9
2.2
2.5
3.5
2.6
1.6
4.5
2.2
Musculoskeletal
Muscle cramps
Myalgia
0.5
1.7
0.6
2.6
0.8
1.8
1.1
2.2
1.0
3.0
Nervous System/
Psychiatric
Dizziness
Headache
0.7
2.7
0.7
2.6
1.2
2.8
0.5
2.1
0.5
3.2
Skin
Rash
0.7
0.8
1.0
1.2
1.3
Special Senses
Blurred vision
0.8
1.1
0.9
0.9
1.2
Other clinical adverse experiences reported as possibly, probably or definitely drug-related in 0.5 to
1.0 percent of patients in any drug-treated group are listed below. In all these cases the incidence on
drug and placebo was not statistically different. Body as a Whole: chest pain; Gastrointestinal: acid
regurgitation, dry mouth, vomiting; Musculoskeletal: leg pain, shoulder pain, arthralgia; Nervous
System/Psychiatric: insomnia, paresthesia; Skin: alopecia, pruritus; Special Senses: eye irritation.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
782535378253XX
15
In the EXCEL study (see CLINICAL PHARMACOLOGY, Clinical Studies), 4.6% of the patients treated
up to 48 weeks were discontinued due to clinical or laboratory adverse experiences which were rated by
the investigator as possibly, probably or definitely related to therapy with MEVACOR. The value for the
placebo group was 2.5%.
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
In AFCAPS/TexCAPS (see CLINICAL PHARMACOLOGY, Clinical Studies) involving 6,605
participants treated with 20-40 mg/day of MEVACOR (n=3,304) or placebo (n=3,301), the safety and
tolerability profile of the group treated with MEVACOR was comparable to that of the group treated with
placebo during a median of 5.1 years of follow-up. The adverse experiences reported in
AFCAPS/TexCAPS were similar to those reported in EXCEL (see ADVERSE REACTIONS, Expanded
Clinical Evaluation of Lovastatin (EXCEL) Study).
Concomitant Therapy
In controlled clinical studies in which lovastatin was administered concomitantly with cholestyramine,
no adverse reactions peculiar to this concomitant treatment were observed. The adverse reactions that
occurred were limited to those reported previously with lovastatin or cholestyramine. Other lipid-lowering
agents were not administered concomitantly with lovastatin during controlled clinical studies. Preliminary
data suggests that the addition of gemfibrozil to therapy with lovastatin is not associated with greater
reduction in LDL-C than that achieved with lovastatin alone. In uncontrolled clinical studies, most of the
patients who have developed myopathy were receiving concomitant therapy with cyclosporine,
gemfibrozil or niacin (nicotinic acid). The combined use of lovastatin at doses exceeding 20 mg/day with
cyclosporine, gemfibrozil, other fibrates or lipid-lowering doses (≥1 g/day) of niacin should be avoided
(see WARNINGS, Myopathy/Rhabdomyolysis).
The following effects have been reported with drugs in this class. Not all the effects listed below have
necessarily been associated with lovastatin therapy.
Skeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias.
Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-
ocular movement, facial paresis), tremor, dizziness, vertigo, memory loss, paresthesia, peripheral
neuropathy, peripheral nerve palsy, psychic disturbances, anxiety, insomnia, depression.
Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which
has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like
syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia,
hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia,
photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme,
including Stevens-Johnson syndrome.
Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty
change in liver; and rarely, cirrhosis, fulminant hepatic necrosis, and hepatoma; anorexia, vomiting.
Skin: alopecia, pruritus. A variety of skin changes (e.g., nodules, discoloration, dryness of
skin/mucous membranes, changes to hair/nails) have been reported.
Reproductive: gynecomastia, loss of libido, erectile dysfunction.
Eye: progression of cataracts (lens opacities), ophthalmoplegia.
Laboratory Abnormalities: elevated transaminases, alkaline phosphatase, γ-glutamyl transpeptidase,
and bilirubin; thyroid function abnormalities.
Adolescent Patients (ages 10-17 years)
In a 48-week controlled study in adolescent boys with heFH (n=132) and a 24-week controlled study
in girls who were at least 1 year post-menarche with heFH (n=54), the safety and tolerability profile of the
groups treated with MEVACOR (10 to 40 mg daily) was generally similar to that of the groups treated with
placebo (see CLINICAL PHARMACOLOGY, Clinical Studies in Adolescent Patients and PRECAUTIONS,
Pediatric Use).
OVERDOSAGE
After oral administration of MEVACOR to mice, the median lethal dose observed was >15 g/m2.
Five healthy human volunteers have received up to 200 mg of lovastatin as a single dose without
clinically significant adverse experiences. A few cases of accidental overdosage have been reported; no
patients had any specific symptoms, and all patients recovered without sequelae. The maximum dose
taken was 5-6 g.
Until further experience is obtained, no specific treatment of overdosage with MEVACOR can be
recommended.
The dialyzability of lovastatin and its metabolites in man is not known at present.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
782535378253XX
16
DOSAGE AND ADMINISTRATION
The patient should be placed on a standard cholesterol-lowering diet before receiving MEVACOR and
should continue on this diet during treatment with MEVACOR (see NCEP Treatment Guidelines for
details on dietary therapy). MEVACOR should be given with meals.
Adult Patients
The usual recommended starting dose is 20 mg once a day given with the evening meal. The
recommended dosing range is 10-80 mg/day in single or two divided doses; the maximum recommended
dose is 80 mg/day. Doses should be individualized according to the recommended goal of therapy (see
NCEP Guidelines and CLINICAL PHARMACOLOGY). Patients requiring reductions in LDL-C of 20% or
more to achieve their goal (see INDICATIONS AND USAGE) should be started on 20 mg/day of
MEVACOR. A starting dose of 10 mg may be considered for patients requiring smaller reductions.
Adjustments should be made at intervals of 4 weeks or more.
Cholesterol levels should be monitored periodically and consideration should be given to reducing the
dosage of MEVACOR if cholesterol levels fall significantly below the targeted range.
Dosage in Patients taking Cyclosporine or Danazol
In patients taking cyclosporine or danazol concomitantly with lovastatin (see WARNINGS,
Myopathy/Rhabdomyolysis), therapy should begin with 10 mg of MEVACOR and should not exceed
20 mg/day.
Dosage in Patients taking Amiodarone or Verapamil
In patients taking amiodarone or verapamil concomitantly with MEVACOR, the dose should not
exceed 40 mg/day (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions,
Other drug interactions).
Adolescent Patients (10-17 years of age) with Heterozygous Familial Hypercholesterolemia
The recommended dosing range is 10-40 mg/day; the maximum recommended dose is 40 mg/day.
Doses should be individualized according to the recommended goal of therapy (see NCEP Pediatric
Panel Guidelines††, CLINICAL PHARMACOLOGY, and INDICATIONS AND USAGE). Patients requiring
reductions in LDL-C of 20% or more to achieve their goal should be started on 20 mg/day of MEVACOR.
A starting dose of 10 mg may be considered for patients requiring smaller reductions. Adjustments should
be made at intervals of 4 weeks or more.
Concomitant Lipid-Lowering Therapy
MEVACOR is effective alone or when used concomitantly with bile-acid sequestrants. If MEVACOR is
used in combination with gemfibrozil, other fibrates or lipid-lowering doses (≥ 1g/day) of niacin, the dose
of MEVACOR should not exceed 20 mg/day (see WARNINGS, Myopathy/Rhabdomyolysis and
PRECAUTIONS, Drug Interactions).
Dosage in Patients with Renal Insufficiency
In patients with severe renal insufficiency (creatinine clearance <30 mL/min), dosage increases above
20 mg/day should be carefully considered and, if deemed necessary, implemented cautiously (see
CLINICAL PHARMACOLOGY and WARNINGS, Myopathy/Rhabdomyolysis).
HOW SUPPLIED
No. 3560 — Tablets MEVACOR 10 mg are peach, octagonal tablets, coded MSD 730 on one side and
MEVACOR on the other. They are supplied as follows:
NDC 0006-0730-61 unit of use bottles of 60.
No. 3561 — Tablets MEVACOR 20 mg are light blue, octagonal tablets, coded MSD 731 on one side
and MEVACOR on the other. They are supplied as follows:
NDC 0006-0731-61 unit of use bottles of 60
NDC 0006-0731-94 unit of use bottles of 90
NDC 0006-0731-28 unit dose packages of 100
NDC 0006-0731-82 bottles of 1,000
NDC 0006-0731-87 bottles of 10,000.
No. 3562 — Tablets MEVACOR 40 mg are green, octagonal tablets, coded MSD 732 on one side and
MEVACOR on the other. They are supplied as follows:
NDC 0006-0732-61 unit of use bottles of 60
NDC 0006-0732-94 unit of use bottles of 90
NDC 0006-0732-82 bottles of 1,000
†† National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and
Adolescents. Pediatrics. 89(3):495-501. 1992.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR (Lovastatin)
782535378253XX
17
NDC 0006-0732-87 bottles of 10,000.
Storage
Store between 5-30°C (41-86°F). Tablets MEVACOR must be protected from light and stored in a
well-closed, light-resistant container.
Issued April 2005
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:36.077470
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/019643s076lbl.pdf', 'application_number': 19643, 'submission_type': 'SUPPL ', 'submission_number': 76}
|
11,589
|
company logo
9844661
014-874-01
TABLETS
MEVACOR®
(LOVASTATIN)
DESCRIPTION
MEVACOR* (Lovastatin) is a cholesterol lowering agent isolated from a strain of Aspergillus terreus.
After oral ingestion, lovastatin, which is an inactive lactone, is hydrolyzed to the corresponding β
hydroxyacid form. This is a principal metabolite and an inhibitor of 3-hydroxy-3-methylglutaryl
coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate,
which is an early and rate limiting step in the biosynthesis of cholesterol.
Lovastatin
is
[1S-[1α(R*),3α,7β,8β(2S*,4S*),
8aβ]]-1,2,3,7,
8,8a-hexahydro-3,7-dimethyl-8-[2
(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl
2-methylbutanoate.
The
empirical
formula of lovastatin is C24H36O5 and its molecular weight is 404.55. Its structural formula is: structural formula
Lovastatin is a white, nonhygroscopic crystalline powder that is insoluble in water and sparingly
soluble in ethanol, methanol, and acetonitrile.
Tablets MEVACOR are supplied as 20 mg and 40 mg tablets for oral administration. In addition to the
active ingredient lovastatin, each tablet contains the following inactive ingredients: cellulose, lactose,
magnesium stearate, and starch. Butylated hydroxyanisole (BHA) is added as a preservative. Tablets
MEVACOR 20 mg also contain FD&C Blue 2 aluminum lake. Tablets MEVACOR 40 mg also contain
D&C Yellow 10 aluminum lake and FD&C Blue 2 aluminum lake.
CLINICAL PHARMACOLOGY
The involvement of low-density lipoprotein cholesterol (LDL-C) in atherogenesis has been well-
documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological
and clinical studies have established that high LDL-C and low high-density lipoprotein cholesterol (HDL
C) are both associated with coronary heart disease. However, the risk of developing coronary heart
disease is continuous and graded over the range of cholesterol levels and many coronary events do
occur in patients with total cholesterol (total-C) and LDL-C in the lower end of this range.
MEVACOR has been shown to reduce both normal and elevated LDL-C concentrations. LDL is
formed from very low-density lipoprotein (VLDL) and is catabolized predominantly by the high affinity LDL
receptor. The mechanism of the LDL-lowering effect of MEVACOR may involve both reduction of VLDL-C
concentration, and induction of the LDL receptor, leading to reduced production and/or increased
catabolism of LDL-C. Apolipoprotein B also falls substantially during treatment with MEVACOR. Since
each LDL particle contains one molecule of apolipoprotein B, and since little apolipoprotein B is found in
other lipoproteins, this strongly suggests that MEVACOR does not merely cause cholesterol to be lost
from LDL, but also reduces the concentration of circulating LDL particles. In addition, MEVACOR can
* Registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
Copyright © 1987-2007 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved
Reference ID: 2899643
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844661
014-874-01
produce increases of variable magnitude in HDL-C, and modestly reduces VLDL-C and plasma
triglycerides (TG) (see Tables I-III under Clinical Studies). The effects of MEVACOR on Lp(a), fibrinogen,
and certain other independent biochemical risk markers for coronary heart disease are unknown.
MEVACOR is a specific inhibitor of HMG-CoA reductase, the enzyme which catalyzes the conversion
of HMG-CoA to mevalonate. The conversion of HMG-CoA to mevalonate is an early step in the
biosynthetic pathway for cholesterol.
Pharmacokinetics
Lovastatin is a lactone which is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent
inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in
pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base
hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of lovastatin.
Following an oral dose of 14C-labeled lovastatin in man, 10% of the dose was excreted in urine and
83% in feces. The latter represents absorbed drug equivalents excreted in bile, as well as any
unabsorbed drug. Plasma concentrations of total radioactivity (lovastatin plus 14C-metabolites) peaked at
2 hours and declined rapidly to about 10% of peak by 24 hours postdose. Absorption of lovastatin,
estimated relative to an intravenous reference dose, in each of four animal species tested, averaged
about 30% of an oral dose. In animal studies, after oral dosing, lovastatin had high selectivity for the liver,
where it achieved substantially higher concentrations than in non-target tissues. Lovastatin undergoes
extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug
equivalents in the bile. As a consequence of extensive hepatic extraction of lovastatin, the availability of
drug to the general circulation is low and variable. In a single dose study in four hypercholesterolemic
patients, it was estimated that less than 5% of an oral dose of lovastatin reaches the general circulation
as active inhibitors. Following administration of lovastatin tablets the coefficient of variation, based on
between-subject variability, was approximately 40% for the area under the curve (AUC) of total inhibitory
activity in the general circulation.
Both lovastatin and its β-hydroxyacid metabolite are highly bound (>95%) to human plasma proteins.
Animal studies demonstrated that lovastatin crosses the blood-brain and placental barriers.
The major active metabolites present in human plasma are the β-hydroxyacid of lovastatin, its
6′-hydroxy derivative, and two additional metabolites. Peak plasma concentrations of both active and total
inhibitors were attained within 2 to 4 hours of dose administration. While the recommended therapeutic
dose range is 10 to 80 mg/day, linearity of inhibitory activity in the general circulation was established by
a single dose study employing lovastatin tablet dosages from 60 to as high as 120 mg. With a once-a-day
dosing regimen, plasma concentrations of total inhibitors over a dosing interval achieved a steady state
between the second and third days of therapy and were about 1.5 times those following a single dose.
When lovastatin was given under fasting conditions, plasma concentrations of total inhibitors were on
average about two-thirds those found when lovastatin was administered immediately after a standard test
meal.
In a study of patients with severe renal insufficiency (creatinine clearance 10-30 mL/min), the plasma
concentrations of total inhibitors after a single dose of lovastatin were approximately two-fold higher than
those in healthy volunteers.
In a study including 16 elderly patients between 70-78 years of age who received MEVACOR
80 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately
45% compared with 18 patients between 18-30 years of age (see PRECAUTIONS, Geriatric Use).
Although the mechanism is not fully understood, cyclosporine has been shown to increase the AUC of
HMG-CoA reductase inhibitors. The increase in AUC for lovastatin and lovastatin acid is presumably due,
in part, to inhibition of CYP3A4.
The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.
Potent inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and
increase the risk of myopathy (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug
Interactions).
Lovastatin is a substrate for cytochrome P450 isoform 3A4 (CYP3A4) (see PRECAUTIONS, Drug
Interactions). Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase
2
Reference ID: 2899643
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844661
014-874-01
the plasma concentrations of drugs metabolized by CYP3A4. In one study**, 10 subjects consumed 200
mL of double-strength grapefruit juice (one can of frozen concentrate diluted with one rather than 3 cans
of water) three times daily for 2 days and an additional 200 mL double-strength grapefruit juice together
with and 30 and 90 minutes following a single dose of 80 mg lovastatin on the third day. This regimen of
grapefruit juice resulted in a mean increase in the serum concentration of lovastatin and its β-hydroxyacid
metabolite (as measured by the area under the concentration-time curve) of 15-fold and 5-fold,
respectively [as measured using a chemical assay — high performance liquid chromatography]. In a
second study, 15 subjects consumed one 8 oz glass of single-strength grapefruit juice (one can of frozen
concentrate diluted with 3 cans of water) with breakfast for 3 consecutive days and a single dose of
40 mg lovastatin in the evening of the third day. This regimen of grapefruit juice resulted in a mean
increase in the plasma concentration (as measured by the area under the concentration-time curve) of
active and total HMG-CoA reductase inhibitory activity [using an enzyme inhibition assay both before (for
active inhibitors) and after (for total inhibitors) base hydrolysis] of 1.34-fold and 1.36-fold, respectively,
and of lovastatin and its β-hydroxyacid metabolite [measured using a chemical assay — liquid
chromatography/tandem mass spectrometry — different from that used in the first** study] of 1.94-fold
and 1.57-fold, respectively. The effect of amounts of grapefruit juice between those used in these two
studies on lovastatin pharmacokinetics has not been studied.
Clinical Studies in Adults
MEVACOR has been shown to be highly effective in reducing total-C and LDL-C in heterozygous
familial and non-familial forms of primary hypercholesterolemia and in mixed hyperlipidemia. A marked
response was seen within 2 weeks, and the maximum therapeutic response occurred within 4-6 weeks.
The response was maintained during continuation of therapy. Single daily doses given in the evening
were more effective than the same dose given in the morning, perhaps because cholesterol is
synthesized mainly at night.
In multicenter, double-blind studies in patients with familial or non-familial hypercholesterolemia,
MEVACOR, administered in doses ranging from 10 mg q.p.m. to 40 mg b.i.d., was compared to placebo.
MEVACOR consistently and significantly decreased plasma total-C, LDL-C, total-C/HDL-C ratio and LDL
C/HDL-C ratio. In addition, MEVACOR produced increases of variable magnitude in HDL-C, and
modestly decreased VLDL-C and plasma TG (see Tables I through III for dose response results).
The results of a study in patients with primary hypercholesterolemia are presented in Table I.
TABLE I
MEVACOR vs. Placebo
(Mean Percent Change from Baseline After 6 Weeks)
LDL-C/
TOTAL-C/
DOSAGE
N
TOTAL-C
LDL-C
HDL-C
HDL-C
HDL-C
TG.
Placebo
33
–2
–1
–1
0
+1
+9
MEVACOR
10 mg q.p.m.
33
–16
–21
+5
–24
–19
–10
20 mg q.p.m.
33
–19
–27
+6
–30
–23
+9
10 mg b.i.d.
32
–19
–28
+8
–33
–25
–7
40 mg q.p.m.
33
–22
–31
+5
–33
–25
–8
20 mg b.i.d.
36
–24
–32
+2
–32
–24
–6
MEVACOR was compared to cholestyramine in a randomized open parallel study. The study was
performed with patients with hypercholesterolemia who were at high risk of myocardial infarction.
Summary results are presented in Table II.
** Kantola, T, et al., Clin Pharmacol Ther 1998; 63(4):397-402.
3
Reference ID: 2899643
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844661
014-874-01
TABLE II
MEVACOR vs. Cholestyramine
(Percent Change from Baseline After 12 Weeks)
LDL-C/
TOTAL-C/
TREATMENT
N
TOTAL-C
LDL-C
HDL-C
HDL-C
HDL-C
VLDL-C
TG.
(mean)
(mean)
(mean)
(mean)
(mean)
(median)
(mean)
MEVACOR
20 mg b.i.d.
85
–27
–32
+9
–36
–31
–34
–21
40 mg b.i.d.
88
–34
–42
+8
–44
–37
–31
–27
Cholestyramine
12 g b.i.d.
88
–17
–23
+8
–27
–21
+2
+11
MEVACOR was studied in controlled trials in hypercholesterolemic patients with well-controlled non-
insulin dependent diabetes mellitus with normal renal function. The effect of MEVACOR on lipids and
lipoproteins and the safety profile of MEVACOR were similar to that demonstrated in studies in
nondiabetics. MEVACOR had no clinically important effect on glycemic control or on the dose
requirement of oral hypoglycemic agents.
Expanded Clinical Evaluation of Lovastatin (EXCEL) Study
MEVACOR was compared to placebo in 8,245 patients with hypercholesterolemia (total-C 240-300
mg/dL [6.2 mmol/L - 7.6 mmol/L], LDL-C >160 mg/dL [4.1 mmol/L]) in the randomized, double-blind,
parallel, 48-week EXCEL study. All changes in the lipid measurements (Table III) in MEVACOR treated
patients were dose-related and significantly different from placebo (p≤0.001). These results were
sustained throughout the study.
TABLE III
MEVACOR vs. Placebo
(Percent Change from Baseline —
Average Values Between Weeks 12 and 48)
LDL-C/
TOTAL-C/
N**
DOSAGE
TOTAL-C
LDL-C
HDL-C
HDL-C
HDL-C
TG.
(mean)
(mean)
(mean)
(mean)
(mean)
(median)
Placebo
1663
+0.7
+0.4
+2.0
+0.2
+0.6
+4
MEVACOR
20 mg q.p.m.
1642
–17
–24
+6.6
–27
–21
–10
40 mg q.p.m.
1645
–22
–30
+7.2
–34
–26
–14
20 mg b.i.d.
1646
–24
–34
+8.6
–38
–29
–16
40 mg b.i.d.
1649
–29
–40
+9.5
–44
–34
–19
**Patients enrolled
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), a double-blind,
randomized, placebo-controlled, primary prevention study, demonstrated that treatment with MEVACOR
decreased the rate of acute major coronary events (composite endpoint of myocardial infarction, unstable
angina, and sudden cardiac death) compared with placebo during a median of 5.1 years of follow-up.
Participants were middle-aged and elderly men (ages 45-73) and women (ages 55-73) without
symptomatic cardiovascular disease with average to moderately elevated total-C and LDL-C, below
average HDL-C, and who were at high risk based on elevated total-C/HDL-C. In addition to age, 63% of
the participants had at least one other risk factor (baseline HDL-C <35 mg/dL, hypertension, family
history, smoking and diabetes).
AFCAPS/TexCAPS enrolled 6,605 participants (5,608 men, 997 women) based on the following lipid
entry criteria: total-C range of 180-264 mg/dL, LDL-C range of 130-190 mg/dL, HDL-C of ≤45 mg/dL for
men and ≤47 mg/dL for women, and TG of ≤400 mg/dL. Participants were treated with standard care,
including diet, and either MEVACOR 20-40 mg daily (n= 3,304) or placebo (n= 3,301). Approximately
50% of the participants treated with MEVACOR were titrated to 40 mg daily when their LDL-C remained
>110 mg/dL at the 20-mg starting dose.
MEVACOR reduced the risk of a first acute major coronary event, the primary efficacy endpoint, by
37% (MEVACOR 3.5%, placebo 5.5%; p<0.001; Figure 1). A first acute major coronary event was defined
4
Reference ID: 2899643
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844661
014-874-01
as myocardial infarction (54 participants on MEVACOR, 94 on placebo) or unstable angina (54 vs. 80) or
sudden cardiac death (8 vs. 9). Furthermore, among the secondary endpoints, MEVACOR reduced the
risk of unstable angina by 32% (1.8 vs. 2.6%; p=0.023), of myocardial infarction by 40% (1.7 vs. 2.9%;
p=0.002), and of undergoing coronary revascularization procedures (e.g., coronary artery bypass grafting
or percutaneous transluminal coronary angioplasty) by 33% (3.2 vs. 4.8%; p=0.001). Trends in risk
reduction associated with treatment with MEVACOR were consistent across men and women, smokers
and non-smokers, hypertensives and non-hypertensives, and older and younger participants. Participants
with ≥2 risk factors had risk reductions (RR) in both acute major coronary events (RR 43%) and coronary
revascularization procedures (RR 37%). Because there were too few events among those participants
with age as their only risk factor in this study, the effect of MEVACOR on outcomes could not be
graph
Atherosclerosis
In the Canadian Coronary Atherosclerosis Intervention Trial (CCAIT), the effect of therapy with
lovastatin on coronary atherosclerosis was assessed by coronary angiography in hyperlipidemic patients.
In the randomized, double-blind, controlled clinical trial, patients were treated with conventional measures
(usually diet and 325 mg of aspirin every other day) and either lovastatin 20-80 mg daily or placebo.
Angiograms were evaluated at baseline and at two years by computerized quantitative coronary
angiography (QCA). Lovastatin significantly slowed the progression of lesions as measured by the mean
change per-patient in minimum lumen diameter (the primary endpoint) and percent diameter stenosis,
and decreased the proportions of patients categorized with disease progression (33% vs. 50%) and with
new lesions (16% vs. 32%).
In a similarly designed trial, the Monitored Atherosclerosis Regression Study (MARS), patients were
treated with diet and either lovastatin 80 mg daily or placebo. No statistically significant difference
between lovastatin and placebo was seen for the primary endpoint (mean change per patient in percent
diameter stenosis of all lesions), or for most secondary QCA endpoints. Visual assessment by
angiographers who formed a consensus opinion of overall angiographic change (Global Change Score)
5
Reference ID: 2899643
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844661
014-874-01
was also a secondary endpoint. By this endpoint, significant slowing of disease was seen, with regression
in 23% of patients treated with lovastatin compared to 11% of placebo patients.
In the Familial Atherosclerosis Treatment Study (FATS), either lovastatin or niacin in combination with
a bile acid sequestrant for 2.5 years in hyperlipidemic subjects significantly reduced the frequency of
progression and increased the frequency of regression of coronary atherosclerotic lesions by QCA
compared to diet and, in some cases, low-dose resin.
The effect of lovastatin on the progression of atherosclerosis in the coronary arteries has been
corroborated by similar findings in another vasculature. In the Asymptomatic Carotid Artery Progression
Study (ACAPS), the effect of therapy with lovastatin on carotid atherosclerosis was assessed by B-mode
ultrasonography in hyperlipidemic patients with early carotid lesions and without known coronary heart
disease at baseline. In this double-blind, controlled clinical trial, 919 patients were randomized in a 2 x 2
factorial design to placebo, lovastatin 10-40 mg daily and/or warfarin. Ultrasonograms of the carotid walls
were used to determine the change per patient from baseline to three years in mean maximum intimal-
medial thickness (IMT) of 12 measured segments. There was a significant regression of carotid lesions in
patients receiving lovastatin alone compared to those receiving placebo alone (p=0.001). The predictive
value of changes in IMT for stroke has not yet been established. In the lovastatin group there was a
significant reduction in the number of patients with major cardiovascular events relative to the placebo
group (5 vs. 14) and a significant reduction in all-cause mortality (1 vs. 8).
Eye
There was a high prevalence of baseline lenticular opacities in the patient population included in the
early clinical trials with lovastatin. During these trials the appearance of new opacities was noted in both
the lovastatin and placebo groups. There was no clinically significant change in visual acuity in the
patients who had new opacities reported nor was any patient, including those with opacities noted at
baseline, discontinued from therapy because of a decrease in visual acuity.
A three-year, double-blind, placebo-controlled study in hypercholesterolemic patients to assess the
effect of lovastatin on the human lens demonstrated that there were no clinically or statistically significant
differences between the lovastatin and placebo groups in the incidence, type or progression of lenticular
opacities. There are no controlled clinical data assessing the lens available for treatment beyond three
years.
Clinical Studies in Adolescent Patients
Efficacy of Lovastatin in Adolescent Boys with Heterozygous Familial Hypercholesterolemia
In a double-blind, placebo-controlled study, 132 boys 10-17 years of age (mean age 12.7 yrs) with
heterozygous familial hypercholesterolemia (heFH) were randomized to lovastatin (n=67) or placebo
(n=65) for 48 weeks. Inclusion in the study required a baseline LDL-C level between 189 and 500 mg/dL
and at least one parent with an LDL-C level >189 mg/dL. The mean baseline LDL-C value was
253.1 mg/dL (range: 171-379 mg/dL) in the MEVACOR group compared to 248.2 mg/dL (range:
158.5-413.5 mg/dL) in the placebo group. The dosage of lovastatin (once daily in the evening) was 10 mg
for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter.
MEVACOR significantly decreased plasma levels of total-C, LDL-C and apolipoprotein B (see
Table IV).
TABLE IV
Lipid-lowering Effects of Lovastatin in Adolescent Boys with Heterozygous Familial Hypercholesterolemia
(Mean Percent Change from Baseline at Week 48 in Intention-to-Treat Population)
DOSAGE
N
TOTAL-C
LDL-C
HDL-C
TG.*
Apolipoprotein B
Placebo
61
-1.1
-1.4
-2.2
-1.4
-4.4
MEVACOR
64
-19.3
-24.2
+1.1
-1.9
-21
*data presented as median percent changes
The mean achieved LDL-C value was 190.9 mg/dL (range: 108-336 mg/dL) in the MEVACOR group
compared to 244.8 mg/dL (range: 135-404 mg/dL) in the placebo group.
6
Reference ID: 2899643
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844661
014-874-01
Efficacy of Lovastatin in Post-Menarchal Girls with Heterozygous Familial Hypercholesterolemia
In a double-blind, placebo-controlled study, 54 girls 10-17 years of age who were at least 1 year
post-menarche with heFH were randomized to lovastatin (n=35) or placebo (n=19) for 24 weeks.
Inclusion in the study required a baseline LDL-C level of 160-400 mg/dL and a parental history of familial
hypercholesterolemia. The mean baseline LDL-C value was 218.3 mg/dL (range: 136.3-363.7 mg/dL) in
the MEVACOR group compared to 198.8 mg/dL (range: 151.1-283.1 mg/dL) in the placebo group. The
dosage of lovastatin (once daily in the evening) was 20 mg for the first 4 weeks, and 40 mg thereafter.
MEVACOR significantly decreased plasma levels of total-C, LDL-C, and apolipoprotein B (see
Table V).
TABLE V
Lipid-lowering Effects of Lovastatin in Post-Menarchal Girls with Heterozygous Familial Hypercholesterolemia
(Mean Percent Change from Baseline at Week 24 in Intention-to-Treat Population)
DOSAGE
N
TOTAL-C
LDL-C
HDL-C
TG.*
Apolipoprotein B
Placebo
18
+3.6
+2.5
+4.8
-3.0
+6.4
MEVACOR
35
-22.4
-29.2
+2.4
-22.7
-24.4
*data presented as median percent changes
The mean achieved LDL-C value was 154.5 mg/dL (range: 82-286 mg/dL) in the MEVACOR group
compared to 203.5 mg/dL (range: 135-304 mg/dL) in the placebo group.
The safety and efficacy of doses above 40 mg daily have not been studied in children. The long-term
efficacy of lovastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been
established.
INDICATIONS AND USAGE
Therapy with MEVACOR should be a component of multiple risk factor intervention in those
individuals with dyslipidemia at risk for atherosclerotic vascular disease. MEVACOR should be used in
addition to a diet restricted in saturated fat and cholesterol as part of a treatment strategy to lower total-C
and LDL-C to target levels when the response to diet and other nonpharmacological measures alone has
been inadequate to reduce risk.
Primary Prevention of Coronary Heart Disease
In individuals without symptomatic cardiovascular disease, average to moderately elevated total-C
and LDL-C, and below average HDL-C, MEVACOR is indicated to reduce the risk of:
- Myocardial infarction
- Unstable angina
- Coronary revascularization procedures
(See CLINICAL PHARMACOLOGY, Clinical Studies.)
Coronary Heart Disease
MEVACOR is indicated to slow the progression of coronary atherosclerosis in patients with coronary
heart disease as part of a treatment strategy to lower total-C and LDL-C to target levels.
7
Reference ID: 2899643
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844661
014-874-01
Hypercholesterolemia
Therapy with lipid-altering agents should be a component of multiple risk factor intervention in those
individuals
at
significantly
increased
risk
for
atherosclerotic
vascular
disease
due
to
hypercholesterolemia. MEVACOR is indicated as an adjunct to diet for the reduction of elevated total-C
and LDL-C levels in patients with primary hypercholesterolemia (Types IIa and IIb***), when the response
to diet restricted in saturated fat and cholesterol and to other nonpharmacological measures alone has
been inadequate.
Adolescent Patients with Heterozygous Familial Hypercholesterolemia
MEVACOR is indicated as an adjunct to diet to reduce total-C, LDL-C and apolipoprotein B levels in
adolescent boys and girls who are at least one year post-menarche, 10-17 years of age, with heFH if
after an adequate trial of diet therapy the following findings are present:
1. LDL-C remains >189 mg/dL or
2. LDL-C remains >160 mg/dL and:
•
there is a positive family history of premature cardiovascular disease or
•
two or more other CVD risk factors are present in the adolescent patient
General Recommendations
Prior to initiating therapy with lovastatin, secondary causes for hypercholesterolemia (e.g., poorly
controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver
disease, other drug therapy, alcoholism) should be excluded, and a lipid profile performed to measure
total-C, HDL-C, and TG. For patients with TG less than 400 mg/dL (<4.5 mmol/L), LDL-C can be
estimated using the following equation:
LDL-C = total-C – [0.2 × (TG) + HDL-C]
For TG levels >400 mg/dL (>4.5 mmol/L), this equation is less accurate and LDL-C concentrations
should be determined by ultracentrifugation. In hypertriglyceridemic patients, LDL-C may be low or
normal despite elevated total-C. In such cases, MEVACOR is not indicated.
The National Cholesterol Education Program (NCEP) Treatment Guidelines are summarized below:
NCEP Treatment Guidelines:
LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes
and Drug Therapy in Different Risk Categories
LDL Level at Which to
LDL Level at Which to
Risk Category
LDL Goal
Initiate Therapeutic Lifestyle Changes
Consider Drug Therapy
(mg/dL)
(mg/dL)
(mg/dL)
CHD† or CHD risk equivalents
<100
≥100
≥130
(10-year risk >20%)
(100-129: drug optional)††
2+ Risk factors
<130
≥130
10-year risk 10-20%: ≥130
(10 year risk ≤20%)
10-year risk <10%: ≥ 160
0-1 Risk factor†††
<160
≥160
≥190
(160-189: LDL-lowering drug
optional)
†
CHD, coronary heart disease
††
Some authorities recommend use of LDL-lowering drugs in this category if an LDL-C level of <100 mg/dL cannot be achieved by therapeutic
lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL-C, e.g., nicotinic acid or fibrate. Clinical judgment also
may call for deferring drug therapy in this subcategory.
†††
Almost all people with 0-1 risk factor have a 10-year risk <10%; thus, 10-year risk assessment in people with 0-1 risk factor is not necessary.
*** Classification of Hyperlipoproteinemias
Lipid
Lipoproteins
Elevations
Type
elevated
major
minor
I
chylomicrons
TG
↑→C
IIa
LDL
C
—
IIb
LDL, VLDL
C
TG
III (rare)
IDL
C/TG
—
IV
VLDL
TG
↑→C
V (rare)
chylomicrons, VLDL
TG
↑→C
IDL = intermediate-density lipoprotein.
8
Reference ID: 2899643
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844661
014-874-01
After the LDL-C goal has been achieved, if the TG is still ≥200 mg/dL, non-HDL-C (total-C minus HDL
C) becomes a secondary target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals
for each risk category.
At the time of hospitalization for an acute coronary event, consideration can be given to initiating drug
therapy at discharge if the LDL-C is ≥130 mg/dL (see NCEP Guidelines above).
Since the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C levels be used to
initiate and assess treatment response. Only if LDL-C levels are not available, should the total-C be used
to monitor therapy.
Although MEVACOR may be useful to reduce elevated LDL-C levels in patients with combined
hypercholesterolemia and hypertriglyceridemia where hypercholesterolemia is the major abnormality
(Type IIb hyperlipoproteinemia), it has not been studied in conditions where the major abnormality is
elevation of chylomicrons, VLDL or IDL (i.e., hyperlipoproteinemia types I, III, IV, or V).***
The NCEP classification of cholesterol levels in pediatric patients with a familial history of
hypercholesterolemia or premature cardiovascular disease is summarized below:
Category
Total-C (mg/dL)
LDL-C (mg/dL)
Acceptable
Borderline
High
<170
170-199
≥200
<110
110-129
≥130
Children treated with lovastatin in adolescence should be re-evaluated in adulthood and appropriate
changes made to their cholesterol-lowering regimen to achieve adult goals for LDL-C.
CONTRAINDICATIONS
Hypersensitivity to any component of this medication.
Active liver disease or unexplained persistent elevations of serum transaminases (see WARNINGS).
Pregnancy and lactation (see PRECAUTIONS, Pregnancy and Nursing Mothers). Atherosclerosis is a
chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact
on the outcome of long-term therapy of primary hypercholesterolemia. Moreover, cholesterol and other
products of the cholesterol biosynthesis pathway are essential components for fetal development,
including synthesis of steroids and cell membranes. Because of the ability of inhibitors of HMG-CoA
reductase such as MEVACOR to decrease the synthesis of cholesterol and possibly other products of the
cholesterol biosynthesis pathway, MEVACOR is contraindicated during pregnancy and in nursing
mothers. MEVACOR should be administered to women of childbearing age only when such
patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug,
MEVACOR should be discontinued immediately and the patient should be apprised of the potential
hazard to the fetus (see PRECAUTIONS, Pregnancy).
WARNINGS
Myopathy/Rhabdomyolysis
Lovastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as
muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal
(ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure
secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high
levels of HMG-CoA reductase inhibitory activity in plasma.
As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose
related. In a clinical study (EXCEL) in which patients were carefully monitored and some interacting
drugs were excluded, there was one case of myopathy among 4933 patients randomized to lovastatin 20
40 mg daily for 48 weeks, and 4 among 1649 patients randomized to 80 mg daily.
All patients starting therapy with lovastatin, or whose dose of lovastatin is being increased,
should be advised of the risk of myopathy and told to report promptly any unexplained muscle
pain, tenderness or weakness. Lovastatin therapy should be discontinued immediately if
9
Reference ID: 2899643
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844661
014-874-01
myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved
when treatment was promptly discontinued. Periodic CK determinations may be considered in patients
starting therapy with lovastatin or whose dose is being increased, but there is no assurance that such
monitoring will prevent myopathy.
Many of the patients who have developed rhabdomyolysis on therapy with lovastatin have had
complicated medical histories, including renal insufficiency usually as a consequence of long-standing
diabetes mellitus. Such patients merit closer monitoring. Therapy with lovastatin should be temporarily
stopped a few days prior to elective major surgery and when any major medical or surgical condition
supervenes.
The risk of myopathy/rhabdomyolysis is increased by concomitant use of lovastatin with the
following:
Potent inhibitors of CYP3A4: Lovastatin, like several other inhibitors of HMG-CoA reductase, is a
substrate of cytochrome P450 3A4 (CYP3A4). When lovastatin is used with a potent inhibitor of
CYP3A4, elevated plasma levels of HMG-CoA reductase inhibitory activity can increase the risk of
myopathy and rhabdomyolysis, particularly with higher doses of lovastatin.
The use of lovastatin concomitantly with the potent CYP3A4 inhibitors itraconazole,
ketoconazole,
erythromycin,
clarithromycin,
telithromycin,
HIV
protease
inhibitors,
nefazodone, or large quantities of grapefruit juice (>1 quart daily) should be avoided.
Concomitant use of other medicines labeled as having a potent inhibitory effect on CYP3A4 should
be avoided unless the benefits of combined therapy outweigh the increased risk. If treatment with
itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with
lovastatin should be suspended during the course of treatment.
Gemfibrozil, particularly with higher doses of lovastatin: The dose of lovastatin should not
exceed 20 mg daily in patients receiving concomitant medication with gemfibrozil. The
combined use of lovastatin with gemfibrozil should be avoided, unless the benefits are likely
to outweigh the increased risks of this drug combination.
Other lipid-lowering drugs (other fibrates or ≥1 g/day of niacin): The dose of lovastatin should
not exceed 20 mg daily in patients receiving concomitant medication with other fibrates or
≥1 g/day of niacin. Caution should be used when prescribing other fibrates or lipid-lowering doses
(≥1 g/day) of niacin with lovastatin, as these agents can cause myopathy when given alone. The
benefit of further alterations in lipid levels by the combined use of lovastatin with other
fibrates or niacin should be carefully weighed against the potential risks of these
combinations.
Cyclosporine or danazol, with higher doses of lovastatin: The dose of lovastatin should not
exceed 20 mg daily in patients receiving concomitant medication with cyclosporine or
danazol. The benefits of the use of lovastatin in patients receiving cyclosporine or danazol should be
carefully weighed against the risks of these combinations.
Amiodarone or verapamil: The dose of lovastatin should not exceed 40 mg daily in patients
receiving concomitant medication with amiodarone or verapamil. The combined use of
lovastatin at doses higher than 40 mg daily with amiodarone or verapamil should be avoided unless
the clinical benefit is likely to outweigh the increased risk of myopathy. The risk of
myopathy/rhabdomyolysis is increased when either amiodarone or verapamil is used concomitantly
with higher doses of a closely related member of the HMG-CoA reductase inhibitor class.
10
Reference ID: 2899643
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844661
014-874-01
Prescribing recommendations for interacting agents are summarized in Table VI (see also CLINICAL
PHARMACOLOGY,
Pharmacokinetics;
PRECAUTIONS,
Drug
Interactions;
DOSAGE
AND
ADMINISTRATION).
Table VI
Drug Interactions Associated with Increased
Risk of Myopathy/Rhabdomyolysis
Interacting Agents
Prescribing Recommendations
Itraconazole
Ketoconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors
Nefazodone
Avoid lovastatin
Gemfibrozil
Other fibrates
Lipid-lowering doses (≥1 g/day)
of niacin
Cyclosporine
Danazol
Do not exceed 20 mg lovastatin daily
Amiodarone
Verapamil
Do not exceed 40 mg lovastatin daily
Grapefruit juice
Avoid large quantities of grapefruit juice
(>1 quart daily)
Liver Dysfunction
Persistent increases (to more than 3 times the upper limit of normal) in serum transaminases
occurred in 1.9% of adult patients who received lovastatin for at least one year in early clinical
trials (see ADVERSE REACTIONS). When the drug was interrupted or discontinued in these patients,
the transaminase levels usually fell slowly to pretreatment levels. The increases usually appeared 3 to 12
months after the start of therapy with lovastatin, and were not associated with jaundice or other clinical
signs or symptoms. There was no evidence of hypersensitivity. In the EXCEL study (see CLINICAL
PHARMACOLOGY, Clinical Studies), the incidence of persistent increases in serum transaminases over
48 weeks was 0.1% for placebo, 0.1% at 20 mg/day, 0.9% at 40 mg/day, and 1.5% at 80 mg/day in
patients on lovastatin. However, in post-marketing experience with MEVACOR, symptomatic liver disease
has been reported rarely at all dosages (see ADVERSE REACTIONS).
In AFCAPS/TexCAPS, the number of participants with consecutive elevations of either alanine
aminotransferase (ALT) or aspartate aminotransferase (AST) (> 3 times the upper limit of normal), over a
median of 5.1 years of follow-up, was not significantly different between the MEVACOR and placebo
groups (18 [0.6%] vs. 11 [0.3%]). The starting dose of MEVACOR was 20 mg/day; 50% of the MEVACOR
treated participants were titrated to 40 mg/day at Week 18. Of the 18 participants on MEVACOR with
consecutive elevations of either ALT or AST, 11 (0.7%) elevations occurred in participants taking 20
mg/day, while 7 (0.4%) elevations occurred in participants titrated to 40 mg/day. Elevated transaminases
resulted in discontinuation of 6 (0.2%) participants from therapy in the MEVACOR group (n=3,304) and 4
(0.1%) in the placebo group (n=3,301).
It is recommended that liver function tests be performed prior to initiation of therapy in patients with a
history of liver disease, or when otherwise clinically indicated. It is recommended that liver function tests
be performed in all patients prior to use of 40 mg or more daily and thereafter when clinically indicated.
Patients who develop increased transaminase levels should be monitored with a second liver function
evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the
abnormality(ies) returns to normal. Should an increase in AST or ALT of three times the upper limit of
normal or greater persist, withdrawal of therapy with MEVACOR is recommended.
The drug should be used with caution in patients who consume substantial quantities of alcohol and/or
have a past history of liver disease. Active liver disease or unexplained transaminase elevations are
contraindications to the use of lovastatin.
As with other lipid-lowering agents, moderate (less than three times the upper limit of normal)
elevations of serum transaminases have been reported following therapy with MEVACOR (see
ADVERSE REACTIONS). These changes appeared soon after initiation of therapy with MEVACOR, were
often transient, were not accompanied by any symptoms and interruption of treatment was not required.
11
Reference ID: 2899643
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844661
014-874-01
PRECAUTIONS
General
Lovastatin may elevate creatine phosphokinase and transaminase levels (see WARNINGS and
ADVERSE REACTIONS). This should be considered in the differential diagnosis of chest pain in a patient
on therapy with lovastatin.
Homozygous Familial Hypercholesterolemia
MEVACOR is less effective in patients with the rare homozygous familial hypercholesterolemia,
possibly because these patients have no functional LDL receptors. MEVACOR appears to be more likely
to raise serum transaminases (see ADVERSE REACTIONS) in these homozygous patients.
Information for Patients
Patients should be advised about substances they should not take concomitantly with
lovastatin and be advised to report promptly unexplained muscle pain, tenderness, or weakness
(see list below and WARNINGS, Myopathy/Rhabdomyolysis). Patients should also be advised to
inform other physicians prescribing a new medication that they are taking MEVACOR.
Drug Interactions
CYP3A4 Interactions
Lovastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not
expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. Potent inhibitors of
CYP3A4 (below) increase the risk of myopathy by reducing the elimination of lovastatin.
See
WARNINGS,
Myopathy/Rhabdomyolysis,
and
CLINICAL
PHARMACOLOGY,
Pharmacokinetics.
Itraconazole
Ketoconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors
Nefazodone
Large quantities of grapefruit juice (>1 quart daily)
Interactions With Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone
The risk of myopathy is also increased by the following lipid-lowering drugs that are not potent
CYP3A4 inhibitors, but which can cause myopathy when given alone.
See WARNINGS, Myopathy/Rhabdomyolysis.
Gemfibrozil
Other fibrates
Niacin (nicotinic acid) (≥1 g/day)
Other Drug Interactions
Cyclosporine or Danazol: The risk of myopathy/rhabdomyolysis is increased by concomitant
administration of cyclosporine or danazol particularly with higher doses of lovastatin (see WARNINGS,
Myopathy/Rhabdomyolysis; CLINICAL PHARMACOLOGY, Pharmacokinetics).
Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased when either amiodarone
or verapamil is used concomitantly with a closely related member of the HMG-CoA reductase inhibitor
class (see WARNINGS, Myopathy/Rhabdomyolysis).
Coumarin Anticoagulants: In a small clinical trial in which lovastatin was administered to warfarin
treated patients, no effect on prothrombin time was detected. However, another HMG-CoA reductase
inhibitor has been found to produce a less than two-second increase in prothrombin time in healthy
volunteers receiving low doses of warfarin. Also, bleeding and/or increased prothrombin time have been
reported in a few patients taking coumarin anticoagulants concomitantly with lovastatin. It is
recommended that in patients taking anticoagulants, prothrombin time be determined before starting
12
Reference ID: 2899643
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844661
014-874-01
lovastatin and frequently enough during early therapy to insure that no significant alteration of
prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can
be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose
of lovastatin is changed, the same procedure should be repeated. Lovastatin therapy has not been
associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
Propranolol: In normal volunteers, there was no clinically significant pharmacokinetic or
pharmacodynamic interaction with concomitant administration of single doses of lovastatin and
propranolol.
Digoxin: In patients with hypercholesterolemia, concomitant administration of lovastatin and digoxin
resulted in no effect on digoxin plasma concentrations.
Oral Hypoglycemic Agents: In pharmacokinetic studies of MEVACOR in hypercholesterolemic non-
insulin dependent diabetic patients, there was no drug interaction with glipizide or with chlorpropamide
(see CLINICAL PHARMACOLOGY, Clinical Studies).
Endocrine Function
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically
blunt adrenal and/or gonadal steroid production. Results of clinical trials with drugs in this class have
been inconsistent with regard to drug effects on basal and reserve steroid levels. However, clinical
studies have shown that lovastatin does not reduce basal plasma cortisol concentration or impair adrenal
reserve, and does not reduce basal plasma testosterone concentration. Another HMG-CoA reductase
inhibitor has been shown to reduce the plasma testosterone response to HCG. In the same study, the
mean testosterone response to HCG was slightly but not significantly reduced after treatment with
lovastatin 40 mg daily for 16 weeks in 21 men. The effects of HMG-CoA reductase inhibitors on male
fertility have not been studied in adequate numbers of male patients. The effects, if any, on the pituitary-
gonadal axis in pre-menopausal women are unknown. Patients treated with lovastatin who develop
clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be
exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is
administered to patients also receiving other drugs (e.g., ketoconazole, spironolactone, cimetidine) that
may decrease the levels or activity of endogenous steroid hormones.
CNS Toxicity
Lovastatin produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in
clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean
plasma drug levels about 30 times higher than the mean drug level in humans taking the highest
recommended dose (as measured by total enzyme inhibitory activity). Vestibulocochlear Wallerian-like
degeneration and retinal ganglion cell chromatolysis were also seen in dogs treated for 14 weeks at 180
mg/kg/day, a dose which resulted in a mean plasma drug level (Cmax) similar to that seen with the 60
mg/kg/day dose.
CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell
infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels, were seen in
dogs treated with lovastatin at a dose of 180 mg/kg/day, a dose which produced plasma drug levels
(Cmax) which were about 30 times higher than the mean values in humans taking 80 mg/day.
Similar optic nerve and CNS vascular lesions have been observed with other drugs of this class.
Cataracts were seen in dogs treated for 11 and 28 weeks at 180 mg/kg/day and 1 year at
60 mg/kg/day.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 21-month carcinogenic study in mice, there was a statistically significant increase in the incidence
of hepatocellular carcinomas and adenomas in both males and females at 500 mg/kg/day. This dose
produced a total plasma drug exposure 3 to 4 times that of humans given the highest recommended dose
of lovastatin (drug exposure was measured as total HMG-CoA reductase inhibitory activity in extracted
plasma). Tumor increases were not seen at 20 and 100 mg/kg/day, doses that produced drug exposures
of 0.3 to 2 times that of humans at the 80 mg/day dose. A statistically significant increase in pulmonary
adenomas was seen in female mice at approximately 4 times the human drug exposure. (Although mice
were given 300 times the human dose [HD] on a mg/kg body weight basis, plasma levels of total
inhibitory activity were only 4 times higher in mice than in humans given 80 mg of MEVACOR.)
13
Reference ID: 2899643
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844661
014-874-01
There was an increase in incidence of papilloma in the non-glandular mucosa of the stomach of mice
beginning at exposures of 1 to 2 times that of humans. The glandular mucosa was not affected. The
human stomach contains only glandular mucosa.
In a 24-month carcinogenicity study in rats, there was a positive dose response relationship for
hepatocellular carcinogenicity in males at drug exposures between 2-7 times that of human exposure at
80 mg/day (doses in rats were 5, 30 and 180 mg/kg/day).
An increased incidence of thyroid neoplasms in rats appears to be a response that has been seen
with other HMG-CoA reductase inhibitors.
A chemically similar drug in this class was administered to mice for 72 weeks at 25, 100, and
400 mg/kg body weight, which resulted in mean serum drug levels approximately 3, 15, and 33 times
higher than the mean human serum drug concentration (as total inhibitory activity) after a 40 mg oral
dose. Liver carcinomas were significantly increased in high dose females and mid- and high dose males,
with a maximum incidence of 90 percent in males. The incidence of adenomas of the liver was
significantly increased in mid- and high dose females. Drug treatment also significantly increased the
incidence of lung adenomas in mid- and high dose males and females. Adenomas of the Harderian gland
(a gland of the eye of rodents) were significantly higher in high dose mice than in controls.
No evidence of mutagenicity was observed in a microbial mutagen test using mutant strains of
Salmonella typhimurium with or without rat or mouse liver metabolic activation. In addition, no evidence of
damage to genetic material was noted in an in vitro alkaline elution assay using rat or mouse
hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in
CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow.
Drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant
cell formation were seen in dogs starting at 20 mg/kg/day. Similar findings were seen with another drug in
this class. No drug-related effects on fertility were found in studies with lovastatin in rats. However, in
studies with a similar drug in this class, there was decreased fertility in male rats treated for 34 weeks at
25 mg/kg body weight, although this effect was not observed in a subsequent fertility study when this
same dose was administered for 11 weeks (the entire cycle of spermatogenesis, including epididymal
maturation). In rats treated with this same reductase inhibitor at 180 mg/kg/day, seminiferous tubule
degeneration (necrosis and loss of spermatogenic epithelium) was observed. No microscopic changes
were observed in the testes from rats of either study. The clinical significance of these findings is unclear.
Pregnancy
Pregnancy Category X
See CONTRAINDICATIONS.
Safety in pregnant women has not been established.
Lovastatin has been shown to produce skeletal malformations in offspring of pregnant mice and rats
dosed during gestation at 80 mg/kg/day (affected mouse fetuses/total: 8/307 compared to 4/289 in the
control group; affected rat fetuses/total: 6/324 compared to 2/308 in the control group). Female rats
dosed before mating through gestation at 80 mg/kg/day also had fetuses with skeletal malformations
(affected fetuses/total: 1/152 compared to 0/171 in the control group). The 80 mg/kg/day dose in mice is 7
times the human dose based on body surface area and in rats results in 5 times the human exposure
based on AUC. In pregnant rats given doses of 2, 20, or 200 mg/kg/day and treated through lactation, the
following effects were observed: neonatal mortality (4.1%, 3.5%, and 46%, respectively, compared to
0.6% in the control group), decreased pup body weights throughout lactation (up to 5%, 8%, and 38%,
respectively, below control), supernumerary ribs in dead pups (affected fetuses/total: 0/7, 1/17, and
11/79, respectively, compared to 0/5 in the control group), delays in ossification in dead pups (affected
fetuses/total: 0/7, 0/17, and 1/79, respectively, compared to 0/5 in the control group) and delays in pup
development (delays in the appearance of an auditory startle response at 200 mg/kg/day and free-fall
righting reflexes at 20 and 200 mg/kg/day).
Direct dosing of neonatal rats by subcutaneous injection with 10 mg/kg/day of the open hydroxyacid
form of lovastatin resulted in delayed passive avoidance learning in female rats (mean of 8.3 trials to
criterion, compared to 7.3 and 6.4 in untreated and vehicle-treated controls; no effects on retention 1
week later) at exposures 4 times the human systemic exposure at 80 mg/day based on AUC. No effect
was seen in male rats. No evidence of malformations was observed when pregnant rabbits were given 5
14
Reference ID: 2899643
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844661
014-874-01
mg/kg/day (doses equivalent to a human dose of 80 mg/day based on body surface area) or a maternally
toxic dose of 15 mg/kg/day (3 times the human dose of 80 mg/day based on body surface area).
Rare clinical reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase
inhibitors have been received. However, in an analysis† of greater than 200 prospectively followed
pregnancies exposed during the first trimester to MEVACOR or another closely related HMG-CoA
reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general
population. This number of pregnancies was sufficient to exclude a 3-fold or greater increase in
congenital anomalies over the background incidence.
Maternal treatment with MEVACOR may reduce the fetal levels of mevalonate, which is a precursor of
cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-
lowering drugs during pregnancy should have little impact on the long-term risk associated with primary
hypercholesterolemia. For these reasons, MEVACOR should not be used in women who are pregnant, or
can become pregnant (see CONTRAINDICATIONS). MEVACOR should be administered to women of
child-bearing potential only when such patients are highly unlikely to conceive and have been informed of
the potential hazards. Treatment should be immediately discontinued as soon as pregnancy is
recognized.
Nursing Mothers
It is not known whether lovastatin is excreted in human milk. Because a small amount of another drug
in this class is excreted in human breast milk and because of the potential for serious adverse reactions
in nursing infants, women taking MEVACOR should not nurse their infants (see CONTRAINDICATIONS).
Pediatric Use
Safety and effectiveness in patients 10-17 years of age with heFH have been evaluated in controlled
clinical trials of 48 weeks duration in adolescent boys and controlled clinical trials of 24 weeks duration in
girls who were at least 1 year post-menarche. Patients treated with lovastatin had an adverse experience
profile generally similar to that of patients treated with placebo. Doses greater than 40 mg have not
been studied in this population. In these limited controlled studies, there was no detectable effect on
growth or sexual maturation in the adolescent boys or on menstrual cycle length in girls. See CLINICAL
PHARMACOLOGY, Clinical Studies in Adolescent Patients; ADVERSE REACTIONS, Adolescent
Patients; and DOSAGE AND ADMINISTRATION, Adolescent Patients (10-17 years of age) with
Heterozygous Familial Hypercholesterolemia. Adolescent females should be counseled on appropriate
contraceptive methods while on lovastatin therapy (see CONTRAINDICATIONS and PRECAUTIONS,
Pregnancy). Lovastatin has not been studied in pre-pubertal patients or patients younger than
10 years of age.
Geriatric Use
A pharmacokinetic study with lovastatin showed the mean plasma level of HMG-CoA reductase
inhibitory activity to be approximately 45% higher in elderly patients between 70-78 years of age
compared with patients between 18-30 years of age; however, clinical study experience in the elderly
indicates that dosage adjustment based on this age-related pharmacokinetic difference is not needed. In
the two large clinical studies conducted with lovastatin (EXCEL and AFCAPS/TexCAPS), 21%
(3094/14850) of patients were ≥65 years of age. Lipid-lowering efficacy with lovastatin was at least as
great in elderly patients compared with younger patients, and there were no overall differences in safety
over the 20 to 80 mg/day dosage range (see CLINICAL PHARMACOLOGY).
ADVERSE REACTIONS
MEVACOR is generally well tolerated; adverse reactions usually have been mild and transient.
Phase III Clinical Studies
In Phase III controlled clinical studies involving 613 patients treated with MEVACOR, the adverse
experience profile was similar to that shown below for the 8,245-patient EXCEL study (see Expanded
Clinical Evaluation of Lovastatin [EXCEL] Study).
Persistent increases of serum transaminases have been noted (see WARNINGS, Liver Dysfunction).
About 11% of patients had elevations of CK levels of at least twice the normal value on one or more
† Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During
Pregnancy. Reproductive Toxicology. 10(6):439-446. 1996.
15
Reference ID: 2899643
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844661
014-874-01
occasions. The corresponding values for the control agent cholestyramine was 9 percent. This was
attributable to the noncardiac fraction of CK. Large increases in CK have sometimes been reported (see
WARNINGS, Myopathy/Rhabdomyolysis).
Expanded Clinical Evaluation of Lovastatin (EXCEL) Study
MEVACOR was compared to placebo in 8,245 patients with hypercholesterolemia (total-C 240-300
mg/dL [6.2-7.8 mmol/L]) in the randomized, double-blind, parallel, 48-week EXCEL study. Clinical
adverse experiences reported as possibly, probably or definitely drug-related in ≥1% in any treatment
group are shown in the table below. For no event was the incidence on drug and placebo statistically
different.
Placebo
(N = 1663)
%
MEVACOR
20 mg q.p.m.
(N = 1642)
%
MEVACOR
40 mg q.p.m.
(N = 1645)
%
MEVACOR
20 mg b.i.d.
(N = 1646)
%
MEVACOR
40 mg b.i.d.
(N = 1649)
%
Body As a Whole
Asthenia
1.4
1.7
1.4
1.5
1.2
Gastrointestinal
Abdominal pain
Constipation
Diarrhea
Dyspepsia
Flatulence
Nausea
1.6
1.9
2.3
1.9
4.2
2.5
2.0
2.0
2.6
1.3
3.7
1.9
2.0
3.2
2.4
1.3
4.3
2.5
2.2
3.2
2.2
1.0
3.9
2.2
2.5
3.5
2.6
1.6
4.5
2.2
Musculoskeletal
Muscle cramps
Myalgia
0.5
1.7
0.6
2.6
0.8
1.8
1.1
2.2
1.0
3.0
Nervous System/
Psychiatric
Dizziness
Headache
0.7
2.7
0.7
2.6
1.2
2.8
0.5
2.1
0.5
3.2
Skin
Rash
0.7
0.8
1.0
1.2
1.3
Special Senses
Blurred vision
0.8
1.1
0.9
0.9
1.2
Other clinical adverse experiences reported as possibly, probably or definitely drug-related in 0.5 to
1.0 percent of patients in any drug-treated group are listed below. In all these cases the incidence on
drug and placebo was not statistically different. Body as a Whole: chest pain; Gastrointestinal: acid
regurgitation, dry mouth, vomiting; Musculoskeletal: leg pain, shoulder pain, arthralgia; Nervous
System/Psychiatric: insomnia, paresthesia; Skin: alopecia, pruritus; Special Senses: eye irritation.
In the EXCEL study (see CLINICAL PHARMACOLOGY, Clinical Studies), 4.6% of the patients treated
up to 48 weeks were discontinued due to clinical or laboratory adverse experiences which were rated by
the investigator as possibly, probably or definitely related to therapy with MEVACOR. The value for the
placebo group was 2.5%.
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
In AFCAPS/TexCAPS (see CLINICAL PHARMACOLOGY, Clinical Studies) involving 6,605
participants treated with 20-40 mg/day of MEVACOR (n=3,304) or placebo (n=3,301), the safety and
tolerability profile of the group treated with MEVACOR was comparable to that of the group treated with
placebo during a median of 5.1 years of follow-up. The adverse experiences reported in
AFCAPS/TexCAPS were similar to those reported in EXCEL (see ADVERSE REACTIONS, Expanded
Clinical Evaluation of Lovastatin (EXCEL) Study).
Concomitant Therapy
In controlled clinical studies in which lovastatin was administered concomitantly with cholestyramine,
no adverse reactions peculiar to this concomitant treatment were observed. The adverse reactions that
occurred were limited to those reported previously with lovastatin or cholestyramine. Other lipid-lowering
agents were not administered concomitantly with lovastatin during controlled clinical studies. Preliminary
data suggests that the addition of gemfibrozil to therapy with lovastatin is not associated with greater
16
Reference ID: 2899643
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844661
014-874-01
reduction in LDL-C than that achieved with lovastatin alone. In uncontrolled clinical studies, most of the
patients who have developed myopathy were receiving concomitant therapy with cyclosporine,
gemfibrozil or niacin (nicotinic acid). The combined use of lovastatin at doses exceeding 20 mg/day with
cyclosporine, gemfibrozil, other fibrates or lipid-lowering doses (≥1 g/day) of niacin should be avoided
(see WARNINGS, Myopathy/Rhabdomyolysis).
The following effects have been reported with drugs in this class. Not all the effects listed below have
necessarily been associated with lovastatin therapy.
Skeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias.
Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra
ocular movement, facial paresis), tremor, dizziness, vertigo, memory loss, paresthesia, peripheral
neuropathy, peripheral nerve palsy, psychic disturbances, anxiety, insomnia, depression.
Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which
has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like
syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia,
hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia,
photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme,
including Stevens-Johnson syndrome.
Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty
change in liver; and rarely, cirrhosis, fulminant hepatic necrosis, and hepatoma; anorexia, vomiting.
Skin: alopecia, pruritus. A variety of skin changes (e.g., nodules, discoloration, dryness of
skin/mucous membranes, changes to hair/nails) have been reported.
Reproductive: gynecomastia, loss of libido, erectile dysfunction.
Eye: progression of cataracts (lens opacities), ophthalmoplegia.
Laboratory Abnormalities: elevated transaminases, alkaline phosphatase, γ-glutamyl transpeptidase,
and bilirubin; thyroid function abnormalities.
Adolescent Patients (ages 10-17 years)
In a 48-week controlled study in adolescent boys with heFH (n=132) and a 24-week controlled study
in girls who were at least 1 year post-menarche with heFH (n=54), the safety and tolerability profile of the
groups treated with MEVACOR (10 to 40 mg daily) was generally similar to that of the groups treated with
placebo (see CLINICAL PHARMACOLOGY, Clinical Studies in Adolescent Patients and PRECAUTIONS,
Pediatric Use).
OVERDOSAGE
After oral administration of MEVACOR to mice, the median lethal dose observed was >15 g/m2.
Five healthy human volunteers have received up to 200 mg of lovastatin as a single dose without
clinically significant adverse experiences. A few cases of accidental overdosage have been reported; no
patients had any specific symptoms, and all patients recovered without sequelae. The maximum dose
taken was 5-6 g.
Until further experience is obtained, no specific treatment of overdosage with MEVACOR can be
recommended.
The dialyzability of lovastatin and its metabolites in man is not known at present.
DOSAGE AND ADMINISTRATION
The patient should be placed on a standard cholesterol-lowering diet before receiving MEVACOR and
should continue on this diet during treatment with MEVACOR (see NCEP Treatment Guidelines for
details on dietary therapy). MEVACOR should be given with meals.
Adult Patients
The usual recommended starting dose is 20 mg once a day given with the evening meal. The
recommended dosing range of lovastatin is 10-80 mg/day in single or two divided doses; the maximum
recommended dose is 80 mg/day. Doses should be individualized according to the recommended goal of
therapy (see NCEP Guidelines and CLINICAL PHARMACOLOGY). Patients requiring reductions in LDL
C of 20% or more to achieve their goal (see INDICATIONS AND USAGE) should be started on
17
Reference ID: 2899643
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
company logo
MEVACOR® (Lovastatin)
9844661
014-874-01
20 mg/day of MEVACOR. A starting dose of 10 mg of lovastatin may be considered for patients requiring
smaller reductions. Adjustments should be made at intervals of 4 weeks or more. The 10 mg dosage is
provided for information purposes only. Although lovastatin tablets 10 mg are available in the
marketplace, MEVACOR is no longer marketed in the 10 mg strength.
Cholesterol levels should be monitored periodically and consideration should be given to reducing the
dosage of MEVACOR if cholesterol levels fall significantly below the targeted range.
Dosage in Patients taking Cyclosporine or Danazol
In patients taking cyclosporine or danazol concomitantly with lovastatin (see WARNINGS,
Myopathy/Rhabdomyolysis), therapy should begin with 10 mg of lovastatin and should not exceed
20 mg/day.
Dosage in Patients taking Amiodarone or Verapamil
In patients taking amiodarone or verapamil concomitantly with MEVACOR, the dose should not
exceed 40 mg/day (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions,
Other drug interactions).
Adolescent Patients (10-17 years of age) with Heterozygous Familial Hypercholesterolemia
The recommended dosing range of lovastatin is 10-40 mg/day; the maximum recommended dose is
40 mg/day. Doses should be individualized according to the recommended goal of therapy (see NCEP
Pediatric Panel Guidelines††, CLINICAL PHARMACOLOGY, and INDICATIONS AND USAGE). Patients
requiring reductions in LDL-C of 20% or more to achieve their goal should be started on 20 mg/day of
MEVACOR. A starting dose of 10 mg of lovastatin may be considered for patients requiring smaller
reductions. Adjustments should be made at intervals of 4 weeks or more.
Concomitant Lipid-Lowering Therapy
MEVACOR is effective alone or when used concomitantly with bile-acid sequestrants. If MEVACOR is
used in combination with gemfibrozil, other fibrates or lipid-lowering doses (≥ 1g/day) of niacin, the dose
of MEVACOR should not exceed 20 mg/day (see WARNINGS, Myopathy/Rhabdomyolysis and
PRECAUTIONS, Drug Interactions).
Dosage in Patients with Renal Insufficiency
In patients with severe renal insufficiency (creatinine clearance <30 mL/min), dosage increases above
20 mg/day should be carefully considered and, if deemed necessary, implemented cautiously (see
CLINICAL PHARMACOLOGY and WARNINGS, Myopathy/Rhabdomyolysis).
HOW SUPPLIED
No. 8123 — Tablets MEVACOR 20 mg are blue, octagonal tablets, coded MSD 731 on one side and
plain on the other. They are supplied as follows:
NDC 0006-0731-61 unit of use bottles of 60.
No. 8124 — Tablets MEVACOR 40 mg are green, octagonal tablets, coded MSD 732 on one side and
plain on the other. They are supplied as follows:
NDC 0006-0732-61 unit of use bottles of 60.
Storage
Store at 20-25°C (68-77°F). [See USP Controlled Room Temperature.] Tablets MEVACOR must be
protected from light and stored in a well-closed, light-resistant container.
By:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505, USA
OR
†† National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and
Adolescents. Pediatrics. 89(3):495-501. 1992.
18
Reference ID: 2899643
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844661
014-874-01
Mylan Pharmaceuticals ULC
Etobicoke, Ontario, Canada M8Z 2S6
Issued May 2010
19
Reference ID: 2899643
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:36.549180
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019643s084lbl.pdf', 'application_number': 19643, 'submission_type': 'SUPPL ', 'submission_number': 84}
|
11,591
|
TABLETS
MEVACOR®
(LOVASTATIN)
DESCRIPTION
MEVACOR® (Lovastatin) is a cholesterol lowering agent isolated from a strain of Aspergillus terreus.
After oral ingestion, lovastatin, which is an inactive lactone, is hydrolyzed to the corresponding β
hydroxyacid form. This is a principal metabolite and an inhibitor of 3-hydroxy-3-methylglutaryl
coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate,
which is an early and rate limiting step in the biosynthesis of cholesterol.
Lovastatin
is
[1S-[1α(R*),3α,7β,8β(2S*,4S*),
8aβ]]-1,2,3,7,
8,8a-hexahydro-3,7-dimethyl-8-[2
(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl
2-methylbutanoate.
The
empirical
formula of lovastatin is C24H36O5 and its molecular weight is 404.55. Its structural formula is: chemical structure
Lovastatin is a white, nonhygroscopic crystalline powder that is insoluble in water and sparingly
soluble in ethanol, methanol, and acetonitrile.
Tablets MEVACOR are supplied as 20 mg and 40 mg tablets for oral administration. In addition to the
active ingredient lovastatin, each tablet contains the following inactive ingredients: cellulose, lactose,
magnesium stearate, and starch. Butylated hydroxyanisole (BHA) is added as a preservative. Tablets
MEVACOR 20 mg also contain FD&C Blue 2 aluminum lake. Tablets MEVACOR 40 mg also contain
D&C Yellow 10 aluminum lake and FD&C Blue 2 aluminum lake.
CLINICAL PHARMACOLOGY
The involvement of low-density lipoprotein cholesterol (LDL-C) in atherogenesis has been well-
documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological
and clinical studies have established that high LDL-C and low high-density lipoprotein cholesterol (HDL
C) are both associated with coronary heart disease. However, the risk of developing coronary heart
disease is continuous and graded over the range of cholesterol levels and many coronary events do
occur in patients with total cholesterol (total-C) and LDL-C in the lower end of this range.
MEVACOR has been shown to reduce both normal and elevated LDL-C concentrations. LDL is
formed from very low-density lipoprotein (VLDL) and is catabolized predominantly by the high affinity LDL
receptor. The mechanism of the LDL-lowering effect of MEVACOR may involve both reduction of VLDL-C
concentration, and induction of the LDL receptor, leading to reduced production and/or increased
catabolism of LDL-C. Apolipoprotein B also falls substantially during treatment with MEVACOR. Since
each LDL particle contains one molecule of apolipoprotein B, and since little apolipoprotein B is found in
other lipoproteins, this strongly suggests that MEVACOR does not merely cause cholesterol to be lost
from LDL, but also reduces the concentration of circulating LDL particles. In addition, MEVACOR can
produce increases of variable magnitude in HDL-C, and modestly reduces VLDL-C and plasma
triglycerides (TG) (see Tables II-IV under Clinical Studies). The effects of MEVACOR on Lp(a),
fibrinogen, and certain other independent biochemical risk markers for coronary heart disease are
unknown.
MEVACOR is a specific inhibitor of HMG-CoA reductase, the enzyme which catalyzes the conversion
of HMG-CoA to mevalonate. The conversion of HMG-CoA to mevalonate is an early step in the
biosynthetic pathway for cholesterol.
Reference ID: 3210294
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pharmacokinetics
Lovastatin is a lactone which is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a strong
inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in
pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base
hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of lovastatin.
Following an oral dose of 14C-labeled lovastatin in man, 10% of the dose was excreted in urine and
83% in feces. The latter represents absorbed drug equivalents excreted in bile, as well as any
unabsorbed drug. Plasma concentrations of total radioactivity (lovastatin plus 14C-metabolites) peaked at
2 hours and declined rapidly to about 10% of peak by 24 hours postdose. Absorption of lovastatin,
estimated relative to an intravenous reference dose, in each of four animal species tested, averaged
about 30% of an oral dose. In animal studies, after oral dosing, lovastatin had high selectivity for the liver,
where it achieved substantially higher concentrations than in non-target tissues. Lovastatin undergoes
extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug
equivalents in the bile. As a consequence of extensive hepatic extraction of lovastatin, the availability of
drug to the general circulation is low and variable. In a single dose study in four hypercholesterolemic
patients, it was estimated that less than 5% of an oral dose of lovastatin reaches the general circulation
as active inhibitors. Following administration of lovastatin tablets the coefficient of variation, based on
between-subject variability, was approximately 40% for the area under the curve (AUC) of total inhibitory
activity in the general circulation.
Both lovastatin and its β-hydroxyacid metabolite are highly bound (>95%) to human plasma proteins.
Animal studies demonstrated that lovastatin crosses the blood-brain and placental barriers.
The major active metabolites present in human plasma are the β-hydroxyacid of lovastatin, its
6′-hydroxy derivative, and two additional metabolites. Peak plasma concentrations of both active and total
inhibitors were attained within 2 to 4 hours of dose administration. While the recommended therapeutic
dose range is 10 to 80 mg/day, linearity of inhibitory activity in the general circulation was established by
a single dose study employing lovastatin tablet dosages from 60 to as high as 120 mg. With a once-a-day
dosing regimen, plasma concentrations of total inhibitors over a dosing interval achieved a steady state
between the second and third days of therapy and were about 1.5 times those following a single dose.
When lovastatin was given under fasting conditions, plasma concentrations of total inhibitors were on
average about two-thirds those found when lovastatin was administered immediately after a standard test
meal.
In a study of patients with severe renal insufficiency (creatinine clearance 10-30 mL/min), the plasma
concentrations of total inhibitors after a single dose of lovastatin were approximately two-fold higher than
those in healthy volunteers.
In a study including 16 elderly patients between 70-78 years of age who received MEVACOR
80 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately
45% compared with 18 patients between 18-30 years of age (see PRECAUTIONS, Geriatric Use).
Although the mechanism is not fully understood, cyclosporine has been shown to increase the AUC of
HMG-CoA reductase inhibitors. The increase in AUC for lovastatin and lovastatin acid is presumably due,
in part, to inhibition of CYP3A4.
The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.
Strong inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and
increase the risk of myopathy (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug
Interactions).
Lovastatin is a substrate for cytochrome P450 isoform 3A4 (CYP3A4) (see PRECAUTIONS, Drug
Interactions). Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase
the plasma concentrations of drugs metabolized by CYP3A4. In one study1, 10 subjects consumed 200
mL of double-strength grapefruit juice (one can of frozen concentrate diluted with one rather than 3 cans
of water) three times daily for 2 days and an additional 200 mL double-strength grapefruit juice together
with and 30 and 90 minutes following a single dose of 80 mg lovastatin on the third day. This regimen of
grapefruit juice resulted in a mean increase in the serum concentration of lovastatin and its β-hydroxyacid
metabolite (as measured by the area under the concentration-time curve) of 15-fold and 5-fold,
respectively [as measured using a chemical assay — high performance liquid chromatography]. In a
1 Kantola, T, et al., Clin Pharmacol Ther 1998; 63(4):397-402.
2
USPI-T-08031210
Reference ID: 3210294
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
second study, 15 subjects consumed one 8 oz glass of single-strength grapefruit juice (one can of frozen
concentrate diluted with 3 cans of water) with breakfast for 3 consecutive days and a single dose of
40 mg lovastatin in the evening of the third day. This regimen of grapefruit juice resulted in a mean
increase in the plasma concentration (as measured by the area under the concentration-time curve) of
active and total HMG-CoA reductase inhibitory activity [using an enzyme inhibition assay both before (for
active inhibitors) and after (for total inhibitors) base hydrolysis] of 1.34-fold and 1.36-fold, respectively,
and of lovastatin and its β-hydroxyacid metabolite [measured using a chemical assay — liquid
chromatography/tandem mass spectrometry — different from that used in the first1 study] of 1.94-fold and
1.57-fold, respectively. The effect of amounts of grapefruit juice between those used in these two studies
on lovastatin pharmacokinetics has not been studied.
TABLE I
The Effect of Other Drugs on Lovastatin Exposure When Both Were Co-administered
Number of
Subjects
Dosing of Coadministered
Drug or Grapefruit Juice
Dosing of
Lovastatin
AUC Ratio*
(with / without
coadministered drug)
No Effect = 1.00
Lovastatin
Lovastatin acid†
Gemfibrozil
11
600 mg BID for 3 days
40 mg
0.96
2.80
Itraconazole‡
12
200 mg QD for 4 days
40 mg on Day 4
> 36§
22
10
100 mg QD for 4 days
40 mg on Day 4
> 14.8§
15.4
Grapefruit Juice¶
(high dose)
10
200 mL of double-strength
TID#
80 mg single dose
15.3
5.0
Grapefruit Juice¶
(low dose)
16
8 oz (about 250 mL) of
single-strengthÞ for 4 days
40 mg single dose
1.94
1.57
Cyclosporine
16
Not describedß
10 mg QD for
10 days
5- to 8-fold
NDà
Number of
Subjects
Dosing of Coadministered
Drug or Grapefruit Juice
Dosing of
Lovastatin
AUC Ratio*
(with / without
coadministered drug)
No Effect = 1.00
Total Lovastatin acidè
Diltiazem
10
120 mg BID for 14 days
20 mg
3.57è
* Results based on a chemical assay.
† Lovastatin acid refers to the β-hydroxyacid of lovastatin.
‡ The mean total AUC of lovastatin without itraconazole phase could not be determined accurately. Results could be representative of
strong CYP3A4 inhibitors such as ketoconazole, posaconazole, clarithromycin, telithromycin, HIV protease inhibitors, and nefazodone.
§ Estimated minimum change.
¶ The effect of amounts of grapefruit juice between those used in these two studies on lovastatin pharmacokinetics has not been studied.
# Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200
mL together with single dose lovastatin and 30 and 90 minutes following single dose lovastatin on Day 3.
Þ Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days,
and lovastatin was administered in the evening on Day 3.
ß Cyclosporine-treated patients with psoriasis or post kidney or heart transplant patients with stable graft function, transplanted at least 9
months prior to study.
à ND = Analyte not determined.
è Lactone converted to acid by hydrolysis prior to analysis. Figure represents total unmetabolized acid and lactone.
Clinical Studies in Adults
MEVACOR has been shown to be highly effective in reducing total-C and LDL-C in heterozygous
familial and non-familial forms of primary hypercholesterolemia and in mixed hyperlipidemia. A marked
response was seen within 2 weeks, and the maximum therapeutic response occurred within 4-6 weeks.
The response was maintained during continuation of therapy. Single daily doses given in the evening
were more effective than the same dose given in the morning, perhaps because cholesterol is
synthesized mainly at night.
3
USPI-T-08031210
Reference ID: 3210294
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In multicenter, double-blind studies in patients with familial or non-familial hypercholesterolemia,
MEVACOR, administered in doses ranging from 10 mg q.p.m. to 40 mg b.i.d., was compared to placebo.
MEVACOR consistently and significantly decreased plasma total-C, LDL-C, total-C/HDL-C ratio and LDL
C/HDL-C ratio. In addition, MEVACOR produced increases of variable magnitude in HDL-C, and
modestly decreased VLDL-C and plasma TG (see Tables II through IV for dose response results).
The results of a study in patients with primary hypercholesterolemia are presented in Table II.
TABLE II
MEVACOR vs. Placebo
(Mean Percent Change from Baseline After 6 Weeks)
LDL-C/
TOTAL-C/
DOSAGE
N
TOTAL-C
LDL-C
HDL-C
HDL-C
HDL-C
TG.
Placebo
33
–2
–1
–1
0
+1
+9
MEVACOR
10 mg q.p.m.
33
–16
–21
+5
–24
–19
–10
20 mg q.p.m.
33
–19
–27
+6
–30
–23
+9
10 mg b.i.d.
32
–19
–28
+8
–33
–25
–7
40 mg q.p.m.
33
–22
–31
+5
–33
–25
–8
20 mg b.i.d.
36
–24
–32
+2
–32
–24
–6
MEVACOR was compared to cholestyramine in a randomized open parallel study. The study was
performed with patients with hypercholesterolemia who were at high risk of myocardial infarction.
Summary results are presented in Table III.
TABLE III
MEVACOR vs. Cholestyramine
(Percent Change from Baseline After 12 Weeks)
LDL-C/
TOTAL-C/
TREATMENT
N
TOTAL-C
LDL-C
HDL-C
HDL-C
HDL-C
VLDL-C
TG.
(mean)
(mean)
(mean)
(mean)
(mean)
(median)
(mean)
MEVACOR
20 mg b.i.d.
85
–27
–32
+9
–36
–31
–34
–21
40 mg b.i.d.
88
–34
–42
+8
–44
–37
–31
–27
Cholestyramine
12 g b.i.d.
88
–17
–23
+8
–27
–21
+2
+11
MEVACOR was studied in controlled trials in hypercholesterolemic patients with well-controlled non-
insulin dependent diabetes mellitus with normal renal function. The effect of MEVACOR on lipids and
lipoproteins and the safety profile of MEVACOR were similar to that demonstrated in studies in
nondiabetics. MEVACOR had no clinically important effect on glycemic control or on the dose
requirement of oral hypoglycemic agents.
Expanded Clinical Evaluation of Lovastatin (EXCEL) Study
MEVACOR was compared to placebo in 8,245 patients with hypercholesterolemia (total-C 240-300
mg/dL [6.2 mmol/L - 7.6 mmol/L], LDL-C >160 mg/dL [4.1 mmol/L]) in the randomized, double-blind,
parallel, 48-week EXCEL study. All changes in the lipid measurements (Table IV) in MEVACOR treated
patients were dose-related and significantly different from placebo (p≤0.001). These results were
sustained throughout the study.
4
USPI-T-08031210
Reference ID: 3210294
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
TABLE IV
MEVACOR vs. Placebo
(Percent Change from Baseline —
Average Values Between Weeks 12 and 48)
DOSAGE
N**
TOTAL-C
LDL-C
HDL-C
LDL-C/
HDL-C
TOTAL-C/
HDL-C
TG.
(mean)
(mean)
(mean)
(mean)
(mean)
(median)
Placebo
1663
+0.7
+0.4
+2.0
+0.2
+0.6
+4
MEVACOR
20 mg q.p.m.
40 mg q.p.m.
1642
1645
–17
–22
–24
–30
+6.6
+7.2
–27
–34
–21
–26
–10
–14
20 mg b.i.d.
40 mg b.i.d.
1646
1649
–24
–29
–34
–40
+8.6
+9.5
–38
–44
–29
–34
–16
–19
**Patients enrolled
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), a double-blind,
randomized, placebo-controlled, primary prevention study, demonstrated that treatment with MEVACOR
decreased the rate of acute major coronary events (composite endpoint of myocardial infarction, unstable
angina, and sudden cardiac death) compared with placebo during a median of 5.1 years of follow-up.
Participants were middle-aged and elderly men (ages 45-73) and women (ages 55-73) without
symptomatic cardiovascular disease with average to moderately elevated total-C and LDL-C, below
average HDL-C, and who were at high risk based on elevated total-C/HDL-C. In addition to age, 63% of
the participants had at least one other risk factor (baseline HDL-C <35 mg/dL, hypertension, family
history, smoking and diabetes).
AFCAPS/TexCAPS enrolled 6,605 participants (5,608 men, 997 women) based on the following lipid
entry criteria: total-C range of 180-264 mg/dL, LDL-C range of 130-190 mg/dL, HDL-C of ≤45 mg/dL for
men and ≤47 mg/dL for women, and TG of ≤400 mg/dL. Participants were treated with standard care,
including diet, and either MEVACOR 20-40 mg daily (n= 3,304) or placebo (n= 3,301). Approximately
50% of the participants treated with MEVACOR were titrated to 40 mg daily when their LDL-C remained
>110 mg/dL at the 20-mg starting dose.
MEVACOR reduced the risk of a first acute major coronary event, the primary efficacy endpoint, by
37% (MEVACOR 3.5%, placebo 5.5%; p<0.001; Figure 1). A first acute major coronary event was defined
as myocardial infarction (54 participants on MEVACOR, 94 on placebo) or unstable angina (54 vs. 80) or
sudden cardiac death (8 vs. 9). Furthermore, among the secondary endpoints, MEVACOR reduced the
risk of unstable angina by 32% (1.8 vs. 2.6%; p=0.023), of myocardial infarction by 40% (1.7 vs. 2.9%;
p=0.002), and of undergoing coronary revascularization procedures (e.g., coronary artery bypass grafting
or percutaneous transluminal coronary angioplasty) by 33% (3.2 vs. 4.8%; p=0.001). Trends in risk
reduction associated with treatment with MEVACOR were consistent across men and women, smokers
and non-smokers, hypertensives and non-hypertensives, and older and younger participants. Participants
with ≥2 risk factors had risk reductions (RR) in both acute major coronary events (RR 43%) and coronary
revascularization procedures (RR 37%). Because there were too few events among those participants
with age as their only risk factor in this study, the effect of MEVACOR on outcomes could not be
adequately assessed in this subgroup.
5
USPI-T-08031210
Reference ID: 3210294
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Acute Major Coronary Events
Atherosclerosis
In the Canadian Coronary Atherosclerosis Intervention Trial (CCAIT), the effect of therapy with
lovastatin on coronary atherosclerosis was assessed by coronary angiography in hyperlipidemic patients.
In the randomized, double-blind, controlled clinical trial, patients were treated with conventional measures
(usually diet and 325 mg of aspirin every other day) and either lovastatin 20-80 mg daily or placebo.
Angiograms were evaluated at baseline and at two years by computerized quantitative coronary
angiography (QCA). Lovastatin significantly slowed the progression of lesions as measured by the mean
change per-patient in minimum lumen diameter (the primary endpoint) and percent diameter stenosis,
and decreased the proportions of patients categorized with disease progression (33% vs. 50%) and with
new lesions (16% vs. 32%).
In a similarly designed trial, the Monitored Atherosclerosis Regression Study (MARS), patients were
treated with diet and either lovastatin 80 mg daily or placebo. No statistically significant difference
between lovastatin and placebo was seen for the primary endpoint (mean change per patient in percent
diameter stenosis of all lesions), or for most secondary QCA endpoints. Visual assessment by
angiographers who formed a consensus opinion of overall angiographic change (Global Change Score)
was also a secondary endpoint. By this endpoint, significant slowing of disease was seen, with regression
in 23% of patients treated with lovastatin compared to 11% of placebo patients.
In the Familial Atherosclerosis Treatment Study (FATS), either lovastatin or niacin in combination with
a bile acid sequestrant for 2.5 years in hyperlipidemic subjects significantly reduced the frequency of
progression and increased the frequency of regression of coronary atherosclerotic lesions by QCA
compared to diet and, in some cases, low-dose resin.
The effect of lovastatin on the progression of atherosclerosis in the coronary arteries has been
corroborated by similar findings in another vasculature. In the Asymptomatic Carotid Artery Progression
Study (ACAPS), the effect of therapy with lovastatin on carotid atherosclerosis was assessed by B-mode
ultrasonography in hyperlipidemic patients with early carotid lesions and without known coronary heart
disease at baseline. In this double-blind, controlled clinical trial, 919 patients were randomized in a 2 x 2
factorial design to placebo, lovastatin 10-40 mg daily and/or warfarin. Ultrasonograms of the carotid walls
were used to determine the change per patient from baseline to three years in mean maximum intimal
6
USPI-T-08031210
Reference ID: 3210294
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
medial thickness (IMT) of 12 measured segments. There was a significant regression of carotid lesions in
patients receiving lovastatin alone compared to those receiving placebo alone (p=0.001). The predictive
value of changes in IMT for stroke has not yet been established. In the lovastatin group there was a
significant reduction in the number of patients with major cardiovascular events relative to the placebo
group (5 vs. 14) and a significant reduction in all-cause mortality (1 vs. 8).
Eye
There was a high prevalence of baseline lenticular opacities in the patient population included in the
early clinical trials with lovastatin. During these trials the appearance of new opacities was noted in both
the lovastatin and placebo groups. There was no clinically significant change in visual acuity in the
patients who had new opacities reported nor was any patient, including those with opacities noted at
baseline, discontinued from therapy because of a decrease in visual acuity.
A three-year, double-blind, placebo-controlled study in hypercholesterolemic patients to assess the
effect of lovastatin on the human lens demonstrated that there were no clinically or statistically significant
differences between the lovastatin and placebo groups in the incidence, type or progression of lenticular
opacities. There are no controlled clinical data assessing the lens available for treatment beyond three
years.
Clinical Studies in Adolescent Patients
Efficacy of Lovastatin in Adolescent Boys with Heterozygous Familial Hypercholesterolemia
In a double-blind, placebo-controlled study, 132 boys 10-17 years of age (mean age 12.7 yrs) with
heterozygous familial hypercholesterolemia (heFH) were randomized to lovastatin (n=67) or placebo
(n=65) for 48 weeks. Inclusion in the study required a baseline LDL-C level between 189 and 500 mg/dL
and at least one parent with an LDL-C level >189 mg/dL. The mean baseline LDL-C value was
253.1 mg/dL (range: 171-379 mg/dL) in the MEVACOR group compared to 248.2 mg/dL (range:
158.5-413.5 mg/dL) in the placebo group. The dosage of lovastatin (once daily in the evening) was 10 mg
for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter.
MEVACOR significantly decreased plasma levels of total-C, LDL-C and apolipoprotein B (see
Table V).
TABLE V
Lipid-lowering Effects of Lovastatin in Adolescent Boys with Heterozygous Familial Hypercholesterolemia
(Mean Percent Change from Baseline at Week 48 in Intention-to-Treat Population)
DOSAGE
N
TOTAL-C
LDL-C
HDL-C
TG.*
Apolipoprotein B
Placebo
61
-1.1
-1.4
-2.2
-1.4
-4.4
MEVACOR
64
-19.3
-24.2
+1.1
-1.9
-21
*data presented as median percent changes
The mean achieved LDL-C value was 190.9 mg/dL (range: 108-336 mg/dL) in the MEVACOR group
compared to 244.8 mg/dL (range: 135-404 mg/dL) in the placebo group.
Efficacy of Lovastatin in Post-Menarchal Girls with Heterozygous Familial Hypercholesterolemia
In a double-blind, placebo-controlled study, 54 girls 10-17 years of age who were at least 1 year
post-menarche with heFH were randomized to lovastatin (n=35) or placebo (n=19) for 24 weeks.
Inclusion in the study required a baseline LDL-C level of 160-400 mg/dL and a parental history of familial
hypercholesterolemia. The mean baseline LDL-C value was 218.3 mg/dL (range: 136.3-363.7 mg/dL) in
the MEVACOR group compared to 198.8 mg/dL (range: 151.1-283.1 mg/dL) in the placebo group. The
dosage of lovastatin (once daily in the evening) was 20 mg for the first 4 weeks, and 40 mg thereafter.
MEVACOR significantly decreased plasma levels of total-C, LDL-C, and apolipoprotein B (see
Table VI).
7
USPI-T-08031210
Reference ID: 3210294
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
TABLE VI
Lipid-lowering Effects of Lovastatin in Post-Menarchal Girls with Heterozygous Familial Hypercholesterolemia
(Mean Percent Change from Baseline at Week 24 in Intention-to-Treat Population)
DOSAGE
N
TOTAL-C
LDL-C
HDL-C
TG.*
Apolipoprotein B
Placebo
18
+3.6
+2.5
+4.8
-3.0
+6.4
MEVACOR
35
-22.4
-29.2
+2.4
-22.7
-24.4
*data presented as median percent changes
The mean achieved LDL-C value was 154.5 mg/dL (range: 82-286 mg/dL) in the MEVACOR group
compared to 203.5 mg/dL (range: 135-304 mg/dL) in the placebo group.
The safety and efficacy of doses above 40 mg daily have not been studied in children. The long-term
efficacy of lovastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been
established.
INDICATIONS AND USAGE
Therapy with MEVACOR should be a component of multiple risk factor intervention in those
individuals with dyslipidemia at risk for atherosclerotic vascular disease. MEVACOR should be used in
addition to a diet restricted in saturated fat and cholesterol as part of a treatment strategy to lower total-C
and LDL-C to target levels when the response to diet and other nonpharmacological measures alone has
been inadequate to reduce risk.
Primary Prevention of Coronary Heart Disease
In individuals without symptomatic cardiovascular disease, average to moderately elevated total-C
and LDL-C, and below average HDL-C, MEVACOR is indicated to reduce the risk of:
- Myocardial infarction
- Unstable angina
- Coronary revascularization procedures
(See CLINICAL PHARMACOLOGY, Clinical Studies.)
Coronary Heart Disease
MEVACOR is indicated to slow the progression of coronary atherosclerosis in patients with coronary
heart disease as part of a treatment strategy to lower total-C and LDL-C to target levels.
Hypercholesterolemia
Therapy with lipid-altering agents should be a component of multiple risk factor intervention in those
individuals
at
significantly
increased
risk
for
atherosclerotic
vascular
disease
due
to
hypercholesterolemia. MEVACOR is indicated as an adjunct to diet for the reduction of elevated total-C
and LDL-C levels in patients with primary hypercholesterolemia (Types IIa and IIb2), when the response
to diet restricted in saturated fat and cholesterol and to other nonpharmacological measures alone has
been inadequate.
Adolescent Patients with Heterozygous Familial Hypercholesterolemia
MEVACOR is indicated as an adjunct to diet to reduce total-C, LDL-C and apolipoprotein B levels in
adolescent boys and girls who are at least one year post-menarche, 10-17 years of age, with heFH if
after an adequate trial of diet therapy the following findings are present:
1. LDL-C remains >189 mg/dL or
2 Classification of Hyperlipoproteinemias
Lipid
Lipoproteins
Elevations
Type
elevated
major
minor
I
chylomicrons
TG
↑→C
IIa
LDL
C
—
IIb
LDL, VLDL
C
TG
III (rare)
IDL
C/TG
—
IV
VLDL
TG
↑→C
V (rare)
chylomicrons, VLDL
TG
↑→C
IDL = intermediate-density lipoprotein.
8
USPI-T-08031210
Reference ID: 3210294
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2. LDL-C remains >160 mg/dL and:
•
there is a positive family history of premature cardiovascular disease or
•
two or more other CVD risk factors are present in the adolescent patient
General Recommendations
Prior to initiating therapy with lovastatin, secondary causes for hypercholesterolemia (e.g., poorly
controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver
disease, other drug therapy, alcoholism) should be excluded, and a lipid profile performed to measure
total-C, HDL-C, and TG. For patients with TG less than 400 mg/dL (<4.5 mmol/L), LDL-C can be
estimated using the following equation:
LDL-C = total-C – [0.2 × (TG) + HDL-C]
For TG levels >400 mg/dL (>4.5 mmol/L), this equation is less accurate and LDL-C concentrations
should be determined by ultracentrifugation. In hypertriglyceridemic patients, LDL-C may be low or
normal despite elevated total-C. In such cases, MEVACOR is not indicated.
The National Cholesterol Education Program (NCEP) Treatment Guidelines are summarized below:
NCEP Treatment Guidelines:
LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes
and Drug Therapy in Different Risk Categories
LDL Level at Which to
LDL Level at Which to
Risk Category
LDL Goal
Initiate Therapeutic Lifestyle Changes
Consider Drug Therapy
(mg/dL)
(mg/dL)
(mg/dL)
CHD† or CHD risk equivalents
<100
≥100
≥130
(10-year risk >20%)
(100-129: drug optional)††
2+ Risk factors
<130
≥130
10-year risk 10-20%: ≥130
(10 year risk ≤20%)
10-year risk <10%: ≥ 160
0-1 Risk factor†††
<160
≥160
≥190
(160-189: LDL-lowering drug
optional)
†
CHD, coronary heart disease
††
Some authorities recommend use of LDL-lowering drugs in this category if an LDL-C level of <100 mg/dL cannot be achieved by therapeutic
lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL-C, e.g., nicotinic acid or fibrate. Clinical judgment also
may call for deferring drug therapy in this subcategory.
†††
Almost all people with 0-1 risk factor have a 10-year risk <10%; thus, 10-year risk assessment in people with 0-1 risk factor is not necessary.
After the LDL-C goal has been achieved, if the TG is still ≥200 mg/dL, non-HDL-C (total-C minus HDL
C) becomes a secondary target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals
for each risk category.
At the time of hospitalization for an acute coronary event, consideration can be given to initiating drug
therapy at discharge if the LDL-C is ≥130 mg/dL (see NCEP Guidelines above).
Since the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C levels be used to
initiate and assess treatment response. Only if LDL-C levels are not available, should the total-C be used
to monitor therapy.
Although MEVACOR may be useful to reduce elevated LDL-C levels in patients with combined
hypercholesterolemia and hypertriglyceridemia where hypercholesterolemia is the major abnormality
(Type IIb hyperlipoproteinemia), it has not been studied in conditions where the major abnormality is
elevation of chylomicrons, VLDL or IDL (i.e., hyperlipoproteinemia types I, III, IV, or V).2
The NCEP classification of cholesterol levels in pediatric patients with a familial history of
hypercholesterolemia or premature cardiovascular disease is summarized below:
Category
Total-C (mg/dL)
LDL-C (mg/dL)
Acceptable
Borderline
High
<170
170-199
≥200
<110
110-129
≥130
Children treated with lovastatin in adolescence should be re-evaluated in adulthood and appropriate
changes made to their cholesterol-lowering regimen to achieve adult goals for LDL-C.
9
USPI-T-08031210
Reference ID: 3210294
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CONTRAINDICATIONS
Hypersensitivity to any component of this medication.
Active liver disease or unexplained persistent elevations of serum transaminases (see WARNINGS).
Concomitant administration with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole,
posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin,
telithromycin and nefazodone) (see WARNINGS, Myopathy/Rhabdomyolysis).
Pregnancy and lactation (see PRECAUTIONS, Pregnancy and Nursing Mothers). Atherosclerosis is a
chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact
on the outcome of long-term therapy of primary hypercholesterolemia. Moreover, cholesterol and other
products of the cholesterol biosynthesis pathway are essential components for fetal development,
including synthesis of steroids and cell membranes. Because of the ability of inhibitors of HMG-CoA
reductase such as MEVACOR to decrease the synthesis of cholesterol and possibly other products of the
cholesterol biosynthesis pathway, MEVACOR is contraindicated during pregnancy and in nursing
mothers. MEVACOR should be administered to women of childbearing age only when such
patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug,
MEVACOR should be discontinued immediately and the patient should be apprised of the potential
hazard to the fetus (see PRECAUTIONS, Pregnancy).
WARNINGS
Myopathy/Rhabdomyolysis
Lovastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as
muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal
(ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure
secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high
levels of HMG-CoA reductase inhibitory activity in plasma.
As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose
related. In a clinical study (EXCEL) in which patients were carefully monitored and some interacting
drugs were excluded, there was one case of myopathy among 4933 patients randomized to lovastatin 20
40 mg daily for 48 weeks, and 4 among 1649 patients randomized to 80 mg daily.
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune
myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated
serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing
necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
All patients starting therapy with MEVACOR, or whose dose of MEVACOR is being increased,
should be advised of the risk of myopathy and told to report promptly any unexplained muscle
pain, tenderness or weakness particularly if accompanied by malaise or fever or if muscle signs
and symptoms persist after discontinuing MEVACOR. MEVACOR therapy should be discontinued
immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK
increases resolved when treatment was promptly discontinued. Periodic CK determinations may be
considered in patients starting therapy with MEVACOR or whose dose is being increased, but there is no
assurance that such monitoring will prevent myopathy.
Many of the patients who have developed rhabdomyolysis on therapy with lovastatin have had
complicated medical histories, including renal insufficiency usually as a consequence of long-standing
diabetes mellitus. Such patients merit closer monitoring. MEVACOR therapy should be discontinued if
markedly elevated CPK levels occur or myopathy is diagnosed or suspected. MEVACOR therapy should
also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the
development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery;
trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.
The risk of myopathy/rhabdomyolysis is increased by concomitant use of lovastatin with the
following:
10
USPI-T-08031210
Reference ID: 3210294
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Strong inhibitors of CYP3A4: Lovastatin, like several other inhibitors of HMG-CoA reductase, is a
substrate of cytochrome P450 3A4 (CYP3A4). Certain drugs which inhibit this metabolic pathway can
raise the plasma levels of lovastatin and may increase the risk of myopathy. These include
itraconazole, ketoconazole, posaconazole, voriconazole, the macrolide antibiotics erythromycin and
clarithromycin, the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir, or
the antidepressant nefazodone. Combination of these drugs with lovastatin is contraindicated. If
short-term treatment with strong CYP3A4 inhibitors is unavoidable, therapy with lovastatin should be
suspended during the course of treatment (see CONTRAINDICATIONS; PRECAUTIONS, Drug
Interactions).
Gemfibrozil: The combined use of lovastatin with gemfibrozil should be avoided.
Other lipid-lowering drugs (other fibrates or ≥1 g/day of niacin): Caution should be used when
prescribing other fibrates or lipid-lowering doses (≥1 g/day) of niacin with lovastatin, as these agents
can cause myopathy when given alone. The benefit of further alterations in lipid levels by the
combined use of lovastatin with other fibrates or niacin should be carefully weighed against
the potential risks of these combinations.
Cyclosporine: The use of lovastatin with cyclosporine should be avoided.
Danazol, diltiazem, dronedarone or verapamil with higher doses of lovastatin: The dose of
lovastatin should not exceed 20 mg daily in patients receiving concomitant medication with
danazol, diltiazem, dronedarone, or verapamil. The benefits of the use of lovastatin in patients
receiving danazol, diltiazem, dronedarone, or verapamil should be carefully weighed against the risks
of these combinations.
Amiodarone: The dose of lovastatin should not exceed 40 mg daily in patients receiving
concomitant medication with amiodarone. The combined use of lovastatin at doses higher than
40 mg daily with amiodarone should be avoided unless the clinical benefit is likely to outweigh the
increased risk of myopathy. The risk of myopathy/rhabdomyolysis is increased when amiodarone is
used concomitantly with higher doses of a closely related member of the HMG-CoA reductase
inhibitor class.
Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with lovastatin
coadministered with colchicine, and caution should be exercised when prescribing lovastatin with
colchicine (see PRECAUTIONS, Drug Interactions).
Ranolazine: The risk of myopathy, including rhabdomyolysis, may be increased by concomitant
administration of ranolazine. Dose adjustment of lovastatin may be considered during co
administration with ranolazine.
Prescribing recommendations for interacting agents are summarized in Table VII (see also CLINICAL
PHARMACOLOGY,
Pharmacokinetics;
PRECAUTIONS,
Drug
Interactions;
DOSAGE
AND
ADMINISTRATION).
11
USPI-T-08031210
Reference ID: 3210294
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table VII
Drug Interactions Associated with Increased
Risk of Myopathy/Rhabdomyolysis
Interacting Agents
Prescribing Recommendations
Strong CYP3A4 inhibitors, e.g.:
Ketoconazole
Itraconazole
Posaconazole
Voriconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors
Boceprevir
Telaprevir
Nefazodone
Contraindicated with lovastatin
Gemfibrozil
Cyclosporine
Avoid with lovastatin
Danazol
Diltiazem
Dronedarone
Verapamil
Do not exceed 20 mg lovastatin daily
Amiodarone
Do not exceed 40 mg lovastatin daily
Grapefruit juice
Avoid grapefruit juice
Liver Dysfunction
Persistent increases (to more than 3 times the upper limit of normal) in serum transaminases
occurred in 1.9% of adult patients who received lovastatin for at least one year in early clinical
trials (see ADVERSE REACTIONS). When the drug was interrupted or discontinued in these patients,
the transaminase levels usually fell slowly to pretreatment levels. The increases usually appeared 3 to 12
months after the start of therapy with lovastatin, and were not associated with jaundice or other clinical
signs or symptoms. There was no evidence of hypersensitivity. In the EXCEL study (see CLINICAL
PHARMACOLOGY, Clinical Studies), the incidence of persistent increases in serum transaminases over
48 weeks was 0.1% for placebo, 0.1% at 20 mg/day, 0.9% at 40 mg/day, and 1.5% at 80 mg/day in
patients on lovastatin. However, in post-marketing experience with MEVACOR, symptomatic liver disease
has been reported rarely at all dosages (see ADVERSE REACTIONS).
In AFCAPS/TexCAPS, the number of participants with consecutive elevations of either alanine
aminotransferase (ALT) or aspartate aminotransferase (AST) (> 3 times the upper limit of normal), over a
median of 5.1 years of follow-up, was not significantly different between the MEVACOR and placebo
groups (18 [0.6%] vs. 11 [0.3%]). The starting dose of MEVACOR was 20 mg/day; 50% of the MEVACOR
treated participants were titrated to 40 mg/day at Week 18. Of the 18 participants on MEVACOR with
consecutive elevations of either ALT or AST, 11 (0.7%) elevations occurred in participants taking 20
mg/day, while 7 (0.4%) elevations occurred in participants titrated to 40 mg/day. Elevated transaminases
resulted in discontinuation of 6 (0.2%) participants from therapy in the MEVACOR group (n=3,304) and 4
(0.1%) in the placebo group (n=3,301).
It is recommended that liver enzyme tests be obtained prior to initiating therapy with MEVACOR and
repeated as clinically indicated.
There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking
statins, including lovastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or
jaundice occurs during treatment with MEVACOR, promptly interrupt therapy. If an alternate etiology is
not found do not restart MEVACOR.
The drug should be used with caution in patients who consume substantial quantities of alcohol and/or
have a past history of liver disease. Active liver disease or unexplained transaminase elevations are
contraindications to the use of lovastatin.
As with other lipid-lowering agents, moderate (less than three times the upper limit of normal)
elevations of serum transaminases have been reported following therapy with MEVACOR (see
ADVERSE REACTIONS). These changes appeared soon after initiation of therapy with MEVACOR, were
often transient, were not accompanied by any symptoms and interruption of treatment was not required.
12
USPI-T-08031210
Reference ID: 3210294
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PRECAUTIONS
General
Lovastatin may elevate creatine phosphokinase and transaminase levels (see WARNINGS and
ADVERSE REACTIONS). This should be considered in the differential diagnosis of chest pain in a patient
on therapy with lovastatin.
Homozygous Familial Hypercholesterolemia
MEVACOR is less effective in patients with the rare homozygous familial hypercholesterolemia,
possibly because these patients have no functional LDL receptors. MEVACOR appears to be more likely
to raise serum transaminases (see ADVERSE REACTIONS) in these homozygous patients.
Information for Patients
Patients should be advised about substances they should not take concomitantly with
MEVACOR and be advised to report promptly unexplained muscle pain, tenderness, or weakness
particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after
discontinuing MEVACOR (see list below and WARNINGS, Myopathy/Rhabdomyolysis). Patients
should also be advised to inform other physicians prescribing a new medication that they are
taking MEVACOR.
It is recommended that liver enzymes be checked before starting therapy, and if signs or symptoms of
liver injury occur. All patients treated with MEVACOR should be advised to report promptly any symptoms
that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or
jaundice.
Drug Interactions
CYP3A4 Interactions
Lovastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not
expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. Strong inhibitors of
CYP3A4 (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, HIV
protease inhibitors, boceprevir, telaprevir, nefazodone, and erythromycin), and grapefruit juice increase
the risk of myopathy by reducing the elimination of lovastatin. (See CONTRAINDICATIONS,
WARNINGS, Myopathy/Rhabdomyolysis, and CLINICAL PHARMACOLOGY, Pharmacokinetics.)
Interactions With Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone
The risk of myopathy is also increased by the following lipid-lowering drugs that are not strong
CYP3A4 inhibitors, but which can cause myopathy when given alone.
See WARNINGS, Myopathy/Rhabdomyolysis.
Gemfibrozil
Other fibrates
Niacin (nicotinic acid) (≥1 g/day)
Other Drug Interactions
Cyclosporine: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of
cyclosporine (see WARNINGS, Myopathy/Rhabdomyolysis).
Danazol, Diltiazem, Dronedarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased by
concomitant administration of danazol, diltiazem, dronedarone or verapamil particularly with higher doses
of
lovastatin
(see
WARNINGS,
Myopathy/Rhabdomyolysis;
CLINICAL
PHARMACOLOGY,
Pharmacokinetics).
Amiodarone: The risk of myopathy/rhabdomyolysis is increased when amiodarone is used
concomitantly with a closely related member of the HMG-CoA reductase inhibitor class (see WARNINGS,
Myopathy/Rhabdomyolysis).
Coumarin Anticoagulants: In a small clinical trial in which lovastatin was administered to warfarin
treated patients, no effect on prothrombin time was detected. However, another HMG-CoA reductase
inhibitor has been found to produce a less than two-second increase in prothrombin time in healthy
volunteers receiving low doses of warfarin. Also, bleeding and/or increased prothrombin time have been
reported in a few patients taking coumarin anticoagulants concomitantly with lovastatin. It is
13
USPI-T-08031210
Reference ID: 3210294
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
recommended that in patients taking anticoagulants, prothrombin time be determined before starting
lovastatin and frequently enough during early therapy to insure that no significant alteration of
prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can
be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose
of lovastatin is changed, the same procedure should be repeated. Lovastatin therapy has not been
associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with lovastatin
coadministered with colchicine. See WARNINGS, Myopathy/Rhabdomyolysis.
Ranolazine: The risk of myopathy, including rhabdomyolysis, may be increased by concomitant
administration of ranolazine. See WARNINGS, Myopathy/Rhabdomyolysis.
Propranolol: In normal volunteers, there was no clinically significant pharmacokinetic or
pharmacodynamic interaction with concomitant administration of single doses of lovastatin and
propranolol.
Digoxin: In patients with hypercholesterolemia, concomitant administration of lovastatin and digoxin
resulted in no effect on digoxin plasma concentrations.
Oral Hypoglycemic Agents: In pharmacokinetic studies of MEVACOR in hypercholesterolemic non-
insulin dependent diabetic patients, there was no drug interaction with glipizide or with chlorpropamide
(see CLINICAL PHARMACOLOGY, Clinical Studies).
Endocrine Function
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase
inhibitors, including MEVACOR.
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically
blunt adrenal and/or gonadal steroid production. Results of clinical trials with drugs in this class have
been inconsistent with regard to drug effects on basal and reserve steroid levels. However, clinical
studies have shown that lovastatin does not reduce basal plasma cortisol concentration or impair adrenal
reserve, and does not reduce basal plasma testosterone concentration. Another HMG-CoA reductase
inhibitor has been shown to reduce the plasma testosterone response to HCG. In the same study, the
mean testosterone response to HCG was slightly but not significantly reduced after treatment with
lovastatin 40 mg daily for 16 weeks in 21 men. The effects of HMG-CoA reductase inhibitors on male
fertility have not been studied in adequate numbers of male patients. The effects, if any, on the pituitary-
gonadal axis in pre-menopausal women are unknown. Patients treated with lovastatin who develop
clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be
exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is
administered to patients also receiving other drugs (e.g., spironolactone, cimetidine) that may decrease
the levels or activity of endogenous steroid hormones.
CNS Toxicity
Lovastatin produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in
clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean
plasma drug levels about 30 times higher than the mean drug level in humans taking the highest
recommended dose (as measured by total enzyme inhibitory activity). Vestibulocochlear Wallerian-like
degeneration and retinal ganglion cell chromatolysis were also seen in dogs treated for 14 weeks at 180
mg/kg/day, a dose which resulted in a mean plasma drug level (Cmax) similar to that seen with the 60
mg/kg/day dose.
CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell
infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels, were seen in
dogs treated with lovastatin at a dose of 180 mg/kg/day, a dose which produced plasma drug levels
(Cmax) which were about 30 times higher than the mean values in humans taking 80 mg/day.
Similar optic nerve and CNS vascular lesions have been observed with other drugs of this class.
Cataracts were seen in dogs treated for 11 and 28 weeks at 180 mg/kg/day and 1 year at
60 mg/kg/day.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 21-month carcinogenic study in mice, there was a statistically significant increase in the incidence
of hepatocellular carcinomas and adenomas in both males and females at 500 mg/kg/day. This dose
produced a total plasma drug exposure 3 to 4 times that of humans given the highest recommended dose
of lovastatin (drug exposure was measured as total HMG-CoA reductase inhibitory activity in extracted
14
USPI-T-08031210
Reference ID: 3210294
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
plasma). Tumor increases were not seen at 20 and 100 mg/kg/day, doses that produced drug exposures
of 0.3 to 2 times that of humans at the 80 mg/day dose. A statistically significant increase in pulmonary
adenomas was seen in female mice at approximately 4 times the human drug exposure. (Although mice
were given 300 times the human dose [HD] on a mg/kg body weight basis, plasma levels of total
inhibitory activity were only 4 times higher in mice than in humans given 80 mg of MEVACOR.)
There was an increase in incidence of papilloma in the non-glandular mucosa of the stomach of mice
beginning at exposures of 1 to 2 times that of humans. The glandular mucosa was not affected. The
human stomach contains only glandular mucosa.
In a 24-month carcinogenicity study in rats, there was a positive dose response relationship for
hepatocellular carcinogenicity in males at drug exposures between 2-7 times that of human exposure at
80 mg/day (doses in rats were 5, 30 and 180 mg/kg/day).
An increased incidence of thyroid neoplasms in rats appears to be a response that has been seen
with other HMG-CoA reductase inhibitors.
A chemically similar drug in this class was administered to mice for 72 weeks at 25, 100, and
400 mg/kg body weight, which resulted in mean serum drug levels approximately 3, 15, and 33 times
higher than the mean human serum drug concentration (as total inhibitory activity) after a 40 mg oral
dose. Liver carcinomas were significantly increased in high dose females and mid- and high dose males,
with a maximum incidence of 90 percent in males. The incidence of adenomas of the liver was
significantly increased in mid- and high dose females. Drug treatment also significantly increased the
incidence of lung adenomas in mid- and high dose males and females. Adenomas of the Harderian gland
(a gland of the eye of rodents) were significantly higher in high dose mice than in controls.
No evidence of mutagenicity was observed in a microbial mutagen test using mutant strains of
Salmonella typhimurium with or without rat or mouse liver metabolic activation. In addition, no evidence of
damage to genetic material was noted in an in vitro alkaline elution assay using rat or mouse
hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in
CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow.
Drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant
cell formation were seen in dogs starting at 20 mg/kg/day. Similar findings were seen with another drug in
this class. No drug-related effects on fertility were found in studies with lovastatin in rats. However, in
studies with a similar drug in this class, there was decreased fertility in male rats treated for 34 weeks at
25 mg/kg body weight, although this effect was not observed in a subsequent fertility study when this
same dose was administered for 11 weeks (the entire cycle of spermatogenesis, including epididymal
maturation). In rats treated with this same reductase inhibitor at 180 mg/kg/day, seminiferous tubule
degeneration (necrosis and loss of spermatogenic epithelium) was observed. No microscopic changes
were observed in the testes from rats of either study. The clinical significance of these findings is unclear.
Pregnancy
Pregnancy Category X
See CONTRAINDICATIONS.
Safety in pregnant women has not been established.
Lovastatin has been shown to produce skeletal malformations in offspring of pregnant mice and rats
dosed during gestation at 80 mg/kg/day (affected mouse fetuses/total: 8/307 compared to 4/289 in the
control group; affected rat fetuses/total: 6/324 compared to 2/308 in the control group). Female rats
dosed before mating through gestation at 80 mg/kg/day also had fetuses with skeletal malformations
(affected fetuses/total: 1/152 compared to 0/171 in the control group). The 80 mg/kg/day dose in mice is 7
times the human dose based on body surface area and in rats results in 5 times the human exposure
based on AUC. In pregnant rats given doses of 2, 20, or 200 mg/kg/day and treated through lactation, the
following effects were observed: neonatal mortality (4.1%, 3.5%, and 46%, respectively, compared to
0.6% in the control group), decreased pup body weights throughout lactation (up to 5%, 8%, and 38%,
respectively, below control), supernumerary ribs in dead pups (affected fetuses/total: 0/7, 1/17, and
11/79, respectively, compared to 0/5 in the control group), delays in ossification in dead pups (affected
fetuses/total: 0/7, 0/17, and 1/79, respectively, compared to 0/5 in the control group) and delays in pup
development (delays in the appearance of an auditory startle response at 200 mg/kg/day and free-fall
righting reflexes at 20 and 200 mg/kg/day).
Direct dosing of neonatal rats by subcutaneous injection with 10 mg/kg/day of the open hydroxyacid
form of lovastatin resulted in delayed passive avoidance learning in female rats (mean of 8.3 trials to
15
USPI-T-08031210
Reference ID: 3210294
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
criterion, compared to 7.3 and 6.4 in untreated and vehicle-treated controls; no effects on retention 1
week later) at exposures 4 times the human systemic exposure at 80 mg/day based on AUC. No effect
was seen in male rats. No evidence of malformations was observed when pregnant rabbits were given 5
mg/kg/day (doses equivalent to a human dose of 80 mg/day based on body surface area) or a maternally
toxic dose of 15 mg/kg/day (3 times the human dose of 80 mg/day based on body surface area).
Rare clinical reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase
inhibitors have been received. However, in an analysis3 of greater than 200 prospectively followed
pregnancies exposed during the first trimester to MEVACOR or another closely related HMG-CoA
reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general
population. This number of pregnancies was sufficient to exclude a 3-fold or greater increase in
congenital anomalies over the background incidence.
Maternal treatment with MEVACOR may reduce the fetal levels of mevalonate, which is a precursor of
cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-
lowering drugs during pregnancy should have little impact on the long-term risk associated with primary
hypercholesterolemia. For these reasons, MEVACOR should not be used in women who are pregnant, or
can become pregnant (see CONTRAINDICATIONS). MEVACOR should be administered to women of
child-bearing potential only when such patients are highly unlikely to conceive and have been informed of
the potential hazards. Treatment should be immediately discontinued as soon as pregnancy is
recognized.
Nursing Mothers
It is not known whether lovastatin is excreted in human milk. Because a small amount of another drug
in this class is excreted in human breast milk and because of the potential for serious adverse reactions
in nursing infants, women taking MEVACOR should not nurse their infants (see CONTRAINDICATIONS).
Pediatric Use
Safety and effectiveness in patients 10-17 years of age with heFH have been evaluated in controlled
clinical trials of 48 weeks duration in adolescent boys and controlled clinical trials of 24 weeks duration in
girls who were at least 1 year post-menarche. Patients treated with lovastatin had an adverse experience
profile generally similar to that of patients treated with placebo. Doses greater than 40 mg have not
been studied in this population. In these limited controlled studies, there was no detectable effect on
growth or sexual maturation in the adolescent boys or on menstrual cycle length in girls. See CLINICAL
PHARMACOLOGY, Clinical Studies in Adolescent Patients; ADVERSE REACTIONS, Adolescent
Patients; and DOSAGE AND ADMINISTRATION, Adolescent Patients (10-17 years of age) with
Heterozygous Familial Hypercholesterolemia. Adolescent females should be counseled on appropriate
contraceptive methods while on lovastatin therapy (see CONTRAINDICATIONS and PRECAUTIONS,
Pregnancy). Lovastatin has not been studied in pre-pubertal patients or patients younger than
10 years of age.
Geriatric Use
A pharmacokinetic study with lovastatin showed the mean plasma level of HMG-CoA reductase
inhibitory activity to be approximately 45% higher in elderly patients between 70-78 years of age
compared with patients between 18-30 years of age; however, clinical study experience in the elderly
indicates that dosage adjustment based on this age-related pharmacokinetic difference is not needed. In
the two large clinical studies conducted with lovastatin (EXCEL and AFCAPS/TexCAPS), 21%
(3094/14850) of patients were ≥65 years of age. Lipid-lowering efficacy with lovastatin was at least as
great in elderly patients compared with younger patients, and there were no overall differences in safety
over the 20 to 80 mg/day dosage range (see CLINICAL PHARMACOLOGY).
ADVERSE REACTIONS
MEVACOR is generally well tolerated; adverse reactions usually have been mild and transient.
3
Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin
Exposure During Pregnancy. Reproductive Toxicology. 10(6):439-446. 1996.
16
USPI-T-08031210
Reference ID: 3210294
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Phase III Clinical Studies
In Phase III controlled clinical studies involving 613 patients treated with MEVACOR, the adverse
experience profile was similar to that shown below for the 8,245-patient EXCEL study (see Expanded
Clinical Evaluation of Lovastatin [EXCEL] Study).
Persistent increases of serum transaminases have been noted (see WARNINGS, Liver Dysfunction).
About 11% of patients had elevations of CK levels of at least twice the normal value on one or more
occasions. The corresponding values for the control agent cholestyramine was 9 percent. This was
attributable to the noncardiac fraction of CK. Large increases in CK have sometimes been reported (see
WARNINGS, Myopathy/Rhabdomyolysis).
Expanded Clinical Evaluation of Lovastatin (EXCEL) Study
MEVACOR was compared to placebo in 8,245 patients with hypercholesterolemia (total-C 240-300
mg/dL [6.2-7.8 mmol/L]) in the randomized, double-blind, parallel, 48-week EXCEL study. Clinical
adverse experiences reported as possibly, probably or definitely drug-related in ≥1% in any treatment
group are shown in the table below. For no event was the incidence on drug and placebo statistically
different.
Placebo
(N = 1663)
%
MEVACOR
20 mg q.p.m.
(N = 1642)
%
MEVACOR
40 mg q.p.m.
(N = 1645)
%
MEVACOR
20 mg b.i.d.
(N = 1646)
%
MEVACOR
40 mg b.i.d.
(N = 1649)
%
Body As a Whole
Asthenia
1.4
1.7
1.4
1.5
1.2
Gastrointestinal
Abdominal pain
Constipation
Diarrhea
Dyspepsia
Flatulence
Nausea
1.6
1.9
2.3
1.9
4.2
2.5
2.0
2.0
2.6
1.3
3.7
1.9
2.0
3.2
2.4
1.3
4.3
2.5
2.2
3.2
2.2
1.0
3.9
2.2
2.5
3.5
2.6
1.6
4.5
2.2
Musculoskeletal
Muscle cramps
Myalgia
0.5
1.7
0.6
2.6
0.8
1.8
1.1
2.2
1.0
3.0
Nervous System/
Psychiatric
Dizziness
Headache
0.7
2.7
0.7
2.6
1.2
2.8
0.5
2.1
0.5
3.2
Skin
Rash
0.7
0.8
1.0
1.2
1.3
Special Senses
Blurred vision
0.8
1.1
0.9
0.9
1.2
Other clinical adverse experiences reported as possibly, probably or definitely drug-related in 0.5 to
1.0 percent of patients in any drug-treated group are listed below. In all these cases the incidence on
drug and placebo was not statistically different. Body as a Whole: chest pain; Gastrointestinal: acid
regurgitation, dry mouth, vomiting; Musculoskeletal: leg pain, shoulder pain, arthralgia; Nervous
System/Psychiatric: insomnia, paresthesia; Skin: alopecia, pruritus; Special Senses: eye irritation.
In the EXCEL study (see CLINICAL PHARMACOLOGY, Clinical Studies), 4.6% of the patients treated
up to 48 weeks were discontinued due to clinical or laboratory adverse experiences which were rated by
the investigator as possibly, probably or definitely related to therapy with MEVACOR. The value for the
placebo group was 2.5%.
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
In AFCAPS/TexCAPS (see CLINICAL PHARMACOLOGY, Clinical Studies) involving 6,605
participants treated with 20-40 mg/day of MEVACOR (n=3,304) or placebo (n=3,301), the safety and
tolerability profile of the group treated with MEVACOR was comparable to that of the group treated with
placebo during a median of 5.1 years of follow-up. The adverse experiences reported in
AFCAPS/TexCAPS were similar to those reported in EXCEL (see ADVERSE REACTIONS, Expanded
Clinical Evaluation of Lovastatin (EXCEL) Study).
17
USPI-T-08031210
Reference ID: 3210294
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Concomitant Therapy
In controlled clinical studies in which lovastatin was administered concomitantly with cholestyramine,
no adverse reactions peculiar to this concomitant treatment were observed. The adverse reactions that
occurred were limited to those reported previously with lovastatin or cholestyramine. Other lipid-lowering
agents were not administered concomitantly with lovastatin during controlled clinical studies. Preliminary
data suggests that the addition of gemfibrozil to therapy with lovastatin is not associated with greater
reduction in LDL-C than that achieved with lovastatin alone. In uncontrolled clinical studies, most of the
patients who have developed myopathy were receiving concomitant therapy with cyclosporine,
gemfibrozil or niacin (nicotinic acid). The combined use of lovastatin with cyclosporine or gemfibrozil
should be avoided. Caution should be used when prescribing other fibrates or lipid-lowering doses
(≥1 g/day) of niacin with lovastatin (see WARNINGS, Myopathy/Rhabdomyolysis).
The following effects have been reported with drugs in this class. Not all the effects listed below have
necessarily been associated with lovastatin therapy.
Skeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias.
There have been rare reports of immune-mediated necrotizing myopathy associated with statin use
(see WARNINGS, Myopathy/Rhabdomyolysis).
Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-
ocular movement, facial paresis), tremor, dizziness, vertigo, paresthesia, peripheral neuropathy,
peripheral nerve palsy, psychic disturbances, anxiety, insomnia, depression.
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness,
amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been
reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation,
with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which
has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like
syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia,
hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia,
photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme,
including Stevens-Johnson syndrome.
Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty
change in liver; and rarely, cirrhosis, fulminant hepatic necrosis, and hepatoma; anorexia, vomiting, fatal
and non-fatal hepatic failure.
Skin: alopecia, pruritus. A variety of skin changes (e.g., nodules, discoloration, dryness of
skin/mucous membranes, changes to hair/nails) have been reported.
Reproductive: gynecomastia, loss of libido, erectile dysfunction.
Eye: progression of cataracts (lens opacities), ophthalmoplegia.
Laboratory Abnormalities: elevated transaminases, alkaline phosphatase, γ-glutamyl transpeptidase,
and bilirubin; thyroid function abnormalities.
Adolescent Patients (ages 10-17 years)
In a 48-week controlled study in adolescent boys with heFH (n=132) and a 24-week controlled study
in girls who were at least 1 year post-menarche with heFH (n=54), the safety and tolerability profile of the
groups treated with MEVACOR (10 to 40 mg daily) was generally similar to that of the groups treated with
placebo (see CLINICAL PHARMACOLOGY, Clinical Studies in Adolescent Patients and PRECAUTIONS,
Pediatric Use).
OVERDOSAGE
After oral administration of MEVACOR to mice, the median lethal dose observed was >15 g/m2.
Five healthy human volunteers have received up to 200 mg of lovastatin as a single dose without
clinically significant adverse experiences. A few cases of accidental overdosage have been reported; no
patients had any specific symptoms, and all patients recovered without sequelae. The maximum dose
taken was 5-6 g.
Until further experience is obtained, no specific treatment of overdosage with MEVACOR can be
recommended.
The dialyzability of lovastatin and its metabolites in man is not known at present.
18
USPI-T-08031210
Reference ID: 3210294
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DOSAGE AND ADMINISTRATION
The patient should be placed on a standard cholesterol-lowering diet before receiving MEVACOR and
should continue on this diet during treatment with MEVACOR (see NCEP Treatment Guidelines for
details on dietary therapy). MEVACOR should be given with meals.
Adult Patients
The usual recommended starting dose is 20 mg once a day given with the evening meal. The
recommended dosing range of lovastatin is 10-80 mg/day in single or two divided doses; the maximum
recommended dose is 80 mg/day. Doses should be individualized according to the recommended goal of
therapy (see NCEP Guidelines and CLINICAL PHARMACOLOGY). Patients requiring reductions in LDL
C of 20% or more to achieve their goal (see INDICATIONS AND USAGE) should be started on
20 mg/day of MEVACOR. A starting dose of 10 mg of lovastatin may be considered for patients requiring
smaller reductions. Adjustments should be made at intervals of 4 weeks or more. The 10 mg dosage is
provided for information purposes only. Although lovastatin tablets 10 mg are available in the
marketplace, MEVACOR is no longer marketed in the 10 mg strength.
Cholesterol levels should be monitored periodically and consideration should be given to reducing the
dosage of MEVACOR if cholesterol levels fall significantly below the targeted range.
Dosage in Patients taking Danazol, Diltiazem, Dronedarone or Verapamil
In patients taking danazol, diltiazem, dronedarone or verapamil concomitantly with lovastatin, therapy
should begin with 10 mg of lovastatin and should not exceed 20 mg/day (see CLINICAL
PHARMACOLOGY, Pharmacokinetics, WARNINGS, Myopathy/Rhabdomyolysis, PRECAUTIONS, Drug
Interactions, Other Drug Interactions).
Dosage in Patients taking Amiodarone
In patients taking amiodarone concomitantly with MEVACOR, the dose should not exceed 40 mg/day
(see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions, Other Drug
Interactions).
Adolescent Patients (10-17 years of age) with Heterozygous Familial Hypercholesterolemia
The recommended dosing range of lovastatin is 10-40 mg/day; the maximum recommended dose is
40 mg/day. Doses should be individualized according to the recommended goal of therapy (see NCEP
Pediatric Panel Guidelines4, CLINICAL PHARMACOLOGY, and INDICATIONS AND USAGE). Patients
requiring reductions in LDL-C of 20% or more to achieve their goal should be started on 20 mg/day of
MEVACOR. A starting dose of 10 mg of lovastatin may be considered for patients requiring smaller
reductions. Adjustments should be made at intervals of 4 weeks or more.
Concomitant Lipid-Lowering Therapy
MEVACOR is effective alone or when used concomitantly with bile-acid sequestrants (see
WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions).
Dosage in Patients with Renal Insufficiency
In patients with severe renal insufficiency (creatinine clearance <30 mL/min), dosage increases above
20 mg/day should be carefully considered and, if deemed necessary, implemented cautiously (see
CLINICAL PHARMACOLOGY and WARNINGS, Myopathy/Rhabdomyolysis).
HOW SUPPLIED
No. 8123 — Tablets MEVACOR 20 mg are blue, octagonal tablets, coded MSD 731 on one side and
plain on the other. They are supplied as follows:
NDC 0006-0731-61 unit of use bottles of 60.
No. 8124 — Tablets MEVACOR 40 mg are green, octagonal tablets, coded MSD 732 on one side and
plain on the other. They are supplied as follows:
NDC 0006-0732-61 unit of use bottles of 60.
Storage
Store at 20-25°C (68-77°F). [See USP Controlled Room Temperature.] Tablets MEVACOR must be
protected from light and stored in a well-closed, light-resistant container.
4
National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in
Children and Adolescents. Pediatrics. 89(3):495-501. 1992.
19
USPI-T-08031210
Reference ID: 3210294
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Merck logo
By:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505, USA
OR
Mylan Pharmaceuticals ULC
Etobicoke, Ontario, Canada M8Z 2S6
Copyright © 1987-XXXX Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.
Revised: XX/XXXX
USPI-T-0803XXXXRXXX
20
USPI-T-08031210
Reference ID: 3210294
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:36.635525
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019643s086087lbl.pdf', 'application_number': 19643, 'submission_type': 'SUPPL ', 'submission_number': 87}
|
11,590
|
Merck logo
9844662
TABLETS
MEVACOR®
(LOVASTATIN)
DESCRIPTION
MEVACOR* (Lovastatin) is a cholesterol lowering agent isolated from a strain of Aspergillus terreus.
After oral ingestion, lovastatin, which is an inactive lactone, is hydrolyzed to the corresponding β
hydroxyacid form. This is a principal metabolite and an inhibitor of 3-hydroxy-3-methylglutaryl
coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate,
which is an early and rate limiting step in the biosynthesis of cholesterol.
Lovastatin
is
[1S-[1α(R*),3α,7β,8β(2S*,4S*),
8aβ]]-1,2,3,7,
8,8a-hexahydro-3,7-dimethyl-8-[2
(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl
2-methylbutanoate.
The
empirical
formula of lovastatin is C24H36O5 and its molecular weight is 404.55. Its structural formula is: chemical structure
Lovastatin is a white, nonhygroscopic crystalline powder that is insoluble in water and sparingly
soluble in ethanol, methanol, and acetonitrile.
Tablets MEVACOR are supplied as 20 mg and 40 mg tablets for oral administration. In addition to the
active ingredient lovastatin, each tablet contains the following inactive ingredients: cellulose, lactose,
magnesium stearate, and starch. Butylated hydroxyanisole (BHA) is added as a preservative. Tablets
MEVACOR 20 mg also contain FD&C Blue 2 aluminum lake. Tablets MEVACOR 40 mg also contain
D&C Yellow 10 aluminum lake and FD&C Blue 2 aluminum lake.
CLINICAL PHARMACOLOGY
The involvement of low-density lipoprotein cholesterol (LDL-C) in atherogenesis has been well-
documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological
and clinical studies have established that high LDL-C and low high-density lipoprotein cholesterol (HDL
C) are both associated with coronary heart disease. However, the risk of developing coronary heart
disease is continuous and graded over the range of cholesterol levels and many coronary events do
occur in patients with total cholesterol (total-C) and LDL-C in the lower end of this range.
MEVACOR has been shown to reduce both normal and elevated LDL-C concentrations. LDL is
formed from very low-density lipoprotein (VLDL) and is catabolized predominantly by the high affinity LDL
receptor. The mechanism of the LDL-lowering effect of MEVACOR may involve both reduction of VLDL-C
concentration, and induction of the LDL receptor, leading to reduced production and/or increased
catabolism of LDL-C. Apolipoprotein B also falls substantially during treatment with MEVACOR. Since
each LDL particle contains one molecule of apolipoprotein B, and since little apolipoprotein B is found in
other lipoproteins, this strongly suggests that MEVACOR does not merely cause cholesterol to be lost
from LDL, but also reduces the concentration of circulating LDL particles. In addition, MEVACOR can
produce increases of variable magnitude in HDL-C, and modestly reduces VLDL-C and plasma
*
Copyright © 1987-2012 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved
Reference ID: 3093010
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844662
triglycerides (TG) (see Tables II-IV under Clinical Studies). The effects of MEVACOR on Lp(a),
fibrinogen, and certain other independent biochemical risk markers for coronary heart disease are
unknown.
MEVACOR is a specific inhibitor of HMG-CoA reductase, the enzyme which catalyzes the conversion
of HMG-CoA to mevalonate. The conversion of HMG-CoA to mevalonate is an early step in the
biosynthetic pathway for cholesterol.
Pharmacokinetics
Lovastatin is a lactone which is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a strong
inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in
pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base
hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of lovastatin.
Following an oral dose of 14C-labeled lovastatin in man, 10% of the dose was excreted in urine and
83% in feces. The latter represents absorbed drug equivalents excreted in bile, as well as any
unabsorbed drug. Plasma concentrations of total radioactivity (lovastatin plus 14C-metabolites) peaked at
2 hours and declined rapidly to about 10% of peak by 24 hours postdose. Absorption of lovastatin,
estimated relative to an intravenous reference dose, in each of four animal species tested, averaged
about 30% of an oral dose. In animal studies, after oral dosing, lovastatin had high selectivity for the liver,
where it achieved substantially higher concentrations than in non-target tissues. Lovastatin undergoes
extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug
equivalents in the bile. As a consequence of extensive hepatic extraction of lovastatin, the availability of
drug to the general circulation is low and variable. In a single dose study in four hypercholesterolemic
patients, it was estimated that less than 5% of an oral dose of lovastatin reaches the general circulation
as active inhibitors. Following administration of lovastatin tablets the coefficient of variation, based on
between-subject variability, was approximately 40% for the area under the curve (AUC) of total inhibitory
activity in the general circulation.
Both lovastatin and its β-hydroxyacid metabolite are highly bound (>95%) to human plasma proteins.
Animal studies demonstrated that lovastatin crosses the blood-brain and placental barriers.
The major active metabolites present in human plasma are the β-hydroxyacid of lovastatin, its
6′-hydroxy derivative, and two additional metabolites. Peak plasma concentrations of both active and total
inhibitors were attained within 2 to 4 hours of dose administration. While the recommended therapeutic
dose range is 10 to 80 mg/day, linearity of inhibitory activity in the general circulation was established by
a single dose study employing lovastatin tablet dosages from 60 to as high as 120 mg. With a once-a-day
dosing regimen, plasma concentrations of total inhibitors over a dosing interval achieved a steady state
between the second and third days of therapy and were about 1.5 times those following a single dose.
When lovastatin was given under fasting conditions, plasma concentrations of total inhibitors were on
average about two-thirds those found when lovastatin was administered immediately after a standard test
meal.
In a study of patients with severe renal insufficiency (creatinine clearance 10-30 mL/min), the plasma
concentrations of total inhibitors after a single dose of lovastatin were approximately two-fold higher than
those in healthy volunteers.
In a study including 16 elderly patients between 70-78 years of age who received MEVACOR
80 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately
45% compared with 18 patients between 18-30 years of age (see PRECAUTIONS, Geriatric Use).
Although the mechanism is not fully understood, cyclosporine has been shown to increase the AUC of
HMG-CoA reductase inhibitors. The increase in AUC for lovastatin and lovastatin acid is presumably due,
in part, to inhibition of CYP3A4.
The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.
Strong inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and
increase the risk of myopathy (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug
Interactions).
Lovastatin is a substrate for cytochrome P450 isoform 3A4 (CYP3A4) (see PRECAUTIONS, Drug
Interactions). Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase
2
Reference ID: 3093010
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844662
the plasma concentrations of drugs metabolized by CYP3A4. In one study**, 10 subjects consumed 200
mL of double-strength grapefruit juice (one can of frozen concentrate diluted with one rather than 3 cans
of water) three times daily for 2 days and an additional 200 mL double-strength grapefruit juice together
with and 30 and 90 minutes following a single dose of 80 mg lovastatin on the third day. This regimen of
grapefruit juice resulted in a mean increase in the serum concentration of lovastatin and its β-hydroxyacid
metabolite (as measured by the area under the concentration-time curve) of 15-fold and 5-fold,
respectively [as measured using a chemical assay — high performance liquid chromatography]. In a
second study, 15 subjects consumed one 8 oz glass of single-strength grapefruit juice (one can of frozen
concentrate diluted with 3 cans of water) with breakfast for 3 consecutive days and a single dose of
40 mg lovastatin in the evening of the third day. This regimen of grapefruit juice resulted in a mean
increase in the plasma concentration (as measured by the area under the concentration-time curve) of
active and total HMG-CoA reductase inhibitory activity [using an enzyme inhibition assay both before (for
active inhibitors) and after (for total inhibitors) base hydrolysis] of 1.34-fold and 1.36-fold, respectively,
and of lovastatin and its β-hydroxyacid metabolite [measured using a chemical assay — liquid
chromatography/tandem mass spectrometry — different from that used in the first** study] of 1.94-fold
and 1.57-fold, respectively. The effect of amounts of grapefruit juice between those used in these two
studies on lovastatin pharmacokinetics has not been studied.
TABLE I
The Effect of Other Drugs on Lovastatin Exposure When Both Were Co-administered
Number of
Subjects
Dosing of Coadministered
Drug or Grapefruit Juice
Dosing of
Lovastatin
AUC Ratio*
(with / without
coadministered drug)
No Effect = 1.00
Lovastatin
Lovastatin acid†
Gemfibrozil
11
600 mg BID for 3 days
40 mg
0.96
2.80
Itraconazole‡
12
200 mg QD for 4 days
40 mg on Day 4
> 36§
22
10
100 mg QD for 4 days
40 mg on Day 4
> 14.8§
15.4
Grapefruit Juice¶
(high dose)
10
200 mL of double-strength
TID#
80 mg single dose
15.3
5.0
Grapefruit Juice¶
(low dose)
16
8 oz (about 250 mL) of
single-strengthÞ for 4 days
40 mg single dose
1.94
1.57
Cyclosporine
16
Not describedß
10 mg QD for
10 days
5- to 8-fold
NDà
Number of
Subjects
Dosing of Coadministered
Drug or Grapefruit Juice
Dosing of
Lovastatin
AUC Ratio*
(with / without
coadministered drug)
No Effect = 1.00
Total Lovastatin acidè
Diltiazem
10
120 mg BID for 14 days
20 mg
3.57è
* Results based on a chemical assay.
† Lovastatin acid refers to the β-hydroxyacid of lovastatin.
‡ The mean total AUC of lovastatin without itraconazole phase could not be determined accurately. Results could be representative of
strong CYP3A4 inhibitors such as ketoconazole, posaconazole, clarithromycin, telithromycin, HIV protease inhibitors, and nefazodone.
§
Estimated minimum change.
¶
The effect of amounts of grapefruit juice between those used in these two studies on lovastatin pharmacokinetics has not been studied.
#
Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200
mL together with single dose lovastatin and 30 and 90 minutes following single dose lovastatin on Day 3.
Þ Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days,
and lovastatin was administered in the evening on Day 3.
ß Cyclosporine-treated patients with psoriasis or post kidney or heart transplant patients with stable graft function, transplanted at least 9
months prior to study.
à
ND = Analyte not determined.
** Kantola, T, et al., Clin Pharmacol Ther 1998; 63(4):397-402.
3
Reference ID: 3093010
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844662
è
Lactone converted to acid by hydrolysis prior to analysis. Figure represents total unmetabolized acid and lactone.
Clinical Studies in Adults
MEVACOR has been shown to be highly effective in reducing total-C and LDL-C in heterozygous
familial and non-familial forms of primary hypercholesterolemia and in mixed hyperlipidemia. A marked
response was seen within 2 weeks, and the maximum therapeutic response occurred within 4-6 weeks.
The response was maintained during continuation of therapy. Single daily doses given in the evening
were more effective than the same dose given in the morning, perhaps because cholesterol is
synthesized mainly at night.
In multicenter, double-blind studies in patients with familial or non-familial hypercholesterolemia,
MEVACOR, administered in doses ranging from 10 mg q.p.m. to 40 mg b.i.d., was compared to placebo.
MEVACOR consistently and significantly decreased plasma total-C, LDL-C, total-C/HDL-C ratio and LDL
C/HDL-C ratio. In addition, MEVACOR produced increases of variable magnitude in HDL-C, and
modestly decreased VLDL-C and plasma TG (see Tables II through IV for dose response results).
The results of a study in patients with primary hypercholesterolemia are presented in Table II.
TABLE II
MEVACOR vs. Placebo
(Mean Percent Change from Baseline After 6 Weeks)
LDL-C/
TOTAL-C/
DOSAGE
N
TOTAL-C
LDL-C
HDL-C
HDL-C
HDL-C
TG.
Placebo
33
–2
–1
–1
0
+1
+9
MEVACOR
10 mg q.p.m.
33
–16
–21
+5
–24
–19
–10
20 mg q.p.m.
33
–19
–27
+6
–30
–23
+9
10 mg b.i.d.
32
–19
–28
+8
–33
–25
–7
40 mg q.p.m.
33
–22
–31
+5
–33
–25
–8
20 mg b.i.d.
36
–24
–32
+2
–32
–24
–6
MEVACOR was compared to cholestyramine in a randomized open parallel study. The study was
performed with patients with hypercholesterolemia who were at high risk of myocardial infarction.
Summary results are presented in Table III.
TABLE III
MEVACOR vs. Cholestyramine
(Percent Change from Baseline After 12 Weeks)
LDL-C/
TOTAL-C/
TREATMENT
N
TOTAL-C
LDL-C
HDL-C
HDL-C
HDL-C
VLDL-C
TG.
(mean)
(mean)
(mean)
(mean)
(mean)
(median)
(mean)
MEVACOR
20 mg b.i.d.
85
–27
–32
+9
–36
–31
–34
–21
40 mg b.i.d.
88
–34
–42
+8
–44
–37
–31
–27
Cholestyramine
12 g b.i.d.
88
–17
–23
+8
–27
–21
+2
+11
MEVACOR was studied in controlled trials in hypercholesterolemic patients with well-controlled non-
insulin dependent diabetes mellitus with normal renal function. The effect of MEVACOR on lipids and
lipoproteins and the safety profile of MEVACOR were similar to that demonstrated in studies in
nondiabetics. MEVACOR had no clinically important effect on glycemic control or on the dose
requirement of oral hypoglycemic agents.
Expanded Clinical Evaluation of Lovastatin (EXCEL) Study
MEVACOR was compared to placebo in 8,245 patients with hypercholesterolemia (total-C 240-300
mg/dL [6.2 mmol/L - 7.6 mmol/L], LDL-C >160 mg/dL [4.1 mmol/L]) in the randomized, double-blind,
parallel, 48-week EXCEL study. All changes in the lipid measurements (Table IV) in MEVACOR treated
patients were dose-related and significantly different from placebo (p≤0.001). These results were
sustained throughout the study.
4
Reference ID: 3093010
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844662
TABLE IV
MEVACOR vs. Placebo
(Percent Change from Baseline —
Average Values Between Weeks 12 and 48)
DOSAGE
N**
TOTAL-C
LDL-C
HDL-C
LDL-C/
HDL-C
TOTAL-C/
HDL-C
TG.
(mean)
(mean)
(mean)
(mean)
(mean)
(median)
Placebo
1663
+0.7
+0.4
+2.0
+0.2
+0.6
+4
MEVACOR
20 mg q.p.m.
40 mg q.p.m.
20 mg b.i.d.
40 mg b.i.d.
1642
1645
1646
1649
–17
–22
–24
–29
–24
–30
–34
–40
+6.6
+7.2
+8.6
+9.5
–27
–34
–38
–44
–21
–26
–29
–34
–10
–14
–16
–19
**Patients enrolled
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), a double-blind,
randomized, placebo-controlled, primary prevention study, demonstrated that treatment with MEVACOR
decreased the rate of acute major coronary events (composite endpoint of myocardial infarction, unstable
angina, and sudden cardiac death) compared with placebo during a median of 5.1 years of follow-up.
Participants were middle-aged and elderly men (ages 45-73) and women (ages 55-73) without
symptomatic cardiovascular disease with average to moderately elevated total-C and LDL-C, below
average HDL-C, and who were at high risk based on elevated total-C/HDL-C. In addition to age, 63% of
the participants had at least one other risk factor (baseline HDL-C <35 mg/dL, hypertension, family
history, smoking and diabetes).
AFCAPS/TexCAPS enrolled 6,605 participants (5,608 men, 997 women) based on the following lipid
entry criteria: total-C range of 180-264 mg/dL, LDL-C range of 130-190 mg/dL, HDL-C of ≤45 mg/dL for
men and ≤47 mg/dL for women, and TG of ≤400 mg/dL. Participants were treated with standard care,
including diet, and either MEVACOR 20-40 mg daily (n= 3,304) or placebo (n= 3,301). Approximately
50% of the participants treated with MEVACOR were titrated to 40 mg daily when their LDL-C remained
>110 mg/dL at the 20-mg starting dose.
MEVACOR reduced the risk of a first acute major coronary event, the primary efficacy endpoint, by
37% (MEVACOR 3.5%, placebo 5.5%; p<0.001; Figure 1). A first acute major coronary event was defined
as myocardial infarction (54 participants on MEVACOR, 94 on placebo) or unstable angina (54 vs. 80) or
sudden cardiac death (8 vs. 9). Furthermore, among the secondary endpoints, MEVACOR reduced the
risk of unstable angina by 32% (1.8 vs. 2.6%; p=0.023), of myocardial infarction by 40% (1.7 vs. 2.9%;
p=0.002), and of undergoing coronary revascularization procedures (e.g., coronary artery bypass grafting
or percutaneous transluminal coronary angioplasty) by 33% (3.2 vs. 4.8%; p=0.001). Trends in risk
reduction associated with treatment with MEVACOR were consistent across men and women, smokers
and non-smokers, hypertensives and non-hypertensives, and older and younger participants. Participants
with ≥2 risk factors had risk reductions (RR) in both acute major coronary events (RR 43%) and coronary
revascularization procedures (RR 37%). Because there were too few events among those participants
with age as their only risk factor in this study, the effect of MEVACOR on outcomes could not be
adequately assessed in this subgroup.
5
Reference ID: 3093010
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844662 Acute Major Coronary Events
Atherosclerosis
In the Canadian Coronary Atherosclerosis Intervention Trial (CCAIT), the effect of therapy with
lovastatin on coronary atherosclerosis was assessed by coronary angiography in hyperlipidemic patients.
In the randomized, double-blind, controlled clinical trial, patients were treated with conventional measures
(usually diet and 325 mg of aspirin every other day) and either lovastatin 20-80 mg daily or placebo.
Angiograms were evaluated at baseline and at two years by computerized quantitative coronary
angiography (QCA). Lovastatin significantly slowed the progression of lesions as measured by the mean
change per-patient in minimum lumen diameter (the primary endpoint) and percent diameter stenosis,
and decreased the proportions of patients categorized with disease progression (33% vs. 50%) and with
new lesions (16% vs. 32%).
In a similarly designed trial, the Monitored Atherosclerosis Regression Study (MARS), patients were
treated with diet and either lovastatin 80 mg daily or placebo. No statistically significant difference
between lovastatin and placebo was seen for the primary endpoint (mean change per patient in percent
diameter stenosis of all lesions), or for most secondary QCA endpoints. Visual assessment by
angiographers who formed a consensus opinion of overall angiographic change (Global Change Score)
was also a secondary endpoint. By this endpoint, significant slowing of disease was seen, with regression
in 23% of patients treated with lovastatin compared to 11% of placebo patients.
In the Familial Atherosclerosis Treatment Study (FATS), either lovastatin or niacin in combination with
a bile acid sequestrant for 2.5 years in hyperlipidemic subjects significantly reduced the frequency of
progression and increased the frequency of regression of coronary atherosclerotic lesions by QCA
compared to diet and, in some cases, low-dose resin.
The effect of lovastatin on the progression of atherosclerosis in the coronary arteries has been
corroborated by similar findings in another vasculature. In the Asymptomatic Carotid Artery Progression
Study (ACAPS), the effect of therapy with lovastatin on carotid atherosclerosis was assessed by B-mode
ultrasonography in hyperlipidemic patients with early carotid lesions and without known coronary heart
disease at baseline. In this double-blind, controlled clinical trial, 919 patients were randomized in a 2 x 2
factorial design to placebo, lovastatin 10-40 mg daily and/or warfarin. Ultrasonograms of the carotid walls
6
Reference ID: 3093010
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844662
were used to determine the change per patient from baseline to three years in mean maximum intimal
medial thickness (IMT) of 12 measured segments. There was a significant regression of carotid lesions in
patients receiving lovastatin alone compared to those receiving placebo alone (p=0.001). The predictive
value of changes in IMT for stroke has not yet been established. In the lovastatin group there was a
significant reduction in the number of patients with major cardiovascular events relative to the placebo
group (5 vs. 14) and a significant reduction in all-cause mortality (1 vs. 8).
Eye
There was a high prevalence of baseline lenticular opacities in the patient population included in the
early clinical trials with lovastatin. During these trials the appearance of new opacities was noted in both
the lovastatin and placebo groups. There was no clinically significant change in visual acuity in the
patients who had new opacities reported nor was any patient, including those with opacities noted at
baseline, discontinued from therapy because of a decrease in visual acuity.
A three-year, double-blind, placebo-controlled study in hypercholesterolemic patients to assess the
effect of lovastatin on the human lens demonstrated that there were no clinically or statistically significant
differences between the lovastatin and placebo groups in the incidence, type or progression of lenticular
opacities. There are no controlled clinical data assessing the lens available for treatment beyond three
years.
Clinical Studies in Adolescent Patients
Efficacy of Lovastatin in Adolescent Boys with Heterozygous Familial Hypercholesterolemia
In a double-blind, placebo-controlled study, 132 boys 10-17 years of age (mean age 12.7 yrs) with
heterozygous familial hypercholesterolemia (heFH) were randomized to lovastatin (n=67) or placebo
(n=65) for 48 weeks. Inclusion in the study required a baseline LDL-C level between 189 and 500 mg/dL
and at least one parent with an LDL-C level >189 mg/dL. The mean baseline LDL-C value was
253.1 mg/dL (range: 171-379 mg/dL) in the MEVACOR group compared to 248.2 mg/dL (range:
158.5-413.5 mg/dL) in the placebo group. The dosage of lovastatin (once daily in the evening) was 10 mg
for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter.
MEVACOR significantly decreased plasma levels of total-C, LDL-C and apolipoprotein B (see
Table V).
TABLE V
Lipid-lowering Effects of Lovastatin in Adolescent Boys with Heterozygous Familial Hypercholesterolemia
(Mean Percent Change from Baseline at Week 48 in Intention-to-Treat Population)
DOSAGE
N
TOTAL-C
LDL-C
HDL-C
TG.*
Apolipoprotein B
Placebo
61
-1.1
-1.4
-2.2
-1.4
-4.4
MEVACOR
64
-19.3
-24.2
+1.1
-1.9
-21
*data presented as median percent changes
The mean achieved LDL-C value was 190.9 mg/dL (range: 108-336 mg/dL) in the MEVACOR group
compared to 244.8 mg/dL (range: 135-404 mg/dL) in the placebo group.
Efficacy of Lovastatin in Post-Menarchal Girls with Heterozygous Familial Hypercholesterolemia
In a double-blind, placebo-controlled study, 54 girls 10-17 years of age who were at least 1 year
post-menarche with heFH were randomized to lovastatin (n=35) or placebo (n=19) for 24 weeks.
Inclusion in the study required a baseline LDL-C level of 160-400 mg/dL and a parental history of familial
hypercholesterolemia. The mean baseline LDL-C value was 218.3 mg/dL (range: 136.3-363.7 mg/dL) in
the MEVACOR group compared to 198.8 mg/dL (range: 151.1-283.1 mg/dL) in the placebo group. The
dosage of lovastatin (once daily in the evening) was 20 mg for the first 4 weeks, and 40 mg thereafter.
MEVACOR significantly decreased plasma levels of total-C, LDL-C, and apolipoprotein B (see
Table VI).
7
Reference ID: 3093010
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844662
TABLE VI
Lipid-lowering Effects of Lovastatin in Post-Menarchal Girls with Heterozygous Familial Hypercholesterolemia
(Mean Percent Change from Baseline at Week 24 in Intention-to-Treat Population)
DOSAGE
N
TOTAL-C
LDL-C
HDL-C
TG.*
Apolipoprotein B
Placebo
18
+3.6
+2.5
+4.8
-3.0
+6.4
MEVACOR
35
-22.4
-29.2
+2.4
-22.7
-24.4
*data presented as median percent changes
The mean achieved LDL-C value was 154.5 mg/dL (range: 82-286 mg/dL) in the MEVACOR group
compared to 203.5 mg/dL (range: 135-304 mg/dL) in the placebo group.
The safety and efficacy of doses above 40 mg daily have not been studied in children. The long-term
efficacy of lovastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been
established.
INDICATIONS AND USAGE
Therapy with MEVACOR should be a component of multiple risk factor intervention in those
individuals with dyslipidemia at risk for atherosclerotic vascular disease. MEVACOR should be used in
addition to a diet restricted in saturated fat and cholesterol as part of a treatment strategy to lower total-C
and LDL-C to target levels when the response to diet and other nonpharmacological measures alone has
been inadequate to reduce risk.
Primary Prevention of Coronary Heart Disease
In individuals without symptomatic cardiovascular disease, average to moderately elevated total-C
and LDL-C, and below average HDL-C, MEVACOR is indicated to reduce the risk of:
- Myocardial infarction
- Unstable angina
- Coronary revascularization procedures
(See CLINICAL PHARMACOLOGY, Clinical Studies.)
Coronary Heart Disease
MEVACOR is indicated to slow the progression of coronary atherosclerosis in patients with coronary
heart disease as part of a treatment strategy to lower total-C and LDL-C to target levels.
Hypercholesterolemia
Therapy with lipid-altering agents should be a component of multiple risk factor intervention in those
individuals
at
significantly
increased
risk
for
atherosclerotic
vascular
disease
due
to
hypercholesterolemia. MEVACOR is indicated as an adjunct to diet for the reduction of elevated total-C
and LDL-C levels in patients with primary hypercholesterolemia (Types IIa and IIb***), when the response
to diet restricted in saturated fat and cholesterol and to other nonpharmacological measures alone has
been inadequate.
Adolescent Patients with Heterozygous Familial Hypercholesterolemia
MEVACOR is indicated as an adjunct to diet to reduce total-C, LDL-C and apolipoprotein B levels in
adolescent boys and girls who are at least one year post-menarche, 10-17 years of age, with heFH if
after an adequate trial of diet therapy the following findings are present:
*** Classification of Hyperlipoproteinemias
Lipid
Lipoproteins
Elevations
Type
elevated
major
minor
I
chylomicrons
TG
↑→C
IIa
LDL
C
—
IIb
LDL, VLDL
C
TG
III (rare)
IDL
C/TG
—
IV
VLDL
TG
↑→C
V (rare)
chylomicrons, VLDL
TG
↑→C
IDL = intermediate-density lipoprotein.
8
Reference ID: 3093010
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844662
1. LDL-C remains >189 mg/dL or
2. LDL-C remains >160 mg/dL and:
•
there is a positive family history of premature cardiovascular disease or
•
two or more other CVD risk factors are present in the adolescent patient
General Recommendations
Prior to initiating therapy with lovastatin, secondary causes for hypercholesterolemia (e.g., poorly
controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver
disease, other drug therapy, alcoholism) should be excluded, and a lipid profile performed to measure
total-C, HDL-C, and TG. For patients with TG less than 400 mg/dL (<4.5 mmol/L), LDL-C can be
estimated using the following equation:
LDL-C = total-C – [0.2 × (TG) + HDL-C]
For TG levels >400 mg/dL (>4.5 mmol/L), this equation is less accurate and LDL-C concentrations
should be determined by ultracentrifugation. In hypertriglyceridemic patients, LDL-C may be low or
normal despite elevated total-C. In such cases, MEVACOR is not indicated.
The National Cholesterol Education Program (NCEP) Treatment Guidelines are summarized below:
NCEP Treatment Guidelines:
LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes
and Drug Therapy in Different Risk Categories
LDL Level at Which to
LDL Level at Which to
Risk Category
LDL Goal
Initiate Therapeutic Lifestyle Changes
Consider Drug Therapy
(mg/dL)
(mg/dL)
(mg/dL)
CHD† or CHD risk equivalents
<100
≥100
≥130
(10-year risk >20%)
(100-129: drug optional)††
2+ Risk factors
<130
≥130
10-year risk 10-20%: ≥130
(10 year risk ≤20%)
10-year risk <10%: ≥ 160
0-1 Risk factor†††
<160
≥160
≥190
(160-189: LDL-lowering drug
optional)
†
CHD, coronary heart disease
††
Some authorities recommend use of LDL-lowering drugs in this category if an LDL-C level of <100 mg/dL cannot be achieved by therapeutic
lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL-C, e.g., nicotinic acid or fibrate. Clinical judgment also
may call for deferring drug therapy in this subcategory.
†††
Almost all people with 0-1 risk factor have a 10-year risk <10%; thus, 10-year risk assessment in people with 0-1 risk factor is not necessary.
After the LDL-C goal has been achieved, if the TG is still ≥200 mg/dL, non-HDL-C (total-C minus HDL
C) becomes a secondary target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals
for each risk category.
At the time of hospitalization for an acute coronary event, consideration can be given to initiating drug
therapy at discharge if the LDL-C is ≥130 mg/dL (see NCEP Guidelines above).
Since the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C levels be used to
initiate and assess treatment response. Only if LDL-C levels are not available, should the total-C be used
to monitor therapy.
Although MEVACOR may be useful to reduce elevated LDL-C levels in patients with combined
hypercholesterolemia and hypertriglyceridemia where hypercholesterolemia is the major abnormality
(Type IIb hyperlipoproteinemia), it has not been studied in conditions where the major abnormality is
elevation of chylomicrons, VLDL or IDL (i.e., hyperlipoproteinemia types I, III, IV, or V).***
The NCEP classification of cholesterol levels in pediatric patients with a familial history of
hypercholesterolemia or premature cardiovascular disease is summarized below:
Category
Total-C (mg/dL)
LDL-C (mg/dL)
Acceptable
Borderline
High
<170
170-199
≥200
<110
110-129
≥130
9
Reference ID: 3093010
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844662
Children treated with lovastatin in adolescence should be re-evaluated in adulthood and appropriate
changes made to their cholesterol-lowering regimen to achieve adult goals for LDL-C.
CONTRAINDICATIONS
Hypersensitivity to any component of this medication.
Active liver disease or unexplained persistent elevations of serum transaminases (see WARNINGS).
Concomitant administration with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole,
posaconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin
and nefazodone) (see WARNINGS, Myopathy/Rhabdomyolysis).
Pregnancy and lactation (see PRECAUTIONS, Pregnancy and Nursing Mothers). Atherosclerosis is a
chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact
on the outcome of long-term therapy of primary hypercholesterolemia. Moreover, cholesterol and other
products of the cholesterol biosynthesis pathway are essential components for fetal development,
including synthesis of steroids and cell membranes. Because of the ability of inhibitors of HMG-CoA
reductase such as MEVACOR to decrease the synthesis of cholesterol and possibly other products of the
cholesterol biosynthesis pathway, MEVACOR is contraindicated during pregnancy and in nursing
mothers. MEVACOR should be administered to women of childbearing age only when such
patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug,
MEVACOR should be discontinued immediately and the patient should be apprised of the potential
hazard to the fetus (see PRECAUTIONS, Pregnancy).
WARNINGS
Myopathy/Rhabdomyolysis
Lovastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as
muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal
(ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure
secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high
levels of HMG-CoA reductase inhibitory activity in plasma.
As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose
related. In a clinical study (EXCEL) in which patients were carefully monitored and some interacting
drugs were excluded, there was one case of myopathy among 4933 patients randomized to lovastatin 20
40 mg daily for 48 weeks, and 4 among 1649 patients randomized to 80 mg daily.
All patients starting therapy with lovastatin, or whose dose of lovastatin is being increased,
should be advised of the risk of myopathy and told to report promptly any unexplained muscle
pain, tenderness or weakness. Lovastatin therapy should be discontinued immediately if
myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved
when treatment was promptly discontinued. Periodic CK determinations may be considered in patients
starting therapy with lovastatin or whose dose is being increased, but there is no assurance that such
monitoring will prevent myopathy.
Many of the patients who have developed rhabdomyolysis on therapy with lovastatin have had
complicated medical histories, including renal insufficiency usually as a consequence of long-standing
diabetes mellitus. Such patients merit closer monitoring. MEVACOR therapy should be discontinued if
markedly elevated CPK levels occur or myopathy is diagnosed or suspected. MEVACOR therapy should
also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the
development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery;
trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.
The risk of myopathy/rhabdomyolysis is increased by concomitant use of lovastatin with the
following:
Strong inhibitors of CYP3A4: Lovastatin, like several other inhibitors of HMG-CoA reductase, is a
substrate of cytochrome P450 3A4 (CYP3A4). Certain drugs which inhibit this metabolic pathway can
10
Reference ID: 3093010
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844662
raise the plasma levels of lovastatin and may increase the risk of myopathy. These include
itraconazole, ketoconazole, and posaconazole, the macrolide antibiotics erythromycin and
clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir,
or the antidepressant nefazodone. Combination of these drugs with lovastatin is contraindicated. If
treatment
with
itraconazole,
ketoconazole,
posaconazole, erythromycin, clarithromycin or
telithromycin is unavoidable, therapy with lovastatin should be suspended during the course of
treatment (see CONTRAINDICATIONS; PRECAUTIONS, Drug Interactions).
Although not studied clinically, voriconazole has been shown to inhibit lovastatin metabolism in vitro
(human liver microsomes). Therefore, voriconazole is likely to increase the plasma concentration of
lovastatin. It is recommended that dose adjustment of lovastatin be considered during
coadministration. Increased lovastatin concentration in plasma has been associated with an
increased risk of myopathy/rhabdomyolysis.
Gemfibrozil: The combined use of lovastatin with gemfibrozil should be avoided.
Other lipid-lowering drugs (other fibrates or ≥1 g/day of niacin): Caution should be used when
prescribing other fibrates or lipid-lowering doses (≥1 g/day) of niacin with lovastatin, as these agents
can cause myopathy when given alone. The benefit of further alterations in lipid levels by the
combined use of lovastatin with other fibrates or niacin should be carefully weighed against
the potential risks of these combinations.
Cyclosporine: The use of lovastatin with cyclosporine should be avoided.
Danazol, diltiazem or verapamil with higher doses of lovastatin: The dose of lovastatin should
not exceed 20 mg daily in patients receiving concomitant medication with danazol, diltiazem,
or verapamil. The benefits of the use of lovastatin in patients receiving danazol, diltiazem, or
verapamil should be carefully weighed against the risks of these combinations.
Amiodarone: The dose of lovastatin should not exceed 40 mg daily in patients receiving
concomitant medication with amiodarone. The combined use of lovastatin at doses higher than
40 mg daily with amiodarone should be avoided unless the clinical benefit is likely to outweigh the
increased risk of myopathy. The risk of myopathy/rhabdomyolysis is increased when amiodarone is
used concomitantly with higher doses of a closely related member of the HMG-CoA reductase
inhibitor class.
Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with lovastatin
coadministered with colchicine, and caution should be exercised when prescribing lovastatin with
colchicine (see PRECAUTIONS, Drug Interactions).
Ranolazine: The risk of myopathy, including rhabdomyolysis, may be increased by concomitant
administration of ranolazine. Dose adjustment of lovastatin may be considered during co
administration with ranolazine.
Prescribing recommendations for interacting agents are summarized in Table VII (see also CLINICAL
PHARMACOLOGY,
Pharmacokinetics;
PRECAUTIONS,
Drug
Interactions;
DOSAGE
AND
ADMINISTRATION).
11
Reference ID: 3093010
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844662
Table VII
Drug Interactions Associated with Increased
Risk of Myopathy/Rhabdomyolysis
Interacting Agents
Prescribing Recommendations
Strong CYP3A4 inhibitors, e.g.:
Ketoconazole
Itraconazole
Posaconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors
Boceprevir
Telaprevir
Nefazodone
Contraindicated with lovastatin
Gemfibrozil
Cyclosporine
Avoid with lovastatin
Danazol
Diltiazem
Verapamil
Do not exceed 20 mg lovastatin daily
Amiodarone
Do not exceed 40 mg lovastatin daily
Grapefruit juice
Avoid large quantities of grapefruit juice
(>1 quart daily)
Liver Dysfunction
Persistent increases (to more than 3 times the upper limit of normal) in serum transaminases
occurred in 1.9% of adult patients who received lovastatin for at least one year in early clinical
trials (see ADVERSE REACTIONS). When the drug was interrupted or discontinued in these patients,
the transaminase levels usually fell slowly to pretreatment levels. The increases usually appeared 3 to 12
months after the start of therapy with lovastatin, and were not associated with jaundice or other clinical
signs or symptoms. There was no evidence of hypersensitivity. In the EXCEL study (see CLINICAL
PHARMACOLOGY, Clinical Studies), the incidence of persistent increases in serum transaminases over
48 weeks was 0.1% for placebo, 0.1% at 20 mg/day, 0.9% at 40 mg/day, and 1.5% at 80 mg/day in
patients on lovastatin. However, in post-marketing experience with MEVACOR, symptomatic liver disease
has been reported rarely at all dosages (see ADVERSE REACTIONS).
In AFCAPS/TexCAPS, the number of participants with consecutive elevations of either alanine
aminotransferase (ALT) or aspartate aminotransferase (AST) (> 3 times the upper limit of normal), over a
median of 5.1 years of follow-up, was not significantly different between the MEVACOR and placebo
groups (18 [0.6%] vs. 11 [0.3%]). The starting dose of MEVACOR was 20 mg/day; 50% of the MEVACOR
treated participants were titrated to 40 mg/day at Week 18. Of the 18 participants on MEVACOR with
consecutive elevations of either ALT or AST, 11 (0.7%) elevations occurred in participants taking 20
mg/day, while 7 (0.4%) elevations occurred in participants titrated to 40 mg/day. Elevated transaminases
resulted in discontinuation of 6 (0.2%) participants from therapy in the MEVACOR group (n=3,304) and 4
(0.1%) in the placebo group (n=3,301).
It is recommended that liver enzyme tests be obtained prior to initiating therapy with MEVACOR and
repeated as clinically indicated.
There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking
statins, including lovastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or
jaundice occurs during treatment with MEVACOR, promptly interrupt therapy. If an alternate etiology is
not found do not restart MEVACOR.
The drug should be used with caution in patients who consume substantial quantities of alcohol and/or
have a past history of liver disease. Active liver disease or unexplained transaminase elevations are
contraindications to the use of lovastatin.
As with other lipid-lowering agents, moderate (less than three times the upper limit of normal)
elevations of serum transaminases have been reported following therapy with MEVACOR (see
ADVERSE REACTIONS). These changes appeared soon after initiation of therapy with MEVACOR, were
often transient, were not accompanied by any symptoms and interruption of treatment was not required.
12
Reference ID: 3093010
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844662
PRECAUTIONS
General
Lovastatin may elevate creatine phosphokinase and transaminase levels (see WARNINGS and
ADVERSE REACTIONS). This should be considered in the differential diagnosis of chest pain in a patient
on therapy with lovastatin.
Homozygous Familial Hypercholesterolemia
MEVACOR is less effective in patients with the rare homozygous familial hypercholesterolemia,
possibly because these patients have no functional LDL receptors. MEVACOR appears to be more likely
to raise serum transaminases (see ADVERSE REACTIONS) in these homozygous patients.
Information for Patients
Patients should be advised about substances they should not take concomitantly with
lovastatin and be advised to report promptly unexplained muscle pain, tenderness, or weakness
(see list below and WARNINGS, Myopathy/Rhabdomyolysis). Patients should also be advised to
inform other physicians prescribing a new medication that they are taking MEVACOR.
It is recommended that liver enzymes be checked before starting therapy, and if signs or symptoms of
liver injury occur. All patients treated with MEVACOR should be advised to report promptly any symptoms
that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or
jaundice.
Drug Interactions
CYP3A4 Interactions
Lovastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not
expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. Strong inhibitors of
CYP3A4 (e.g., itraconazole, ketoconazole, posaconazole, clarithromycin, telithromycin, HIV protease
inhibitors, boceprevir, telaprevir, nefazodone, and erythromycin), and large quantities of grapefruit juice
(>1 quart daily) increase the risk of myopathy by reducing the elimination of lovastatin. (See
CONTRAINDICATIONS,
WARNINGS,
Myopathy/Rhabdomyolysis,
and
CLINICAL
PHARMACOLOGY, Pharmacokinetics.)
In vitro studies have demonstrated that voriconazole inhibits the metabolism of lovastatin. Adjustment
of the lovastatin dose may be needed to reduce the risk of myopathy, including rhabdomyolysis, if
voriconazole must be used concomitantly with lovastatin.
Interactions With Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone
The risk of myopathy is also increased by the following lipid-lowering drugs that are not strong
CYP3A4 inhibitors, but which can cause myopathy when given alone.
See WARNINGS, Myopathy/Rhabdomyolysis.
Gemfibrozil
Other fibrates
Niacin (nicotinic acid) (≥1 g/day)
Other Drug Interactions
Cyclosporine: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of
cyclosporine (see WARNINGS, Myopathy/Rhabdomyolysis).
Danazol, Diltiazem, or Verapamil: The risk of myopathy/rhabdomyolysis is increased by concomitant
administration of danazol, diltiazem, or verapamil particularly with higher doses of lovastatin (see
WARNINGS, Myopathy/Rhabdomyolysis; CLINICAL PHARMACOLOGY, Pharmacokinetics).
Amiodarone: The risk of myopathy/rhabdomyolysis is increased when amiodarone is used
concomitantly with a closely related member of the HMG-CoA reductase inhibitor class (see WARNINGS,
Myopathy/Rhabdomyolysis).
Coumarin Anticoagulants: In a small clinical trial in which lovastatin was administered to warfarin
treated patients, no effect on prothrombin time was detected. However, another HMG-CoA reductase
inhibitor has been found to produce a less than two-second increase in prothrombin time in healthy
13
Reference ID: 3093010
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844662
volunteers receiving low doses of warfarin. Also, bleeding and/or increased prothrombin time have been
reported in a few patients taking coumarin anticoagulants concomitantly with lovastatin. It is
recommended that in patients taking anticoagulants, prothrombin time be determined before starting
lovastatin and frequently enough during early therapy to insure that no significant alteration of
prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can
be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose
of lovastatin is changed, the same procedure should be repeated. Lovastatin therapy has not been
associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with lovastatin
coadministered with colchicine. See WARNINGS, Myopathy/Rhabdomyolysis.
Ranolazine: The risk of myopathy, including rhabdomyolysis, may be increased by concomitant
administration of ranolazine. See WARNINGS, Myopathy/Rhabdomyolysis.
Propranolol: In normal volunteers, there was no clinically significant pharmacokinetic or
pharmacodynamic interaction with concomitant administration of single doses of lovastatin and
propranolol.
Digoxin: In patients with hypercholesterolemia, concomitant administration of lovastatin and digoxin
resulted in no effect on digoxin plasma concentrations.
Oral Hypoglycemic Agents: In pharmacokinetic studies of MEVACOR in hypercholesterolemic non-
insulin dependent diabetic patients, there was no drug interaction with glipizide or with chlorpropamide
(see CLINICAL PHARMACOLOGY, Clinical Studies).
Endocrine Function
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase
inhibitors, including MEVACOR.
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically
blunt adrenal and/or gonadal steroid production. Results of clinical trials with drugs in this class have
been inconsistent with regard to drug effects on basal and reserve steroid levels. However, clinical
studies have shown that lovastatin does not reduce basal plasma cortisol concentration or impair adrenal
reserve, and does not reduce basal plasma testosterone concentration. Another HMG-CoA reductase
inhibitor has been shown to reduce the plasma testosterone response to HCG. In the same study, the
mean testosterone response to HCG was slightly but not significantly reduced after treatment with
lovastatin 40 mg daily for 16 weeks in 21 men. The effects of HMG-CoA reductase inhibitors on male
fertility have not been studied in adequate numbers of male patients. The effects, if any, on the pituitary-
gonadal axis in pre-menopausal women are unknown. Patients treated with lovastatin who develop
clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be
exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is
administered to patients also receiving other drugs (e.g., spironolactone, cimetidine) that may decrease
the levels or activity of endogenous steroid hormones.
CNS Toxicity
Lovastatin produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in
clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean
plasma drug levels about 30 times higher than the mean drug level in humans taking the highest
recommended dose (as measured by total enzyme inhibitory activity). Vestibulocochlear Wallerian-like
degeneration and retinal ganglion cell chromatolysis were also seen in dogs treated for 14 weeks at 180
mg/kg/day, a dose which resulted in a mean plasma drug level (Cmax) similar to that seen with the 60
mg/kg/day dose.
CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell
infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels, were seen in
dogs treated with lovastatin at a dose of 180 mg/kg/day, a dose which produced plasma drug levels
(Cmax) which were about 30 times higher than the mean values in humans taking 80 mg/day.
Similar optic nerve and CNS vascular lesions have been observed with other drugs of this class.
Cataracts were seen in dogs treated for 11 and 28 weeks at 180 mg/kg/day and 1 year at
60 mg/kg/day.
14
Reference ID: 3093010
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844662
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 21-month carcinogenic study in mice, there was a statistically significant increase in the incidence
of hepatocellular carcinomas and adenomas in both males and females at 500 mg/kg/day. This dose
produced a total plasma drug exposure 3 to 4 times that of humans given the highest recommended dose
of lovastatin (drug exposure was measured as total HMG-CoA reductase inhibitory activity in extracted
plasma). Tumor increases were not seen at 20 and 100 mg/kg/day, doses that produced drug exposures
of 0.3 to 2 times that of humans at the 80 mg/day dose. A statistically significant increase in pulmonary
adenomas was seen in female mice at approximately 4 times the human drug exposure. (Although mice
were given 300 times the human dose [HD] on a mg/kg body weight basis, plasma levels of total
inhibitory activity were only 4 times higher in mice than in humans given 80 mg of MEVACOR.)
There was an increase in incidence of papilloma in the non-glandular mucosa of the stomach of mice
beginning at exposures of 1 to 2 times that of humans. The glandular mucosa was not affected. The
human stomach contains only glandular mucosa.
In a 24-month carcinogenicity study in rats, there was a positive dose response relationship for
hepatocellular carcinogenicity in males at drug exposures between 2-7 times that of human exposure at
80 mg/day (doses in rats were 5, 30 and 180 mg/kg/day).
An increased incidence of thyroid neoplasms in rats appears to be a response that has been seen
with other HMG-CoA reductase inhibitors.
A chemically similar drug in this class was administered to mice for 72 weeks at 25, 100, and
400 mg/kg body weight, which resulted in mean serum drug levels approximately 3, 15, and 33 times
higher than the mean human serum drug concentration (as total inhibitory activity) after a 40 mg oral
dose. Liver carcinomas were significantly increased in high dose females and mid- and high dose males,
with a maximum incidence of 90 percent in males. The incidence of adenomas of the liver was
significantly increased in mid- and high dose females. Drug treatment also significantly increased the
incidence of lung adenomas in mid- and high dose males and females. Adenomas of the Harderian gland
(a gland of the eye of rodents) were significantly higher in high dose mice than in controls.
No evidence of mutagenicity was observed in a microbial mutagen test using mutant strains of
Salmonella typhimurium with or without rat or mouse liver metabolic activation. In addition, no evidence of
damage to genetic material was noted in an in vitro alkaline elution assay using rat or mouse
hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in
CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow.
Drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant
cell formation were seen in dogs starting at 20 mg/kg/day. Similar findings were seen with another drug in
this class. No drug-related effects on fertility were found in studies with lovastatin in rats. However, in
studies with a similar drug in this class, there was decreased fertility in male rats treated for 34 weeks at
25 mg/kg body weight, although this effect was not observed in a subsequent fertility study when this
same dose was administered for 11 weeks (the entire cycle of spermatogenesis, including epididymal
maturation). In rats treated with this same reductase inhibitor at 180 mg/kg/day, seminiferous tubule
degeneration (necrosis and loss of spermatogenic epithelium) was observed. No microscopic changes
were observed in the testes from rats of either study. The clinical significance of these findings is unclear.
Pregnancy
Pregnancy Category X
See CONTRAINDICATIONS.
Safety in pregnant women has not been established.
Lovastatin has been shown to produce skeletal malformations in offspring of pregnant mice and rats
dosed during gestation at 80 mg/kg/day (affected mouse fetuses/total: 8/307 compared to 4/289 in the
control group; affected rat fetuses/total: 6/324 compared to 2/308 in the control group). Female rats
dosed before mating through gestation at 80 mg/kg/day also had fetuses with skeletal malformations
(affected fetuses/total: 1/152 compared to 0/171 in the control group). The 80 mg/kg/day dose in mice is 7
times the human dose based on body surface area and in rats results in 5 times the human exposure
based on AUC. In pregnant rats given doses of 2, 20, or 200 mg/kg/day and treated through lactation, the
following effects were observed: neonatal mortality (4.1%, 3.5%, and 46%, respectively, compared to
0.6% in the control group), decreased pup body weights throughout lactation (up to 5%, 8%, and 38%,
respectively, below control), supernumerary ribs in dead pups (affected fetuses/total: 0/7, 1/17, and
15
Reference ID: 3093010
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844662
11/79, respectively, compared to 0/5 in the control group), delays in ossification in dead pups (affected
fetuses/total: 0/7, 0/17, and 1/79, respectively, compared to 0/5 in the control group) and delays in pup
development (delays in the appearance of an auditory startle response at 200 mg/kg/day and free-fall
righting reflexes at 20 and 200 mg/kg/day).
Direct dosing of neonatal rats by subcutaneous injection with 10 mg/kg/day of the open hydroxyacid
form of lovastatin resulted in delayed passive avoidance learning in female rats (mean of 8.3 trials to
criterion, compared to 7.3 and 6.4 in untreated and vehicle-treated controls; no effects on retention 1
week later) at exposures 4 times the human systemic exposure at 80 mg/day based on AUC. No effect
was seen in male rats. No evidence of malformations was observed when pregnant rabbits were given 5
mg/kg/day (doses equivalent to a human dose of 80 mg/day based on body surface area) or a maternally
toxic dose of 15 mg/kg/day (3 times the human dose of 80 mg/day based on body surface area).
Rare clinical reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase
inhibitors have been received. However, in an analysis† of greater than 200 prospectively followed
pregnancies exposed during the first trimester to MEVACOR or another closely related HMG-CoA
reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general
population. This number of pregnancies was sufficient to exclude a 3-fold or greater increase in
congenital anomalies over the background incidence.
Maternal treatment with MEVACOR may reduce the fetal levels of mevalonate, which is a precursor of
cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-
lowering drugs during pregnancy should have little impact on the long-term risk associated with primary
hypercholesterolemia. For these reasons, MEVACOR should not be used in women who are pregnant, or
can become pregnant (see CONTRAINDICATIONS). MEVACOR should be administered to women of
child-bearing potential only when such patients are highly unlikely to conceive and have been informed of
the potential hazards. Treatment should be immediately discontinued as soon as pregnancy is
recognized.
Nursing Mothers
It is not known whether lovastatin is excreted in human milk. Because a small amount of another drug
in this class is excreted in human breast milk and because of the potential for serious adverse reactions
in nursing infants, women taking MEVACOR should not nurse their infants (see CONTRAINDICATIONS).
Pediatric Use
Safety and effectiveness in patients 10-17 years of age with heFH have been evaluated in controlled
clinical trials of 48 weeks duration in adolescent boys and controlled clinical trials of 24 weeks duration in
girls who were at least 1 year post-menarche. Patients treated with lovastatin had an adverse experience
profile generally similar to that of patients treated with placebo. Doses greater than 40 mg have not
been studied in this population. In these limited controlled studies, there was no detectable effect on
growth or sexual maturation in the adolescent boys or on menstrual cycle length in girls. See CLINICAL
PHARMACOLOGY, Clinical Studies in Adolescent Patients; ADVERSE REACTIONS, Adolescent
Patients; and DOSAGE AND ADMINISTRATION, Adolescent Patients (10-17 years of age) with
Heterozygous Familial Hypercholesterolemia. Adolescent females should be counseled on appropriate
contraceptive methods while on lovastatin therapy (see CONTRAINDICATIONS and PRECAUTIONS,
Pregnancy). Lovastatin has not been studied in pre-pubertal patients or patients younger than
10 years of age.
Geriatric Use
A pharmacokinetic study with lovastatin showed the mean plasma level of HMG-CoA reductase
inhibitory activity to be approximately 45% higher in elderly patients between 70-78 years of age
compared with patients between 18-30 years of age; however, clinical study experience in the elderly
indicates that dosage adjustment based on this age-related pharmacokinetic difference is not needed. In
the two large clinical studies conducted with lovastatin (EXCEL and AFCAPS/TexCAPS), 21%
(3094/14850) of patients were ≥65 years of age. Lipid-lowering efficacy with lovastatin was at least as
great in elderly patients compared with younger patients, and there were no overall differences in safety
over the 20 to 80 mg/day dosage range (see CLINICAL PHARMACOLOGY).
† Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During
Pregnancy. Reproductive Toxicology. 10(6):439-446. 1996.
16
Reference ID: 3093010
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844662
ADVERSE REACTIONS
MEVACOR is generally well tolerated; adverse reactions usually have been mild and transient.
Phase III Clinical Studies
In Phase III controlled clinical studies involving 613 patients treated with MEVACOR, the adverse
experience profile was similar to that shown below for the 8,245-patient EXCEL study (see Expanded
Clinical Evaluation of Lovastatin [EXCEL] Study).
Persistent increases of serum transaminases have been noted (see WARNINGS, Liver Dysfunction).
About 11% of patients had elevations of CK levels of at least twice the normal value on one or more
occasions. The corresponding values for the control agent cholestyramine was 9 percent. This was
attributable to the noncardiac fraction of CK. Large increases in CK have sometimes been reported (see
WARNINGS, Myopathy/Rhabdomyolysis).
Expanded Clinical Evaluation of Lovastatin (EXCEL) Study
MEVACOR was compared to placebo in 8,245 patients with hypercholesterolemia (total-C 240-300
mg/dL [6.2-7.8 mmol/L]) in the randomized, double-blind, parallel, 48-week EXCEL study. Clinical
adverse experiences reported as possibly, probably or definitely drug-related in ≥1% in any treatment
group are shown in the table below. For no event was the incidence on drug and placebo statistically
different.
Placebo
(N = 1663)
%
MEVACOR
20 mg q.p.m.
(N = 1642)
%
MEVACOR
40 mg q.p.m.
(N = 1645)
%
MEVACOR
20 mg b.i.d.
(N = 1646)
%
MEVACOR
40 mg b.i.d.
(N = 1649)
%
Body As a Whole
Asthenia
1.4
1.7
1.4
1.5
1.2
Gastrointestinal
Abdominal pain
Constipation
Diarrhea
Dyspepsia
Flatulence
Nausea
1.6
1.9
2.3
1.9
4.2
2.5
2.0
2.0
2.6
1.3
3.7
1.9
2.0
3.2
2.4
1.3
4.3
2.5
2.2
3.2
2.2
1.0
3.9
2.2
2.5
3.5
2.6
1.6
4.5
2.2
Musculoskeletal
Muscle cramps
Myalgia
0.5
1.7
0.6
2.6
0.8
1.8
1.1
2.2
1.0
3.0
Nervous System/
Psychiatric
Dizziness
Headache
0.7
2.7
0.7
2.6
1.2
2.8
0.5
2.1
0.5
3.2
Skin
Rash
0.7
0.8
1.0
1.2
1.3
Special Senses
Blurred vision
0.8
1.1
0.9
0.9
1.2
Other clinical adverse experiences reported as possibly, probably or definitely drug-related in 0.5 to
1.0 percent of patients in any drug-treated group are listed below. In all these cases the incidence on
drug and placebo was not statistically different. Body as a Whole: chest pain; Gastrointestinal: acid
regurgitation, dry mouth, vomiting; Musculoskeletal: leg pain, shoulder pain, arthralgia; Nervous
System/Psychiatric: insomnia, paresthesia; Skin: alopecia, pruritus; Special Senses: eye irritation.
In the EXCEL study (see CLINICAL PHARMACOLOGY, Clinical Studies), 4.6% of the patients treated
up to 48 weeks were discontinued due to clinical or laboratory adverse experiences which were rated by
the investigator as possibly, probably or definitely related to therapy with MEVACOR. The value for the
placebo group was 2.5%.
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
In AFCAPS/TexCAPS (see CLINICAL PHARMACOLOGY, Clinical Studies) involving 6,605
participants treated with 20-40 mg/day of MEVACOR (n=3,304) or placebo (n=3,301), the safety and
tolerability profile of the group treated with MEVACOR was comparable to that of the group treated with
placebo during a median of 5.1 years of follow-up. The adverse experiences reported in
17
Reference ID: 3093010
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844662
AFCAPS/TexCAPS were similar to those reported in EXCEL (see ADVERSE REACTIONS, Expanded
Clinical Evaluation of Lovastatin (EXCEL) Study).
Concomitant Therapy
In controlled clinical studies in which lovastatin was administered concomitantly with cholestyramine,
no adverse reactions peculiar to this concomitant treatment were observed. The adverse reactions that
occurred were limited to those reported previously with lovastatin or cholestyramine. Other lipid-lowering
agents were not administered concomitantly with lovastatin during controlled clinical studies. Preliminary
data suggests that the addition of gemfibrozil to therapy with lovastatin is not associated with greater
reduction in LDL-C than that achieved with lovastatin alone. In uncontrolled clinical studies, most of the
patients who have developed myopathy were receiving concomitant therapy with cyclosporine,
gemfibrozil or niacin (nicotinic acid). The combined use of lovastatin with cyclosporine or gemfibrozil
should be avoided. Caution should be used when prescribing other fibrates or lipid-lowering doses
(≥1 g/day) of niacin with lovastatin (see WARNINGS, Myopathy/Rhabdomyolysis).
The following effects have been reported with drugs in this class. Not all the effects listed below have
necessarily been associated with lovastatin therapy.
Skeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias.
Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-
ocular movement, facial paresis), tremor, dizziness, vertigo, paresthesia, peripheral neuropathy,
peripheral nerve palsy, psychic disturbances, anxiety, insomnia, depression.
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness,
amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been
reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation,
with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which
has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like
syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia,
hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia,
photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme,
including Stevens-Johnson syndrome.
Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty
change in liver; and rarely, cirrhosis, fulminant hepatic necrosis, and hepatoma; anorexia, vomiting, fatal
and non-fatal hepatic failure.
Skin: alopecia, pruritus. A variety of skin changes (e.g., nodules, discoloration, dryness of
skin/mucous membranes, changes to hair/nails) have been reported.
Reproductive: gynecomastia, loss of libido, erectile dysfunction.
Eye: progression of cataracts (lens opacities), ophthalmoplegia.
Laboratory Abnormalities: elevated transaminases, alkaline phosphatase, γ-glutamyl transpeptidase,
and bilirubin; thyroid function abnormalities.
Adolescent Patients (ages 10-17 years)
In a 48-week controlled study in adolescent boys with heFH (n=132) and a 24-week controlled study
in girls who were at least 1 year post-menarche with heFH (n=54), the safety and tolerability profile of the
groups treated with MEVACOR (10 to 40 mg daily) was generally similar to that of the groups treated with
placebo (see CLINICAL PHARMACOLOGY, Clinical Studies in Adolescent Patients and PRECAUTIONS,
Pediatric Use).
OVERDOSAGE
After oral administration of MEVACOR to mice, the median lethal dose observed was >15 g/m2.
Five healthy human volunteers have received up to 200 mg of lovastatin as a single dose without
clinically significant adverse experiences. A few cases of accidental overdosage have been reported; no
patients had any specific symptoms, and all patients recovered without sequelae. The maximum dose
taken was 5-6 g.
Until further experience is obtained, no specific treatment of overdosage with MEVACOR can be
recommended.
18
Reference ID: 3093010
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844662
The dialyzability of lovastatin and its metabolites in man is not known at present.
DOSAGE AND ADMINISTRATION
The patient should be placed on a standard cholesterol-lowering diet before receiving MEVACOR and
should continue on this diet during treatment with MEVACOR (see NCEP Treatment Guidelines for
details on dietary therapy). MEVACOR should be given with meals.
Adult Patients
The usual recommended starting dose is 20 mg once a day given with the evening meal. The
recommended dosing range of lovastatin is 10-80 mg/day in single or two divided doses; the maximum
recommended dose is 80 mg/day. Doses should be individualized according to the recommended goal of
therapy (see NCEP Guidelines and CLINICAL PHARMACOLOGY). Patients requiring reductions in LDL
C of 20% or more to achieve their goal (see INDICATIONS AND USAGE) should be started on
20 mg/day of MEVACOR. A starting dose of 10 mg of lovastatin may be considered for patients requiring
smaller reductions. Adjustments should be made at intervals of 4 weeks or more. The 10 mg dosage is
provided for information purposes only. Although lovastatin tablets 10 mg are available in the
marketplace, MEVACOR is no longer marketed in the 10 mg strength.
Cholesterol levels should be monitored periodically and consideration should be given to reducing the
dosage of MEVACOR if cholesterol levels fall significantly below the targeted range.
Dosage in Patients taking Danazol, Diltiazem, or Verapamil
In patients taking danazol, diltiazem, or verapamil concomitantly with lovastatin, therapy should begin
with 10 mg of lovastatin and should not exceed 20 mg/day (see CLINICAL PHARMACOLOGY,
Pharmacokinetics, WARNINGS, Myopathy/Rhabdomyolysis, PRECAUTIONS, Drug Interactions, Other
Drug Interactions).
Dosage in Patients taking Amiodarone
In patients taking amiodarone concomitantly with MEVACOR, the dose should not exceed 40 mg/day
(see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions, Other Drug
Interactions).
Adolescent Patients (10-17 years of age) with Heterozygous Familial Hypercholesterolemia
The recommended dosing range of lovastatin is 10-40 mg/day; the maximum recommended dose is
40 mg/day. Doses should be individualized according to the recommended goal of therapy (see NCEP
Pediatric Panel Guidelines††, CLINICAL PHARMACOLOGY, and INDICATIONS AND USAGE). Patients
requiring reductions in LDL-C of 20% or more to achieve their goal should be started on 20 mg/day of
MEVACOR. A starting dose of 10 mg of lovastatin may be considered for patients requiring smaller
reductions. Adjustments should be made at intervals of 4 weeks or more.
Concomitant Lipid-Lowering Therapy
MEVACOR is effective alone or when used concomitantly with bile-acid sequestrants (see
WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions).
Dosage in Patients with Renal Insufficiency
In patients with severe renal insufficiency (creatinine clearance <30 mL/min), dosage increases above
20 mg/day should be carefully considered and, if deemed necessary, implemented cautiously (see
CLINICAL PHARMACOLOGY and WARNINGS, Myopathy/Rhabdomyolysis).
HOW SUPPLIED
No. 8123 — Tablets MEVACOR 20 mg are blue, octagonal tablets, coded MSD 731 on one side and
plain on the other. They are supplied as follows:
NDC 0006-0731-61 unit of use bottles of 60.
No. 8124 — Tablets MEVACOR 40 mg are green, octagonal tablets, coded MSD 732 on one side and
plain on the other. They are supplied as follows:
NDC 0006-0732-61 unit of use bottles of 60.
†† National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and
Adolescents. Pediatrics. 89(3):495-501. 1992.
19
Reference ID: 3093010
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEVACOR® (Lovastatin)
9844662
Storage
Store at 20-25°C (68-77°F). [See USP Controlled Room Temperature.] Tablets MEVACOR must be
protected from light and stored in a well-closed, light-resistant container. Merck logo
By:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505, USA
OR
Mylan Pharmaceuticals ULC
Etobicoke, Ontario, Canada M8Z 2S6
Revised: 02/2012
9844662
20
Reference ID: 3093010
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:36.807151
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019643s085lbl.pdf', 'application_number': 19643, 'submission_type': 'SUPPL ', 'submission_number': 85}
|
11,592
|
1
TORADOL® ORAL
2
3
4
(ketorolac tromethamine tablets)
Rx only
WARNING
5
TORADOLORAL (ketorolac tromethamine), a nonsteroidal anti-inflammatory drug
6
(NSAID), is indicated for the short-term (up to 5 days in adults), management of
7
moderately severe acute pain that requires analgesia at the opioid level and only as
8
continuation treatment following IV or IM dosing of ketorolac tromethamine, if
9
necessary. The total combined duration of use of TORADOLORAL and ketorolac
10
tromethamine should not exceed 5 days.
11
12
TORADOLORAL is not indicated for use in pediatric patients and it is NOT indicated
13
for minor or chronic painful conditions. Increasing the dose of TORADOLORAL
14
beyond a daily maximum of 40 mg in adults will not provide better efficacy but will
15
increase the risk of developing serious adverse events.
16
17
GASTROINTESTINAL RISK
18
19
Ketorolac
tromethamine,
including
TORADOL
can
cause
peptic
ulcers,
20
gastrointestinal bleeding and/or perforation of the stomach or intestines, which can be
21
fatal. These events can occur at any time during use and without warning symptoms.
22
Therefore, TORADOL is CONTRAINDICATED in patients with active peptic ulcer
23
disease, in patients with recent gastrointestinal bleeding or perforation, and in patients
24
with a history of peptic ulcer disease or gastrointestinal bleeding. Elderly patients are
at greater risk for serious gastrointestinal events (see WARNINGS).
25
26
CARDIOVASCULAR RISK
27
28
NSAIDs may cause an increased risk of serious cardiovascular thrombotic events,
29
myocardial infarction, and stroke, which can be fatal. This risk may increase with
30
duration of use. Patients with cardiovascular disease or risk factors for cardiovascular
disease may be at greater risk (see WARNINGS and CLINICAL TRIALS).
31
32
TORADOL is CONTRAINDICATED for the treatment of peri-operative pain in the
setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).
33
34
RENAL RISK
35
36
TORADOL is CONTRAINDICATED in patients with advanced renal impairment and in
patients at risk for renal failure due to volume depletion (see WARNINGS).
37
38
RISK OF BLEEDING
39
40
TORADOL inhibits platelet function and is, therefore, CONTRAINDICATED in patients
with suspected or confirmed cerebrovascular bleeding, patients with hemorrhagic
41
diathesis, incomplete hemostasis and those at high risk of bleeding (see WARNINGS
42
and PRECAUTIONS).
43
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
TORADOL is CONTRAINDICATED as prophylactic analgesic before any major
44
surgery.
45
46
RISK DURING LABOR AND DELIVERY
47
48
The use of TORADOL in labor and delivery is contraindicated because it may
49
adversely affect fetal circulation and inhibit uterine contractions. The use of
TORADOL is contraindicated in nursing mothers because of the potential adverse
50
51
effects of prostaglandin-inhibiting drugs on neonates.
52
CONCOMITANT USE WITH NSAIDS
53
54
TORADOL is CONTRAINDICATED in patients currently receiving aspirin or NSAIDs
because of the cumulative risk of inducing serious NSAID-related side effects.
55
56
SPECIAL POPULATIONS
57
58
Dosage should be adjusted for patients 65 years or older, for patients under 50 kg
(110 lbs) of body weight (see DOSAGE AND ADMINISTRATION) and for
59
patients with moderately elevated serum creatinine (see WARNINGS).
60
61
62
63
64
DESCRIPTION
TORADOL (ketorolac tromethamine) is a member of the pyrrolo-pyrrole group of
nonsteroidal anti-inflammatory drugs (NSAIDs). The chemical name for ketorolac
tromethamine is (±)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, compound
with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1), and the chemical structure is:
65
66
67
68
69
70
71
72
Ketorolac tromethamine is a racemic mixture of [-]S and [+]R ketorolac tromethamine.
Ketorolac tromethamine may exist in three crystal forms. All forms are equally soluble in
water. Ketorolac tromethamine has a pKa of 3.5 and an n-octanol/water partition
coefficient of 0.26. The molecular weight of ketorolac tromethamine is 376.41. Its
molecular formula is C19H24N2O6.
TORADOLORAL is available as round, white, film-coated, red-printed tablets. Each tablet
contains 10 mg ketorolac tromethamine, the active ingredient, with added lactose,
magnesium stearate and microcrystalline cellulose. The white film-coating contains
hydroxypropyl methylcellulose, polyethylene glycol and titanium dioxide.
73
74
75
76
77
78
79
80
81
82
83
The tablets are printed with red ink that includes FD&C Red #40 Aluminum Lake as the
colorant. There is a large T printed on both sides of the tablet, as well as the word
TORADOL on one side, and the word ROCHE on the other.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits
analgesic activity in animal models. The mechanism of action of ketorolac, like that of
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
other NSAIDs, is not completely understood but may be related to prostaglandin
synthetase inhibition. The biological activity of ketorolac tromethamine is associated
with the S-form. Ketorolac tromethamine possesses no sedative or anxiolytic properties.
The peak analgesic effect of TORADOL occurs within 2 to 3 hours and is not statistically
significantly different over the recommended dosage range of TORADOL. The greatest
difference between large and small doses of TORADOL is in the duration of analgesia.
Pharmacokinetics
Ketorolac tromethamine is a racemic mixture of [-]S- and [+]R-enantiomeric forms, with
the S-form having analgesic activity.
Comparison of IV, IM and Oral Pharmacokinetics
The pharmacokinetics of ketorolac tromethamine, following IV and IM doses of
ketorolac tromethamine and oral doses of TORADOL, are compared in Table 1. In
adults, the extent of bioavailability following administration of the ORAL form of
TORADOL and the IM form of ketorolac tromethamine was equal to that following an
IV bolus.
Linear Kinetics
In adults, following administration of single ORAL doses of TORADOL or IM or IV
doses of ketorolac tromethamine in the recommended dosage ranges, the clearance of the
racemate does not change. This implies that the pharmacokinetics of ketorolac
tromethamine in adults, following single or multiple IM or IV doses of ketorolac
tromethamine or recommended oral doses of TORADOL, are linear. At the higher
recommended doses, there is a proportional increase in the concentrations of free and
bound racemate.
Absorption
TORADOL is 100% absorbed after oral administration (see Table 1). Oral administration
of TORADOL after a high-fat meal resulted in decreased peak and delayed time-to-peak
concentrations of ketorolac tromethamine by about 1 hour. Antacids did not affect the
extent of absorption.
Distribution
The mean apparent volume (Vβ) of ketorolac tromethamine following complete
distribution was approximately 13 liters. This parameter was determined from single-
dose data. The ketorolac tromethamine racemate has been shown to be highly protein
bound (99%). Nevertheless, plasma concentrations as high as 10 μg/mL will only occupy
approximately 5% of the albumin binding sites. Thus, the unbound fraction for each
enantiomer will be constant over the therapeutic range. A decrease in serum albumin,
however, will result in increased free drug concentrations.
Ketorolac tromethamine is excreted in human milk (see PRECAUTIONS: Nursing
Mothers).
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
Metabolism
Ketorolac tromethamine is largely metabolized in the liver. The metabolic products are
hydroxylated and conjugated forms of the parent drug. The products of metabolism, and
some unchanged drug, are excreted in the urine.
Excretion
The principal route of elimination of ketorolac and its metabolites is renal. About 92% of
a given dose is found in the urine, approximately 40% as metabolites and 60% as
unchanged ketorolac. Approximately 6% of a dose is excreted in the feces. A single-dose
study with 10 mg TORADOL (n=9) demonstrated that the S-enantiomer is cleared
approximately two times faster than the R-enantiomer and that the clearance was
independent of the route of administration. This means that the ratio of S/R plasma
concentrations decreases with time after each dose. There is little or no inversion of the
R- to S- form in humans. The clearance of the racemate in normal subjects, elderly
individuals and in hepatically and renally impaired patients is outlined in Table 2 (see
CLINICAL PHARMACOLOGY: Kinetics in Special Populations).
The half-life of the ketorolac tromethamine S-enantiomer was approximately 2.5 hours
(SD ± 0.4) compared with 5 hours (SD ± 1.7) for the R-enantiomer. In other studies, the
half-life for the racemate has been reported to lie within the range of 5 to 6 hours.
Accumulation
Ketorolac tromethamine administered as an IV bolus every 6 hours for 5 days to healthy
subjects (n=13), showed no significant difference in Cmax on Day 1 and Day 5. Trough
levels averaged 0.29 μg/mL (SD ± 0.13) on Day 1 and 0.55 μg/mL (SD ± 0.23) on Day 6.
Steady state was approached after the fourth dose.
Accumulation of ketorolac tromethamine has not been studied in special populations
(geriatric, pediatric, renal failure or hepatic disease patients).
Kinetics in Special Populations
Geriatric Patients
Based on single-dose data only, the half-life of the ketorolac tromethamine racemate
increased from 5 to 7 hours in the elderly (65 to 78 years) compared with young healthy
volunteers (24 to 35 years) (see Table 2). There was little difference in the Cmax for the
two
groups
(elderly,
2.52 μg/mL ± 0.77;
young,
2.99 μg/mL ± 1.03)
(see
PRECAUTIONS: Geriatric Use).
Pediatric Patients
Limited information is available regarding the pharmacokinetics of dosing of ketorolac
tromethamine in the pediatric population. Following a single intravenous bolus dose of
0.5 mg/kg in 10 children 4 to 8 years old, the half-life was 5.8 ± 1.6 hours, the average
clearance was 0.042 ± 0.01 L/hr/kg, the volume of distribution during the terminal phase
(Vβ) was 0.34 ± 0.12 L/kg and the volume of distribution at steady state (Vss) was
0.26 ± 0.08 L/kg. The volume of distribution and clearance of ketorolac in pediatric
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
patients was higher than those observed in adult subjects (see Table 1). There are no
pharmacokinetic data available for administration of ketorolac tromethamine by the IM
route in pediatric patients.
Renal Insufficiency
Based on single-dose data only, the mean half-life of ketorolac tromethamine in renally
impaired patients is between 6 and 19 hours and is dependent on the extent of the
impairment. There is poor correlation between creatinine clearance and total ketorolac
tromethamine clearance in the elderly and populations with renal impairment (r=0.5).
In patients with renal disease, the AUC∞ of each enantiomer increased by approximately
100% compared with healthy volunteers. The volume of distribution doubles for the
S-enantiomer and increases by 1/5th for the R-enantiomer. The increase in volume of
distribution of ketorolac tromethamine implies an increase in unbound fraction.
The AUC∞-ratio of the ketorolac tromethamine enantiomers in healthy subjects and
patients remained similar, indicating there was no selective excretion of either enantiomer
in patients compared to healthy subjects (see WARNINGS: Renal Effects).
Hepatic Insufficiency
There was no significant difference in estimates of half-life, AUC∞ and Cmax in 7 patients
with liver disease compared to healthy volunteers (see PRECAUTIONS: Hepatic Effect
and Table 2).
Race
Pharmacokinetic differences due to race have not been identified.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1
Table of Approximate Average Pharmacokinetic Parameters (Mean ± SD) Following Oral,
Intramuscular and Intravenous Doses of Ketorolac Tromethamine
Oral*
Intramuscular†
Intravenous Bolus‡
Pharmacokinetic
Parameters (units)
10 mg
15 mg
30 mg
60 mg
15 mg
30 mg
Bioavailability (extent)
100%
Tmax
1 (min)
44 ± 34
33 ± 21§
44 ± 29
33 ± 21§
1.1 ± 0.7§
2.9 ± 1.8
Cmax
2 (µg/mL) [single-dose]
0.87 ± 0.22
1.14 ± 0.32§
2.42 ± 0.68
4.55 ± 1.27§
2.47 ± 0.51§
4.65 ± 0.96
Cmax (µg/mL) [steady state qid]
1.05 ± 0.26§
1.56 ± 0.44§
3.11 ± 0.87§
N/A||
3.09 ± 1.17§
6.85 ± 2.61
Cmin
3 (µg/mL) [steady state qid]
0.29 ± 0.07§
0.47 ± 0.13§
0.93 ± 0.26§
N/A
0.61 ± 0.21§
1.04 ± 0.35
Cavg
4 (µg/mL) [steady state qid]
0.59 ± 0.20§
0.94 ± 0.29§
1.88 ± 0.59§
N/A
1.09 ± 0.30§
2.17 ± 0.59
Vβ5 (L/kg)
————— 0.175 ± 0.039 ————
0.210 ± 0.044
% Dose metabolized = <50
% Dose excreted in feces = 6
% Dose excreted in urine = 91
% Plasma protein binding = 99
* Derived from PO pharmacokinetic studies in 77 normal fasted volunteers
† Derived from IM pharmacokinetic studies in 54 normal volunteers
‡ Derived from IV pharmacokinetic studies in 24 normal volunteers
§ Mean value was simulated from observed plasma concentration data and standard deviation was simulated from percent
coefficient of variation for observed Cmax and Tmax data
|| Not applicable because 60 mg is only recommended as a single dose
1Time-to-peak plasma concentration
2Peak plasma concentration
3Trough plasma concentration
4Average plasma concentration
5Volume of distribution
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
Table 2
The Influence of Age, Liver, and Kidney Function on the Clearance and Terminal Half-life of
Ketorolac Tromethamine (IM1 and ORAL2) in Adult Populations
Total Clearance [in L/h/kg]3
Terminal Half-life [in hours]
IM
ORAL
IM
ORAL
Type of Subjects
Mean (range)
Mean (range)
Mean (range)
Mean (range)
Normal Subjects
IM (n=54)
mean age=32, range=18–60
Oral (n=77)
mean age=32, range=20–60
0.023
(0.010–0.046)
0.025
(0.013–0.050)
5.3
(3.5–9.2)
5.3
(2.4–9.0)
Healthy Elderly Subjects
IM (n=13), Oral (n=12)
mean age=72, range=65–78
0.019
(0.013–0.034)
0.024
(0.018–0.034)
7.0
(4.7–8.6)
6.1
(4.3–7.6)
Patients with Hepatic Dysfunction
IM and Oral (n=7)
mean age=51, range=43–64
0.029
(0.013–0.066)
0.033
(0.019–0.051)
5.4
(2.2–6.9)
4.5
(1.6–7.6)
Patients with Renal Impairment
IM (n=25), Oral (n=9)
serum creatinine=1.9–5.0 mg/dL,
mean age (IM)=54, range=35–71
mean age (Oral)=57, range=39–70
0.015
(0.005–0.043)
0.016
(0.007–0.052)
10.3
(5.9–19.2)
10.8
(3.4–18.9)
Renal Dialysis Patients
IM and Oral (n=9)
mean age=40, range=27–63
0.016
(0.003–0.036)
—
13.6
(8.0–39.1)
—
1 Estimated from 30 mg single IM doses of ketorolac tromethamine
2 Estimated from 10 mg single oral doses of ketorolac tromethamine
3 Liters/hour/kilogram
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
IV Administration
188
189
190
191
192
193
194
195
In normal adult subjects (n=37), the total clearance of 30 mg IV-administered ketorolac
tromethamine was 0.030 (0.017-0.051) L/h/kg. The terminal half-life was 5.6 (4.0-7.9)
hours. (See Kinetics in Special Populations for use of IV dosing of ketorolac
tromethamine in pediatric patients.)
CLINICAL STUDIES
Adult Patients
In a postoperative study, where all patients received morphine by a PCA device, patients
treated with ketorolac tromethamineIV as fixed intermittent boluses (e.g., 30 mg initial
dose followed by 15 mg q3h), required significantly less morphine (26%) than the
placebo group. Analgesia was significantly superior, at various postdosing pain
assessment times, in the patients receiving ketorolac tromethamine
196
197
198
IV plus PCA morphine
as compared to patients receiving PCA-administered morphine alone.
199
200
201
Pediatric Patients
There are no data available to support the use of TORADOLORAL in pediatric patients.
202
203
204
205
206
207
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of TORADOL and other treatment
options before deciding to use TORADOL. Use the lowest effective dose for the shortest
duration consistent with individual patient treatment goals.
Acute Pain in Adult Patients
TORADOLORAL is indicated for the short-term (≤5 days) management of moderately
severe acute pain that requires analgesia at the opioid level, usually in a postoperative
setting. Therapy should always be initiated with IV or IM dosing of ketorolac
tromethamine, and TORADOL
208
209
210
ORAL is to be used only as continuation treatment, if
necessary.
211
212
The total combined duration of use of TORADOLORAL and ketorolac tromethamine is not
to exceed 5 days of use because of the potential of increasing the frequency and severity
of adverse reactions associated with the recommended doses (see WARNINGS,
PRECAUTIONS,
DOSAGE
AND
ADMINISTRATION,
and
ADVERSE
REACTIONS). Patients should be switched to alternative analgesics as soon as possible,
but TORADOL
213
214
215
216
217
ORAL therapy is not to exceed 5 days.
218
219
220
221
222
223
224
CONTRAINDICATIONS (see also Boxed WARNING)
TORADOL is contraindicated in patients with previously demonstrated hypersensitivity
to ketorolac tromethamine.
TORADOL is contraindicated in patients with active peptic ulcer disease, in patients with
recent gastrointestinal bleeding or perforation and in patients with a history of peptic
ulcer disease or gastrointestinal bleeding.
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
TORADOL 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-like reactions to NSAIDS have been reported in such patients (see
WARNINGS: Anaphylactoid Reactions, and PRECAUTIONS: Preexisting Asthma).
TORADOL is contraindicated as prophylactic analgesic before any major surgery.
TORADOL is contraindicated for the treatment of peri-operative pain in the setting of
coronary artery bypass graft (CABG) surgery (see WARNINGS).
TORADOL is contraindicated in patients with advanced renal impairment or in patients
at risk for renal failure due to volume depletion (see WARNINGS for correction of
volume depletion).
TORADOL is contraindicated in labor and delivery because, through its prostaglandin
synthesis inhibitory effect, it may adversely affect fetal circulation and inhibit uterine
contractions, thus increasing the risk of uterine hemorrhage.
The use of TORADOL is contraindicated in nursing mothers because of the potential
adverse effects of prostaglandin-inhibiting drugs on neonates.
TORADOL inhibits platelet function and is, therefore, contraindicated in patients with
suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, incomplete
hemostasis and those at high risk of bleeding (see WARNINGS and PRECAUTIONS).
TORADOL is contraindicated in patients currently receiving aspirin or NSAIDs because
of the cumulative risks of inducing serious NSAID-related adverse events.
The concomitant use of TORADOL and probenecid is contraindicated.
The concomitant use of ketorolac tromethamine and pentoxifylline is contraindicated.
WARNINGS (see also Boxed WARNING)
The total combined duration of use of TORADOLORAL and IV or IM dosing of ketorolac
tromethamine is not to exceed 5 days in adults. TORADOL
248
ORAL is not indicated for use
in pediatric patients.
249
250
251
252
253
254
255
256
257
258
259
260
261
The most serious risks associated with TORADOL are:
Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation
TORADOL is contraindicated in patients with previously documented peptic ulcers
and/or GI bleeding. Toradol can cause serious gastrointestinal (GI) adverse events
including 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 TORADOL.
Only one in five patients who develop a serious upper GI adverse event on NSAID
therapy is symptomatic. Minor upper gastrointestinal problems, such as dyspepsia, are
common and may also occur at any time during NSAID therapy. The incidence and
severity of gastrointestinal complications increases with increasing dose of, and duration
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
262
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
303
of treatment with, TORADOL. Do not use TORADOL for more than five days.
However, even short-term therapy is not without risk. In addition to past history of ulcer
disease, 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, 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 TORADOL until a serious GI
adverse event is ruled out. For high risk patients, alternate therapies that do not involve
NSAIDs should be considered.
NSAIDs should be given with care to patients with a history of inflammatory bowel
disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated.
Hemorrhage
Because prostaglandins play an important role in hemostasis and NSAIDs affect platelet
aggregation as well, use of TORADOL in patients who have coagulation disorders should
be undertaken very cautiously, and those patients should be carefully monitored. Patients
on therapeutic doses of anticoagulants (eg, heparin or dicumarol derivatives) have an
increased risk of bleeding complications if given TORADOL concurrently; therefore,
physicians should administer such concomitant therapy only extremely cautiously. The
concurrent use of TORADOL and therapy that affects hemostasis, including prophylactic
low-dose heparin (2500 to 5000 units q12h), warfarin and dextrans have not been studied
extensively, but may also be associated with an increased risk of bleeding. Until data
from such studies are available, physicians should carefully weigh the benefits against the
risks and use such concomitant therapy in these patients only extremely cautiously.
Patients receiving therapy that affects hemostasis should be monitored closely.
In postmarketing experience, postoperative hematomas and other signs of wound
bleeding have been reported in association with the peri-operative use of IV or IM dosing
of ketorolac tromethamine. Therefore, peri-operative use of TORADOL should be
avoided and postoperative use be undertaken with caution when hemostasis is critical
(see PRECAUTIONS).
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 NSAID 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, and
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
330
331
332
333
334
335
336
337
338
339
340
341
342
343
344
the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the
pretreatment state.
TORADOL and its metabolites are eliminated primarily by the kidneys, which, in
patients with reduced creatinine clearance, will result in diminished clearance of the drug
(see CLINICAL PHARMACOLOGY). Therefore, TORADOL should be used with
caution
in
patients
with
impaired
renal
function
(see
DOSAGE
AND
ADMINISTRATION) and such patients should be followed closely. With the use of
TORADOL, there have been reports of acute renal failure, interstitial nephritis and
nephrotic syndrome.
Impaired Renal Function
TORADOL is contraindicated in patients with serum creatinine concentrations indicating
advanced renal impairment (see CONTRAINDICATIONS). TORADOL should be used
with caution in patients with impaired renal function or a history of kidney disease
because it is a potent inhibitor of prostaglandin synthesis. Because patients with
underlying renal insufficiency are at increased risk of developing acute renal
decompensation or failure, the risks and benefits should be assessed prior to giving
TORADOL to these patients.
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients without a known
previous exposure or hypersensitivity to TORADOL. TORADOL 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). Anaphylactoid
reactions, like anaphylaxis, may have a fatal outcome. Emergency help should be sought
in cases where an anaphylactoid reaction occurs.
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 Gastrointestinal
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Effects – Risk of Ulceration, Bleeding, and Perforation). 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).
345
346
347
348
349
350
351
352
353
354
355
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
376
377
378
379
380
381
382
Hypertension
NSAIDs, including TORADOL, can lead to onset of new hypertension or worsening of
preexisting 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 TORADOL, 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, edema, retention of NaCl, oliguria, elevations of serum urea nitrogen and
creatinine have been reported in clinical trials with TORADOL. Therefore, TORADOL
should be used only very cautiously in patients with cardiac decompensation,
hypertension or similar conditions.
Skin Reactions
NSAIDS, including TORADOL, 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, mucosal lesions,
or any other sign of hypersensitivity.
Pregnancy
In late pregnancy, as with other NSAIDs, TORADOL should be avoided because it may
cause premature closure of the ductus arteriosus.
PRECAUTIONS
General
TORADOL 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 TORADOL in reducing inflammation may diminish the
utility of this diagnostic sign in detecting complications of presumed noninfectious,
painful conditions.
Hepatic Effect
TORADOL should be used with caution in patients with impaired hepatic function or a
history of liver disease. Borderline elevations of one or more liver tests may occur in up
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
383
384
385
386
387
388
389
390
391
392
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
411
412
413
414
415
416
417
418
to 15% of patients taking NSAIDs including TORADOL. 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 TORADOL. If clinical signs and
symptoms consistent with liver disease develop, or if systemic manifestations occur (eg,
eosinophilia, rash, etc.), TORADOL should be discontinued.
Hematologic Effect
Anemia is sometimes seen in patients receiving NSAIDs, including TORADOL. 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
TORADOL, 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 TORADOL
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,
TORADOL 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
TORADOL is a potent NSAID and may cause serious side effects such as gastrointestinal
bleeding or kidney failure, which may result in hospitalization and even fatal outcome.
Physicians, when prescribing TORADOL, should inform their patients or their guardians
of the potential risks of TORADOL treatment (see Boxed WARNING, WARNINGS,
PRECAUTIONS, and ADVERSE REACTIONS sections), instruct patients to seek
medical advice if they develop treatment-related adverse events, and advise patients not
to give TORADOLORAL to other family members and to discard any unused drug.
419
Remember that the total combined duration of use of TORADOLORAL and IV or IM
dosing of ketorolac tromethamine is not to exceed 5 days in adults. TORADOL
420
ORAL is
not indicated for use in pediatric patients.
421
422
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
423
424
425
426
427
428
429
430
431
432
433
434
435
436
437
438
439
440
441
442
443
444
445
446
447
448
449
450
451
452
453
454
455
456
457
458
459
460
461
462
463
464
465
466
467
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. TORADOL, 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. TORADOL, 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 hematemesis. Patients
should be apprised of the importance of this follow-up (see WARNINGS:
Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation).
3. TORADOL, 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 (eg,
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 anaphylactoid reaction (eg, 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, TORADOL should be avoided because it
will 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 (eg, eosinophilia, rash, etc.) or if abnormal liver tests
persist or worsen, TORADOL should be discontinued.
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Drug Interactions
468
469
470
471
472
473
474
475
476
477
478
479
480
Ketorolac is highly bound to human plasma protein (mean 99.2%). There is no evidence
in animal or human studies that TORADOL induces or inhibits hepatic enzymes capable
of metabolizing itself or other drugs.
Warfarin, Digoxin, Salicylate, and Heparin
The in vitro binding of warfarin to plasma proteins is only slightly reduced by ketorolac
tromethamine (99.5% control vs 99.3%) when ketorolac plasma concentrations reach 5 to
10 μg/mL. Ketorolac does not alter digoxin protein binding. In vitro studies indicate that,
at therapeutic concentrations of salicylate (300 μg/mL), the binding of ketorolac was
reduced from approximately 99.2% to 97.5%, representing a potential twofold increase in
unbound ketorolac plasma levels. Therapeutic concentrations of digoxin, warfarin,
ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin and tolbutamide did not
alter ketorolac tromethamine protein binding.
In a study involving 12 adult volunteers, TORADOLORAL was coadministered with a
single dose of 25 mg warfarin, causing no significant changes in pharmacokinetics or
pharmacodynamics of warfarin. In another study, ketorolac tromethamine
481
482
483
484
485
486
487
488
489
490
491
492
493
494
495
496
497
498
499
500
501
502
503
504
505
dosed IV or IM
was given with two doses of 5000 U of heparin to 11 healthy volunteers, resulting in a
mean template bleeding time of 6.4 minutes (3.2 to 11.4 min) compared to a mean of 6.0
minutes (3.4 to 7.5 min) for heparin alone and 5.1 minutes (3.5 to 8.5 min) for placebo.
Although these results do not indicate a significant interaction between TORADOL and
warfarin or heparin, the administration of TORADOL to patients taking anticoagulants
should be done extremely cautiously, and patients should be closely monitored (see
WARNINGS and PRECAUTIONS: Hematologic Effect).
The effects of warfarin and NSAIDs, in general, on GI bleeding are synergistic, such that
the users of both drugs together have a risk of serious GI bleeding higher than the users
of either drug alone.
Aspirin
When TORADOL is administered with aspirin, its protein binding is reduced, although
the clearance of free TORADOL is not altered. The clinical significance of this
interaction is not known; however, as with other NSAIDs, concomitant administration of
ketorolac tromethamine and aspirin is not generally recommended because of the
potential of increased adverse effects.
Diuretics
Clinical studies, as well as postmarketing observations, have shown that TORADOL can
reduce the natriuretic effect of furosemide and thiazides in some patients. This response
has been attributed to inhibition of renal prostaglandin synthesis. 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.
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
506
Probenecid
Concomitant administration of TORADOLORAL and probenecid resulted in decreased
clearance and volume of distribution of ketorolac and significant increases in ketorolac
plasma levels (total AUC increased approximately threefold from 5.4 to 17.8 μg/h/mL)
and terminal half-life increased approximately twofold from 6.6 to 15.1 hours. Therefore,
concomitant use of TORADOL and probenecid is contraindicated.
507
508
509
510
511
512
513
514
515
516
517
518
519
520
521
522
523
524
525
526
527
528
529
530
531
532
533
534
535
536
537
538
539
540
541
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.
ACE Inhibitors/Angiotension II Receptor Antagonists
Concomitant use of ACE inhibitors and/or angiotension II receptor antagonists may
increase the risk of renal impairment, particularly in volume-depleted patients.
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors
and/or angiotension II receptor antagonists. This interaction should be given
consideration in patients taking NSAIDs concomitantly with ACE inhibitors and/or
angiotension II receptor antagonists.
Antiepileptic Drugs
Sporadic cases of seizures have been reported during concomitant use of TORADOL and
antiepileptic drugs (phenytoin, carbamazepine).
Psychoactive Drugs
Hallucinations have been reported when TORADOL was used in patients taking
psychoactive drugs (fluoxetine, thiothixene, alprazolam).
Pentoxifylline
When ketorolac tromethamine is administered concurrently with pentoxifylline, there is
an increased tendency to bleeding.
Nondepolarizing Muscle Relaxants
In postmarketing experience there have been reports of a possible interaction between
ketorolac tromethamineIV/IM and nondepolarizing muscle relaxants that resulted in
542
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
543
544
545
546
547
548
549
550
551
552
553
554
555
556
557
558
559
560
561
562
563
564
565
566
567
568
569
570
571
572
573
574
575
576
577
578
579
580
apnea. The concurrent use of ketorolac tromethamine with muscle relaxants has not been
formally studied.
Selective Serotonin Reuptake Inhibitors (SSRIs)
There is an increased risk of gastrointestinal bleeding when selective serotonin reuptake
inhibitors (SSRIs) are combined with NSAIDs. Caution should be used when NSAIDs
are administered concomitantly with SSRIs.
Carcinogenesis, Mutagenesis and Impairment of Fertility
An 18-month study in mice with oral doses of ketorolac tromethamine at 2 mg/kg/day
(0.9 times the human systemic exposure at the recommended IM or IV dose of 30 mg qid,
based on area-under-the-plasma-concentration curve [AUC]), and a 24-month study in
rats at 5 mg/kg/day (0.5 times the human AUC) showed no evidence of tumorigenicity.
Ketorolac tromethamine was not mutagenic in the Ames test, unscheduled DNA
synthesis and repair, and in forward mutation assays. Ketorolac tromethamine did not
cause chromosome breakage in the in vivo mouse micronucleus assay. At 1590 μg/mL
and at higher concentrations, ketorolac tromethamine increased the incidence of
chromosomal aberrations in Chinese hamster ovarian cells.
Impairment of fertility did not occur in male or female rats at oral doses of 9 mg/kg
(0.9 times the human AUC) and 16 mg/kg (1.6 times the human AUC) of ketorolac
tromethamine, respectively.
Pregnancy
Teratogenic Effects: Pregnancy Category C
Reproduction studies have been performed during organogenesis using daily oral doses
of ketorolac tromethamine at 3.6 mg/kg (0.37 times the human AUC) in rabbits and at
10 mg/kg (1.0 times the human AUC) in rats. Results of these studies did not reveal
evidence of teratogenicity to the fetus. However, animal reproduction studies are not
always predictive of human response.
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. Oral doses of ketorolac tromethamine at 1.5 mg/kg
(0.14 times the human AUC), administered after gestation Day 17, caused dystocia and
higher pup mortality in rats.
There are no adequate and well-controlled studies of TORADOL in pregnant women.
TORADOL should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
Labor and Delivery
The use of TORADOL is contraindicated in labor and delivery because, through its
prostaglandin synthesis inhibitory effect, it may adversely affect fetal circulation and
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
581
582
583
584
585
586
587
588
589
inhibit uterine contractions, thus increasing the risk of uterine hemorrhage (see
CONTRAINDICATIONS).
Effects on Fertility
The use of ketorolac tromethamine, as with any drug known to inhibit
cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended in
women attempting to conceive. In women who have difficulty conceiving or are
undergoing investigation of infertility, withdrawal of ketorolac tromethamine should be
considered.
Nursing Mothers
After a single administration of 10 mg of TORADOLORAL to humans, the maximum milk
concentration observed was 7.3 ng/mL, and the maximum milk-to-plasma ratio was
0.037. After 1 day of dosing (qid), the maximum milk concentration was 7.9 ng/mL, and
the maximum milk-to-plasma ratio was 0.025. Because of the possible adverse effects of
prostaglandin-inhibiting drugs on neonates, use in nursing mothers is contraindicated.
590
591
592
593
594
595
Pediatric Use
TORADOLORAL is not indicated for use in pediatric patients. The safety and effectiveness
of TORADOL
596
ORAL in pediatric patients below the age of 17 have not been established.
597
598
599
600
601
602
603
604
605
606
607
608
609
610
611
612
613
614
Geriatric Use (≥65 years of age)
Because ketorolac tromethamine may be cleared more slowly by the elderly (see
CLINICAL PHARMACOLOGY) who are also more sensitive to the dose-related
adverse effects of NSAIDs (see WARNINGS: Gastrointestinal Effects – Risk of
Ulceration, Bleeding, and Perforation), extreme caution, reduced dosages (see
DOSAGE AND ADMINISTRATION), and careful clinical monitoring must be used
when treating the elderly with TORADOL.
ADVERSE REACTIONS
Adverse reaction rates increase with higher doses of TORADOL. Practitioners should be
alert for the severe complications of treatment with TORADOL, such as GI ulceration,
bleeding and perforation, postoperative bleeding, acute renal failure, anaphylactic and
anaphylactoid reactions and liver failure (see Boxed WARNING, WARNINGS,
PRECAUTIONS, and DOSAGE AND ADMINISTRATION). These NSAID-related
complications can be serious in certain patients for whom TORADOL is indicated,
especially when the drug is used inappropriately.
In patients taking TORADOL or other NSAIDs in clinical trials, the most frequently
reported adverse experiences in approximately 1% to 10% of patients are:
Gastrointestinal (GI) experiences including:
abdominal pain*
constipation/diarrhea
dyspepsia*
flatulence
GI fullness
GI ulcers (gastric/duodenal)
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
gross bleeding/perforation Heartburn
nausea*
stomatitis
Vomiting
Other experiences:
abnormal renal function
Anemia
dizziness
drowsiness
Edema
elevated liver enzymes
headaches*
Hypertension
increased bleeding time
injection site pain
Pruritus
purpura
rashes
Tinnitus
sweating
*Incidence greater than 10%
615
616
617
618
619
620
621
622
623
624
625
626
627
628
629
630
631
632
633
634
635
636
Additional adverse experiences reported occasionally (<1% in patients taking
TORADOL or other NSAIDs in clinical trials) include:
Body as a Whole: fever, infections, sepsis
Cardiovascular: congestive heart failure, palpitation, pallor, tachycardia, syncope
Dermatologic: alopecia, photosensitivity, urticaria
Gastrointestinal: anorexia, dry mouth, eructation, esophagitis, excessive thirst, gastritis,
glossitis, hematemesis, hepatitis, increased appetite, jaundice, melena, rectal bleeding
Hemic
and
Lymphatic:
ecchymosis,
eosinophilia,
epistaxis,
leukopenia,
thrombocytopenia
Metabolic and Nutritional: weight change
Nervous System: abnormal dreams, abnormal thinking, anxiety, asthenia, confusion,
depression, euphoria, extrapyramidal symptoms, hallucinations, hyperkinesis, inability to
concentrate, insomnia, nervousness, paresthesia, somnolence, stupor, tremors, vertigo,
malaise
Reproductive, female: infertility
Respiratory: asthma, cough, dyspnea, pulmonary edema, rhinitis
Special Senses: abnormal taste, abnormal vision, blurred vision, hearing loss
Urogenital: cystitis, dysuria, hematuria, increased urinary frequency, interstitial
nephritis, oliguria/polyuria, proteinuria, renal failure, urinary retention
Other rarely observed reactions (reported from postmarketing experience in patients
taking TORADOL or other NSAIDs) are:
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Body as a Whole: angioedema, death, hypersensitivity reactions such as anaphylaxis,
anaphylactoid reaction, laryngeal edema, tongue edema (see WARNINGS), myalgia
637
638
639
640
641
642
643
644
645
646
647
648
649
650
651
652
653
654
655
Cardiovascular: arrhythmia, bradycardia, chest pain, flushing, hypotension, myocardial
infarction, vasculitis
Dermatologic: exfoliative dermatitis, erythema multiforme, Lyell’s syndrome, bullous
reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis
Gastrointestinal: acute pancreatitis, liver failure, ulcerative stomatitis, exacerbation of
inflammatory bowel disease (ulcerative colitis, Crohn’s disease)
Hemic and Lymphatic: agranulocytosis, aplastic anemia, hemolytic anemia,
lymphadenopathy, pancytopenia, postoperative wound hemorrhage (rarely requiring
blood transfusion — see Boxed WARNING, WARNINGS, and PRECAUTIONS)
Metabolic and Nutritional: hyperglycemia, hyperkalemia, hyponatremia
Nervous System: aseptic meningitis, convulsions, coma, psychosis
Respiratory: bronchospasm, respiratory depression, pneumonia
Special Senses: conjunctivitis
Urogenital: flank pain with or without hematuria and/or azotemia, hemolytic uremic
syndrome
Postmarketing Surveillance Study
A large postmarketing observational, nonrandomized study, involving approximately
10,000 patients receiving ketorolac tromethamineIV/IM, demonstrated that the risk of
clinically serious gastrointestinal (GI) bleeding was dose-dependent (see Tables 3A and
3B). This was particularly true in elderly patients who received an average daily dose
greater than 60 mg/day of ketorolac tromethamine
656
657
658
IV/IM (see Table 3A).
659
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3
Incidence of Clinically Serious GI Bleeding as Related to
Age, Total Daily Dose, and History of GI Perforation, Ulcer,
Bleeding (PUB) After up to 5 Days of Treatment With
Ketorolac Tromethamine
660
661
662
IV/IM
663
664
A. Adult Patients Without History of PUB
Total Daily Dose of Ketorolac TromethamineIV/IM
Age of Patients
≤60 mg
>60 to 90 mg
>90 to 120 mg >120 mg
<65 years of age
0.4%
0.4%
0.9%
4.6%
≥65 years of age
1.2%
2.8%
2.2%
7.7%
B. Adult Patients With History of PUB
665
Total Daily Dose of Ketorolac TromethamineIV/IM
Age of Patients
≤60 mg
>60 to 90 mg
>90 to 120 mg >120 mg
<65 years of age
2.1%
4.6%
7.8%
15.4%
≥65 years of age
4.7%
3.7%
2.8%
25.0%
666
667
668
669
670
671
672
673
674
675
676
677
678
679
680
681
682
683
684
685
686
687
688
689
OVERDOSAGE
Symptoms and Signs
Symptoms following acute NSAIDs overdoses are usually limited to lethargy,
drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with
supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure,
respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have
been reported with therapeutic ingestion of NSAIDs, and may occur following an
overdose.
Treatment
Patients should be managed by symptomatic and supportive care following a NSAIDs
overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 g to 100 g
in adults, 1 g/kg to 2 g/kg in children) and/or osmotic cathartic may be indicated in
patients seen within 4 hours of ingestion with symptoms or following a large oral
overdose (5 to 10 times the usual dose). Forced diuresis, alkalization of urine,
hemodialysis or hemoperfusion may not be useful due to high protein binding.
Single overdoses of TORADOL have been variously associated with abdominal pain,
nausea, vomiting, hyperventilation, peptic ulcers and/or erosive gastritis and renal
dysfunction which have resolved after discontinuation of dosing.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of TORADOL and other
treatment options before deciding to use TORADOL. Use the lowest effective dose
for the shortest duration consistent with individual patient treatment goals. In
adults, the combined duration of use of IV or IM dosing of ketorolac tromethamine
and TORADOLORAL is not to exceed 5 days. In adults, the use of TORADOLORAL is
690
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
only indicated as continuation therapy to IV or IM dosing of ketorolac
tromethamine.
691
692
693
Transition from IV or IM dosing of ketorolac tromethamine (single- or multiple-
dose) to multiple-dose TORADOLORAL:
694
695
696
697
698
699
700
701
702
Patients age 17 to 64: 20 mg PO once followed by 10 mg q4-6 hours prn not >40 mg/day
Patients age ≥65, renally impaired, and/or weight <50 kg (110 lbs): 10 mg PO once
followed by 10 mg q4-6 hours prn not >40 mg/day
Note:
Oral formulation should not be given as an initial dose
Use minimum effective dose for the individual patient
Do not shorten dosing interval of 4 to 6 hours
Total duration of treatment in adult patients: the combined duration of use of IV or
IM dosing of ketorolac tromethamine and TORADOLORAL is not to exceed 5 days.
703
The following table summarizes TORADOLORAL dosing instructions in terms of age
group:
704
705
706
Table 4
Summary of Dosing Instructions
Patient Population
TORADOLORAL
(following IV or IM dosing of
ketorolac tromethamine)
Age <17 years
Oral not approved
Adult Age 17 to 64 years
20 mg once, then 10 mg q4-6
hours prn not >40 mg/day
Adult Age ≥65 years, renally
impaired, and/or weight <50 kg
10 mg once, then 10 mg q4-6
hours prn not >40 mg/day
707
708
HOW SUPPLIED
TORADOLORAL 10 mg tablets are round, white, film-coated, red printed tablets. There is
a large T printed on both sides of the tablet, with TORADOL on one side, and ROCHE
on the other, available in bottles of 100 tablets (NDC 0004-0273-01).
709
710
711
712
713
Storage
Store bottles at 15° to 30°C (59° to 86°F).
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
MEDICATION GUIDE FOR NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
(NSAIDS)
714
715
716
717
718
719
720
721
722
723
724
725
726
727
728
729
730
731
732
733
734
735
736
737
738
739
740
741
742
743
744
745
746
747
748
749
750
751
752
(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
Nonsteroidal 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 Nonsteroidal 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 Nonsteroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
23
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
753
754
755
756
757
758
759
760
761
762
763
764
765
766
767
• 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.
• 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 Nonsteroidal 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
768
769
770
771
772
773
774
775
776
777
778
779
780
781
Get emergency help right away if you have any of the following symptoms:
• shortness of breath or trouble breathing
• chest pain
• weakness in one part or side of your body
• slurred speech
• swelling of the face or throat
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
• your skin or eyes look yellow
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
782
783
784
785
786
787
788
789
790
791
792
793
794
795
796
797
798
799
800
• stomach pain
• flu-like symptoms
• vomit blood
• there is blood in your bowel movement or it is black and sticky like tar
• unusual weight gain
• skin rash or blisters with fever
• 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 Nonsteroidal 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)
Diflunisal
Dolobid
Etodolac
Lodine, Lodine XL
Fenoprofen
Nalfon, Nalfon 200
Flurbirofen
Ansaid
Ibuprofen
Motrin, Tab-Profen, Vicoprofen* (combined with
hydrocodone), Combunox (combined with
oxycodone)
Indomethacin
Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Ketoprofen
Oruvail
Ketorolac
Toradol
Mefenamic Acid
Ponstel
Meloxicam
Mobic
25
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Nabumetone
Relafen
Naproxen
Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn,
Naprelan, Naprapac (copackaged with lansoprazole)
Oxaprozin
Daypro
Piroxicam
Feldene
Sulindac
Clinoril
Tolmetin
Tolectin, Tolectin DS, Tolectin 600
801
802
803
804
805
806
807
808
809
810
811
812
813
814
815
816
817
818
819
820
821
822
823
824
825
826
827
*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.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Date created: June 15, 2005
Celebrex is a registered trademark of G.D. Searle LLC.
Cataflam, Voltaren are registered trademarks of Novartis Corporation.
Arthrotec (combined with misoprostol) is a registered trademark of G.D. Searle LLC.
Dolobid is a registered trademark of Merck & Co. Inc.
Lodine, Lodine XL are registered trademarks of Wyeth.
Nalfon, Nalfon 200 are registered trademarks of Pedinol Pharmacal Inc.
Ansaid is a registered trademark of Pharmacia & Upjohn Company LLC.
Motrin is a registered trademark of Johnson & Johnson.
Tab-Profen is a registered trademark of L. Perrigo Company.
Vicoprofen (combined with hydrocodone) is a registered trademark of BASF K & F
Corporation.
Combunox (combined with oxycodone) is a registered trademark of Forest Laboratories,
Inc.
Indocin, Indocin SR are registered trademarks of Merck & Co. Inc.
Oruvail is a registered trademark of Imperial Bank, As Agent (formerly registered to
Aventis Pharma S.A.).
Toradol is a registered trademark of Hoffmann-La Roche Inc.
Ponstel is a registered trademark of Lasalle National Bank Association.
Mobic is a registered trademark of Boehringer Ingelheim Pharma GMBG & Co. Kg.
Relafen is a registered trademark of SmithKline Beecham Corporation.
26
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
828
829
830
831
832
833
834
835
836
837
838
839
Naprosyn, EC-Naprosyn, Anaprox, Anaprox DS are registered trademarks of Syntex
Pharmaceuticals International Ltd.
Naprelan is a registered trademark of Elan Corporation PLC.
Naprapac (copackaged with lansoprazole) is a registered trademark of Syntex
Pharmaceuticals International Ltd.
Daypro is a registered trademark of G.D. Searle LLC.
Feldene is a registered trademark of Pfizer.
Clinoril is a registered trademark of Merck & Co. Inc.
Tolectin, Tolectin DS, Tolectin 600 are registered trademarks of Johnson & Johnson
Corporation.
Distributed by:
840
841
842
843
Month Year
Copyright © 1997-200x by Roche Laboratories Inc. All rights reserved
27
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:36.854218
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/019645s017lbl.pdf', 'application_number': 19645, 'submission_type': 'SUPPL ', 'submission_number': 17}
|
11,593
|
1
TORADOL ORAL
(ketorolac tromethamine tablets)
Rx only
WARNING
TORADOLORAL (ketorolac tromethamine), a nonsteroidal anti-inflammatory drug
(NSAID), is indicated for the short-term (up to 5 days in adults), management of
moderately severe acute pain that requires analgesia at the opioid level and only as
continuation treatment following IV or IM dosing of ketorolac tromethamine, if
necessary. The total combined duration of use of TORADOLORAL and ketorolac
tromethamine should not exceed 5 days.
TORADOLORAL is not indicated for use in pediatric patients and it is NOT indicated
for minor or chronic painful conditions. Increasing the dose of TORADOLORAL
beyond a daily maximum of 40 mg in adults will not provide better efficacy but will
increase the risk of developing serious adverse events.
GASTROINTESTINAL RISK
Ketorolac
tromethamine,
including
TORADOL
can
cause
peptic
ulcers,
gastrointestinal bleeding and/or perforation of the stomach or intestines, which can be
fatal. These events can occur at any time during use and without warning symptoms.
Therefore, TORADOL is CONTRAINDICATED in patients with active peptic ulcer
disease, in patients with recent gastrointestinal bleeding or perforation, and in patients
with a history of peptic ulcer disease or gastrointestinal bleeding. Elderly patients are
at greater risk for serious gastrointestinal events (see WARNINGS).
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 and CLINICAL STUDIES).
TORADOL is CONTRAINDICATED for the treatment of peri-operative pain in the
setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).
RENAL RISK
TORADOL is CONTRAINDICATED in patients with advanced renal impairment and in
patients at risk for renal failure due to volume depletion (see WARNINGS).
RISK OF BLEEDING
TORADOL inhibits platelet function and is, therefore, CONTRAINDICATED in patients
with suspected or confirmed cerebrovascular bleeding, patients with hemorrhagic
diathesis, incomplete hemostasis and those at high risk of bleeding (see WARNINGS
and PRECAUTIONS).
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2
TORADOL is CONTRAINDICATED as prophylactic analgesic before any major
surgery.
RISK DURING LABOR AND DELIVERY
The use of TORADOL in labor and delivery is contraindicated because it may adversely
affect fetal circulation and inhibit uterine contractions.
CONCOMITANT USE WITH NSAIDS
TORADOL is CONTRAINDICATED in patients currently receiving aspirin or NSAIDs
because of the cumulative risk of inducing serious NSAID-related side effects.
SPECIAL POPULATIONS
Dosage should be adjusted for patients 65 years or older, for patients under 50 kg
(110 lbs) of body weight (see DOSAGE AND ADMINISTRATION) and for
patients with moderately elevated serum creatinine (see WARNINGS).
DESCRIPTION
TORADOL (ketorolac tromethamine) is a member of the pyrrolo-pyrrole group of
nonsteroidal anti-inflammatory drugs (NSAIDs). The chemical name for ketorolac
tromethamine is ()-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, compound
with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1), and the chemical structure is:
Ketorolac tromethamine is a racemic mixture of [-]S and [+]R ketorolac tromethamine.
Ketorolac tromethamine may exist in three crystal forms. All forms are equally soluble in
water. Ketorolac tromethamine has a pKa of 3.5 and an n-octanol/water partition
coefficient of 0.26. The molecular weight of ketorolac tromethamine is 376.41. Its
molecular formula is C19H24N2O6.
TORADOLORAL is available as round, white, film-coated, red-printed tablets. Each tablet
contains 10 mg ketorolac tromethamine, the active ingredient, with added lactose,
magnesium stearate and microcrystalline cellulose. The white film-coating contains
hydroxypropyl methylcellulose, polyethylene glycol and titanium dioxide.
The tablets are printed with red ink that includes FD&C Red #40 Aluminum Lake as the
colorant. There is a large T printed on both sides of the tablet, as well as the word
TORADOL on one side, and the word ROCHE on the other.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits
analgesic activity in animal models. The mechanism of action of ketorolac, like that of
other NSAIDs, is not completely understood but may be related to prostaglandin
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3
synthetase inhibition. The biological activity of ketorolac tromethamine is associated
with the S-form. Ketorolac tromethamine possesses no sedative or anxiolytic properties.
The peak analgesic effect of TORADOL occurs within 2 to 3 hours and is not statistically
significantly different over the recommended dosage range of TORADOL. The greatest
difference between large and small doses of TORADOL is in the duration of analgesia.
Pharmacokinetics
Ketorolac tromethamine is a racemic mixture of [-]S- and [+]R-enantiomeric forms, with
the S-form having analgesic activity.
Comparison of IV, IM and Oral Pharmacokinetics
The pharmacokinetics of ketorolac tromethamine, following IV and IM doses of
ketorolac tromethamine and oral doses of TORADOL, are compared in Table 1. In
adults, the extent of bioavailability following administration of the ORAL form of
TORADOL and the IM form of ketorolac tromethamine was equal to that following an
IV bolus.
Linear Kinetics
In adults, following administration of single ORAL doses of TORADOL or IM or IV
doses of ketorolac tromethamine in the recommended dosage ranges, the clearance of the
racemate does not change. This implies that the pharmacokinetics of ketorolac
tromethamine in adults, following single or multiple IM or IV doses of ketorolac
tromethamine or recommended oral doses of TORADOL, are linear. At the higher
recommended doses, there is a proportional increase in the concentrations of free and
bound racemate.
Absorption
TORADOL is 100% absorbed after oral administration (see Table 1). Oral administration
of TORADOL after a high-fat meal resulted in decreased peak and delayed time-to-peak
concentrations of ketorolac tromethamine by about 1 hour. Antacids did not affect the
extent of absorption.
Distribution
The mean apparent volume (V) of ketorolac tromethamine following complete
distribution was approximately 13 liters. This parameter was determined from single-
dose data. The ketorolac tromethamine racemate has been shown to be highly protein
bound (99%). Nevertheless, plasma concentrations as high as 10 g/mL will only occupy
approximately 5% of the albumin binding sites. Thus, the unbound fraction for each
enantiomer will be constant over the therapeutic range. A decrease in serum albumin,
however, will result in increased free drug concentrations.
Ketorolac tromethamine is excreted in human milk (see PRECAUTIONS: Nursing
Mothers).
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
Metabolism
Ketorolac tromethamine is largely metabolized in the liver. The metabolic products are
hydroxylated and conjugated forms of the parent drug. The products of metabolism, and
some unchanged drug, are excreted in the urine.
Excretion
The principal route of elimination of ketorolac and its metabolites is renal. About 92% of
a given dose is found in the urine, approximately 40% as metabolites and 60% as
unchanged ketorolac. Approximately 6% of a dose is excreted in the feces. A single-dose
study with 10 mg TORADOL (n=9) demonstrated that the S-enantiomer is cleared
approximately two times faster than the R-enantiomer and that the clearance was
independent of the route of administration. This means that the ratio of S/R plasma
concentrations decreases with time after each dose. There is little or no inversion of the
R- to S- form in humans. The clearance of the racemate in normal subjects, elderly
individuals and in hepatically and renally impaired patients is outlined in Table 2 (see
CLINICAL PHARMACOLOGY: Kinetics in Special Populations).
The half-life of the ketorolac tromethamine S-enantiomer was approximately 2.5 hours
(SD 0.4) compared with 5 hours (SD 1.7) for the R-enantiomer. In other studies, the
half-life for the racemate has been reported to lie within the range of 5 to 6 hours.
Accumulation
Ketorolac tromethamine administered as an IV bolus every 6 hours for 5 days to healthy
subjects (n=13), showed no significant difference in Cmax on Day 1 and Day 5. Trough
levels averaged 0.29 g/mL (SD 0.13) on Day 1 and 0.55 g/mL (SD 0.23) on Day 6.
Steady state was approached after the fourth dose.
Accumulation of ketorolac tromethamine has not been studied in special populations
(geriatric, pediatric, renal failure or hepatic disease patients).
Kinetics in Special Populations
Geriatric Patients
Based on single-dose data only, the half-life of the ketorolac tromethamine racemate
increased from 5 to 7 hours in the elderly (65 to 78 years) compared with young healthy
volunteers (24 to 35 years) (see Table 2). There was little difference in the Cmax for the
two
groups
(elderly,
2.52 g/mL 0.77;
young,
2.99 g/mL 1.03)
(see
PRECAUTIONS: Geriatric Use).
Pediatric Patients
Limited information is available regarding the pharmacokinetics of dosing of ketorolac
tromethamine in the pediatric population. Following a single intravenous bolus dose of
0.5 mg/kg in 10 children 4 to 8 years old, the half-life was 5.8 1.6 hours, the average
clearance was 0.042 0.01 L/hr/kg, the volume of distribution during the terminal phase
(V) was 0.34 0.12 L/kg and the volume of distribution at steady state (Vss) was
0.26 0.08 L/kg. The volume of distribution and clearance of ketorolac in pediatric
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5
patients was higher than those observed in adult subjects (see Table 1). There are no
pharmacokinetic data available for administration of ketorolac tromethamine by the IM
route in pediatric patients.
Renal Insufficiency
Based on single-dose data only, the mean half-life of ketorolac tromethamine in renally
impaired patients is between 6 and 19 hours and is dependent on the extent of the
impairment. There is poor correlation between creatinine clearance and total ketorolac
tromethamine clearance in the elderly and populations with renal impairment (r=0.5).
In patients with renal disease, the AUC of each enantiomer increased by approximately
100% compared with healthy volunteers. The volume of distribution doubles for the
S-enantiomer and increases by 1/5th for the R-enantiomer. The increase in volume of
distribution of ketorolac tromethamine implies an increase in unbound fraction.
The AUC-ratio of the ketorolac tromethamine enantiomers in healthy subjects and
patients remained similar, indicating there was no selective excretion of either enantiomer
in patients compared to healthy subjects (see WARNINGS: Renal Effects).
Hepatic Insufficiency
There was no significant difference in estimates of half-life, AUC and Cmax in 7 patients
with liver disease compared to healthy volunteers (see PRECAUTIONS: Hepatic Effect
and Table 2).
Race
Pharmacokinetic differences due to race have not been identified.
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6
Table 1
Table of Approximate Average Pharmacokinetic Parameters (Mean SD) Following Oral,
Intramuscular and Intravenous Doses of Ketorolac Tromethamine
Oral*
Intramuscular†
Intravenous Bolus‡
Pharmacokinetic
Parameters (units)
10 mg
15 mg
30 mg
60 mg
15 mg
30 mg
Bioavailability (extent)
100%
Tmax
1 (min)
44 34
33 21§
44 29
33 21§
1.1 0.7§
2.9 1.8
Cmax
2 (µg/mL) [single-dose]
0.87 0.22
1.14 0.32§
2.42 0.68
4.55 1.27§
2.47 0.51§
4.65 0.96
Cmax (µg/mL) [steady state qid]
1.05 0.26§
1.56 0.44§
3.11 0.87§
N/A||
3.09 1.17§
6.85 2.61
Cmin
3 (µg/mL) [steady state qid]
0.29 0.07§
0.47 0.13§
0.93 0.26§
N/A
0.61 0.21§
1.04 0.35
Cavg
4 (µg/mL) [steady state qid]
0.59 0.20§
0.94 0.29§
1.88 0.59§
N/A
1.09 0.30§
2.17 0.59
V5 (L/kg)
————— 0.175 0.039 ————
0.210 0.044
% Dose metabolized = <50
% Dose excreted in feces = 6
% Dose excreted in urine = 91
% Plasma protein binding = 99
* Derived from PO pharmacokinetic studies in 77 normal fasted volunteers
† Derived from IM pharmacokinetic studies in 54 normal volunteers
‡ Derived from IV pharmacokinetic studies in 24 normal volunteers
§ Mean value was simulated from observed plasma concentration data and standard deviation was simulated from percent
coefficient of variation for observed Cmax and Tmax data
|| Not applicable because 60 mg is only recommended as a single dose
1Time-to-peak plasma concentration
2Peak plasma concentration
3Trough plasma concentration
4Average plasma concentration
5Volume of distribution
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
Table 2
The Influence of Age, Liver, and Kidney Function on the Clearance and Terminal Half-life of
Ketorolac Tromethamine (IM1 and ORAL2) in Adult Populations
Total Clearance [in L/h/kg]3
Terminal Half-life [in hours]
IM
ORAL
IM
ORAL
Type of Subjects
Mean (range)
Mean (range)
Mean (range)
Mean (range)
Normal Subjects
IM (n=54)
mean age=32, range=18–60
Oral (n=77)
mean age=32, range=20–60
0.023
(0.010–0.046)
0.025
(0.013–0.050)
5.3
(3.5–9.2)
5.3
(2.4–9.0)
Healthy Elderly Subjects
IM (n=13), Oral (n=12)
mean age=72, range=65–78
0.019
(0.013–0.034)
0.024
(0.018–0.034)
7.0
(4.7–8.6)
6.1
(4.3–7.6)
Patients with Hepatic Dysfunction
IM and Oral (n=7)
mean age=51, range=43–64
0.029
(0.013–0.066)
0.033
(0.019–0.051)
5.4
(2.2–6.9)
4.5
(1.6–7.6)
Patients with Renal Impairment
IM (n=25), Oral (n=9)
serum creatinine=1.9–5.0 mg/dL,
mean age (IM)=54, range=35–71
mean age (Oral)=57, range=39–70
0.015
(0.005–0.043)
0.016
(0.007–0.052)
10.3
(5.9–19.2)
10.8
(3.4–18.9)
Renal Dialysis Patients
IM and Oral (n=9)
mean age=40, range=27–63
0.016
(0.003–0.036)
—
13.6
(8.0–39.1)
—
1 Estimated from 30 mg single IM doses of ketorolac tromethamine
2 Estimated from 10 mg single oral doses of ketorolac tromethamine
3 Liters/hour/kilogram
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
IV Administration
In normal adult subjects (n=37), the total clearance of 30 mg IV-administered ketorolac
tromethamine was 0.030 (0.017-0.051) L/h/kg. The terminal half-life was 5.6 (4.0-7.9)
hours. (See Kinetics in Special Populations for use of IV dosing of ketorolac
tromethamine in pediatric patients.)
CLINICAL STUDIES
Adult Patients
In a postoperative study, where all patients received morphine by a PCA device, patients
treated with ketorolac tromethamineIV as fixed intermittent boluses (e.g., 30 mg initial
dose followed by 15 mg q3h), required significantly less morphine (26%) than the
placebo group. Analgesia was significantly superior, at various postdosing pain
assessment times, in the patients receiving ketorolac tromethamineIV plus PCA morphine
as compared to patients receiving PCA-administered morphine alone.
Pediatric Patients
There are no data available to support the use of TORADOLORAL in pediatric patients.
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of TORADOL and other treatment
options before deciding to use TORADOL. Use the lowest effective dose for the shortest
duration consistent with individual patient treatment goals.
Acute Pain in Adult Patients
TORADOLORAL is indicated for the short-term (5 days) management of moderately
severe acute pain that requires analgesia at the opioid level, usually in a postoperative
setting. Therapy should always be initiated with IV or IM dosing of ketorolac
tromethamine, and TORADOLORAL is to be used only as continuation treatment, if
necessary.
The total combined duration of use of TORADOLORAL and ketorolac tromethamine is not
to exceed 5 days of use because of the potential of increasing the frequency and severity
of adverse reactions associated with the recommended doses (see WARNINGS,
PRECAUTIONS,
DOSAGE
AND
ADMINISTRATION,
and
ADVERSE
REACTIONS). Patients should be switched to alternative analgesics as soon as possible,
but TORADOLORAL therapy is not to exceed 5 days.
CONTRAINDICATIONS (see also Boxed WARNING)
TORADOL is contraindicated in patients with previously demonstrated hypersensitivity
to ketorolac tromethamine.
TORADOL is contraindicated in patients with active peptic ulcer disease, in patients with
recent gastrointestinal bleeding or perforation and in patients with a history of peptic
ulcer disease or gastrointestinal bleeding.
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
9
TORADOL 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-like reactions to NSAIDs have been reported in such patients (see
WARNINGS: Anaphylactoid Reactions, and PRECAUTIONS: Preexisting Asthma).
TORADOL is contraindicated as prophylactic analgesic before any major surgery.
TORADOL is contraindicated for the treatment of peri-operative pain in the setting of
coronary artery bypass graft (CABG) surgery (see WARNINGS).
TORADOL is contraindicated in patients with advanced renal impairment or in patients
at risk for renal failure due to volume depletion (see WARNINGS for correction of
volume depletion).
TORADOL is contraindicated in labor and delivery because, through its prostaglandin
synthesis inhibitory effect, it may adversely affect fetal circulation and inhibit uterine
contractions, thus increasing the risk of uterine hemorrhage.
TORADOL inhibits platelet function and is, therefore, contraindicated in patients with
suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, incomplete
hemostasis and those at high risk of bleeding (see WARNINGS and PRECAUTIONS).
TORADOL is contraindicated in patients currently receiving aspirin or NSAIDs because
of the cumulative risks of inducing serious NSAID-related adverse events.
The concomitant use of TORADOL and probenecid is contraindicated.
The concomitant use of ketorolac tromethamine and pentoxifylline is contraindicated.
WARNINGS (see also Boxed WARNING)
The total combined duration of use of TORADOLORAL and IV or IM dosing of ketorolac
tromethamine is not to exceed 5 days in adults. TORADOLORAL is not indicated for use
in pediatric patients.
The most serious risks associated with TORADOL are:
Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation
TORADOL is contraindicated in patients with previously documented peptic ulcers
and/or GI bleeding. Toradol can cause serious gastrointestinal (GI) adverse events
including 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 TORADOL.
Only one in five patients who develop a serious upper GI adverse event on NSAID
therapy is symptomatic. Minor upper gastrointestinal problems, such as dyspepsia, are
common and may also occur at any time during NSAID therapy. The incidence and
severity of gastrointestinal complications increases with increasing dose of, and duration
of treatment with, TORADOL. Do not use TORADOL for more than five days.
However, even short-term therapy is not without risk. In addition to past history of ulcer
disease, other factors that increase the risk for GI bleeding in patients treated with
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
10
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, 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 TORADOL until a serious GI
adverse event is ruled out. For high risk patients, alternate therapies that do not involve
NSAIDs should be considered.
NSAIDs should be given with care to patients with a history of inflammatory bowel
disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated.
Hemorrhage
Because prostaglandins play an important role in hemostasis and NSAIDs affect platelet
aggregation as well, use of TORADOL in patients who have coagulation disorders should
be undertaken very cautiously, and those patients should be carefully monitored. Patients
on therapeutic doses of anticoagulants (e.g., heparin or dicumarol derivatives) have an
increased risk of bleeding complications if given TORADOL concurrently; therefore,
physicians should administer such concomitant therapy only extremely cautiously. The
concurrent use of TORADOL and therapy that affects hemostasis, including prophylactic
low-dose heparin (2500 to 5000 units q12h), warfarin and dextrans have not been studied
extensively, but may also be associated with an increased risk of bleeding. Until data
from such studies are available, physicians should carefully weigh the benefits against the
risks and use such concomitant therapy in these patients only extremely cautiously.
Patients receiving therapy that affects hemostasis should be monitored closely.
In postmarketing experience, postoperative hematomas and other signs of wound
bleeding have been reported in association with the peri-operative use of IV or IM dosing
of ketorolac tromethamine. Therefore, peri-operative use of TORADOL should be
avoided and postoperative use be undertaken with caution when hemostasis is critical
(see PRECAUTIONS).
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 NSAID 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, and
the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the
pretreatment state.
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11
TORADOL and its metabolites are eliminated primarily by the kidneys, which, in
patients with reduced creatinine clearance, will result in diminished clearance of the drug
(see CLINICAL PHARMACOLOGY). Therefore, TORADOL should be used with
caution
in
patients
with
impaired
renal
function
(see
DOSAGE
AND
ADMINISTRATION) and such patients should be followed closely. With the use of
TORADOL, there have been reports of acute renal failure, interstitial nephritis and
nephrotic syndrome.
Impaired Renal Function
TORADOL is contraindicated in patients with serum creatinine concentrations indicating
advanced renal impairment (see CONTRAINDICATIONS). TORADOL should be used
with caution in patients with impaired renal function or a history of kidney disease
because it is a potent inhibitor of prostaglandin synthesis. Because patients with
underlying renal insufficiency are at increased risk of developing acute renal
decompensation or failure, the risks and benefits should be assessed prior to giving
TORADOL to these patients.
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients without a known
previous exposure or hypersensitivity to TORADOL. TORADOL 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). Anaphylactoid
reactions, like anaphylaxis, may have a fatal outcome. Emergency help should be sought
in cases where an anaphylactoid reaction occurs.
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 Gastrointestinal
Effects – Risk of Ulceration, Bleeding, and Perforation). Two large, controlled clinical
trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12
following CABG surgery found an increased incidence of myocardial infarction and
stroke (see CONTRAINDICATIONS).
Hypertension
NSAIDs, including TORADOL, can lead to onset of new hypertension or worsening of
preexisting 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 TORADOL, 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, edema, retention of NaCl, oliguria, elevations of serum urea nitrogen and
creatinine have been reported in clinical trials with TORADOL. Therefore, TORADOL
should be used only very cautiously in patients with cardiac decompensation,
hypertension or similar conditions.
Skin Reactions
NSAIDs, including TORADOL, 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, mucosal lesions, or any
other sign of hypersensitivity.
Pregnancy
In late pregnancy, as with other NSAIDs, TORADOL should be avoided because it may
cause premature closure of the ductus arteriosus.
PRECAUTIONS
General
TORADOL 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 TORADOL in reducing inflammation may diminish the
utility of this diagnostic sign in detecting complications of presumed noninfectious,
painful conditions.
Hepatic Effect
TORADOL should be used with caution in patients with impaired hepatic function or a
history of liver disease. Borderline elevations of one or more liver tests may occur in up
to 15% of patients taking NSAIDs including TORADOL. These laboratory abnormalities
may progress, may remain unchanged, or may be transient with continuing therapy.
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13
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 TORADOL. If clinical signs and
symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g.,
eosinophilia, rash, etc.), TORADOL should be discontinued.
Hematologic Effect
Anemia is sometimes seen in patients receiving NSAIDs, including TORADOL. 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
TORADOL, 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 TORADOL
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,
TORADOL 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
TORADOL is a potent NSAID and may cause serious side effects such as gastrointestinal
bleeding or kidney failure, which may result in hospitalization and even fatal outcome.
Physicians, when prescribing TORADOL, should inform their patients or their guardians
of the potential risks of TORADOL treatment (see Boxed WARNING, WARNINGS,
PRECAUTIONS, and ADVERSE REACTIONS sections), instruct patients to seek
medical advice if they develop treatment-related adverse events, and advise patients not
to give TORADOLORAL to other family members and to discard any unused drug.
Remember that the total combined duration of use of TORADOLORAL and IV or IM
dosing of ketorolac tromethamine is not to exceed 5 days in adults. TORADOLORAL is
not indicated for use in pediatric 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
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14
encouraged to read the NSAID Medication Guide that accompanies each prescription
dispensed.
1. TORADOL, 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. TORADOL, 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 hematemesis. Patients
should be apprised of the importance of this follow-up (see WARNINGS:
Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation).
3. TORADOL, 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 (eg,
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 anaphylactoid reaction (eg, 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, TORADOL should be avoided because it
will 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, TORADOL should be discontinued.
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
15
Drug Interactions
Ketorolac is highly bound to human plasma protein (mean 99.2%). There is no evidence
in animal or human studies that TORADOL induces or inhibits hepatic enzymes capable
of metabolizing itself or other drugs.
Warfarin, Digoxin, Salicylate, and Heparin
The in vitro binding of warfarin to plasma proteins is only slightly reduced by ketorolac
tromethamine (99.5% control vs 99.3%) when ketorolac plasma concentrations reach 5 to
10 g/mL. Ketorolac does not alter digoxin protein binding. In vitro studies indicate that,
at therapeutic concentrations of salicylate (300 g/mL), the binding of ketorolac was
reduced from approximately 99.2% to 97.5%, representing a potential twofold increase in
unbound ketorolac plasma levels. Therapeutic concentrations of digoxin, warfarin,
ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin and tolbutamide did not
alter ketorolac tromethamine protein binding.
In a study involving 12 adult volunteers, TORADOLORAL was coadministered with a
single dose of 25 mg warfarin, causing no significant changes in pharmacokinetics or
pharmacodynamics of warfarin. In another study, ketorolac tromethamine dosed IV or IM
was given with two doses of 5000 U of heparin to 11 healthy volunteers, resulting in a
mean template bleeding time of 6.4 minutes (3.2 to 11.4 min) compared to a mean of 6.0
minutes (3.4 to 7.5 min) for heparin alone and 5.1 minutes (3.5 to 8.5 min) for placebo.
Although these results do not indicate a significant interaction between TORADOL and
warfarin or heparin, the administration of TORADOL to patients taking anticoagulants
should be done extremely cautiously, and patients should be closely monitored (see
WARNINGS and PRECAUTIONS: Hematologic Effect).
The effects of warfarin and NSAIDs, in general, on GI bleeding are synergistic, such that
the users of both drugs together have a risk of serious GI bleeding higher than the users
of either drug alone.
Aspirin
When TORADOL is administered with aspirin, its protein binding is reduced, although
the clearance of free TORADOL is not altered. The clinical significance of this
interaction is not known; however, as with other NSAIDs, concomitant administration of
ketorolac tromethamine and aspirin is not generally recommended because of the
potential of increased adverse effects.
Diuretics
Clinical studies, as well as postmarketing observations, have shown that TORADOL can
reduce the natriuretic effect of furosemide and thiazides in some patients. This response
has been attributed to inhibition of renal prostaglandin synthesis. 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.
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16
Probenecid
Concomitant administration of TORADOLORAL and probenecid resulted in decreased
clearance and volume of distribution of ketorolac and significant increases in ketorolac
plasma levels (total AUC increased approximately threefold from 5.4 to 17.8 g/h/mL)
and terminal half-life increased approximately twofold from 6.6 to 15.1 hours. Therefore,
concomitant use of TORADOL and probenecid is contraindicated.
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.
ACE Inhibitors/Angiotensin II Receptor Antagonists
Concomitant use of ACE inhibitors and/or angiotensin II receptor antagonists may
increase the risk of renal impairment, particularly in volume-depleted patients.
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors
and/or angiotensin II receptor antagonists. This interaction should be given consideration
in patients taking NSAIDs concomitantly with ACE inhibitors and/or angiotensin II
receptor antagonists.
Antiepileptic Drugs
Sporadic cases of seizures have been reported during concomitant use of TORADOL and
antiepileptic drugs (phenytoin, carbamazepine).
Psychoactive Drugs
Hallucinations have been reported when TORADOL was used in patients taking
psychoactive drugs (fluoxetine, thiothixene, alprazolam).
Pentoxifylline
When ketorolac tromethamine is administered concurrently with pentoxifylline, there is
an increased tendency to bleeding.
Nondepolarizing Muscle Relaxants
In postmarketing experience there have been reports of a possible interaction between
ketorolac tromethamineIV/IM and nondepolarizing muscle relaxants that resulted in
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17
apnea. The concurrent use of ketorolac tromethamine with muscle relaxants has not been
formally studied.
Selective Serotonin Reuptake Inhibitors (SSRIs)
There is an increased risk of gastrointestinal bleeding when selective serotonin reuptake
inhibitors (SSRIs) are combined with NSAIDs. Caution should be used when NSAIDs
are administered concomitantly with SSRIs.
Carcinogenesis, Mutagenesis and Impairment of Fertility
An 18-month study in mice with oral doses of ketorolac tromethamine at 2 mg/kg/day
(0.9 times the human systemic exposure at the recommended IM or IV dose of 30 mg qid,
based on area-under-the-plasma-concentration curve [AUC]), and a 24-month study in
rats at 5 mg/kg/day (0.5 times the human AUC) showed no evidence of tumorigenicity.
Ketorolac tromethamine was not mutagenic in the Ames test, unscheduled DNA
synthesis and repair, and in forward mutation assays. Ketorolac tromethamine did not
cause chromosome breakage in the in vivo mouse micronucleus assay. At 1590 g/mL
and at higher concentrations, ketorolac tromethamine increased the incidence of
chromosomal aberrations in Chinese hamster ovarian cells.
Impairment of fertility did not occur in male or female rats at oral doses of 9 mg/kg
(0.9 times the human AUC) and 16 mg/kg (1.6 times the human AUC) of ketorolac
tromethamine, respectively.
Pregnancy
Teratogenic Effects: Pregnancy Category C
Reproduction studies have been performed during organogenesis using daily oral doses
of ketorolac tromethamine at 3.6 mg/kg (0.37 times the human AUC) in rabbits and at
10 mg/kg (1.0 times the human AUC) in rats. Results of these studies did not reveal
evidence of teratogenicity to the fetus. However, animal reproduction studies are not
always predictive of human response.
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. Oral doses of ketorolac tromethamine at 1.5 mg/kg
(0.14 times the human AUC), administered after gestation Day 17, caused dystocia and
higher pup mortality in rats.
There are no adequate and well-controlled studies of TORADOL in pregnant women.
TORADOL should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
Labor and Delivery
The use of TORADOL is contraindicated in labor and delivery because, through its
prostaglandin synthesis inhibitory effect, it may adversely affect fetal circulation and
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
18
inhibit uterine contractions, thus increasing the risk of uterine hemorrhage (see
CONTRAINDICATIONS).
Effects on Fertility
The use of ketorolac tromethamine, as with any drug known to inhibit
cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended in
women attempting to conceive. In women who have difficulty conceiving or are
undergoing investigation of infertility, withdrawal of ketorolac tromethamine should be
considered.
Nursing Mothers
Limited data from one published study involving 10 breastfeeding women 2-6 days
postpartum showed low levels of ketorolac in breast milk. Levels were undetectable (less
than 5 ng/mL) in 4 of the patients. After a single administration of 10 mg of
TORADOLORAL, the maximum milk concentration observed was 7.3 ng/mL, and the
maximum milk-to-plasma ratio was 0.037. After 1 day of dosing (10 mg every 6 hours),
the maximum milk concentration was 7.9 ng/mL, and the maximum milk-to-plasma ratio
was 0.025. Assuming a daily intake of 400-1,000 mL of human milk per day and a
maternal body weight of 60 kg, the calculated maximum daily infant exposure was
0.00263 mg/kg/day, which is 0.4% of the maternal weight-adjusted dose.
Exercise caution when ketorolac is administered to a nursing woman. Available
information has not shown any specific adverse events in nursing infants; however,
instruct patients to contact their infant's health care provider if they note any adverse
events.
Pediatric Use
TORADOLORAL is not indicated for use in pediatric patients. The safety and effectiveness
of TORADOLORAL in pediatric patients below the age of 17 have not been established.
Geriatric Use (65 years of age)
Because ketorolac tromethamine may be cleared more slowly by the elderly (see
CLINICAL PHARMACOLOGY) who are also more sensitive to the dose-related
adverse effects of NSAIDs (see WARNINGS: Gastrointestinal Effects – Risk of
Ulceration, Bleeding, and Perforation), extreme caution, reduced dosages (see
DOSAGE AND ADMINISTRATION), and careful clinical monitoring must be used
when treating the elderly with TORADOL.
ADVERSE REACTIONS
Adverse reaction rates increase with higher doses of TORADOL. Practitioners should be
alert for the severe complications of treatment with TORADOL, such as GI ulceration,
bleeding and perforation, postoperative bleeding, acute renal failure, anaphylactic and
anaphylactoid reactions and liver failure (see Boxed WARNING, WARNINGS,
PRECAUTIONS, and DOSAGE AND ADMINISTRATION). These NSAID-related
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
19
complications can be serious in certain patients for whom TORADOL is indicated,
especially when the drug is used inappropriately.
In patients taking TORADOL or other NSAIDs in clinical trials, the most frequently
reported adverse experiences in approximately 1% to 10% of patients are:
Gastrointestinal (GI) experiences including:
abdominal pain*
constipation/diarrhea
dyspepsia*
flatulence
GI fullness
GI ulcers (gastric/duodenal)
gross bleeding/perforation heartburn
nausea*
stomatitis
vomiting
Other experiences:
abnormal renal function
anemia
dizziness
drowsiness
edema
elevated liver enzymes
headaches*
hypertension
increased bleeding time
injection site pain
pruritus
purpura
rashes
tinnitus
sweating
*Incidence greater than 10%
Additional adverse experiences reported occasionally (<1% in patients taking
TORADOL or other NSAIDs in clinical trials) include:
Body as a Whole: fever, infections, sepsis
Cardiovascular: congestive heart failure, palpitation, pallor, tachycardia, syncope
Dermatologic: alopecia, photosensitivity, urticaria
Gastrointestinal: anorexia, dry mouth, eructation, esophagitis, excessive thirst, gastritis,
glossitis, hematemesis, hepatitis, increased appetite, jaundice, melena, rectal bleeding
Hemic
and
Lymphatic:
ecchymosis,
eosinophilia,
epistaxis,
leukopenia,
thrombocytopenia
Metabolic and Nutritional: weight change
Nervous System: abnormal dreams, abnormal thinking, anxiety, asthenia, confusion,
depression, euphoria, extrapyramidal symptoms, hallucinations, hyperkinesis, inability to
concentrate, insomnia, nervousness, paresthesia, somnolence, stupor, tremors, vertigo,
malaise
Reproductive, female: infertility
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
20
Respiratory: asthma, cough, dyspnea, pulmonary edema, rhinitis
Special Senses: abnormal taste, abnormal vision, blurred vision, hearing loss
Urogenital: cystitis, dysuria, hematuria, increased urinary frequency, interstitial
nephritis, oliguria/polyuria, proteinuria, renal failure, urinary retention
Other rarely observed reactions (reported from postmarketing experience in patients
taking TORADOL or other NSAIDs) are:
Body as a Whole: angioedema, death, hypersensitivity reactions such as anaphylaxis,
anaphylactoid reaction, laryngeal edema, tongue edema (see WARNINGS), myalgia
Cardiovascular: arrhythmia, bradycardia, chest pain, flushing, hypotension, myocardial
infarction, vasculitis
Dermatologic: exfoliative dermatitis, erythema multiforme, Lyell’s syndrome, bullous
reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis
Gastrointestinal: acute pancreatitis, liver failure, ulcerative stomatitis, exacerbation of
inflammatory bowel disease (ulcerative colitis, Crohn’s disease)
Hemic and Lymphatic: agranulocytosis, aplastic anemia, hemolytic anemia,
lymphadenopathy, pancytopenia, postoperative wound hemorrhage (rarely requiring
blood transfusion — see Boxed WARNING, WARNINGS, and PRECAUTIONS)
Metabolic and Nutritional: hyperglycemia, hyperkalemia, hyponatremia
Nervous System: aseptic meningitis, convulsions, coma, psychosis
Respiratory: bronchospasm, respiratory depression, pneumonia
Special Senses: conjunctivitis
Urogenital: flank pain with or without hematuria and/or azotemia, hemolytic uremic
syndrome
Postmarketing Surveillance Study
A large postmarketing observational, nonrandomized study, involving approximately
10,000 patients receiving ketorolac tromethamineIV/IM, demonstrated that the risk of
clinically serious gastrointestinal (GI) bleeding was dose-dependent (see Tables 3A and
3B). This was particularly true in elderly patients who received an average daily dose
greater than 60 mg/day of ketorolac tromethamineIV/IM (see Table 3A).
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
21
Table 3
Incidence of Clinically Serious GI Bleeding as Related to
Age, Total Daily Dose, and History of GI Perforation, Ulcer,
Bleeding (PUB) After up to 5 Days of Treatment With
Ketorolac TromethamineIV/IM
A. Adult Patients Without History of PUB
Total Daily Dose of Ketorolac TromethamineIV/IM
Age of Patients
60 mg
>60 to 90 mg
>90 to 120 mg >120 mg
<65 years of age
0.4%
0.4%
0.9%
4.6%
65 years of age
1.2%
2.8%
2.2%
7.7%
B. Adult Patients With History of PUB
Total Daily Dose of Ketorolac TromethamineIV/IM
Age of Patients
60 mg
>60 to 90 mg
>90 to 120 mg >120 mg
<65 years of age
2.1%
4.6%
7.8%
15.4%
65 years of age
4.7%
3.7%
2.8%
25.0%
OVERDOSAGE
Symptoms and Signs
Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness,
nausea, vomiting, and epigastric pain, which are generally reversible with supportive
care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory
depression and coma may occur, but are rare. Anaphylactoid reactions have been reported
with therapeutic ingestion of NSAIDs, and may occur following an overdose.
Treatment
Patients should be managed by symptomatic and supportive care following a NSAIDs
overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 g to 100 g
in adults, 1 g/kg to 2 g/kg in children) and/or osmotic cathartic may be indicated in
patients seen within 4 hours of ingestion with symptoms or following a large oral
overdose (5 to 10 times the usual dose). Forced diuresis, alkalization of urine,
hemodialysis or hemoperfusion may not be useful due to high protein binding.
Single overdoses of TORADOL have been variously associated with abdominal pain,
nausea, vomiting, hyperventilation, peptic ulcers and/or erosive gastritis and renal
dysfunction which have resolved after discontinuation of dosing.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of TORADOL and other
treatment options before deciding to use TORADOL. Use the lowest effective dose
for the shortest duration consistent with individual patient treatment goals. In
adults, the combined duration of use of IV or IM dosing of ketorolac tromethamine
and TORADOLORAL is not to exceed 5 days. In adults, the use of TORADOLORAL is
only indicated as continuation therapy to IV or IM dosing of ketorolac
tromethamine.
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
22
Transition from IV or IM dosing of ketorolac tromethamine (single- or multiple-
dose) to multiple-dose TORADOLORAL:
Patients age 17 to 64: 20 mg PO once followed by 10 mg q4-6 hours prn not >40 mg/day
Patients age 65, renally impaired, and/or weight <50 kg (110 lbs): 10 mg PO once
followed by 10 mg q4-6 hours prn not >40 mg/day
Note:
Oral formulation should not be given as an initial dose
Use minimum effective dose for the individual patient
Do not shorten dosing interval of 4 to 6 hours
Total duration of treatment in adult patients: the combined duration of use of IV or
IM dosing of ketorolac tromethamine and TORADOLORAL is not to exceed 5 days.
The following table summarizes TORADOLORAL dosing instructions in terms of age
group:
Table 4
Summary of Dosing Instructions
Patient Population
TORADOLORAL
(following IV or IM dosing of
ketorolac tromethamine)
Age <17 years
Oral not approved
Adult Age 17 to 64 years
20 mg once, then 10 mg q4-6
hours prn not >40 mg/day
Adult Age 65 years, renally
impaired, and/or weight <50 kg
10 mg once, then 10 mg q4-6
hours prn not >40 mg/day
HOW SUPPLIED
TORADOLORAL 10 mg tablets are round, white, film-coated, red printed tablets. There is
a large T printed on both sides of the tablet, with TORADOL on one side, and ROCHE
on the other, available in bottles of 100 tablets (NDC 0004-0273-01).
Storage
Store bottles at 15° to 30°C (59° to 86°F).
Package Insert Revised: February 2013
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
23
MEDICATION GUIDE FOR NONSTEROIDAL 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
Nonsteroidal 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 Nonsteroidal 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 Nonsteroidal 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
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
24
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.
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 Nonsteroidal 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
chest pain
weakness in one part or side of your body
slurred speech
swelling of the face or throat
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
your skin or eyes look yellow
stomach pain
flu-like symptoms
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
25
vomit blood
there is blood in your bowel movement or it is black and sticky like tar
unusual weight gain
skin rash or blisters with fever
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. Call your doctor for
medical advice about side effects. You may report side effects to FDA at 1-800-FDA-
1088.
Other information about Nonsteroidal 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)
Diflunisal
Dolobid
Etodolac
Lodine, Lodine XL
Fenoprofen
Nalfon, Nalfon 200
Flurbirofen
Ansaid
Ibuprofen
Motrin, Tab-Profen, Vicoprofen* (combined with
hydrocodone), Combunox (combined with
oxycodone)
Indomethacin
Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Ketoprofen
Oruvail
Ketorolac
Toradol
Mefenamic Acid
Ponstel
Meloxicam
Mobic
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
26
Nabumetone
Relafen
Naproxen
Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn,
Naprelan, Naprapac (copackaged with lansoprazole)
Oxaprozin
Daypro
Piroxicam
Feldene
Sulindac
Clinoril
Tolmetin
Tolectin, Tolectin DS, Tolectin 600
*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.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Medication Guide Revised: December 2008
Celebrex is a registered trademark of G.D. Searle LLC.
Cataflam, Voltaren are registered trademarks of Novartis Corporation.
Arthrotec (combined with misoprostol) is a registered trademark of G.D. Searle LLC.
Dolobid is a registered trademark of Merck & Co. Inc.
Lodine, Lodine XL are registered trademarks of Wyeth.
Nalfon, Nalfon 200 are registered trademarks of Pedinol Pharmacal Inc.
Ansaid is a registered trademark of Pharmacia & Upjohn Company LLC.
Motrin is a registered trademark of Johnson & Johnson.
Tab-Profen is a registered trademark of L. Perrigo Company.
Vicoprofen (combined with hydrocodone) is a registered trademark of BASF K & F
Corporation.
Combunox (combined with oxycodone) is a registered trademark of Forest Laboratories,
Inc.
Indocin, Indocin SR are registered trademarks of Merck & Co. Inc.
Oruvail is a registered trademark of Imperial Bank, As Agent (formerly registered to
Aventis Pharma S.A.).
Toradol is a registered trademark of Hoffmann-La Roche Inc.
Ponstel is a registered trademark of Lasalle National Bank Association.
Mobic is a registered trademark of Boehringer Ingelheim Pharma GMBH & Co. Kg.
Relafen is a registered trademark of SmithKline Beecham Corporation.
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
27
Naprosyn, EC-Naprosyn, Anaprox, Anaprox DS are registered trademarks of Syntex
Pharmaceuticals International Ltd.
Naprelan is a registered trademark of Elan Corporation PLC.
Naprapac (copackaged with lansoprazole) is a registered trademark of Syntex
Pharmaceuticals International Ltd.
Daypro is a registered trademark of G.D. Searle LLC.
Feldene is a registered trademark of Pfizer.
Clinoril is a registered trademark of Merck & Co. Inc.
Tolectin, Tolectin DS, Tolectin 600 are registered trademarks of Johnson & Johnson
Corporation.
Distributed by:
Copyright © 1997-2013 by Roche Laboratories Inc. All rights reserved.
Reference ID: 3281582
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:36.974888
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019645s019lbl.pdf', 'application_number': 19645, 'submission_type': 'SUPPL ', 'submission_number': 19}
|
11,594
|
Flumadine® Tablets
(rimantadine hydrochloride tablets)
Flumadine® Syrup
(rimantadine hydrochloride syrup)
DESCRIPTION: Flumadine¨ (rimantadine hydrochloride) is a synthetic antiviral drug available as a
100 mg film-coated tablet and as a syrup for oral administration. Each film-coated tablet contains
100 mg of rimantadine hydrochloride plus hydroxypropyl methylcellulose, magnesium stearate,
microcrystalline cellulose, sodium starch glycolate, FD&C Yellow No. 6 Lake and FD&C Yellow
No. 6. The film coat contains hydroxypropyl methylcellulose and polyethylene glycol. Each
teaspoonful (5 mL) of the syrup contains 50 mg of rimantadine hydrochloride in an aqueous solution
containing citric acid, parabens (methyl and propyl), saccharin sodium, sorbitol, D&C Red No. 33
and flavors.
Rimantadine hydrochloride is a white to off-white crystalline powder which is freely soluble in water
(50 mg/mL at 20¡C). Chemically, rimantadine hydrochloride is alpha-methyltricyclo-
[3.3.1.1/3.7]decane-1-methanamine hydrochloride, with an empirical formula of C12H21N¥HCI, a
molecular weight of 215.77 and the following structural formula:
CLINICAL PHARMACOLOGY: MECHANISM OF ACTION: The mechanism of action of
rimantadine is not fully understood. Rimantadine appears to exert its inhibitory effect early in the
viral replicative cycle, possibly inhibiting the uncoating of the virus. Genetic studies suggest that a
virus protein specified by the virion M2 gene plays an important role in the susceptibility of
influenza A virus to inhibition by rimantadine.
MICROBIOLOGY: Rimantadine is inhibitory to the in vitro replication of influenza A virus isolates
from each of the three antigenic subtypes, i.e., H1N1, H2N2 and H3N2, that have been isolated from
man. Rimantadine has little or no activity against influenza B virus (Ref. 1,2). Rimantadine does not
appear to interfere with the immunogenicity of inactivated influenza A vaccine.
A quantitative relationship between the in vitro susceptibility of influenza A virus to rimantadine and
clinical response to therapy has not been established.
Susceptibility test results, expressed as the concentration of the drug required to inhibit virus
replication by 50% or more in a cell culture system, vary greatly (from 4 ng/mL to 20 µg/mL)
depending upon the assay protocol used, size of the virus inoculum, isolates of the influenza A virus
strains tested, and the cell types used (Ref. 2).
Rimantadine-resistant strains of influenza A virus have emerged among freshly isolated epidemic
strains in closed settings where rimantadine has been used. Resistant viruses have been shown to be
transmissible and to cause typical influenza illness. (Ref. 3)
PHARMACOKINETICS: Although the pharmacokinetic profile of Flumadine has been described,
no pharmacodynamic data establishing a correlation between plasma concentration and its antiviral
effect are available.
The tablet and syrup formulations of Flumadine are equally absorbed after oral administration. The
mean ± SD peak plasma concentration after a single 100 mg dose of Flumadine was 74 ± 22 ng/mL
(range: 45 to 138 ng/mL). The time to peak concentration was 6 ± 1 hours in healthy adults (age 20
to 44 years). The single dose elimination half-life in this population was 25.4 ± 6.3 hours (range: 13
to 65 hours). The single dose elimination half-life in a group of healthy 71 to 79 year-old subjects
was 32 ± 16 hours (range: 20 to 65 hours).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
After the administration of rimantadine 100 mg twice daily to healthy volunteers (age 18 to 70 years)
for 10 days, area
under the curve (AUC) values were approximately 30% greater than predicted from a single dose.
Plasma trough levels at steady state ranged between 118 and 468 ng/mL. In these patients no age-
related differences in pharmacokinetics were detected. However, in a comparison of three groups of
healthy older subjects (age 50-60, 61-70 and 71-79 years), the 71 to 79 year-old group had average
AUC values, peak concentrations and elimination half-life values at steady state that were 20 to 30%
higher than the other two groups. Steady-state concentrations in elderly nursing home patients (age
68 to 102 years) were 2- to 4-fold higher than those seen in healthy young and elderly adults.
The pharmacokinetic profile of rimantadine in children has not been established. In a group (n=10)
of children 4 to 8 years old who were given a single dose (6.6 mg/kg) of Flumadine syrup, plasma
concentrations of rimantadine ranged from 446 to 988 ng/mL at 5 to 6 hours and from 170 to 424
ng/mL at 24 hours. In some children drug was detected in plasma 72 hours after the last dose.
Following oral administration, rimantadine is extensively metabolized in the liver with less than 25%
of the dose excreted in the urine as unchanged drug. Three hydroxylated metabolites have been
found in plasma. These metabolites, an additional conjugated metabolite and parent drug account for
74 ± 10% (n=4) of a single 200 mg dose of rimantadine excreted in urine over 72 hours.
In a group (n=14) of patients with chronic liver disease, the majority of whom were stabilized
cirrhotics, the pharmacokinetics of rimantadine were not appreciably altered following a single 200
mg oral dose compared to 6 healthy subjects who were sex, age and weight matched to 6 of the
patients with liver disease. After administration of a single
200 mg dose to patients (n=10) with severe hepatic dysfunction, AUC was approximately 3-fold
larger, elimination half-life was approximately 2-fold longer and apparent clearance was about 50%
lower when compared to historic data from healthy subjects.
Studies of the effects of renal insufficiency on the pharmacokinetics of rimantadine have given
inconsistent results. Following administration of a single 200 mg oral dose of rimantadine to 8
patients with a creatinine clearance (CLcr) of 31-50 mL/min and 6 patients with a CLcr of 11-30
mL/min, the apparent clearance was 37% and 16% lower, respectively, and plasma metabolite
concentrations were higher when compared to weight-, age-, and sex-matched healthy subjects (n=9,
CLcr > 50 mL/min). After a single 200 mg oral dose of rimantadine was given to 8 hemodialysis
patients (CLcr 0-10
mL/min), there was a 1.6-fold increase in the elimination half-life and a 40% decrease in apparent
clearance compared to age-matched healthy subjects. Hemodialysis did not contribute to the
clearance of rimantadine.
The in vitro human plasma protein binding of rimantadine is about 40% over typical plasma
concentrations. Albumin is the major binding protein.
INDICATIONS AND USAGE: Flumadine is indicated for the prophylaxis and treatment of illness
caused by various strains of influenza A virus in adults.
Flumadine is indicated for prophylaxis against influenza A virus in children.
PROPHYLAXIS: In controlled studies of children over the age of 1 year, healthy adults and elderly
patients, Flumadine
has been shown to be safe and effective in preventing signs and symptoms of infection caused by
various strains of influenza A virus. Early vaccination on an annual basis as recommended by the
Centers for Disease ControlÕs Immunization Practices Advisory Committee is the method of choice
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
in the prophylaxis of influenza unless vaccination is contraindicated, not available or not feasible.
Since Flumadine does not completely prevent the host immune response to influenza A infection,
individuals who take this drug may still develop immune responses to natural disease or vaccination
and may be protected when later exposed to antigenically-related viruses. Following vaccination
during an influenza outbreak, Flumadine prophylaxis should be considered for the 2 to 4 week time
period required to develop an antibody response. However, the safety and effectiveness of Flumadine
prophylaxis have not been demonstrated for longer than 6 weeks.
TREATMENT: Flumadine therapy should be considered for adults who develop an influenza-like
illness during known or suspected influenza A infection in the community. When administered
within 48 hours after onset of signs and symptoms of infection caused by influenza A virus strains,
Flumadine has been shown to reduce the duration of fever and systemic symptoms.
CONTRAINDICATIONS: Flumadine is contraindicated in patients with known hypersensitivity to
drugs of the adamantane class, including rimantadine and amantadine.
PRECAUTIONS: GENERAL: An increased incidence of seizures has been reported in patients with
a history of epilepsy who received the related drug amantadine. In clinical trials of Flumadine, the
occurrence of seizure-like activity was observed in a small number of patients with a history of
seizures who were not receiving anticonvulsant medication while taking Flumadine. If seizures
develop, Flumadine should be discontinued.
The safety and pharmacokinetics of rimantadine in renal and hepatic insufficiency have only been
evaluated after single dose administration. In a single dose study of patients with anuric renal failure,
the apparent clearance of rimantadine was approximately 40% lower and the elimination half-life
was 1.6-fold greater than that in healthy age-matched controls. In a study of 14 persons with chronic
liver disease (mostly stabilized cirrhotics), no alterations in the pharmacokinetics were observed after
the administration of a single dose of rimantadine. However, the apparent clearance of rimantadine
following a single dose to 10 patients with severe liver dysfunction was 50% lower than reported for
healthy subjects. Because of the potential for accumulation of rimantadine and its metabolites in
plasma, caution should be exercised when patients with renal or hepatic insufficiency are treated
with rimantadine.
Transmission of rimantadine resistant virus should be considered when treating patients whose
contacts are at high risk for influenza A illness. Influenza A virus strains resistant to rimantadine can
emerge during treatment and such resistant strains have been shown to be transmissible and to cause
typical influenza illness (Ref. 3). Although the frequency, rapidity, and clinical significance of the
emergence of drug-resistant virus are not yet established, several small studies have demonstrated
that 10% to 30% of patients with initially sensitive virus, upon treatment with rimantadine, shed
rimantadine resistant virus. (Ref. 3, 4, 5, 6)
Clinical response to rimantadine, although slower in those patients who subsequently shed resistant
virus, was not significantly different from those who did not shed resistant virus. (Ref. 3) No data are
available in humans that address the activity or effectiveness of rimantadine therapy in subjects
infected with resistant virus.
DRUG INTERACTIONS: Cimetidine: The effects of chronic cimetidine use on the metabolism of
rimantadine are not
known. When a single 100 mg dose of Flumadine was administered one hour after the initiation of
cimetidine (300 mg four times a day), the apparent total rimantadine clearance of this single dose in
normal healthy adults was reduced by 18% (compared to the apparent total rimantadine clearance in
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
the same subjects in the absence of cimetidine).
Acetaminophen: Flumadine, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On
day 11,
acetaminophen (650 mg four times daily) was started and continued for 8 days. The
pharmacokinetics of rimantadine were assessed on days 11 and 13. Coadministration with
acetaminophen reduced the peak concentration and AUC values for rimantadine by approximately
11%.
Aspirin: Flumadine, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11,
aspirin (650 mg, four times daily) was started and continued for 8 days. The pharmacokinetics of
rimantadine were assessed on days 11 and 13. Peak plasma concentrations and AUC of rimantadine
were reduced approximately 10% in the presence of aspirin.
CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY: Carcinogenesis:
Carcinogenicity studies in animals have not been performed.
Mutagenesis: No mutagenic effects were seen when rimantadine was evaluated in several standard
assays for mutagenicity.
Impairment of Fertility: A reproduction study in male and female rats did not show detectable
impairment of fertility at dosages up to 60 mg/kg/day (3 times the maximum human dose based on
body surface area comparisons).
PREGNANCY: Teratogenic Effects: Pregnancy Category C. There are no adequate and well-
controlled studies in pregnant women. Rimantadine is reported to cross the placenta in mice.
Rimantadine has been shown to be embryotoxic in rats
when given at a dose of 200 mg/kg/day (11 times the recommended human dose based on body
surface area comparisons). At this dose the embryotoxic effect consisted of increased fetal resorption
in rats; this dose also produced a variety of maternal effects including ataxia, tremors, convulsions
and significantly reduced weight gain. No embryotoxicity was observed when rabbits were given
doses up to 50 mg/kg/day (5 times the recommended human dose based on body surface area
comparisons). However, there was evidence of a developmental abnormality in the form of a change
in the ratio of fetuses with 12 or 13 ribs. This ratio is normally about 50:50 in a litter but was 80:20
after rimantadine treatment.
Nonteratogenic Effects: Rimantadine was administered to pregnant rats in a peri- and postnatal
reproduction toxicity study at doses of 30, 60 and 120 mg/kg/day (1.7, 3.4 and 6.8 times the
recommended human dose based on body surface area comparisons). Maternal toxicity during
gestation was noted at the two higher doses of rimantadine, and at the highest dose, 120 mg/kg/day,
there was an increase in pup mortality during the first 2 to 4 days postpartum. Decreased fertility of
the F1 generation was also noted for the two higher doses.
For these reasons, Flumadine should be used during pregnancy only if the potential benefit justifies
the risk to the fetus.
NURSING MOTHERS: Flumadine should not be administered to nursing mothers because of the
adverse effects noted in offspring of rats treated with rimantadine during the nursing period.
Rimantadine is concentrated in rat milk in a dose-
related manner: 2 to 3 hours following administration of rimantadine, rat breast milk levels were
approximately twice those observed in the serum.
PEDIATRIC USE: In children, Flumadine is recommended for the prophylaxis of influenza A. The
safety and effectiveness of Flumadine in the treatment of symptomatic influenza infection in children
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
have not been established. Prophylaxis studies with Flumadine have not been performed in children
below the age of 1 year.
ADVERSE REACTIONS: In 1,027 patients treated with Flumadine in controlled clinical trials at the
recommended dose of 200 mg daily, the most frequently reported adverse events involved the
gastrointestinal and nervous systems.
Incidence >1%: Adverse events reported most frequently (1-3%) at the recommended dose in
controlled clinical trials are shown in the table below.
Rimantadine
Control
(n=1027)
(n=986)
Nervous System
Insomnia
2.1%
0 9%
Dizziness
1.9%
1.1%
Headache
1.4%
1.3%
Nervousness
1.3%
0.6%
Fatigue1.0%
0.9%
Gastrointestinal System
Nausea2.8%
1.6%
Vomiting
1.7%
0.6%
Anorexia
1.6%
0.8%
Dry mouth
1.5%
0.6%
Abdominal Pain
1.4%
0.8%
Body as a Whole
Asthenia
1.4%
0.5%
Less frequent adverse events (0.3 to 1%) at the recommended dose in controlled clinical trials were:
Gastrointestinal System: diarrhea, dyspepsia; Nervous System: impairment of concentration, ataxia,
somnolence, agitation, depression; Skin and Appendages: rash; Hearing and Vestibular: tinnitus;
Respiratory: dyspnea.
Additional adverse events (less than 0.3%) reported at recommended doses in controlled clinical
trials were: Nervous System: gait abnormality, euphoria, hyperkinesia, tremor, hallucination,
confusion, convulsions; Respiratory: bronchospasm, cough; Cardiovascular: pallor, palpitation,
hypertension, cerebrovascular disorder, cardiac failure, pedal edema, heart block, tachycardia,
syncope; Reproduction: non-puerperal lactation; Special Senses: taste loss/change, parosmia.
Rates of adverse events, particularly those involving the gastrointestinal and nervous systems,
increased significantly in controlled studies using higher than recommended doses of Flumadine. In
most cases, symptoms resolved rapidly with discontinuation of treatment. In addition to the adverse
events reported above, the following were also reported at higher than recommended doses:
increased lacrimation, increased micturition frequency, fever, rigors, agitation, constipation,
diaphoresis, dysphagia, stomatitis, hypesthesia and eye pain.
Adverse Reactions in Trials of Rimantadine and Amantadine: In a six-week prophylaxis study of 436
healthy adults comparing rimantadine with amantadine and placebo, the following adverse reactions
were reported with an incidence
>1 %.
Rimantadine
Placebo
Amantadine
200 mg/day
200 mg/day
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(n=145) (n=143)
(n=148)
Nervous System
Insomnia
3.4%
0.7%
7.0%
Nervousness
2.1%
0.7%
2.8%
Impaired Concentration
2.1%
1.4%
2.1%
Dizziness
0.7%
0.0%
2.1%
Depression
0.7%
0.7%
3.5%
Total % of subjects with
adverse reactions
6.9%
4.1%
14.7%
Total % of subjects withdrawn
due to adverse reactions
6.9%
3.4%
14.0%
GERIATRIC USE: Approximately 200 patients over the age of 64 were evaluated for safety in
controlled clinical trials with Flumadine¨ (rimantadine hydrochloride). Geriatric subjects who
received either 200 mg or 400 mg of rimantadine daily for 1 to 50 days experienced considerably
more central nervous system and gastrointestinal adverse events than comparable geriatric subjects
receiving placebo. Central nervous system events including dizziness, headache, anxiety, asthenia,
and fatigue, occurred up to two times more often in subjects treated with rimantadine than in those
treated with placebo. Gastrointestinal symptoms, particularly nausea, vomiting, and abdominal pain
occurred at least twice as frequently in subjects receiving rimantadine than in those receiving
placebo. The gastrointestinal symptoms appeared to be dose related. In patients over 64, the
recommended dose is 100 mg, daily (see Clinical Pharmacology and Dosage and Administration).
OVERDOSAGE: As with any overdose, supportive therapy should be administered as indicated.
Overdoses of a related drug, amantadine, have been reported with adverse reactions consisting of
agitation, hallucinations, cardiac arrhythmia and death. The administration of intravenous
physostigmine (a cholinergic agent) at doses of 1 to 2 mg in adults (Ref. 7) and 0.5 mg in children
(Ref. 8) repeated as needed as long as the dose did not exceed 2 mg/hour has been reported
anecdotally to be beneficial in patients with central nervous system effects from overdoses of
amantadine.
DOSAGE AND ADMINISTRATION: FOR PROPHYLAXIS IN ADULTS AND CHILDREN:
Adults: The recommended adult dose of Flumadine is 100 mg twice a day. In patients with severe
hepatic dysfunction, renal failure (CrCI ² 10 mL/min.) and elderly nursing home patients, a dose
reduction to 100 mg daily is recommended. There are currently no data available regarding the safety
of rimantadine during multiple dosing in subjects with renal or hepatic impairment. Because of the
potential for accumulation of rimantadine metabolites during multiple dosing, patients with any
degree of renal insufficiency should be monitored for adverse effects, with dosage adjustments being
made as necessary.
Children: In children less than 10 years of age, Flumadine should be administered once a day, at a
dose of 5 mg/kg but not exceeding 150 mg. For children 10 years of age or older, use the adult dose.
FOR TREATMENT IN ADULTS: The recommended adult dose of Flumadine is 100 mg twice a
day. In patients with severe hepatic dysfunction, renal failure (CrCI ² 10 mL/min) and elderly nursing
home patients, a dose reduction to 100 mg daily is recommended. There are currently no data
available regarding the safety of rimantadine during multiple dosing in subjects with renal or hepatic
impairment. Because of the potential for accumulation of rimantadine metabolites during multiple
dosing, patients with any degree of renal insufficiency should be monitored for adverse effects, with
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
dosage adjustments being made as necessary. Flumadine therapy should be initiated as soon as
possible, preferably within 48 hours after
onset of signs and symptoms of influenza A infection. Therapy should be continued for
approximately seven days from the initial onset of symptoms.
HOW SUPPLIED: Flumadine¨ tablets (rimantadine hydrochloride tablets) are supplied as 100 mg
tablets (orange, oval-shaped, film-coated) in bottles of 100 (NDC 0456-0521-01). Imprint on tablets:
(Front) FLUMADINE 100; (Back) FOREST.
Flumadine¨ syrup (rimantadine hydrochloride syrup) containing 50 mg of rimantadine hydrochloride
per teaspoonful (5 mL) (purplish-red, raspberry-flavored) is supplied in bottles of 8 oz (NDC 0456-
0527-08).
Tablets and syrup should be stored at 15¡ - 30¡C (59¡ - 86¡F).
Rx only
REFERENCES:
1. Belshe, R.B., Burk, B., Newman, F., Cerruti, R.L. and Sim, I.S. (1989) J. Infect. Dis. 159, 430-
435.
2. Sim, I.S., Cerruti, R.L. and Connell, E.V., (1989) J. Resp. Dis. (Suppl.), S46-S51.
3. Hayden, F.G., Belshe, R.B., Clover, R.D. et al (1989) N.Engl. J. Med. 321 (25), 1696-1702.
4. Hall, C.B., Dolin, R., Gala, C.L., et al (1987) Pediatrics 80, 275-282.
5. Thompson, J., Fleet, W., Lawrence, E. et al (1987) J. Med. Vir. 21, 249-255.
6. Belshe, R.B., Smith, M.H., Hall, C.B., et al (1988) J. Virol. 62, 1508-1512.
7. Casey, D.F. N. Engl. J. Med. 1978:298:516.
8. Berkowitz, C.D. J. Pediatrics 1979:95:144.
Rev. 9/00
MG #9040 (09)
FOREST PHARMACEUTICALS, INC.
Subsidiary of Forest Laboratories, Inc.
St. Louis, MO 63045
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:37.045869
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/19650S4lbl.pdf', 'application_number': 19649, 'submission_type': 'SUPPL ', 'submission_number': 6}
|
11,596
|
Flumadine® Tablets
(rimantadine hydrochloride tablets)
Flumadine® Syrup
(rimantadine hydrochloride syrup)
DESCRIPTION: Flumadine¨ (rimantadine hydrochloride) is a synthetic antiviral drug available as a
100 mg film-coated tablet and as a syrup for oral administration. Each film-coated tablet contains
100 mg of rimantadine hydrochloride plus hydroxypropyl methylcellulose, magnesium stearate,
microcrystalline cellulose, sodium starch glycolate, FD&C Yellow No. 6 Lake and FD&C Yellow
No. 6. The film coat contains hydroxypropyl methylcellulose and polyethylene glycol. Each
teaspoonful (5 mL) of the syrup contains 50 mg of rimantadine hydrochloride in an aqueous solution
containing citric acid, parabens (methyl and propyl), saccharin sodium, sorbitol, D&C Red No. 33
and flavors.
Rimantadine hydrochloride is a white to off-white crystalline powder which is freely soluble in water
(50 mg/mL at 20¡C). Chemically, rimantadine hydrochloride is alpha-methyltricyclo-
[3.3.1.1/3.7]decane-1-methanamine hydrochloride, with an empirical formula of C12H21N¥HCI, a
molecular weight of 215.77 and the following structural formula:
CLINICAL PHARMACOLOGY: MECHANISM OF ACTION: The mechanism of action of
rimantadine is not fully understood. Rimantadine appears to exert its inhibitory effect early in the
viral replicative cycle, possibly inhibiting the uncoating of the virus. Genetic studies suggest that a
virus protein specified by the virion M2 gene plays an important role in the susceptibility of
influenza A virus to inhibition by rimantadine.
MICROBIOLOGY: Rimantadine is inhibitory to the in vitro replication of influenza A virus isolates
from each of the three antigenic subtypes, i.e., H1N1, H2N2 and H3N2, that have been isolated from
man. Rimantadine has little or no activity against influenza B virus (Ref. 1,2). Rimantadine does not
appear to interfere with the immunogenicity of inactivated influenza A vaccine.
A quantitative relationship between the in vitro susceptibility of influenza A virus to rimantadine and
clinical response to therapy has not been established.
Susceptibility test results, expressed as the concentration of the drug required to inhibit virus
replication by 50% or more in a cell culture system, vary greatly (from 4 ng/mL to 20 µg/mL)
depending upon the assay protocol used, size of the virus inoculum, isolates of the influenza A virus
strains tested, and the cell types used (Ref. 2).
Rimantadine-resistant strains of influenza A virus have emerged among freshly isolated epidemic
strains in closed settings where rimantadine has been used. Resistant viruses have been shown to be
transmissible and to cause typical influenza illness. (Ref. 3)
PHARMACOKINETICS: Although the pharmacokinetic profile of Flumadine has been described,
no pharmacodynamic data establishing a correlation between plasma concentration and its antiviral
effect are available.
The tablet and syrup formulations of Flumadine are equally absorbed after oral administration. The
mean ± SD peak plasma concentration after a single 100 mg dose of Flumadine was 74 ± 22 ng/mL
(range: 45 to 138 ng/mL). The time to peak concentration was 6 ± 1 hours in healthy adults (age 20
to 44 years). The single dose elimination half-life in this population was 25.4 ± 6.3 hours (range: 13
to 65 hours). The single dose elimination half-life in a group of healthy 71 to 79 year-old subjects
was 32 ± 16 hours (range: 20 to 65 hours).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
After the administration of rimantadine 100 mg twice daily to healthy volunteers (age 18 to 70 years)
for 10 days, area
under the curve (AUC) values were approximately 30% greater than predicted from a single dose.
Plasma trough levels at steady state ranged between 118 and 468 ng/mL. In these patients no age-
related differences in pharmacokinetics were detected. However, in a comparison of three groups of
healthy older subjects (age 50-60, 61-70 and 71-79 years), the 71 to 79 year-old group had average
AUC values, peak concentrations and elimination half-life values at steady state that were 20 to 30%
higher than the other two groups. Steady-state concentrations in elderly nursing home patients (age
68 to 102 years) were 2- to 4-fold higher than those seen in healthy young and elderly adults.
The pharmacokinetic profile of rimantadine in children has not been established. In a group (n=10)
of children 4 to 8 years old who were given a single dose (6.6 mg/kg) of Flumadine syrup, plasma
concentrations of rimantadine ranged from 446 to 988 ng/mL at 5 to 6 hours and from 170 to 424
ng/mL at 24 hours. In some children drug was detected in plasma 72 hours after the last dose.
Following oral administration, rimantadine is extensively metabolized in the liver with less than 25%
of the dose excreted in the urine as unchanged drug. Three hydroxylated metabolites have been
found in plasma. These metabolites, an additional conjugated metabolite and parent drug account for
74 ± 10% (n=4) of a single 200 mg dose of rimantadine excreted in urine over 72 hours.
In a group (n=14) of patients with chronic liver disease, the majority of whom were stabilized
cirrhotics, the pharmacokinetics of rimantadine were not appreciably altered following a single 200
mg oral dose compared to 6 healthy subjects who were sex, age and weight matched to 6 of the
patients with liver disease. After administration of a single
200 mg dose to patients (n=10) with severe hepatic dysfunction, AUC was approximately 3-fold
larger, elimination half-life was approximately 2-fold longer and apparent clearance was about 50%
lower when compared to historic data from healthy subjects.
Studies of the effects of renal insufficiency on the pharmacokinetics of rimantadine have given
inconsistent results. Following administration of a single 200 mg oral dose of rimantadine to 8
patients with a creatinine clearance (CLcr) of 31-50 mL/min and 6 patients with a CLcr of 11-30
mL/min, the apparent clearance was 37% and 16% lower, respectively, and plasma metabolite
concentrations were higher when compared to weight-, age-, and sex-matched healthy subjects (n=9,
CLcr > 50 mL/min). After a single 200 mg oral dose of rimantadine was given to 8 hemodialysis
patients (CLcr 0-10
mL/min), there was a 1.6-fold increase in the elimination half-life and a 40% decrease in apparent
clearance compared to age-matched healthy subjects. Hemodialysis did not contribute to the
clearance of rimantadine.
The in vitro human plasma protein binding of rimantadine is about 40% over typical plasma
concentrations. Albumin is the major binding protein.
INDICATIONS AND USAGE: Flumadine is indicated for the prophylaxis and treatment of illness
caused by various strains of influenza A virus in adults.
Flumadine is indicated for prophylaxis against influenza A virus in children.
PROPHYLAXIS: In controlled studies of children over the age of 1 year, healthy adults and elderly
patients, Flumadine
has been shown to be safe and effective in preventing signs and symptoms of infection caused by
various strains of influenza A virus. Early vaccination on an annual basis as recommended by the
Centers for Disease ControlÕs Immunization Practices Advisory Committee is the method of choice
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
in the prophylaxis of influenza unless vaccination is contraindicated, not available or not feasible.
Since Flumadine does not completely prevent the host immune response to influenza A infection,
individuals who take this drug may still develop immune responses to natural disease or vaccination
and may be protected when later exposed to antigenically-related viruses. Following vaccination
during an influenza outbreak, Flumadine prophylaxis should be considered for the 2 to 4 week time
period required to develop an antibody response. However, the safety and effectiveness of Flumadine
prophylaxis have not been demonstrated for longer than 6 weeks.
TREATMENT: Flumadine therapy should be considered for adults who develop an influenza-like
illness during known or suspected influenza A infection in the community. When administered
within 48 hours after onset of signs and symptoms of infection caused by influenza A virus strains,
Flumadine has been shown to reduce the duration of fever and systemic symptoms.
CONTRAINDICATIONS: Flumadine is contraindicated in patients with known hypersensitivity to
drugs of the adamantane class, including rimantadine and amantadine.
PRECAUTIONS: GENERAL: An increased incidence of seizures has been reported in patients with
a history of epilepsy who received the related drug amantadine. In clinical trials of Flumadine, the
occurrence of seizure-like activity was observed in a small number of patients with a history of
seizures who were not receiving anticonvulsant medication while taking Flumadine. If seizures
develop, Flumadine should be discontinued.
The safety and pharmacokinetics of rimantadine in renal and hepatic insufficiency have only been
evaluated after single dose administration. In a single dose study of patients with anuric renal failure,
the apparent clearance of rimantadine was approximately 40% lower and the elimination half-life
was 1.6-fold greater than that in healthy age-matched controls. In a study of 14 persons with chronic
liver disease (mostly stabilized cirrhotics), no alterations in the pharmacokinetics were observed after
the administration of a single dose of rimantadine. However, the apparent clearance of rimantadine
following a single dose to 10 patients with severe liver dysfunction was 50% lower than reported for
healthy subjects. Because of the potential for accumulation of rimantadine and its metabolites in
plasma, caution should be exercised when patients with renal or hepatic insufficiency are treated
with rimantadine.
Transmission of rimantadine resistant virus should be considered when treating patients whose
contacts are at high risk for influenza A illness. Influenza A virus strains resistant to rimantadine can
emerge during treatment and such resistant strains have been shown to be transmissible and to cause
typical influenza illness (Ref. 3). Although the frequency, rapidity, and clinical significance of the
emergence of drug-resistant virus are not yet established, several small studies have demonstrated
that 10% to 30% of patients with initially sensitive virus, upon treatment with rimantadine, shed
rimantadine resistant virus. (Ref. 3, 4, 5, 6)
Clinical response to rimantadine, although slower in those patients who subsequently shed resistant
virus, was not significantly different from those who did not shed resistant virus. (Ref. 3) No data are
available in humans that address the activity or effectiveness of rimantadine therapy in subjects
infected with resistant virus.
DRUG INTERACTIONS: Cimetidine: The effects of chronic cimetidine use on the metabolism of
rimantadine are not
known. When a single 100 mg dose of Flumadine was administered one hour after the initiation of
cimetidine (300 mg four times a day), the apparent total rimantadine clearance of this single dose in
normal healthy adults was reduced by 18% (compared to the apparent total rimantadine clearance in
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
the same subjects in the absence of cimetidine).
Acetaminophen: Flumadine, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On
day 11,
acetaminophen (650 mg four times daily) was started and continued for 8 days. The
pharmacokinetics of rimantadine were assessed on days 11 and 13. Coadministration with
acetaminophen reduced the peak concentration and AUC values for rimantadine by approximately
11%.
Aspirin: Flumadine, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11,
aspirin (650 mg, four times daily) was started and continued for 8 days. The pharmacokinetics of
rimantadine were assessed on days 11 and 13. Peak plasma concentrations and AUC of rimantadine
were reduced approximately 10% in the presence of aspirin.
CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY: Carcinogenesis:
Carcinogenicity studies in animals have not been performed.
Mutagenesis: No mutagenic effects were seen when rimantadine was evaluated in several standard
assays for mutagenicity.
Impairment of Fertility: A reproduction study in male and female rats did not show detectable
impairment of fertility at dosages up to 60 mg/kg/day (3 times the maximum human dose based on
body surface area comparisons).
PREGNANCY: Teratogenic Effects: Pregnancy Category C. There are no adequate and well-
controlled studies in pregnant women. Rimantadine is reported to cross the placenta in mice.
Rimantadine has been shown to be embryotoxic in rats
when given at a dose of 200 mg/kg/day (11 times the recommended human dose based on body
surface area comparisons). At this dose the embryotoxic effect consisted of increased fetal resorption
in rats; this dose also produced a variety of maternal effects including ataxia, tremors, convulsions
and significantly reduced weight gain. No embryotoxicity was observed when rabbits were given
doses up to 50 mg/kg/day (5 times the recommended human dose based on body surface area
comparisons). However, there was evidence of a developmental abnormality in the form of a change
in the ratio of fetuses with 12 or 13 ribs. This ratio is normally about 50:50 in a litter but was 80:20
after rimantadine treatment.
Nonteratogenic Effects: Rimantadine was administered to pregnant rats in a peri- and postnatal
reproduction toxicity study at doses of 30, 60 and 120 mg/kg/day (1.7, 3.4 and 6.8 times the
recommended human dose based on body surface area comparisons). Maternal toxicity during
gestation was noted at the two higher doses of rimantadine, and at the highest dose, 120 mg/kg/day,
there was an increase in pup mortality during the first 2 to 4 days postpartum. Decreased fertility of
the F1 generation was also noted for the two higher doses.
For these reasons, Flumadine should be used during pregnancy only if the potential benefit justifies
the risk to the fetus.
NURSING MOTHERS: Flumadine should not be administered to nursing mothers because of the
adverse effects noted in offspring of rats treated with rimantadine during the nursing period.
Rimantadine is concentrated in rat milk in a dose-
related manner: 2 to 3 hours following administration of rimantadine, rat breast milk levels were
approximately twice those observed in the serum.
PEDIATRIC USE: In children, Flumadine is recommended for the prophylaxis of influenza A. The
safety and effectiveness of Flumadine in the treatment of symptomatic influenza infection in children
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
have not been established. Prophylaxis studies with Flumadine have not been performed in children
below the age of 1 year.
ADVERSE REACTIONS: In 1,027 patients treated with Flumadine in controlled clinical trials at the
recommended dose of 200 mg daily, the most frequently reported adverse events involved the
gastrointestinal and nervous systems.
Incidence >1%: Adverse events reported most frequently (1-3%) at the recommended dose in
controlled clinical trials are shown in the table below.
Rimantadine
Control
(n=1027)
(n=986)
Nervous System
Insomnia
2.1%
0 9%
Dizziness
1.9%
1.1%
Headache
1.4%
1.3%
Nervousness
1.3%
0.6%
Fatigue1.0%
0.9%
Gastrointestinal System
Nausea2.8%
1.6%
Vomiting
1.7%
0.6%
Anorexia
1.6%
0.8%
Dry mouth
1.5%
0.6%
Abdominal Pain
1.4%
0.8%
Body as a Whole
Asthenia
1.4%
0.5%
Less frequent adverse events (0.3 to 1%) at the recommended dose in controlled clinical trials were:
Gastrointestinal System: diarrhea, dyspepsia; Nervous System: impairment of concentration, ataxia,
somnolence, agitation, depression; Skin and Appendages: rash; Hearing and Vestibular: tinnitus;
Respiratory: dyspnea.
Additional adverse events (less than 0.3%) reported at recommended doses in controlled clinical
trials were: Nervous System: gait abnormality, euphoria, hyperkinesia, tremor, hallucination,
confusion, convulsions; Respiratory: bronchospasm, cough; Cardiovascular: pallor, palpitation,
hypertension, cerebrovascular disorder, cardiac failure, pedal edema, heart block, tachycardia,
syncope; Reproduction: non-puerperal lactation; Special Senses: taste loss/change, parosmia.
Rates of adverse events, particularly those involving the gastrointestinal and nervous systems,
increased significantly in controlled studies using higher than recommended doses of Flumadine. In
most cases, symptoms resolved rapidly with discontinuation of treatment. In addition to the adverse
events reported above, the following were also reported at higher than recommended doses:
increased lacrimation, increased micturition frequency, fever, rigors, agitation, constipation,
diaphoresis, dysphagia, stomatitis, hypesthesia and eye pain.
Adverse Reactions in Trials of Rimantadine and Amantadine: In a six-week prophylaxis study of 436
healthy adults comparing rimantadine with amantadine and placebo, the following adverse reactions
were reported with an incidence
>1 %.
Rimantadine
Placebo
Amantadine
200 mg/day
200 mg/day
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(n=145) (n=143)
(n=148)
Nervous System
Insomnia
3.4%
0.7%
7.0%
Nervousness
2.1%
0.7%
2.8%
Impaired Concentration
2.1%
1.4%
2.1%
Dizziness
0.7%
0.0%
2.1%
Depression
0.7%
0.7%
3.5%
Total % of subjects with
adverse reactions
6.9%
4.1%
14.7%
Total % of subjects withdrawn
due to adverse reactions
6.9%
3.4%
14.0%
GERIATRIC USE: Approximately 200 patients over the age of 64 were evaluated for safety in
controlled clinical trials with Flumadine¨ (rimantadine hydrochloride). Geriatric subjects who
received either 200 mg or 400 mg of rimantadine daily for 1 to 50 days experienced considerably
more central nervous system and gastrointestinal adverse events than comparable geriatric subjects
receiving placebo. Central nervous system events including dizziness, headache, anxiety, asthenia,
and fatigue, occurred up to two times more often in subjects treated with rimantadine than in those
treated with placebo. Gastrointestinal symptoms, particularly nausea, vomiting, and abdominal pain
occurred at least twice as frequently in subjects receiving rimantadine than in those receiving
placebo. The gastrointestinal symptoms appeared to be dose related. In patients over 64, the
recommended dose is 100 mg, daily (see Clinical Pharmacology and Dosage and Administration).
OVERDOSAGE: As with any overdose, supportive therapy should be administered as indicated.
Overdoses of a related drug, amantadine, have been reported with adverse reactions consisting of
agitation, hallucinations, cardiac arrhythmia and death. The administration of intravenous
physostigmine (a cholinergic agent) at doses of 1 to 2 mg in adults (Ref. 7) and 0.5 mg in children
(Ref. 8) repeated as needed as long as the dose did not exceed 2 mg/hour has been reported
anecdotally to be beneficial in patients with central nervous system effects from overdoses of
amantadine.
DOSAGE AND ADMINISTRATION: FOR PROPHYLAXIS IN ADULTS AND CHILDREN:
Adults: The recommended adult dose of Flumadine is 100 mg twice a day. In patients with severe
hepatic dysfunction, renal failure (CrCI ² 10 mL/min.) and elderly nursing home patients, a dose
reduction to 100 mg daily is recommended. There are currently no data available regarding the safety
of rimantadine during multiple dosing in subjects with renal or hepatic impairment. Because of the
potential for accumulation of rimantadine metabolites during multiple dosing, patients with any
degree of renal insufficiency should be monitored for adverse effects, with dosage adjustments being
made as necessary.
Children: In children less than 10 years of age, Flumadine should be administered once a day, at a
dose of 5 mg/kg but not exceeding 150 mg. For children 10 years of age or older, use the adult dose.
FOR TREATMENT IN ADULTS: The recommended adult dose of Flumadine is 100 mg twice a
day. In patients with severe hepatic dysfunction, renal failure (CrCI ² 10 mL/min) and elderly nursing
home patients, a dose reduction to 100 mg daily is recommended. There are currently no data
available regarding the safety of rimantadine during multiple dosing in subjects with renal or hepatic
impairment. Because of the potential for accumulation of rimantadine metabolites during multiple
dosing, patients with any degree of renal insufficiency should be monitored for adverse effects, with
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
dosage adjustments being made as necessary. Flumadine therapy should be initiated as soon as
possible, preferably within 48 hours after
onset of signs and symptoms of influenza A infection. Therapy should be continued for
approximately seven days from the initial onset of symptoms.
HOW SUPPLIED: Flumadine¨ tablets (rimantadine hydrochloride tablets) are supplied as 100 mg
tablets (orange, oval-shaped, film-coated) in bottles of 100 (NDC 0456-0521-01). Imprint on tablets:
(Front) FLUMADINE 100; (Back) FOREST.
Flumadine¨ syrup (rimantadine hydrochloride syrup) containing 50 mg of rimantadine hydrochloride
per teaspoonful (5 mL) (purplish-red, raspberry-flavored) is supplied in bottles of 8 oz (NDC 0456-
0527-08).
Tablets and syrup should be stored at 15¡ - 30¡C (59¡ - 86¡F).
Rx only
REFERENCES:
1. Belshe, R.B., Burk, B., Newman, F., Cerruti, R.L. and Sim, I.S. (1989) J. Infect. Dis. 159, 430-
435.
2. Sim, I.S., Cerruti, R.L. and Connell, E.V., (1989) J. Resp. Dis. (Suppl.), S46-S51.
3. Hayden, F.G., Belshe, R.B., Clover, R.D. et al (1989) N.Engl. J. Med. 321 (25), 1696-1702.
4. Hall, C.B., Dolin, R., Gala, C.L., et al (1987) Pediatrics 80, 275-282.
5. Thompson, J., Fleet, W., Lawrence, E. et al (1987) J. Med. Vir. 21, 249-255.
6. Belshe, R.B., Smith, M.H., Hall, C.B., et al (1988) J. Virol. 62, 1508-1512.
7. Casey, D.F. N. Engl. J. Med. 1978:298:516.
8. Berkowitz, C.D. J. Pediatrics 1979:95:144.
Rev. 9/00
MG #9040 (09)
FOREST PHARMACEUTICALS, INC.
Subsidiary of Forest Laboratories, Inc.
St. Louis, MO 63045
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:37.104924
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/19650S4lbl.pdf', 'application_number': 19650, 'submission_type': 'ORIG ', 'submission_number': 1}
|
11,595
|
040510.Final Draft PI clean
Flumadine® Tablets
(rimantadine hydrochloride tablets)
Rx only
DESCRIPTION: Flumadine® (rimantadine hydrochloride) is a synthetic antiviral drug available as a
100 mg film-coated tablet. Each film-coated tablet contains 100 mg of rimantadine hydrochloride plus
hypromellose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, FD&C Yellow
No. 6 Lake and FD&C Yellow No. 6. The film coat contains hypromellose and polyethylene glycol.
Rimantadine hydrochloride is a white to off-white crystalline powder which is freely soluble in water
(50 mg/mL at 20°C). Chemically, rimantadine hydrochloride is alpha-methyltricyclo-
[3.3.1.1/3.7]decane-1-methanamine hydrochloride, with an empirical formula of C12H21N•HCI, a
molecular weight of 215.77 and the following structural formula:
CLINICAL PHARMACOLOGY: MECHANISM OF ACTION: The mechanism of action of rimantadine
is not fully understood. Rimantadine appears to exert its inhibitory effect early in the viral replicative
cycle, possibly inhibiting the uncoating of the virus. Genetic studies suggest that a virus protein
specified by the virion M2 gene plays an important role in the susceptibility of influenza A virus to
inhibition by rimantadine.
MICROBIOLOGY: Rimantadine inhibits the replication in cell culture of influenza A virus isolates from
each of the three antigenic subtypes, i.e., H1N1, H2N2 and H3N2, that have been isolated from man.
Rimantadine has little or no activity against influenza B virus (Ref. 1,2). Rimantadine does not appear
to interfere with the immunogenicity of inactivated influenza A vaccine.
A quantitative relationship between the susceptibility in cell culture of influenza A virus to rimantadine
and clinical response to therapy has not been established.
Susceptibility test results, expressed as the concentration of the drug required to inhibit virus
replication by 50% or more in a cell culture system, vary greatly (from 19 nM to 93 µM) depending
upon the assay protocol used, size of the virus inoculum, isolates of the influenza A virus strains
tested, and the cell types used (Ref. 2).
RESISTANCE: Influenza A virus isolates resistant to rimantadine have been selected in cell culture
and in vivo as a result of treatment. Rimantadine-resistant strains of influenza A virus have emerged
among freshly isolated strains in closed settings where rimantadine has been used. Resistant viruses
have been shown to be transmissible and to cause typical influenza illness. (Ref. 3, 9). Substitutions
at any one of five amino acid positions in the transmembrane domain of M2 confer resistance to
rimantadine. The most common substitution causing resistance among influenza A (H1N1) and A
(H3N2) is S31N. Other less common substitutions that cause resistance include substitutions A30F,
V27A, V30A, and L26F.
Rimantadine resistance has been observed in circulating seasonal influenza and pandemic isolates
from individuals who have not received rimantadine. Swine-origin influenza A (H1N1) (S-OIV) viruses
that were resistant to rimantadine have been shown to contain the S31N substitution. Existing primers
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
used for detection of adamantine resistance in seasonal viruses do not work with all tested S-OIVs
(Ref. 11). The CDC should be consulted for questions regarding resistance to rimantadine in
circulating influenza strains.
CROSS-RESISTANCE: Cross-resistance among the adamantanes, rimantadine and amantadine,
has been observed. Resistance to rimantadine confers cross-resistance to amantadine and vice-
versa. Substitutions that confer resistance to rimantadine include (most frequently) M2 S31N, as well
as the less common changes V27A, V30A, L26F and A30T (Ref. 10).
PHARMACOKINETICS: Although the pharmacokinetic profile of Flumadine has been described, no
pharmacodynamic data establishing a correlation between plasma concentration and its antiviral
effect are available.
Flumadine is absorbed after oral administration. The mean ± SD peak plasma concentration after a
single 100 mg dose of Flumadine was 74 ± 22 ng/mL (range: 45 to 138 ng/mL). The time to peak
concentration was 6 ± 1 hours in healthy adults (age 20 to 44 years). The single dose elimination half-
life in this population was 25.4 ± 6.3 hours (range: 13 to 65 hours). The single dose elimination half-
life in a group of healthy 71 to 79 year-old subjects was 32 ± 16 hours (range: 20 to 65 hours).
After the administration of rimantadine 100 mg twice daily to healthy volunteers (age 18 to 70 years)
for 10 days, area under the curve (AUC) values were approximately 30% greater than predicted from
a single dose. Plasma trough levels at steady state ranged between 118 and 468 ng/mL. In these
patients no age-related differences in pharmacokinetics were detected. However, in a comparison of
three groups of healthy older subjects (age 50-60, 61-70 and 71-79 years), the 71 to 79 year-old
group had average AUC values, peak concentrations and elimination half-life values at steady state
that were 20 to 30% higher than the other two groups. Steady-state concentrations in elderly nursing
home patients (age 68 to 102 years) were 2- to 4-fold higher than those seen in healthy young and
elderly adults.
The pharmacokinetic profile of rimantadine in children has not been established.
Following oral administration, rimantadine is extensively metabolized in the liver with less than 25% of
the dose excreted in the urine as unchanged drug. Three hydroxylated metabolites have been found
in plasma. These metabolites, an additional conjugated metabolite and parent drug account for 74 ±
10% (n=4) of a single 200 mg dose of rimantadine excreted in urine over 72 hours.
In a group (n=14) of patients with chronic liver disease, the majority of whom were stabilized
cirrhotics, the pharmacokinetics of rimantadine were not appreciably altered following a single 200 mg
oral dose compared to six healthy subjects who were sex, age and weight matched to six of the
patients with liver disease. After administration of a single 200 mg dose to patients (n=10) with severe
hepatic dysfunction, AUC was approximately 3-fold larger, elimination half-life was approximately 2-
fold longer and apparent clearance was about 50% lower when compared to historic data from
healthy subjects.
Rimantadine pharmacokinetics were evaluated following administration of 100 mg Flumadine twice
daily for 14 days to subjects with mild (creatinine clearance [CrCl] 50-80 mL/min), moderate (CrCl 30-
49 mL/min), and severe (CrCl 5-29 mL/min) renal impairment and to healthy subjects (CrCl > 80
mL/min). There were no clinically relevant differences in rimantadine Cmax, Cmin, and AUC0-τ between
subjects with mild or moderate renal impairment compared to healthy subjects. In subjects with
severe renal impairment, rimantadine Cmax, Cmin, and AUC0-τ on Day 14 increased by 75%, 82%, and
81%, respectively, compared to healthy subjects. The rimantadine elimination half-life was slightly
prolonged (increase of 18% or less) in subjects with mild and moderate renal impairment but
increased by 49% in subjects with severe renal impairment compared to healthy subjects.
After a single 200 mg oral dose of rimantadine was given to eight hemodialysis patients (CrCl 0-10
mL/min), there was a 1.6-fold increase in the elimination half-life and a 40% decrease in apparent
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
clearance compared to age-matched healthy subjects. Hemodialysis did not contribute to the
clearance of rimantadine.
The in vitro human plasma protein binding of rimantadine is about 40% over typical plasma
concentrations. Albumin is the major binding protein.
INDICATIONS AND USAGE: Flumadine is indicated for the prophylaxis and treatment of illness
caused by various strains of influenza A virus in adults (17 years and older).
Flumadine is indicated for prophylaxis against influenza A virus in children (1 year to 16 years of
age).
PROPHYLAXIS: In controlled studies of children (1 year to 16 years of age), healthy adults (17 years
and older), and elderly patients (65 years of age and older), Flumadine has been shown to be safe
and effective in preventing signs and symptoms of infection caused by various strains of influenza A
virus. Since Flumadine does not completely prevent the host immune response to influenza A
infection, individuals who take this drug may still develop immune responses to natural disease or
vaccination and may be protected when later exposed to antigenically-related viruses. Following
vaccination during an influenza outbreak, Flumadine prophylaxis should be considered for the 2 to 4
week time period required to develop an antibody response. However, the safety and effectiveness of
Flumadine prophylaxis have not been demonstrated for longer than 6 weeks.
TREATMENT: Flumadine therapy should be considered for adults (17 years and older) who develop
an influenza-like illness during known or suspected influenza A infection in the community. When
administered within 48 hours after onset of signs and symptoms of infection caused by influenza A
virus strains, Flumadine has been shown to reduce the duration of fever and systemic symptoms.
The following points should be considered before initiating treatment or prophylaxis with
FLUMADINE:
•
FLUMADINE is not a substitute for early vaccination on an annual basis as recommended by
the Centers for Disease Control and Prevention Advisory Committee on Immunization
Practices.
•
Influenza viruses change over time. Emergence of resistance mutations could decrease drug
effectiveness. Other factors (for example, changes in viral virulence) might also diminish
clinical benefit of antiviral drugs. Prescribers should consider available information on
influenza drug susceptibility patterns and treatment effects when deciding whether to use
FLUMADINE.
CONTRAINDICATIONS: Flumadine is contraindicated in patients with known hypersensitivity to
drugs of the adamantane class, including rimantadine and amantadine.
PRECAUTIONS: GENERAL: An increased incidence of seizures has been reported in patients with a
history of epilepsy who received the related drug amantadine. In clinical trials of Flumadine, the
occurrence of seizure-like activity was observed in a small number of patients with a history of
seizures who were not receiving anticonvulsant medication while taking Flumadine. If seizures
develop, Flumadine should be discontinued.
The safety and pharmacokinetics of rimantadine in hepatic insufficiency have only been evaluated
after single dose administration. In a study of 14 subjects with chronic liver disease (mostly stabilized
cirrhotics), no alterations in the pharmacokinetics were observed after the administration of a single
dose of rimantadine. However, the apparent clearance of rimantadine following a single dose to 10
patients with severe liver dysfunction was 50% lower than reported for healthy subjects. Because of
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
the potential for accumulation of rimantadine and its metabolites in plasma, caution should be
exercised when patients with hepatic insufficiency are treated with rimantadine.
Following multiple-dose administration of rimantadine, there were no clinically relevant differences in
rimantadine systemic exposure between subjects with mild or moderate renal impairment compared
to healthy subjects. In subjects with severe renal impairment, rimantadine systemic exposure
increased by 81%, compared with healthy subjects. Because of the potential for increased
accumulation of rimantadine metabolites in renally impaired subjects, caution should be exercised
when these patients are treated with rimantadine.
Transmission of rimantadine resistant virus should be considered when treating patients whose
contacts are at high risk for influenza A illness. Influenza A virus strains resistant to rimantadine can
emerge during treatment and such resistant strains have been shown to be transmissible and to
cause typical influenza illness (Ref. 3). Although the frequency, rapidity, and clinical significance of
the emergence of drug-resistant virus are not yet established, several small studies have
demonstrated that 10% to 30% of patients with initially sensitive virus, upon treatment with
rimantadine, shed rimantadine resistant virus. (Ref. 3, 4, 5, 6)
Clinical response to rimantadine, although slower in those patients who subsequently shed resistant
virus, was not significantly different from those who did not shed resistant virus. (Ref. 3) No data are
available in humans that address the activity or effectiveness of rimantadine therapy in subjects
infected with resistant virus.
Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as
complications during the course of influenza. FLUMADINE has not been shown to prevent such
complications.
DRUG INTERACTIONS:
Acetaminophen: Flumadine, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On
day 11, acetaminophen (650 mg four times daily) was started and continued for 8 days. The
pharmacokinetics of rimantadine were assessed on days 11 and 13. Coadministration with
acetaminophen reduced the peak concentration and AUC values for rimantadine by approximately
11%.
Aspirin: Flumadine, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11,
aspirin (650 mg, four times daily) was started and continued for 8 days. The pharmacokinetics of
rimantadine were assessed on days 11 and 13. Peak plasma concentrations and AUC of rimantadine
were reduced approximately 10% in the presence of aspirin.
Cimetidine: When a single 100 mg dose of Flumadine was administered with steady-state cimetidine
(300 mg four times a day), there were no statistically significant differences in rimantadine Cmax or
AUC between Flumadine alone and Flumadine in the presence of cimetidine.
Live Attenuated Influenza Vaccine (LAIV): The concurrent use of Flumadine with live attenuated
intranasal influenza vaccine has not been evaluated. However, because of potential interference
between these products, the live attenuated intranasal influenza vaccine should not be administered
until 48 hours after cessation of Flumadine and Flumadine should not be administered until two
weeks after the administration of live attenuated intranasal influenza vaccine unless medically
indicated. The concern about potential interference arises principally from the potential for antiviral
drugs to inhibit replication of live vaccine virus.
CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY: Carcinogenesis:
Oral administration of rimantadine to rats for 2 years at doses up to 100 mg/kg/d [approximately 11-
14 times the maximum recommended human dose (MRHD) based on AUC] showed no evidence of
increased tumor incidence.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Mutagenesis: No mutagenic effects were seen when rimantadine was evaluated in several standard
assays for mutagenicity.
Impairment of Fertility: A reproduction study in male and female rats did not show detectable
impairment of fertility at dosages up to 60 mg/kg/d (3 times the MRHD based on mg/m2).
PREGNANCY: Teratogenic Effects: Pregnancy Category C. There are no adequate and well-
controlled studies in pregnant women. Rimantadine is reported to cross the placenta in mice.
Rimantadine has been shown to be embryotoxic in rats when given at a dose of 200 mg/kg/d (11
times the MRHD based on mg/m2). At this dose the embryotoxic effect consisted of increased fetal
resorption in rats; this dose also produced a variety of maternal effects including ataxia, tremors,
convulsions and significantly reduced weight gain. No embryotoxicity was observed when rabbits
were given doses up to 50 mg/kg/d (approximately 0.1 times the MRHD based on AUC), but evidence
of a developmental abnormality in the form of a change in the ratio of fetuses with 12 or 13 ribs was
noted. This ratio is normally about 50:50 in a litter but was 80:20 after rimantadine treatment.
However, in a repeat embryofetal toxicity study in rabbits at doses up to 50 mg/kg/d (approximately
0.1 times the MRHD based on AUC), this abnormality was not observed.
Nonteratogenic Effects: Rimantadine was administered to pregnant rats in a peri- and postnatal
reproduction toxicity study at doses of 30, 60 and 120 mg/kg/d (1.7, 3.4 and 6.8 times the MRHD
based on mg/m2). Maternal toxicity during gestation was noted at the two higher doses of
rimantadine, and at the highest dose, 120 mg/kg/day, there was an increase in pup mortality during
the first 2 to 4 days postpartum. Decreased fertility of the F1 generation was also noted for the two
higher doses.
For these reasons, Flumadine should be used during pregnancy only if the potential benefit justifies
the risk to the fetus.
NURSING MOTHERS: Flumadine should not be administered to nursing mothers because of the
adverse effects noted in offspring of rats treated with rimantadine during the nursing period.
Rimantadine is concentrated in rat milk in a dose-related manner: 2 to 3 hours following
administration of rimantadine, rat breast milk levels were approximately twice those observed in the
serum.
PEDIATRIC USE: In children (1 year to 16 years of age), Flumadine is recommended for the
prophylaxis of influenza A. The safety and effectiveness of Flumadine in the treatment of symptomatic
influenza infection in children (1 year to 16 years of age) have not been established. Prophylaxis
studies with Flumadine have not been performed in children below the age of 1 year.
ADVERSE REACTIONS: In 1,027 patients treated with Flumadine in controlled clinical trials at the
recommended dose of 200 mg daily, the most frequently reported adverse events involved the
gastrointestinal and nervous systems.
Incidence >1%: Adverse events reported most frequently (1-3%) at the recommended dose in
controlled clinical trials are shown in the table below.
Rimantadine
Control
(n=1027)
(n=986)
Nervous System
Insomnia
2.1%
0.9%
Dizziness
1.9%
1.1%
Headache
1.4%
1.3%
Nervousness
1.3%
0.6%
Fatigue
1.0%
0.9%
Gastrointestinal System
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Nausea
2.8%
1.6%
Vomiting
1.7%
0.6%
Anorexia
1.6%
0.8%
Dry mouth
1.5%
0.6%
Abdominal Pain
1.4%
0.8%
Body as a Whole
Asthenia
1.4%
0.5%
Less frequent adverse events (0.3 to 1%) at the recommended dose in controlled clinical trials were:
Gastrointestinal System: diarrhea, dyspepsia; Nervous System: impairment of concentration, ataxia,
somnolence, agitation, depression; Skin and Appendages: rash; Hearing and Vestibular: tinnitus;
Respiratory: dyspnea.
Additional adverse events (less than 0.3%) reported at recommended doses in controlled clinical
trials were: Nervous System: gait abnormality, euphoria, hyperkinesia, tremor, hallucination,
confusion, convulsions; Respiratory: bronchospasm, cough; Cardiovascular: pallor, palpitation,
hypertension, cerebrovascular disorder, cardiac failure, pedal edema, heart block, tachycardia,
syncope; Reproduction: non-puerperal lactation; Special Senses: taste loss/change, parosmia.
Rates of adverse events, particularly those involving the gastrointestinal and nervous systems,
increased significantly in controlled studies using higher than recommended doses of Flumadine. In
most cases, symptoms resolved rapidly with discontinuation of treatment. In addition to the adverse
events reported above, the following were also reported at higher than recommended doses:
increased lacrimation, increased micturition frequency, fever, rigors, agitation, constipation,
diaphoresis, dysphagia, stomatitis, hypesthesia and eye pain.
Adverse Reactions in Trials of Rimantadine and Amantadine: In a six-week prophylaxis study of 436
healthy adults comparing rimantadine with amantadine and placebo, the following adverse reactions
were reported with an incidence >1 %.
Rimantadine
Placebo
Amantadine
200 mg/day
200 mg/day
(n=145)
(n=143)
(n=148)
Nervous System
Insomnia
3.4%
0.7%
7.0%
Nervousness
2.1%
0.7%
2.8%
Impaired Concentration
2.1%
1.4%
2.1%
Dizziness
0.7%
0.0%
2.1%
Depression
0.7%
0.7%
3.5%
Total % of subjects with
adverse reactions
6.9%
4.1%
14.7%
Total % of subjects withdrawn
due to adverse reactions
6.9%
3.4%
14.0%
GERIATRIC USE: Approximately 200 subjects over the age of 65 were evaluated for safety in
controlled clinical trials with Flumadine (rimantadine hydrochloride). Geriatric subjects who received
either 200 mg or 400 mg of rimantadine daily for 1 to 50 days experienced considerably more central
nervous system and gastrointestinal adverse events than comparable geriatric subjects receiving
placebo. Central nervous system events including dizziness, headache, anxiety, asthenia, and
fatigue, occurred up to two times more often in subjects treated with rimantadine than in those treated
with placebo. Gastrointestinal symptoms, particularly nausea, vomiting, and abdominal pain occurred
at least twice as frequently in subjects receiving rimantadine than in those receiving placebo. The
gastrointestinal symptoms appeared to be dose related. In patients over 65, the recommended dose
is 100 mg, daily (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
OVERDOSAGE: As with any overdose, supportive therapy should be administered as indicated.
Overdoses of a related drug, amantadine, have been reported with adverse reactions consisting of
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
agitation, hallucinations, cardiac arrhythmia and death. The administration of intravenous
physostigmine (a cholinergic agent) at doses of 1 to 2 mg in adults (Ref. 7) and 0.5 mg in children
(Ref. 8) repeated as needed as long as the dose did not exceed 2 mg/hour has been reported
anecdotally to be beneficial in patients with central nervous system effects from overdoses of
amantadine.
DOSAGE AND ADMINISTRATION:
FOR PROPHYLAXIS IN ADULTS AND CHILDREN:
Adults (17 years and older):
The recommended adult dose of Flumadine is 100 mg twice a day. Study durations ranged from 11
days to 6 weeks in adult and elderly patients. In patients with severe hepatic dysfunction, severe
renal impairment (CrCl 5 to 29 mL/min) or renal failure (CrCI ≤ 10 mL/min) and in elderly nursing
home patients, a dose reduction to 100 mg daily is recommended. Because of the potential for
accumulation of rimantadine metabolites during multiple dosing, patients with hepatic or renal
impairment should be monitored for adverse effects.
Children (1 year to 16 years of age):
•
Study durations ranged from 5 weeks to 6 weeks in pediatric subjects.
•
In children 1 year to 9 years of age, Flumadine should be administered once a day, at a dose
of 5 mg/kg but not exceeding 150 mg.
•
For children 10 to 16 years of age, use the adult dose.
(see Directions for Compounding of an Oral Suspension from Flumadine Tablets to prepare an
oral suspension for administration to children and patients with difficulty swallowing tablets).
Children (Birth to 11 months):
The safety and efficacy of Flumadine for prophylaxis of influenza in pediatric patients younger than
1 year of age have not been established.
FOR TREATMENT IN ADULTS
Adults(17 years and older):
The recommended adult dose of Flumadine is 100 mg twice a day for 7 days. In patients with severe
hepatic dysfunction, severe renal impairment (CrCl 5 to 29 mL/min) or renal failure (CrCI ≤ 10
mL/min) and elderly nursing home patients, a dose reduction to 100 mg daily is recommended.
Because of the potential for accumulation of rimantadine metabolites during multiple dosing, patients
with hepatic or renal impairment should be monitored for adverse effects. Flumadine therapy should
be initiated as soon as possible, preferably within 48 hours after onset of signs and symptoms of
influenza A infection. Therapy should be continued for approximately seven days from the initial onset
of symptoms.
Children (16 years of age and younger):
Flumadine is not indicated for treatment of influenza in pediatric patients 16 years or younger.
Directions for the Compounding of an Oral Suspension from FLUMADINE Tablets (Final
Concentration = 10 mg/mL) 1
These directions are provided for use only during emergency situations, for patients who have
difficulty swallowing tablets or where lower doses are needed. The pharmacist may compound a
suspension (10 mg/mL) from Flumadine (rimantadine HCl) Tablets, 100 mg using Ora-Sweet®. †
Other vehicles have not been studied.
To make an oral suspension (10 mg/mL) from 100 mg Flumadine tablets, you will need the following:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
o
100 mg tablets of Flumadine
o
Ora-Sweet® (a vehicle manufactured by Paddock Laboratories)
o
a graduated cylinder
o
a mortar and pestle
o
an Amber Glass or Polyethylene terephthalate plastic (PET) bottle
o
a funnel (optional)
Compounding Procedures:
A 100 mg tablet of Flumadine is required for each 10 mL of compounded oral suspension to
make a concentration of 10 mg/mL
A compounded oral suspension is stable for 14 days. Therefore, the maximum amount of oral
suspension that can be dispensed to a patient should not exceed a 14 day supply.
Step A: Guidance for how to determine the Number of Tablets and Total Volume needed to
compound a 10 mg/mL oral suspension for each patient
1. Verify the prescribed dose is correct.
2. Calculate the mg amount of Flumadine needed for the duration of therapy.
(Daily Dose) x (Number of days) = (mg of Flumadine)
For example, 75 mg/day x 10 days = 750 mg
3. Round up the mg of Flumadine amount to the next 100 mg designation.
For example, Round up 750 mg to 800 mg
4. Calculate the Number of 100 mg tablets that are required for the compounded oral suspension.
(Rounded mg of Flumadine) ÷ (100 mg/tablet) = (Number of tablets)
For example, 800 mg ÷ 100 mg/tablet = 8 tablets
5. Calculate the Total Volume of compounded oral suspension (10 mg/mL)
(Rounded mg of Flumadine) ÷ (10 mg/mL) = (Total Volume)
For example, 800 mg ÷ 10 mg/mL = 80 mL
Step B: Once the total Number of Tablets and Volume are determined then follow the
procedures below for compounding the oral suspension (10 mg/mL) from Flumadine Tablets
100 mg
Verify your calculations before you begin to compound an oral suspension.
A 100 mg tablet of Flumadine is required for each 10 mL’s of
compounded oral suspension to make a concentration of 10 mg/mL.
1. Place the required number of Flumadine 100 mg Tablets into a clean mortar of sufficient size
to contain the tablets and volume of vehicle, Ora-Sweet® used in Step 3.
2. Grind the tablets and triturate to a fine powder using a pestle. Powder on the sides of the
mortar or pestle should be removed using a spatula and incorporated into the trituration
throughout the process.
3. Slowly add approximately one-third (1/3) of the total volume of vehicle to the mortar while
triturating until a uniform suspension is achieved.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4. Transfer the suspension to an amber glass or PET plastic bottle. Other types of bottles,
such as non- PET plastic or uncolored bottles, have not been evaluated and should not be
used. A funnel may be used to eliminate any spillage.
5. Slowly add the second one-third (1/3) of the total volume of vehicle to the mortar, rinse the
pestle and mortar by a triturating motion and transfer the contents into the bottle.
6. Repeat the rinsing (Step 5) with the remaining one-third (1/3) of the vehicle, transferring the
remaining contents to the fullest extent possible. Verify that the suspension is at the desired
total volume or add additional vehicle if needed.
7. Close the bottle using a child-resistant cap.
8. Shake well to ensure homogeneous suspension. (Note: The active drug, rimantadine HCl
readily dissolves in the specified vehicle. The suspension is caused by some of the inert
ingredients of Flumadine Tablets 100 mg which are insoluble in this vehicle.)
Labeling and Dispensing Information for the Compounded Oral Suspension
1. Include an ancillary label on the bottle indicating "Shake Gently Before Use." This
compounded suspension should be gently shaken prior to administration to minimize the
tendency for air entrapment with the Ora-Sweet® preparation. The need to shake the
compounded oral suspension gently prior to administration should be reviewed with the
parent or guardian when the suspension is dispensed.
2. Provide an oral dosing device (a graduated oral syringe or spoon) that will measure the
prescribed dose (in mL). If possible, mark or highlight the graduation corresponding to the
appropriate dose on the oral syringe or spoon for each patient.
3. Include an Expiration Date label according to storage condition (see below) and a “Discard
any Unused Portion” label to the bottle. Instruct the parent or guardian that any remaining
material following completion of therapy or after the expiration date on the label must be
discarded.
STORAGE OF THE PHARMACY-COMPOUNDED SUSPENSION:
Room Temperature: Stable for 14 days when stored in ambient room temperature conditions.
Other storage conditions have not been studied.
Note: The storage conditions are based on stability studies of compounded oral suspensions,
using the above mentioned vehicle, which was placed in amber glass and PET plastic bottles
at 25°C (77°F). Stability studies have not been conducted with other vehicles or bottle types.
†Ora-Sweet® is a registered trademark of Paddock Laboratories
HOW SUPPLIED: Flumadine® tablets (rimantadine hydrochloride tablets) are supplied as 100 mg
tablets (orange, oval-shaped, film-coated) in bottles of 100 (NDC 49708-521-88). Imprint on tablets:
(Front) FLUMADINE 100; (Back) FOREST.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
Temperature]
REFERENCES:
1. Belshe RB, Burk B, Newman F, et al. J Infect Dis. 1989;159(3):430-435.
2. Sim IS, Cerruti RL, Connell EV. J Respir Dis. 1989(Suppl):S46-S51.
3. Hayden FG, Belshe RB, Clover RD, et al. N Engl J Med. 1989;321(25):1696-1702.
4. Hall CB, Dolin R, Gala CL, et al. Pediatrics. 1987;80(2):275-282.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5. Thompson J, Fleet W, Lawrence E, et al. J Med Virol. 1987;21(3):249-255.
6. Belshe RB, Smith MH, Hall CB, et al. J Virol. 1988;62(5):1508-1512.
7. Casey DE. N Engl J Med. 1978;298(9):516.
8. Berkowitz CD. J Pediatr. 1979;95(1):144-145.
9. Hayden FG, Sperber SJ, Belshe RB, et al. Antimicrob Agents Chemother. 1991;35(9):1741-1747.
10. Deyde VM, Xu X, Bright RA, et al. J Infect Dis. 2007;196(2):249-257.
11. CDC. MMWR Morb Mortal Wkly Rep. 2009;58(16):433-435.
Rev. 4/2010
MG #9040 (11)
Manufactured by:
Forest Pharmaceuticals, Inc.
Subsidiary of Forest Laboratories, Inc.
St. Louis, MO 63045
Distributed By:
Caraco Pharmaceutical Laboratories, Ltd.
1150 Elijah McCoy Drive
Detroit, MI 48202
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:37.278621
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019649s015lbl.pdf', 'application_number': 19649, 'submission_type': 'SUPPL ', 'submission_number': 15}
|
11,597
|
Flumadine® Tablets
(rimantadine hydrochloride tablets)
Flumadine® Syrup
(rimantadine hydrochloride syrup)
Rx only
DESCRIPTION: Flumadine® (rimantadine hydrochloride) is a synthetic antiviral drug
available as a 100 mg film-coated tablet and as a syrup for oral administration. Each film-
coated tablet contains 100 mg of rimantadine hydrochloride plus hypromellose, magnesium
stearate, microcrystalline cellulose, sodium starch glycolate, FD&C Yellow No. 6 Lake and
FD&C Yellow No. 6. The film coat contains hypromellose and polyethylene glycol. Each
teaspoonful (5 mL) of the syrup contains 50 mg of rimantadine hydrochloride in a dye-free,
aqueous solution containing citric acid, parabens (methyl and propyl), saccharin sodium,
sorbitol and flavors.
Rimantadine hydrochloride is a white to off-white crystalline powder which is freely soluble in
water (50 mg/mL at 20°C). Chemically, rimantadine hydrochloride is alpha-methyltricyclo-
[3.3.1.1/3.7]decane-1-methanamine hydrochloride, with an empirical formula of
C12H21N•HCI, a molecular weight of 215.77 and the following structural formula:
CLINICAL PHARMACOLOGY: MECHANISM OF ACTION: The mechanism of action of
rimantadine is not fully understood. Rimantadine appears to exert its inhibitory effect early in
the viral replicative cycle, possibly inhibiting the uncoating of the virus. Genetic studies
suggest that a virus protein specified by the virion M2 gene plays an important role in the
susceptibility of influenza A virus to inhibition by rimantadine.
MICROBIOLOGY: Rimantadine is inhibitory to the in vitro replication of influenza A virus
isolates from each of the three antigenic subtypes, i.e., H1N1, H2N2 and H3N2, that have
been isolated from man. Rimantadine has little or no activity against influenza B virus (Ref.
1,2). Rimantadine does not appear to interfere with the immunogenicity of inactivated
influenza A vaccine.
A quantitative relationship between the in vitro susceptibility of influenza A virus to
rimantadine and clinical response to therapy has not been established.
Susceptibility test results, expressed as the concentration of the drug required to inhibit virus
replication by 50% or more in a cell culture system, vary greatly (from 4 ng/mL to 20 µg/mL)
depending upon the assay protocol used, size of the virus inoculum, isolates of the influenza
A virus strains tested, and the cell types used (Ref. 2).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Rimantadine-resistant strains of influenza A virus have emerged among freshly isolated
epidemic strains in closed settings where rimantadine has been used. Resistant viruses have
been shown to be transmissible and to cause typical influenza illness. (Ref. 3)
PHARMACOKINETICS: Although the pharmacokinetic profile of Flumadine has been
described, no pharmacodynamic data establishing a correlation between plasma
concentration and its antiviral effect are available.
The tablet and syrup formulations of Flumadine are equally absorbed after oral
administration. The mean ± SD peak plasma concentration after a single 100 mg dose of
Flumadine was 74 ± 22 ng/mL (range: 45 to 138 ng/mL). The time to peak concentration was
6 ± 1 hours in healthy adults (age 20 to 44 years). The single dose elimination half-life in this
population was 25.4 ± 6.3 hours (range: 13 to 65 hours). The single dose elimination half-life
in a group of healthy 71 to 79 year-old subjects was 32 ± 16 hours (range: 20 to 65 hours).
After the administration of rimantadine 100 mg twice daily to healthy volunteers (age 18 to 70
years) for 10 days, area under the curve (AUC) values were approximately 30% greater than
predicted from a single dose. Plasma trough levels at steady state ranged between 118 and
468 ng/mL. In these patients no age-related differences in pharmacokinetics were detected.
However, in a comparison of three groups of healthy older subjects (age 50-60, 61-70 and
71-79 years), the 71 to 79 year-old group had average AUC values, peak concentrations and
elimination half-life values at steady state that were 20 to 30% higher than the other two
groups. Steady-state concentrations in elderly nursing home patients (age 68 to 102 years)
were 2- to 4-fold higher than those seen in healthy young and elderly adults.
The pharmacokinetic profile of rimantadine in children has not been established. In a group
(n=10) of children 4 to 8 years old who were given a single dose (6.6 mg/kg) of Flumadine
syrup, plasma concentrations of rimantadine ranged from 446 to 988 ng/mL at 5 to 6 hours
and from 170 to 424 ng/mL at 24 hours. In some children drug was detected in plasma 72
hours after the last dose.
Following oral administration, rimantadine is extensively metabolized in the liver with less
than 25% of the dose excreted in the urine as unchanged drug. Three hydroxylated
metabolites have been found in plasma. These metabolites, an additional conjugated
metabolite and parent drug account for 74 ± 10% (n=4) of a single 200 mg dose of
rimantadine excreted in urine over 72 hours.
In a group (n=14) of patients with chronic liver disease, the majority of whom were stabilized
cirrhotics, the pharmacokinetics of rimantadine were not appreciably altered following a single
200 mg oral dose compared to 6 healthy subjects who were sex, age and weight matched to
6 of the patients with liver disease. After administration of a single 200 mg dose to patients
(n=10) with severe hepatic dysfunction, AUC was approximately 3-fold larger, elimination
half-life was approximately 2-fold longer and apparent clearance was about 50% lower when
compared to historic data from healthy subjects.
Studies of the effects of renal insufficiency on the pharmacokinetics of rimantadine have
given inconsistent results. Following administration of a single 200 mg oral dose of
rimantadine to 8 patients with a creatinine clearance (CLcr) of 31-50 mL/min and 6 patients
with a CLcr of 11-30 mL/min, the apparent clearance was 37% and 16% lower, respectively,
and plasma metabolite concentrations were higher when compared to weight-, age-, and sex-
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
matched healthy subjects (n=9, CLcr > 50 mL/min). After a single 200 mg oral dose of
rimantadine was given to 8 hemodialysis patients (CLcr 0-10 mL/min), there was a 1.6-fold
increase in the elimination half-life and a 40% decrease in apparent clearance compared to
age-matched healthy subjects. Hemodialysis did not contribute to the clearance of
rimantadine.
The in vitro human plasma protein binding of rimantadine is about 40% over typical plasma
concentrations. Albumin is the major binding protein.
INDICATIONS AND USAGE: Flumadine is indicated for the prophylaxis and treatment of
illness caused by various strains of influenza A virus in adults.
Flumadine is indicated for prophylaxis against influenza A virus in children.
PROPHYLAXIS: In controlled studies of children over the age of 1 year, healthy adults and
elderly patients, Flumadine has been shown to be safe and effective in preventing signs and
symptoms of infection caused by various strains of influenza A virus. Early vaccination on an
annual basis as recommended by the Centers for Disease Control’s Immunization Practices
Advisory Committee is the method of choice in the prophylaxis of influenza unless
vaccination is contraindicated, not available or not feasible. Since Flumadine does not
completely prevent the host immune response to influenza A infection, individuals who take
this drug may still develop immune responses to natural disease or vaccination and may be
protected when later exposed to antigenically-related viruses. Following vaccination during an
influenza outbreak, Flumadine prophylaxis should be considered for the 2 to 4 week time
period required to develop an antibody response. However, the safety and effectiveness of
Flumadine prophylaxis have not been demonstrated for longer than 6 weeks.
TREATMENT: Flumadine therapy should be considered for adults who develop an influenza-
like illness during known or suspected influenza A infection in the community. When
administered within 48 hours after onset of signs and symptoms of infection caused by
influenza A virus strains, Flumadine has been shown to reduce the duration of fever and
systemic symptoms.
CONTRAINDICATIONS: Flumadine is contraindicated in patients with known hypersensitivity
to drugs of the adamantane class, including rimantadine and amantadine.
PRECAUTIONS: GENERAL: An increased incidence of seizures has been reported in
patients with a history of epilepsy who received the related drug amantadine. In clinical trials
of Flumadine, the occurrence of seizure-like activity was observed in a small number of
patients with a history of seizures who were not receiving anticonvulsant medication while
taking Flumadine. If seizures develop, Flumadine should be discontinued.
The safety and pharmacokinetics of rimantadine in renal and hepatic insufficiency have only
been evaluated after single dose administration. In a single dose study of patients with anuric
renal failure, the apparent clearance of rimantadine was approximately 40% lower and the
elimination half-life was 1.6-fold greater than that in healthy age-matched controls. In a study
of 14 persons with chronic liver disease (mostly stabilized cirrhotics), no alterations in the
pharmacokinetics were observed after the administration of a single dose of rimantadine.
However, the apparent clearance of rimantadine following a single dose to 10 patients with
severe liver dysfunction was 50% lower than reported for healthy subjects. Because of the
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
potential for accumulation of rimantadine and its metabolites in plasma, caution should be
exercised when patients with renal or hepatic insufficiency are treated with rimantadine.
Transmission of rimantadine resistant virus should be considered when treating patients
whose contacts are at high risk for influenza A illness. Influenza A virus strains resistant to
rimantadine can emerge during treatment and such resistant strains have been shown to be
transmissible and to cause typical influenza illness (Ref. 3). Although the frequency, rapidity,
and clinical significance of the emergence of drug-resistant virus are not yet established,
several small studies have demonstrated that 10% to 30% of patients with initially sensitive
virus, upon treatment with rimantadine, shed rimantadine resistant virus. (Ref. 3, 4, 5, 6)
Clinical response to rimantadine, although slower in those patients who subsequently shed
resistant virus, was not significantly different from those who did not shed resistant virus.
(Ref. 3) No data are available in humans that address the activity or effectiveness of
rimantadine therapy in subjects infected with resistant virus.
DRUG INTERACTIONS: Cimetidine: The effects of chronic cimetidine use on the metabolism
of rimantadine are not known. When a single 100 mg dose of Flumadine was administered
one hour after the initiation of cimetidine (300 mg four times a day), the apparent total
rimantadine clearance of this single dose in normal healthy adults was reduced by 18%
(compared to the apparent total rimantadine clearance in the same subjects in the absence of
cimetidine).
Acetaminophen: Flumadine, 100 mg, was given twice daily for 13 days to 12 healthy
volunteers. On day 11, acetaminophen (650 mg four times daily) was started and continued
for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13.
Coadministration with acetaminophen reduced the peak concentration and AUC values for
rimantadine by approximately 11%.
Aspirin: Flumadine, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On
day 11, aspirin (650 mg, four times daily) was started and continued for 8 days. The
pharmacokinetics of rimantadine were assessed on days 11 and 13. Peak plasma
concentrations and AUC of rimantadine were reduced approximately 10% in the presence of
aspirin.
Influenza Virus Vaccine Live, Intranasal (FluMist®): The concurrent use of Flumadine with
Influenza Virus Vaccine Live, Intranasal (FluMist®) has not been evaluated. However,
because of potential interference between Flumadine and Flumist®, it is advisable that
Flumist® not be administered until 48 hours after cessation of Flumadine and that Flumadine
not be administered until two weeks after the administration of Flumist® unless medically
indicated. The concern about potential interference arises principally from the potential for
antiviral drugs to inhibit replication of live vaccine virus.
CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY: Carcinogenesis:
Carcinogenicity studies in animals have not been performed.
Mutagenesis: No mutagenic effects were seen when rimantadine was evaluated in several
standard assays for mutagenicity.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Impairment of Fertility: A reproduction study in male and female rats did not show detectable
impairment of fertility at dosages up to 60 mg/kg/day (3 times the maximum human dose
based on body surface area comparisons).
PREGNANCY: Teratogenic Effects: Pregnancy Category C. There are no adequate and well-
controlled studies in pregnant women. Rimantadine is reported to cross the placenta in mice.
Rimantadine has been shown to be embryotoxic in rats when given at a dose of 200
mg/kg/day (11 times the recommended human dose based on body surface area
comparisons). At this dose the embryotoxic effect consisted of increased fetal resorption in
rats; this dose also produced a variety of maternal effects including ataxia, tremors,
convulsions and significantly reduced weight gain. No embryotoxicity was observed when
rabbits were given doses up to 50 mg/kg/day (5 times the recommended human dose based
on body surface area comparisons). However, there was evidence of a developmental
abnormality in the form of a change in the ratio of fetuses with 12 or 13 ribs. This ratio is
normally about 50:50 in a litter but was 80:20 after rimantadine treatment.
Nonteratogenic Effects: Rimantadine was administered to pregnant rats in a peri- and
postnatal reproduction toxicity study at doses of 30, 60 and 120 mg/kg/day (1.7, 3.4 and 6.8
times the recommended human dose based on body surface area comparisons). Maternal
toxicity during gestation was noted at the two higher doses of rimantadine, and at the highest
dose, 120 mg/kg/day, there was an increase in pup mortality during the first 2 to 4 days
postpartum. Decreased fertility of the F1 generation was also noted for the two higher doses.
For these reasons, Flumadine should be used during pregnancy only if the potential benefit
justifies the risk to the fetus.
NURSING MOTHERS: Flumadine should not be administered to nursing mothers because of
the adverse effects noted in offspring of rats treated with rimantadine during the nursing
period. Rimantadine is concentrated in rat milk in a dose-related manner: 2 to 3 hours
following administration of rimantadine, rat breast milk levels were approximately twice those
observed in the serum.
PEDIATRIC USE: In children, Flumadine is recommended for the prophylaxis of influenza A.
The safety and effectiveness of Flumadine in the treatment of symptomatic influenza infection
in children have not been established. Prophylaxis studies with Flumadine have not been
performed in children below the age of 1 year.
ADVERSE REACTIONS: In 1,027 patients treated with Flumadine in controlled clinical trials
at the recommended dose of 200 mg daily, the most frequently reported adverse events
involved the gastrointestinal and nervous systems.
Incidence >1%: Adverse events reported most frequently (1-3%) at the recommended dose in
controlled clinical trials are shown in the table below.
Rimantadine
Control
(n=1027)
(n=986)
Nervous System
Insomnia
2.1%
0.9%
Dizziness
1.9%
1.1%
Headache
1.4%
1.3%
Nervousness
1.3%
0.6%
Fatigue
1.0%
0.9%
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Gastrointestinal System
Nausea
2.8%
1.6%
Vomiting
1.7%
0.6%
Anorexia
1.6%
0.8%
Dry mouth
1.5%
0.6%
Abdominal Pain
1.4%
0.8%
Body as a Whole
Asthenia
1.4%
0.5%
Less frequent adverse events (0.3 to 1%) at the recommended dose in controlled clinical
trials were: Gastrointestinal System: diarrhea, dyspepsia; Nervous System: impairment of
concentration, ataxia, somnolence, agitation, depression; Skin and Appendages: rash;
Hearing and Vestibular: tinnitus; Respiratory: dyspnea.
Additional adverse events (less than 0.3%) reported at recommended doses in controlled
clinical trials were: Nervous System: gait abnormality, euphoria, hyperkinesia, tremor,
hallucination, confusion, convulsions; Respiratory: bronchospasm, cough; Cardiovascular:
pallor, palpitation, hypertension, cerebrovascular disorder, cardiac failure, pedal edema, heart
block, tachycardia, syncope; Reproduction: non-puerperal lactation; Special Senses: taste
loss/change, parosmia.
Rates of adverse events, particularly those involving the gastrointestinal and nervous
systems, increased significantly in controlled studies using higher than recommended doses
of Flumadine. In most cases, symptoms resolved rapidly with discontinuation of treatment. In
addition to the adverse events reported above, the following were also reported at higher
than recommended doses: increased lacrimation, increased micturition frequency, fever,
rigors, agitation, constipation, diaphoresis, dysphagia, stomatitis, hypesthesia and eye pain.
Adverse Reactions in Trials of Rimantadine and Amantadine: In a six-week prophylaxis study
of 436 healthy adults comparing rimantadine with amantadine and placebo, the following
adverse reactions were reported with an incidence
>1 %.
Rimantadine
Placebo
Amantadine
200 mg/day
200 mg/day
(n=145)
(n=143)
(n=148)
Nervous System
Insomnia
3.4%
0.7%
7.0%
Nervousness
2.1%
0.7%
2.8%
Impaired Concentration
2.1%
1.4%
2.1%
Dizziness
0.7%
0.0%
2.1%
Depression
0.7%
0.7%
3.5%
Total % of subjects with
adverse reactions
6.9%
4.1%
14.7%
Total % of subjects withdrawn
due to adverse reactions 6.9%
3.4%
14.0%
GERIATRIC USE: Approximately 200 patients over the age of 64 were evaluated for safety in
controlled clinical trials with Flumadine® (rimantadine hydrochloride). Geriatric subjects who
received either 200 mg or 400 mg of rimantadine daily for 1 to 50 days experienced
considerably more central nervous system and gastrointestinal adverse events than
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
comparable geriatric subjects receiving placebo. Central nervous system events including
dizziness, headache, anxiety, asthenia, and fatigue, occurred up to two times more often in
subjects treated with rimantadine than in those treated with placebo. Gastrointestinal
symptoms, particularly nausea, vomiting, and abdominal pain occurred at least twice as
frequently in subjects receiving rimantadine than in those receiving placebo. The
gastrointestinal symptoms appeared to be dose related. In patients over 64, the
recommended dose is 100 mg, daily (see Clinical Pharmacology and Dosage and
Administration).
OVERDOSAGE: As with any overdose, supportive therapy should be administered as
indicated. Overdoses of a related drug, amantadine, have been reported with adverse
reactions consisting of agitation, hallucinations, cardiac arrhythmia and death. The
administration of intravenous physostigmine (a cholinergic agent) at doses of 1 to 2 mg in
adults (Ref. 7) and 0.5 mg in children (Ref. 8) repeated as needed as long as the dose did
not exceed 2 mg/hour has been reported anecdotally to be beneficial in patients with central
nervous system effects from overdoses of amantadine.
DOSAGE AND ADMINISTRATION: FOR PROPHYLAXIS IN ADULTS AND CHILDREN:
Adults: The recommended adult dose of Flumadine is 100 mg twice a day. In patients with
severe hepatic dysfunction, renal failure (CrCI 10 mL/min.) and elderly nursing home
patients, a dose reduction to 100 mg daily is recommended. There are currently no data
available regarding the safety of rimantadine during multiple dosing in subjects with renal or
hepatic impairment. Because of the potential for accumulation of rimantadine metabolites
during multiple dosing, patients with any degree of renal insufficiency should be monitored for
adverse effects, with dosage adjustments being made as necessary.
Children: In children less than 10 years of age, Flumadine should be administered once a
day, at a dose of 5 mg/kg but not exceeding 150 mg. For children 10 years of age or older,
use the adult dose.
FOR TREATMENT IN ADULTS: The recommended adult dose of Flumadine is 100 mg twice
a day. In patients with severe hepatic dysfunction, renal failure (CrCI 10 mL/min) and
elderly nursing home patients, a dose reduction to 100 mg daily is recommended. There are
currently no data available regarding the safety of rimantadine during multiple dosing in
subjects with renal or hepatic impairment. Because of the potential for accumulation of
rimantadine metabolites during multiple dosing, patients with any degree of renal insufficiency
should be monitored for adverse effects, with dosage adjustments being made as necessary.
Flumadine therapy should be initiated as soon as possible, preferably within 48 hours after
onset of signs and symptoms of influenza A infection. Therapy should be continued for
approximately seven days from the initial onset of symptoms.
HOW SUPPLIED: Flumadine® tablets (rimantadine hydrochloride tablets) are supplied as
100 mg tablets (orange, oval-shaped, film-coated) in bottles of 100 (NDC 0456-0521-01).
Imprint on tablets: (Front) FLUMADINE 100; (Back) FOREST.
Flumadine® syrup (rimantadine hydrochloride syrup) containing 50 mg of rimantadine
hydrochloride per teaspoonful (5 mL) (clear, colorless, raspberry-flavored) is supplied in
bottles of 8 oz (NDC 0456-0527-08).
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
Temperature]
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
REFERENCES:
1. Belshe, R.B., Burk, B., Newman, F., Cerruti, R.L. and Sim, I.S. (1989) J. Infect. Dis. 159,
430-435.
2. Sim, I.S., Cerruti, R.L. and Connell, E.V., (1989) J. Resp. Dis. (Suppl.), S46-S51.
3. Hayden, F.G., Belshe, R.B., Clover, R.D. et al (1989) N.Engl. J. Med. 321 (25), 1696-1702.
4. Hall, C.B., Dolin, R., Gala, C.L., et al (1987) Pediatrics 80, 275-282.
5. Thompson, J., Fleet, W., Lawrence, E. et al (1987) J. Med. Vir. 21, 249-255.
6. Belshe, R.B., Smith, M.H., Hall, C.B., et al (1988) J. Virol. 62, 1508-1512.
7. Casey, D.F. N. Engl. J. Med. 1978:298:516.
8. Berkowitz, C.D. J. Pediatrics 1979:95:144.
Rev. 06/06
MG #9040 (11)
FOREST PHARMACEUTICALS, INC.
Subsidiary of Forest Laboratories, Inc.
St. Louis, MO 63045
© 2006 Forest Laboratories, Inc.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:37.344925
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/019649s010,019650s007lbl.pdf', 'application_number': 19650, 'submission_type': 'SUPPL ', 'submission_number': 7}
|
11,598
|
Asacol®
(mesalamine)
Delayed-Release Tablets
DESCRIPTION: Each Asacol delayed-release tablet for oral administration contains 400 mg of
mesalamine, an anti-inflammatory drug. The Asacol delayed-release tablets are coated with
acrylic based resin, Eudragit S (methacrylic acid copolymer B, NF), which dissolves at pH 7 or
greater, releasing mesalamine in the terminal ileum and beyond for topical anti-inflammatory
action in the colon. Mesalamine has the chemical name 5-amino-2-hydroxybenzoic acid; its
structural formula is: structural formula
Molecular Weight:
153.1
Molecular Formula:
C7H7NO3
Inactive Ingredients: Each tablet contains colloidal silicon dioxide, dibutyl phthalate, edible
black ink, iron oxide red, iron oxide yellow, lactose monohydrate, magnesium stearate,
methacrylic acid copolymer B (Eudragit S), polyethylene glycol, povidone, sodium starch
glycolate, and talc.
CLINICAL PHARMACOLOGY: Mesalamine is thought to be the major therapeutically active
part of the sulfasalazine molecule in the treatment of ulcerative colitis. Sulfasalazine is
converted to equimolar amounts of sulfapyridine and mesalamine by bacterial action in the
colon. The usual oral dose of sulfasalazine for active ulcerative colitis is 3 to 4 grams daily in
divided doses, which provides 1.2 to 1.6 grams of mesalamine to the colon.
The mechanism of action of mesalamine (and sulfasalazine) is unknown, but appears to be
topical rather than systemic. Mucosal production of arachidonic acid (AA) metabolites, both
through the cyclooxygenase pathways, i.e., prostanoids, and through the lipoxygenase
pathways, i.e., leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs), is increased in
patients with chronic inflammatory bowel disease, and it is possible that mesalamine diminishes
inflammation by blocking cyclooxygenase and inhibiting prostaglandin (PG) production in the
colon.
Pharmacokinetics: Asacol tablets are coated with an acrylic-based resin that delays release
of mesalamine until it reaches the terminal ileum and beyond. This has been demonstrated in
human studies conducted with radiological and serum markers. Approximately 28% of the
mesalamine in Asacol tablets is absorbed after oral ingestion, leaving the remainder available
for topical action and excretion in the feces. Absorption of mesalamine is similar in fasted and
fed subjects. The absorbed mesalamine is rapidly acetylated in the gut mucosal wall and by the
liver. It is excreted mainly by the kidney as N-acetyl-5-aminosalicylic acid.
Mesalamine from orally administered Asacol tablets appears to be more extensively absorbed
than the mesalamine released from sulfasalazine. Maximum plasma levels of mesalamine and
N-acetyl-5-aminosalicylic acid following multiple Asacol doses are about 1.5 to 2 times higher
than those following an equivalent dose of mesalamine in the form of sulfasalazine. Combined
Asacol (mesalamine) May 2010
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Asacol (mesalamine)
mesalamine and N-acetyl-5-aminosalicylic acid AUC’s and urine drug dose recoveries following
multiple doses of Asacol tablets are about 1.3 to 1.5 times higher than those following an
equivalent dose of mesalamine in the form of sulfasalazine.
The tmax for mesalamine and its metabolite, N-acetyl-5-aminosalicylic acid, is usually delayed,
reflecting the delayed release, and ranges from 4 to 12 hours. The half-lives of elimination
(t1/2elm) for mesalamine and N-acetyl-5-aminosalicylic acid are usually about 12 hours, but are
variable, ranging from 2 to 15 hours. There is a large intersubject variability in the plasma
concentrations of mesalamine and N-acetyl-5-aminosalicylic acid and in their elimination half-
lives following administration of Asacol tablets.
Clinical Studies:
Mildly to moderately active ulcerative colitis: Two placebo-controlled studies have
demonstrated the efficacy of Asacol tablets in patients with mildly to moderately active
ulcerative colitis. In one randomized, double-blind, multi-center trial of 158 patients, Asacol
doses of 1.6 g/day and 2.4 g/day were compared to placebo. At the dose of 2.4 g/day, Asacol
tablets reduced the disease activity, with 21 of 43 (49%) Asacol patients showing improvement
in sigmoidoscopic appearance of the bowel compared to 12 of 44 (27%) placebo patients
(p = 0.048). In addition, significantly more patients in the Asacol 2.4 g/day group showed
improvement in rectal bleeding and stool frequency. The 1.6 g/day dose did not produce
consistent evidence of effectiveness.
In a second randomized, double-blind, placebo-controlled clinical trial of 6 weeks duration in 87
ulcerative colitis patients, Asacol tablets, at a dose of 4.8 g/day, gave sigmoidoscopic
improvement in 28 of 38 (74%) patients compared to 10 of 38 (26%) placebo patients
(p < 0.001). Also, more patients in the Asacol 4.8 g/day group showed improvement in overall
symptoms.
Maintenance of remission of ulcerative colitis: A 6-month, randomized, double-blind,
placebo-controlled, multi-center study involved 264 patients treated with Asacol 0.8 g/day
(n = 90), 1.6 g/day (n = 87), or placebo (n = 87). The proportion of patients treated with 0.8
g/day who maintained endoscopic remission was not statistically significant compared to
placebo. In the intention to treat (ITT) analysis of all 174 patients treated with Asacol 1.6 g/day
or placebo, Asacol maintained endoscopic remission of ulcerative colitis in 61 of 87 (70.1%) of
patients, compared to 42 of 87 (48.3%) of placebo recipients (p = 0.005).
A pooled efficacy analysis of 4 maintenance trials compared Asacol, at doses of 0.8 g/day to
2.8 g/day, with sulfasalazine, at doses of 2 g/day to 4 g/day (n = 200). Treatment success was
59 of 98 (59%) for Asacol and 70 of 102 (69%) for sulfasalazine, a non-significant difference.
Study to assess the effect on male fertility: The effect of Asacol (mesalamine) on
sulfasalazine-induced impairment of male fertility was examined in an open-label study. Nine
patients (age < 40 years) with chronic ulcerative colitis in clinical remission on sulfasalazine
2 g/day to 3 g/day were crossed over to an equivalent Asacol dose (0.8 g/day to 1.2 g/day) for
3 months. Improvement in sperm count (p < 0.02) and morphology (p < 0.02) occurred in all
cases. Improvement in sperm motility (p < 0.001) occurred in 8 of the 9 patients.
INDICATIONS AND USAGE: Asacol tablets are indicated for the treatment of mildly to
moderately active ulcerative colitis and for the maintenance of remission of ulcerative colitis.
CONTRAINDICATIONS: Asacol tablets are contraindicated in patients with hypersensitivity to
salicylates or to any of the components of the Asacol tablet.
Asacol (mesalamine) May 2010
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Asacol (mesalamine)
PRECAUTIONS:
General: Patients with pyloric stenosis may have prolonged gastric retention of Asacol tablets
which could delay release of mesalamine in the colon.
Exacerbation of the symptoms of colitis has been reported in 3% of Asacol-treated patients in
controlled clinical trials. This acute reaction, characterized by cramping, abdominal pain, bloody
diarrhea, and occasionally by fever, headache, malaise, pruritus, rash, and conjunctivitis, has
been reported after the initiation of Asacol tablets as well as other mesalamine products.
Symptoms usually abate when Asacol tablets are discontinued.
Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a
similar reaction to Asacol tablets or to other compounds which contain or are converted to
mesalamine.
Renal: Renal impairment, including minimal change nephropathy, acute and chronic interstitial
nephritis, and, rarely, renal failure has been reported in patients taking Asacol tablets as well as
other compounds which contain or are converted to mesalamine. In animal studies (rats, dogs),
the kidney is the principal target organ for toxicity. At doses of approximately 750 mg/kg to
1000 mg/kg [15 to 20 times the administered recommended human dose (based on a 50 kg
person) on a mg/kg basis and 3 to 4 times on a mg/m2 basis], mesalamine causes renal
papillary necrosis. Therefore, caution should be exercised when using Asacol (or other
compounds which contain or are converted to mesalamine or its metabolites) in patients
with known renal dysfunction or history of renal disease. It is recommended that all
patients have an evaluation of renal function prior to initiation of Asacol tablets and
periodically while on Asacol therapy.
Use in Hepatic Impairment: There have been reports of hepatic failure in patients with pre
existing liver disease who have been administered mesalamine. Caution should be exercised
when administering Asacol to patients with liver disease.
Information for Patients: Patients should be instructed to swallow the Asacol tablets whole,
taking care not to break, cut, or chew the tablets, because the coating is an important part of the
delayed-release formulation. In 2% to 3% of patients in clinical studies, intact or partially intact
tablets have been reported in the stool. If this occurs repeatedly, patients should contact their
physician.
Patients with ulcerative colitis should be made aware that ulcerative colitis rarely remits
completely, and that the risk of relapse can be substantially reduced by continued
administration of Asacol at a maintenance dosage.
Drug Interactions: There are no known drug interactions.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Dietary mesalamine was not
carcinogenic in rats at doses as high as 480 mg/kg/day, or in mice at 2000 mg/kg/day. These
doses are 2.4 and 5.1 times the maximum recommended human maintenance dose of Asacol
of 1.6 g/day (32 mg/kg/day if 50 kg body weight assumed or 1184 mg/m2), respectively, based
on body surface area. Mesalamine was negative in the Ames assay for mutagenesis, negative
for induction of sister chromatid exchanges (SCE) and chromosomal aberrations in Chinese
hamster ovary cells in vitro, and negative for induction of micronuclei (MN) in mouse bone
marrow polychromatic erythrocytes. Mesalamine, at oral doses up to 480 mg/kg/day (about 1.6
Asacol (mesalamine) May 2010
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Asacol (mesalamine)
times the recommended human treatment dose on a body surface area basis), was found to
have no effect on fertility or reproductive performance of male and female rats.
Pregnancy: Pregnancy Category C: There are no adequate and well controlled studies of
Asacol use in pregnant women. Limited published human data on mesalamine show no
increase in the overall rate of congenital malformations. Some data show an increased rate of
preterm birth, stillbirth, and low birth weight; however, these adverse pregnancy outcomes are
also associated with active inflammatory bowel disease. Animal reproduction studies of
mesalamine found no evidence of fetal harm. However, dibutyl phthalate (DBP) is an inactive
ingredient in Asacol’s enteric coating, and in animal studies at doses >190 times the human
dose based on body surface area, maternal DBP was associated with external and skeletal
malformations and adverse effects on the male reproductive system. Asacol should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Mesalamine crosses the placenta. In prospective and retrospective studies of over 600 women
exposed to mesalamine during pregnancy, the observed rate of congenital malformations was
not increased above the background rate in the general population. Some data show an
increased rate of preterm birth, stillbirth, and low birth weight, but it is unclear whether this was
due to underlying maternal disease, drug exposure, or both, as active inflammatory bowel
disease is also associated with adverse pregnancy outcomes.
Reproduction studies with mesalamine were performed during organogenesis in rats and rabbits
at oral doses up to 480 mg/kg/day. There was no evidence of impaired fertility or harm to the
fetus. These mesalamine doses were about 1.6 times (rat) and 3.2 times (rabbit) the
recommended human dose, based on body surface area.
Dibutyl phthalate (DBP) is an inactive ingredient in Asacol’s enteric coating. The human daily
intake of DBP from the maximum recommended dose of Asacol tablets is about 21 mg.
Published reports in rats show that male rat offspring exposed in utero to DBP (≥100 mg/kg/day,
approximately 39 times the human dose based on body surface area), display reproductive
system aberrations compatible with disruption of androgenic dependent development. The
clinical significance of this finding in rats is unknown. At higher dosages (≥500 mg/kg/day,
approximately 194 times the human dose based on body surface area), additional effects,
including cryptorchidism, hypospadias, atrophy or agenesis of sex accessory organs, testicular
injury, reduced daily sperm production, permanent retention of nipples, and decreased
anogenital distance are noted. Female offspring are unaffected. High doses of DBP,
administered to pregnant rats was associated with increased incidences of developmental
abnormalities, such as cleft palate (≥630 mg/kg/day, about 244 times the human dose, based
on body surface area) and skeletal abnormalities (≥750 mg/kg/day, about 290 times the human
dose based on body surface area) in the offspring.
Nursing Mothers: Mesalamine and its N-acetyl metabolite are excreted into human milk. In
published lactation studies, maternal mesalamine doses from various oral and rectal
formulations and products ranged from 500 mg to 3 g daily. The concentration of mesalamine
in milk ranged from non-detectable to 0.11 mg/L. The concentration of the N-acetyl-5
aminosalicylic acid metabolite ranged from 5 to 18.1 mg/L. Based on these concentrations,
estimated infant daily doses for an exclusively breastfed infant are 0 - 0.017 mg/kg/day of
mesalamine and 0.75-2.72 mg/kg/day of N-acetyl-5-aminosalicylic acid. Caution should be
exercised when Asacol is administered to a nursing woman.
Dibutyl phthalate (DBP), an inactive ingredient in the enteric coating of Asacol tablets, and its
primary metabolite mono-butyl phthalate (MBP) are excreted into human milk. In pregnant rats,
Asacol (mesalamine) May 2010
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Asacol (mesalamine)
DBP causes fetal reproductive system aberrations/malformations in male offspring [see
PRECAUTIONS, Pregnancy]. The clinical significance of this is has not been determined.
Pediatric Use: Safety and effectiveness of Asacol tablets in pediatric patients have not been
established.
Geriatric Use: Clinical studies of Asacol 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, the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy in elderly patients should be
considered when prescribing Asacol. Reports from uncontrolled clinical studies and post-
marketing reporting systems suggest a higher incidence of blood dyscrasias, i.e.,
agranulocytosis, neutropenia, pancytopenia, in subjects receiving Asacol who are 65 years or
older. Caution should be taken to closely monitor blood cell counts during 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 when prescribing this drug
therapy. As stated in the PRECAUTIONS section, it is recommended that all patients have an
evaluation of renal function prior to initiation of Asacol tablets and periodically while on Asacol
therapy.
ADVERSE REACTIONS: Asacol tablets have been evaluated in 3685 inflammatory bowel
disease patients (most patients with ulcerative colitis) in controlled and open-label studies.
Adverse events seen in clinical trials with Asacol tablets have generally been mild and
reversible. Adverse events presented in the following sections may occur regardless of length
of therapy and similar events have been reported in short- and long-term studies and in the
post-marketing setting.
In two short-term (6 weeks) placebo-controlled clinical studies involving 245 patients, 155 of
whom were randomized to Asacol tablets, five (3.2%) of the Asacol patients discontinued
Asacol therapy because of adverse events as compared to two (2.2%) of the placebo patients.
Adverse reactions leading to withdrawal from Asacol tablets included (each in one patient):
diarrhea and colitis flare; dizziness, nausea, joint pain, and headache; rash, lethargy and
constipation; dry mouth, malaise, lower back discomfort, mild disorientation, mild indigestion
and cramping; headache, nausea, aching, vomiting, muscle cramps, a stuffy head, plugged
ears, and fever.
Adverse events occurring in Asacol-treated patients at a frequency of 2% or greater in the two
short-term, double-blind, placebo-controlled trials mentioned above are listed in Table 1 below.
Overall, the incidence of adverse events seen with Asacol tablets was similar to placebo.
Asacol (mesalamine) May 2010
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Asacol (mesalamine)
Table 1
Frequency (%) of Common Adverse Events Reported in Ulcerative Colitis Patients Treated with
Asacol Tablets or Placebo in Short-Term (6-Week) Double-Blind Controlled Studies
Percent of Patients
with Adverse Events
Placebo
Asacol tablets
Event
(n = 87)
(n = 152)
Headache
36
35
Abdominal pain
14
18
Eructation
15
16
Pain
8
14
Nausea
15
13
Pharyngitis
9
11
Dizziness
8
8
Asthenia
15
7
Diarrhea
9
7
Back pain
5
7
Fever
8
6
Rash
3
6
Dyspepsia
1
6
Rhinitis
5
5
Arthralgia
3
5
Hypertonia
3
5
Vomiting
2
5
Constipation
1
5
Flatulence
7
3
Dysmenorrhea
3
3
Chest pain
2
3
Chills
2
3
Flu syndrome
2
3
Peripheral edema
2
3
Myalgia
1
3
Sweating
1
3
Colitis exacerbation
0
3
Pruritus
0
3
Acne
1
2
Increased cough
1
2
Malaise
1
2
Arthritis
0
2
Conjunctivitis
0
2
Insomnia
0
2
Of these adverse events, only rash showed a consistently higher frequency with increasing
Asacol dose in these studies.
In a 6-month placebo-controlled maintenance trial involving 264 patients, 177 of whom were
randomized to Asacol tablets, six (3.4%) of the Asacol patients discontinued Asacol therapy
because of adverse events, as compared to four (4.6%) of the placebo patients. Adverse
reactions leading to withdrawal from Asacol tablets included (each in one patient): anxiety;
headache; pruritus; decreased libido; rheumatoid arthritis; and stomatitis and asthenia.
Asacol (mesalamine) May 2010
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Asacol (mesalamine)
In the 6-month placebo-controlled maintenance trial, the incidence of adverse events seen with
Asacol tablets was similar to that seen with placebo. In addition to events listed in Table 1, the
following adverse events occurred in Asacol-treated patients at a frequency of 2% or greater in
this study: abdominal enlargement, anxiety, bronchitis, ear disorder, ear pain, gastroenteritis,
gastrointestinal hemorrhage, infection, joint disorder, migraine, nervousness, paresthesia, rectal
disorder, rectal hemorrhage, sinusitis, stool abnormalities, tenesmus, urinary frequency,
vasodilation, and vision abnormalities.
In 3342 patients in uncontrolled clinical studies, the following adverse events occurred at a
frequency of 5% or greater and appeared to increase in frequency with increasing dose:
asthenia, fever, flu syndrome, pain, abdominal pain, back pain, flatulence, gastrointestinal
bleeding, arthralgia, and rhinitis.
In addition to the adverse events listed above, the following events have been reported in
clinical studies, literature reports, and postmarketing use of products which contain (or have
been metabolized to) mesalamine. Because many of these events were reported voluntarily
from a population of unknown size, estimates of frequency cannot be made. These events have
been chosen for inclusion due to their seriousness or potential causal connection to
mesalamine:
Body as a Whole: Neck pain, facial edema, edema, lupus-like syndrome, drug fever (rare).
Cardiovascular: Pericarditis (rare), myocarditis (rare).
Gastrointestinal: Anorexia, pancreatitis, gastritis, increased appetite, cholecystitis, dry mouth,
oral ulcers, perforated peptic ulcer (rare), bloody diarrhea. There have been rare reports of
hepatotoxicity including, jaundice, cholestatic jaundice, hepatitis, and possible hepatocellular
damage including liver necrosis and liver failure. Some of these cases were fatal.
Asymptomatic elevations of liver enzymes which usually resolve during continued use or with
discontinuation of the drug have also been reported. One case of Kawasaki-like syndrome
which included changes in liver enzymes was also reported.
Hematologic: Agranulocytosis (rare), aplastic anemia (rare), thrombocytopenia, eosinophilia,
leukopenia, anemia, lymphadenopathy.
Musculoskeletal: Gout.
Nervous: Depression, somnolence, emotional lability, hyperesthesia, vertigo, confusion,
tremor, peripheral neuropathy (rare), transverse myelitis (rare), Guillain-Barré syndrome (rare).
Respiratory/Pulmonary: Eosinophilic pneumonia, interstitial pneumonitis, asthma
exacerbation, pleuritis.
Skin: Alopecia, psoriasis (rare), pyoderma gangrenosum (rare), dry skin, erythema nodosum,
urticaria.
Special Senses: Eye pain, taste perversion, blurred vision, tinnitus.
Urogenital: Renal Failure (rare), interstitial nephritis, minimal change nephropathy (See also
Renal subsection in PRECAUTIONS). Dysuria, urinary urgency, hematuria, epididymitis,
menorrhagia.
Asacol (mesalamine) May 2010
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Asacol (mesalamine)
Laboratory Abnormalities: Elevated AST (SGOT) or ALT (SGPT), elevated alkaline
phosphatase, elevated GGT, elevated LDH, elevated bilirubin, elevated serum creatinine and
BUN.
DRUG ABUSE AND DEPENDENCY:
Abuse: None reported.
Dependency: Drug dependence has not been reported with chronic administration of
mesalamine.
OVERDOSAGE: Two cases of pediatric overdosage have been reported. A 3-year-old male
who ingested 2 grams of Asacol tablets was treated with ipecac and activated charcoal; no
adverse events occurred. Another 3-year-old male, approximately 16 kg, ingested an unknown
amount of a maximum of 24 grams of Asacol crushed in solution (i.e., uncoated mesalamine);
he was treated with orange juice and activated charcoal, and experienced no adverse events.
In dogs, single doses of 6 grams of delayed-release Asacol tablets resulted in renal papillary
necrosis but were not fatal. This was approximately 12.5 times the recommended human dose
(based on a dose of 2.4 g/day in a 50 kg person). Single oral doses of uncoated mesalamine in
mice and rats of 5000 mg/kg and 4595 mg/kg, respectively, or of 3000 mg/kg in cynomolgus
monkeys, caused significant lethality.
DOSAGE AND ADMINISTRATION:
For the treatment of mildly to moderately active ulcerative colitis: The usual dosage in
adults is two 400-mg tablets to be taken three times a day for a total daily dose of 2.4 grams for
a duration of 6 weeks.
For the maintenance of remission of ulcerative colitis: The recommended dosage in adults
is 1.6 grams daily, in divided doses. Treatment duration in the prospective, well-controlled trial
was 6 months.
Two Asacol 400 mg tablets have not been shown to be bioequivalent to one Asacol® HD
(mesalamine) delayed-release 800 mg tablet.
HOW SUPPLIED: Asacol tablets are available as red-brown, capsule-shaped tablets
containing 400 mg mesalamine and imprinted “Asacol NE” in black.
NDC 0149-0752-15 Bottle of 180
Store at controlled room temperature 20°- 25°C (68°- 77°F) [See USP].
Manufactured by:
Warner Chilcott Deutschland GmbH
D-64331 Weiterstadt
Germany
Marketed by:
Warner Chilcott Pharmaceuticals Inc.
Mason, OH 45040
1-800-836-0658
Asacol (mesalamine) May 2010
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Asacol (mesalamine)
Under license from Medeva Pharma Suisse AG (registered trademark owner).
U.S. Patent Nos. 5,541,170 and 5,541,171
To report SUSPECTED ADVERSE REACTIONS, contact Warner Chilcott at 1-800-836-0658
or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
REVISED May 2010 company logo
Asacol (mesalamine) May 2010
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:37.358810
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019651s023lbl.pdf', 'application_number': 19651, 'submission_type': 'SUPPL ', 'submission_number': 23}
|
11,599
|
__________________________________________________________________________________________
__________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
-------------------WARNINGS AND PRECAUTIONS--------------------
These highlights do not include all the information needed to use
• Development of Renal Impairment (for example, minimal change
ASACOL safely and effectively. See full prescribing information for
nephropathy, acute and chronic interstitial nephritis, renal failure):
ASACOL.
Assess renal function at beginning of treatment and periodically during
treatment (5.1)
ASACOL (mesalamine) delayed-release tablets, for oral use
•
Mesalamine-induced Acute Intolerance Syndrome: Has been reported.
Initial U.S. Approval: 1987
Observe patients closely for worsening of these symptoms while on
treatment (5.2)
-----------------------RECENT MAJOR CHANGES-------------------------------
• Hypersensitivity Reactions: Use caution when treating patients who are
Indications and Usage (1.1)
10/2013
hypersensitive to sulfasalazine. Mesalamine-induced cardiac
Dosage and Administration (2.1)
10/2013
hypersensitivity reactions (myocarditis and pericarditis) have been
reported (5.3)
-----------------------INDICATIONS AND USAGE--------------------------------
• Hepatic Failure: Has been reported in patients with pre-existing liver
Asacol is an aminosalicylate indicated for:
disease. Use caution when treating patients with liver disease (5.4)
• Treatment of mildly to moderately active ulcerative colitis in patients 5
• Prolonged Gastric Retention in Patients with Upper Gastrointestinal
years of age and older (1.1).
Obstruction: May lead to a delay in onset of action (5.5)
• Maintenance of remission of ulcerative colitis in adults (1.2)
--------------------------ADVERSE REACTIONS---------------------------
-----------------DOSAGE AND ADMINISTRATION-----------------------------
The most common adverse reactions (observed in greater than or equal to 5
• Treatment of mildly to moderately active ulcerative colitis (2.1):
percent of adults in controlled clinical studies) were abdominal pain,
o Adults: 800 mg three times daily (2.4 grams/day) for 6 weeks
eructation, pain, back pain, rash, dyspepsia, rhinitis, flu syndrome, asthenia,
o Pediatric Patients 5 years or older: Total daily dose is weight-based up to
flatulence, vomiting, fever, arthralgia, constipation, and gastrointestinal
Weight Group
(kg)
Daily Dose
(mg/kg/day)
Maximum Daily Dose
(grams/day)
17 to <33
36 to 71
1.2
33 to <54
37 to 61
2.0
54 to 90
27 to 44
2.4
a maximum of 2.4 grams/day (see table below); twice daily dosing
bleeding (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Warner
Chilcott at 1-800-521-8813 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch
--------------------------DRUG INTERACTIONS--------------------------------
• Maintenance of remission of ulcerative colitis in adults: 1.6 grams daily, in
• Nephrotoxic Agents including NSAIDs: Renal reactions have been reported
divided doses (2.2)
(7.1)
• Instruct patients to swallow tablets whole without cutting, breaking, or
• Azathioprine or 6-mercaptopurine: Blood disorders have been reported
chewing and to take tablets with or without food (2.3)
(7.2)
• Two Asacol 400 mg tablets cannot be substituted for one Asacol HD
------------------------USE IN SPECIFIC POPULATIONS--------------------
(mesalamine) delayed-release 800 mg tablet (2.3)
• Renal Impairment: Use Asacol with caution in patients with a history of
• Recommend that renal function be evaluated prior to initiation of Asacol
renal disease (5.1, 7.1, 8.6)
(2.4, 5.1)
• Pregnancy: May cause fetal harm, based on animal data for dibutyl
phthalate (inactive ingredient in Asacol enteric coating) (8.1)
------------------------DOSAGE FORMS AND STRENGTHS------------------
• Nursing Mothers: Prescribers should carefully evaluate the risks and
Delayed-release tablets: 400 mg (3)
benefits when Asacol is administered to a nursing mother (8.3)
• Geriatric Patients: Monitor blood cell counts in geriatric patients (8.5)
------------------------CONTRAINDICATIONS---------------------------
Patients with known hypersensitivity to salicylates or aminosalicylates or to
See 17 for PATIENT COUNSELING INFORMATION.
any of the ingredients of Asacol tablets (4, 5.3)
Revised: 10/2013
FULL PRESCRIBING INFORMATION: CONTENTS*
7
DRUG INTERACTIONS
1
INDICATIONS AND USAGE
7.1
Nephrotoxic Agents, Including Non-Steroidal Anti
1.1
Treatment of Mildly to Moderately Active Ulcerative Colitis
Inflammatory Drugs
1.2
Maintenance of Remission of Ulcerative Colitis in Adults
7.2
Azathioprine or 6-mercaptopurine
2
DOSAGE AND ADMINISTRATION
8
USE IN SPECIFIC POPULATIONS
2.1
Dosage for Treatment of Mildly to Moderatively Active
8.1
Pregnancy
Ulcerative Colitis
8.3
Nursing Mothers
2.2
Dosage for Maintenance of Remission of Ulcerative Colitis
8.4
Pediatric Use
in Adults
8.5
Geriatric Use
2.3
Important Administration Instructions
8.6
Renal Impairment
2.4
Testing Prior to Asacol Administration
10
OVERDOSAGE
3
DOSAGE FORMS AND STRENGTHS
11
DESCRIPTION
4
CONTRAINDICATIONS
12
CLINICAL PHARMACOLOGY
5
WARNINGS AND PRECAUTIONS
12.1
Mechanism of Action
5.1
Renal Impairment
12.3
Pharmacokinetics
5.2
Mesalamine-Induced Acute Intolerance Syndrome
13
NONCLINICAL TOXICOLOGY
5.3
Hypersensitivity Reactions
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
5.4
Hepatic Failure
13.2
Animal Toxicology and/or Pharmacology
5.5
Prolonged Gastric Retention in Patients with Upper
14
CLINICAL STUDIES
Gastrointestinal Obstruction
14.1
Treatment of Mildly to Moderately Active Ulcerative Colitis
6
ADVERSE REACTIONS
14.2
Maintenance of Remission of Ulcerative Colitis in Adults
6.1
Clinical Trials Experience
16
HOW SUPPLIED/STORAGE AND HANDLING
6.2
Postmarketing Experience
17
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not listed.
1
Reference ID: 3393080
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
Treatment of Mildly to Moderately Active Ulcerative Colitis
Asacol® (mesalamine) delayed-release tablets are indicated for the treatment of mildly to moderately
active ulcerative colitis in patients 5 years of age and older.
1.2
Maintenance of Remission of Ulcerative Colitis in Adults
Asacol (mesalamine) delayed-release tablets are indicated for the maintenance of remission of ulcerative
colitis in adults. The safety and effectiveness of Asacol for the maintenance of remission of ulcerative
colitis in pediatric patients have not been established.
2
DOSAGE AND ADMINISTRATION
2.1
Dosage for Treatment of Mildly to Moderately Active Ulcerative Colitis
Adults
For adults, the recommended dosage of Asacol is two 400 mg tablets to be taken three times daily with
or without food (total daily dose of 2.4 grams), for a duration of 6 weeks [see Clinical Studies (14.1)].
Pediatrics
For pediatric patients, the recommended total daily dose of Asacol is weight-based (up to maximum of
2.4 grams/day) (see Table 1). Asacol tablets are to be taken twice daily with or without food for a
duration of 6 weeks [see Clinical Studies (14.1)].
Table 1. Pediatric Dosage by Weight
Weight Group
(kg)
Daily Dose
(mg/kg/day)
Maximum Daily Dose
(grams/day)
17 to <33
36 to 71
1.2
33 to <54
37 to 61
2.0
54 to 90
27 to 44
2.4
2.2
Dosage for Maintenance of Remission of Ulcerative Colitis in Adults
For adults, the recommended dosage of Asacol is 1.6 grams daily, in divided doses, with or without food
[see Clinical Studies (14.2)].
2.3
Important Administration Instructions
Swallow Asacol tablets whole. Do not cut, break or chew the tablets.
Two Asacol 400 mg tablets have not been shown to be bioequivalent to one Asacol® HD (mesalamine)
delayed-release 800 mg tablet and should not be used interchangeably.
2
Reference ID: 3393080
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.4
Testing Prior to Asacol Administration
Evaluate renal function prior to initiation of Asacol [see Warnings and Precautions (5.1)].
3
DOSAGE FORMS AND STRENGTHS
Asacol (mesalamine) Delayed-Release Tablets: 400 mg (red-brown, capsule-shaped and imprinted with
“0752 DR” in black).
4
CONTRAINDICATIONS
Asacol is contraindicated in patients with known hypersensitivity to salicylates or aminosalicylates or to
any of the ingredients of Asacol [see Warnings and Precautions (5.3), Adverse Reactions (6.2), and
Description (11)].
5
WARNINGS AND PRECAUTIONS
5.1
Renal Impairment
Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis, and
renal failure, has been reported in patients taking products such as Asacol that contain mesalamine or are
converted to mesalamine.
It is recommended that patients have an evaluation of renal function prior to initiation of Asacol and
periodically while on therapy.
Prescribers should carefully evaluate the risks and benefits when using Asacol in patients with known
renal impairment or history of renal disease [see Drug Interactions (7.1) and Nonclinical Toxicology
(13.2)].
5.2
Mesalamine-Induced Acute Intolerance Syndrome
Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish
from an exacerbation of ulcerative colitis. Although the exact frequency of occurrence has not been
determined, it has occurred in 3 percent of controlled clinical trials of mesalamine or sulfasalazine.
Symptoms include cramping, abdominal pain, bloody diarrhea, and sometimes fever, headache, and rash.
Observe patients closely for worsening of these symptoms while on treatment. If acute intolerance
syndrome is suspected, promptly discontinue treatment with Asacol.
5.3
Hypersensitivity Reactions
Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar
reaction to Asacol or to other compounds that contain or are converted to mesalamine.
Mesalamine-induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported
with Asacol and other mesalamine medications. Caution should be taken in prescribing this medicine to
patients with conditions predisposing them to the development of myocarditis or pericarditis.
3
Reference ID: 3393080
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.4
Hepatic Failure
There have been reports of hepatic failure in patients with pre-existing liver disease who have been
administered mesalamine. Caution should be exercised when administering Asacol to patients with liver
disease.
5.5
Prolonged Gastric Retention in Patients with Upper Gastrointestinal Obstruction
Organic or functional obstruction in the upper gastrointestinal tract may cause prolonged gastric
retention of Asacol which would delay release of mesalamine in the colon.
6
ADVERSE REACTIONS
The most serious adverse reactions seen in Asacol clinical trials or with other products that contain
mesalamine or are metabolized to mesalamine are:
• Renal impairment, including renal failure [see Warnings and Precautions (5.1)]
• Acute intolerance syndrome [see Warnings and Precautions (5.2)]
• Hypersensitivity reactions [see Warnings and Precautions (5.3)]
• Hepatic failure [see Warnings and Precautions (5.4)]
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 to rates in the clinical trials of another drug and
may not reflect the rates observed in practice.
In total, Asacol tablets have been evaluated in 2,690 patients with ulcerative colitis in controlled and
open-label trials. Adverse reactions presented in the following sections may occur regardless of length of
therapy and similar reactions have been reported in short- and long-term studies and in the postmarketing
setting.
Clinical studies supporting Asacol use for the treatment of mildly to moderately active ulcerative colitis
included two 6-week, placebo-controlled, randomized, double-blind studies in adults with mildly to
moderately active ulcerative colitis (Studies 1 and 2), and one 6-week, randomized, double-blind, study
of 2 dose levels in children with mildly to moderately active ulcerative colitis. Clinical studies supporting
the use of Asacol tablets in the maintenance of remission of ulcerative colitis included a 6-month,
randomized, double-blind, placebo-controlled, multi-center study and four active-controlled maintenance
trials comparing Asacol tablets with sulfasalazine. Asacol has been evaluated in 427 adults and 82
children with ulcerative colitis in these controlled studies.
Treatment of Mildly to Moderately Active Ulcerative Colitis in Adults
In two 6-week placebo-controlled clinical studies (Studies 1 and 2) involving 245 patients, 155 of whom
were randomized to Asacol [see Clinical Studies (14.1)], 3.2 percent of the Asacol-treated patients
discontinued therapy because of adverse reactions as compared to 2.2 percent of the placebo-treated
patients. The average age of patients in Study 1 was 42 years and 48 percent of patients were male. The
average age of patients in Study 2 was 42 years and 59 percent of patients were male. Adverse reactions
leading to withdrawal from Asacol included (each in one patient): diarrhea and colitis flare; dizziness,
nausea, joint pain, and headache; rash, lethargy and constipation; dry mouth, malaise, lower back
discomfort, mild disorientation, mild indigestion and cramping; headache, nausea, aching, vomiting,
muscle cramps, a stuffy head, plugged ears, and fever.
4
Reference ID: 3393080
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Adverse reactions in patients treated with Asacol occurring at a frequency of at least 2 percent and at a
rate greater than placebo in 6-week, double-blind, placebo-controlled trials (Studies 1 and 2) are listed in
Table 2 below.
Table 2. Adverse Reactions Reported in Two Pooled Six-Week, Placebo-Controlled Trials
(Studies 1 and 2) Experienced by at Least 2 percent of Patients in the Asacol Group
and at a Rate Greater than Placebo
% of Patients with Adverse Reactions
Adverse Reaction
Asacol
Placebo
(n = 152)
(n = 87)
Abdominal pain
18
14
Eructation
16
15
Pain
14
8
Back pain
7
5
Rash
6
3
Dyspepsia
6
1
Arthralgia
5
3
Vomiting
5
2
Constipation
5
1
Chest pain
3
2
Chills
3
2
Peripheral edema
3
2
Myalgia
3
1
Sweating
3
1
Pruritus
3
0
Acne
2
1
Malaise
2
1
Arthritis
2
0
Treatment of Mildly to Moderately Active Ulcerative Colitis in Pediatric Patients 5 to 17 Years
Old
A randomized, double-blind, 6-week study of 2 dose levels of Asacol (Study 3) was conducted in 82
pediatric patients 5 to 17 years of age with mildly to moderately active ulcerative colitis. All patients
were divided by body weight category (17 to less than 33 kg, 33 to less than 54 kg, and 54 to 90 kg) and
randomly assigned to receive a low dose (1.2, 2.0, and 2.4 g/day for the respective body weight category)
or a high dose (2.0, 3.6, and 4.8 g/day).
The high dose is not an approved dosage because it was not found to be more effective than the approved
dose [see Dosage and Administration (2.1) and Clinical Studies (14.1)].
Duration of exposure to mesalamine among the 82 patients in the study ranged from 12 to 50 days (mean
of 40 days in each dose group). The majority (88 percent) of patients in each group were treated for more
than 5 weeks. Table 3 provides a summary of the specific reported adverse reactions (ARs).
5
Reference ID: 3393080
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3. Adverse Reactions Reported in One Six-Week Trial (Study 3) Experienced by at
Least 5% of Patients in the Low Dose Group or High Dose Group
% of Patients with Adverse Reactions
Low Dose
High Dose
Adverse Reaction
(n=41)
(n=41)
Nasopharyngitis
15
12
Ulcerative Colitis
12
5
Headache
10
5
Abdominal pain
10
2
Dizziness
7
2
Sinusitis
7
0
Rash
5
5
Cough
5
0
Diarrhea
5
0
Fatigue
2
10
Pyrexia
0
7
Increased Lipase
0
5
Low Dose = Asacol 1.2 – 2.4 g/day; High Dose = Asacol 2.0 – 4.8 g/day. Dosage was dependent on body weight.
Adverse Reactions reported at the 1-week telephone follow-up visit are included.
Twelve percent of the patients in the low dose group and 5 percent of the patients in the high dose
group had serious adverse reactions (ARs). Ulcerative colitis was reported as a serious AR in one subject
in each group. Other serious ARs consisted of sinusitis, abdominal pain, decreased body mass index,
adenovirus infection, bloody diarrhea, sclerosing cholangitis, and pancreatitis in one subject each in the
low dose group and anemia and syncope in one subject each in the high dose group.
Seven patients were withdrawn from the study because of ARs: 5 (12 percent) in the low dose group
(ulcerative colitis, adenovirus infection, sclerosing cholangitis, pancreatitis) and 2 (5 percent) in the high
dose group (increased amylase and increased lipase, upper abdominal pain).
In general, the nature and severity of reactions in the pediatric population was similar to those reported in
adult populations of patients with ulcerative colitis.
Maintenance of Remission of Ulcerative Colitis in Adults
In a 6-month placebo-controlled maintenance trial involving 264 patients (Study 4) 177 of whom were
randomized to Asacol, six (3.4 percent) of the patients using Asacol discontinued therapy because of
adverse reactions, as compared to four (4.6 percent) of patients using placebo [see Clinical Studies
(14.2)]. The average age of patients in Study 4 was 42 years and 55 percent of patients were male.
Adverse reactions leading to study withdrawal in patients using Asacol included (each in one patient):
anxiety; headache; pruritus; decreased libido; rheumatoid arthritis; and stomatitis and asthenia.
In addition to reactions listed in Table 2, the following adverse reactions occurred in patients using
Asacol at a frequency of 2 percent or greater in Study 4: abdominal enlargement, gastroenteritis,
gastrointestinal hemorrhage, infection, joint disorder, migraine, nervousness, paresthesia, rectal disorder,
rectal hemorrhage, stool abnormalities, tenesmus, urinary frequency, vasodilation, and vision
abnormalities.
6
Reference ID: 3393080
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In 3342 patients in uncontrolled clinical studies, the following adverse reactions occurred at a frequency
of 5 percent or greater and appeared to increase in frequency with increasing dose: asthenia, fever, flu
syndrome, pain, abdominal pain, back pain, flatulence, gastrointestinal bleeding, arthralgia, and rhinitis.
6.2
Postmarketing Experience
In addition to the adverse reactions reported above in clinical trials involving Asacol, the adverse
reactions listed below have been identified during post-approval use of Asacol and other mesalamine
containing products. 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 as a Whole: Neck pain, facial edema, edema, lupus-like syndrome, drug fever.
Cardiovascular: Pericarditis, myocarditis [see Warnings and Precautions (5.3)].
Gastrointestinal: Anorexia, pancreatitis, gastritis, increased appetite, cholecystitis, dry mouth, oral
ulcers, perforated peptic ulcer bloody diarrhea.
Hematologic: Agranulocytosis aplastic anemia, thrombocytopenia, eosinophilia, leukopenia, anemia,
lymphadenopathy.
Musculoskeletal: Gout.
Nervous: Depression, somnolence, emotional lability, hyperesthesia, vertigo, confusion, tremor,
peripheral neuropathy, transverse myelitis, Guillain-Barré syndrome.
Renal: Renal failure, interstitial nephritis, minimal change nephropathy [see Warnings and Precautions
(5.1)].
Respiratory/Pulmonary: Eosinophilic pneumonia, interstitial pneumonitis, asthma exacerbation,
pleuritis.
Skin: Alopecia, psoriasis, pyoderma gangrenosus, dry skin, erythema nodosum, urticaria.
Special Senses: Eye pain, taste perversion, blurred vision, tinnitus.
Urogenital: Dysuria, urinary urgency, hematuria, epididymitis, menorrhagia, reversible oligospermia.
Laboratory Abnormalities: Elevated AST (SGOT) or ALT (SGPT), elevated alkaline phosphatase,
elevated GGT, elevated LDH, elevated bilirubin, elevated serum creatinine and BUN.
7
DRUG INTERACTIONS
No formal drug interaction studies have been performed using Asacol with other drugs. However, the
following interactions between mesalamine-containing products and other drugs have been reported.
7.1
Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory Drugs
The concurrent use of mesalamine with known nephrotoxic agents, including nonsteroidal anti-
inflammatory drugs (NSAIDs) may increase the risk of renal reactions [see Warnings and Precautions
(5.1)].
7
Reference ID: 3393080
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7.2
Azathioprine or 6-mercaptopurine
The concurrent use of mesalamine with azathioprine or 6-mercaptopurine may increase the risk for blood
disorders.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category C
Risk Summary
There are no adequate and well controlled studies of Asacol use in pregnant women. Limited published
human data on mesalamine show no increase in the overall rate of congenital malformations. Some data
show an increased rate of preterm birth, stillbirth, and low birth weight; however, these adverse
pregnancy outcomes are also associated with active inflammatory bowel disease. Furthermore, all
pregnancies, regardless of drug exposure, have a background rate of 2 to 4 percent for major
malformations, and 15 to 20 percent for pregnancy loss. No evidence of fetal harm was observed in
animal reproduction studies of mesalamine in rats and rabbits at oral doses approximately 1.9 times (rat)
and 3.9 times (rabbit) the recommended human dose. However, dibutyl phthalate (DBP) is an inactive
ingredient in Asacol’s enteric coating, and in animal studies in rats at doses greater than 190 times the
human dose based on body surface area, maternal DBP was associated with external and skeletal
malformations and adverse effects on the male reproductive system. Asacol should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Human Data
Mesalamine crosses the placenta. In prospective and retrospective studies of over 600 women exposed to
mesalamine during pregnancy, the observed rate of congenital malformations was not increased above
the background rate in the general population. Some data show an increased rate of preterm birth,
stillbirth, and low birth weight, but it is unclear whether this was due to underlying maternal disease,
drug exposure, or both, as active inflammatory bowel disease is also associated with adverse pregnancy
outcomes.
Animal data
Reproduction studies with mesalamine were performed during organogenesis in rats and rabbits at oral
doses up to 480 mg/kg/day. There was no evidence of impaired fertility or harm to the fetus. These
mesalamine doses were about 1.9 times (rat) and 3.9 times (rabbit) the recommended human dose, based
on body surface area.
Dibutyl phthalate (DBP) is an inactive ingredient in Asacol’s enteric coating. The human daily intake of
DBP from the maximum recommended dose of Asacol tablets is about 21 mg. Published reports in rats
show that male rat offspring exposed in utero to DBP (greater than or equal to 100 mg/kg/day,
approximately 39 times the human dose based on body surface area), display reproductive system
aberrations compatible with disruption of androgenic dependent development. The clinical significance
of this finding in rats is unknown. At higher dosages (greater than or equal to 500 mg/kg/day,
approximately 194 times the human dose based on body surface area), additional effects, including
cryptorchidism, hypospadias, atrophy or agenesis of sex accessory organs, testicular injury, reduced daily
sperm production, permanent retention of nipples, and decreased anogenital distance are noted. Female
offspring are unaffected. High doses of DBP, administered to pregnant rats was associated with increased
incidences of developmental abnormalities, such as cleft palate (greater than or equal to 630 mg/kg/day,
8
Reference ID: 3393080
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
about 244 times the human dose, based on body surface area) and skeletal abnormalities (greater than or
equal to 750 mg/kg/day, about 290 times the human dose based on body surface area) in the offspring.
8.3
Nursing Mothers
Mesalamine and its N-acetyl metabolite are present in human milk. In published lactation studies,
maternal mesalamine doses from various oral and rectal formulations and products ranged from 500 mg
to 3 g daily. The concentration of mesalamine in milk ranged from non-detectable to 0.11 mg/L. The
concentration of the N-acetyl-5-aminosalicylic acid metabolite ranged from 5 to 18.1 mg/L. Based on
these concentrations, estimated infant daily doses for an exclusively breastfed infant are 0 to 0.017
mg/kg/day of mesalamine and 0.75 to 2.72 mg/kg/day of N-acetyl-5-aminosalicylic acid.
Dibutyl phthalate (DBP), an inactive ingredient in the enteric coating of Asacol tablets, and its primary
metabolite mono-butyl phthalate (MBP) are excreted into human milk. The clinical significance of this
has not been determined.
The developmental and health benefits of breastfeeding should be considered along with the mother’s
clinical need for Asacol and any potential adverse effects on the breastfed child from the drug or from
the underlying maternal condition. Exercise caution when Asacol is administered to a nursing woman.
8.4
Pediatric Use
The safety and effectiveness of Asacol in pediatric patients 5 to 17 years of age for treatment of mildly to
moderately active ulcerative colitis have been established over a 6-week period. Use of Asacol in these
age groups is supported by evidence from adequate and well controlled studies of Asacol in adults and a
single study in pediatric patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and
Clinical Studies (14.1)].
Asacol was studied in a randomized, double-blind, parallel-group, 6-week treatment study of two dose
levels of Asacol in 82 pediatric patients 5 to 17 years of age with mildly to moderately active ulcerative
colitis. All patients were divided by weight category (17 to less than 33 kg, 33 to less than 54 kg, and 54
to 90 kg) and randomly assigned to receive a low dose (1.2, 2.0, and 2.4 g/day for the respective weight
category) or a high dose (2.0, 3.6, and 4.8 g/day). Baseline and screening visits were followed by a
treatment period of 6 weeks [see Dosage and Administration (2.1)]. The high dose was not more
effective than the low dose and is not an approved dosage [see Clinical Studies (14.1)].
The safety and effectiveness of Asacol in pediatric patients below the age of 5 years have not been
established. The safety and effectiveness of Asacol in the maintenance of remission of ulcerative colitis
in pediatric patients have not been established.
8.5
Geriatric Use
Clinical studies of Asacol did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently than younger subjects. Other reported clinical experience has not
identified differences in response between the elderly and younger patients. In general, the greater
frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug
therapy in elderly patients should be considered when prescribing Asacol. Reports from uncontrolled
clinical studies and postmarketing reporting systems suggest a higher incidence of blood dyscrasias, that
is, agranulocytosis, neutropenia, pancytopenia, in subjects receiving Asacol who are 65 years or older.
Caution should be taken to closely monitor blood cell counts during treatment with Asacol.
9
Reference ID: 3393080
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8.6
Renal Impairment
Mesalamine 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 when prescribing this drug therapy. It is
recommended that all patients have an evaluation of renal function prior to initiation of Asacol therapy
and periodically while on Asacol therapy [see Dosage and Administration (2.4), Warnings and
Precautions (5.1)].
10 OVERDOSAGE
There is no specific antidote for mesalamine overdose and treatment for suspected acute severe toxicity
with Asacol should be symptomatic and supportive. This may include prevention of further
gastrointestinal tract absorption, correction of fluid electrolyte imbalance, and maintenance of adequate
renal function. Asacol is a pH dependent delayed-release product and this factor should be considered
when treating a suspected overdose.
11 DESCRIPTION
Each Asacol (mesalamine) delayed-release tablet for oral administration contains 400 mg of mesalamine,
an aminosalicylate. Asacol (mesalamine) Delayed-Release Tablets contain acrylic based resin, Eudragit
S (methacrylic acid copolymer type B, NF), which dissolves at pH 7 or greater and releases mesalamine
in the terminal ileum and beyond for topical anti-inflammatory action in the colon. Mesalamine (also
referred to as 5-aminosalicylic acid or 5-ASA) has the chemical name 5-amino-2-hydroxybenzoic acid.
Its structural formula is: structural formula
Inactive Ingredients: Each tablet contains colloidal silicon dioxide, dibutyl phthalate, edible black ink,
ferric oxide red, ferric oxide yellow, lactose monohydrate, magnesium stearate, methacrylic acid
copolymer B (Eudragit S), polyethylene glycol, povidone, sodium starch glycolate, and talc.
12 CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
The mechanism of action of mesalamine is unknown, but appears to be topical rather than systemic.
Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways, that is,
prostanoids, and through the lipoxygenase pathways, that is, leukotrienes and hydroxyeicosatetraenoic
acids, is increased in patients with chronic ulcerative colitis, and it is possible that mesalamine
diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the
colon.
10
Reference ID: 3393080
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12.3
Pharmacokinetics
Absorption
Approximately 28 percent of mesalamine in Asacol tablets is absorbed after oral ingestion. Absorption of
mesalamine is similar in fasted and fed subjects. The T max for mesalamine and its metabolite, is usually
delayed, reflecting the delayed-release, and ranges from 4 to 16 hours.
Metabolism
The absorbed mesalamine is rapidly acetylated in the gut mucosal wall and by the liver to N-acetyl-5
aminosalicylic acid.
Excretion
Absorbed mesalamine is excreted mainly by the kidney as N-acetyl-5-aminosalicylic acid. Unabsorbed
mesalamine is excreted in feces.
After intravenous administration, the elimination half-life of mesalamine is reported to be approximately
40 minutes. After oral dosing, the terminal t1/2 values for mesalamine and N-acetyl-5-aminosalicylic
acid are usually about 12 hours, but are variable, ranging from 2 to 15 hours. There is a large inter-
subject and intra-subject variability in the plasma concentrations of mesalamine and N-acetyl-5
aminosalicylic acid and in their elimination half-lives following administration of Asacol.
Specific Populations
Pediatric Patients
In a dose-ranging PK study evaluating 30, 60 and 90 mg/kg/day doses of Asacol administered twice
daily for four weeks, the mean Cavg values of mesalamine in pediatric ulcerative colitis patients ranged
from approximately 400 ng/mL to 2100 ng/mL based on data from all dose levels.
In a study in pediatric ulcerative colitis patients (Study 3), mean plasma concentrations of mesalamine
(based on sparse sampling) were 820 to 988 ng/mL at the low dose level (that is, 1.2, 2.0 or 2.4 g/day
based on body weight strata of 17 to greater than 33 kg, 33 to less than 54 kg, and 54 to less than 90 kg,
respectively).
13 NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Mesalamine was not carcinogenic at dietary doses of up to 480 mg/kg/day in rats and 2000 mg/kg/day in
mice, which are about 2.9 and 6.1 times the maximum recommended maintenance dose of Asacol of 1.6
g/day or 26.7 mg/kg/day, based on 60 kg body weight, respectively, based on body surface area.
Mutagenesis
Mesalamine was negative in the Ames assay for mutagenesis, negative for induction of sister chromatid
exchanges (SCE) and chromosomal aberrations in Chinese hamster ovary cells in vitro, and negative for
induction of micronuclei (MN) in mouse bone marrow polychromatic erythrocytes.
Impairment of Fertility
Mesalamine, at oral doses up to 480 mg/kg/day (about 1.9 times the recommended human treatment dose
on a body surface area basis), was found to have no effect on fertility or reproductive performance of
male and female rats.
11
Reference ID: 3393080
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
13.2
Animal Toxicology and/or Pharmacology
In animal studies (rats, mice, dogs), the kidney was the principal organ for toxicity. (In the following,
comparisons of animal dosing to recommended human dosing are based on body surface area and a
2.4 g/day dose for a 60 kg person.)
Mesalamine causes renal papillary necrosis in rats at single doses of approximately 750 mg/kg to
1000 mg/kg (approximately 3 to 4 times the recommended human dose based on body surface area).
Doses of 170 and 360 mg/kg/day (about 0.7 and 1.5 times the recommended human dose based on
body surface area) given to rats for six months produced papillary necrosis, papillary edema, tubular
degeneration, tubular mineralization, and urothelial hyperplasia.
In mice, oral doses of 4000 mg/kg/day mesalamine (approximately 8 times the recommended human
dose based on body surface area) for three months produced tubular nephrosis, multifocal/diffuse
tubulo-interstitial inflammation, and multifocal/diffuse papillary necrosis.
In dogs, single doses of 6000 mg (approximately 8 times the recommended human dose based on body
surface area) of delayed-release mesalamine tablets resulted in renal papillary necrosis but were not fatal.
Renal changes have occurred in dogs given chronic administration of mesalamine at doses of 80
mg/kg/day (1.1 times the recommended human dose based on body surface area).
14 CLINICAL STUDIES
14.1
Treatment of Mildly to Moderately Active Ulcerative Colitis
Adults
Two placebo-controlled studies (Studies 1 and 2) have demonstrated the efficacy of Asacol tablets in
patients with mildly to moderately active ulcerative colitis.
In one randomized, double-blind, multi-center trial of 158 patients (Study 1), Asacol doses of 1.6 g/day
and 2.4 g/day for 6 weeks were compared to placebo. The scoring system for determination of treatment
efficacy included assessment of stool frequency, rectal bleeding, sigmoidoscopic findings, patient’s
functional assessment, and physician global assessment. At the dose of 2.4 g/day, 21 of 43 (49 percent)
patients using Asacol tablets showed an improvement in sigmoidoscopic appearance of the bowel
compared to 12 of 44 (27 percent) patients using placebo (p = 0.048). In addition, significantly more
patients in the Asacol tablets 2.4 g/day group showed improvement in rectal bleeding and stool
frequency. The 1.6 g/day dose did not produce consistent evidence of effectiveness.
In a second randomized, double-blind, placebo-controlled clinical trial of 6 weeks duration in 87 patients
(Study 2), Asacol tablets, at a dose of 4.8 g/day, for 6 weeks, resulted in sigmoidoscopic improvement in
28 of 38 (74 percent) patients compared to 10 of 38 (26 percent) placebo patients (p less than 0.001).
Also, more patients in the Asacol tablets 4.8 g/day group than the placebo group showed improvement in
overall symptoms.
The 4.8 g/day dose is not an approved dosage for the treatment of mildly to moderately active ulcerative
colitis.
Pediatrics
12
Reference ID: 3393080
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The safety and effectiveness of Asacol in pediatric patients 5 to 17 years of age for treatment of mildly to
moderately active ulcerative colitis are supported by evidence from adequate and well controlled studies
of Asacol in adults and a single study in pediatric patients.
A randomized, double-blind, 6-week study of 2 dose levels of Asacol (Study 3) was conducted in 82
pediatric patients 5 to 17 years of age with mildly or moderately active ulcerative colitis. All patients
were divided by weight category (17 to less than 33 kg, 33 to less than 54 kg, and 54 to 90 kg) and
randomly assigned to receive a low dose (1.2, 2.0, and 2.4 g/day for the respective weight category) or a
high dose (2.0, 3.6, and 4.8 g/day). Doses were administered every 12 hours.
The proportion of patients who achieved success based on the Truncated Mayo Score (TM-Mayo) (based
on the stool frequency and rectal bleeding subscores of the Mayo Score) and based on the Pediatric
Ulcerative Colitis Activity Index (PUCAI) (which included assessment of abdominal pain, rectal
bleeding, stool consistency and frequency, presence of nocturnal bowel movement and level of activity)
was measured after 6 weeks of treatment. Success based on TM-Mayo was defined as either partial
response (improvement from baseline in stool frequency or rectal bleeding subscores with no worsening
in the other) or complete response (both stool frequency and rectal bleeding subscores equal 0). Success
based on PUCAI was defined as either partial response (PUCAI reduction of greater than or equal to 20
points from Baseline to Week 6 with Week 6 score greater than or equal to 10) or complete response
(PUCAI less than 10 at Week 6).
There were 41 patients in the low dose group and 41 patients in the high dose group who received at least
one dose of Asacol; 36 patients in each dose group completed the study. Patients were considered
treatment failures if they did not achieve success or dropped out due to adverse reaction or lack of
efficacy.
At Week 6, 73.2 percent of the patients in the low dose group, and 70.0 percent of the patients in the high
dose group achieved success based on the TM-Mayo; 34.1 percent of the patients in the low dose group
and 42.5 percent of the patients in the high dose group achieved complete response. At Week 6, 56.1
percent of the patients in the low dose group, and 55.0 percent of the patients in the high dose group
achieved success based on the PUCAI; 46.3 percent of the patients in the low dose group and 42.5
percent of the patients in the high dose group achieved complete response.
The high dose was not more effective than the low dose and is not an approved dosage [see Dosage and
Administration (2.1)].
14.2
Maintenance of Remission of Ulcerative Colitis in Adults
A 6-month, randomized, double-blind, placebo-controlled, multi-center study (Study 4) involved 264
patients treated with Asacol tablets 0.8 g/day (n = 90), 1.6 g/day (n = 87), or placebo (n = 87). In the 0.8
g/day arm, patients were dosed twice daily; in the 1.6 g/day arm, patients were dosed four times daily.
The proportion of patients treated with 0.8 g/day who maintained endoscopic remission was not
statistically significant compared to placebo. The proportion of patients using Asacol tablets 1.6 g/day
who maintained endoscopic remission of ulcerative colitis was in 61 of 87 (70.1 percent) compared with
42 of 87 (48.3 percent) of placebo patients (p = 0.005).
A pooled efficacy analysis of 4 maintenance trials compared Asacol tablets, at doses of 0.8 g/day to 2.8
g/day, in divided doses ranging from twice daily to four times per day, with sulfasalazine, at doses of 2
g/day to 4 g/day. Treatment success was seen in 59 of 98 (59 percent) patients using Asacol tablets and
70 of 102 (69 percent) of patients using sulfasalazine, a non-significant difference.
13
Reference ID: 3393080
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16 HOW SUPPLIED/STORAGE AND HANDLING
Asacol (mesalamine) Delayed-Release Tablets are available as red-brown, capsule-shaped tablets
containing 400 mg mesalamine and imprinted with “0752 DR” in black.
NDC 0430-0752-27
Bottle of 180 tablets
Store at 20° to 25° C (68° to 77° F); excursions permitted 15° to 30° C (59° to 86° F) [See USP
Controlled Room Temperature].
17 PATIENT COUNSELING INFORMATION
• Instruct patients to swallow the Asacol tablets whole, taking care not to break, cut, or chew the
tablets, because the coating is an important part of the delayed-release formulation.
• Inform patients that if they are switching from a previous oral mesalamine therapy to Asacol they
should discontinue their previous oral mesalamine therapy and follow the dosing instructions for
Asacol. Inform patients that they should not substitute two Asacol 400 mg tablets with one Asacol
HD 800 mg tablet [see Dosage and Administration (2.3)].
• Inform patients that intact, partially intact, and/or tablet shells have been reported in the stool.
Instruct patients to contact their physician if this occurs repeatedly.
• Instruct patients to protect Asacol tablets from moisture. Instruct patients to close the container
tightly and to leave any desiccant pouches present in the bottle along with the tablets.
• Advise women who are pregnant, breastfeeding, or of childbearing potential that Asacol contains
dibutyl phthalate, which was associated with malformations and adverse effects on the male
reproductive system in animal studies. Dibutyl phthalate is excreted in human milk.
Manufactured by:
Warner Chilcott Deutschland GmbH
D-64331 Weiterstadt
Germany
Marketed by:
Warner Chilcott (US), LLC
Rockaway, NJ 07866
Under license from Medeva Pharma Suisse AG (registered trademark owner). company logo
0752G016
14
Reference ID: 3393080
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:37.689661
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019651s024lbl.pdf', 'application_number': 19651, 'submission_type': 'SUPPL ', 'submission_number': 24}
|
11,600
|
_______________________________________________________________________________________________________________________________________
_______________________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
-------------------------WARNINGS AND PRECAUTIONS--------------------
These highlights do not include all the information needed to use
• Renal Impairment: Evaluate the risks and benefits in patients with known
ASACOL safely and effectively. See full prescribing information for
renal impairment or taking nephrotoxic drugs; monitor renal function (5.1,
ASACOL.
7.1, 8.6, 13.2)
• Mesalamine-induced Acute Intolerance Syndrome: Symptoms may be
ASACOL (mesalamine) delayed-release tablets, for oral use
difficult to distinguish from a UC exacerbation; monitor for worsening
Initial U.S. Approval: 1987
symptoms; discontinue if acute intolerance syndrome suspected (5.2)
• Hypersensitivity Reactions, including Myocarditis and Pericarditis:
-----------------------INDICATIONS AND USAGE-------------------------------
Evaluate patients immediately and discontinue if a hypersensitivity
Asacol is an aminosalicylate indicated for:
reaction is suspected (5.3)
• Treatment of mildly to moderately active ulcerative colitis (UC) in patients
• Hepatic Failure: Evaluate the risks and benefits in patients with known
5 years of age and older (1.1).
liver impairment (5.4)
• Maintenance of remission of mildly to moderately active UC adults (1.2)
--------------------------------ADVERSE REACTIONS---------------------------
-------------------------DOSAGE AND ADMINISTRATION--------------------
The most common adverse reactions (≥5%) for the treatment of mild to
Important Administration Instructions:
moderate UC are (6.1):
• Evaluate renal function prior to initiation of Asacol and periodically while
• Adults: eructation, abdominal pain, constipation, dizziness, rhinitis, back
on therapy (2.1, 5.1)
pain, and rash
• Two Asacol 400 mg tablets are not interchangeable or substitutable with
• Pediatric Patients 5 to 17 years of age: nasopharyngitis, headache,
one mesalamine delayed-release 800 mg tablet (2.1)
abdominal pain, dizziness, sinusitis, rash, cough and diarrhea
Treatment of mildly to moderately active UC (2.2):
To report SUSPECTED ADVERSE REACTIONS, contact Warner
• Adults: 800 mg (two 400 mg tablets) three times daily for 6 weeks
Chilcott at 1-800-521-8813 or FDA at 1-800-FDA-1088 or
• Pediatric Patients 5 years or older: Total daily dosage is weight-based up to
www.fda.gov/medwatch
a maximum of 2.4 grams/day divided into two daily doses (see Table 1)
--------------------------DRUG INTERACTIONS--------------------------------
Maintenance of remission of mildly to moderately active UC (2.3)
• Nephrotoxic Agents including NSAIDs: Increased risk of nephrotoxicity;
• Adults: 1.6 grams (four 400 mg tablets) daily in two to four divided doses.
monitor for changes in renal function and mesalamine-related adverse
------------------------DOSAGE FORMS AND STRENGTHS------------------
reactions. (7.1)
Delayed-release tablets: 400 mg (3)
• Azathioprine or 6-Mercaptopurine: Increased risk of blood disorders;
monitor complete blood cell counts and platelet counts (7.2)
-------------------------------CONTRAINDICATIONS-----------------------------
Known or suspected hypersensitivity to salicylates or aminosalicylates or to
------------------------USE IN SPECIFIC POPULATIONS--------------------
any of the ingredients of Asacol tablets (4, 5.3)
• Pregnancy: Contains dibutyl phthalate; may cause fetal harm (8.1)
• Geriatric Patients: Increased risk of blood dyscrasias; monitor complete
blood cell counts and platelet counts (8.5)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 05/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
8
USE IN SPECIFIC POPULATIONS
1.1
Treatment of Mildly to Moderately Active Ulcerative Colitis
8.1
Pregnancy
1.2
Maintenance of Remission of Mildly to Moderately Active
8.2
Lactation
Ulcerative Colitis
8.4
Pediatric Use
2
DOSAGE AND ADMINISTRATION
8.5
Geriatric Use
2.1
Important Administration Instructions
8.6
Renal Impairment
2.2
Dosage for Treatment of Mildly to Moderately Active
10
OVERDOSAGE
Ulcerative Colitis
11
DESCRIPTION
2.3
Dosage for Maintenance of Remission of Mildly to
12
CLINICAL PHARMACOLOGY
Moderately Active Ulcerative Colitis
12.1
Mechanism of Action
3
DOSAGE FORMS AND STRENGTHS
12.3
Pharmacokinetics
4
CONTRAINDICATIONS
13
NONCLINICAL TOXICOLOGY
5
WARNINGS AND PRECAUTIONS
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
5.1
Renal Impairment
13.2
Animal Toxicology and/or Pharmacology
5.2
Mesalamine-Induced Acute Intolerance Syndrome
14
CLINICAL STUDIES
5.3
Hypersensitivity Reactions
14.1
Treatment of Mildly to Moderately Active Ulcerative Colitis
5.4
Hepatic Failure
14.2
Maintenance of Remission of Mildly to Moderately Active
6
ADVERSE REACTIONS
Ulcerative Colitis
6.1
Clinical Trials Experience
15
REFERENCES
6.2
Postmarketing Experience
16
HOW SUPPLIED/STORAGE AND HANDLING
7
DRUG INTERACTIONS
17
PATIENT COUNSELING INFORMATION
7.1
Nephrotoxic Agents, Including Non-Steroidal Anti-
Inflammatory Drugs
*Sections or subsections omitted from the full prescribing information are not
7.2
Azathioprine or 6-Mercaptopurine
listed.
1
Reference ID: 3766053
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 Treatment of Mildly to Moderately Active Ulcerative Colitis
Asacol® is indicated for the treatment of mildly to moderately active ulcerative colitis in patients 5 years
of age and older.
1.2 Maintenance of Remission of Mildly to Moderately Active
Ulcerative Colitis
Asacol is indicated for the maintenance of remission of mildly to moderately active ulcerative colitis in
adults.
2 DOSAGE AND ADMINISTRATION
2.1 Important Administration Instructions
• Two Asacol 400 mg tablets are not interchangeable or substitutable with one mesalamine
delayed-release 800 mg tablet.
• Evaluate renal function prior to initiation of Asacol
• Take Asacol tablets with or without food.
• Swallow Asacol tablets whole. Do not cut, break or chew the tablets.
• Intact, partially intact, and/or tablet shells have been reported in the stool; Instruct patients to
contact their physician if this occurs repeatedly.
• Protect Asacol tablets from moisture. Close the container tightly and to leave any desiccant
pouches present in the bottle along with the tablets.
2.2 Dosage for Treatment of Mildly to Moderately Active Ulcerative
Colitis
Adults
For adults, the recommended dosage of Asacol is 800 mg (two 400 mg tablets) three times daily (total
daily dosage of 2.4 grams) for a duration of 6 weeks.
Pediatrics
For pediatric patients 5 years of age and older, the recommended total daily dosage of Asacol is weight-
based (up to maximum of 2.4 grams/day) divided into two daily doses for a duration of 6 weeks (see
Table 1).
2
Reference ID: 3766053
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1. Pediatric Dosage by Weight
Weight Group
(kg)
Daily Dosage
(mg/kg/day)
Maximum
Daily Dosage
(grams/day)
Morning
Dosage
Afternoon
Dosage
17 to <33
36 to 71
1.2
two 400 mg
tablets
one 400 mg
tablet
33 to <54
37 to 61
2
three 400 mg
tablets
two 400 mg
tablets
54 to 90
27 to 44
2.4
three 400 mg
tablets
three 400 mg
tablets
2.3 Dosage for Maintenance of Remission of Mildly to Moderately
Active Ulcerative Colitis
For adults the recommended dosage of Asacol is 1.6 grams (four 400 mg tablets) daily in two to four
divided doses.
3 DOSAGE FORMS AND STRENGTHS
Asacol (mesalamine) Delayed-Release Tablets: 400 mg (red-brown, capsule-shaped and imprinted with
“0752 DR” in black).
4 CONTRAINDICATIONS
Asacol is contraindicated in patients with known or suspected hypersensitivity to salicylates or
aminosalicylates or to any of the ingredients of Asacol [see Warnings and Precautions (5.3), Adverse
Reactions (6.2), and Description (11)].
5 WARNINGS AND PRECAUTIONS
5.1 Renal Impairment
Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis, and
renal failure, has been reported in patients taking products such as Asacol that contain mesalamine or are
converted to mesalamine [see Adverse Reactions (6.2)].
Evaluate renal function prior to initiation of Asacol and periodically while on therapy.
Evaluate the risks and benefits of using Asacol in patients with known renal impairment or history of
renal disease or taking concomitant nephrotoxic drugs [see Drug Interactions (7.1), Use in Specific
Populations (8.6) and Nonclinical Toxicology (13.2)].
5.2 Mesalamine-Induced Acute Intolerance Syndrome
Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish
from an exacerbation of ulcerative colitis. Although the exact frequency of occurrence has not been
determined, it has occurred in 3% of controlled clinical trials of mesalamine or sulfasalazine.
3
Reference ID: 3766053
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Symptoms include cramping, abdominal pain, bloody diarrhea, and sometimes fever, headache, and rash.
Monitor patients for worsening of these symptoms while on treatment. If acute intolerance syndrome is
suspected, promptly discontinue treatment with Asacol.
5.3
Hypersensitivity Reactions
Hypersensitivity reactions have been reported in patients taking sulfasalazine. Some patients may have a
similar reaction to Asacol or to other compounds that contain or are converted to mesalamine.
As with sulfasalazine, mesalamine-induced hypersensitivity reactions may present as internal organ
involvement, including myocarditis, pericarditis, nephritis, hepatitis, pneumonitis, and hematologic
abnormalities. Evaluate patients immediately if signs or symptoms of a hypersensitivity reaction are
present. Discontinue Asacol if an alternative etiology for the signs or symptoms cannot be established.
5.4
Hepatic Failure
There have been reports of hepatic failure in patients with pre-existing liver disease who have been
administered mesalamine. Evaluate the risks and benefits of using Asacol in patients with known liver
impairment.
6 ADVERSE REACTIONS
The most serious adverse reactions seen in Asacol clinical trials or with other products that contain
mesalamine or are metabolized to mesalamine are:
• Renal Impairment [see Warnings and Precautions (5.1)]
• Mesalamine-Induced Acute Intolerance Syndrome [see Warnings and Precautions (5.2)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
• Hepatic Failure [see Warnings and Precautions (5.4)]
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 to rates in the clinical trials of another drug, and
may not reflect the rates observed in practice.
In total, Asacol tablets have been evaluated in 2,690 patients with ulcerative colitis in controlled and
open-label trials.
Clinical studies supporting Asacol use for the treatment of mildly to moderately active ulcerative colitis
included two 6-week, placebo-controlled, randomized, double-blind studies in adults with mildly to
moderately active ulcerative colitis (Studies 1 and 2), and one 6-week, randomized, double-blind, study
of 2 dosage levels in children with mildly to moderately active ulcerative colitis (Study 3). Clinical
studies supporting the use of Asacol tablets in the maintenance of remission of mildly to moderately
active ulcerative colitis included a 6-month, randomized, double-blind, placebo-controlled, multi-center
study (Study 4) and four active-controlled maintenance trials comparing Asacol tablets with
sulfasalazine. Asacol has been evaluated in 427 adults and 82 children with ulcerative colitis in these
controlled studies.
4
Reference ID: 3766053
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Treatment of Mildly to Moderately Active Ulcerative Colitis
Adults
In a 6-week placebo-controlled clinical study (Study 1) involving 105 patients, 53 of whom were
randomized to Asacol 2.4 grams/day [see Clinical Studies (14.1)], 4% of the Asacol-treated patients in
2.4 grams/day group discontinued therapy because of adverse reactions as compared to 0% of the
placebo-treated patients. The average age of patients was 41 years and 49% of patients were male.
Adverse reactions leading to withdrawal from Asacol included (each in one patient): diarrhea and colitis
flare; dizziness, nausea, joint pain, and headache.
The most common adverse reactions in patients treated with Asacol 2.4 grams/day in Study 1 are listed
in Table 2 below.
Table 2. Most Common Adverse Reactions Reported in Study 1 for the Treatment of
Mildly to Moderately Active Ulcerative Colitis in Adults*
Adverse Reaction
% of Patients with Adverse Reactions
Asacol 2.4 grams/day
Placebo
(n = 53)
(n = 52)
Eructation
26
19
Abdominal pain
21
12
Constipation
11
0
Dizziness
9
8
Rhinitis
8
6
Back pain
6
4
Rash
6
4
Dyspepsia
4
0
Flu syndrome
4
2
* At Least 2% of Patients in the Asacol Group and at a Rate Greater than Placebo
Pediatric Patients 5 to 17 Years Old
A randomized, double-blind, 6-week study of 2 dosage levels of Asacol (Study 3) was conducted in 82
pediatric patients 5 to 17 years of age with mildly to moderately active ulcerative colitis. All patients
were divided by body weight category (17 to less than 33 kg, 33 to less than 54 kg, and 54 to 90 kg) and
randomly assigned to receive a low dosage (1.2, 2, and 2.4 grams/day for the respective body weight
category) or a high dosage (2, 3.6, and 4.8 grams/day).
The high dosage regimen is not recommended because it was not found to be more effective than the
recommended low dosage regimen [see Dosage and Administration (2.1) and Clinical Studies (14.1)].
Duration of exposure to Asacol among the 82 patients in the study ranged from 12 to 50 days (mean of
40 days in each dosage group). The majority (88%) of patients in each group were treated for more than
5 weeks. Table 3 provides a summary of the specific reported adverse reactions.
5
Reference ID: 3766053
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3. Adverse Reactions ≥ 5% Reported in Study 3 for the Treatment of Mildly to
Moderately Active Ulcerative Colitis in Pediatric Patients*
Adverse Reaction
% of Patients with Adverse Reactions
Asacol Low Dosage
Asacol High Dosage
(n=41)
(n=41)
Nasopharyngitis
15
12
Headache
10
5
Abdominal pain
10
2
Dizziness
7
2
Sinusitis
7
0
Rash
5
5
Cough
5
0
Diarrhea
5
0
Fatigue
2
10
Pyrexia
0
7
Increased Lipase
0
5
Low Dosage = Asacol 1.2 to 2.4 grams/day; High Dosage = Asacol 2.0 to 4.8 grams/day. Dosage was dependent on body
weight.
Adverse Reactions reported at the 1-week telephone follow-up visit are included.
* At Least 5% of Patients in the low dosage or high dosage group
Twelve percent of the patients in the low dosage group (5 patients) and 2% of the patients in the high
dosage group (1 patient) had serious adverse reactions. The serious adverse reactions consisted of
sinusitis, adenovirus infection, and pancreatitis in one patient each in the low dosage group. Abdominal
pain and decreased body mass index occurred in one patient and bloody diarrhea and sclerosing
cholangitis also occurred in one patient in the low dosage group. Anemia and syncope occurred in one
patient in the high dosage group.
Five patients were withdrawn from the study due to adverse reactions: 3 (7%) in the low dosage group (1
patient each with adenovirus infection, sclerosing cholangitis, and pancreatitis) and 2 patients (5%) in the
high dosage group (1 patient with increased amylase and increased lipase, and 1 patient with upper
abdominal pain).
In general, the nature and severity of reactions in the pediatric population was similar to those reported in
adult populations of patients with ulcerative colitis.
Maintenance of Remission of Mildly to Moderately Active Ulcerative Colitis
Clinical studies supporting the use of Asacol tablets in the maintenance of remission of mildly to
moderately active ulcerative colitis in adults included a randomized, double-blind, multi-center, placebo-
controlled clinical trial of 6 months’ duration in 264 patients (Study 4 [see Clinical Studies (14.2)].
In Study 4, a randomized, double-blind, multi-center, placebo-controlled clinical trial of 6 months’
duration, 87 patients were randomized to receive Asacol 1.6 grams/day compared to 87 patients
randomized to placebo. The average age of patients in Study 4 was 42 years and 55 % of patients were
male. Adverse reactions leading to study withdrawal in patients using Asacol included (each in one
patient): anxiety, stomatitis and asthenia.
6
Reference ID: 3766053
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In addition to the adverse reactions listed in Table 2, the following occurred at a frequency of 2% or
greater in patients who received Asacol in Study 4: abdominal enlargement, gastroenteritis,
gastrointestinal hemorrhage, infection, joint disorder, nervousness, paresthesia, hemorrhoids, tenesmus,
urinary frequency, and vision abnormalities.
6.2
Postmarketing Experience
In addition to the adverse reactions reported above in clinical trials involving Asacol, the adverse
reactions listed below have been identified during post-approval use of Asacol and other mesalamine
containing products. 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 as a Whole: Neck pain, facial edema, edema, lupus-like syndrome, drug fever.
Cardiovascular: Pericarditis, myocarditis [see Warnings and Precautions (5.3)].
Gastrointestinal: Anorexia, pancreatitis, gastritis, increased appetite, cholecystitis, dry mouth, oral
ulcers, perforated peptic ulcer, bloody diarrhea.
Hematologic: Agranulocytosis aplastic anemia, thrombocytopenia, eosinophilia, leukopenia, anemia,
lymphadenopathy.
Musculoskeletal: Gout.
Nervous: Depression, somnolence, emotional lability, hyperesthesia, vertigo, confusion, tremor,
peripheral neuropathy, transverse myelitis, Guillain-Barré syndrome.
Renal: Renal failure, interstitial nephritis, minimal change nephropathy [see Warnings and Precautions
(5.1)].
Respiratory/Pulmonary: Eosinophilic pneumonia, interstitial pneumonitis, asthma exacerbation,
pleuritis.
Skin: Alopecia, psoriasis, pyoderma gangrenosus, dry skin, erythema nodosum, urticaria.
Special Senses: Eye pain, taste perversion, blurred vision, tinnitus.
Urogenital: Dysuria, urinary urgency, hematuria, epididymitis, menorrhagia, reversible oligospermia.
Laboratory Abnormalities: Elevated AST (SGOT) or ALT (SGPT), elevated alkaline phosphatase,
elevated GGT, elevated LDH, elevated bilirubin, elevated serum creatinine and BUN.
7
Reference ID: 3766053
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7 DRUG INTERACTIONS
7.1 Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory
Drugs
The concurrent use of mesalamine with known nephrotoxic agents, including nonsteroidal anti-
inflammatory drugs (NSAIDs) may increase the risk of nephrotoxicity. Monitor patients taking
nephrotoxic drugs for changes in renal function and mesalamine-related adverse reactions [see Warnings
and Precautions (5.1)].
7.2 Azathioprine or 6-Mercaptopurine
The concurrent use of mesalamine with azathioprine or 6-mercaptopurine may increase the risk for blood
disorders. If concomitant use of Asacol and azathioprine or 6-mercaptopurine cannot be avoided,
monitor blood tests, including complete blood cell counts and platelet counts.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Limited published data on mesalamine use in pregnant women are insufficient to inform a drug-
associated risk. No fetal harm was observed in animal reproduction studies of mesalamine in rats and
rabbits at oral doses approximately 1.9 times (rat) and 3.9 times (rabbit) the recommended human dose
[see Data]. However, dibutyl phthalate (DBP) is an inactive ingredient in Asacol’s enteric coating, and
in animal studies in rats at doses greater than 190 times the human dose, maternal DBP was associated
with external and skeletal malformations and adverse effects on the reproductive system of male
offspring. Advise pregnant women of the potential risk to the fetus.
The estimated background risk of major birth defects and miscarriage for the indicated populations is
unknown. In the U.S. general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
Reproduction studies with mesalamine were performed during organogenesis in rats and rabbits at oral
doses up to 480 mg/kg/day. There was no evidence of impaired fertility or harm to the fetus. These
mesalamine doses were about 1.9 times (rat) and 3.9 times (rabbit) the recommended human dose, based
on body surface area.
DBP is an inactive ingredient in Asacol’s enteric coating. The human daily intake of DBP from the
maximum recommended dose of Asacol tablets is about 21 mg. Published reports in rats show that male
rat offspring exposed in utero to DBP (greater than or equal to 100 mg/kg/day, approximately 39 times
the human dose based on body surface area), display reproductive system aberrations compatible with
disruption of androgenic dependent development. The clinical significance of this finding in rats is
unknown. At higher dosages (greater than or equal to 500 mg/kg/day, approximately 194 times the
human dose based on body surface area), additional effects, including cryptorchidism, hypospadias,
atrophy or agenesis of sex accessory organs, testicular injury, reduced daily sperm production, permanent
retention of nipples, and decreased anogenital distance are noted. Female offspring are unaffected. High
8
Reference ID: 3766053
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
doses of DBP, administered to pregnant rats was associated with increased incidences of developmental
abnormalities, such as cleft palate (greater than or equal to 630 mg/kg/day, about 244 times the human
dose, based on body surface area) and skeletal abnormalities (greater than or equal to 750 mg/kg/day,
about 290 times the human dose based on body surface area) in the offspring.
8.2
Lactation
Risk Summary
Mesalamine and its N-acetyl metabolite are present in human milk in undetectable to small amounts [see
Data]. There are limited reports of diarrhea in breastfed infants. There is no information on the effects
of the drug on milk production. Additionally, DBP, an inactive ingredient in the enteric coating of
Asacol tablets, and its primary metabolite mono-butyl phthalate (MBP) are present in human milk, but
the clinical significance is unknown. The developmental and health benefits of breastfeeding should be
considered along with the mother’s clinical need for Asacol and any potential adverse effects on the
breastfed infant from the drug or from the underlying maternal condition.
Clinical Considerations
Monitor breastfed infants for diarrhea.
Data
Human Data
In published lactation studies, maternal mesalamine doses from various oral and rectal formulations and
products ranged from 500 mg to 3 g daily. The concentration of mesalamine in milk ranged from non-
detectable to 0.11 mg/L. The concentration of the N-acetyl-5-aminosalicylic acid metabolite ranged from
5 to 18.1 mg/L. Based on these concentrations, estimated infant daily dosages for an exclusively
breastfed infant are 0 to 0.017 mg/kg/day of mesalamine and 0.75 to 2.72 mg/kg/day of N-acetyl-5
aminosalicylic acid.
8.4
Pediatric Use
The safety and effectiveness of Asacol in pediatric patients 5 to 17 years of age for treatment of mildly to
moderately active ulcerative colitis have been established over a 6-week period. Use of Asacol in these
age groups is supported by evidence from adequate and well controlled studies of Asacol in adults and a
single study in 82 pediatric patients 5 to 17 years of age [see Adverse Reactions (6.1), Clinical
Pharmacology (12.3), and Clinical Studies (14.1)].
The safety and effectiveness of Asacol for the maintenance of remission of mildly to moderately active
ulcerative colitis in pediatric patients have not been established. Efficacy was not demonstrated in a
randomized, double-blind 26-week trial of two dosage levels for maintenance of remission of mildly to
moderately active ulcerative colitis initiated in 39 patients aged 5 to 17 years. Possible factors
contributing to this outcome included the dose range studied and premature termination of the trial.
8.5
Geriatric Use
Clinical studies of Asacol did not include sufficient numbers of patients aged 65 and over to determine
whether they respond differently than younger patients. Reports from uncontrolled clinical studies and
postmarketing experience suggest a higher incidence of blood dyscrasias (agranulocytosis, neutropenia,
pancytopenia) in patients receiving Asacol who are 65 years or older compared to younger patients.
Monitor complete blood cell counts and platelet counts in elderly patients during treatment with Asacol.
9
Reference ID: 3766053
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or other drug therapy in elderly patients should be considered when prescribing Asacol [see Use
in Specific Populations (8.6)].
8.6
Renal Impairment
Mesalamine is known to be substantially excreted by the kidney, and the risk of adverse reactions may be
greater in patients with impaired renal function. Evaluate renal function in all patients prior to initiation
and periodically while on Asacol therapy. Monitor patients with known renal impairment or history of
renal disease or taking nephrotoxic drugs for decreased renal function and mesalamine-related adverse
reactions [see Warnings and Precautions (5.1), Drug Interactions (7.1) and Adverse Reactions (6.2)].
10 OVERDOSAGE
There is no specific antidote for mesalamine overdose and treatment for suspected acute severe toxicity
with Asacol should be symptomatic and supportive. This may include prevention of further
gastrointestinal tract absorption, correction of fluid electrolyte imbalance, and maintenance of adequate
renal function. Asacol is a pH dependent delayed-release product and this factor should be considered
when treating a suspected overdose.
11 DESCRIPTION
Each Asacol (mesalamine) delayed-release tablet for oral administration contains 400 mg of mesalamine,
an aminosalicylate. Asacol (mesalamine) Delayed-Release Tablets contain acrylic based resin, Eudragit
S (methacrylic acid and methyl methancrylate copolymer), which dissolves at pH 7 or greater and
releases mesalamine in the terminal ileum and beyond for topical anti-inflammatory action in the colon.
Mesalamine (also referred to as 5-aminosalicylic acid or 5-ASA) has the chemical name 5-amino-2
hydroxybenzoic acid. Its structural formula is: structural formula
Inactive Ingredients: Each tablet contains colloidal silicon dioxide, dibutyl phthalate, edible black ink,
ferric oxide red, ferric oxide yellow, lactose monohydrate, magnesium stearate, methacrylic acid and
methyl methancrylate copolymer (Eudragit S), polyethylene glycol, povidone, sodium starch glycolate,
and talc.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism of action of mesalamine is unknown, but appears to be topical rather than systemic.
Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways, that is,
prostanoids, and through the lipoxygenase pathways, that is, leukotrienes and hydroxyeicosatetraenoic
acids, is increased in patients with chronic ulcerative colitis, and it is possible that mesalamine
10
Reference ID: 3766053
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the
colon.
12.3 Pharmacokinetics
Absorption
Approximately 28% of mesalamine in Asacol tablets is absorbed after oral ingestion. Absorption of
mesalamine is similar in fasted and fed subjects. The Tmax for mesalamine and its metabolite, is usually
delayed, reflecting the delayed-release, and ranges from 4 to 16 hours.
Elimination
Metabolism
The absorbed mesalamine is rapidly acetylated in the gut mucosal wall and by the liver to N-acetyl-5
aminosalicylic acid.
Excretion
Absorbed mesalamine is excreted mainly by the kidney as N-acetyl-5-aminosalicylic acid. Unabsorbed
mesalamine is excreted in feces.
After intravenous administration, the elimination half-life of mesalamine is reported to be approximately
40 minutes. After oral dosing, the terminal t1/2 values for mesalamine and N-acetyl-5-aminosalicylic
acid are usually about 12 hours, but are variable, ranging from 2 to 15 hours. There is a large inter-
subject and intra-subject variability in the plasma concentrations of mesalamine and N-acetyl-5
aminosalicylic acid and in their elimination half-lives following administration of Asacol.
Specific Populations
Pediatric Patients
In a dose-ranging pharmacokinetic study evaluating 30, 60 and 90 mg/kg/day doses of Asacol
administered twice daily for four weeks, the mean average concentration (Cavg) values of mesalamine in
pediatric ulcerative colitis patients ranged from approximately 400 ng/mL to 2100 ng/mL based on data
from all dose levels.
In a study in pediatric ulcerative colitis patients (Study 3), mean plasma concentrations of mesalamine
(based on sparse sampling) were 820 to 988 ng/mL at the low dosage level (that is, 1.2, 2 or 2.4
grams/day based on body weight strata of 17 to less than 33 kg, 33 to less than 54 kg, and 54 to 90 kg,
respectively).
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Mesalamine was not carcinogenic at dietary dosages of up to 480 mg/kg/day in rats and 2000 mg/kg/day
in mice, which are about 2.9 and 6.1 times of the maximum recommended maintenance dosage of
Asacol of 1.6 grams/day or 26.7 mg/kg/day, based on 60 kg body weight, respectively, based on body
surface area.
Mutagenesis
11
Reference ID: 3766053
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Mesalamine was negative in the Ames assay for mutagenesis, negative for induction of sister chromatid
exchanges (SCE) and chromosomal aberrations in Chinese hamster ovary cells in vitro, and negative for
induction of micronuclei (MN) in mouse bone marrow polychromatic erythrocytes.
Impairment of Fertility
Mesalamine, at oral dosages up to 480 mg/kg/day (about 1.9 times the recommended human treatment
dosage on a body surface area basis), was found to have no effect on fertility or reproductive
performance of male and female rats.
13.2 Animal Toxicology and/or Pharmacology
In animal studies (rats, mice, dogs), the kidney was the principal organ for toxicity. (In the following,
comparisons of animal dosing to recommended human dosing are based on body surface area and a
2.4 grams/day dose for a 60 kg person.)
Mesalamine causes renal papillary necrosis in rats at single doses of approximately 750 mg/kg to
1000 mg/kg (approximately 3 to 4 times the recommended human dose based on body surface area).
Doses of 170 and 360 mg/kg/day (about 0.7 and 1.5 times the recommended human dose based on
body surface area) given to rats for six months produced papillary necrosis, papillary edema, tubular
degeneration, tubular mineralization, and urothelial hyperplasia.
In mice, oral doses of 4000 mg/kg/day mesalamine (approximately 8 times the recommended human
dose based on body surface area) for three months produced tubular nephrosis, multifocal/diffuse
tubulo-interstitial inflammation, and multifocal/diffuse papillary necrosis.
In dogs, single doses of 6000 mg (approximately 8 times the recommended human dose based on body
surface area) of delayed-release mesalamine tablets resulted in renal papillary necrosis but were not fatal.
Renal changes have occurred in dogs given chronic administration of mesalamine at doses of 80
mg/kg/day (1.1 times the recommended human dose based on body surface area).
14 CLINICAL STUDIES
14.1 Treatment of Mildly to Moderately Active Ulcerative Colitis
Adults
Two placebo-controlled studies (Studies 1 and 2) have demonstrated the efficacy of Asacol in patients
with mildly to moderately active ulcerative colitis.
In one randomized, double-blind, multi-center, placebo-controlled clinical trial of 6 weeks’ duration in
158 patients (Study 1), patients received Asacol dosages of 1.6 grams/day (800 mg twice a day; n=53)
and 2.4 grams/day (800 mg three times a day; n=53), compared to placebo (n=52). The scoring system
for determination of treatment efficacy included assessment of stool frequency, rectal bleeding,
sigmoidoscopic findings, patient’s functional assessment, and physician global assessment. At the dosage
of 2.4 grams/day, 21 of 43 (49%) patients using Asacol showed an improvement in sigmoidoscopic
appearance of the bowel compared to 12 of 44 (27%) patients using placebo (p = 0.048). In addition,
significantly more patients in the Asacol 2.4 grams/day group showed improvement in rectal bleeding
and stool frequency. The 1.6 grams/day dosage regimen is not recommended because it did not produce
consistent evidence of effectiveness [see Dosage and Administration (2.2)].
12
Reference ID: 3766053
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In a second randomized, double-blind, placebo-controlled clinical trial of 6 weeks’ duration in 87
patients (Study 2), patients received Asacol dosages of 1.6 grams/day (400 mg four times a day; n=11)
and 4.8 grams/day (1.2 g four times a day; n=38), compared to placebo four times a day (n=38). Asacol
4.8 grams/day for 6 weeks resulted in sigmoidoscopic improvement in 28 of 38 (74 %) patients
compared to 10 of 38 (26 %) placebo patients (p less than 0.001). Also, more patients in the Asacol 4.8
grams/day group than the placebo group showed improvement in overall symptoms. The 4.8 grams/day
dosage regimen is not recommended because greater efficacy was not demonstrated with this dosage
compared to the 2.4 grams/day dosage [see Dosage and Administration (2.2).
Pediatrics
The safety and effectiveness of Asacol in pediatric patients 5 to 17 years of age for treatment of mildly to
moderately active ulcerative colitis are supported by evidence from adequate and well controlled studies
of Asacol in adults and a single study in pediatric patients.
A randomized, double-blind, 6-week study of two dosage levels of Asacol (Study 3) was conducted in 82
pediatric patients 5 to 17 years of age with mildly or moderately active ulcerative colitis defined as a
score of 10 to 55 on the Pediatric Ulcerative Colitis Activity Index (PUCAI) (which includes assessment
of abdominal pain, rectal bleeding, stool consistency, number of stools per 24 hours, presence of
nocturnal bowel movement and activity level, and has a total maximum score of 85; each of the
subscales are scored from 0 to 10 except rectal bleeding which is scored from 0 to 30, and number of
stools per 24 hours which is scored from 0 to 15) and rectal bleeding and stool frequency Mayo subscale
scores of ≥1 (each of these subscales are scored from zero (normal) to three (most severe)).1,2
All patients were divided by weight category (17 to less than 33 kg, 33 to less than 54 kg, and 54 to 90
kg) and randomly assigned to receive a low dosage (1.2, 2, and 2.4 grams/day for the respective weight
category) or a high dosage (2, 3.6, and 4.8 grams/day). Doses were administered every 12 hours.
The proportion of patients who achieved success based on the Truncated Mayo Score (TM-Mayo) (based
on the stool frequency and rectal bleeding subscales of the Mayo Score) and based on the PUCAI was
measured after 6 weeks of treatment. Success based on TM-Mayo was defined as either partial response
(improvement from baseline in stool frequency or rectal bleeding subscores with no worsening in the
other) or complete response (both stool frequency and rectal bleeding subscores equal 0). Success based
on PUCAI was defined as either partial response (PUCAI reduction of greater than or equal to 20 points
from Baseline to Week 6 with Week 6 score greater than or equal to 10) or complete response (PUCAI
less than 10 at Week 6).
There were 41 patients in the low dosage group and 41 patients in the high dosage group who received at
least one dose of Asacol; 36 patients in each dosage group completed the study. Patients were considered
treatment failures if they did not achieve success or dropped out due to adverse reaction or lack of
efficacy.
At Week 6, 73% of the patients in the low dosage group, and 70% of the patients in the high dosage
group achieved success based on the TM-Mayo; 34% of the patients in the low dosage group and 43% of
the patients in the high dosage group achieved complete response. At Week 6, 56% of the patients in the
low dosage group, and 55% of the patients in the high dosage group achieved success based on the
PUCAI; 46% of the patients in the low dosage group and 43% of the patients in the high dosage group
achieved complete response.
The high dosage regimen is not recommended because it was not more effective than the low dosage
regimen [see Dosage and Administration (2.2)].
13
Reference ID: 3766053
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14.2 Maintenance of Remission of Mildly to Moderately Active
Ulcerative Colitis
Adults
In a randomized, double-blind, multi-center, placebo-controlled clinical trial of 6 months’ duration in
264 patients (Study 4), patients received Asacol dosages of 0.8 grams/day (400 mg twice a day; n = 90)
and 1.6 grams/day (400 mg four times a day; n = 87), compared to placebo four times a day (n = 87). The
proportion of patients treated with 0.8 grams/day who maintained endoscopic remission was not
statistically significant compared to placebo; the 0.8 grams/day dosage regimen is not recommended [see
Dosage and Administration (2.2)]. The number of patients using Asacol 1.6 grams/day who maintained
endoscopic remission of ulcerative colitis was 61 of 87 (70%) compared with 42 of 87 (48%) of placebo
patients (p = 0.005).
A pooled efficacy analysis of 4 maintenance trials compared Asacol at dosages of 0.8 to 2.8 grams/day,
in divided doses ranging from twice daily to four times per day, with sulfasalazine, at dosages of 2 to 4
grams/day. Treatment success was seen in 59 of 98 (59%) patients using Asacol and 70 of 102 (69%)
patients using sulfasalazine, a non-significant difference.
15 REFERENCES
1. Turner D, Otley AR, Mack D, et al. Development, validation, and evaluation of a pediatric ulcerative
colitis activity index: A prospective multicenter study. Gastroenterology. 2007;133:423–432.
2. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to
moderately active ulcerative colitis. N Engl J Med. 1987;317(26):1625-9.
16 HOW SUPPLIED/STORAGE AND HANDLING
Asacol Delayed-Release Tablets: 400 mg (red-brown, capsule-shaped tablets containing 400 mg
mesalamine and imprinted with “0752 DR” in black.
NDC 0430-0752-27
Bottle of 180 tablets
Store at 20° to 25° C (68° to 77° F); excursions permitted 15° to 30° C (59° to 86° F) [See USP
Controlled Room Temperature].
17 PATIENT COUNSELING INFORMATION
Administration
• Inform patients that if they are switching from a previous oral mesalamine therapy to Asacol to
discontinue their previous oral mesalamine therapy and follow the dosing instructions for Asacol.
Inform patients that two Asacol 400 mg tablets cannot be substituted for one Asacol HD 800 mg
tablet.
• Inform patients that Asacol tablets can be taken with or without food.
• Instruct patients to swallow the Asacol tablets whole, taking care not to break, cut, or chew the
tablets, because the coating is an important part of the delayed-release formulation.
14
Reference ID: 3766053
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Inform patients that intact, partially intact, and/or tablet shells have been reported in the stool.
Instruct patients to contact their physician if this occurs repeatedly.
• Instruct patients to protect Asacol tablets from moisture. Instruct patients to close the container
tightly and to leave any desiccant pouches present in the bottle along with the tablets.
Renal Impairment
• Inform patients that Asacol may decrease their renal function, especially if they have known
renal impairment or are taking nephrotoxic drugs, and periodic monitoring of renal function will
be performed while they are on therapy. Advise patients to complete all blood tests ordered by
their physician.
Mesalamine-Induced Acute Intolerance Syndrome
• Instruct patients to report to their physician if they experience new or worsening symptoms of
cramping, abdominal pain, bloody diarrhea, and sometimes fever, headache, and rash.
Hypersensitivity Reactions
• Inform patients of the signs and symptoms of hypersensitivity reactions, and advise them seek
immediate medical care should signs and symptoms occur.
Pregnant Women/Nursing Mothers
• Advise women who are pregnant, breastfeeding, or of childbearing potential that Asacol contains
dibutyl phthalate, which was associated with malformations and adverse effects on the male
reproductive system in animal studies. Dibutyl phthalate is excreted in human milk.
Hepatic Failure
• Inform patients with known liver disease of the signs and symptoms of worsening liver function
and advise them to report to their physician if they experience such signs or symptoms.
Blood Disorders
• Inform elderly patients and those taking azathioprine or 6-mercaptopurine of the risk for blood
disorders and the need for periodic monitoring of complete blood cell counts and platelet counts
while on therapy. Advise patients to complete all blood tests ordered by their physician.
Manufactured by:
Warner Chilcott Deutschland GmbH
D-64331 Weiterstadt
Germany
Marketed by:
Warner Chilcott (US), LLC
Rockaway, NJ 07866
Under license from Medeva Pharma Suisse AG (registered trademark owner). company logo
15
Reference ID: 3766053
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:37.830400
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019651s025lbl.pdf', 'application_number': 19651, 'submission_type': 'SUPPL ', 'submission_number': 25}
|
11,601
|
NDA 19-653/S-037
NDA 19-697/S-034
Package Insert
Page 1
PHYSICIANS' PACKAGE INSERT
ORTHO TRI-CYCLEN® TABLETS
ORTHO-CYCLEN® TABLETS
(norgestimate/ethinyl estradiol)
Patients should be counseled that this product does not protect against HIV infection (AIDS) and
other sexually transmitted diseases.
DESCRIPTION
Each of the following products is a combination oral contraceptive containing the progestational
compound norgestimate and the estrogenic compound ethinyl estradiol.
ORTHO TRI-CYCLEN® Tablets.
Each white tablet contains 0.180 mg of the progestational compound, norgestimate (18,19-Dinor-17-
pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-, oxime,(17α)-(+)-) and 0.035 mg of the estrogenic
compound, ethinyl estradiol (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients
include lactose, magnesium stearate, and pregelatinized corn starch.
Each light blue tablet contains 0.215 mg of the progestational compound norgestimate (18,19-Dinor-
17-pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-,oxime,(17α)-(+)-) and 0.035 mg of the estrogenic
compound, ethinyl estradiol (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients
include FD & C Blue No. 2 Aluminum Lake, lactose, magnesium stearate, and pregelatinized corn
starch.
Each blue tablet contains 0.250 mg of the progestational compound norgestimate (18,19-Dinor-17-
pregn-4-en-20-yn-3-one, 17-(acetyloxy)-13-ethyl-,oxime,(17α)-(+)-) and 0.035 mg of the estrogenic
compound, ethinyl estradiol (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients
include FD & C Blue No. 2 Aluminum Lake, lactose, magnesium stearate, and pregelatinized corn
starch.
Each green tablet contains only inert ingredients, as follows: D & C Yellow No. 10 Aluminum Lake,
FD & C Blue No. 2 Aluminum Lake, lactose, magnesium stearate, microcrystalline cellulose and
pregelatinized corn starch.
ORTHO-CYCLEN® Tablets.
Each blue tablet contains 0.250 mg of the progestational compound norgestimate (18,19-Dinor-17-
pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-,oxime,(17α)-(+)-) and 0.035 mg of the estrogenic
compound, ethinyl estradiol (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 2
include FD & C Blue No. 2 Aluminum Lake, lactose, magnesium stearate, and pregelatinized corn
starch.
Each green tablet contains only inert ingredients, as follows: D & C Yellow No. 10 Aluminum Lake,
FD & C Blue No. 2 Aluminum Lake, lactose, magnesium stearate, microcrystalline cellulose and
pregelatinized corn starch.
CLINICAL PHARMACOLOGY
Oral Contraception
Combination oral contraceptives act by suppression of gonadotropins. Although the primary
mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical
mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which
reduce the likelihood of implantation).
Receptor binding studies, as well as studies in animals and humans, have shown that norgestimate and
17-deacetyl norgestimate, the major serum metabolite, combine high progestational activity with
minimal intrinsic androgenicity (90-93). Norgestimate, in combination with ethinyl estradiol, does not
counteract the estrogen-induced increases in sex hormone binding globulin (SHBG), resulting in lower
serum testosterone (90,91,94).
Acne
Acne is a skin condition with a multifactorial etiology, including androgen stimulation of sebum
production. While the combination of ethinyl estradiol and norgestimate increases sex hormone
binding globulin (SHBG) and decreases free testosterone, the relationship between these changes and a
decrease in the severity of facial acne in otherwise healthy women with this skin condition has not
been established.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 3
PHARMACOKINETICS
Absorption
Norgestimate (NGM) and ethinyl estradiol (EE) are rapidly absorbed following oral administration.
Norgestimate is rapidly and completely metabolized by firstpass (intestinal and/or hepatic)
mechanisms to norelgestromin (NGMN) and norgestrel (NG), which are the major active metabolites
of norgestimate.
Peak serum concentrations of NGMN and EE are generally reached by 2 hours after administration of
ORTHO-CYCLEN® or ORTHO TRI-CYCLEN®. Accumulation following multiple dosing of the 250
μg NGM / 35 μg dose is approximately 2-fold for NGMN and EE compared with single dose
administration. The pharmacokinetics of NGMN is dose proportional following NGM doses of 180 μg
to 250 μg. Steady-state concentration of EE is achieved by Day 7 of each dosing cycle. Steady-state
concentrations of NGMN and NG are achieved by Day 21. Non-linear accumulation (approximately 8
fold) of norgestrel is observed as a result of high affinity binding to SHBG (sex hormone-binding
globulin), which limits its biological activity.
Table 1. Summary of norelgestromin, norgestrel and ethinyl estradiol pharmacokinetic parameters.
Mean (SD) Pharmacokinetic Parameters of ORTHO TRI-CYCLEN During
a Three Cycle Study
Analyte
Cycle Day
Cmax
tmax (h)
AUC0-24h
t1/2 (h)
NGMN
3
7
1.80 (0.46)
1.42 (0.73)
15.0
(3.88)
NC
14
2.12 (0.56)
1.21 (0.26)
16.1
(4.97)
NC
21
2.66 (0.47)
1.29 (0.26)
21.4
(3.46)
22.3
(6.54)
NG
3
7
1.94 (0.82)
3.15 (4.05)
34.8
(16.5)
NC
14
3.00 (1.04)
2.21 (2.03)
55.2
(23.5)
NC
21
3.66 (1.15)
2.58 (2.97)
69.3
(23.8)
40.2
(15.4)
EE
3
7
124 (39.5)
1.27 (0.26)
1130
(420)
NC
14
128 (38.4)
1.32 (0.25)
1130
(324)
NC
21
126 (34.7)
1.31 (0.56)
1090
(359)
15.9
(4.39)
Mean (SD) Pharmacokinetic Parameters of ORTHO-CYCLEN During a
Three Cycle Study
Analyte
Cycle Day
Cmax
tmax (h)
AUC0-24h
t1/2 (h)
NGMN
1
1
1.78
(0.397)
1.19
(0.250)
9.90
(3.25)
18.4
(5.91)
3
21
2.19
(0.655)
1.43
(0.680)
18.1
(5.53)
24.9
(9.04)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 4
NG
1
1
0.649
(0.49)
1.42 (0.69)
6.22
(2.46)
37.8
(14.0)
3
21
2.65 (1.11)
1.67 (1.32)
48.2
(20.5)
45.0
(20.4)
EE
1
1
92.2 (24.5)
1.2 (0.26)
629 (138) 10.1
(1.90)
3
21
147 (41.5)
1.13 (0.23)
1210
(294)
15.0
(2.36)
Cmax = peak serum concentration, tmax = time to reach peak serum concentration,
AUC0-24h = area under serum concentration vs time curve from 0 to 24 hours, t1/2
= elimination half-life, NC = not calculated.
NGMN and NG: Cmax = ng/mL, AUC0-24h=h•ng/mL
EE: Cmax=pg/mL, AUC0-24h=h•pg/mL
The effect of food on the pharmacokinetics of ORTHO-CYCLEN or ORTHO TRI-CYCLEN has not
been studied.
Distribution
Norelgestromin and norgestrel are highly bound (>97%) to serum proteins. Norelgestromin is bound to
albumin and not to SHBG, while norgestrel is bound primarily to SHBG. Ethinyl estradiol is
extensively bound (> 97%) to serum albumin and induces an increase in the serum concentrations of
SHBG.
Metabolism
Norgestimate is extensively metabolized by first-pass mechanisms in the gastrointestinal tract and/or
liver. Norgestimate’s primary active metabolite is norelgestromin. Subsequent hepatic metabolism of
norelgestromin occurs and metabolites include norgestrel, which is also active and various
hydroxylated and conjugated metabolites. Ethinyl estradiol is also metabolized to various hydroxylated
products and their glucuronide and sulfate conjugates.
Excretion
The metabolites of norelgestromin and ethinyl estradiol are eliminated by renal and fecal pathways.
Following administration of 14C-norgestimate, 47% (45-49%) and 37% (16-49%) of the administered
radioactivity was eliminated in the urine and feces, respectively. Unchanged norgestimate was not
detected in the urine. In addition to 17-deacetyl norgestimate, a number of metabolites of norgestimate
have been identified in human urine following administration of radiolabeled norgestimate. These
include 18, 19-Dinor-17-pregn-4-en-20-yn-3-one,17-hydroxy-13-ethyl,(17 )-(-);18,19-Dinor-5 -17-
pregnan-20-yn,3 ,17-dihydroxy-13-ethyl,(17 ), various hydroxylated metabolites and conjugates of
these metabolites.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 5
Special Populations
The effects of body weight, body surface area or age on the pharmacokinetics of ORTHO-CYCLEN®
or ORTHO TRI-CYCLEN® have not been studied.
Hepatic Impairment
The effects of hepatic impairment on the pharmacokinetics of
ORTHO-CYCLEN® or ORTHO TRI-CYCLEN® have not been studied. However, steroid hormones
may be poorly metabolized in women with impaired liver function (see PRECAUTIONS).
Renal Impairment
The effects of renal impairment on the pharmacokinetics of ORTHO-CYCLEN® or ORTHO TRI-
CYCLEN® have not been studied.
Drug-Drug Interactions
No formal drug-drug interaction studies were conducted with ORTHO-CYCLEN® or ORTHO TRI-
CYCLEN®. Interactions between contraceptive steroids and other drugs have been reported in the
literature (see PRECAUTIONS).
Although norelgestromin and its metabolites inhibit a variety of P450 enzymes in human liver
microsomes, under the recommended dosing regimen, the in vivo concentrations of norelgestromin and
its metabolites, even at the peak serum levels, are relatively low compared to the inhibitory constant
(Ki).
INDICATIONS AND USAGE
ORTHO-CYCLEN® and ORTHO TRI-CYCLEN® Tablets are indicated for the prevention of
pregnancy in women who elect to use oral contraceptives as a method of contraception.
ORTHO TRI-CYCLEN is indicated for the treatment of moderate acne vulgaris in females at least
15 years of age, who have no known contraindications to oral contraceptive therapy and have achieved
menarche. ORTHO TRI-CYCLEN should be used for the treatment of acne only if the patient desires
an oral contraceptive for birth control.
Oral contraceptives are highly effective for pregnancy prevention. Table II lists the typical accidental
pregnancy rates for users of combination oral contraceptives and other methods of contraception. The
efficacy of these contraceptive methods, except sterilization, the IUD, and the Norplant System,
depends upon the reliability with which they are used. Correct and consistent use of methods can result
in lower failure rates.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 6
Table II: Percentage of Women Experiencing an Unintended Pregnancy During the First Year of
Typical Use and the First Year of Perfect Use of Contraception and the Percentage
Continuing Use at the End of the First Year. United States.
% of Women Experiencing an
Unintended Pregnancy within the First
Year of Use
% of Women Continuing
Use at One Year3
Method
(1)
Typical Use 1
(2)
Perfect Use2
(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 T380A
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
Hatcher et al, 1998, Ref. # 1.
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 highly effective, temporary method of contraception.10
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 other 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 percent who would become pregnant within one year
among women now relying on reversible methods of contraception if they abandoned contraception
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 7
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. The Food and Drug Administration has declared the following brands
of oral contraceptives 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 2 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 six months of age.
ORTHO-CYCLEN and ORTHO TRI-CYCLEN have not been studied for and are
not indicated for use in emergency contraception.
In clinical trials with ORTHO-CYCLEN, 1,651 subjects completed 24,272 cycles and the overall use-
efficacy (typical user efficacy) pregnancy rate was approximately 1 pregnancy per 100 women-years.
This rate includes patients who did not take the drug correctly.
In four clinical trials with ORTHO TRI-CYCLEN, a total of 4,756 subjects completed 45,244 cycles,
and the use-efficacy pregnancy rate was approximately 1 pregnancy per 100 women-years.
ORTHO TRI-CYCLEN was evaluated for the treatment of acne vulgaris in two randomized, double-
blind, placebo-controlled, multicenter, Phase 3, six (28 day) cycle studies. 221 patients received
ORTHO TRI-CYCLEN and 234 patients received placebo. Mean age at enrollment for both groups
was 28 years. At the end of 6 months, the mean total lesion count changes from 55 to 31 (42%
reduction) in patients treated with ORTHO TRI-CYCLEN and from 54 to 38 (27% reduction) in
patients similarly treated with placebo. Table III summarizes the changes in lesion count for each type
of lesion in the ITT population. Based on the investigator’s global assessment conducted at the final
visit, patients treated with ORTHO TRI-CYCLEN showed a statistically significant improvement in
total lesions compared to those treated with placebo.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 8
Table III:
Acne Vulgaris Indication. Combined Results: Two Multicenter, Placebo-Controlled
Trials. Observed Means at Six Months (LOCF)* and at Baseline. Intent-to-Treat
Population.
ORTHO TRI-CYCLEN
(N=221)
Placebo
(N=234)
Difference in Counts
between ORTHO
TRI-CYCLEN and
Placebo at 6 Months
# of Lesions
Counts
% Reduction
Counts
%
Reduction
INFLAMMATORY
LESIONS
Baseline Mean
Sixth Month Mean
19
10
48%
19
13
30%
3 (95 % CI: -1.2, 5.1)
NON-
INFLAMMATORY
LESIONS
Baseline Mean
Sixth Month Mean
36
22
34%
35
25
21%
3 (95% CI: -0.2, 7.8)
TOTAL LESIONS
Baseline Mean
Sixth Month Mean
55
31
42%
54
38
27%
7 (95% CI: 2.0, 11.9)
*LOCF: Last Observation Carried Forward
CONTRAINDICATIONS
Oral contraceptives should not be used in women who currently have the following conditions:
• Thrombophlebitis or thromboembolic disorders
• A past history of deep vein thrombophlebitis or thromboembolic disorders
• Cerebral vascular or coronary artery disease (current or past history)
• Valvular heart disease with complications
• Severe hypertension
• Diabetes with vascular involvement
• Headaches with focal neurological symptoms
• Major surgery with prolonged immobilization
• Known or suspected carcinoma of the breast or personal history of breast cancer
• Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia
• Undiagnosed abnormal genital bleeding
• Cholestatic jaundice of pregnancy or jaundice with prior pill use
• Acute or chronic hepatocellular disease with abnormal liver function
• Hepatic adenomas or carcinomas
• Known or suspected pregnancy
• Hypersensitivity to any component of this product
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 9
WARNINGS
Cigarette smoking increases the risk of serious cardiovascular side
effects from oral contraceptive use. This risk increases with age and with
heavy smoking (15 or more cigarettes per day) and is quite marked in
women over 35 years of age. Women who use oral contraceptives should
be strongly advised not to smoke.
The use of oral contraceptives is associated with increased risks of several serious conditions including
myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, although
the risk of serious morbidity or mortality is very small in healthy women without underlying risk
factors. The risk of morbidity and mortality increases significantly in the presence of other underlying
risk factors such as hypertension, hyperlipidemias, obesity and diabetes.
Practitioners prescribing oral contraceptives should be familiar with the following information relating
to these risks.
The information contained in this package insert is principally based on studies carried out in patients
who used oral contraceptives with higher formulations of estrogens and progestogens than those in
common use today. The effect of long-term use of the oral contraceptives with lower formulations of
both estrogens and progestogens remains to be determined.
Throughout this labeling, epidemiological studies reported are of two types: retrospective or case
control studies and prospective or cohort studies. Case control studies provide a measure of the relative
risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that
among nonusers. The relative risk does not provide information on the actual clinical occurrence of a
disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence
of disease between oral contraceptive users and nonusers. The attributable risk does provide
information about the actual occurrence of a disease in the population (adapted from refs. 2 and 3 with
the author's permission). For further information, the reader is referred to a text on epidemiological
methods.
1.
Thromboembolic Disorders and Other Vascular Problems
a.
Myocardial Infarction
An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is
primarily in smokers or women with other underlying risk factors for coronary artery disease such as
hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for
current oral contraceptive users has been estimated to be two to six (4-10). The risk is very low under
the age of 30.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 10
Smoking in combination with oral contraceptive use has been shown to contribute substantially to the
incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting
for the majority of excess cases (11). Mortality rates associated with circulatory disease have been
shown to increase substantially in smokers, especially in those 35 years of age and older and in
nonsmokers over the age of 40 among women who use oral contraceptives.
Figure 1.
Circulatory Disease Mortality Rates Per 100,000 Women-Years By Age, Smoking Status and Oral
Contraceptive Use
(Adapted from P.M. Layde and V. Beral, ref. #12.)
Oral contraceptives may compound the effects of well-known risk factors, such as hypertension,
diabetes, hyperlipidemias, age and obesity (13). In particular, some progestogens are known to
decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of
hyperinsulinism (14-18). Oral contraceptives have been shown to increase blood pressure among users
(see Section 9 in WARNINGS). Similar effects on risk factors have been associated with an increased
risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular
disease risk factors.
Norgestimate has minimal androgenic activity (see CLINICAL PHARMACOLOGY), and there is
some evidence that the risk of myocardial infarction associated with oral contraceptives is lower when
the progestogen has minimal androgenic activity than when the activity is greater (97).
b.
Thromboembolism
An increased risk of thromboembolic and thrombotic disease associated with the use of oral
contraceptives is well established. Case control studies have found the relative risk of users compared
to nonusers to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein
thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous
thromboembolic disease (2,3,19-24). Cohort studies have shown the relative risk to be somewhat
lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization (25). The risk of
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 11
thromboembolic disease associated with oral contraceptives is not related to length of use and
disappears after pill use is stopped (2).
A two- to four-fold increase in relative risk of post-operative thromboembolic complications has been
reported with the use of oral contraceptives (9). The relative risk of venous thrombosis in women who
have predisposing conditions is twice that of women without such medical conditions (26). If feasible,
oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective
surgery of a type associated with an increase in risk of thromboembolism and during and following
prolonged immobilization. Since the immediate postpartum period is also associated with an increased
risk of thromboembolism, oral contraceptives should be started no earlier than four weeks after
delivery in women who elect not to breast feed.
c.
Cerebrovascular Diseases
Oral contraceptives have been shown to increase both the relative and attributable risks of
cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest
among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk
factor for both users and nonusers, for both types of strokes, and smoking interacted to increase the
risk of stroke (27-29).
In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for
normotensive users to 14 for users with severe hypertension (30). The relative risk of hemorrhagic
stroke is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who did not
use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and
25.7 for users with severe hypertension (30). The attributable risk is also greater in older women (3).
d.
Dose-Related Risk of Vascular Disease From Oral Contraceptives
A positive association has been observed between the amount of estrogen and progestogen in oral
contraceptives and the risk of vascular disease (31-33). A decline in serum high density lipoproteins
(HDL) has been reported with many progestational agents (14-16). A decline in serum high density
lipoproteins has been associated with an increased incidence of ischemic heart disease. Because
estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance
achieved between doses of estrogen and progestogen and the activity of the progestogen used in the
contraceptives. The activity and amount of both hormones should be considered in the choice of an
oral contraceptive.
Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics.
For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one
which contains the least amount of estrogen and progestogen that is compatible with a low failure rate
and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 12
preparations containing the lowest estrogen content which is judged appropriate for the individual
patient.
e.
Persistence of Risk of Vascular Disease
There are two studies which have shown persistence of risk of vascular disease for ever-users of oral
contraceptives. In a study in the United States, the risk of developing myocardial infarction after
discontinuing oral contraceptives persists for at least 9 years for women 40-49 years who had used oral
contraceptives for five or more years, but this increased risk was not demonstrated in other age groups
(8). In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at
least 6 years after discontinuation of oral contraceptives, although excess risk was very small (34).
However, both studies were performed with oral contraceptive formulations containing 50 micrograms
or higher of estrogens.
2.
Estimates of Mortality From Contraceptive Use
One study gathered data from a variety of sources which have estimated the mortality rate associated
with different methods of contraception at different ages (Table IV). These estimates include the
combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in
the event of method failure. Each method of contraception has its specific benefits and risks. The study
concluded that with the exception of oral contraceptive users 35 and older who smoke, and 40 and
older who do not smoke, mortality associated with all methods of birth control is low and below that
associated with childbirth. The observation of an increase in risk of mortality with age for oral
contraceptive users is based on data gathered in the 1970's (35). Current clinical recommendation
involves the use of lower estrogen dose formulations and a careful consideration of risk factors. In
1989, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the use of oral
contraceptives in women 40 years of age and over. The Committee concluded that although
cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy non-
smoking women (even with the newer low-dose formulations), there are also greater potential health
risks associated with pregnancy in older women and with the alternative surgical and medical
procedures which may be necessary if such women do not have access to effective and acceptable
means of contraception. The Committee recommended that the benefits of low-dose oral contraceptive
use by healthy non-smoking women over 40 may outweigh the possible risks.
Of course, older women, as all women, who take oral contraceptives, should take an oral contraceptive
which contains the least amount of estrogen and progestogen that is compatible with a low failure rate
and individual patient needs.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 13
Table IV:
Annual Number of Birth-Related or Method-Related Deaths Associated With
Control of Fertility Per 100,000 Non-Sterile Women, by Fertility Control Method
According to Age
Method of control and
outcome
15-19
20-24
25-29
30-34
35-39
40-44
No fertility control
methods*
7.0
7.4
9.1
14.8
25.7
28.2
Oral contraceptives non-
smoker**
0.3
0.5
0.9
1.9
13.8
31.6
Oral contraceptives,
smoker**
2.2
3.4
6.6
13.5
51.1
117.2
IUD**
0.8
0.8
1.0
1.0
1.4
1.4
Condom*
1.1
1.6
0.7
0.2
0.3
0.4
Diaphragm/spermicide*
1.9
1.2
1.2
1.3
2.2
2.8
Periodic abstinence*
2.5
1.6
1.6
1.7
2.9
3.6
* Deaths are birth-related
**Deaths are method-related
Adapted from H.W. Ory, ref. #35.
3.
Carcinoma of the Reproductive Organs and Breasts
Numerous epidemiological studies have been performed on the incidence of breast, endometrial,
ovarian, and cervical cancer in women using oral contraceptives. The risk of having breast cancer
diagnosed may be slightly increased among current and recent users of combination oral
contraceptives (COCs). However, this excess risk appears to decrease over time after COC
discontinuation and by 10 years after cessation the increased risk disappears. Some studies report an
increased risk with duration of use while other studies do not and no consistent relationships have been
found with dose or type of steroid. Some studies have found a small increase in risk for women who
first use COCs before age 20. Most studies show a similar pattern of risk with COC use regardless of a
woman’s reproductive history or her family breast cancer history.
Breast cancers diagnosed in current or previous oral contraceptive users tend to be less clinically
advanced than nonusers. Women who currently have or have had breast cancer should not use oral
contraceptives because breast cancer is usually a hormonally-sensitive tumor.
Some studies suggest that oral contraceptive use has been associated with an increase in the risk of
cervical intraepithelial neoplasia in some populations of women (45-48). However, there continues to
be controversy about the extent to which such findings may be due to differences in sexual behavior
and other factors. In spite of many studies of the relationship between oral contraceptive use and breast
and cervical cancers, a cause-and-effect relationship has not been established.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 14
4.
Hepatic Neoplasia
Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign
tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the
range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use especially
with oral contraceptives of higher dose (49). Rupture of benign, hepatic adenomas may cause death
through intra-abdominal hemorrhage (50,51).
Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-
term (>8 years) oral contraceptive users. However, these cancers are extremely rare in the U.S. and the
attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than
one per million users.
5.
Ocular Lesions
There have been clinical case reports of retinal thrombosis associated with the use of oral
contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete
loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate
diagnostic and therapeutic measures should be undertaken immediately.
6.
Oral Contraceptive Use Before or During Early Pregnancy
Extensive epidemiological studies have revealed no increased risk of birth defects in women who have
used oral contraceptives prior to pregnancy (56,57). The majority of recent studies also do not indicate
a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are
concerned (55,56,58,59), when taken inadvertently during early pregnancy.
The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test
for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual
abortion.
It is recommended that for any patient who has missed two consecutive periods, pregnancy should be
ruled out. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should
be considered at the time of the first missed period. Oral contraceptive use should be discontinued if
pregnancy is confirmed.
7.
Gallbladder Disease
Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral
contraceptives and estrogens (60,61). More recent studies, however, have shown that the relative risk
of developing gallbladder disease among oral contraceptive users may be minimal (62-64). The recent
findings of minimal risk may be related to the use of oral contraceptive formulations containing lower
hormonal doses of estrogens and progestogens.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 15
8.
Carbohydrate and Lipid Metabolic Effects
Oral contraceptives have been shown to cause a decrease in glucose tolerance in a significant
percentage of users (17). This effect has been shown to be directly related to estrogen dose (65).
Progestogens increase insulin secretion and create insulin resistance, this effect varying with different
progestational agents (17,66). However, in the non-diabetic woman, oral contraceptives appear to have
no effect on fasting blood glucose (67). Because of these demonstrated effects, prediabetic and diabetic
women in particular should be carefully monitored while taking oral contraceptives.
A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed
earlier (see WARNINGS 1a and 1d), changes in serum triglycerides and lipoprotein levels have been
reported in oral contraceptive users.
In clinical studies with ORTHO-CYCLEN® there were no clinically significant changes in fasting
blood glucose levels. No statistically significant changes in mean fasting blood glucose levels were
observed over 24 cycles of use. Glucose tolerance tests showed minimal, clinically insignificant
changes from baseline to cycles 3, 12, and 24.
In clinical studies with ORTHO TRI-CYCLEN® there were no clinically significant changes in fasting
blood glucose levels. Minimal statistically significant changes were noted in glucose levels over 24
cycles of use. Glucose tolerance tests showed no clinically significant changes from baseline to cycles
3, 12, and 24.
9.
Elevated Blood Pressure
Women with significant hypertension should not be started on hormonal contraception (98). An
increase in blood pressure has been reported in women taking oral contraceptives (68) and this increase
is more likely in older oral contraceptive users (69) and with extended duration of use (61). Data from
the Royal College of General Practitioners (12) and subsequent randomized trials have shown that the
incidence of hypertension increases with increasing progestational activity.
Women with a history of hypertension or hypertension-related diseases, or renal disease (70) should be
encouraged to use another method of contraception. If women elect to use oral contraceptives, they
should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives
should be discontinued. For most women, elevated blood pressure will return to normal after stopping
oral contraceptives, and there is no difference in the occurrence of hypertension between former and
never users (68-71). It should be noted that in two separate large clinical trials (N=633 and N=911), no
statistically significant changes in mean blood pressure were observed with ORTHO-CYCLEN®.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 16
10.
Headache
The onset or exacerbation of migraine or development of headache with a new pattern which is
recurrent, persistent or severe requires discontinuation of oral contraceptives and evaluation of the
cause.
11.
Bleeding Irregularities
Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives,
especially during the first three months of use. Non-hormonal causes should be considered and
adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough
bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a
change to another formulation may solve the problem. In the event of amenorrhea, pregnancy should
be ruled out.
Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a
condition was preexistent.
12.
Ectopic Pregnancy
Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.
PRECAUTIONS
1.
General
Patients should be counseled that this product does not protect against HIV infection (AIDS) and other
sexually transmitted diseases.
2.
Physical Examination and Follow Up
It is good medical practice for all women to have annual history and physical examinations, including
women using oral contraceptives. The physical examination, however, may be deferred until after
initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The
physical examination should include special reference to blood pressure, breasts, abdomen and pelvic
organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or
recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out
malignancy. Women with a strong family history of breast cancer or who have breast nodules should
be monitored with particular care.
3.
Lipid Disorders
Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral
contraceptives. Some progestogens may elevate LDL levels and may render the control of
hyperlipidemias more difficult.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 17
4.
Liver Function
If jaundice develops in any woman receiving such drugs, the medication should be discontinued.
Steroid hormones may be poorly metabolized in patients with impaired liver function.
5.
Fluid Retention
Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution,
and only with careful monitoring, in patients with conditions which might be aggravated by fluid
retention.
6.
Emotional Disorders
Women with a history of depression should be carefully observed and the drug discontinued if
depression recurs to a serious degree.
7.
Contact Lenses
Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an
ophthalmologist.
8.
Drug Interactions
Changes in contraceptive effectiveness associated with co-administration of other products
Contraceptive effectiveness may be reduced when hormonal contraceptives are co-administered with
antibiotics, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids.
This could result in unintended pregnancy or breakthrough bleeding. Examples include rifampin,
barbiturates, phenylbutazone, phenytoin, carbamazepine, felbamate, oxcarbazepine, topiramate, and
griseofulvin.
Several of the anti-HIV protease inhibitors have been studied with co-administration of oral
combination hormonal contraceptives; significant changes (increase and decrease) in the plasma levels
of the estrogen and progestin have been noted in some cases. The safety and efficacy of oral
contraceptive products may be affected with co-administration of anti-HIV protease inhibitors.
Healthcare professionals should refer to the label of the individual anti-HIV protease inhibitors for
further drug-drug interaction information.
Herbal products containing St. John’s Wort (hypericum perforatum) may induce hepatic enzymes
(cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive
steroids. This may also result in breakthrough bleeding.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 18
Increase in plasma levels associated with co-administered drugs
Co-administration of atorvastatin and certain oral contraceptives containing ethinyl estradiol increase
AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may
increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP 3A4 inhibitors
such as itraconazole or ketoconazole may increase plasma hormone levels.
Changes in plasma levels of co-administered drugs
Combination hormonal contraceptives containing some synthetic estrogens (e.g., ethinyl estradiol) may
inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporine,
prednisolone, and theophylline have been reported with concomitant administration of oral
contraceptives. Decreased plasma concentrations of acetaminophen and increased clearance of
temazepam, salicylic acid, morphine and clofibric acid, due to induction of conjugation, have been
noted when these drugs were administered with oral contraceptives.
9.
Interactions with Laboratory Tests
Certain endocrine and liver function tests and blood components may be affected by oral
contraceptives:
a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased
norepinephrine-induced platelet aggregability.
b. Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as
measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin
uptake is decreased, reflecting the elevated TBG, free T4 concentration is unaltered.
c. Other binding proteins may be elevated in serum.
d. Sex hormone binding globulins are increased and result in elevated levels of total circulating sex
steroids; however, free or biologically active levels either decrease or remain unchanged.
e. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected.
f. Glucose tolerance may be decreased.
g. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical
significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.
10.
Carcinogenesis
See WARNINGS Section.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 19
11.
Pregnancy
Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS Sections.
12.
Nursing Mothers
Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and a
few adverse effects on the child have been reported, including jaundice and breast enlargement. In
addition, combination oral contraceptives given in the postpartum period may interfere with lactation
by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised
not to use combination oral contraceptives but to use other forms of contraception until she has
completely weaned her child.
13.
Pediatric Use
Safety and efficacy of ORTHO TRI-CYCLEN® Tablets and ORTHO-CYCLEN® Tablets have been
established in women of reproductive age. Safety and efficacy are expected to be the same for
postpubertal adolescents under the age of 16 and for users 16 years and older. There was no significant
difference between ORTHO TRI-CYCLEN Tablets and placebo in mean change in total lumbar spine
(L1-L4) and total hip bone mineral density between baseline and Cycle 13 in 123 adolescent females
with anorexia nervosa in a double-blind, placebo-controlled, multicenter, one-year treatment duration
clinical trial for the Intent To Treat (ITT) population. Use of this product before menarche is not
indicated.
14. Geriatric Use
This product has not been studied in women over 65 years of age and is not indicated in this
population.
INFORMATION FOR THE PATIENT
See Patient Labeling printed below.
ADVERSE REACTIONS
An increased risk of the following serious adverse reactions has been associated with the use of oral
contraceptives (see WARNINGS Section).
• Thrombophlebitis and venous thrombosis with or without embolism
• Arterial thromboembolism
• Pulmonary embolism
• Myocardial infarction
• Cerebral hemorrhage
• Cerebral thrombosis
• Hypertension
• Gallbladder disease
• Hepatic adenomas or benign liver tumors
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 20
There is evidence of an association between the following conditions and the use of oral
contraceptives:
• Mesenteric thrombosis
• Retinal thrombosis
The following adverse reactions have been reported in patients receiving oral contraceptives and are
believed to be drug-related:
• Nausea
• Vomiting
• Gastrointestinal symptoms (such as abdominal cramps and bloating)
• Breakthrough bleeding
• Spotting
• Change in menstrual flow
• Amenorrhea
• Temporary infertility after discontinuation of treatment
• Edema
• Melasma which may persist
• Breast changes: tenderness, enlargement, secretion
• Change in weight (increase or decrease)
• Change in cervical erosion and secretion
• Diminution in lactation when given immediately postpartum
• Cholestatic jaundice
• Migraine
• Rash (allergic)
• Mental depression
• Reduced tolerance to carbohydrates
• Vaginal candidiasis
• Change in corneal curvature (steepening)
• Intolerance to contact lenses
The following adverse reactions have been reported in users of oral contraceptives and a causal
association has been neither confirmed nor refuted:
• Pre-menstrual syndrome
• Cataracts
• Changes in appetite
• Cystitis-like syndrome
• Headache
• Nervousness
• Dizziness
• Hirsutism
• Loss of scalp hair
• Erythema multiforme
• Erythema nodosum
• Hemorrhagic eruption
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 21
• Vaginitis
• Porphyria
• Impaired renal function
• Hemolytic uremic syndrome
• Acne
• Changes in libido
• Colitis
• Budd-Chiari Syndrome
OVERDOSAGE
Serious ill effects have not been reported following acute ingestion of large doses of oral
contraceptives by young children. Overdosage may cause nausea and withdrawal bleeding may occur
in females.
NON-CONTRACEPTIVE HEALTH BENEFITS
The following non-contraceptive health benefits related to the use of combination oral contraceptives
are supported by epidemiological studies which largely utilized oral contraceptive formulations
containing estrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg mestranol (73-78).
Effects on menses:
• increased menstrual cycle regularity
• decreased blood loss and decreased incidence of iron deficiency anemia
• decreased incidence of dysmenorrhea
Effects related to inhibition of ovulation:
• decreased incidence of functional ovarian cysts
• decreased incidence of ectopic pregnancies
Other effects:
• decreased incidence of fibroadenomas and fibrocystic disease of the breast
• decreased incidence of acute pelvic inflammatory disease
• decreased incidence of endometrial cancer
• decreased incidence of ovarian cancer
DOSAGE AND ADMINISTRATION
Oral Contraception
To achieve maximum contraceptive effectiveness, ORTHO TRI-CYCLEN® Tablets and ORTHO-
CYCLEN® Tablets must be taken exactly as directed and at intervals not exceeding 24 hours. The
possibility of ovulation and conception prior to initiation of medication should be considered. ORTHO
TRI-CYCLEN and ORTHO-CYCLEN are available in the DIALPAK® Tablet Dispenser which is
preset for a Sunday Start. Day 1 Start is also provided.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 22
Sunday Start
When taking ORTHO TRI-CYCLEN® and ORTHO-CYCLEN® the first tablet should be taken on the
first Sunday after menstruation begins. If period begins on Sunday, the first tablet should be taken that
day. Take one active tablet daily for 21 days followed by one green inactive tablet daily for 7 days.
After 28 tablets have been taken, a new course is started the next day (Sunday). For the first cycle of a
Sunday Start regimen, another method of contraception should be used until after the first 7
consecutive days of administration.
If the patient misses one (1) active tablet in Weeks 1, 2, or 3, the tablet should be taken as soon as she
remembers. If the patient misses two (2) active tablets in Week 1 or Week 2, the patient should take
two (2) tablets the day she remembers and two (2) tablets the next day; and then continue taking one
(1) tablet a day until she finishes the pack. The patient should be instructed to use a back-up method of
birth control such as condoms or spermicide if she has sex in the seven (7) days after missing pills. If
the patient misses two (2) active tablets in the third week or misses three (3) or more active tablets in a
row, the patient should continue taking one tablet every day until Sunday. On Sunday the patient
should throw out the rest of the pack and start a new pack that same day. The patient should be
instructed to use a back-up method of birth control if she has sex in the seven (7) days after missing
pills.
Complete instructions to facilitate patient counseling on proper pill usage may be found in the Detailed
Patient Labeling ("How to Take the Pill" section).
Day 1 Start
The dosage of ORTHO TRI-CYCLEN® and ORTHO-CYCLEN® , for the initial cycle of therapy is
one active tablet administered daily from the 1st day through the 21st day of the menstrual cycle,
counting the first day of menstrual flow as "Day 1" followed by one green inactive tablet daily for 7
days. Tablets are taken without interruption for 28 days. After 28 tablets have been taken, a new course
is started the next day.
If the patient misses one (1) active tablet in Weeks 1, 2, or 3, the tablet should be taken as soon as she
remembers. If the patient misses two (2) active tablets in Week 1 or Week 2, the patient should take
two (2) tablets the day she remembers and two (2) tablets the next day; and then continue taking one
(1) tablet a day until she finishes the pack. The patient should be instructed to use a back-up method of
birth control such as condoms or spermicide if she has sex in the seven (7) days after missing pills. If
the patient misses two (2) active tablets in the third week or misses three (3) or more active tablets in a
row, the patient should throw out the rest of the pack and start a new pack that same day. The patient
should be instructed to use a back-up method of birth control if she has sex in the seven (7) days after
missing pills.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 23
Complete instructions to facilitate patient counseling on proper pill usage may be found in the Detailed
Patient Labeling ("How to Take the Pill" section).
The use of ORTHO TRI-CYCLEN and ORTHO-CYCLEN for contraception may be initiated 4 weeks
postpartum in women who elect not to breast feed. When the tablets are administered during the
postpartum period, the increased risk of thromboembolic disease associated with the postpartum period
must be considered. (See CONTRAINDICATIONS and WARNINGS concerning thromboembolic
disease. See also PRECAUTIONS for "Nursing Mothers.") The possibility of ovulation and conception
prior to initiation of medication should be considered.
(See Discussion of Dose-Related Risk of Vascular Disease from Oral Contraceptives.)
ADDITIONAL INSTRUCTIONS
Breakthrough bleeding, spotting, and amenorrhea are frequent reasons for patients discontinuing oral
contraceptives. In breakthrough bleeding, as in all cases of irregular bleeding from the vagina,
nonfunctional causes should be borne in mind. In undiagnosed persistent or recurrent abnormal
bleeding from the vagina, adequate diagnostic measures are indicated to rule out pregnancy or
malignancy. If pathology has been excluded, time or a change to another formulation may solve the
problem. Changing to an oral contraceptive with a higher estrogen content, while potentially useful in
minimizing menstrual irregularity, should be done only if necessary since this may increase the risk of
thromboembolic disease.
Use of oral contraceptives in the event of a missed menstrual period:
1. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be
considered at the time of the first missed period and oral contraceptive use should be discontinued
if pregnancy is confirmed.
2. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy
should be ruled out.
ACNE
The timing of initiation of dosing with ORTHO TRI-CYCLEN® for acne should follow the guidelines
for use of ORTHO TRI-CYCLEN as an oral contraceptive. Consult the DOSAGE AND
ADMINISTRATION section for oral contraceptives. The dosage regimen for ORTHO TRI-
CYCLEN for treatment of facial acne, as available in a DIALPAK® Tablet Dispenser, utilizes a 21-day
active and a 7-day placebo schedule. Take one active tablet daily for 21 days followed by one green
inactive tablet for 7 days. After 28 tablets have been taken, a new course is started the next day.
HOW SUPPLIED
ORTHO TRI-CYCLEN® Tablets are available in a DIALPAK® Tablet Dispenser (NDC 0062-1903-
15) containing 28 tablets. Each white tablet contains 0.180 mg of the progestational compound,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 24
norgestimate, together with 0.035 mg of the estrogenic compound, ethinyl estradiol. Each light blue
tablet contains 0.215 mg of the progestational compound, norgestimate, together with 0.035 mg of the
estrogenic compound, ethinyl estradiol. Each blue tablet contains 0.250 mg of the progestational
compound, norgestimate, together with 0.035 mg of the estrogenic compound, ethinyl estradiol. Each
green tablet contains inert ingredients.
The white tablets are unscored, with "Ortho" and "180" debossed on each side; the light blue tablets are
unscored with "Ortho" and "215" debossed on each side; the blue tablets are unscored with "Ortho"
and "250" debossed on each side.
ORTHO TRI-CYCLEN® Tablets are also available as Refills (NDC 0062-1903-23).
ORTHO TRI-CYCLEN® Tablets are available for clinic usage in a VERIDATE® Tablet Dispenser
(unfilled) and VERIDATE Refills (NDC 0062-1903-20).
ORTHO-CYCLEN® Tablets are available in a DIALPAK® Tablet Dispenser (NDC 0062-1901-15)
containing 28 tablets as follows: 21 blue tablets containing 0.250 mg of the progestational compound,
norgestimate, together with 0.035 mg of the estrogenic compound, ethinyl estradiol which are unscored
with “Ortho” and “250” debossed on each side, and 7 green tablets containing inert ingredients.
ORTHO-CYCLEN® Tablets are also available as Refills (NDC 0062-1901-23).
ORTHO-CYCLEN® Tablets are available for clinic usage in a VERIDATE® Tablet Dispenser (unfilled)
and VERIDATE Refills (NDC 0062-1901-20).
Store at 25° C (77° F); excursions permitted to 15° - 30° C (59° - 86°F).
Protect from light.
Rx only
REFERENCES
1. Trussel J. Contraceptive efficacy. In Hatcher RA, Trussel J, Stewart F, Cates W, Stewart GK,
Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington
Publishers, 1998, in press 2. Stadel BV, Oral contraceptives and cardiovascular disease. (Pt.1). N Engl
J Med 1981; 305:612-618. 3. Stadel BV, Oral contraceptives and cardiovascular disease. (Pt.2). N
Engl J Med 1981; 305:672-677. 4. Adam SA, Thorogood M. Oral contraception and myocardial
infarction revisited: the effects of new preparations and prescribing patterns. Br J Obstet Gynaecol
1981; 88:838-845. 5. Mann Jl, Inman WH. Oral contraceptives and death from myocardial infarction.
Br Med J 1975; 2(5965):245-248. 6. Mann Jl, Vessey MP, Thorogood M, Doll R. Myocardial
infarction in young women with special reference to oral contraceptive practice. Br Med J 1975;
2(5956):241-245. 7. Royal College of General Practitioners' Oral Contraception Study: Further
analyses of mortality in oral contraceptive users. Lancet 1981; 1:541-546. 8. Slone D, Shapiro S,
Kaufman DW, Rosenberg L, Miettinen OS, Stolley PD. Risk of myocardial infarction in relation to
current and discontinued use of oral contraceptives. N Engl J Med 1981:305:420-424. 9. Vessey MP.
Female hormones and vascular disease-an epidemiological overview. Br J Fam Plann 1980;
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 25
6(Supplement): 1-12. 10. Russell-Briefel RG, Ezzati TM, Fulwood R, Perlman JA, Murphy RS.
Cardiovascular risk status and oral contraceptive use, United States, 1976-80. Prevent Med 1986;
15:352-362. 11. Goldbaum GM, Kendrick JS, Hogelin GC, Gentry EM. The relative impact of
smoking and oral contraceptive use on women in the United States. JAMA 1987; 258:1339-1342. 12.
Layde PM, Beral V. Further analyses of mortality in oral contraceptive users; Royal College of
General Practitioners' Oral Contraception Study. (Table 5) Lancet 1981; 1:541-546. 13. Knopp RH.
Arteriosclerosis risk: the roles of oral contraceptives and postmenopausal estrogens. J Reprod Med
1986; 31(9) (Supplement):913-921. 14. Krauss RM, Roy S, Mishell DR, Casagrande J, Pike MC.
Effects of two low-dose oral contraceptives on serum lipids and lipoproteins: Differential changes in
high-density lipoproteins subclasses. Am J Obstet 1983; 145:446-452. 15. Wahl P, Walden C, Knopp
R, Hoover J, Wallace R, Heiss G, Rifkind B. Effect of estrogen/progestin potency on lipid/lipoprotein
cholesterol. N Engl J Med 1983; 308:862-867. 16. Wynn V, Niththyananthan R. The effect of
progestin in combined oral contraceptives on serum lipids with special reference to high density
lipoproteins. Am J Obstet Gynecol 1982;142:766-771. 17. Wynn V, Godsland I. Effects of oral
contraceptives on carbohydrate metabolism. J Reprod Med 1986;31(9)(Supplement):892-897. 18.
LaRosa JC. Atherosclerotic risk factors in cardiovascular disease. J Reprod Med
1986;31(9)(Supplement):906-912. 19. Inman WH, Vessey MP. Investigation of death from pulmonary,
coronary, and cerebral thrombosis and embolism in women of child-bearing age. Br Med J
1968;2(5599):193-199. 20. Maguire MG, Tonascia J, Sartwell PE, Stolley PD, Tockman MS.
Increased risk of thrombosis due to oral contraceptives: a further report. Am J Epidemiol
1979;110(2):188-195. 21. Petitti DB, Wingerd J, Pellegrin F, Ramacharan S. Risk of vascular disease
in women: smoking, oral contraceptives, noncontraceptive estrogens, and other factors. JAMA
1979;242:1150-1154. 22. Vessey MP, Doll R, Investigation of relation between use of oral
contraceptives and thromboembolic disease. Br Med J 1968;2(5599):199-205. 23. Vessey MP, Doll R.
Investigation of relation between use of oral contraceptives and thromboembolic disease. A further
report. Br Med J 1969; 2(5658):651-657. 24. Porter JB, Hunter JR, Danielson DA, Jick H, Stergachis
A. Oral contraceptives and non-fatal vascular disease-recent experience. Obstet Gynecol
1982;59(3):299-302. 25. Vessey M, Doll R, Peto R, Johnson B, Wiggins P. A long-term follow-up
study of women using different methods of contraception: an interim report. J Biosocial Sci
1976;8:375-427. 26. Royal College of General Practitioners: Oral Contraceptives, venous thrombosis,
and varicose veins. J Royal Coll Gen Pract 1978; 28:393-399. 27. Collaborative Group for the Study of
Stroke in Young Women: Oral contraception and increased risk of cerebral ischemia or thrombosis. N
Engl J Med 1973;288:871-878. 28. Petitti DB, Wingerd J. Use of oral contraceptives, cigarette
smoking, and risk of subarachnoid hemorrhage. Lancet 1978;2:234-236. 29. Inman WH. Oral
contraceptives and fatal subarachnoid hemorrhage. Br Med J 1979:2(6203):1468-1470. 30.
Collaborative Group for the Study of Stroke in Young Women: Oral Contraceptives and stroke in
young women: associated risk factors. JAMA 1975; 231:718-722. 31. Inman WH, Vessey MP,
Westerholm B, Engelund A. Thromboembolic disease and the steroidal content of oral contraceptives.
A report to the Committee on Safety of Drugs. Br Med J 1970;2:203-209. 32. Meade TW, Greenberg
G, Thompson SG. Progestogens and cardiovascular reactions associated with oral contraceptives and a
comparison of the safety of 50- and 35-mcg oestrogen preparations. Br Med J 1980;280(6224):1157-
1161. 33. Kay CR. Progestogens and arterial disease-evidence from the Royal College of General
Practitioners' Study. Am J Obstet Gynecol 1982;142:762-765. 34. Royal College of General
Practitioners: Incidence of arterial disease among oral contraceptive users. J Royal Coll Gen Pract
1983;33:75-82. 35. Ory HW. Mortality associated with fertility and fertility control: 1983. Family
Planning Perspectives 1983;15:50-56. 36. The Cancer and Steroid Hormone Study of the Centers for
Disease Control and the National Institute of Child Health and Human Development: Oral
contraceptive use and the risk of breast cancer. N Engl J Med 1986;315:405-411. 37. Pike MC,
Henderson BE, Krailo MD, Duke A, Roy S. Breast cancer in young women and use of oral
contraceptives: possible modifying effect of formulation and age at use. Lancet 1983;2:926-929. 38.
Paul C, Skegg DG, Spears GFS, Kaldor JM. Oral contraceptives and breast cancer: A national study.
Br Med J 1986; 293:723-725. 39. Miller DR, Rosenberg L, Kaufman DW, Schottenfeld D, Stolley PD,
Shapiro S. Breast cancer risk in relation to early oral contraceptive use. Obstet Gynecol 1986;68:863-
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 26
868. 40. Olsson H, Olsson ML, Moller TR, Ranstam J, Holm P. Oral contraceptive use and breast
cancer in young women in Sweden (letter). Lancet 1985; 1(8431):748-749. 41. McPherson K, Vessey
M, Neil A, Doll R, Jones L, Roberts M. Early contraceptive use and breast cancer: Results of another
case-control study. Br J Cancer 1987; 56:653-660. 42. Huggins GR, Zucker PF. Oral contraceptives
and neoplasia; 1987 update. Fertil Steril 1987; 47:733-761. 43. McPherson K, Drife JO. The pill and
breast cancer: why the uncertainty? Br Med J 1986; 293:709-710. 44. Shapiro S. Oral contraceptives-
time to take stock. N Engl J Med 1987; 315:450-451. 45. Ory H, Naib Z, Conger SB, Hatcher RA,
Tyler CW. Contraceptive choice and prevalence of cervical dysplasia and carcinoma in situ. Am J
Obstet Gynecol 1976; 124:573-577. 46. Vessey MP, Lawless M, McPherson K, Yeates D. Neoplasia
of the cervix uteri and contraception: a possible adverse effect of the pill. Lancet 1983; 2:930. 47.
Brinton LA, Huggins GR, Lehman HF, Malli K, Savitz DA, Trapido E, Rosenthal J, Hoover R. Long
term use of oral contraceptives and risk of invasive cervical cancer. Int J Cancer 1986; 38:339-344. 48.
WHO Collaborative Study of Neoplasia and Steroid Contraceptives: Invasive cervical cancer and
combined oral contraceptives. Br Med J 1985; 290:961-965. 49. Rooks JB, Ory HW, Ishak KG,
Strauss LT, Greenspan JR, Hill AP, Tyler CW. Epidemiology of hepatocellular adenoma: the role of
oral contraceptive use. JAMA 1979; 242:644-648. 50. Bein NN, Goldsmith HS. Recurrent massive
hemorrhage from benign hepatic tumors secondary to oral contraceptives. Br J Surg 1977; 64:433-435.
51. Klatskin G. Hepatic tumors: possible relationship to use of oral contraceptives. Gastroenterology
1977; 73:386-394. 52. Henderson BE, Preston-Martin S, Edmondson HA, Peters RL, Pike MC.
Hepatocellular carcinoma and oral contraceptives. Br J Cancer 1983;48:437-440. 53. Neuberger J,
Forman D, Doll R, Williams R. Oral contraceptives and hepatocellular carcinoma. Br Med J 1986;
292:1355-1357. 54. Forman D, Vincent TJ, Doll R, Cancer of the liver and oral contraceptives. Br Med
J 1986; 292:1357-1361. 55. Harlap S, Eldor J. Births following oral contraceptive failures. Obstet
Gynecol 1980; 55:447-452. 56. Savolainen E, Saksela E, Saxen L. Teratogenic hazards of oral
contraceptives analyzed in a national malformation register. Am J Obstet Gynecol 1981: 140:521-524.
57. Janerich DT, Piper JM, Glebatis DM. Oral contraceptives and birth defects. Am J Epidemiol 1980;
112:73-79. 58. Ferencz C, Matanoski GM, Wilson PD, Rubin JD, Neill CA, Gutberlet R. Maternal
hormone therapy and congenital heart disease. Teratology 1980; 21:225-239. 59. Rothman KJ, Fyler
DC, Goldblatt A, Kreidberg MB. Exogenous hormones and other drug exposures of children with
congenital heart disease. Am J Epidemiol 1979; 109:433-439. 60. Boston Collaborative Drug
Surveillance Program: Oral contraceptives and venous thromboembolic disease, surgically confirmed
gallbladder disease, and breast tumors. Lancet 1973; 1:1399-1404. 61. Royal College of General
Practitioners: Oral contraceptives and health. New York, Pittman 1974. 62. Layde PM, Vessey MP,
Yeates D. Risk of gallbladder disease: a cohort study of young women attending family planning
clinics. J Epidemiol Community Health 1982; 36:274-278. 63. Rome Group for Epidemiology and
Prevention of Cholelithiasis (GREPCO): Prevalence of gallstone disease in an Italian adult female
population. Am J Epidemiol 1984; 119:796-805. 64. Storm BL, Tamragouri RT, Morse ML, Lazar EL,
West SL, Stolley PD, Jones JK. Oral contraceptives and other risk factors for gallbladder disease. Clin
Pharmacol Ther 1986; 39:335-341. 65. Wynn V, Adams PW, Godsland IF, Melrose J, Niththyananthan
R, Oakley NW, Seedj A. Comparison of effects of different combined oral contraceptive formulations
on carbohydrate and lipid metabolism. Lancet 1979; 1:1045-1049. 66. Wynn V. Effect of progesterone
and progestins on carbohydrate metabolism. In: Progesterone and Progestin. Bardin CW, Milgrom E,
Mauvis-Jarvis P. eds. New York, Raven Press 1983; pp. 395-410. 67. Perlman JA, Roussell-Briefel
RG, Ezzati TM, Lieberknecht G. Oral glucose tolerance and the potency of oral contraceptive
progestogens. J Chronic Dis 1985;38:857-864. 68. Royal College of General Practitioners' Oral
Contraception Study: Effect on hypertension and benign breast disease of progestogen component in
combined oral contraceptives. Lancet 1977; 1:624. 69. Fisch IR, Frank J. Oral contraceptives and
blood pressure. JAMA 1977; 237:2499-2503. 70. Laragh AJ. Oral contraceptive induced hypertension-
nine years later. Am J Obstet Gynecol 1976; 126:141-147. 71. Ramcharan S, Peritz E, Pellegrin FA,
Williams WT. Incidence of hypertension in the Walnut Creek Contraceptive Drug Study cohort: In:
Pharmacology of steroid contraceptive drugs. Garattini S, Berendes HW. Eds. New York, Raven Press,
1977; pp. 277-288, (Monographs of the Mario Negri Institute for Pharmacological Research Milan.)
72. Stockley I. Interactions with oral contraceptives. J Pharm 1976;216:140-143. 73. The Cancer and
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 27
Steriod Hormone Study of the Centers for Disease Control and the National Institute of Child Health
and Human Development: Oral contraceptive use and the risk of ovarian cancer. JAMA 1983;
249:1596-1599. 74. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the
National Institute of Child Health and Human Development: Combination oral contraceptive use and
the risk of endometrial cancer. JAMA 1987; 257:796-800. 75. Ory HW. Functional ovarian cysts and
oral contraceptives: negative association confirmed surgically. JAMA 1974; 228:68-69. 76. Ory HW,
Cole P, MacMahon B, Hoover R. Oral contraceptives and reduced risk of benign breast disease. N
Engl J Med 1976; 294:419-422. 77. Ory HW. The noncontraceptive health benefits from oral
contraceptive use. Fam Plann Perspect 1982; 14:182-184. 78. Ory HW, Forrest JD, Lincoln R. Making
choices: Evaluating the health risks and benefits of birth control methods. New York, The Alan
Guttmacher Institute, 1983; p.1. 79. Schlesselman J, Stadel BV, Murray P, Lai S. Breast cancer in
relation to early use of oral contraceptives. JAMA 1988; 259:1828-1833. 80. Hennekens CH, Speizer
FE, Lipnick RJ, Rosner B, Bain C, Belanger C, Stampfer MJ, Willett W, Peto R. A case-control study
of oral contraceptive use and breast cancer. JNCI 1984; 72:39-42. 81. LaVecchia C, Decarli A, Fasoli
M, Franceschi S, Gentile A, Negri E, Parazzini F, Tognoni G. Oral contraceptives and cancers of the
breast and of the female genital tract. Interim results from a case-control study. Br J Cancer 1986;
54:311-317. 82. Meirik O, Lund E, Adami H, Bergstrom R, Christoffersen T, Bergsjo P. Oral
contraceptive use and breast cancer in young women. A Joint National Case-control study in Sweden
and Norway. Lancet 1986; 11:650-654. 83. Kay CR, Hannaford PC. Breast cancer and the pill-A
further report from the Royal College of General Practitioners' oral contraception study. Br J Cancer
1988;58:675-680. 84. Stadel BV, Lai S, Schlesselman JJ, Murray P. Oral contraceptives and
premenopausal breast cancer in nulliparous women. Contraception 1988; 38:287-299. 85. Miller DR,
Rosenberg L, Kaufman DW, Stolley P, Warshauer ME, Shapiro S. Breast cancer before age 45 and
oral contraceptive use: New Findings. Am J Epidemiol 1989; 129:269-280. 86. The UK National Case-
Control Study Group, Oral contraceptive use and breast cancer risk in young women. Lancet 1989;
1:973-982. 87. Schlesselman JJ. Cancer of the breast and reproductive tract in relation to use of oral
contraceptives. Contraception 1989; 40:1-38. 88. Vessey MP, McPherson K, Villard-Mackintosh L,
Yeates D. Oral contraceptives and breast cancer: latest findings in a large cohort study. Br J Cancer
1989; 59:613-617. 89. Jick SS, Walker AM, Stergachis A, Jick H. Oral contraceptives and breast
cancer. Br J Cancer 1989; 59:618-621. 90. Anderson FD, Selectivity and minimal androgenicity of
norgestimate in monophasic and triphasic oral contraceptives. Acta Obstet Gynecol Scand 1992; 156
(Supplement):15-21. 91. Chapdelaine A, Desmaris J-L, Derman RJ. Clinical evidence of minimal
androgenic activity of norgestimate. Int J Fertil 1989; 34(51):347-352. 92. Phillips A, Demarest K,
Hahn DW, Wong F, McGuire JL. Progestational and androgenic receptor binding affinities and in vivo
activities of norgestimate and other progestins. Contraception 1989; 41(4):399-409. 93. Phillips A,
Hahn DW, Klimek S, McGuire JL. A comparison of the potencies and activities of progestogens used
in contraceptives. Contraception 1987; 36(2):181-192. 94. Janaud A, Rouffy J, Upmalis D, Dain M-P.
A comparison study of lipid and androgen metabolism with triphasic oral contraceptive formulations
containing norgestimate or levonorgestrel Acta Obstet Gynecol Scand 1992; 156 (Supplement):34-38.
95. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal
contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and
100 239 women without breast cancer from 54 epidemiological studies. Lancet 1996; 347:1713-1727.
96. Palmer JR, Rosenberg L, Kaufman DW, Warshauer ME, Stolley P, Shapiro S. Oral Contraceptive
Use and Liver Cancer. Am J Epidemiol 1989;130:878-882. 97. Lewis M, Spitzer WO, Heinemann
LAJ, MacRae KD, Bruppacher R, Thorogood M on behalf of Transnational Research Group on Oral
Contraceptives and Health of Young Women. Third generation oral contraceptives and risk of
myocardial infarction: an international case-control study. Br Med J, 1996;312:88-90. 98. Improving
access to quality care in family planning: Medical eligibility criteria for contraceptive use. Geneva,
WHO, Family and Reproductive Health, 1996.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 28
BRIEF SUMMARY PATIENT PACKAGE INSERT
This product (like all oral contraceptives) does not protect against HIV infection (AIDS) and
other sexually transmitted diseases.
Oral contraceptives, also known as "birth control pills" or "the pill," are taken to prevent pregnancy.
When taken correctly to prevent pregnancy, oral contraceptives have a failure rate of approximately
1% per year (1 pregnancy per 100 women per year of use) when used without missing any pills. The
typical failure rate is approximately 5% per year (5 pregnancies per 100 women per year of use) when
women who miss pills are included. For most women oral contraceptives are also free of serious or
unpleasant side effects. However, forgetting to take pills considerably increases the chances of
pregnancy.
ORTHO TRI-CYCLEN® may also be taken to treat moderate acne in females at least 15 years of age,
who have started having menstrual periods, are able to take the pill and want to use the pill for birth
control.
For the majority of women, oral contraceptives can be taken safely. But there are some women who
are at high risk of developing certain serious diseases that can be fatal or may cause temporary or
permanent disability. The risks associated with taking oral contraceptives increase significantly if you:
•
smoke
•
have high blood pressure, diabetes, high cholesterol
•
have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer of the
breast or sex organs, jaundice or malignant or benign liver tumors
Although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in
healthy, non-smoking women (even with the newer low-dose formulations), there are also greater
potential health risks associated with pregnancy in older women.
You should not take the pill if you suspect you are pregnant or have unexplained vaginal bleeding.
Cigarette smoking increases the risk of serious cardiovascular side effects
from oral contraceptive use. This risk increases with age and with heavy
smoking (15 or more cigarettes per day) and is quite marked in women
over 35 years of age. Women who use oral contraceptives are strongly
advised not to smoke.
Most side effects of the pill are not serious. The most common such effects are nausea, vomiting,
bleeding between menstrual periods, weight gain, breast tenderness, and difficulty wearing contact
lenses. These side effects, especially nausea and vomiting, may subside within the first three months of
use.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 29
The serious side effects of the pill occur very infrequently, especially if you are in good health and are
young. However, you should know that the following medical conditions have been associated with or
made worse by the pill:
1. Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), stoppage or rupture of a
blood vessel in the brain (stroke), blockage of blood vessels in the heart (heart attack or angina
pectoris) or other organs of the body. As mentioned above, smoking increases the risk of heart
attacks and strokes and subsequent serious medical consequences.
2. In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These benign liver
tumors can rupture and cause fatal internal bleeding. In addition, some studies report an increased
risk of developing liver cancer. However, liver cancers are rare.
3. High blood pressure, although blood pressure usually returns to normal when the pill is stopped.
The symptoms associated with these serious side effects are discussed in the detailed leaflet given to
you with your supply of pills. Notify your healthcare professional if you notice any unusual physical
disturbances while taking the pill. In addition, drugs such as rifampin, as well as some anticonvulsants
and some antibiotics may decrease oral contraceptive effectiveness.
Various studies give conflicting reports on the relationship between breast cancer and oral
contraceptive use. Oral contraceptive use may slightly increase your chance of having breast cancer
diagnosed, particularly after using hormonal contraceptives at a younger age. After you stop using
hormonal contraceptives, the chances of having breast cancer diagnosed begin to go back down. You
should have regular breast examinations by a healthcare professional and examine your own breasts
monthly. Tell your healthcare professional if you have a family history of breast cancer or if you have
had breast nodules or an abnormal mammogram. Women who currently have or have had breast cancer
should not use oral contraceptives because breast cancer is usually a hormone-sensitive tumor.
Some studies have found an increase in the incidence of cancer of the cervix in women who use oral
contraceptives. However, this finding may be related to factors other than the use of oral
contraceptives. There is insufficient evidence to rule out the possibility that the pill may cause such
cancers.
Taking the combination pill provides some important non-contraceptive benefits. These include
less painful menstruation, less menstrual blood loss and anemia, fewer pelvic infections, and fewer
cancers of the ovary and the lining of the uterus.
Be sure to discuss any medical condition you may have with your healthcare professional. Your
healthcare professional will take a medical and family history before prescribing oral contraceptives
and will examine you. The physical examination may be delayed to another time if you request it and
the healthcare professional believes that it is a good medical practice to postpone it. You should be
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 30
reexamined at least once a year while taking oral contraceptives. Your pharmacist should have given
you the detailed patient information labeling which gives you further information which you should
read and discuss with your healthcare professional.
H OW TO TAKE THE PILL
IMPORTANT POINTS TO REMEMBER
BEFORE YOU START TAKING YOUR PILLS:
1.
BE SURE TO READ THESE DIRECTIONS:
Before you start taking your pills.
Anytime you are not sure what to do.
2.
THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE
SAME TIME.
If you miss pills you could get pregnant. This includes starting the pack late.
The more pills you miss, the more likely you are to get pregnant.
3.
MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO
THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you feel sick to your
stomach or have spotting or light bleeding, do not stop taking the pill. The problem will usually
go away. If it doesn't go away, check with your healthcare professional.
4.
MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you
make up these missed pills.
On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your
stomach.
5.
IF YOU HAVE VOMITING OR DIARRHEA, OR IF YOU TAKE SOME MEDICINES,
including some antibiotics, your pills may not work as well.
Use a back-up method (such as condoms or spermicide) until you check with your healthcare
professional.
6.
IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your healthcare
professional about how to make pill-taking easier or about using another method of birth
control.
7.
IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN
THIS LEAFLET, call your healthcare professional.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 31
BEFORE YOU START TAKING YOUR PILLS
1.
DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.
It is important to take it at about the same time every day.
2.
LOOK AT YOUR PILL PACK
The pill pack has 21 "active" pills (with hormones) to take for 3 weeks. This is followed by 1
week of "reminder" green pills (without hormones).
ORTHO TRI-CYCLEN®: There are 7 white "active" pills, 7 light blue "active" pills, 7 blue
"active" pills, and 7 green "reminder" pills.
ORTHO-CYCLEN®: There are 21 blue "active" pills, and 7 green "reminder" pills.
3.
ALSO FIND:
1) where on the pack to start taking pills,
2) in what order to take the pills.
4.
BE SURE YOU HAVE READY AT ALL TIMES:
ANOTHER KIND OF BIRTH CONTROL (such as condoms or spermicide) to use as a back-
up method in case you miss pills.
AN EXTRA, FULL PILL PACK.
WHEN TO START THE FIRST PACK OF PILLS
You have a choice of which day to start taking your first pack of pills. ORTHO TRI-CYCLEN® and
ORTHO-CYCLEN® are available in the DIALPAK® Tablet Dispenser which is preset for a Sunday
Start. Day 1 Start is also provided. Decide with your healthcare professional which is the best day for
you. Pick a time of day which will be easy to remember.
Sunday Start:
ORTHO TRI-CYCLEN®: Take the first white "active" pill of the first pack on the Sunday after your
period starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same
day.
ORTHO-CYCLEN®: Take the first blue "active" pill of the first pack on the Sunday after your period
starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same day.
Use another method of birth control such as condoms or spermicide as a back-up method if you have
sex anytime from the Sunday you start your first pack until the next Sunday (7 days).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 32
Day 1 Start:
ORTHO TRI-CYCLEN®: Take the first white "active" pill of the first pack during the first 24 hours
of your period.
ORTHO-CYCLEN®: Take the first blue "active" pill of the first pack during the first 24 hours of your
period.
You will not need to use a back-up method of birth control, since you are starting the pill at the
beginning of your period.
WHAT TO DO DURING THE MONTH
1.
TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS EMPTY.
Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to
your stomach (nausea).
Do not skip pills even if you do not have sex very often.
2.
WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS:
Start the next pack on the day after your last "reminder" pill. Do not wait any days between
packs.
WHAT TO DO IF YOU MISS PILLS
ORTHO TRI-CYCLEN®:
If you MISS 1 white, light blue or blue "active" pill:
1.
Take it as soon as you remember. Take the next pill at your regular time. This means you may
take 2 pills in 1 day.
2.
You do not need to use a back-up birth control method if you have sex.
If you MISS 2 white or light blue "active" pills in a row in WEEK 1 OR WEEK 2 of your pack:
1.
Take 2 pills on the day you remember and 2 pills the next day.
2.
Then take 1 pill a day until you finish the pack.
3.
You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You
MUST use another birth control method (such as condoms or spermicide) as a back-up method
for those 7 days.
If you MISS 2 blue "active" pills in a row in THE 3RD WEEK:
1.
If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and
start a new pack of pills that same day.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 33
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2.
You may not have your period this month but this is expected. However, if you miss your
period 2 months in a row, call your healthcare professional because you might be pregnant.
3.
You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You
MUST use another birth control method (such as condoms or spermicide) as a back-up method
for those 7 days.
If you MISS 3 OR MORE white, light blue or blue "active" pills in a row (during the first 3 weeks):
1.
If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and
start a new pack of pills that same day.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2.
You may not have your period this month but this is expected. However, if you miss your
period 2 months in a row, call your healthcare professional because you might be pregnant.
3.
You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You
MUST use another birth control method (such as condoms or spermicide) as a back-up method
for those 7 days.
ORTHO-CYCLEN®:
If you MISS 1 blue "active" pill:
1.
Take it as soon as you remember. Take the next pill at your regular time. This means you may
take 2 pills in 1 day.
2.
You do not need to use a back-up birth control method if you have sex.
If you MISS 2 blue "active" pills in a row in WEEK 1 OR WEEK 2 of your pack:
1.
Take 2 pills on the day you remember and 2 pills the next day.
2.
Then take 1 pill a day until you finish the pack.
3.
You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You
MUST use another birth control method (such as condoms or spermicide) as a back-up method
for those 7 days.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 34
If you MISS 2 blue "active" pills in a row in THE 3RD WEEK:
1.
If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and
start a new pack of pills that same day.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2.
You may not have your period this month but this is expected. However, if you miss your
period 2 months in a row, call your healthcare professional because you might be pregnant.
3.
You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You
MUST use another birth control method (such as condoms or spermicide) as a back-up method
for those 7 days.
If you MISS 3 OR MORE blue "active" pills in a row (during the first 3 weeks):
1.
If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and
start a new pack of pills that same day.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2.
You may not have your period this month but this is expected. However, if you miss your
period 2 months in a row, call your healthcare professional because you might be pregnant.
3.
You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You
MUST use another birth control method (such as condoms or spermicide) as a back-up method
for those 7 days.
A REMINDER:
If you forget any of the 7 green "reminder" pills in Week 4:
THROW AWAY the pills you missed.
Keep taking 1 pill each day until the pack is empty.
You do not need a back-up method.
FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE
MISSED:
Use a BACK-UP METHOD anytime you have sex.
KEEP TAKING ONE "ACTIVE" PILL EACH DAY until you can reach your healthcare professional.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 35
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 36
DETAILED PATIENT LABELING
PLEASE NOTE: This labeling is revised from time to time as important new medical
information becomes available. Therefore, please review this labeling carefully.
This product (like all oral contraceptives) does not protect against HIV infection (AIDS) and
other sexually transmitted diseases.
ORTHO TRI-CYCLEN® Regimen
Each white tablet contains 0.180 mg norgestimate and 0.035 mg ethinyl estradiol. Each light blue
tablet contains 0.215 mg norgestimate and 0.035 mg ethinyl estradiol. Each blue tablet contains 0.250
mg norgestimate and 0.035 mg ethinyl estradiol. Each green tablet contains inert ingredients.
ORTHO-CYCLEN® Regimen
Each blue tablet contains 0.250 mg norgestimate and 0.035 mg ethinyl estradiol. Each green tablet
contains inert ingredients.
INTRODUCTION
Any woman who considers using oral contraceptives (the birth control pill or the pill) should
understand the benefits and risks of using this form of birth control. This patient labeling will give you
much of the information you will need to make this decision and will also help you determine if you
are at risk of developing any of the serious side effects of the pill. It will tell you how to use the pill
properly so that it will be as effective as possible. However, this labeling is not a replacement for a
careful discussion between you and your healthcare professional. You should discuss the information
provided in this labeling with him or her, both when you first start taking the pill and during your
revisits. You should also follow your healthcare professional’s advice with regard to regular check-ups
while you are on the pill.
EFFECTIVENESS OF ORAL CONTRACEPTIVES FOR CONTRACEPTION
Oral contraceptives or "birth control pills" or "the pill" are used to prevent pregnancy and are more
effective than most other non-surgical methods of birth control. When they are taken correctly without
missing any pills, the chance of becoming pregnant is approximately 1% per year (1 pregnancy per 100
women per year of use). Typical failure rates, including women who do not always take the pill
correctly, are approximately 5% per year (5 pregnancies per 100 women per year of use). The chance
of becoming pregnant increases with each missed pill during a menstrual cycle.
In comparison, typical failure rates for other non-surgical methods of birth control during the first year
of use are as follows:
Implant: <1%
Male sterilization: <1%
Injection: <1%
Cervical Cap with spermicides: 20 to 40%
IUD: 1 to 2%
Condom alone (male): 14%
Diaphragm with spermicides: 20%
Condom alone (female): 21%
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 37
Spermicides alone: 26%
Periodic abstinence: 25%
Vaginal sponge: 20 to 40%
Withdrawal: 19%
Female sterilization: <1%
No methods: 85%
ORTHO TRI-CYCLEN® may also be taken to treat moderate acne if all of the following are true:
•
You have started having menstrual cycles
•
You are at least 15 years old
•
Your healthcare professional says it is safe for you to use the pill
•
You want to use the pill for birth control
WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES
Cigarette smoking increases the risk of serious cardiovascular side
effects from oral contraceptive use. This risk increases with age and with
heavy smoking (15 or more cigarettes per day) and is quite marked in
women over 35 years of age. Women who use oral contraceptives are
strongly advised not to smoke.
Some women should not use the pill. For example, you should not take the pill if you have any of the
following conditions:
•
A history of heart attack or stroke
•
Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes
•
A history of blood clots in the deep veins of your legs
•
Chest pain (angina pectoris)
•
Known or suspected breast cancer or cancer of the lining of the uterus, cervix or vagina
•
Unexplained vaginal bleeding (until a diagnosis is reached by your healthcare
professional)
•
Yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or during
previous use of the pill
•
Liver tumor (benign or cancerous) or active liver disease
•
Known or suspected pregnancy
•
Valvular heart disease with complications
•
Severe hypertension
•
Diabetes with vascular involvement
•
Headaches with focal neurological symptoms
•
Major surgery with prolonged immobilization
•
Hypersensitivity to any component of this product
Tell your healthcare professional if you have had any of these conditions. Your healthcare professional
can recommend a safer method of birth control.
OTHER CONSIDERATIONS BEFORE TAKING ORAL CONTRACEPTIVES
Tell your healthcare professional if you have or have had:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 38
•
Breast nodules, fibrocystic disease of the breast, an abnormal breast x-ray or mammogram
•
Diabetes
•
Elevated cholesterol or triglycerides
•
High blood pressure
•
Migraine or other headaches or epilepsy
•
Mental depression
•
Gallbladder, liver, heart or kidney disease
•
History of scanty or irregular menstrual periods
Women with any of these conditions should be checked often by their healthcare professional if they
choose to use oral contraceptives.
Also, be sure to inform your healthcare professional if you smoke or are on any medications.
RISKS OF TAKING ORAL CONTRACEPTIVES
1.
Risk of Developing Blood Clots
Blood clots and blockage of blood vessels are one of the most serious side effects of taking oral
contraceptives and can cause death or serious disability. In particular, a clot in the legs can cause
thrombophlebitis and a clot that travels to the lungs can cause a sudden blocking of the vessel carrying
blood to the lungs. Rarely, clots occur in the blood vessels of the eye and may cause blindness, double
vision, or impaired vision.
If you take oral contraceptives and need elective surgery, need to stay in bed for a prolonged illness or
injury or have recently delivered a baby, you may be at risk of developing blood clots. You should
consult your healthcare professional about stopping oral contraceptives four weeks before surgery and
not taking oral contraceptives for two weeks after surgery or during bed rest. You should also not take
oral contraceptives soon after delivery of a baby. It is advisable to wait for at least four weeks after
delivery if you are not breast feeding. If you are breast feeding, you should wait until you have weaned
your child before using the pill. (See also the section on Breast Feeding in General Precautions.)
The risk of circulatory disease in oral contraceptive users may be higher in users of high- dose pills and
may be greater with longer duration of oral contraceptive use. In addition, some of these increased
risks may continue for a number of years after stopping oral contraceptives. The risk of abnormal
blood clotting increases with age in both users and nonusers of oral contraceptives, but the increased
risk from the oral contraceptive appears to be present at all ages. For women aged 20 to 44 it is
estimated that about 1 in 2,000 using oral contraceptives will be hospitalized each year because of
abnormal clotting. Among nonusers in the same age group, about 1 in 20,000 would be hospitalized
each year. For oral contraceptive users in general, it has been estimated that in women between the
ages of 15 and 34 the risk of death due to a circulatory disorder is about 1 in 12,000 per year, whereas
for nonusers the rate is about 1 in 50,000 per year. In the age group 35 to 44, the risk is estimated to be
about 1 in 2,500 per year for oral contraceptive users and about 1 in 10,000 per year for nonusers.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 39
2.
Heart Attacks and Strokes
Oral contraceptives may increase the tendency to develop strokes (stoppage or rupture of blood vessels
in the brain) and angina pectoris and heart attacks (blockage of blood vessels in the heart). Any of
these conditions can cause death or serious disability.
Smoking greatly increases the possibility of suffering heart attacks and strokes. Furthermore, smoking
and the use of oral contraceptives greatly increase the chances of developing and dying of heart
disease.
3.
Gallbladder Disease
Oral contraceptive users probably have a greater risk than nonusers of having gallbladder disease,
although this risk may be related to pills containing high doses of estrogens.
4.
Liver Tumors
In rare cases, oral contraceptives can cause benign but dangerous liver tumors. These benign liver
tumors can rupture and cause fatal internal bleeding. In addition, some studies report an increased risk
of developing liver cancer. However, liver cancers are rare.
5.
Cancer of the Reproductive Organs and Breasts
Various studies give conflicting reports on the relationship between breast cancer and oral
contraceptive use. Oral contraceptive use may slightly increase your chance of having breast cancer
diagnosed, particularly after using hormonal contraceptives at a younger age. After you stop using
hormonal contraceptives, the chances of having breast cancer diagnosed begin to go back down. You
should have regular breast examinations by a healthcare professional and examine your own breasts
monthly. Tell your healthcare professional if you have a family history of breast cancer or if you have
had breast nodules or an abnormal mammogram. Women who currently have or have had breast cancer
should not use oral contraceptives because breast cancer is usually a hormone-sensitive tumor.
Some studies have found an increase in the incidence of cancer of the cervix in women who use oral
contraceptives. However, this finding may be related to factors other than the use of oral
contraceptives. There is insufficient evidence to rule out the possibility that the pill may cause such
cancers.
ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD OR PREGNANCY
All methods of birth control and pregnancy are associated with a risk of developing certain diseases
which may lead to disability or death. An estimate of the number of deaths associated with different
methods of birth control and pregnancy has been calculated and is shown 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 19-653/S-037
NDA 19-697/S-034
Page 40
Annual Number of Birth-Related or Method-Related Deaths Associated With Control of
Fertility Per 100,000 Non-Sterile Women, by Fertility Control Method According To Age
Method of control
and outcome
15-19
20-24
25-29
30-34
35-39
40-44
No fertility
control methods
7.0
7.4
9.1
14.8
25.7
28.2
Oral contraceptives
non-smoker
0.3
0.5
0.9
1.9
13.8
31.6
Oral contraceptives
smoker**
2.2
3.4
6.6
13.5
51.1
117.2
IUD**
0.8
0.8
1.0
1.0
1.4
1.4
Condom*
1.1
1.6
0.7
0.2
0.3
0.4
Diaphragm/
spermicide*
1.9
1.2
1.2
1.3
2.2
2.8
Periodic
abstinence*
2.5
1.6
1.6
1.7
2.9
3.6
*Deaths are birth-related
**Deaths are method-related
Adapted from H.W. Ory, ref. #35.
In the above table, the risk of death from any birth control method is less than the risk of childbirth,
except for oral contraceptive users over the age of 35 who smoke and pill users over the age of 40 even
if they do not smoke. It can be seen in the table that for women aged 15 to 39, the risk of death was
highest with pregnancy (7 to 26 deaths per 100,000 women, depending on age). Among pill users who
do not smoke, the risk of death was always lower than that associated with pregnancy for any age
group less than 40. Over the age of 40, the risk increases to 32 deaths per 100,000 women, compared
to 28 associated with pregnancy in that age group. However, for pill users who smoke and are over the
age of 35, the estimated number of deaths exceeds those for other methods of birth control. If a woman
is over the age of 40 and smokes, her estimated risk of death is four times higher (117/100,000 women)
than the estimated risk associated with pregnancy (28/100,000 women) in that age group.
The suggestion that women over 40 who do not smoke should not take oral contraceptives is based on
information from older, higher-dose pills. An Advisory Committee of the FDA discussed this issue in
1989 and recommended that the benefits of low-dose oral contraceptive use by healthy, non-smoking
women over 40 years of age may outweigh the possible risks. Older women, as all women, who take
oral contraceptives, should take an oral contraceptive which contains the least amount of estrogen and
progestogen that is compatible with the individual patient needs.
WARNING SIGNALS
If any of these adverse effects occur while you are taking oral contraceptives, call your healthcare
professional immediately:
• Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible
clot in the lung)
• Pain in the calf (indicating a possible clot in the leg)
• Crushing chest pain or heaviness in the chest (indicating a possible heart attack)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 41
• Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or
speech, weakness, or numbness in an arm or leg (indicating a possible stroke)
• Sudden partial or complete loss of vision (indicating a possible clot in the eye)
• Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your
healthcare professional to show you how to examine your breasts)
• Severe pain or tenderness in the stomach area (indicating a possibly ruptured liver tumor)
• Difficulty in sleeping, weakness, lack of energy, fatigue, or change in mood (possibly
indicating severe depression)
• Jaundice or a yellowing of the skin or eyeballs, accompanied frequently by fever, fatigue,
loss of appetite, dark colored urine, or light colored bowel movements (indicating possible
liver problems)
SIDE EFFECTS OF ORAL CONTRACEPTIVES
In addition to the risks and more serious side effects discussed above, the following may also occur:
1.
Irregular vaginal bleeding
Irregular vaginal bleeding or spotting may occur while you are taking the pills. Irregular bleeding may
vary from slight staining between menstrual periods to breakthrough bleeding which is a flow much
like a regular period. Irregular bleeding occurs most often during the first few months of oral
contraceptive use, but may also occur after you have been taking the pill for some time. Such bleeding
may be temporary and usually does not indicate any serious problems. It is important to continue
taking your pills on schedule. If the bleeding occurs in more than one cycle or lasts for more than a few
days, talk to your healthcare professional.
2.
Contact Lenses
If you wear contact lenses and notice a change in vision or an inability to wear your lenses, contact
your healthcare professional.
3.
Fluid Retention
Oral contraceptives may cause edema (fluid retention) with swelling of the fingers or ankles and may
raise your blood pressure. If you experience fluid retention, contact your healthcare professional.
4.
Melasma
A spotty darkening of the skin is possible, particularly of the face, which may persist.
5.
Other Side Effects
Other side effects may include nausea and vomiting, change in appetite, headache, nervousness,
depression, dizziness, loss of scalp hair, rash, and vaginal infections.
If any of these side effects bother you, call your healthcare professional.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 42
GENERAL PRECAUTIONS
1.
Missed Periods and Use of Oral Contraceptives Before or During
Early Pregnancy
There may be times when you may not menstruate regularly after you have completed taking a cycle of
pills. If you have taken your pills regularly and miss one menstrual period, continue taking your pills
for the next cycle but be sure to inform your healthcare professional. If you have not taken the pills
daily as instructed and missed a menstrual period, or if you missed two consecutive menstrual periods,
you may be pregnant. . Check with your healthcare professional immediately to determine whether you
are pregnant. Stop taking your pills if you are pregnant.
There is no conclusive evidence that oral contraceptive use is associated with an increase in birth
defects, when taken inadvertently during early pregnancy. Previously, a few studies had reported that
oral contraceptives might be associated with birth defects, but these findings have not been seen in
more recent studies. Nevertheless, oral contraceptives should not be used during pregnancy. You
should check with your healthcare professional about risks to your unborn child of any medication
taken during pregnancy.
2.
While Breast Feeding
If you are breast feeding, consult your healthcare professional before starting oral contraceptives.
Some of the drug will be passed on to the child in the milk. A few adverse effects on the child have
been reported, including yellowing of the skin (jaundice) and breast enlargement. In addition,
combination oral contraceptives may decrease the amount and quality of your milk. If possible, do not
use combination oral contraceptives while breast feeding. You should use another method of
contraception since breast feeding provides only partial protection from becoming pregnant and this
partial protection decreases significantly as you breast feed for longer periods of time. You should
consider starting combination oral contraceptives only after you have weaned your child completely.
3.
Laboratory Tests
If you are scheduled for any laboratory tests, tell your healthcare professional you are taking birth
control pills. Certain blood tests may be affected by birth control pills.
4.
Drug Interactions
Certain drugs may interact with birth control pills to make them less effective in preventing pregnancy
or cause an increase in breakthrough bleeding. Such drugs include rifampin, drugs used for epilepsy
such as barbiturates (for example, phenobarbital), topiramate (Topamax®), carbamazepine (Tegretol®
is one brand of this drug), or phenytoin (Dilantin® is one brand of this drug), phenylbutazone
(Butazolidin® is one brand), certain drugs used in the treatment of HIV or AIDS, and possibly certain
antibiotics. Pregnancies and breakthrough bleeding have been reported by women who also used
some form of the herbal supplement St. John’s Wort while using combined hormonal contraceptives.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 43
You may need to use additional contraception when you take drugs which can make oral
contraceptives less effective. Be sure to tell your healthcare professional if you are taking or start
taking any medications while taking birth control pills.
5.
Sexually Transmitted Diseases
ORTHO-CYCLEN® and ORTHO TRI-CYCLEN® (like all oral contraceptives) are intended to prevent
pregnancy. Oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually
transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and
syphilis.
HOW TO TAKE THE PILL
IMPORTANT POINTS TO REMEMBER
BEFORE YOU START TAKING YOUR PILLS:
1.
BE SURE TO READ THESE DIRECTIONS:
Before you start taking your pills.
Anytime you are not sure what to do.
2.
THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT THE
SAME TIME.
If you miss pills you could get pregnant. This includes starting the pack late.
The more pills you miss, the more likely you are to get pregnant.
3.
MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK TO
THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you feel sick to your
stomach or have spotting or light bleeding, do not stop taking the pill. The problem will usually
go away. If it doesn't go away, check with your healthcare professional.
4.
MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even when you
make up these missed pills.
On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your
stomach.
5.
IF YOU HAVE VOMITING OR DIARRHEA, OR IF YOU TAKE SOME MEDICINES,
including some antibiotics, your pills may not work as well.
Use a back-up method (such as condoms or spermicide) until you check with your healthcare
professional.
6.
IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your healthcare
professional about how to make pill-taking easier or about using another method of birth
control.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 44
7.
IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE INFORMATION IN
THIS LEAFLET, call your healthcare professional.
BEFORE YOU START TAKING YOUR PILLS
1.
DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.
It is important to take it at about the same time every day.
2.
LOOK AT YOUR PILL PACK
The pill pack has 21 "active" pills (with hormones) to take for 3 weeks. This is followed by 1
week of "reminder" green pills (without hormones).
ORTHO TRI-CYCLEN®: There are 7 white "active" pills, 7 light blue "active" pills, 7 blue
"active" pills, and 7 green "reminder" pills.
ORTHO-CYCLEN®: There are 21 blue "active" pills and 7 green "reminder" pills.
3.
ALSO FIND:
1) where on the pack to start taking pills,
2) in what order to take the pills.
CHECK PICTURE OF PILL PACK AND ADDITIONAL INSTRUCTIONS FOR USING THIS
PACKAGE IN THE BRIEF SUMMARY PATIENT PACKAGE INSERT.
4.
BE SURE YOU HAVE READY AT ALL TIMES:
ANOTHER KIND OF BIRTH CONTROL (such as condoms or spermicide) to use as a back-
up method in case you miss pills.
AN EXTRA, FULL PILL PACK.
WHEN TO START THE FIRST PACK OF PILLS
You have a choice of which day to start taking your first pack of pills. ORTHO TRI-CYCLEN® and
ORTHO-CYCLEN® are available in the DIALPAK® Tablet Dispenser which is preset for a Sunday
Start. Day 1 Start is also provided. Decide with your healthcare professional which is the best day for
you. Pick a time of day which will be easy to remember.
Sunday Start:
ORTHO TRI-CYCLEN®: Take the first white "active" pill of the first pack on the Sunday after your
period starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same
day.
ORTHO-CYCLEN®: Take the first blue "active" pill of the first pack on the Sunday after your period
starts, even if you are still bleeding. If your period begins on Sunday, start the pack that same day.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 45
Use another method of birth control such as condoms or spermicide as a back-up method if you have
sex anytime from the Sunday you start your first pack until the next Sunday (7 days).
Day 1 Start:
ORTHO TRI-CYCLEN®: Take the first white "active" pill of the first pack during the first 24 hours
of your period.
ORTHO-CYCLEN®: Take the first blue "active" pill of the first pack during the first 24 hours of your
period.
You will not need to use a back-up method of birth control, since you are starting the pill at the
beginning of your period.
WHAT TO DO DURING THE MONTH
1.
Take One Pill at the Same Time Every Day Until the Pack is Empty.
Do not skip pills even if you are spotting or bleeding between monthly periods or feel sick to
your stomach (nausea).
Do not skip pills even if you do not have sex very often.
2.
When You Finish a Pack or Switch Your Brand of Pills:
Start the next pack on the day after your last "reminder" pill. Do not wait any days between
packs.
WHAT TO DO IF YOU MISS PILLS
ORTHO TRI-CYCLEN®:
If you MISS 1 white, light blue or blue "active" pill:
1.
Take it as soon as you remember. Take the next pill at your regular time. This means you may
take 2 pills in 1 day.
2.
You do not need to use a back-up birth control method if you have sex.
If you MISS 2 white or light blue "active" pills in a row in WEEK 1 OR WEEK 2 of your pack:
1.
Take 2 pills on the day you remember and 2 pills the next day.
2.
Then take 1 pill a day until you finish the pack.
3.
You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You
MUST use another birth control method (such as condoms or spermicide) as a back-up method
for those 7 days.
If you MISS 2 blue "active" pills in a row in THE 3RD WEEK:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 46
1.
If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and
start a new pack of pills that same day.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2.
You may not have your period this month but this is expected. However, if you miss your
period 2 months in a row, call your healthcare professional because you might be pregnant.
3.
You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You
MUST use another birth control method (such as condoms or spermicide) as a back-up method
for those 7 days.
If you MISS 3 OR MORE white, light blue or blue "active" pills in a row (during the first 3 weeks):
1.
If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and
start a new pack of pills that same day.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2.
You may not have your period this month but this is expected. However, if you miss your
period 2 months in a row, call your healthcare professional because you might be pregnant.
3.
You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You
MUST use another birth control method (such as condoms or spermicide) as a back-up method
for those 7 days.
ORTHO-CYCLEN®:
If you MISS 1 blue "active" pill:
1.
Take it as soon as you remember. Take the next pill at your regular time. This means you may
take 2 pills in 1 day.
2.
You do not need to use a back-up birth control method if you have sex.
If you MISS 2 blue "active" pills in a row in WEEK 1 OR WEEK 2 of your pack:
1.
Take 2 pills on the day you remember and 2 pills the next day.
2.
Then take 1 pill a day until you finish the pack.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 47
3.
You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You
MUST use another birth control method (such as condoms or spermicide) as a back-up method
for those 7 days.
If you MISS 2 blue "active" pills in a row in THE 3RD WEEK:
1.
If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and
start a new pack of pills that same day.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2.
You may not have your period this month but this is expected. However, if you miss your
period 2 months in a row, call your healthcare professional because you might be pregnant.
3.
You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You
MUST use another birth control method (such as condoms or spermicide) as a back-up method
for those 7 days.
If you MISS 3 OR MORE blue "active" pills in a row (during the first 3 weeks):
1.
If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of the pack and
start a new pack of pills that same day.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2.
You may not have your period this month but this is expected. However, if you miss your
period 2 months in a row, call your healthcare professional because you might be pregnant.
3.
You COULD BECOME PREGNANT if you have sex in the 7 days after you miss pills. You
MUST use another birth control method (such as condoms or spermicide) as a back-up method
for those 7 days.
A REMINDER:
If you forget any of the 7 green "reminder" pills in Week 4:
THROW AWAY the pills you missed.
Keep taking 1 pill each day until the pack is empty.
You do not need a back-up method.
FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE
MISSED:
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 48
Use a BACK-UP METHOD anytime you have sex.
KEEP TAKING ONE "ACTIVE" PILL EACH DAY until you can reach your healthcare professional.
PREGNANCY DUE TO PILL FAILURE
The incidence of pill failure resulting in pregnancy is approximately 5%, including women who do not
always take the pills exactly as directed. If failure does occur, the risk to the fetus is minimal.
PREGNANCY AFTER STOPPING THE PILL
There may be some delay in becoming pregnant after you stop using oral contraceptives, especially if
you had irregular menstrual cycles before you used oral contraceptives. It may be advisable to
postpone conception until you begin menstruating regularly once you have stopped taking the pill and
desire pregnancy.
There does not appear to be any increase in birth defects in newborn babies when pregnancy occurs
soon after stopping the pill.
OVERDOSAGE
Serious ill effects have not been reported following ingestion of large doses of oral contraceptives by
young children. Overdosage may cause nausea and withdrawal bleeding in females. In case of
overdosage, contact your healthcare professional or pharmacist.
OTHER INFORMATION
Your healthcare professional will take a medical and family history before prescribing oral
contraceptives and will examine you. The physical examination may be delayed to another time if you
request it and the healthcare professional believes that it is a good medical practice to postpone it. You
should be reexamined at least once a year. Be sure to inform your healthcare professional if there is a
family history of any of the conditions listed previously in this leaflet. Be sure to keep all appointments
with your healthcare professional, because this is a time to determine if there are early signs of side
effects of oral contraceptive use.
Do not use the drug for any condition other than the one for which it was prescribed. This drug has
been prescribed specifically for you; do not give it to others who may want birth control pills.
HEALTH BENEFITS FROM ORAL CONTRACEPTIVES
In addition to preventing pregnancy, use of combination oral contraceptives may provide certain
benefits. They are:
•
menstrual cycles may become more regular
•
blood flow during menstruation may be lighter and less iron may be lost. Therefore,
anemia due to iron deficiency is less likely to occur
•
pain or other symptoms during menstruation may be encountered less frequently
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-653/S-037
NDA 19-697/S-034
Page 49
•
ectopic (tubal) pregnancy may occur less frequently
•
noncancerous cysts or lumps in the breast may occur less frequently
•
acute pelvic inflammatory disease may occur less frequently
•
oral contraceptive use may provide some protection against developing two forms of
cancer: cancer of the ovaries and cancer of the lining of the uterus.
If you want more information about birth control pills, ask your healthcare professional or pharmacist.
They have a more technical leaflet called the Professional Labeling, which you may wish to read. The
professional labeling is also published in a book entitled Physicians' Desk Reference, available in many
book stores and public libraries.
(LOGO)
ORTHO-McNEIL PHARMACEUTICAL, INC.
Raritan, New Jersey 08869
© OPC 1998
Revised January 2007
635-50-900-X
Printed in U.S.A.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:37.991853
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/019653s037,019697s034lbl.pdf', 'application_number': 19653, 'submission_type': 'SUPPL ', 'submission_number': 37}
|
11,602
|
ORTHO TRI-CYCLEN TABLETS (norgestimate/ethinyl estradiol)
and ORTHO-CYCLEN TABLETS (norgestimate/ethinyl estradiol)
WARNINGS: CARDIOVASCULAR RISK ASSOCIATED WITH
SMOKING
Cigarette smoking increases the risk of serious cardiovascular events from
combination oral contraceptive use. This risk increases with age, particularly in
women over 35 years of age, and with the number of cigarettes smoked. For this
reason, combination oral contraceptives, including ORTHO TRI-CYCLEN and
ORTHO-CYCLEN, should not be used by women who are over 35 years of
age and smoke.
Patients should be counseled that this product does not protect against HIV
infection (AIDS) and other sexually transmitted diseases.
DESCRIPTION
Each of the following products is a combination oral contraceptive containing
the progestational compound norgestimate and the estrogenic compound ethinyl
estradiol.
ORTHO TRI-CYCLEN Tablets.
Each white tablet contains 0.180 mg of the progestational compound,
norgestimate (18,19-Dinor-17-pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl
, oxime,(17)-(+)-) and 0.035 mg of the estrogenic compound, ethinyl estradiol
(19-nor-17-pregna,1,3,5(10)-trien-20-yne-3,17-diol).
Inactive
ingredients
include carnauba wax, croscarmellose sodium, hypromellose, lactose,
magnesium stearate, microcrystalline cellulose, polyethylene glycol, purified
water and titanium dioxide.
Each light blue tablet contains 0.215 mg of the progestational compound
norgestimate
(18,19-Dinor-17-pregn-4-en-20-yn-3-one,17-(acetyloxy)-13
ethyl-,oxime,(17)-(+)-) and 0.035 mg of the estrogenic compound, ethinyl
estradiol
(19-nor-17-pregna,1,3,5(10)-trien-20-yne-3,17-diol).
Inactive
ingredients include FD & C Blue No. 2 Aluminum Lake, carnauba wax,
croscarmellose
sodium,
hypromellose,
lactose,
magnesium
stearate,
microcrystalline cellulose, polyethylene glycol, purified water and titanium
dioxide.
Each blue tablet contains 0.250 mg of the progestational compound
norgestimate
(18,19-Dinor-17-pregn-4-en-20-yn-3-one,
17-(acetyloxy)-13
ethyl-,oxime,(17)-(+)-) and 0.035 mg of the estrogenic compound, ethinyl
estradiol
(19-nor-17-pregna,1,3,5(10)-trien-20-yne-3,17-diol).
Inactive
Reference ID: 3383539
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ingredients include FD & C Blue No. 2 Aluminum Lake, carnauba wax,
croscarmellose
sodium,
hypromellose,
lactose,
magnesium
stearate,
microcrystalline cellulose, polyethylene glycol, polysorbate 80, purified water
and titanium dioxide.
Each dark green tablet contains only inert ingredients, as follows: FD & C Blue
No. 2 Aluminum Lake, ferric oxide, hypromellose, lactose, magnesium stearate,
polyethylene glycol, pregelatinized corn starch, purified water, talc and titanium
dioxide.
ORTHO-CYCLEN Tablets.
Each blue tablet contains 0.250 mg of the progestational compound
norgestimate (18,19-Dinor-17-pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl
,oxime,(17)-(+)-) and 0.035 mg of the estrogenic compound, ethinyl estradiol
(19-nor-17-pregna,1,3,5(10)-trien-20-yne-3,17-diol).
Inactive
ingredients
include FD & C Blue No. 2 Aluminum Lake, carnauba wax, croscarmellose
sodium, hypromellose, lactose, magnesium stearate, microcrystalline cellulose,
polyethylene glycol, polysorbate 80, purified water and titanium dioxide.
Each dark green tablet contains only inert ingredients, as follows: FD & C Blue
No. 2 Aluminum Lake, ferric oxide, hypromellose, lactose, magnesium stearate,
polyethylene glycol, pregelatinized corn starch, purified water, talc and titanium
dioxide.
Reference ID: 3383539
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINICAL PHARMACOLOGY
Oral Contraception
Combination oral contraceptives act by suppression of gonadotropins. Although
the primary mechanism of this action is inhibition of ovulation, other alterations
include changes in the cervical mucus (which increase the difficulty of sperm
entry into the uterus) and the endometrium (which reduce the likelihood of
implantation).
Receptor binding studies, as well as studies in animals and humans, have shown
that norgestimate and 17-deacetyl norgestimate, the major serum metabolite,
combine high progestational activity with minimal intrinsic androgenicity90-93
Norgestimate, in combination with ethinyl estradiol, does not counteract the
estrogen-induced increases in sex hormone binding globulin (SHBG), resulting
in lower serum testosterone.90,91,94
Acne
Acne is a skin condition with a multifactorial etiology, including androgen
stimulation of sebum production. While the combination of ethinyl estradiol and
norgestimate increases sex hormone binding globulin (SHBG) and decreases
free testosterone, the relationship between these changes and a decrease in the
severity of facial acne in otherwise healthy women with this skin condition has
not been established.
PHARMACOKINETICS
Absorption
Norgestimate (NGM) and ethinyl estradiol (EE) are rapidly absorbed following
oral administration. Norgestimate is rapidly and completely metabolized by
first pass (intestinal and/or hepatic) mechanisms to norelgestromin (NGMN) and
norgestrel (NG), which are the major active metabolites of norgestimate.
Peak serum concentrations of NGMN and EE are generally reached by 2 hours
after administration of ORTHO-CYCLEN or ORTHO TRI-CYCLEN .
Accumulation following multiple dosing of the 250 mcg NGM / 35 mcg dose is
approximately 2-fold for NGMN and EE compared with single dose
administration. The pharmacokinetics of NGMN is dose proportional following
NGM doses of 180 mcg to 250 mcg. Steady-state concentration of EE is
achieved by Day 7 of each dosing cycle. Steady-state concentrations of NGMN
and NG are achieved by Day 21. Non-linear accumulation (approximately
8 fold) of norgestrel is observed as a result of high affinity binding to SHBG
(sex hormone-binding globulin), which limits its biological activity.
Reference ID: 3383539
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1:
Summary of norelgestromin, norgestrel and ethinyl estradiol
pharmacokinetic parameters.
Mean (SD) Pharmacokinetic Parameters of ORTHO TRI-CYCLEN® During a Three
Cycle Study
Analyte
Cycle
Day
Cmax
tmax (h)
AUC0-24h
t1/2 (h)
NGMN
3
7
1.80 (0.46)
1.42 (0.73)
15.0 (3.88)
NC
14
2.12 (0.56)
1.21 (0.26)
16.1 (4.97)
NC
21
2.66 (0.47)
1.29 (0.26)
21.4 (3.46)
22.3 (6.54)
NG
3
7
1.94 (0.82)
3.15 (4.05)
34.8 (16.5)
NC
14
3.00 (1.04)
2.21 (2.03)
55.2 (23.5)
NC
21
3.66 (1.15)
2.58 (2.97)
69.3 (23.8)
40.2 (15.4)
EE
3
7
124 (39.5)
1.27 (0.26)
1130 (420)
NC
14
128 (38.4)
1.32 (0.25)
1130 (324)
NC
21
126 (34.7)
1.31 (0.56)
1090 (359)
15.9 (4.39)
Mean (SD) Pharmacokinetic Parameters of ORTHO-CYCLEN® During a Three Cycle
Study
Analyte
Cycle
Day
Cmax
tmax (h)
AUC0-24h
t1/2 (h)
NGMN
1
1
1.78 (0.397)
1.19 (0.250)
9.90 (3.25)
18.4 (5.91)
3
21
2.19 (0.655)
1.43 (0.680)
18.1 (5.53)
24.9 (9.04)
NG
1
1
0.649 (0.49)
1.42 (0.69)
6.22 (2.46)
37.8 (14.0)
3
21
2.65 (1.11)
1.67 (1.32)
48.2 (20.5)
45.0 (20.4)
EE
1
1
92.2 (24.5)
1.2 (0.26)
629 (138)
10.1 (1.90)
3
21
147 (41.5)
1.13 (0.23)
1210 (294)
15.0 (2.36)
Cmax = peak serum concentration, tmax = time to reach peak serum concentration, AUC0-24h = area
under serum concentration vs time curve from 0 to 24 hours, t1/2 = elimination half-life, NC =
not calculated.
NGMN and NG: Cmax = ng/mL, AUC0-24h = hng/mL
EE: Cmax = pg/mL, AUC0-24h = hpg/mL
The effect of food on the pharmacokinetics of ORTHO-CYCLEN® or
ORTHO TRI-CYCLEN® has not been studied.
Distribution
Norelgestromin and norgestrel are highly bound (>97%) to serum proteins.
Norelgestromin is bound to albumin and not to SHBG, while norgestrel is bound
primarily to SHBG. Ethinyl estradiol is extensively bound (>97%) to serum
albumin and induces an increase in the serum concentrations of SHBG.
Metabolism
Norgestimate is extensively metabolized by first-pass mechanisms in the
gastrointestinal tract and/or liver. Norgestimate’s primary active metabolite is
norelgestromin. Subsequent hepatic metabolism of norelgestromin occurs and
metabolites include norgestrel, which is also active, and various hydroxylated
and conjugated metabolites. Ethinyl estradiol is also metabolized to various
hydroxylated products and their glucuronide and sulfate conjugates.
Reference ID: 3383539
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Excretion
The metabolites of norelgestromin and ethinyl estradiol are eliminated by renal
and fecal pathways. Following administration of 14C-norgestimate, 47%
(45-49%) and 37% (16-49%) of the administered radioactivity was eliminated in
the urine and feces, respectively. Unchanged norgestimate was not detected in
the urine. In addition to 17-deacetyl norgestimate, a number of metabolites of
norgestimate have been identified in human urine following administration of
radiolabeled norgestimate. These include 18, 19-Dinor-17-pregn-4-en-20-yn-3
one,17-hydroxy-13-ethyl,(17α)-(-);18,19-Dinor-5β-17-pregnan-20-yn,3α,17β
dihydroxy-13-ethyl,(17α), various hydroxylated metabolites and conjugates of
these metabolites.
Special Populations
The effects of body weight, body surface area or age on the pharmacokinetics of
ORTHO-CYCLEN or ORTHO TRI-CYCLEN have not been studied.
Hepatic Impairment
The
effects
of
hepatic
impairment
on
the
pharmacokinetics
of
ORTHO-CYCLEN or ORTHO TRI-CYCLEN have not been studied.
However, steroid hormones may be poorly metabolized in women with impaired
liver function (see PRECAUTIONS).
Renal Impairment
The effects of renal impairment on the pharmacokinetics of ORTHO-CYCLEN
or ORTHO TRI-CYCLEN have not been studied.
Drug-Drug Interactions
No
formal
drug-drug
interaction
studies
were
conducted
with
ORTHO-CYCLEN or ORTHO TRI-CYCLEN . Interactions between
contraceptive steroids and other drugs have been reported in the literature (see
PRECAUTIONS).
Although norelgestromin and its metabolites inhibit a variety of P450 enzymes
in human liver microsomes, under the recommended dosing regimen, the in vivo
concentrations of norelgestromin and its metabolites, even at the peak serum
levels, are relatively low compared to the inhibitory constant (Ki).
INDICATIONS AND USAGE
ORTHO-CYCLEN and ORTHO TRI-CYCLEN Tablets are indicated for the
prevention of pregnancy in women who elect to use oral contraceptives as a
method of contraception.
Reference ID: 3383539
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ORTHO TRI-CYCLEN® is indicated for the treatment of moderate acne
vulgaris in females at least 15 years of age, who have no known
contraindications to oral contraceptive therapy and have achieved menarche.
ORTHO TRI-CYCLEN® should be used for the treatment of acne only if the
patient desires an oral contraceptive for birth control.
Oral contraceptives are highly effective for pregnancy prevention. Table 2 lists
the typical accidental pregnancy rates for users of combination oral
contraceptives and other methods of contraception. The efficacy of these
contraceptive methods, except sterilization, the IUD, and the Norplant® System,
depends upon the reliability with which they are used. Correct and consistent
use of methods can result in lower failure rates.
Table 2:
Percentage of Women Experiencing an Unintended Pregnancy During the First
Year of Typical Use and the First Year of Perfect Use of Contraception and the
Percentage Continuing Use at the End of the First Year. United States.
% of Women Experiencing an
Unintended Pregnancy within the First
% of Women Continuing
Use at One Year*
Year of Use
Method
Typical Use†
Perfect Use‡
(1)
Chance#
(2)
85
(3)
85
(4)
SpermicidesÞ
26
6
40
Periodic abstinence
25
63
Calendar
9
Ovulation Method
3
Sympto-Thermalβ
2
Post-Ovulation
1
Capà
Parous Women
40
26
42
Nulliparous Women
20
9
56
Sponge
Parous Women
40
20
42
Nulliparous Women
Diaphragmà
20
20
9
6
56
56
Withdrawal
19
4
Condomè
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 T380A
0.8
0.6
78
LNg 20
Depo-Provera®
Norplant® and Norplant-2®
0.1
0.3
0.05
0.1
0.3
0.05
81
70
88
Female Sterilization
0.5
0.5
100
Male Sterilization
0.15
0.10
100
Reference ID: 3383539
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 2:
Percentage of Women Experiencing an Unintended Pregnancy During the First
Year of Typical Use and the First Year of Perfect Use of Contraception and the
Percentage Continuing Use at the End of the First Year. United States.
% of Women Experiencing an
% of Women Continuing
Unintended Pregnancy within the First
Use at One Year*
Year of Use
Method
Typical Use†
Perfect Use‡
(1)
(2)
(3)
(4)
Hatcher et al, 1998, Ref. #1.
Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse
reduces the risk of pregnancy by at least 75%.§
Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception.¶
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.
* Among couples attempting to avoid pregnancy, the percentage who continue to use a method for
one year.
† 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.
‡ 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 other reason.
§ The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second
dose 12 hours after the first dose. The Food and Drug Administration has declared the following
brands of oral contraceptives 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 2 light-orange
pills), Lo/Ovral (1 dose is 4 white pills), Triphasil or Tri-Levlen (1 dose is 4 yellow pills).
¶ 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 six months of age.
# 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 percent who would become pregnant within one
year among women now relying on reversible methods of contraception if they abandoned
contraception altogether.
Þ Foams, creams, gels, vaginal suppositories, and vaginal film.
β Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body
temperature in the post-ovulatory phases.
à With spermicidal cream or jelly.
è Without spermicides.
ORTHO-CYCLEN® and ORTHO TRI-CYCLEN® have not been studied for
and are not indicated for use in emergency contraception.
In clinical trials with ORTHO-CYCLEN®, 1,651 subjects completed 24,272
cycles and the overall use-efficacy (typical user efficacy) pregnancy rate was
approximately 1 pregnancy per 100 women-years. This rate includes patients
who did not take the drug correctly.
Reference ID: 3383539
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In four clinical trials with ORTHO TRI-CYCLEN®, a total of 4,756 subjects
completed 45,244 cycles, and the use-efficacy pregnancy rate was
approximately 1 pregnancy per 100 women-years.
ORTHO TRI-CYCLEN® was evaluated for the treatment of acne vulgaris in two
randomized, double-blind, placebo-controlled, multicenter, Phase 3, six (28 day)
cycle studies. 221 patients received ORTHO TRI-CYCLEN® and 234 patients
received placebo. Mean age at enrollment for both groups was 28 years. At the
end of 6 months, the mean total lesion count changes from 55 to 31 (42%
reduction) in patients treated with ORTHO TRI-CYCLEN® and from 54 to
38 (27% reduction) in patients similarly treated with placebo. Table 3
summarizes the changes in lesion count for each type of lesion in the ITT
population. Based on the investigator’s global assessment conducted at the final
visit, patients treated with ORTHO TRI-CYCLEN® showed a statistically
significant improvement in total lesions compared to those treated with placebo.
Table 3:
Acne Vulgaris Indication. Combined Results: Two Multicenter, Placebo-
Controlled Trials. Observed Means at Six Months (LOCF)* and at Baseline.
Intent-to-Treat Population.
ORTHO TRI-
Placebo
Difference in Counts
CYCLEN®
(N=221)
(N=234)
between ORTHO
TRI-CYCLEN® and
Placebo at 6 Months
# of Lesions
Counts
% Reduction
Counts
%
Reduction
INFLAMMATORY
LESIONS
Baseline Mean
19
19
Sixth Month Mean
10
48%
13
30%
3 (95% CI: -1.2, 5.1)
NON
INFLAMMATORY
LESIONS
Baseline Mean
36
35
Sixth Month Mean
22
34%
25
21%
3 (95% CI: -0.2, 7.8)
TOTAL LESIONS
Baseline Mean
55
54
Sixth Month Mean
31
42%
38
27%
7 (95% CI: 2.0, 11.9)
*LOCF: Last Observation Carried Forward
CONTRAINDICATIONS
Oral contraceptives should not be used in women who currently have the
following conditions:
Thrombophlebitis or thromboembolic disorders
A past history of deep vein thrombophlebitis or thromboembolic disorders
Known thrombophilic conditions
Reference ID: 3383539
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Cerebral vascular or coronary artery disease (current or past history)
Valvular heart disease with complications
Persistent blood pressure values of 160 mm Hg systolic or 100 mg Hg
diastolic102
Diabetes with vascular involvement
Headaches with focal neurological symptoms
Major surgery with prolonged immobilization
Known or suspected carcinoma of the breast or personal history of breast
cancer
Carcinoma
of
the
endometrium
or
other
known
or
suspected
estrogen-dependent neoplasia
Undiagnosed abnormal genital bleeding
Cholestatic jaundice of pregnancy or jaundice with prior pill use
Acute or chronic hepatocellular disease with abnormal liver function
Hepatic adenomas or carcinomas
Known or suspected pregnancy
Hypersensitivity to any component of this product
WARNINGS
Cigarette smoking increases the risk of serious cardiovascular events from
combination oral contraceptive use. This risk increases with age,
particularly in women over 35 years of age, and with the number of
cigarettes smoked. For this reason, combination oral contraceptives,
including ORTHO TRI-CYCLEN and ORTHO-CYCLEN, should not be
used by women who are over 35 years of age and smoke.
The use of oral contraceptives is associated with increased risks of several
serious conditions including myocardial infarction, thromboembolism, stroke,
hepatic neoplasia, and gallbladder disease, although the risk of serious morbidity
or mortality is very small in healthy women without underlying risk factors. The
risk of morbidity and mortality increases significantly in the presence of other
underlying risk factors such as hypertension, hyperlipidemias, obesity and
diabetes.
Practitioners prescribing oral contraceptives should be familiar with the
following information relating to these risks.
The information contained in this package insert is principally based on studies
carried out in patients who used oral contraceptives with higher formulations of
Reference ID: 3383539
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
estrogens and progestogens than those in common use today. The effect of
long-term use of the oral contraceptives with lower formulations of both
estrogens and progestogens remains to be determined.
Throughout this labeling, epidemiological studies reported are of two
types: retrospective or case control studies and prospective or cohort studies.
Case control studies provide a measure of the relative risk of a disease, namely,
a ratio of the incidence of a disease among oral contraceptive users to that
among nonusers. The relative risk does not provide information on the actual
clinical occurrence of a disease. Cohort studies provide a measure of attributable
risk, which is the difference in the incidence of disease between oral
contraceptive users and nonusers. The attributable risk does provide information
about the actual occurrence of a disease in the population (adapted from refs. 2
and 3 with the author's permission). For further information, the reader is
referred to a text on epidemiological methods.
1. Thromboembolic Disorders and Other Vascular Problems
a. Myocardial Infarction
An increased risk of myocardial infarction has been attributed to oral
contraceptive use. This risk is primarily in smokers or women with other
underlying risk factors for coronary artery disease such as hypertension,
hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart
attack for current oral contraceptive users has been estimated to be two to six.4-10
The risk is very low under the age of 30.
Smoking in combination with oral contraceptive use has been shown to
contribute substantially to the incidence of myocardial infarctions in women in
their mid-thirties or older with smoking accounting for the majority of excess
cases.11 Mortality rates associated with circulatory disease have been shown to
increase substantially in smokers, especially in those 35 years of age and older,
and in nonsmokers over the age of 40 among women who use oral
contraceptives. (See Figure 1.)
Reference ID: 3383539
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Figure 1.
Circulatory Disease Mortality Rates per 100,000 Women-Years by Age,
Smoking Status and Oral Contraceptive Use
(Adapted from P.M. Layde and V. Beral, ref. #12.)
Oral contraceptives may compound the effects of well-known risk factors, such
as hypertension, diabetes, hyperlipidemias, age and obesity.13 In particular,
some progestogens are known to decrease HDL cholesterol and cause glucose
intolerance, while estrogens may create a state of hyperinsulinism.14-18 Oral
contraceptives have been shown to increase blood pressure among users (see
Section 9 in WARNINGS). Similar effects on risk factors have been associated
with an increased risk of heart disease. Oral contraceptives must be used with
caution in women with cardiovascular disease risk factors.
Norgestimate
has
minimal
androgenic
activity
(see
CLINICAL
PHARMACOLOGY), and there is some evidence that the risk of myocardial
infarction associated with oral contraceptives is lower when the progestogen has
minimal androgenic activity than when the activity is greater.97
b. Thromboembolism
An increased risk of thromboembolic and thrombotic disease associated with the
use of oral contraceptives is well established. Case control studies have found
the relative risk of users compared to nonusers to be 3 for the first episode of
superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary
embolism, and 1.5 to 6 for women with predisposing conditions for venous
thromboembolic disease.2,3,19-24 Cohort studies have shown the relative risk to be
somewhat lower, about 3 for new cases and about 4.5 for new cases requiring
hospitalization.25 The risk of thromboembolic disease associated with oral
contraceptives is not related to length of use and disappears after pill use is
stopped.2
A two- to four-fold increase in relative risk of post-operative thromboembolic
complications has been reported with the use of oral contraceptives.9 The
Reference ID: 3383539
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
relative risk of venous thrombosis in women who have predisposing conditions
is twice that of women without such medical conditions.26 If feasible, oral
contraceptives should be discontinued at least four weeks prior to and for two
weeks after elective surgery of a type associated with an increase in risk of
thromboembolism and during and following prolonged immobilization. Since
the immediate postpartum period is also associated with an increased risk of
thromboembolism, oral contraceptives should be started no earlier than four
weeks after delivery in women who elect not to breastfeed.
c. Cerebrovascular Diseases
Oral contraceptives have been shown to increase both the relative and
attributable risks of cerebrovascular events (thrombotic and hemorrhagic
strokes), although, in general, the risk is greatest among older (>35 years),
hypertensive women who also smoke. Hypertension was found to be a risk
factor for both users and nonusers, for both types of strokes, and smoking
interacted to increase the risk of stroke.27-29
In a large study, the relative risk of thrombotic strokes has been shown to range
from 3 for normotensive users to 14 for users with severe hypertension.30 The
relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who
used oral contraceptives, 2.6 for smokers who did not use oral contraceptives,
7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and
25.7 for users with severe hypertension.30 The attributable risk is also greater in
older women.3
d. Dose-Related Risk of Vascular Disease From Oral Contraceptives
A positive association has been observed between the amount of estrogen and
progestogen in oral contraceptives and the risk of vascular disease.31-33 A
decline in serum high density lipoproteins (HDL) has been reported with many
progestational agents.14-16 A decline in serum high density lipoproteins has been
associated with an increased incidence of ischemic heart disease. Because
estrogens increase HDL cholesterol, the net effect of an oral contraceptive
depends on a balance achieved between doses of estrogen and progestogen and
the activity of the progestogen used in the contraceptives. The activity and
amount of both hormones should be considered in the choice of an oral
contraceptive.
Minimizing exposure to estrogen and progestogen is in keeping with good
principles of therapeutics. For any particular estrogen/progestogen combination,
the dosage regimen prescribed should be one which contains the least amount of
Reference ID: 3383539
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
estrogen and progestogen that is compatible with a low failure rate and the needs
of the individual patient. New acceptors of oral contraceptive agents should be
started on preparations containing the lowest estrogen content which is judged
appropriate for the individual patient.
e. Persistence of Risk of Vascular Disease
There are two studies which have shown persistence of risk of vascular disease
for ever-users of oral contraceptives. In a study in the United States, the risk of
developing myocardial infarction after discontinuing oral contraceptives persists
for at least 9 years for women 40-49 years who had used oral contraceptives for
five or more years, but this increased risk was not demonstrated in other age
groups.8 In another study in Great Britain, the risk of developing
cerebrovascular disease persisted for at least 6 years after discontinuation of oral
contraceptives, although excess risk was very small.34 However, both studies
were performed with oral contraceptive formulations containing 50 micrograms
or higher of estrogens.
2. Estimates of Mortality From Contraceptive Use
One study gathered data from a variety of sources which have estimated the
mortality rate associated with different methods of contraception at different
ages (Table 4). These estimates include the combined risk of death associated
with contraceptive methods plus the risk attributable to pregnancy in the event
of method failure. Each method of contraception has its specific benefits and
risks. The study concluded that with the exception of oral contraceptive users 35
and older who smoke, and 40 and older who do not smoke, mortality associated
with all methods of birth control is low and below that associated with
childbirth. The observation of an increase in risk of mortality with age for oral
contraceptive users is based on data gathered in the 1970's.35 Current clinical
recommendation involves the use of lower estrogen dose formulations and a
careful consideration of risk factors. In 1989, the Fertility and Maternal Health
Drugs Advisory Committee was asked to review the use of oral contraceptives
in women 40 years of age and over. The Committee concluded that although
cardiovascular disease risks may be increased with oral contraceptive use after
age 40 in healthy non-smoking women (even with the newer low-dose
formulations), there are also greater potential health risks associated with
pregnancy in older women and with the alternative surgical and medical
procedures which may be necessary if such women do not have access to
effective and acceptable means of contraception. The Committee recommended
Reference ID: 3383539
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
that the benefits of low-dose oral contraceptive use by healthy non-smoking
women over 40 may outweigh the possible risks.
Of course, older women, as all women, who take oral contraceptives, should
take an oral contraceptive which contains the least amount of estrogen and
progestogen that is compatible with a low failure rate and individual patient
needs.
Table 4:
Annual Number of Birth-Related or Method-Related Deaths Associated
with Control of Fertility per 100,000 Non-Sterile Women, by Fertility
Control Method According to Age
Method of control and
15-19
20-24
25-29
30-34
35-39
40-44
outcome
No fertility control
7.0
7.4
9.1
14.8
25.7
28.2
methods*
Oral contraceptives non-
0.3
0.5
0.9
1.9
13.8
31.6
smoker†
Oral contraceptives, smoker†
2.2
3.4
6.6
13.5
51.1
117.2
IUD†
0.8
0.8
1.0
1.0
1.4
1.4
Condom*
1.1
1.6
0.7
0.2
0.3
0.4
Diaphragm/spermicide*
1.9
1.2
1.2
1.3
2.2
2.8
Periodic abstinence*
2.5
1.6
1.6
1.7
2.9
3.6
Adapted from H.W. Ory, ref. #35.
* Deaths are birth-related
† Deaths are method-related
3. Carcinoma of the Reproductive Organs and Breasts
Numerous epidemiological studies have been performed on the incidence of
breast, endometrial, ovarian, and cervical cancer in women using oral
contraceptives.
The risk of having breast cancer diagnosed may be slightly increased among
current and recent users of combination oral contraceptives (COCs). However,
this excess risk appears to decrease over time after COC discontinuation and by
10 years after cessation the increased risk disappears. Some studies report an
increased risk with duration of use while other studies do not and no consistent
relationships have been found with dose or type of steroid. Some studies have
found a small increase in risk for women who first use COCs before age 20.
Most studies show a similar pattern of risk with COC use regardless of a
woman’s reproductive history or her family breast cancer history.
Breast cancers diagnosed in current or previous oral contraceptive users tend to
be less clinically advanced than in nonusers. Women who currently have or have
Reference ID: 3383539
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
had breast cancer should not use oral contraceptives because breast cancer is
usually a hormonally-sensitive tumor.
Some studies suggest that oral contraceptive use has been associated with an
increase in the risk of cervical intraepithelial neoplasia in some populations of
45-48
women.
However, there continues to be controversy about the extent to
which such findings may be due to differences in sexual behavior and other
factors. In spite of many studies of the relationship between oral contraceptive
use and breast and cervical cancers, a cause-and-effect relationship has not been
established.
4. Hepatic Neoplasia
Benign hepatic adenomas are associated with oral contraceptive use, although
the incidence of benign tumors is rare in the United States. Indirect calculations
have estimated the attributable risk to be in the range of 3.3 cases/100,000 for
users, a risk that increases after four or more years of use especially with oral
contraceptives of higher dose.49 Rupture of benign, hepatic adenomas may cause
death through intra-abdominal hemorrhage.50,51
Studies from Britain have shown an increased risk of developing hepatocellular
carcinoma in long-term (>8 years) oral contraceptive users. However, these
cancers are extremely rare in the U.S. and the attributable risk (the excess
incidence) of liver cancers in oral contraceptive users approaches less than one
per million users.
5. Ocular Lesions
There have been clinical case reports of retinal thrombosis associated with the
use of oral contraceptives. Oral contraceptives should be discontinued if there is
unexplained partial or complete loss of vision; onset of proptosis or diplopia;
papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic
measures should be undertaken immediately.
6. Oral Contraceptive Use Before or During Early Pregnancy
Extensive epidemiological studies have revealed no increased risk of birth
defects in women who have used oral contraceptives prior to pregnancy.56,57 The
majority of recent studies also do not indicate a teratogenic effect, particularly in
so far as cardiac anomalies and limb reduction defects are concerned55,56,58,59
when taken inadvertently during early pregnancy.
Reference ID: 3383539
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The administration of oral contraceptives to induce withdrawal bleeding should
not be used as a test for pregnancy. Oral contraceptives should not be used
during pregnancy to treat threatened or habitual abortion.
It is recommended that for any patient who has missed two consecutive periods,
pregnancy should be ruled out. If the patient has not adhered to the prescribed
schedule, the possibility of pregnancy should be considered at the time of the
first missed period. Oral contraceptive use should be discontinued if pregnancy
is confirmed.
7. Gallbladder Disease
Earlier studies have reported an increased lifetime relative risk of gallbladder
surgery in users of oral contraceptives and estrogens.60,61 More recent studies,
however, have shown that the relative risk of developing gallbladder disease
among oral contraceptive users may be minimal.62-64 The recent findings of
minimal risk may be related to the use of oral contraceptive formulations
containing lower hormonal doses of estrogens and progestogens.
8. Carbohydrate and Lipid Metabolic Effects
Oral contraceptives have been shown to cause a decrease in glucose tolerance in
a significant percentage of users.17 This effect has been shown to be directly
related to estrogen dose.65 Progestogens increase insulin secretion and create
insulin resistance, this effect varying with different progestational agents.17,66
However, in the non-diabetic woman, oral contraceptives appear to have no
effect on fasting blood glucose.67 Because of these demonstrated effects,
prediabetic and diabetic women in particular should be carefully monitored
while taking oral contraceptives.
A small proportion of women will have persistent hypertriglyceridemia while on
the pill. As discussed earlier (see WARNINGS 1a and 1d), changes in serum
triglycerides and lipoprotein levels have been reported in oral contraceptive
users.
In clinical studies with ORTHO-CYCLEN there were no clinically significant
changes in fasting blood glucose levels. No statistically significant changes in
mean fasting blood glucose levels were observed over 24 cycles of use. Glucose
tolerance tests showed minimal, clinically insignificant changes from baseline to
cycles 3, 12, and 24.
In clinical studies with ORTHO TRI-CYCLEN there were no clinically
significant changes in fasting blood glucose levels. Minimal statistically
Reference ID: 3383539
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
significant changes were noted in glucose levels over 24 cycles of use. Glucose
tolerance tests showed no clinically significant changes from baseline to cycles
3, 12, and 24.
9. Elevated Blood Pressure
Women with significant hypertension should not be started on hormonal
contraception.98 An increase in blood pressure has been reported in women
taking oral contraceptives68 and this increase is more likely in older oral
contraceptive users69 and with extended duration of use.61 Data from the Royal
College of General Practitioners12 and subsequent randomized trials have shown
that the incidence of hypertension increases with increasing progestational
activity.
Women with a history of hypertension or hypertension-related diseases, or renal
disease70 should be encouraged to use another method of contraception. If these
women elect to use oral contraceptives, they should be monitored closely and if
a clinically significant persistent elevation of blood pressure (BP) occurs
( 160 mm Hg systolic or 100 mm Hg diastolic) and cannot be adequately
controlled, oral contraceptives should be discontinued. In general, women who
develop hypertension during hormonal contraceptive therapy should be switched
to a non-hormonal contraceptive. If other contraceptive methods are not
suitable, hormonal contraceptive therapy may continue combined with
antihypertensive therapy. Regular monitoring of BP throughout hormonal
contraceptive therapy is recommended.102 For most women, elevated blood
pressure will return to normal after stopping oral contraceptives, and there is no
difference in the occurrence of hypertension between former and never users.68
71 It should be noted that in two separate large clinical trials (N=633 and
N=911), no statistically significant changes in mean blood pressure were
observed with ORTHO-CYCLEN .
10.Headache
The onset or exacerbation of migraine or development of headache with a new
pattern which is recurrent, persistent or severe requires discontinuation of oral
contraceptives and evaluation of the cause.
11. Bleeding Irregularities
Breakthrough bleeding and spotting are sometimes encountered in patients on
oral contraceptives, especially during the first three months of use.
Non-hormonal causes should be considered and adequate diagnostic measures
taken to rule out malignancy or pregnancy in the event of breakthrough
Reference ID: 3383539
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been
excluded, time or a change to another formulation may solve the problem. In the
event of amenorrhea, pregnancy should be ruled out.
Some women may encounter post-pill amenorrhea or oligomenorrhea, especially
when such a condition was preexistent.
12. Ectopic Pregnancy
Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.
PRECAUTIONS
1. General
Patients should be counseled that this product does not protect against HIV
infection (AIDS) and other sexually transmitted diseases.
2. Physical Examination and Follow-up
It is good medical practice for all women to have annual history and physical
examinations, including women using oral contraceptives. The physical
examination, however, may be deferred until after initiation of oral
contraceptives if requested by the woman and judged appropriate by the
clinician. The physical examination should include special reference to blood
pressure, breasts, abdomen and pelvic organs, including cervical cytology, and
relevant laboratory tests. In case of undiagnosed, persistent or recurrent
abnormal vaginal bleeding, appropriate measures should be conducted to rule
out malignancy. Women with a strong family history of breast cancer or who
have breast nodules should be monitored with particular care.
3. Lipid Disorders
Women who are being treated for hyperlipidemias should be followed closely if
they elect to use oral contraceptives. Some progestogens may elevate LDL
levels and may render the control of hyperlipidemias more difficult.
4. Liver Function
If jaundice develops in any woman receiving such drugs, the medication should
be discontinued. Steroid hormones may be poorly metabolized in patients with
impaired liver function.
5. Fluid Retention
Oral contraceptives may cause some degree of fluid retention. They should be
prescribed with caution, and only with careful monitoring, in patients with
conditions which might be aggravated by fluid retention.
Reference ID: 3383539
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6. Emotional Disorders
Women with a history of depression should be carefully observed and the drug
discontinued if depression recurs to a serious degree.
7. Contact Lenses
Contact lens wearers who develop visual changes or changes in lens tolerance
should be assessed by an ophthalmologist.
8. Drug Interactions
Consult the labeling of concurrently-used drugs to obtain further information
about interactions with hormonal contraceptives or the potential for enzyme
alterations.
Effects of Other Drugs on Combined Hormonal Contraceptives
Substances decreasing the plasma concentrations of COCs and
potentially diminishing the efficacy of COCs:
Drugs or herbal products that induce certain enzymes, including cytochrome
P450 3A4 (CYP3A4), may decrease the plasma concentrations of COCs and
potentially diminish the effectiveness of CHCs or increase breakthrough
bleeding. Some drugs or herbal products that may decrease the effectiveness of
hormonal contraceptives include phenytoin, barbiturates, carbamazepine,
bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate,
rifabutin, rufinamide, aprepitant, and products containing St. John’s wort.
Interactions between hormonal contraceptives and other drugs may lead to
breakthrough bleeding and/or contraceptive failure. Counsel women to use an
alternative method of contraception or a back-up method when enzyme inducers
are used with CHCs, and to continue back-up contraception for 28 days after
discontinuing the enzyme inducer to ensure contraceptive reliability.
Substances increasing the plasma concentrations of COCs:
Co-administration of atorvastatin or rosuvastatin and certain COCs containing
EE increase AUC values for EE by approximately 20-25%. Ascorbic acid and
acetaminophen may increase plasma EE concentrations, possibly by inhibition
of conjugation. CYP3A4 inhibitors such as itraconazole, voriconazole,
fluconazole, grapefruit juice, or ketoconazole may increase plasma hormone
concentrations.
Human immunodeficiency virus (HIV)/ Hepatitis C virus (HCV) protease
inhibitors and non-nucleoside reverse transcriptase inhibitors:
Significant changes (increase or decrease) in the plasma concentrations of
estrogen and/or progestin have been noted in some cases of co-administration
Reference ID: 3383539
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
with
HIV
protease
inhibitors
(decrease
[e.g.,
nelfinavir,
ritonavir,
darunavir/ritonavir,
(fos)amprenavir/ritonavir,
lopinavir/ritonavir,
and
tipranavir/ritonavir] or increase [e.g., indinavir and atazanavir/ritonavir]) /HCV
protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with non
nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or
increase [e.g., etravirine]).
Colesevelam: Colesevelam, a bile acid sequestrant, given together with a
combination oral hormonal contraceptive, has been shown to significantly
decrease the AUC of EE. A drug interaction between the contraceptive and
colesevelam was decreased when the two drug products were given 4 hours
apart.
Effects of Combined Hormonal Contraceptives on Other Drugs
COCs containing EE may inhibit the metabolism of other compounds (e.g.,
cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole) and
increase their plasma concentrations. COCs have been shown to decrease
plasma concentrations of acetaminophen, clofibric acid, morphine, salicylic
acid, temazepam and lamotrigine. Significant decrease in plasma concentration
of lamotrigine has been shown, likely due to induction of lamotrigine
glucuronidation. This may reduce seizure control; therefore, dosage adjustments
of lamotrigine may be necessary.
Women on thyroid hormone replacement therapy may need increased doses of
thyroid hormone because serum concentrations of thyroid-binding globulin
increases with use of COCs.
9. Interactions with Laboratory Tests
Certain endocrine and liver function tests and blood components may be
affected by oral contraceptives:
a. Increased prothrombin and factors VII, VIII, IX, and X; decreased
antithrombin 3; increased norepinephrine-induced platelet aggregability.
b. Increased thyroid binding globulin (TBG) leading to increased circulating
total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by
column or by radioimmunoassay. Free T3 resin uptake is decreased,
reflecting the elevated TBG, free T4 concentration is unaltered.
c. Other binding proteins may be elevated in serum.
Reference ID: 3383539
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
d. Sex hormone binding globulins are increased and result in elevated levels of
total circulating sex steroids; however, free or biologically active levels
either decrease or remain unchanged.
e. Triglycerides may be increased and levels of various other lipids and
lipoproteins may be affected.
f. Glucose tolerance may be decreased.
g. Serum folate levels may be depressed by oral contraceptive therapy. This
may be of clinical significance if a woman becomes pregnant shortly after
discontinuing oral contraceptives.
10.Carcinogenesis
See WARNINGS.
11.Pregnancy
Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS.
12. Nursing Mothers
Small amounts of oral contraceptive steroids have been identified in the milk of
nursing mothers and a few adverse effects on the child have been reported,
including jaundice and breast enlargement. In addition, combination oral
contraceptives given in the postpartum period may interfere with lactation by
decreasing the quantity and quality of breast milk. If possible, the nursing
mother should be advised not to use combination oral contraceptives but to use
other forms of contraception until she has completely weaned her child.
13. Pediatric Use
Safety
and
efficacy
of
ORTHO
TRI-CYCLEN
Tablets
and
ORTHO-CYCLEN Tablets have been established in women of reproductive
age. Safety and efficacy are expected to be the same for postpubertal adolescents
under the age of 16 and for users 16 years and older. There was no significant
difference between ORTHO TRI-CYCLEN® Tablets and placebo in mean
change in total lumbar spine (L1-L4) and total hip bone mineral density between
baseline and Cycle 13 in 123 adolescent females with anorexia nervosa in a
double-blind, placebo-controlled, multicenter, one-year treatment duration
clinical trial for the Intent To Treat (ITT) population. Use of this product before
menarche is not indicated.
Reference ID: 3383539
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
14. Geriatric Use
This product has not been studied in women over 65 years of age and is not
indicated in this population.
INFORMATION FOR THE PATIENT
See Patient Labeling printed below.
ADVERSE REACTIONS
An increased risk of the following serious adverse reactions has been associated
with the use of oral contraceptives (see WARNINGS).
Thrombophlebitis and venous thrombosis with or without embolism
Arterial thromboembolism
Pulmonary embolism
Myocardial infarction
Cerebral hemorrhage
Cerebral thrombosis
Hypertension
Gallbladder disease
Hepatic adenomas or benign liver tumors
There is evidence of an association between the following conditions and the
use of oral contraceptives:
Mesenteric thrombosis
Retinal thrombosis
The following adverse reactions have been reported in patients receiving oral
contraceptives and are believed to be drug-related:
Nausea
Vomiting
Gastrointestinal symptoms (such as abdominal cramps and bloating)
Breakthrough bleeding
Spotting
Change in menstrual flow
Amenorrhea
Temporary infertility after discontinuation of treatment
Edema
Melasma which may persist
Breast changes: tenderness, enlargement, secretion
Reference ID: 3383539
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Change in weight (increase or decrease)
Change in cervical erosion and secretion
Diminution in lactation when given immediately postpartum
Cholestatic jaundice
Migraine
Allergic reaction, including rash, urticaria, angioedema
Mental depression
Reduced tolerance to carbohydrates
Vaginal candidiasis
Change in corneal curvature (steepening)
Intolerance to contact lenses
The following adverse reactions have been reported in users of oral
contraceptives and a causal association has been neither confirmed nor refuted:
Pre-menstrual syndrome
Cataracts
Changes in appetite
Cystitis-like syndrome
Headache
Nervousness
Dizziness
Hirsutism
Loss of scalp hair
Erythema multiforme
Erythema nodosum
Hemorrhagic eruption
Vaginitis
Porphyria
Impaired renal function
Hemolytic uremic syndrome
Acne
Changes in libido
Colitis
Budd-Chiari Syndrome
Reference ID: 3383539
23
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 also reported in clinical trials or during
post-marketing experience: Infections and Infestations: vaginal infection,
urinary tract infection; Psychiatric Disorders: mood altered, anxiety, insomnia;
Gastrointestinal Disorders: flatulence, pancreatitis, diarrhea, constipation;
Reproductive System and Breast Disorders: dysmenorrhea; ovarian cyst,
vulvovaginal dryness; Neoplasms Benign, Malignant and Unspecified
(Including Cysts and Polyps): benign breast neoplasm, fibroadenoma of breast,
breast cyst; Nervous System Disorders: syncope, convulsion, paraesthesia; Eye
Disorders: visual impairment, dry eye; Ear and Labyrinth Disorders: vertigo;
Cardiac Disorders: tachycardia, palpitations; Vascular Disorders: hot flush;
Respiratory, Thoracic and Mediastinal Disorders: dyspnoea; Hepatobiliary
Disorders: hepatitis; Skin and Subcutaneous Tissue Disorders: night sweats,
hyperhidrosis, photosensitivity reaction, pruritus; Musculoskeletal, Connective
Tissue, and Bone Disorders: muscle spasms, pain in extremity, myalgia, back
pain; General Disorders and Administration Site Conditions: chest pain,
asthenic conditions.
OVERDOSAGE
Serious ill effects have not been reported following acute ingestion of large
doses of oral contraceptives by young children. Overdosage may cause nausea
and withdrawal bleeding may occur in females.
NON-CONTRACEPTIVE HEALTH BENEFITS
The following non-contraceptive health benefits related to the use of
combination oral contraceptives are supported by epidemiological studies which
largely utilized oral contraceptive formulations containing estrogen doses
exceeding 0.035 mg of ethinyl estradiol or 0.05 mg mestranol.73-78
Effects on menses:
increased menstrual cycle regularity
decreased blood loss and decreased incidence of iron deficiency anemia
decreased incidence of dysmenorrhea
Effects related to inhibition of ovulation:
decreased incidence of functional ovarian cysts
decreased incidence of ectopic pregnancies
Other effects:
decreased incidence of fibroadenomas and fibrocystic disease of the breast
decreased incidence of acute pelvic inflammatory disease
decreased incidence of endometrial cancer
Reference ID: 3383539
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
decreased incidence of ovarian cancer
DOSAGE AND ADMINISTRATION
Oral Contraception
To achieve maximum contraceptive effectiveness, ORTHO TRI-CYCLEN®
Tablets and ORTHO-CYCLEN® Tablets must be taken exactly as directed and
at intervals not exceeding 24 hours. The possibility of ovulation and conception
prior to initiation of medication should be considered. ORTHO TRI-CYCLEN®
and ORTHO-CYCLEN® are available with the DIALPAK® Tablet Dispenser
which is preset for a Sunday Start. Day 1 Start is also provided.
Sunday Start
When taking ORTHO TRI-CYCLEN® and ORTHO-CYCLEN® the first tablet
should be taken on the first Sunday after menstruation begins. If the period
begins on Sunday, the first tablet should be taken that day. Take one active
tablet daily for 21 days followed by one dark green inactive tablet daily for 7
days. After 28 tablets have been taken, a new course is started the next day
(Sunday). For the first cycle of a Sunday Start regimen, another method of
contraception should be used until after the first 7 consecutive days of
administration.
If the patient misses one (1) active tablet in Weeks 1, 2, or 3, the tablet should
be taken as soon as she remembers. If the patient misses two (2) active tablets in
Week 1 or Week 2, the patient should take two (2) tablets the day she
remembers and two (2) tablets the next day; and then continue taking one (1)
tablet a day until she finishes the pack. The patient should be instructed to use a
back-up method of birth control such as a condom or spermicide if she has sex
in the seven (7) days after missing pills. If the patient misses two (2) active
tablets in the third week or misses three (3) or more active tablets in a row, the
patient should continue taking one tablet every day until Sunday. On Sunday the
patient should throw out the rest of the pack and start a new pack that same day.
The patient should be instructed to use a back-up method of birth control if she
has sex in the seven (7) days after missing pills.
Complete instructions to facilitate patient counseling on proper pill usage may
be found in the Detailed Patient Labeling ("How to Take the Pill" section).
Day 1 Start
The dosage of ORTHO TRI-CYCLEN® and ORTHO-CYCLEN®, for the initial
cycle of therapy, is one active tablet administered daily from the 1st day through
the 21st day of the menstrual cycle, counting the first day of menstrual flow as
Reference ID: 3383539
25
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
"Day 1" followed by one dark green inactive tablet daily for 7 days. Tablets are
taken without interruption for 28 days. After 28 tablets have been taken, a new
course is started the next day.
If the patient misses one (1) active tablet in Weeks 1, 2, or 3, the tablet should
be taken as soon as she remembers. If the patient misses two (2) active tablets in
Week 1 or Week 2, the patient should take two (2) tablets the day she
remembers and two (2) tablets the next day; and then continue taking one (1)
tablet a day until she finishes the pack. The patient should be instructed to use a
back-up method of birth control such as a condom or spermicide if she has sex
in the seven (7) days after missing pills. If the patient misses two (2) active
tablets in the third week or misses three (3) or more active tablets in a row, the
patient should throw out the rest of the pack and start a new pack that same day.
The patient should be instructed to use a back-up method of birth control if she
has sex in the seven (7) days after missing pills.
Complete instructions to facilitate patient counseling on proper pill usage may
be found in the Detailed Patient Labeling ("How to Take the Pill" section).
The use of ORTHO TRI-CYCLEN® and ORTHO-CYCLEN® for contraception
may be initiated 4 weeks postpartum in women who elect not to breastfeed.
When the tablets are administered during the postpartum period, the increased
risk of thromboembolic disease associated with the postpartum period must be
considered. (See CONTRAINDICATIONS and WARNINGS concerning
thromboembolic disease. See also PRECAUTIONS: Nursing Mothers.) The
possibility of ovulation and conception prior to initiation of medication should
be considered.
(See Discussion of Dose-Related Risk of Vascular Disease from Oral
Contraceptives.)
ADDITIONAL INSTRUCTIONS
Breakthrough bleeding, spotting, and amenorrhea are frequent reasons for
patients discontinuing oral contraceptives. In breakthrough bleeding, as in all
cases of irregular bleeding from the vagina, nonfunctional causes should be
borne in mind. In undiagnosed persistent or recurrent abnormal bleeding from
the vagina, adequate diagnostic measures are indicated to rule out pregnancy or
malignancy. If pathology has been excluded, time or a change to another
formulation may solve the problem. Changing to an oral contraceptive with a
higher estrogen content, while potentially useful in minimizing menstrual
Reference ID: 3383539
26
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
irregularity, should be done only if necessary since this may increase the risk of
thromboembolic disease.
Use of oral contraceptives in the event of a missed menstrual period:
1. If the patient has not adhered to the prescribed schedule, the possibility of
pregnancy should be considered at the time of the first missed period and
oral contraceptive use should be discontinued if pregnancy is confirmed.
2. If the patient has adhered to the prescribed regimen and misses two
consecutive periods, pregnancy should be ruled out.
ACNE
The timing of initiation of dosing with ORTHO TRI-CYCLEN for acne should
follow the guidelines for use of ORTHO TRI-CYCLEN® as an oral
contraceptive. Consult the DOSAGE AND ADMINISTRATION section for
oral contraceptives. The dosage regimen for ORTHO TRI-CYCLEN® for
treatment of facial acne, as available with a DIALPAK® Tablet Dispenser,
utilizes a 21-day active and a 7-day placebo schedule. Take one active tablet
daily for 21 days followed by one dark green inactive tablet for 7 days. After
28 tablets have been taken, a new course is started the next day.
HOW SUPPLIED
ORTHO
TRI-CYCLEN®
Tablets
are
available
in
a
blister
card
(NDC 50458-191-00) with a DIALPAK® Tablet Dispenser (unfilled). The
blister card contains 28 tablets. Each white tablet contains 0.180 mg of the
progestational compound, norgestimate, together with 0.035 mg of the
estrogenic compound, ethinyl estradiol. Each light blue tablet contains 0.215 mg
of the progestational compound, norgestimate, together with 0.035 mg of the
estrogenic compound, ethinyl estradiol. Each blue tablet contains 0.250 mg of
the progestational compound, norgestimate, together with 0.035 mg of the
estrogenic compound, ethinyl estradiol. Each dark green tablet contains inert
ingredients. ORTHO TRI-CYCLEN® Tablets are packaged in a carton
(NDC 50458-191-15) containing 6 blister cards and 6 unfilled DIALPAK®
Tablet Dispensers.
0.180/0.035 mg tablets - White, round, biconvex, coated tablet imprinted
“O 180” on one side and “35” on the other side of the tablet.
0.215/0.035 mg tablets - Light blue, round, biconvex, coated tablet imprinted
“O 215” on one side and “35” on the other side of the tablet.
Reference ID: 3383539
27
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
0.250/0.035 mg tablets - Blue, round, biconvex, coated tablet imprinted “O 250”
on one side and “35” on the other side of the tablet.
Each dark green reminder pill is a round, biconvex, coated tablet imprinted
“O-M” on one side and “P” on the other side.
ORTHO TRI-CYCLEN® Tablets are available for clinic usage in a
VERIDATE®
Tablet
Dispenser
(unfilled)
and
VERIDATE®
refills
(NDC 50458-191-20).
ORTHO-CYCLEN® Tablets are available in a blister card (NDC 50458-197-00)
with a DIALPAK® Tablet Dispenser (unfilled). The blister card contains
28 tablets as follows: 21 blue tablets containing 0.250 mg of the progestational
compound, norgestimate, together with 0.035 mg of the estrogenic compound,
ethinyl estradiol, and 7 dark green tablets containing inert ingredients. ORTHO
CYCLEN® Tablets are packaged in a carton (NDC 50458-197-15) containing
6 blister cards and 6 unfilled DIALPAK® Tablet Dispensers.
ORTHO-CYCLEN® Tablets are available for clinic usage in a VERIDATE®
Tablet Dispenser (unfilled) and VERIDATE® refills (NDC 50458-197-20).
Keep out of reach of children.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
Protect from light.
REFERENCES
1. 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.
2. Stadel BV, Oral contraceptives and cardiovascular disease. (Pt.1). N Engl J
Med 1981; 305:612-618.
3. Stadel BV, Oral contraceptives and cardiovascular disease. (Pt.2). N Engl J
Med 1981; 305:672-677.
4. Adam SA, Thorogood M. Oral contraception and myocardial infarction
revisited: the effects of new preparations and prescribing patterns. Br J Obstet
Gynaecol 1981; 88:838-845.
5. Mann Jl, Inman WH. Oral contraceptives and death from myocardial infarction.
Br Med J 1975; 2(5965):245-248.
Reference ID: 3383539
28
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6. Mann Jl, Vessey MP, Thorogood M, Doll R. Myocardial infarction in young
women with special reference to oral contraceptive practice. Br Med J 1975;
2(5956):241-245.
7. Royal College of General Practitioners' Oral Contraception Study: Further
analyses of mortality in oral contraceptive users. Lancet 1981; 1:541-546.
8. Slone D, Shapiro S, Kaufman DW, Rosenberg L, Miettinen OS, Stolley PD.
Risk of myocardial infarction in relation to current and discontinued use of oral
contraceptives. N Engl J Med 1981:305:420-424.
9. Vessey MP. Female hormones and vascular disease-an epidemiological
overview. Br J Fam Plann 1980; 6(Supplement): 1-12.
10. Russell-Briefel RG, Ezzati TM, Fulwood R, Perlman JA, Murphy RS.
Cardiovascular risk status and oral contraceptive use, United States, 1976-80.
Prevent Med 1986; 15:352-362.
11. Goldbaum GM, Kendrick JS, Hogelin GC, Gentry EM. The relative impact of
smoking and oral contraceptive use on women in the United States. JAMA
1987; 258:1339-1342.
12. Layde PM, Beral V. Further analyses of mortality in oral contraceptive users;
Royal College of General Practitioners' Oral Contraception Study. (Table 5)
Lancet 1981; 1:541-546.
13. Knopp RH. Arteriosclerosis risk: the roles of oral contraceptives and
postmenopausal estrogens. J Reprod Med 1986; 31(9) (Supplement):913-921.
14. Krauss RM, Roy S, Mishell DR, Casagrande J, Pike MC. Effects of two low-
dose oral contraceptives on serum lipids and lipoproteins: Differential changes
in high-density lipoproteins subclasses. Am J Obstet 1983; 145:446-452.
15. Wahl P, Walden C, Knopp R, Hoover J, Wallace R, Heiss G, Rifkind B. Effect
of estrogen/progestin potency on lipid/lipoprotein cholesterol. N Engl J Med
1983; 308:862-867.
16. Wynn V, Niththyananthan R. The effect of progestin in combined oral
contraceptives on serum lipids with special reference to high density
lipoproteins. Am J Obstet Gynecol 1982;142:766-771.
17. Wynn V, Godsland I. Effects of oral contraceptives on carbohydrate
metabolism. J Reprod Med 1986;31(9)(Supplement):892-897.
18. LaRosa JC. Atherosclerotic risk factors in cardiovascular disease. J Reprod
Med 1986;31(9)(Supplement):906-912.
19. Inman WH, Vessey MP. Investigation of death from pulmonary, coronary, and
cerebral thrombosis and embolism in women of child-bearing age. Br Med J
1968;2(5599):193-199.
Reference ID: 3383539
29
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
20. Maguire MG, Tonascia J, Sartwell PE, Stolley PD, Tockman MS. Increased
risk of thrombosis due to oral contraceptives: a further report. Am J Epidemiol
1979;110(2):188-195.
21. Petitti DB, Wingerd J, Pellegrin F, Ramacharan S. Risk of vascular disease in
women: smoking, oral contraceptives, noncontraceptive estrogens, and other
factors. JAMA 1979;242:1150-1154.
22. Vessey MP, Doll R, Investigation of relation between use of oral contraceptives
and thromboembolic disease. Br Med J 1968;2(5599):199-205.
23. Vessey MP, Doll R. Investigation of relation between use of oral contraceptives
and thromboembolic disease. A further report. Br Med J 1969;
2(5658):651-657.
24. Porter JB, Hunter JR, Danielson DA, Jick H, Stergachis A. Oral contraceptives
and
non-fatal
vascular
disease-recent
experience.
Obstet
Gynecol
1982;59(3):299-302.
25. Vessey M, Doll R, Peto R, Johnson B, Wiggins P. A long-term follow-up study
of women using different methods of contraception: an interim report. J
Biosocial Sci 1976;8:375-427.
26. Royal College of General Practitioners: Oral Contraceptives, venous
thrombosis, and varicose veins. J Royal Coll Gen Pract 1978; 28:393-399.
27. Collaborative Group for the Study of Stroke in Young Women: Oral
contraception and increased risk of cerebral ischemia or thrombosis. N Engl J
Med 1973;288:871-878.
28. Petitti DB, Wingerd J. Use of oral contraceptives, cigarette smoking, and risk of
subarachnoid hemorrhage. Lancet 1978;2:234-236.
29. Inman WH. Oral contraceptives and fatal subarachnoid hemorrhage. Br Med J
1979:2(6203):1468-1470.
30. Collaborative Group for the Study of Stroke in Young Women: Oral
Contraceptives and stroke in young women: associated risk factors. JAMA
1975; 231:718-722.
31. Inman WH, Vessey MP, Westerholm B, Engelund A. Thromboembolic
disease and the steroidal content of oral contraceptives. A report to the
Committee on Safety of Drugs. Br Med J 1970;2:203-209.
32. Meade TW, Greenberg G, Thompson SG. Progestogens and cardiovascular
reactions associated with oral contraceptives and a comparison of the safety of
50- and 35-mcg oestrogen preparations. Br Med J 1980;280(6224):1157-1161.
33. Kay CR. Progestogens and arterial disease-evidence from the Royal College of
General Practitioners' Study. Am J Obstet Gynecol 1982;142:762-765.
Reference ID: 3383539
30
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
34. Royal College of General Practitioners: Incidence of arterial disease among oral
contraceptive users. J Royal Coll Gen Pract 1983;33:75-82.
35. Ory HW. Mortality associated with fertility and fertility control: 1983. Family
Planning Perspectives 1983;15:50-56.
36. The Cancer and Steroid Hormone Study of the Centers for Disease Control and
the National Institute of Child Health and Human Development: Oral
contraceptive use and the risk of breast cancer. N Engl J Med
1986;315:405-411.
37. Pike MC, Henderson BE, Krailo MD, Duke A, Roy S. Breast cancer in young
women and use of oral contraceptives: possible modifying effect of formulation
and age at use. Lancet 1983;2:926-929.
38. Paul C, Skegg DG, Spears GFS, Kaldor JM. Oral contraceptives and breast
cancer: A national study. Br Med J 1986; 293:723-725.
39. Miller DR, Rosenberg L, Kaufman DW, Schottenfeld D, Stolley PD, Shapiro S.
Breast cancer risk in relation to early oral contraceptive use. Obstet Gynecol
1986;68:863-868.
40. Olsson H, Olsson ML, Moller TR, Ranstam J, Holm P. Oral contraceptive use
and breast cancer in young women in Sweden (letter). Lancet 1985;
1(8431):748-749.
41. McPherson K, Vessey M, Neil A, Doll R, Jones L, Roberts M. Early
contraceptive use and breast cancer: Results of another case-control study. Br J
Cancer 1987; 56:653-660.
42. Huggins GR, Zucker PF. Oral contraceptives and neoplasia; 1987 update. Fertil
Steril 1987; 47:733-761.
43. McPherson K, Drife JO. The pill and breast cancer: why the uncertainty? Br
Med J 1986; 293:709-710.
44. Shapiro S. Oral contraceptives-time to take stock. N Engl J Med 1987;
315:450-451.
45. Ory H, Naib Z, Conger SB, Hatcher RA, Tyler CW. Contraceptive choice and
prevalence of cervical dysplasia and carcinoma in situ. Am J Obstet Gynecol
1976; 124:573-577.
46. Vessey MP, Lawless M, McPherson K, Yeates D. Neoplasia of the cervix uteri
and contraception: a possible adverse effect of the pill. Lancet 1983; 2:930.
47. Brinton LA, Huggins GR, Lehman HF, Malli K, Savitz DA, Trapido E,
Rosenthal J, Hoover R. Long term use of oral contraceptives and risk of
invasive cervical cancer. Int J Cancer 1986; 38:339-344.
Reference ID: 3383539
31
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
48. WHO Collaborative Study of Neoplasia and Steroid Contraceptives: Invasive
cervical cancer and combined oral contraceptives. Br Med J 1985;
290:961-965.
49. Rooks JB, Ory HW, Ishak KG, Strauss LT, Greenspan JR, Hill AP, Tyler CW.
Epidemiology of hepatocellular adenoma: the role of oral contraceptive use.
JAMA 1979; 242:644-648.
50. Bein NN, Goldsmith HS. Recurrent massive hemorrhage from benign hepatic
tumors secondary to oral contraceptives. Br J Surg 1977; 64:433-435.
51. Klatskin G. Hepatic tumors: possible relationship to use of oral contraceptives.
Gastroenterology 1977; 73:386-394.
52. Henderson BE, Preston-Martin S, Edmondson HA, Peters RL, Pike MC.
Hepatocellular
carcinoma
and
oral
contraceptives.
Br
J
Cancer
1983;48:437-440.
53. Neuberger J, Forman D, Doll R, Williams R. Oral contraceptives and
hepatocellular carcinoma. Br Med J 1986; 292:1355-1357.
54. Forman D, Vincent TJ, Doll R, Cancer of the liver and oral contraceptives. Br
Med J 1986; 292:1357-1361.
55. Harlap S, Eldor J. Births following oral contraceptive failures. Obstet Gynecol
1980; 55:447-452.
56. Savolainen E, Saksela E, Saxen L. Teratogenic hazards of oral contraceptives
analyzed in a national malformation register. Am J Obstet Gynecol 1981:
140:521-524.
57. Janerich DT, Piper JM, Glebatis DM. Oral contraceptives and birth defects. Am
J Epidemiol 1980; 112:73-79.
58. Ferencz C, Matanoski GM, Wilson PD, Rubin JD, Neill CA, Gutberlet R.
Maternal hormone therapy and congenital heart disease. Teratology 1980;
21:225-239.
59. Rothman KJ, Fyler DC, Goldblatt A, Kreidberg MB. Exogenous hormones and
other drug exposures of children with congenital heart disease. Am J Epidemiol
1979; 109:433-439.
60. Boston Collaborative Drug Surveillance Program: Oral contraceptives and
venous thromboembolic disease, surgically confirmed gallbladder disease, and
breast tumors. Lancet 1973; 1:1399-1404.
61. Royal College of General Practitioners: Oral contraceptives and health. New
York, Pittman 1974.
62. Layde PM, Vessey MP, Yeates D. Risk of gallbladder disease: a cohort study
of young women attending family planning clinics. J Epidemiol Community
Health 1982; 36:274-278.
Reference ID: 3383539
32
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
63. Rome Group for Epidemiology and Prevention of Cholelithiasis (GREPCO):
Prevalence of gallstone disease in an Italian adult female population. Am J
Epidemiol 1984; 119:796-805.
64. Storm BL, Tamragouri RT, Morse ML, Lazar EL, West SL, Stolley PD, Jones
JK. Oral contraceptives and other risk factors for gallbladder disease. Clin
Pharmacol Ther 1986; 39:335-341.
65. Wynn V, Adams PW, Godsland IF, Melrose J, Niththyananthan R, Oakley
NW, Seedj A. Comparison of effects of different combined oral contraceptive
formulations on carbohydrate and lipid metabolism. Lancet 1979; 1:1045-1049.
66. Wynn V. Effect of progesterone and progestins on carbohydrate metabolism.
In: Progesterone and Progestin. Bardin CW, Milgrom E, Mauvis-Jarvis P. eds.
New York, Raven Press 1983; pp. 395-410.
67. Perlman JA, Roussell-Briefel RG, Ezzati TM, Lieberknecht G. Oral glucose
tolerance and the potency of oral contraceptive progestogens. J Chronic Dis
1985;38:857-864.
68. Royal College of General Practitioners' Oral Contraception Study: Effect on
hypertension and benign breast disease of progestogen component in combined
oral contraceptives. Lancet 1977; 1:624.
69. Fisch IR, Frank J. Oral contraceptives and blood pressure. JAMA 1977;
237:2499-2503.
70. Laragh AJ. Oral contraceptive induced hypertension-nine years later. Am J
Obstet Gynecol 1976; 126:141-147.
71. Ramcharan S, Peritz E, Pellegrin FA, Williams WT. Incidence of hypertension
in the Walnut Creek Contraceptive Drug Study cohort: In: Pharmacology of
steroid contraceptive drugs. Garattini S, Berendes HW. Eds. New York, Raven
Press, 1977; pp. 277-288, (Monographs of the Mario Negri Institute for
Pharmacological Research Milan.)
72. Stockley I. Interactions with oral contraceptives. J Pharm 1976;216:140-143.
73. The Cancer and Steroid Hormone Study of the Centers for Disease Control and
the National Institute of Child Health and Human Development: Oral
contraceptive use and the risk of ovarian cancer. JAMA 1983; 249:1596-1599.
74. The Cancer and Steroid Hormone Study of the Centers for Disease Control and
the National Institute of Child Health and Human Development: Combination
oral contraceptive use and the risk of endometrial cancer. JAMA 1987;
257:796-800.
75. Ory HW. Functional ovarian cysts and oral contraceptives: negative association
confirmed surgically. JAMA 1974; 228:68-69.
76. Ory HW, Cole P, MacMahon B, Hoover R. Oral contraceptives and reduced
risk of benign breast disease. N Engl J Med 1976; 294:419-422.
Reference ID: 3383539
33
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
77. Ory HW. The noncontraceptive health benefits from oral contraceptive use.
Fam Plann Perspect 1982; 14:182-184.
78. Ory HW, Forrest JD, Lincoln R. Making choices: Evaluating the health risks
and benefits of birth control methods. New York, The Alan Guttmacher
Institute, 1983; p.1.
79. Schlesselman J, Stadel BV, Murray P, Lai S. Breast cancer in relation to early
use of oral contraceptives. JAMA 1988; 259:1828-1833.
80. Hennekens CH, Speizer FE, Lipnick RJ, Rosner B, Bain C, Belanger C,
Stampfer MJ, Willett W, Peto R. A case-control study of oral contraceptive use
and breast cancer. JNCI 1984; 72:39-42.
81. LaVecchia C, Decarli A, Fasoli M, Franceschi S, Gentile A, Negri E, Parazzini
F, Tognoni G. Oral contraceptives and cancers of the breast and of the female
genital tract. Interim results from a case-control study. Br J Cancer 1986;
54:311-317.
82. Meirik O, Lund E, Adami H, Bergstrom R, Christoffersen T, Bergsjo P. Oral
contraceptive use and breast cancer in young women. A Joint National Case-
control study in Sweden and Norway. Lancet 1986; 11:650-654.
83. Kay CR, Hannaford PC. Breast cancer and the pill-A further report from the
Royal College of General Practitioners' oral contraception study. Br J Cancer
1988;58:675-680.
84. Stadel BV, Lai S, Schlesselman JJ, Murray P. Oral contraceptives and
premenopausal breast cancer in nulliparous women. Contraception 1988;
38:287-299.
85. Miller DR, Rosenberg L, Kaufman DW, Stolley P, Warshauer ME, Shapiro S.
Breast cancer before age 45 and oral contraceptive use: New Findings. Am J
Epidemiol 1989; 129:269-280.
86. The UK National Case-Control Study Group, Oral contraceptive use and breast
cancer risk in young women. Lancet 1989; 1:973-982.
87. Schlesselman JJ. Cancer of the breast and reproductive tract in relation to use of
oral contraceptives. Contraception 1989; 40:1-38.
88. Vessey MP, McPherson K, Villard-Mackintosh L, Yeates D. Oral
contraceptives and breast cancer: latest findings in a large cohort study. Br J
Cancer 1989; 59:613-617.
89. Jick SS, Walker AM, Stergachis A, Jick H. Oral contraceptives and breast
cancer. Br J Cancer 1989; 59:618-621.
90. Anderson FD, Selectivity and minimal androgenicity of norgestimate in
monophasic and triphasic oral contraceptives. Acta Obstet Gynecol Scand
1992; 156 (Supplement):15-21.
Reference ID: 3383539
34
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
91. Chapdelaine A, Desmaris J-L, Derman RJ. Clinical evidence of minimal
androgenic activity of norgestimate. Int J Fertil 1989; 34(51):347-352.
92. Phillips A, Demarest K, Hahn DW, Wong F, McGuire JL. Progestational and
androgenic receptor binding affinities and in vivo activities of norgestimate and
other progestins. Contraception 1989; 41(4):399-409.
93. Phillips A, Hahn DW, Klimek S, McGuire JL. A comparison of the potencies
and activities of progestogens used in contraceptives. Contraception 1987;
36(2):181-192.
94. Janaud A, Rouffy J, Upmalis D, Dain M-P. A comparison study of lipid and
androgen metabolism with triphasic oral contraceptive formulations containing
norgestimate or levonorgestrel. Acta Obstet Gynecol Scand 1992; 156
(Supplement):34-38.
95. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and
hormonal contraceptives: collaborative reanalysis of individual data on 53 297
women with breast cancer and 100 239 women without breast cancer from 54
epidemiological studies. Lancet 1996; 347:1713-1727.
96. Palmer JR, Rosenberg L, Kaufman DW, Warshauer ME, Stolley P, Shapiro S.
Oral Contraceptive Use and Liver Cancer. Am J Epidemiol 1989;130:878-882.
97. Lewis M, Spitzer WO, Heinemann LAJ, MacRae KD, Bruppacher R,
Thorogood M on behalf of Transnational Research Group on Oral
Contraceptives and Health of Young Women. Third generation oral
contraceptives and risk of myocardial infarction: an international case-control
study. Br Med J, 1996;312:88-90.
98. Improving access to quality care in family planning: Medical eligibility criteria
for contraceptive use. Geneva, WHO, Family and Reproductive Health, 1996.
99. Bork K, Fischer B, DeWald G. Recurrent episodes of skin angioedema and
severe attacks of abdominal pain induced by oral contraceptives or hormone
replacement therapy. Am J Med 2003;114:294-298.
100. Van Giersbergen PLM, Halabi A, Dingemanse J. Pharmacokinetic interaction
between bosentan and the oral contraceptives norethisterone and ethinyl
estradiol. Int J Clin Pharmacol Ther 2006;44(3):113-118.
101. Christensen J, Petrenaite V, Atterman J, et al. Oral contraceptives induce
lamotrigine metabolism: evidence from a double-blind, placebo-controlled trial.
Epilepsia 2007;48(3):484-489.
102.Chobanian et al. Seventh report of the joint national committee on
prevention, detection, evaluation, and treatment of high blood pressure.
Hypertension 2003;42;1206-1252.
Reference ID: 3383539
35
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
103.Brown KS, Armstrong IC, Wang A, Walker JR, Noveck RJ, Swearingen D,
Allison M, Kissling JC, Kisicki J, Salazar D. Effect of the bile acid
sequestrant colesevelam on the pharmacokinetics of pioglitazone,
repaglinide, estrogen estradiol, norethindrone, levothyroxine, and glyburide.
J Clin Pharmacol 2010;50:554-565.
BRIEF SUMMARY PATIENT PACKAGE INSERT
This product (like all oral contraceptives) does not protect against HIV
infection (AIDS) and other sexually transmitted diseases.
Oral contraceptives, also known as "birth control pills" or "the pill," are taken to
prevent pregnancy. When taken correctly to prevent pregnancy, oral
contraceptives have a failure rate of approximately 1% per year (1 pregnancy
per 100 women per year of use) when used without missing any pills. The
typical failure rate is approximately 5% per year (5 pregnancies per 100 women
per year of use) when women who miss pills are included. For most women oral
contraceptives are also free of serious or unpleasant side effects. However,
forgetting to take pills considerably increases the chances of pregnancy.
ORTHO TRI-CYCLEN may also be taken to treat moderate acne in females at
least 15 years of age, who have started having menstrual periods, are able to
take the pill and want to use the pill for birth control.
For the majority of women, oral contraceptives can be taken safely. But there
are some women who are at high risk of developing certain serious diseases that
can be fatal or may cause temporary or permanent disability. The risks
associated with taking oral contraceptives increase significantly if you:
smoke
have high blood pressure, diabetes, high cholesterol
have or have had clotting disorders, heart attack, stroke, angina
pectoris, cancer of the breast or sex organs, jaundice or malignant
or benign liver tumors
Although cardiovascular disease risks may be increased with oral contraceptive
use after age 40 in healthy, non-smoking women (even with the newer low-dose
formulations), there are also greater potential health risks associated with
pregnancy in older women.
You should not take the pill if you suspect you are pregnant or have unexplained
vaginal bleeding.
Reference ID: 3383539
36
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Do not use ORTHO TRI-CYCLEN® or ORTHO-CYCLEN® if you smoke
cigarettes and are over 35 years old. Smoking increases your risk of
serious cardiovascular side effects (heart and blood vessel problems) from
combination oral contraceptives, including death from heart attack, blood
clots or stroke. This risk increases with age and the number of cigarettes
you smoke.
Most side effects of the pill are not serious. The most common side effects are
nausea, vomiting, bleeding between menstrual periods, weight gain, breast
tenderness, and difficulty wearing contact lenses. These side effects, especially
nausea and vomiting, may subside within the first three months of use.
The serious side effects of the pill occur very infrequently, especially if you are
in good health and are young. However, you should know that the following
medical conditions have been associated with or made worse by the pill:
1. Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism),
stoppage or rupture of a blood vessel in the brain (stroke), blockage of blood
vessels in the heart (heart attack or angina pectoris) or other organs of the
body. As mentioned above, smoking increases the risk of heart attacks and
strokes and subsequent serious medical consequences.
2. In rare cases, oral contraceptives can cause benign but dangerous liver
tumors. These benign liver tumors can rupture and cause fatal internal
bleeding. In addition, some studies report an increased risk of developing
liver cancer. However, liver cancers are rare.
3. High blood pressure, although blood pressure usually returns to normal
when the pill is stopped.
The symptoms associated with these serious side effects are discussed in the
detailed leaflet given to you with your supply of pills. Notify your healthcare
professional if you notice any unusual physical disturbances while taking the
pill. In addition, drugs such as rifampin, bosentan, as well as some seizure
medicines and herbal preparations containing St. John’s wort (Hypericum
perforatum) may decrease oral contraceptive effectiveness.
Oral contraceptives may interact with lamotrigine (LAMICTAL®), a seizure
medicine used for epilepsy. This may increase the risk of seizures so your
healthcare professional may need to adjust the dose of lamotrigine.
Reference ID: 3383539
37
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Various studies give conflicting reports on the relationship between breast
cancer and oral contraceptive use. Oral contraceptive use may slightly increase
your chance of having breast cancer diagnosed, particularly after using
hormonal contraceptives at a younger age. After you stop using hormonal
contraceptives, the chances of having breast cancer diagnosed begin to go back
down. You should have regular breast examinations by a healthcare professional
and examine your own breasts monthly. Tell your healthcare professional if you
have a family history of breast cancer or if you have had breast nodules or an
abnormal mammogram. Women who currently have or have had breast cancer
should not use oral contraceptives because breast cancer is usually a
hormone-sensitive tumor.
Some studies have found an increase in the incidence of cancer of the cervix in
women who use oral contraceptives. However, this finding may be related to
factors other than the use of oral contraceptives. There is insufficient evidence
to rule out the possibility that the pill may cause such cancers.
Taking the combination pill provides some important non-contraceptive
benefits. These include less painful menstruation, less menstrual blood loss and
anemia, fewer pelvic infections, and fewer cancers of the ovary and the lining of
the uterus.
Be sure to discuss any medical condition you may have with your healthcare
professional. Your healthcare professional will take a medical and family history
before prescribing oral contraceptives and will examine you. The physical
examination may be delayed to another time if you request it and the healthcare
professional believes that it is a good medical practice to postpone it. You
should be reexamined at least once a year while taking oral contraceptives. Your
pharmacist should have given you the detailed patient information labeling
which gives you further information which you should read and discuss with
your healthcare professional.
HOW TO TAKE THE PILL
IMPORTANT POINTS TO REMEMBER
BEFORE YOU START TAKING YOUR PILLS:
1.
BE SURE TO READ THESE DIRECTIONS:
Before you start taking your pills.
Anytime you are not sure what to do.
Reference ID: 3383539
38
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.
THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL
EVERY DAY AT THE SAME TIME.
If you miss pills you could get pregnant. This includes starting the pack
late.
The more pills you miss, the more likely you are to get pregnant.
3.
MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR
MAY FEEL SICK TO THEIR STOMACH DURING THE FIRST 1-3
PACKS OF PILLS. If you feel sick to your stomach or have spotting or
light bleeding, do not stop taking the pill. The problem will usually go
away. If it doesn't go away, check with your healthcare professional.
4.
MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT
BLEEDING, even when you make up these missed pills.
On the days you take 2 pills to make up for missed pills, you could also
feel a little sick to your stomach.
5.
IF YOU HAVE VOMITING OR DIARRHEA, OR IF YOU TAKE
SOME MEDICINES, your pills may not work as well.
Use a back-up method (such as a condom or spermicide) until you check
with your healthcare professional.
6.
IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL,
talk to your healthcare professional about how to make pill-taking easier
or about using another method of birth control.
Reference ID: 3383539
39
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7.
IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE
INFORMATION IN THIS LEAFLET, call your healthcare professional.
BEFORE YOU START TAKING YOUR PILLS
1.
DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.
It is important to take it at about the same time every day.
2.
LOOK AT YOUR PILL PACK
The pill pack has 21 "active" pills (with hormones) to take for 3 weeks.
This is followed by 1 week of "reminder" dark green pills (without
hormones).
ORTHO TRI-CYCLEN: There are 7 white "active" pills, 7 light blue
"active" pills, 7 blue "active" pills, and 7 dark green "reminder" pills.
ORTHO-CYCLEN: There are 21 blue "active" pills, and 7 dark green
"reminder" pills.
3.
ALSO FIND:
1) where on the pack to start taking pills,
2) in what order to take the pills.
4.
BE SURE YOU HAVE READY AT ALL TIMES:
ANOTHER KIND OF BIRTH CONTROL (such as a condom or
spermicide) to use as a back-up method in case you miss pills.
AN EXTRA, FULL PILL PACK.
WHEN TO START THE FIRST PACK OF PILLS
You have a choice of which day to start taking your first pack of pills. ORTHO
TRI-CYCLEN and ORTHO-CYCLEN are available with the DIALPAK®
Tablet Dispenser which is preset for a Sunday Start. Day 1 Start is also
provided. Decide with your healthcare professional which is the best day for
you. Pick a time of day that will be easy to remember.
Sunday Start:
ORTHO TRI-CYCLEN: Take the first white "active" pill of the first pack on
the Sunday after your period starts, even if you are still bleeding. If your period
begins on Sunday, start the pack that same day.
Reference ID: 3383539
40
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ORTHO-CYCLEN: Take the first blue "active" pill of the first pack on the
Sunday after your period starts, even if you are still bleeding. If your period
begins on Sunday, start the pack that same day.
Use another method of birth control such as a condom or spermicide as a
back-up method if you have sex anytime from the Sunday you start your first
pack until the next Sunday (7 days).
Day 1 Start:
ORTHO TRI-CYCLEN: Take the first white "active" pill of the first pack
during the first 24 hours of your period.
ORTHO-CYCLEN: Take the first blue "active" pill of the first pack during
the first 24 hours of your period.
You will not need to use a back-up method of birth control, since you are
starting the pill at the beginning of your period.
WHAT TO DO DURING THE MONTH
1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE
PACK IS EMPTY.
Do not skip pills even if you are spotting or bleeding between monthly
periods or feel sick to your stomach (nausea).
Do not skip pills even if you do not have sex very often.
2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS:
Start the next pack on the day after your last "reminder" pill. Do not wait
any days between packs.
WHAT TO DO IF YOU MISS PILLS
ORTHO TRI-CYCLEN:
If you MISS 1 white, light blue, or blue "active" pill:
1. Take it as soon as you remember. Take the next pill at your regular time.
This means you may take 2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 white or light blue "active" pills in a row in WEEK 1 OR
WEEK 2 of your pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
Reference ID: 3383539
41
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2. Then take 1 pill a day until you finish the pack.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you
miss pills. You MUST use another birth control method (such as a condom
or spermicide) as a back-up method for those 7 days.
If you MISS 2 blue "active" pills in a row in THE 3RD WEEK:
1. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the
rest of the pack and start a new pack of pills that same day.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if
you miss your period 2 months in a row, call your healthcare professional
because you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you
miss pills. You MUST use another birth control method (such as a condom
or spermicide) as a back-up method for those 7 days.
If you MISS 3 OR MORE white, light blue, or blue "active" pills in a row
(during the first 3 weeks):
1. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the
rest of the pack and start a new pack of pills that same day.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if
you miss your period 2 months in a row, call your healthcare professional
because you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you
miss pills. You MUST use another birth control method (such as a condom
or spermicide) as a back-up method for those 7 days.
ORTHO-CYCLEN:
If you MISS 1 blue "active" pill:
1. Take it as soon as you remember. Take the next pill at your regular time.
This means you may take 2 pills in 1 day.
Reference ID: 3383539
42
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 blue "active" pills in a row in WEEK 1 OR WEEK 2 of your
pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you
miss pills. You MUST use another birth control method (such as a condom
or spermicide) as a back-up method for those 7 days.
If you MISS 2 blue "active" pills in a row in THE 3RD WEEK:
1. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the
rest of the pack and start a new pack of pills that same day.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if
you miss your period 2 months in a row, call your healthcare professional
because you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you
miss pills. You MUST use another birth control method (such as a condom
or spermicide) as a back-up method for those 7 days.
If you MISS 3 OR MORE blue "active" pills in a row (during the first
3 weeks):
1. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the
rest of the pack and start a new pack of pills that same day.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if
you miss your period 2 months in a row, call your healthcare professional
because you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you
miss pills. You MUST use another birth control method (such as a condom
or spermicide) as a back-up method for those 7 days.
Reference ID: 3383539
43
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
A REMINDER:
If you forget any of the 7 dark green "reminder" pills in WEEK 4:
THROW AWAY the pills you missed.
Keep taking 1 pill each day until the pack is empty.
You do not need a back-up method.
FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE
PILLS YOU HAVE MISSED:
Use a BACK-UP METHOD anytime you have sex.
KEEP TAKING ONE "ACTIVE" PILL EACH DAY until you can reach your
healthcare professional.
Reference ID: 3383539
44
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Reference ID: 3383539
45
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DETAILED PATIENT LABELING
PLEASE NOTE: This labeling is revised from time to time as important
new medical information becomes available. Therefore, please review this
labeling carefully.
This product (like all oral contraceptives) does not protect against HIV
infection (AIDS) and other sexually transmitted diseases.
ORTHO TRI-CYCLEN Regimen
Each white tablet contains 0.180 mg norgestimate and 0.035 mg ethinyl
estradiol. Each light blue tablet contains 0.215 mg norgestimate and 0.035 mg
ethinyl estradiol. Each blue tablet contains 0.250 mg norgestimate and 0.035 mg
ethinyl estradiol. Each dark green tablet contains inert ingredients.
ORTHO-CYCLEN Regimen
Each blue tablet contains 0.250 mg norgestimate and 0.035 mg ethinyl estradiol.
Each dark green tablet contains inert ingredients.
INTRODUCTION
Any woman who considers using oral contraceptives (the birth control pill or the
pill) should understand the benefits and risks of using this form of birth control.
This patient labeling will give you much of the information you will need to
make this decision and will also help you determine if you are at risk of
developing any of the serious side effects of the pill. It will tell you how to use
the pill properly so that it will be as effective as possible. However, this labeling
is not a replacement for a careful discussion between you and your healthcare
professional. You should discuss the information provided in this labeling with
him or her, both when you first start taking the pill and during your revisits. You
should also follow your healthcare professional’s advice with regard to regular
check-ups while you are on the pill.
EFFECTIVENESS OF ORAL CONTRACEPTIVES FOR
CONTRACEPTION
Oral contraceptives or "birth control pills" or "the pill" are used to prevent
pregnancy and are more effective than most other non-surgical methods of birth
control. When they are taken correctly without missing any pills, the chance of
becoming pregnant is approximately 1% per year (1 pregnancy per 100 women
per year of use). Typical failure rates, including women who do not always take
the pill correctly, are approximately 5% per year (5 pregnancies per 100 women
per year of use). The chance of becoming pregnant increases with each missed
pill during a menstrual cycle.
Reference ID: 3383539
46
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In comparison, typical failure rates for other non-surgical methods of birth
control during the first year of use are as follows:
Implant: <1%
Male sterilization: <1%
Injection: <1%
Cervical Cap with spermicides: 20 to 40%
IUD: 1 to 2%
Condom alone (male): 14%
Diaphragm with spermicides: 20%
Condom alone (female): 21%
Spermicides alone: 26%
Periodic abstinence: 25%
Vaginal sponge: 20 to 40%
Withdrawal: 19%
Female sterilization: <1%
No methods: 85%
ORTHO TRI-CYCLEN may also be taken to treat moderate acne if all of the
following are true:
You have started having menstrual cycles
You are at least 15 years old
Your healthcare professional says it is safe for you to use the pill
You want to use the pill for birth control
WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES
Do not use ORTHO TRI-CYCLEN® or ORTHO-CYCLEN® if you
smoke cigarettes and are over 35 years old. Smoking increases your risk
of serious cardiovascular side effects (heart and blood vessel problems)
from combination oral contraceptives, including death from heart
attack, blood clots or stroke. This risk increases with age and the
number of cigarettes you smoke.
Some women should not use the pill. For example, you should not take the pill if
you have any of the following conditions:
A history of heart attack or stroke
Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or
eyes
A history of blood clots in the deep veins of your legs
An inherited problem that makes your blood clot more than normal
Chest pain (angina pectoris)
Known or suspected breast cancer or cancer of the lining of the uterus,
cervix or vagina
Unexplained vaginal bleeding (until a diagnosis is reached by your
healthcare professional)
Yellowing of the whites of the eyes or of the skin (jaundice) during
pregnancy or during previous use of the pill
Reference ID: 3383539
47
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Liver tumor (benign or cancerous) or active liver disease
Known or suspected pregnancy
Valvular heart disease with complications
Severe hypertension
Diabetes with vascular involvement
Headaches with focal neurological symptoms
Major surgery with prolonged immobilization
Hypersensitivity to any component of this product
Tell your healthcare professional if you have had any of these conditions. Your
healthcare professional can recommend a safer method of birth control.
OTHER CONSIDERATIONS BEFORE TAKING ORAL
CONTRACEPTIVES
Tell your healthcare professional if you have or have had:
Breast nodules, fibrocystic disease of the breast, an abnormal breast x-ray or
mammogram
Diabetes
Elevated cholesterol or triglycerides
High blood pressure
Migraine or other headaches or epilepsy
Mental depression
Gallbladder, liver, heart or kidney disease
History of scanty or irregular menstrual periods
Women with any of these conditions should be checked often by their healthcare
professional if they choose to use oral contraceptives.
Also, be sure to inform your healthcare professional if you smoke or are on any
medications.
RISKS OF TAKING ORAL CONTRACEPTIVES
1. Risk of Developing Blood Clots
Blood clots and blockage of blood vessels are one of the most serious side
effects of taking oral contraceptives and can cause death or serious disability. In
particular, a clot in the legs can cause thrombophlebitis and a clot that travels to
the lungs can cause a sudden blocking of the vessel carrying blood to the lungs.
Rarely, clots occur in the blood vessels of the eye and may cause blindness,
double vision, or impaired vision.
Reference ID: 3383539
48
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
If you take oral contraceptives and need elective surgery, need to stay in bed for
a prolonged illness or injury or have recently delivered a baby, you may be at
risk of developing blood clots. You should consult your healthcare professional
about stopping oral contraceptives four weeks before surgery and not taking oral
contraceptives for two weeks after surgery or during bed rest. You should also
not take oral contraceptives soon after delivery of a baby. It is advisable to wait
for at least four weeks after delivery if you are not breastfeeding. If you are
breastfeeding, you should wait until you have weaned your child before using
the pill. (See also the section on Breastfeeding in General Precautions.)
The risk of circulatory disease in oral contraceptive users may be higher in users
of high-dose pills and may be greater with longer duration of oral contraceptive
use. In addition, some of these increased risks may continue for a number of
years after stopping oral contraceptives. The risk of abnormal blood clotting
increases with age in both users and nonusers of oral contraceptives, but the
increased risk from the oral contraceptive appears to be present at all ages. For
women aged 20 to 44 it is estimated that about 1 in 2,000 using oral
contraceptives will be hospitalized each year because of abnormal clotting.
Among nonusers in the same age group, about 1 in 20,000 would be hospitalized
each year. For oral contraceptive users in general, it has been estimated that in
women between the ages of 15 and 34 the risk of death due to a circulatory
disorder is about 1 in 12,000 per year, whereas for nonusers the rate is about 1 in
50,000 per year. In the age group 35 to 44, the risk is estimated to be about 1 in
2,500 per year for oral contraceptive users and about 1 in 10,000 per year for
nonusers.
2. Heart Attacks and Strokes
Oral contraceptives may increase the tendency to develop strokes (stoppage or
rupture of blood vessels in the brain) and angina pectoris and heart attacks
(blockage of blood vessels in the heart). Any of these conditions can cause death
or serious disability.
Smoking greatly increases the possibility of suffering heart attacks and strokes.
Furthermore, smoking and the use of oral contraceptives greatly increase the
chances of developing and dying of heart disease.
3. Gallbladder Disease
Oral contraceptive users probably have a greater risk than nonusers of having
gallbladder disease, although this risk may be related to pills containing high
doses of estrogens.
Reference ID: 3383539
49
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4. Liver Tumors
In rare cases, oral contraceptives can cause benign but dangerous liver tumors.
These benign liver tumors can rupture and cause fatal internal bleeding. In
addition, some studies report an increased risk of developing liver cancer.
However, liver cancers are rare.
5. Cancer of the Reproductive Organs and Breasts
Various studies give conflicting reports on the relationship between breast
cancer and oral contraceptive use. Oral contraceptive use may slightly increase
your chance of having breast cancer diagnosed, particularly after using
hormonal contraceptives at a younger age. After you stop using hormonal
contraceptives, the chances of having breast cancer diagnosed begin to go back
down. You should have regular breast examinations by a healthcare professional
and examine your own breasts monthly. Tell your healthcare professional if you
have a family history of breast cancer or if you have had breast nodules or an
abnormal mammogram. Women who currently have or have had breast cancer
should not use oral contraceptives because breast cancer is usually a
hormone-sensitive tumor.
Some studies have found an increase in the incidence of cancer of the cervix in
women who use oral contraceptives. However, this finding may be related to
factors other than the use of oral contraceptives. There is insufficient evidence
to rule out the possibility that the pill may cause such cancers.
ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD
OR PREGNANCY
All methods of birth control and pregnancy are associated with a risk of
developing certain diseases which may lead to disability or death. An estimate
of the number of deaths associated with different methods of birth control and
pregnancy has been calculated and is shown in the following table.
Annual Number of Birth-Related or Method-Related Deaths Associated with Control of
Fertility per 100,000 Nonsterile Women, by Fertility Control Method According to Age
Method of control
15-19
20-24
25-29
30-34
35-39
40-44
and outcome
No fertility
7.0
7.4
9.1
14.8
25.7
28.2
control methods*
Oral contraceptives
non-smoker†
0.3
0.5
0.9
1.9
13.8
31.6
Oral contraceptives
smoker†
2.2
3.4
6.6
13.5
51.1
117.2
IUD†
0.8
0.8
1.0
1.0
1.4
1.4
Condom*
1.1
1.6
0.7
0.2
0.3
0.4
Diaphragm/
1.9
1.2
1.2
1.3
2.2
2.8
spermicide*
Reference ID: 3383539
50
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3.6
Periodic
2.5
1.6
1.6
1.7
2.9
abstinence*
Adapted from H.W. Ory, ref. #35.
* Deaths are birth-related
† Deaths are method-related
In the above table, the risk of death from any birth control method is less than
the risk of childbirth, except for oral contraceptive users over the age of 35 who
smoke and pill users over the age of 40 even if they do not smoke. It can be seen
in the table that for women aged 15 to 39, the risk of death was highest with
pregnancy (7 to 26 deaths per 100,000 women, depending on age). Among pill
users who do not smoke, the risk of death was always lower than that associated
with pregnancy for any age group less than 40. Over the age of 40, the risk
increases to 32 deaths per 100,000 women, compared to 28 associated with
pregnancy in that age group. However, for pill users who smoke and are over
the age of 35, the estimated number of deaths exceeds those for other methods
of birth control. If a woman is over the age of 40 and smokes, her estimated risk
of death is four times higher (117/100,000 women) than the estimated risk
associated with pregnancy (28/100,000 women) in that age group.
The suggestion that women over 40 who do not smoke should not take oral
contraceptives is based on information from older, higher-dose pills. An
Advisory Committee of the FDA discussed this issue in 1989 and recommended
that the benefits of low-dose oral contraceptive use by healthy, non-smoking
women over 40 years of age may outweigh the possible risks. Older women, as
all women, who take oral contraceptives, should take an oral contraceptive
which contains the least amount of estrogen and progestogen that is compatible
with the individual patient needs.
WARNING SIGNALS
If any of these adverse effects occur while you are taking oral contraceptives,
call your healthcare professional immediately:
Sharp chest pain, coughing of blood, or sudden shortness of breath
(indicating a possible clot in the lung)
Pain in the calf (indicating a possible clot in the leg)
Crushing chest pain, heaviness in the chest, irregular heart beat or
palpitations (indicating a possible heart attack)
Sudden severe headache or vomiting, dizziness or fainting, disturbances of
vision or speech, weakness, or numbness in an arm or leg (indicating a
possible stroke)
Reference ID: 3383539
51
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Sudden partial or complete loss of vision (indicating a possible clot in the
eye)
Breast lumps (indicating possible breast cancer or fibrocystic disease of the
breast; ask your healthcare professional to show you how to examine your
breasts)
Severe pain or tenderness in the stomach area (indicating a possibly ruptured
liver tumor)
Difficulty in sleeping, weakness, lack of energy, fatigue, or change in mood
(possibly indicating severe depression)
Jaundice or a yellowing of the skin or eyeballs, accompanied frequently by
fever, fatigue, loss of appetite, dark colored urine, or light colored bowel
movements (indicating possible liver problems)
SIDE EFFECTS OF ORAL CONTRACEPTIVES
In addition to the risks and more serious side effects discussed above, the
following may also occur:
1. Irregular Vaginal Bleeding
Irregular vaginal bleeding or spotting may occur while you are taking the pills.
Irregular bleeding may vary from slight staining between menstrual periods to
breakthrough bleeding which is a flow much like a regular period. Irregular
bleeding occurs most often during the first few months of oral contraceptive use,
but may also occur after you have been taking the pill for some time. Such
bleeding may be temporary and usually does not indicate any serious problems.
It is important to continue taking your pills on schedule. If the bleeding occurs
in more than one cycle or lasts for more than a few days, talk to your healthcare
professional.
2. Contact Lenses
If you wear contact lenses and notice a change in vision or an inability to wear
your lenses, contact your healthcare professional.
3. Fluid Retention
Oral contraceptives may cause edema (fluid retention) with swelling of the
fingers or ankles and may raise your blood pressure. If you experience fluid
retention, contact your healthcare professional.
4. Melasma
A spotty darkening of the skin is possible, particularly of the face, which may
persist.
Reference ID: 3383539
52
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5. Other Side Effects
Other side effects may include nausea, vomiting, diarrhea and constipation,
change in appetite, headache, nervousness, depression, dizziness, muscle
cramps, loss of scalp hair, rash, skin sensitivity to the sun or ultraviolet light,
vaginal infections, urinary tract infections, vertigo, pancreatitis and allergic
reactions.
If any of these side effects bother you, call your healthcare professional.
GENERAL PRECAUTIONS
1.
Missed Periods and Use of Oral Contraceptives Before or
During Early Pregnancy
There may be times when you may not menstruate regularly after you have
completed taking a cycle of pills. If you have taken your pills regularly and miss
one menstrual period, continue taking your pills for the next cycle but be sure to
inform your healthcare professional. If you have not taken the pills daily as
instructed and missed a menstrual period, or if you missed two consecutive
menstrual periods, you may be pregnant. Check with your healthcare
professional immediately to determine whether you are pregnant. Stop taking
your pills if you are pregnant.
There is no conclusive evidence that oral contraceptive use is associated with an
increase in birth defects, when taken inadvertently during early pregnancy.
Previously, a few studies had reported that oral contraceptives might be
associated with birth defects, but these findings have not been seen in more
recent studies. Nevertheless, oral contraceptives should not be used during
pregnancy. You should check with your healthcare professional about risks to
your unborn child of any medication taken during pregnancy.
2. While Breastfeeding
If you are breastfeeding, consult your healthcare professional before starting
oral contraceptives. Some of the drug will be passed on to the child in the milk.
A few adverse effects on the child have been reported, including yellowing of
the skin (jaundice) and breast enlargement. In addition, combination oral
contraceptives may decrease the amount and quality of your milk. If possible, do
not use combination oral contraceptives while breastfeeding. You should use
another method of contraception since breastfeeding provides only partial
protection from becoming pregnant and this partial protection decreases
significantly as you breastfeed for longer periods of time. You should consider
Reference ID: 3383539
53
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
starting combination oral contraceptives only after you have weaned your child
completely.
3. Laboratory Tests
If you are scheduled for any laboratory tests, tell your healthcare professional
you are taking birth control pills. Certain blood tests may be affected by birth
control pills.
4. Drug Interactions
Tell your healthcare provider about all medicines and herbal products that you
take.
Some medicines and herbal products may make hormonal birth control less
effective, including, but not limited to:
• certain seizure medicines (carbamazepine, felbamate, oxcarbazepine,
phenytoin, rufinamide, and topiramate)
• aprepitant
• barbiturates
• bosentan
• colesevelam
• griseofulvin
• certain combinations of HIV medicines (nelfinavir, ritonavir,
ritonavir-boosted protease inhibitors)
• certain non nucleoside reverse transcriptase inhibitors (nevirapine)
• rifampin and rifabutin
• St. John’s wort
Use another birth control method (such as a condom and spermicide or
diaphragm and spermicide) when you take medicines that may make
ORTHO TRI-CYCLEN® or ORTHO-CYCLEN® less effective.
Some medicines and grapefruit juice may increase your level of the hormone
ethinyl estradiol if used together, including:
• acetaminophen
• ascorbic acid
Reference ID: 3383539
54
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• medicines that affect how your liver breaks down other medicines
(itraconazole, ketoconazole, voriconazole, and fluconazole)
• certain HIV medicines (atazanavir, indinavir)
• atorvastatin
• rosuvastatin
• etravirine
Hormonal birth control methods may interact with lamotrigine, a seizure
medicine used for epilepsy. This may increase the risk of seizures, so your
healthcare provider may need to adjust the dose of lamotrigine.
Women on thyroid replacement therapy may need increased doses of thyroid
hormone.
Know the medicines you take. Keep a list of them to show your doctor and
pharmacist when you get a new medicine.
5. Sexually Transmitted Diseases
ORTHO-CYCLEN and ORTHO TRI-CYCLEN (like all oral contraceptives)
are intended to prevent pregnancy. Oral contraceptives do not protect against
transmission of HIV (AIDS) and other sexually transmitted diseases such as
chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.
HOW TO TAKE THE PILL
IMPORTANT POINTS TO REMEMBER
BEFORE YOU START TAKING YOUR PILLS:
1. BE SURE TO READ THESE DIRECTIONS:
Before you start taking your pills.
Anytime you are not sure what to do.
2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY
DAY AT THE SAME TIME.
If you miss pills you could get pregnant. This includes starting the pack late.
The more pills you miss, the more likely you are to get pregnant.
3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY
FEEL SICK TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF
PILLS. If you feel sick to your stomach or have spotting or light bleeding,
do not stop taking the pill. The problem will usually go away. If it doesn't go
away, check with your healthcare professional.
Reference ID: 3383539
55
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT
BLEEDING, even when you make up these missed pills.
On the days you take 2 pills to make up for missed pills, you could also feel
a little sick to your stomach.
5. IF YOU HAVE VOMITING OR DIARRHEA, OR IF YOU TAKE SOME
MEDICINES, including some antibiotics, your pills may not work as well.
Use a back-up method (such as a condom or spermicide) until you check
with your healthcare professional.
6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to
your healthcare professional about how to make pill-taking easier or about
using another method of birth control.
7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE
INFORMATION IN THIS LEAFLET, call your healthcare professional.
BEFORE YOU START TAKING YOUR PILLS
1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.
It is important to take it at about the same time every day.
2. LOOK AT YOUR PILL PACK
The pill pack has 21 "active" pills (with hormones) to take for 3 weeks. This
is followed by 1 week of "reminder" dark green pills (without hormones).
ORTHO TRI-CYCLEN: There are 7 white "active" pills, 7 light blue
"active" pills, 7 blue "active" pills, and 7 dark green "reminder" pills.
ORTHO-CYCLEN: There are 21 blue "active" pills and 7 dark green
"reminder" pills.
3. ALSO FIND:
1) where on the pack to start taking pills,
2) in what order to take the pills.
CHECK PICTURE OF PILL PACK AND ADDITIONAL INSTRUCTIONS
FOR USING THIS PACKAGE IN THE BRIEF SUMMARY PATIENT
PACKAGE INSERT.
4. BE SURE YOU HAVE READY AT ALL TIMES:
ANOTHER KIND OF BIRTH CONTROL (such as a condom or
spermicide) to use as a back-up method in case you miss pills.
AN EXTRA, FULL PILL PACK.
Reference ID: 3383539
56
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WHEN TO START THE FIRST PACK OF PILLS
You have a choice of which day to start taking your first pack of pills. ORTHO
TRI-CYCLEN and ORTHO-CYCLEN are available with the DIALPAK®
Tablet Dispenser which is preset for a Sunday Start. Day 1 Start is also
provided. Decide with your healthcare professional which is the best day for
you. Pick a time of day that will be easy to remember.
Sunday Start:
ORTHO TRI-CYCLEN: Take the first white "active" pill of the first pack on
the Sunday after your period starts, even if you are still bleeding. If your period
begins on Sunday, start the pack that same day.
ORTHO-CYCLEN: Take the first blue "active" pill of the first pack on the
Sunday after your period starts, even if you are still bleeding. If your period
begins on Sunday, start the pack that same day.
Use another method of birth control such as a condom or spermicide as a
back-up method if you have sex anytime from the Sunday you start your first
pack until the next Sunday (7 days).
Day 1 Start:
ORTHO TRI-CYCLEN: Take the first white "active" pill of the first pack
during the first 24 hours of your period.
ORTHO-CYCLEN: Take the first blue "active" pill of the first pack during
the first 24 hours of your period.
You will not need to use a back-up method of birth control, since you are
starting the pill at the beginning of your period.
WHAT TO DO DURING THE MONTH
1. Take One Pill at the Same Time Every Day Until the Pack is Empty.
Do not skip pills even if you are spotting or bleeding between monthly
periods or feel sick to your stomach (nausea).
Do not skip pills even if you do not have sex very often.
2. When You Finish a Pack or Switch Your Brand of Pills:
Start the next pack on the day after your last "reminder" pill. Do not wait
any days between packs.
Reference ID: 3383539
57
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
WHAT TO DO IF YOU MISS PILLS
ORTHO TRI-CYCLEN:
If you MISS 1 white, light blue, or blue "active" pill:
1. Take it as soon as you remember. Take the next pill at your regular time.
This means you may take 2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 white or light blue "active" pills in a row in WEEK 1 OR
WEEK 2 of your pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after
you miss pills. You MUST use another birth control method (such as a
condom or spermicide) as a back-up method for those 7 days.
If you MISS 2 blue "active" pills in a row in THE 3RD WEEK:
1. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT
the rest of the pack and start a new pack of pills that same day.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same
day.
2. You may not have your period this month but this is expected. However,
if you miss your period 2 months in a row, call your healthcare
professional because you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after
you miss pills. You MUST use another birth control method (such as a
condom or spermicide) as a back-up method for those 7 days.
If you MISS 3 OR MORE white, light blue, or blue "active" pills in a row
(during the first 3 weeks):
1. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT
the rest of the pack and start a new pack of pills that same day.
Reference ID: 3383539
58
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same
day.
2. You may not have your period this month but this is expected. However,
if you miss your period 2 months in a row, call your healthcare
professional because you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after
you miss pills. You MUST use another birth control method (such as a
condom or spermicide) as a back-up method for those 7 days.
ORTHO-CYCLEN:
If you MISS 1 blue "active" pill:
1. Take it as soon as you remember. Take the next pill at your regular time.
This means you may take 2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 blue "active" pills in a row in WEEK 1 OR WEEK 2 of your
pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after
you miss pills. You MUST use another birth control method (such as a
condom or spermicide) as a back-up method for those 7 days.
If you MISS 2 blue "active" pills in a row in THE 3RD WEEK:
1. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT
the rest of the pack and start a new pack of pills that same day.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same
day.
2. You may not have your period this month but this is expected. However,
if you miss your period 2 months in a row, call your healthcare
professional because you might be pregnant.
Reference ID: 3383539
59
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
3. You COULD BECOME PREGNANT if you have sex in the 7 days after
you miss pills. You MUST use another birth control method (such as a
condom or spermicide) as a back-up method for those 7 days.
If you MISS 3 OR MORE blue "active" pills in a row (during the first
3 weeks):
1. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT
the rest of the pack and start a new pack of pills that same day.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same
day.
2. You may not have your period this month but this is expected. However,
if you miss your period 2 months in a row, call your healthcare
professional because you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after
you miss pills. You MUST use another birth control method (such as a
condom or spermicide) as a back-up method for those 7 days.
A REMINDER:
If you forget any of the 7 dark green "reminder" pills in WEEK 4:
THROW AWAY the pills you missed.
Keep taking 1 pill each day until the pack is empty.
You do not need a back-up method.
FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE
PILLS YOU HAVE MISSED:
Use a BACK-UP METHOD anytime you have sex.
KEEP TAKING ONE "ACTIVE" PILL EACH DAY until you can reach your
healthcare professional.
PREGNANCY DUE TO PILL FAILURE
The incidence of pill failure resulting in pregnancy is approximately 5%,
including women who do not always take the pills exactly as directed. If failure
does occur, the risk to the fetus is minimal.
PREGNANCY AFTER STOPPING THE PILL
There may be some delay in becoming pregnant after you stop using oral
contraceptives, especially if you had irregular menstrual cycles before you used
Reference ID: 3383539
60
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
oral contraceptives. It may be advisable to postpone conception until you begin
menstruating regularly once you have stopped taking the pill and desire
pregnancy.
There does not appear to be any increase in birth defects in newborn babies
when pregnancy occurs soon after stopping the pill.
OVERDOSAGE
Serious ill effects have not been reported following ingestion of large doses of
oral contraceptives by young children. Overdosage may cause nausea and
withdrawal bleeding in females. In case of overdosage, contact your healthcare
professional or pharmacist.
OTHER INFORMATION
Your healthcare professional will take a medical and family history before
prescribing oral contraceptives and will examine you. The physical examination
may be delayed to another time if you request it and the healthcare professional
believes that it is a good medical practice to postpone it. You should be
reexamined at least once a year. Be sure to inform your healthcare professional
if there is a family history of any of the conditions listed previously in this
leaflet. Be sure to keep all appointments with your healthcare professional,
because this is a time to determine if there are early signs of side effects of oral
contraceptive use.
Do not use the drug for any condition other than the one for which it was
prescribed. This drug has been prescribed specifically for you; do not give it to
others who may want birth control pills.
HEALTH BENEFITS FROM ORAL CONTRACEPTIVES
In addition to preventing pregnancy, use of combination oral contraceptives may
provide certain benefits. They are:
menstrual cycles may become more regular
blood flow during menstruation may be lighter and less iron may be lost.
Therefore, anemia due to iron deficiency is less likely to occur
pain or other symptoms during menstruation may be encountered less
frequently
ectopic (tubal) pregnancy may occur less frequently
noncancerous cysts or lumps in the breast may occur less frequently
acute pelvic inflammatory disease may occur less frequently
Reference ID: 3383539
61
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
oral contraceptive use may provide some protection against developing two
forms of cancer: cancer of the ovaries and cancer of the lining of the uterus.
If you want more information about birth control pills, ask your healthcare
professional or pharmacist. They have a more technical leaflet called the
Professional Labeling, which you may wish to read.
Keep out of reach of children.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
Protect from light.
Mfd. by:
Janssen Ortho, LLC
Manati, Puerto Rico 00674
Mfd. for:
Janssen Pharmaceuticals, Inc.
Titusville, New Jersey 08560
© Janssen Pharmaceuticals, Inc. 1998
Revised October 2013
Reference ID: 3383539
62
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:38.106133
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019653Orig1s046,019697Orig1s042lbl.pdf', 'application_number': 19653, 'submission_type': 'SUPPL ', 'submission_number': 46}
|
11,603
|
10305001
barcode
barcode
ORTHO TRI-CYCLEN® TABLETS
ORTHO-CYCLEN® TABLETS
(norgestimate/ethinyl estradiol)
Patients should be counseled that this product does
not protect against HIV infection (AIDS) and other
sexually transmitted diseases.
barcode
DESCRIPTION
Each of the following products is a combination oral contraceptive containing the
progestational compound norgestimate and the estrogenic compound ethinyl estradiol.
ORTHO TRI-CYCLEN® Tablets.
Each white tablet contains 0.180 mg of the progestational compound, norgestimate
(18,19-Dinor-17-pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-,oxime,
(17 )-(+)-) and 0.035 mg of the estrogenic compound, ethinyl estradiol (19-nor
17 -pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients include carnauba
wax, croscarmellose sodium, hypromellose, lactose, magnesium stearate,
microcrystalline cellulose, polyethylene glycol, purified water and titanium dioxide.
Each light blue tablet contains 0.215 mg of the progestational compound norgestimate
(18,19-Dinor-17-pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-,oxime,(17 )-(+)-)
and 0.035 mg of the estrogenic compound, ethinyl estradiol (19-nor-17
pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients include FD & C Blue No. 2
Aluminum Lake, carnauba wax, croscarmellose sodium, hypromellose, lactose,
magnesium stearate, microcrystalline cellulose, polyethylene glycol, purified water and
titanium dioxide.
Each blue tablet contains 0.250 mg of the progestational compound norgestimate
(18,19-Dinor-17-pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-,oxime,(17 )-(+)-)
and 0.035 mg of the estrogenic compound, ethinyl estradiol (19-nor-17
pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients include FD & C Blue
No. 2 Aluminum Lake, carnauba wax, croscarmellose sodium, hypromellose,
lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol,
polysorbate 80, purified water and titanium dioxide.
Each dark green tablet contains only inert ingredients, as follows: FD & C Blue No. 2
Aluminum Lake, ferric oxide, hypromellose, lactose, magnesium stearate,
polyethylene glycol, pregelatinized corn starch, purified water, talc and titanium
dioxide.
ORTHO-CYCLEN® Tablets.
Each blue tablet contains 0.250 mg of the progestational compound norgestimate
(18,19-Dinor-17-pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-,oxime,(17 )-(+)-)
and 0.035 mg of the estrogenic compound, ethinyl estradiol (19-nor-17
pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients include FD & C Blue
No. 2 Aluminum Lake, carnauba wax, croscarmellose sodium, hypromellose,
lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol,
polysorbate 80, purified water and titanium dioxide.
Each dark green tablet contains only inert ingredients, as follows: FD & C Blue No. 2
Aluminum Lake, ferric oxide, hypromellose, lactose, magnesium stearate,
polyethylene glycol, pregelatinized corn starch, purified water, talc and titanium
dioxide.
chemical structurechemical structure
Ethinyl Estradiol
CLINICAL PHARMACOLOGY
Oral Contraception
Combination oral contraceptives act by suppression of gonadotropins. Although the
primary mechanism of this action is inhibition of ovulation, other alterations include
changes in the cervical mucus (which increase the difficulty of sperm entry into the
uterus) and the endometrium (which reduce the likelihood of implantation).
Receptor binding studies, as well as studies in animals and humans, have shown
that norgestimate and 17-deacetyl norgestimate, the major serum metabolite,
combine high progestational activity with minimal intrinsic androgenicity.90-93
Norgestimate, in combination with ethinyl estradiol, does not counteract the
estrogen-induced increases in sex hormone binding globulin (SHBG), resulting in
lower serum testosterone.90,91,94
Acne
Acne is a skin condition with a multifactorial etiology, including androgen stimulation
of sebum production. While the combination of ethinyl estradiol and norgestimate
increases sex hormone binding globulin (SHBG) and decreases free testosterone,
the relationship between these changes and a decrease in the severity of facial
acne in otherwise healthy women with this skin condition has not been established.
PHARMACOKINETICS
Absorption
Norgestimate (NGM) and ethinyl estradiol (EE) are rapidly absorbed following oral
administration. Norgestimate is rapidly and completely metabolized by firstpass
(intestinal and/or hepatic) mechanisms to norelgestromin (NGMN) and norgestrel
(NG), which are the major active metabolites of norgestimate.
Peak serum concentrations of NGMN and EE are generally reached by 2 hours
after administration of ORTHO-CYCLEN® or ORTHO TRI-CYCLEN®. Accumulation
following multiple dosing of the 250 µg NGM / 35 µg dose is approximately 2-fold for
NGMN and EE compared with single dose administration. The pharmacokinetics of
NGMN is dose proportional following NGM doses of 180 µg to 250 µg. Steady-state
concentration of EE is achieved by Day 7 of each dosing cycle. Steady-state
concentrations of NGMN and NG are achieved by Day 21. Non-linear accumulation
(approximately 8 fold) of norgestrel is observed as a result of high affinity binding to
SHBG (sex hormone-binding globulin), which limits its biological activity.
TABLE I. Summary of norelgestromin, norgestrel and
ethinyl estradiol pharmacokinetic parameters.
Mean (SD) Pharmacokinetic Parameters of ORTHO
TRI-CYCLEN During a Three Cycle Study
Analyte
Cycle
Day
Cmax
tmax (h)
AUC0-24h
t1/2 (h)
NGMN
3
7
1.80 (0.46)
1.42 (0.73)
15.0 (3.88)
NC
14
2.12 (0.56)
1.21 (0.26)
16.1 (4.97)
NC
21
2.66 (0.47)
1.29 (0.26)
21.4 (3.46)
22.3 (6.54)
NG
3
7
1.94 (0.82)
3.15 (4.05)
34.8 (16.5)
NC
14
3.00 (1.04)
2.21 (2.03)
55.2 (23.5)
NC
21
3.66 (1.15)
2.58 (2.97)
69.3 (23.8)
40.2 (15.4)
EE
3
7
124 (39.5)
1.27 (0.26)
1130 (420)
NC
14
128 (38.4)
1.32 (0.25)
1130 (324)
NC
21
126 (34.7)
1.31 (0.56)
1090 (359)
15.9 (4.39)
Mean (SD) Pharmacokinetic Parameters of
ORTHO-CYCLEN During a Three Cycle Study
Analyte
Cycle
Day
Cmax
tmax (h)
AUC0-24h
t1/2 (h)
NGMN
1
1
1.78 (0.397) 1.19 (0.250)
9.90 (3.25)
18.4 (5.91)
3
21
2.19 (0.655) 1.43 (0.680)
18.1 (5.53)
24.9 (9.04)
NG
1
1
0.649 (0.49) 1.42 (0.69)
6.22 (2.46)
37.8 (14.0)
3
21
2.65 (1.11)
1.67 (1.32)
48.2 (20.5)
45.0 (20.4)
EE
1
1
92.2 (24.5)
1.2 (0.26)
629 (138)
10.1 (1.90)
3
21
147 (41.5)
1.13 (0.23)
1210 (294)
15.0 (2.36)
Cmax= peak serum concentration, tmax= time to reach peak serum concentration,
AUC0-24h= area under serum concentration vs time curve from 0 to 24 hours,
t1/2= elimination half-life, NC = not calculated.
NGMN and NG: Cmax= ng/mL, AUC0-24h=h•ng/mL
EE: Cmax=pg/mL, AUC0-24h=h•pg/mL
The effect of food on the pharmacokinetics of ORTHO-CYCLEN or ORTHO
TRI-CYCLEN has not been studied.
Distribution
Norelgestromin and norgestrel are highly bound (>97%) to serum proteins.
Norelgestromin is bound to albumin and not to SHBG, while norgestrel is bound
primarily to SHBG. Ethinyl estradiol is extensively bound (> 97%) to serum albumin
and induces an increase in the serum concentrations of SHBG.
Metabolism
Norgestimate is extensively metabolized by first-pass mechanisms in the
gastrointestinal tract and/or liver. Norgestimate’s primary active metabolite is
norelgestromin. Subsequent hepatic metabolism of norelgestromin occurs and
metabolites include norgestrel, which is also active and various hydroxylated and
conjugated metabolites. Ethinyl estradiol is also metabolized to various hydroxylated
products and their glucuronide and sulfate conjugates.
Excretion
The metabolites of norelgestromin and ethinyl estradiol are eliminated by renal and
fecal pathways. Following administration of 14C-norgestimate, 47% (45-49%) and 37%
(16-49%) of the administered radioactivity was eliminated in the urine and feces,
respectively. Unchanged norgestimate was not detected in the urine. In addition to 17
deacetyl norgestimate, a number of metabolites of norgestimate have been identified
in human urine following administration of radiolabeled norgestimate. These include
18, 19-Dinor-17-pregn-4-en-20-yn-3-one,17-hydroxy-13-ethyl,(17α)-(-);18,19-Dinor
5β-17-pregnan-20-yn,3α,17β-dihydroxy-13-ethyl,(17α), various hydroxylated
metabolites and conjugates of these metabolites.
Special Populations
The effects of body weight, body surface area or age on the pharmacokinetics of
ORTHO-CYCLEN® or ORTHO TRI-CYCLEN® have not been studied.
Hepatic Impairment
The effects of hepatic impairment on the pharmacokinetics of ORTHO-CYCLEN® or
ORTHO TRI-CYCLEN® have not been studied. However, steroid hormones may be
poorly metabolized in women with impaired liver function (see PRECAUTIONS).
Renal Impairment
The effects of renal impairment on the pharmacokinetics of ORTHO-CYCLEN® or
ORTHO TRI-CYCLEN® have not been studied.
Drug-Drug Interactions
No formal drug-drug interaction studies were conducted with ORTHO-CYCLEN® or
ORTHO TRI-CYCLEN®. Interactions between contraceptive steroids and other
drugs have been reported in the literature (see PRECAUTIONS).
Although norelgestromin and its metabolites inhibit a variety of P450 enzymes in
human liver microsomes, under the recommended dosing regimen, the in vivo
concentrations of norelgestromin and its metabolites, even at the peak serum levels,
are relatively low compared to the inhibitory constant (Ki).
INDICATIONS AND USAGE
ORTHO-CYCLEN® and ORTHO TRI-CYCLEN® Tablets are indicated for the
prevention of pregnancy in women who elect to use oral contraceptives as a method
of contraception.
ORTHO TRI-CYCLEN is indicated for the treatment of moderate acne vulgaris in
females at least 15 years of age, who have no known contraindications to oral
contraceptive therapy and have achieved menarche. ORTHO TRI-CYCLEN should
be used for the treatment of acne only if the patient desires an oral contraceptive for
birth control.
Oral contraceptives are highly effective for pregnancy prevention. Table II lists the
typical accidental pregnancy rates for users of combination oral contraceptives and
other methods of contraception. The efficacy of these contraceptive methods, except
sterilization, the IUD, and the Norplant System, depends upon the reliability with which
they are used. Correct and consistent use of methods can result in lower failure rates.
TABLE II: Percentage of Women Experiencing an Unintended Pregnancy
During the First Year of Typical Use and the First Year of Perfect Use of
Contraception and the Percentage Continuing
Use at the End of the First Year. United States.
% of Women Experiencing an
% of Women
Unintended Pregnancy
Continuing Use
within the First Year of Use
at 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 T380A
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
Hatcher et al, 1998, Ref. # 1.
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 highly effective, temporary method of
contraception.10
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 other 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
10305001
ORTHO TRI-CYCLEN® TABLETS
ORTHO-CYCLEN® TABLETS
(norgestimate/ethinyl estradiol)
Patients should be counseled that this product does
not protect against HIV infection (AIDS) and other
sexually transmitted diseases.
barcode
pregnant within one year. This estimate was lowered slightly (to 85%) to represent the
percent 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. The Food and Drug Administration
has declared the following brands of oral contraceptives 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 2 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 six months of age.
ORTHO-CYCLEN and ORTHO TRI-CYCLEN have not been studied for and are
not indicated for use in emergency contraception.
In clinical trials with ORTHO-CYCLEN, 1,651 subjects completed 24,272 cycles and
the overall use-efficacy (typical user efficacy) pregnancy rate was approximately 1
pregnancy per 100 women-years. This rate includes patients who did not take the
drug correctly.
In four clinical trials with ORTHO TRI-CYCLEN, a total of 4,756 subjects completed
45,244 cycles, and the use-efficacy pregnancy rate was approximately 1 pregnancy
per 100 women-years.
ORTHO TRI-CYCLEN was evaluated for the treatment of acne vulgaris in two
randomized, double-blind, placebo-controlled, multicenter, Phase 3, six (28 day)
cycle studies. 221 patients received ORTHO TRI-CYCLEN and 234 patients
received placebo. Mean age at enrollment for both groups was 28 years. At the end
of 6 months, the mean total lesion count changes from 55 to 31 (42% reduction) in
patients treated with ORTHO TRI-CYCLEN and from 54 to 38 (27% reduction) in
patients similarly treated with placebo. Table III summarizes the changes in lesion
count for each type of lesion in the ITT population. Based on the investigator’s
global assessment conducted at the final visit, patients treated with ORTHO
TRI-CYCLEN showed a statistically significant improvement in total lesions
compared to those treated with placebo.
Table III: Acne Vulgaris Indication. Combined Results: Two Multicenter, Placebo-
Controlled Trials. Observed Means at Six Months (LOCF)* and at Baseline.
Intent-to-Treat Population.
ORTHO TRI-CYCLEN
Placebo
Difference in
(N=221)
(N=234)
Counts between
ORTHO TRI-CYCLEN
and Placebo at
6 Months
%
%
# of Lesions
Counts
Reduction
Counts
Reduction
INFLAMMATORY
LESIONS
Baseline Mean
19
19
Sixth Month Mean 10
48%
13
30% 3 (95% CI: -1.2, 5.1)
NON
INFLAMMATORY
LESIONS
Baseline Mean
36
35
Sixth Month Mean 22
34%
25
21% 3 (95% CI: -0.2, 7.8)
TOTAL LESIONS
Baseline Mean
55
54
Sixth Month Mean 31
42%
38
27% 7 (95% CI: 2.0, 11.9)
*LOCF: Last Observation Carried Forward
CONTRAINDICATIONS
Oral contraceptives should not be used in women who currently have the following
conditions:
• Thrombophlebitis or thromboembolic disorders
• A past history of deep vein thrombophlebitis or thromboembolic disorders
• Cerebral vascular or coronary artery disease (current or past history)
• Valvular heart disease with complications
• Severe hypertension
• Diabetes with vascular involvement
• Headaches with focal neurological symptoms
• Major surgery with prolonged immobilization
• Known or suspected carcinoma of the breast or personal history of breast
cancer
• Carcinoma of the endometrium or other known or suspected estrogen-dependent
neoplasia
• Undiagnosed abnormal genital bleeding
• Cholestatic jaundice of pregnancy or jaundice with prior pill use
• Acute or chronic hepatocellular disease with abnormal liver function
• Hepatic adenomas or carcinomas
• Known or suspected pregnancy
• Hypersensitivity to any component of this product
WARNINGS
Cigarette smoking increases the risk of serious cardiovascular side
effects from oral contraceptive use. This risk increases with age and
with heavy smoking (15 or more cigarettes per day) and is quite
marked in women over 35 years of age. Women who use oral
contraceptives should be strongly advised not to smoke.
The use of oral contraceptives is associated with increased risks of several serious
conditions including myocardial infarction, thromboembolism, stroke, hepatic
neoplasia, and gallbladder disease, although the risk of serious morbidity or
mortality is very small in healthy women without underlying risk factors. The risk of
morbidity and mortality increases significantly in the presence of other underlying
risk factors such as hypertension, hyperlipidemias, obesity and diabetes.
Practitioners prescribing oral contraceptives should be familiar with the following
information relating to these risks.
The information contained in this package insert is principally based on studies
carried out in patients who used oral contraceptives with higher formulations of
estrogens and progestogens than those in common use today. The effect of long-
term use of the oral contraceptives with lower formulations of both estrogens and
progestogens remains to be determined.
Throughout this labeling, epidemiological studies reported are of two types: retro
spective or case control studies and prospective or cohort studies. Case control
studies provide a measure of the relative risk of a disease, namely, a ratio of the
incidence of a disease among oral contraceptive users to that among nonusers. The
relative risk does not provide information on the actual clinical occurrence of a
disease. Cohort studies provide a measure of attributable risk, which is the difference
in the incidence of disease between oral contraceptive users and nonusers. The
attributable risk does provide information about the actual occurrence of a disease in
the population (adapted from refs. 2 and 3 with the author’s permission). For further
information, the reader is referred to a text on epidemiological methods.
1. Thromboembolic Disorders and Other Vascular Problems
a. Myocardial Infarction
An increased risk of myocardial infarction has been attributed to oral contraceptive
use. This risk is primarily in smokers or women with other underlying risk factors for
coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity,
and diabetes.The relative risk of heart attack for current oral contraceptive users has
been estimated to be two to six.4-10 The risk is very low under the age of 30.
Smoking in combination with oral contraceptive use has been shown to contribute
substantially to the incidence of myocardial infarctions in women in their mid-thirties
or older with smoking accounting for the majority of excess cases.11 Mortality rates
associated with circulatory disease have been shown to increase substantially in
smokers, especially in those 35 years of age and older and in nonsmokers over the
age of 40 among women who use oral contraceptives.
Figure 1. Circulatory Disease Mortality Rates Per 100,000 Women-Years By Age,
Smoking Status and Oral Contraceptive Use Circulatory Disease Mortality Rates Per 100,000 Women-Years By Age,
Smoking Status and Oral Contraceptive Use
(Adapted from P.M. Layde and V. Beral, ref. #12.)
Oral contraceptives may compound the effects of well-known risk factors, such as
hypertension, diabetes, hyperlipidemias, age and obesity.13 In particular, some
progestogens are known to decrease HDL cholesterol and cause glucose
intolerance, while estrogens may create a state of hyperinsulinism.14-18 Oral
contraceptives have been shown to increase blood pressure among users (see
Section 9 in WARNINGS). Similar effects on risk factors have been associated with
an increased risk of heart disease. Oral contraceptives must be used with caution in
women with cardiovascular disease risk factors.
Norgestimate has minimal androgenic activity (see CLINICAL PHARMACOLOGY),
and there is some evidence that the risk of myocardial infarction associated with
oral contraceptives is lower when the progestogen has minimal androgenic activity
than when the activity is greater 97.
b. Thromboembolism
An increased risk of thromboembolic and thrombotic disease associated with the
use of oral contraceptives is well established. Case control studies have found the
relative risk of users compared to nonusers to be 3 for the first episode of superficial
venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and
1.5 to 6 for women with predisposing conditions for venous thromboembolic
disease.2,3,19-24 Cohort studies have shown the relative risk to be somewhat lower,
about 3 for new cases and about 4.5 for new cases requiring hospitalization.25 The
risk of thromboembolic disease associated with oral contraceptives is not related to
length of use and disappears after pill use is stopped.2
A two- to four-fold increase in relative risk of post-operative thromboembolic
complications has been reported with the use of oral contraceptives.9 The relative risk
of venous thrombosis in women who have predisposing conditions is twice that of
women without such medical conditions.26 If feasible, oral contraceptives should be
discontinued at least four weeks prior to and for two weeks after elective surgery of a
type associated with an increase in risk of thromboembolism and during and following
prolonged immobilization. Since the immediate postpartum period is also associated
with an increased risk of thromboembolism, oral contraceptives should be started no
earlier than four weeks after delivery in women who elect not to breast feed.
c. Cerebrovascular Diseases
Oral contraceptives have been shown to increase both the relative and attributable
risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in
general, the risk is greatest among older (>35 years), hypertensive women who also
smoke. Hypertension was found to be a risk factor for both users and nonusers, for
both types of strokes, and smoking interacted to increase the risk of stroke.27-29
In a large study, the relative risk of thrombotic strokes has been shown to range from
3 for normotensive users to 14 for users with severe hypertension.30 The relative risk
of hemorrhagic stroke is reported to be 1.2 for non-smokers who used oral
contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers
who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with
severe hypertension.30 The attributable risk is also greater in older women.3
d. Dose-Related Risk of Vascular Disease From Oral Contraceptives
A positive association has been observed between the amount of estrogen and
progestogen in oral contraceptives and the risk of vascular disease.31-33 A decline in
serum high density lipoproteins (HDL) has been reported with many progestational
agents.14-16 A decline in serum high density lipoproteins has been associated with
an increased incidence of ischemic heart disease. Because estrogens increase
HDL cholesterol, the net effect of an oral contraceptive depends on a balance
achieved between doses of estrogen and progestogen and the activity of the
progestogen used in the contraceptives. The activity and amount of both hormones
should be considered in the choice of an oral contraceptive.
Minimizing exposure to estrogen and progestogen is in keeping with good principles
of therapeutics. For any particular estrogen/progestogen combination, the dosage
regimen prescribed should be one which contains the least amount of estrogen and
progestogen that is compatible with a low failure rate and the needs of the individual
patient. New acceptors of oral contraceptive agents should be started on
preparations containing the lowest estrogen content which is judged appropriate for
the individual patient.
e. Persistence of Risk of Vascular Disease
There are two studies which have shown persistence of risk of vascular disease for
ever-users of oral contraceptives. In a study in the United States, the risk of
developing myocardial infarction after discontinuing oral contraceptives persists for
at least 9 years for women 40-49 years who had used oral contraceptives for five or
more years, but this increased risk was not demonstrated in other age groups.8 In
another study in Great Britain, the risk of developing cerebrovascular disease
persisted for at least 6 years after discontinuation of oral contraceptives, although
excess risk was very small.34 However, both studies were performed with oral
contraceptive formulations containing 50 micrograms or higher of estrogens.
2. Estimates of Mortality From Contraceptive Use
One study gathered data from a variety of sources which have estimated the
mortality rate associated with different methods of contraception at different ages
(Table IV). These estimates include the combined risk of death associated with
contraceptive methods plus the risk attributable to pregnancy in the event of method
failure. Each method of contraception has its specific benefits and risks. The study
concluded that with the exception of oral contraceptive users 35 and older who
smoke, and 40 and older who do not smoke, mortality associated with all methods
of birth control is low and below that associated with childbirth. The observation of
an increase in risk of mortality with age for oral contraceptive users is based on data
ORTHO TRI-CYCLEN® TABLETS
ORTHO-CYCLEN® TABLETS
(norgestimate/ethinyl estradiol)
gathered in the 1970’s.35 Current clinical recommendation involves the use of lower
estrogen dose formulations and a careful consideration of risk factors. In 1989, the
Fertility and Maternal Health Drugs Advisory Committee was asked to review the
use of oral contraceptives in women 40 years of age and over. The Committee
concluded that although cardiovascular disease risks may be increased with oral
contraceptive use after age 40 in healthy non-smoking women (even with the newer
low-dose formulations), there are also greater potential health risks associated with
pregnancy in older women and with the alternative surgical and medical procedures
which may be necessary if such women do not have access to effective and
acceptable means of contraception. The Committee recommended that the benefits
of low-dose oral contraceptive use by healthy non-smoking women over 40 may
outweigh the possible risks.
Of course, older women, as all women, who take oral contraceptives, should take an
oral contraceptive which contains the least amount of estrogen and progestogen
that is compatible with a low failure rate and individual patient needs.
Table IV: Annual Number of Birth-Related or Method-Related Deaths Associated
With Control of Fertility Per 100,000 Non-Sterile Women, by Fertility
Control Method According to Age
Method of control
15-19
20-24
25-29
30-34
35-39
40-44
and outcome
No fertility
7.0
7.4
9.1
14.8
25.7
28.2
control methods*
Oral contraceptives
0.3
0.5
0.9
1.9
13.8
31.6
non-smoker**
Oral contraceptives
2.2
3.4
6.6
13.5
51.1
117.2
smoker**
IUD**
0.8
0.8
1.0
1.0
1.4
1.4
Condom*
1.1
1.6
0.7
0.2
0.3
0.4
Diaphragm/spermicide*
1.9
1.2
1.2
1.3
2.2
2.8
Periodic abstinence*
2.5
1.6
1.6
1.7
2.9
3.6
*Deaths are birth-related
**Deaths are method-related
Adapted from H.W. Ory, ref. #35.
3. Carcinoma of the Reproductive Organs and Breasts
Numerous epidemiological studies have been performed on the incidence of breast,
endometrial, ovarian, and cervical cancer in women using oral contraceptives. The
risk of having breast cancer diagnosed may be slightly increased among current
and recent users of combination oral contraceptives (COCs). However, this excess
risk appears to decrease over time after COC discontinuation and by 10 years after
cessation the increased risk disappears. Some studies report an increased risk with
duration of use while other studies do not and no consistent relationships have been
found with dose or type of steroid. Some studies have found a small increase in risk
for women who first use COCs before age 20. Most studies show a similar pattern of
risk with COC use regardless of a woman’s reproductive history or her family breast
cancer history.
Breast cancers diagnosed in current or previous oral contraceptive users tend to be
less clinically advanced than nonusers. Women who currently have or have had
breast cancer should not use oral contraceptives because breast cancer is usually a
hormonally-sensitive tumor.
Some studies suggest that oral contraceptive use has been associated with an increase
in the risk of cervical intraepithelial neoplasia in some populations of women45-48.
However, there continues to be controversy about the extent to which such findings
may be due to differences in sexual behavior and other factors. In spite of many
studies of the relationship between oral contraceptive use and breast and cervical
cancers, a cause-and-effect relationship has not been established.
4. Hepatic Neoplasia
Benign hepatic adenomas are associated with oral contraceptive use, although the
incidence of benign tumors is rare in the United States. Indirect calculations have
estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a
risk that increases after four or more years of use especially with oral contraceptives
of higher dose.49 Rupture of benign, hepatic adenomas may cause death through
intra-abdominal hemorrhage.50,51
Studies from Britain have shown an increased risk of developing hepatocellular
carcinoma in long-term (>8 years) oral contraceptive users. However, these cancers
are extremely rare in the U.S. and the attributable risk (the excess incidence) of liver
cancers in oral contraceptive users approaches less than one per million users.
5. Ocular Lesions
There have been clinical case reports of retinal thrombosis associated with the use
of oral contraceptives. Oral contraceptives should be discontinued if there is
unexplained partial or complete loss of vision; onset of proptosis or diplopia;
papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic
measures should be undertaken immediately.
6. Oral Contraceptive Use Before or During Early Pregnancy
Extensive epidemiological studies have revealed no increased risk of birth defects in
women who have used oral contraceptives prior to pregnancy.56,57 The majority of
recent studies also do not indicate a teratogenic effect, particularly in so far as
cardiac anomalies and limb reduction defects are concerned,55,56,58,59 when taken
inadvertently during early pregnancy.
The administration of oral contraceptives to induce withdrawal bleeding should not
be used as a test for pregnancy. Oral contraceptives should not be used during
pregnancy to treat threatened or habitual abortion.
It is recommended that for any patient who has missed two consecutive periods,
pregnancy should be ruled out. If the patient has not adhered to the prescribed
schedule, the possibility of pregnancy should be considered at the time of the first
missed period. Oral contraceptive use should be discontinued if pregnancy is
confirmed.
7. Gallbladder Disease
Earlier studies have reported an increased lifetime relative risk of gallbladder
surgery in users of oral contraceptives and estrogens.60,61 More recent studies,
however, have shown that the relative risk of developing gallbladder disease among
oral contraceptive users may be minimal.62-64 The recent findings of minimal risk may
be related to the use of oral contraceptive formulations containing lower hormonal
doses of estrogens and progestogens.
8. Carbohydrate and Lipid Metabolic Effects
Oral contraceptives have been shown to cause a decrease in glucose tolerance in a
significant percentage of users.17 This effect has been shown to be directly related
to estrogen dose.65 Progestogens increase insulin secretion and create insulin
resistance, this effect varying with different progestational agents.17,66 However, in
the non-diabetic woman, oral contraceptives appear to have no effect on fasting
blood glucose.67 Because of these demonstrated effects, prediabetic and diabetic
women in particular should be carefully monitored while taking oral contraceptives.
A small proportion of women will have persistent hypertriglyceridemia while on the
pill. As discussed earlier (see WARNINGS 1a and 1d), changes in serum
triglycerides and lipoprotein levels have been reported in oral contraceptive users.
In clinical studies with ORTHO-CYCLEN® there were no clinically significant changes
in fasting blood glucose levels. No statistically significant changes in mean fasting
blood glucose levels were observed over 24 cycles of use. Glucose tolerance tests
showed minimal, clinically insignificant changes from baseline to cycles 3, 12, and 24.
In clinical studies with ORTHO TRI-CYCLEN® there were no clinically significant
changes in fasting blood glucose levels. Minimal statistically significant changes
were noted in glucose levels over 24 cycles of use. Glucose tolerance tests showed
no clinically significant changes from baseline to cycles 3, 12, and 24.
9. Elevated Blood Pressure
Women with significant hypertension should not be started on hormonal
contraception98. An increase in blood pressure has been reported in women taking
oral contraceptives68 and this increase is more likely in older oral contraceptive
users69 and with extended duration of use.61 Data from the Royal College of General
Practitioners12 and subsequent randomized trials have shown that the incidence of
hypertension increases with increasing progestational activity.
Women with a history of hypertension or hypertension-related diseases, or renal
disease70 should be encouraged to use another method of contraception. If women
elect to use oral contraceptives, they should be monitored closely and if significant
elevation of blood pressure occurs, oral contraceptives should be discontinued. For
most women, elevated blood pressure will return to normal after stopping oral
contraceptives, and there is no difference in the occurrence of hypertension
between former and never users.68-71 It should be noted that in two separate large
clinical trials (N=633 and N=911), no statistically significant changes in mean blood
pressure were observed with ORTHO-CYCLEN®.
10. Headache
The onset or exacerbation of migraine or development of headache with a new
pattern which is recurrent, persistent or severe requires discontinuation of oral
contraceptives and evaluation of the cause.
11. Bleeding Irregularities
Breakthrough bleeding and spotting are sometimes encountered in patients on oral
contraceptives, especially during the first three months of use. Non-hormonal
causes should be considered and adequate diagnostic measures taken to rule out
malignancy or pregnancy in the event of breakthrough bleeding, as in the case of
any abnormal vaginal bleeding. If pathology has been excluded, time or a change to
another formulation may solve the problem. In the event of amenorrhea, pregnancy
should be ruled out.
Some women may encounter post-pill amenorrhea or oligomenorrhea, especially
when such a condition was preexistent.
12. Ectopic Pregnancy
Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.
PRECAUTIONS
1. General
Patients should be counseled that this product does not protect against HIV
infection (AIDS) and other sexually transmitted diseases.
2. Physical Examination and Follow Up
It is good medical practice for all women to have annual history and physical
examinations, including women using oral contraceptives. The physical examination,
however, may be deferred until after initiation of oral contraceptives if requested by
the woman and judged appropriate by the clinician. The physical examination should
include special reference to blood pressure, breasts, abdomen and pelvic organs,
including cervical cytology, and relevant laboratory tests. In case of undiagnosed,
persistent or recurrent abnormal vaginal bleeding, appropriate measures should be
conducted to rule out malignancy. Women with a strong family history of breast
cancer or who have breast nodules should be monitored with particular care.
3. Lipid Disorders
Women who are being treated for hyperlipidemias should be followed closely if they
elect to use oral contraceptives. Some progestogens may elevate LDL levels and
may render the control of hyperlipidemias more difficult.
4. Liver Function
If jaundice develops in any woman receiving such drugs, the medication should be
discontinued. Steroid hormones may be poorly metabolized in patients with
impaired liver function.
5. Fluid Retention
Oral contraceptives may cause some degree of fluid retention. They should be
prescribed with caution, and only with careful monitoring, in patients with conditions
which might be aggravated by fluid retention.
6. Emotional Disorders
Women with a history of depression should be carefully observed and the drug
discontinued if depression recurs to a serious degree.
7. Contact Lenses
Contact lens wearers who develop visual changes or changes in lens tolerance
should be assessed by an ophthalmologist.
8. Drug Interactions
Changes in contraceptive effectiveness associated with co-administration of
other products
Contraceptive effectiveness may be reduced when hormonal contraceptives are co
administered with antibiotics, anticonvulsants, and other drugs that increase the
metabolism of contraceptive steroids. This could result in unintended pregnancy or
breakthrough bleeding. Examples include rifampin, barbiturates, phenylbutazone,
phenytoin, carbamazepine, felbamate, oxcarbazepine, topiramate, griseofulvin and
bosentan.
Several of the anti-HIV protease inhibitors have been studied with co-administration
of oral combination hormonal contraceptives; significant changes (increase and
decrease) in the plasma levels of the estrogen and progestin have been noted in
some cases. The safety and efficacy of oral contraceptive products may be affected
with co-administration of anti-HIV protease inhibitors. Healthcare professionals
should refer to the label of the individual anti-HIV protease inhibitors for further
drug-drug interaction information.
Herbal products containing St. John’s Wort (hypericum perforatum) may induce
hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may
reduce the effectiveness of contraceptive steroids. This may also result in
breakthrough bleeding.
Concurrent use of bosentan and ethinyl estradiol containing products may result in
decreased concentrations of these contraceptive hormones thereby increasing the
risk of unintended pregnancy and unscheduled bleeding.
Increase in plasma levels associated with co-administered drugs
Co-administration of atorvastatin and certain oral contraceptives containing ethinyl
estradiol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic
acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by
inhibition of conjugation. CYP 3A4 inhibitors such as itraconazole or ketoconazole
may increase plasma hormone levels.
Changes in plasma levels of co-administered drugs
Combination hormonal contraceptives containing some synthetic estrogens (e.g.,
ethinyl estradiol) may inhibit the metabolism of other compounds. Increased plasma
concentrations of cyclosporine, prednisolone, and theophylline have been reported
with concomitant administration of oral contraceptives. Decreased plasma
concentrations of acetaminophen and increased clearance of temazepam, salicylic
acid, morphine and clofibric acid, due to induction of conjugation, have been noted
when these drugs were administered with oral contraceptives.
Combined hormonal contraceptives have been shown to significantly decrease
plasma concentrations of lamotrigine when co-administered due to induction of
lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage
adjustments of lamotrigine may be necessary.101
Healthcare professionals are advised to also refer to prescribing information of co
administered drugs for recommendations regarding management of concomitant
therapy.
9. Interactions with Laboratory Tests
Certain endocrine and liver function tests and blood components may be affected by
oral contraceptives:
a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3;
increased norepinephrine-induced platelet aggregability.
b. Increased thyroid binding globulin (TBG) leading to increased circulating total
thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by
radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG,
free T4 concentration is unaltered.
c. Other binding proteins may be elevated in serum.
d. Sex hormone binding globulins are increased and result in elevated levels of total
circulating sex steroids; however, free or biologically active levels either decrease or
remain unchanged.
e. Triglycerides may be increased and levels of various other lipids and lipoproteins
may be affected.
f. Glucose tolerance may be decreased.
g. Serum folate levels may be depressed by oral contraceptive therapy. This may be
of clinical significance if a woman becomes pregnant shortly after discontinuing oral
contraceptives.
10. Carcinogenesis
See WARNINGS Section.
11. Pregnancy
Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS Sections.
12. Nursing Mothers
Small amounts of oral contraceptive steroids have been identified in the milk of
nursing mothers and a few adverse effects on the child have been reported,
including jaundice and breast enlargement. In addition, combination oral
contraceptives given in the postpartum period may interfere with lactation by
decreasing the quantity and quality of breast milk. If possible, the nursing mother
ORTHO TRI-CYCLEN® TABLETS
ORTHO-CYCLEN® TABLETS
(norgestimate/ethinyl estradiol)
should be advised not to use combination oral contraceptives but to use other forms
of contraception until she has completely weaned her child.
13. Pediatric Use
Safety and efficacy of ORTHO TRI-CYCLEN® Tablets and ORTHO-CYCLEN®
Tablets have been established in women of reproductive age. Safety and efficacy
are expected to be the same for postpubertal adolescents under the age of 16 and
for users 16 years and older. There was no significant difference between ORTHO
TRI-CYCLEN Tablets and placebo in mean change in total lumbar spine (L1-L4) and
total hip bone mineral density between baseline and Cycle 13 in 123 adolescent
females with anorexia nervosa in a double-blind, placebo-controlled, multicenter,
one-year treatment duration clinical trial for the Intent To Treat (ITT) population. Use
of this product before menarche is not indicated.
14. Geriatric Use
This product has not been studied in women over 65 years of age and is not
indicated in this population.
INFORMATION FOR THE PATIENT
See Patient Labeling printed below.
ADVERSE REACTIONS
An increased risk of the following serious adverse reactions has been associated
with the use of oral contraceptives (see WARNINGS Section).
• Thrombophlebitis and venous thrombosis
• Cerebral thrombosis
with or without embolism
• Hypertension
• Arterial thromboembolism
• Gallbladder disease
• Pulmonary embolism
• Hepatic adenomas or benign
• Myocardial infarction
liver tumors
• Cerebral hemorrhage
There is evidence of an association between the following conditions and the use of
oral contraceptives:
• Mesenteric thrombosis
• Retinal thrombosis
The following adverse reactions have been reported in patients receiving oral
contraceptives and are believed to be drug-related:
• Nausea
• Change in weight (increase or decrease)
• Vomiting
• Change in cervical erosion and secretion
• Gastrointestinal symptoms (such as
• Diminution in lactation when given
abdominal cramps and bloating)
immediately postpartum
• Breakthrough bleeding
• Cholestatic jaundice
• Spotting
• Migraine
• Change in menstrual flow
• Allergic reaction, including rash, urticaria,
• Amenorrhea
angioedema
• Temporary infertility after
• Mental depression
discontinuation of treatment
• Reduced tolerance to carbohydrates
• Edema
• Vaginal candidiasis
• Melasma which may persist
• Change in corneal curvature (steepening)
• Breast changes: tenderness,
• Intolerance to contact lenses
enlargement, secretion
The following adverse reactions have been reported in users of oral contraceptives
and a causal association has been neither confirmed nor refuted:
• Pre-menstrual syndrome
• Erythema nodosum
• Cataracts
• Hemorrhagic eruption
• Changes in appetite
• Vaginitis
• Cystitis-like syndrome
• Porphyria
• Headache
• Impaired renal function
• Nervousness
• Hemolytic uremic syndrome
• Dizziness
• Acne
• Hirsutism
• Changes in libido
• Loss of scalp hair
• Colitis
• Erythema multiforme
• Budd-Chiari Syndrome
OVERDOSAGE
Serious ill effects have not been reported following acute ingestion of large doses of
oral contraceptives by young children. Overdosage may cause nausea and
withdrawal bleeding may occur in females.
NON-CONTRACEPTIVE HEALTH BENEFITS
The following non-contraceptive health benefits related to the use of combination
oral contraceptives are supported by epidemiological studies which largely utilized
oral contraceptive formulations containing estrogen doses exceeding 0.035 mg of
ethinyl estradiol or 0.05 mg mestranol.73-78
Effects on menses:
• increased menstrual cycle regularity
• decreased blood loss and decreased incidence of iron deficiency anemia
• decreased incidence of dysmenorrhea
Effects related to inhibition of ovulation:
• decreased incidence of functional ovarian cysts
• decreased incidence of ectopic pregnancies
Other effects:
• decreased incidence of fibroadenomas and fibrocystic disease of the breast
• decreased incidence of acute pelvic inflammatory disease
• decreased incidence of endometrial cancer
• decreased incidence of ovarian cancer
DOSAGE AND ADMINISTRATION
Oral Contraception
To achieve maximum contraceptive effectiveness, ORTHO TRI-CYCLEN® Tablets
and ORTHO-CYCLEN® Tablets must be taken exactly as directed and at intervals
not exceeding 24 hours. The possibility of ovulation and conception prior to initiation
of medication should be considered. ORTHO TRI-CYCLEN and ORTHO-CYCLEN
are available in the DIALPAK® Tablet Dispenser which is preset for a Sunday Start.
Day 1 Start is also provided.
Sunday Start
When taking ORTHO TRI-CYCLEN® and ORTHO-CYCLEN® the first tablet should
be taken on the first Sunday after menstruation begins. If period begins on Sunday,
the first tablet should be taken that day. Take one active tablet daily for 21 days
followed by one dark green inactive tablet daily for 7 days. After 28 tablets have
been taken, a new course is started the next day (Sunday). For the first cycle of a
Sunday Start regimen, another method of contraception should be used until after
the first 7 consecutive days of administration.
If the patient misses one (1) active tablet in Weeks 1, 2, or 3, the tablet should be
taken as soon as she remembers. If the patient misses two (2) active tablets in Week
1 or Week 2, the patient should take two (2) tablets the day she remembers and two
(2) tablets the next day; and then continue taking one (1) tablet a day until she
finishes the pack. The patient should be instructed to use a back-up method of birth
control such as condoms or spermicide if she has sex in the seven (7) days after
missing pills. If the patient misses two (2) active tablets in the third week or misses
three (3) or more active tablets in a row, the patient should continue taking one tablet
every day until Sunday. On Sunday the patient should throw out the rest of the pack
and start a new pack that same day. The patient should be instructed to use a back
up method of birth control if she has sex in the seven (7) days after missing pills.
Complete instructions to facilitate patient counseling on proper pill usage may be
found in the Detailed Patient Labeling (“How to Take the Pill” section).
Day 1 Start
The dosage of ORTHO TRI-CYCLEN® and ORTHO-CYCLEN®, for the initial cycle of
therapy is one active tablet administered daily from the 1st day through the 21st day
of the menstrual cycle, counting the first day of menstrual flow as “Day 1” followed
by one dark green inactive tablet daily for 7 days. Tablets are taken without
interruption for 28 days. After 28 tablets have been taken, a new course is started
the next day.
If the patient misses one (1) active tablet in Weeks 1, 2, or 3, the tablet should be
taken as soon as she remembers. If the patient misses two (2) active tablets in Week
1 or Week 2, the patient should take two (2) tablets the day she remembers and two
(2) tablets the next day; and then continue taking one (1) tablet a day until she finishes
the pack. The patient should be instructed to use a back-up method of birth control
such as condoms or spermicide if she has sex in the seven (7) days after missing pills.
If the patient misses two (2) active tablets in the third week or misses three (3) or
more active tablets in a row, the patient should throw out the rest of the pack and start
a new pack that same day. The patient should be instructed to use a back-up method
of birth control if she has sex in the seven (7) days after missing pills.
Complete instructions to facilitate patient counseling on proper pill usage may be
found in the Detailed Patient Labeling (“How to Take the Pill” section).
The use of ORTHO TRI-CYCLEN and ORTHO-CYCLEN for contraception may be
initiated 4 weeks postpartum in women who elect not to breast feed. When the
tablets are administered during the postpartum period, the increased risk of
thromboembolic disease associated with the postpartum period must be considered.
(See CONTRAINDICATIONS and WARNINGS concerning thromboembolic disease.
See also PRECAUTIONS for “Nursing Mothers.”) The possibility of ovulation and
conception prior to initiation of medication should be considered.
(See Discussion of Dose-Related Risk of Vascular Disease from Oral Contraceptives.)
ADDITIONAL INSTRUCTIONS
Breakthrough bleeding, spotting, and amenorrhea are frequent reasons for patients
discontinuing oral contraceptives. In breakthrough bleeding, as in all cases of
irregular bleeding from the vagina, nonfunctional causes should be borne in mind. In
undiagnosed persistent or recurrent abnormal bleeding from the vagina, adequate
diagnostic measures are indicated to rule out pregnancy or malignancy. If pathology
has been excluded, time or a change to another formulation may solve the problem.
Changing to an oral contraceptive with a higher estrogen content, while potentially
useful in minimizing menstrual irregularity, should be done only if necessary since
this may increase the risk of thromboembolic disease.
Use of oral contraceptives in the event of a missed menstrual period:
1. If the patient has not adhered to the prescribed schedule, the possibility of
pregnancy should be considered at the time of the first missed period and oral
contraceptive use should be discontinued if pregnancy is confirmed.
2. If the patient has adhered to the prescribed regimen and misses two consecutive
periods, pregnancy should be ruled out.
ACNE
The timing of initiation of dosing with ORTHO TRI-CYCLEN® for acne should follow
the guidelines for use of ORTHO TRI-CYCLEN as an oral contraceptive. Consult the
DOSAGE AND ADMINISTRATION section for oral contraceptives. The dosage
regimen for ORTHO TRI-CYCLEN for treatment of facial acne, as available in a
DIALPAK® Tablet Dispenser, utilizes a 21-day active and a 7-day placebo schedule.
Take one active tablet daily for 21 days followed by one dark green inactive tablet for
7 days. After 28 tablets have been taken, a new course is started the next day.
HOW SUPPLIED
ORTHO TRI-CYCLEN® Tablets are available in a DIALPAK® Tablet Dispenser (NDC
0062-1910-15) containing 28 tablets. Each white tablet contains 0.180 mg of the
progestational compound, norgestimate, together with 0.035 mg of the estrogenic
compound, ethinyl estradiol. Each light blue tablet contains 0.215 mg of the
progestational compound, norgestimate, together with 0.035 mg of the estrogenic
compound, ethinyl estradiol. Each blue tablet contains 0.250 mg of the
progestational compound, norgestimate, together with 0.035 mg of the estrogenic
compound, ethinyl estradiol. Each dark green tablet contains inert ingredients.
0.180/0.035 mg tablets - White, round, biconvex, coated tablet imprinted “O 180” on
one side and “35” on the other side of the tablet.
0.215/0.035 mg tablets - Light blue, round, biconvex, coated tablet imprinted “O 215”
on one side and “35” on the other side of the tablet.
0.250/0.035 mg tablets - Blue, round, biconvex, coated tablet imprinted “O 250” on
one side and “35” on the other side of the tablet.
Each dark green reminder pill is a round, biconvex, coated tablet imprinted “O-M” on
one side and “P” on the other side.
ORTHO TRI-CYCLEN® Tablets are available for clinic usage in a VERIDATE® Tablet
Dispenser (unfilled) and VERIDATE Refills (NDC 0062-1910-20).
ORTHO-CYCLEN® Tablets are available in a DIALPAK® Tablet Dispenser (NDC
0062-1907-15) containing 28 tablets as follows: 21 blue tablets containing 0.250 mg
of the progestational compound, norgestimate, together with 0.035 mg of the
estrogenic compound, ethinyl estradiol, and 7 dark green tablets containing inert
ingredients.
ORTHO-CYCLEN® Tablets are available for clinic usage in a VERIDATE® Tablet
Dispenser (unfilled) and VERIDATE Refills (NDC 0062-1907-20).
Keep out of reach of children.
Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F).
Protect from light.
REFERENCES
1. Trussel J. Contraceptive efficacy. In Hatcher RA, Trussel J, Stewart F, Cates W,
Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised
Edition. New York NY: Irvington Publishers, 1998, in press. 2. Stadel BV, Oral
contraceptives and cardiovascular disease. (Pt. 1). N Engl J Med 1981; 305:612-618.
3. Stadel BV, Oral contraceptives and cardiovascular disease. (Pt. 2). N Engl J Med
1981; 305:672-677. 4. Adam SA, Thorogood M. Oral contraception and myocardial
infarction revisited: the effects of new preparations and prescribing patterns. Br J
Obstet Gynaecol 1981; 88:838-845. 5. Mann JI, Inman WH. Oral contraceptives and
death from myocardial infarction. Br Med J 1975; 2(5965):245-248. 6. Mann JI,
Vessey MP, Thorogood M, Doll R. Myocardial infarction in young women with special
reference to oral contraceptive practice. Br Med J 1975; 2(5956):241-245. 7. Royal
College of General Practitioners’ Oral Contraception Study: Further analyses of
mortality in oral contraceptive users. Lancet 1981; 1:541-546. 8. Slone D, Shapiro S,
Kaufman DW, Rosenberg L, Miettinen OS, Stolley PD. Risk of myocardial infarction in
relation to current and discontinued use of oral contraceptives. N Engl J Med 1981;
305:420-424. 9. Vessey MP. Female hormones and vascular disease – an
epidemiological overview. Br J Fam Plann 1980; 6 (Supplement): 1-12. 10. Russell-
Briefel RG, Ezzati TM, Fulwood R, Perlman JA, Murphy RS. Cardiovascular risk
status and oral contraceptive use, United States, 1976-80. Prevent Med 1986;
15:352-362. 11. Goldbaum GM, Kendrick JS, Hogelin GC, Gentry EM. The relative
impact of smoking and oral contraceptive use on women in the United States. JAMA
1987; 258:1339-1342. 12. Layde PM, Beral V. Further analyses of mortality in oral
contraceptive users; Royal College of General Practitioners’ Oral Contraception
Study. (Table 5) Lancet 1981; 1:541-546. 13. Knopp RH. Arteriosclerosis risk: the
roles of oral contraceptives and postmenopausal estrogens. J Reprod Med 1986;
31(9) (Supplement): 913-921. 14. Krauss RM, Roy S, Mishell DR, Casagrande J, Pike
MC. Effects of two low-dose oral contraceptives on serum lipids and lipoproteins:
Differential changes in high-density lipoproteins subclasses. Am J Obstet 1983;
145:446-452. 15. Wahl P, Walden C, Knopp R, Hoover J, Wallace R, Heiss G, Rifkind
B. Effect of estrogen/progestin potency on lipid/lipoprotein cholesterol. N Engl J Med
1983; 308:862-867. 16. Wynn V, Niththyananthan R. The effect of progestin in
combined oral contraceptives on serum lipids with special reference to high density
lipoproteins. Am J Obstet Gynecol 1982; 142:766-771. 17. Wynn V, Godsland I.
Effects of oral contraceptives on carbohydrate metabolism. J Reprod Med 1986;
31(9)(Supplement):892-897. 18. LaRosa JC. Atherosclerotic risk factors in
cardiovascular disease. J Reprod Med 1986; 31(9)(Supplement): 906-912. 19. Inman
WH, Vessey MP. Investigation of death from pulmonary, coronary, and cerebral
thrombosis and embolism in women of child-bearing age. Br Med J 1968;
2(5599):193-199. 20. Maguire MG, Tonascia J, Sartwell PE, Stolley PD, Tockman MS.
Increased risk of thrombosis due to oral contraceptives: a further report. Am J
Epidemiol 1979; 110(2):188-195. 21. Petitti DB, Wingerd J, Pellegrin F, Ramacharan
S. Risk of vascular disease in women: smoking, oral contraceptives,
noncontraceptive estrogens, and other factors. JAMA 1979; 242:1150-1154. 22.
Vessey MP, Doll R, Investigation of relation between use of oral contraceptives and
thromboembolic disease. Br Med J 1968; 2(5599):199-205. 23. Vessey MP, Doll R.
Investigation of relation between use of oral contraceptives and thromboembolic
disease. A further report. Br Med J 1969; 2(5658):651-657. 24. Porter JB, Hunter JR,
Danielson DA, Jick H, Stergachis A. Oral contraceptives and non-fatal vascular
disease – recent experience. Obstet Gynecol 1982; 59(3):299-302. 25. Vessey M,
Doll R, Peto R, Johnson B, Wiggins P. A long-term follow-up study of women using
different methods of contraception: an interim report. J Biosocial Sci 1976; 8:375-427.
26. Royal College of General Practitioners: Oral Contraceptives, venous thrombosis,
and varicose veins. J Royal Coll Gen Pract 1978; 28:393-399. 27. Collaborative
Group for the Study of Stroke in Young Women: Oral contraception and increased risk
of cerebral ischemia or thrombosis. N Engl J Med 1973; 288:871-878. 28. Petitti DB,
Wingerd J. Use of oral contraceptives, cigarette smoking, and risk of subarachnoid
hemorrhage. Lancet 1978; 2:234-236. 29. Inman WH. Oral contraceptives and fatal
subarachnoid hemorrhage. Br Med J 1979; 2(6203):1468-1470. 30. Collaborative
Group for the Study of Stroke in Young Women: Oral Contraceptives and stroke in
young women: associated risk factors. JAMA 1975; 231:718-722. 31. Inman WH,
Vessey MP, Westerholm B, Engelund A. Thromboembolic disease and the steroidal
content of oral contraceptives. A report to the Committee on Safety of Drugs. Br Med
J 1970; 2:203-209. 32. Meade TW, Greenberg G, Thompson SG. Progestogens and
cardiovascular reactions associated with oral contraceptives and a comparison of the
safety of 50- and 35-mcg oestrogen preparations. Br Med J 1980; 280(6224):1157
1161. 33. Kay CR. Progestogens and arterial disease – evidence from the Royal
College of General Practitioners’ Study. Am J Obstet Gynecol 1982; 142:762-765. 34.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ORTHO TRI-CYCLEN® TABLETS
ORTHO-CYCLEN® TABLETS
(norgestimate/ethinyl estradiol)
ORTHO TRI-CYCLEN® TABLETS
ORTHO-CYCLEN® TABLETS
(norgestimate/ethinyl estradiol)
ORTHO TRI-CYCLEN® TABLETS
ORTHO-CYCLEN® TABLETS
(norgestimate/ethinyl estradiol)
ORTHO TRI-CYCLEN® TABLETS
ORTHO-CYCLEN® TABLETS
(norgestimate/ethinyl estradiol)
Royal College of General Practitioners: Incidence of arterial disease among oral
contraceptive users. J Royal Coll Gen Pract 1983; 33:75-82. 35. Ory HW. Mortality
associated with fertility and fertility control: 1983. Family Planning Perspectives 1983;
15:50-56. 36. The Cancer and Steroid Hormone Study of the Centers for Disease
Control and the National Institute of Child Health and Human Development: Oral
contraceptive use and the risk of breast cancer. N Engl J Med 1986; 315:405-411. 37.
Pike MC, Henderson BE, Krailo MD, Duke A, Roy S. Breast cancer in young women
and use of oral contraceptives: possible modifying effect of formulation and age at
use. Lancet 1983; 2:926-929. 38. Paul C, Skegg DG, Spears GFS, Kaldor JM. Oral
contraceptives and breast cancer: A national study. Br Med J 1986; 293:723-725. 39.
Miller DR, Rosenberg L, Kaufman DW, Schottenfeld D, Stolley PD, Shapiro S. Breast
cancer risk in relation to early oral contraceptive use. Obstet Gynecol 1986; 68:863
868. 40. Olsson H, Olsson ML, Moller TR, Ranstam J, Holm P. Oral contraceptive use
and breast cancer in young women in Sweden (letter). Lancet 1985; 1(8431):748
749. 41. McPherson K, Vessey M, Neil A, Doll R, Jones L, Roberts M. Early
contraceptive use and breast cancer: Results of another case-control study. Br J
Cancer 1987; 56:653-660. 42. Huggins GR, Zucker PF. Oral contraceptives and
neoplasia; 1987 update. Fertil Steril 1987; 47:733-761. 43. McPherson K, Drife JO.
The pill and breast cancer: why the uncertainty? Br Med J 1986; 293:709-710. 44.
Shapiro S. Oral contraceptives – time to take stock. N Engl J Med 1987; 315:450
451. 45. Ory H, Naib Z, Conger SB, Hatcher RA, Tyler CW. Contraceptive choice and
prevalence of cervical dysplasia and carcinoma in situ. Am J Obstet Gynecol 1976;
124:573-577. 46. Vessey MP, Lawless M, McPherson K, Yeates D. Neoplasia of the
cervix uteri and contraception: a possible adverse effect of the pill. Lancet 1983;
2:930. 47. Brinton LA, Huggins GR, Lehman HF, Malli K, Savitz DA, Trapido E,
Rosenthal J, Hoover R. Long term use of oral contraceptives and risk of invasive
cervical cancer. Int J Cancer 1986; 38:339-344. 48. WHO Collaborative Study of
Neoplasia and Steroid Contraceptives: Invasive cervical cancer and combined oral
contraceptives. Br Med J 1985; 290:961-965. 49. Rooks JB, Ory HW, Ishak KG,
Strauss LT, Greenspan JR, Hill AP, Tyler CW. Epidemiology of hepatocellular
adenoma: the role of oral contraceptive use. JAMA 1979; 242:644-648. 50. Bein NN,
Goldsmith HS. Recurrent massive hemorrhage from benign hepatic tumors
secondary to oral contraceptives. Br J Surg 1977; 64:433-435. 51. Klatskin G. Hepatic
tumors: possible relationship to use of oral contraceptives. Gastroenterology 1977;
73:386-394. 52. Henderson BE, Preston-Martin S, Edmondson HA, Peters RL, Pike
MC. Hepatocellular carcinoma and oral contraceptives. Br J Cancer 1983; 48:437
440. 53. Neuberger J, Forman D, Doll R, Williams R. Oral contraceptives and
hepatocellular carcinoma. Br Med J 1986; 292:1355-1357. 54. Forman D, Vincent TJ,
Doll R, Cancer of the liver and oral contraceptives. Br Med J 1986; 292:1357-1361.
55. Harlap S, Eldor J. Births following oral contraceptive failures. Obstet Gynecol
1980; 55:447-452. 56. Savolainen E, Saksela E, Saxen L. Teratogenic hazards of oral
contraceptives analyzed in a national malformation register. Am J Obstet Gynecol
1981; 140:521-524. 57. Janerich DT, Piper JM, Glebatis DM. Oral contraceptives and
birth defects. Am J Epidemiol 1980; 112:73-79. 58. Ferencz C, Matanoski GM, Wilson
PD, Rubin JD, Neill CA, Gutberlet R. Maternal hormone therapy and congenital heart
disease. Teratology 1980; 21:225-239. 59. Rothman KJ, Fyler DC, Goldblatt A,
Kreidberg MB. Exogenous hormones and other drug exposures of children with
congenital heart disease. Am J Epidemiol 1979; 109:433-439. 60. Boston
Collaborative Drug Surveillance Program: Oral contraceptives and venous
thromboembolic disease, surgically confirmed gallbladder disease, and breast
tumors. Lancet 1973; 1:1399-1404. 61. Royal College of General Practitioners: Oral
contraceptives and health. New York, Pittman 1974. 62. Layde PM, Vessey MP, Yeates
D. Risk of gallbladder disease: a cohort study of young women attending family
planning clinics. J Epidemiol Community Health 1982; 36:274-278. 63. Rome Group
for Epidemiology and Prevention of Cholelithiasis (GREPCO): Prevalence of
gallstone disease in an Italian adult female population. Am J Epidemiol 1984;
119:796-805. 64. Storm BL, Tamragouri RT, Morse ML, Lazar EL, West SL, Stolley
PD, Jones JK. Oral contraceptives and other risk factors for gallbladder disease. Clin
Pharmacol Ther 1986; 39:335-341. 65. Wynn V, Adams PW, Godsland IF, Melrose J,
Niththyananthan R, Oakley NW, Seedj A. Comparison of effects of different combined
oral contraceptive formulations on carbohydrate and lipid metabolism. Lancet 1979;
1:1045-1049. 66. Wynn V. Effect of progesterone and progestins on carbohydrate
metabolism. In: Progesterone and Progestin. Bardin CW, Milgrom E, Mauvis-Jarvis P.
eds. New York, Raven Press 1983; pp. 395-410. 67. Perlman JA, Roussell-Briefel RG,
Ezzati TM, Lieberknecht G. Oral glucose tolerance and the potency of oral
contraceptive progestogens. J Chronic Dis 1985; 38:857-864. 68. Royal College of
General Practitioners’ Oral Contraception Study: Effect on hypertension and benign
breast disease of progestogen component in combined oral contraceptives. Lancet
1977; 1:624. 69. Fisch IR, Frank J. Oral contraceptives and blood pressure. JAMA
1977; 237:2499-2503. 70. Laragh AJ. Oral contraceptive induced hypertension – nine
years later. Am J Obstet Gynecol 1976; 126:141-147. 71. Ramcharan S, Peritz E,
Pellegrin FA, Williams WT. Incidence of hypertension in the Walnut Creek
Contraceptive Drug Study cohort: In: Pharmacology of steroid contraceptive drugs.
Garattini S, Berendes HW. Eds. New York, Raven Press, 1977; pp. 277-288,
(Monographs of the Mario Negri Institute for Pharmacological Research Milan.) 72.
Stockley I. Interactions with oral contraceptives. J Pharm 1976; 216:140-143. 73. The
Cancer and Steroid Hormone Study of the Centers for Disease Control and the
National Institute of Child Health and Human Development: Oral contraceptive use
and the risk of ovarian cancer. JAMA 1983; 249:1596-1599. 74. The Cancer and
Steroid Hormone Study of the Centers for Disease Control and the National Institute
of Child Health and Human Development: Combination oral contraceptive use and
the risk of endometrial cancer. JAMA 1987; 257:796-800. 75. Ory HW. Functional
ovarian cysts and oral contraceptives: negative association confirmed surgically.
JAMA 1974; 228:68-69. 76. Ory HW, Cole P, MacMahon B, Hoover R. Oral
contraceptives and reduced risk of benign breast disease. N Engl J Med 1976;
294:419-422. 77. Ory HW. The noncontraceptive health benefits from oral
contraceptive use. Fam Plann Perspect 1982; 14:182-184. 78. Ory HW, Forrest JD,
Lincoln R. Making choices: Evaluating the health risks and benefits of birth control
methods. New York, The Alan Guttmacher Institute, 1983; p. 1. 79. Schlesselman J,
Stadel BV, Murray P, Lai S. Breast cancer in relation to early use of oral
contraceptives. JAMA 1988; 259:1828-1833. 80. Hennekens CH, Speizer FE, Lipnick
RJ, Rosner B, Bain C, Belanger C, Stampfer MJ, Willett W, Peto R. A case-control
study of oral contraceptive use and breast cancer. JNCI 1984; 72:39-42. 81.
LaVecchia C, Decarli A, Fasoli M, Franceschi S, Gentile A, Negri E, Parazzini F,
Tognoni G. Oral contraceptives and cancers of the breast and of the female genital
tract. Interim results from a case-control study. Br J Cancer 1986; 54:311-317. 82.
Meirik O, Lund E, Adami H, Bergstrom R, Christoffersen T, Bergsjo P. Oral
contraceptive use and breast cancer in young women. A Joint National Case-control
study in Sweden and Norway. Lancet 1986; 11:650-654. 83. Kay CR, Hannaford PC.
Breast cancer and the pill – A further report from the Royal College of General
Practitioners’ oral contraception study. Br J Cancer 1988; 58:675-680. 84. Stadel BV,
Lai S, Schlesselman JJ, Murray P. Oral contraceptives and premenopausal breast
cancer in nulliparous women. Contraception 1988; 38:287-299. 85. Miller DR,
Rosenberg L, Kaufman DW, Stolley P, Warshauer ME, Shapiro S. Breast cancer
before age 45 and oral contraceptive use: New Findings. Am J Epidemiol 1989;
129:269-280. 86. The UK National Case-Control Study Group, Oral contraceptive use
and breast cancer risk in young women. Lancet 1989; 1:973-982. 87. Schlesselman
JJ. Cancer of the breast and reproductive tract in relation to use of oral
contraceptives. Contraception 1989; 40:1-38. 88. Vessey MP, McPherson K, Villard-
Mackintosh L, Yeates D. Oral contraceptives and breast cancer: latest findings in a
large cohort study. Br J Cancer 1989; 59:613-617. 89. Jick SS, Walker AM,
Stergachis A, Jick H. Oral contraceptives and breast cancer. Br J Cancer 1989;
59:618-621. 90. Anderson FD, Selectivity and minimal androgenicity of norgestimate
in monophasic and triphasic oral contraceptives. Acta Obstet Gynecol Scand 1992;
156 (Supplement):15-21. 91. Chapdelaine A, Desmaris J-L, Derman RJ. Clinical
evidence of minimal androgenic activity of norgestimate. Int J Fertil 1989; 34(51):347
352. 92. Phillips A, Demarest K, Hahn DW, Wong F, McGuire JL. Progestational and
androgenic receptor binding affinities and in vivo activities of norgestimate and other
progestins. Contraception 1989; 41(4):399-409. 93. Phillips A, Hahn DW, Klimek S,
McGuire JL. A comparison of the potencies and activities of progestogens used in
contraceptives. Contraception 1987; 36(2):181-192. 94. Janaud A, Rouffy J, Upmalis
D, Dain M-P. A comparison study of lipid and androgen metabolism with triphasic oral
contraceptive formulations containing norgestimate or levonorgestrel. Acta Obstet
Gynecol Scand 1992; 156 (Supplement):34-38. 95. Collaborative Group on Hormonal
Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative
reanalysis of individual data on 53 297 women with breast cancer and 100 239
women without breast cancer from 54 epidemiological studies. Lancet 1996;
347:1713-1727. 96. Palmer JR, Rosenberg L, Kaufman DW, Warshauer ME, Stolley
P, Shapiro S. Oral Contraceptive Use and Liver Cancer. Am J Epidemiol 1989;
130:878-882. 97. Lewis M, Spitzer WO, Heinemann LAJ, MacRae KD, Bruppacher R,
Thorogood M, on behalf of Transnational Research Group on Oral Contraceptives
and Health of Young Women. Third generation oral contraceptives and risk of
myocardial infarction: an international case-control study. Br Med J, 1996;312:88-90.
98. Improving access to quality care in family planning: Medical eligibility criteria for
contraceptive use. Geneva, WHO, Family and Reproductive Health, 1996. 99. Bork K,
Fischer B, DeWald G. Recurrent episodes of skin angioedema and severe attacks of
abdominal pain induced by oral contraceptives or hormone replacement therapy. Am J
Med 2003;114:294-298. 100. Van Giersbergen PLM, Halabi A, Dingemanse J.
Pharmacokinetic interaction between bosentan and the oral contraceptives
norethisterone and ethinyl estradiol. Int J Clin Pharmacol Ther 2006;44(3):113-118. 101.
Christensen J, Petrenaite V, Atterman J, et al. Oral contraceptives induce lamotrigine
metabolism: evidence from a double-blind, placebo-controlled trial. Epilepsia
2007;48(3):484-489.
BRIEF SUMMARY PATIENT PACKAGE INSERT
This product (like all oral contraceptives) does not protect against HIV
infection (AIDS) and other sexually transmitted diseases.
Oral contraceptives, also known as "birth control pills" or "the pill," are taken to
prevent pregnancy. When taken correctly to prevent pregnancy, oral contraceptives
have a failure rate of approximately 1% per year (1 pregnancy per 100 women per
year of use) when used without missing any pills. The typical failure rate is
approximately 5% per year (5 pregnancies per 100 women per year of use) when
women who miss pills are included. For most women oral contraceptives are also
free of serious or unpleasant side effects. However, forgetting to take pills
considerably increases the chances of pregnancy.
ORTHO TRI-CYCLEN® may also be taken to treat moderate acne in females at
least 15 years of age, who have started having menstrual periods, are able to take
the pill and want to use the pill for birth control.
For the majority of women, oral contraceptives can be taken safely. But there are
some women who are at high risk of developing certain serious diseases that can
be fatal or may cause temporary or permanent disability. The risks associated with
taking oral contraceptives increase significantly if you:
• smoke
• have high blood pressure, diabetes, high cholesterol
• have or have had clotting disorders, heart attack, stroke, angina pectoris, cancer
of the breast or sex organs, jaundice or malignant or benign liver tumors
Although cardiovascular disease risks may be increased with oral contraceptive use
after age 40 in healthy, non-smoking women (even with the newer low-dose
formulations), there are also greater potential health risks associated with
pregnancy in older women.
You should not take the pill if you suspect you are pregnant or have unexplained
vaginal bleeding.
Cigarette smoking increases the risk of serious cardiovascular side
effects from oral contraceptive use. This risk increases with age and
with heavy smoking (15 or more cigarettes per day) and is quite
marked in women over 35 years of age. Women who use oral
contraceptives are strongly advised not to smoke.
Most side effects of the pill are not serious. The most common such effects are
nausea, vomiting, bleeding between menstrual periods, weight gain, breast
tenderness, and difficulty wearing contact lenses. These side effects, especially
nausea and vomiting, may subside within the first three months of use.
The serious side effects of the pill occur very infrequently, especially if you are in
good health and are young. However, you should know that the following medical
conditions have been associated with or made worse by the pill:
1. Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism),
stoppage or rupture of a blood vessel in the brain (stroke), blockage of blood
vessels in the heart (heart attack or angina pectoris) or other organs of the
body. As mentioned above, smoking increases the risk of heart attacks and
strokes and subsequent serious medical consequences.
2. In rare cases, oral contraceptives can cause benign but dangerous liver tumors.
These benign liver tumors can rupture and cause fatal internal bleeding. In
addition, some studies report an increased risk of developing liver cancer.
However, liver cancers are rare.
3. High blood pressure, although blood pressure usually returns to normal when
the pill is stopped.
The symptoms associated with these serious side effects are discussed in the
detailed leaflet given to you with your supply of pills. Notify your healthcare
professional if you notice any unusual physical disturbances while taking the pill. In
addition, drugs such as rifampin, as well as some anticonvulsants and some
antibiotics may decrease oral contraceptive effectiveness.
Oral contraceptives may interact with lamotrigine (LAMICTAL®), an anticonvulsant
used for epilepsy. This may increase the risk of seizures so your healthcare
professional may need to adjust the dose of lamotrigine.
Various studies give conflicting reports on the relationship between breast cancer
and oral contraceptive use. Oral contraceptive use may slightly increase your
chance of having breast cancer diagnosed, particularly after using hormonal
contraceptives at a younger age. After you stop using hormonal contraceptives, the
chances of having breast cancer diagnosed begin to go back down.You should have
regular breast examinations by a healthcare professional and examine your own
breasts monthly. Tell your healthcare professional if you have a family history of
breast cancer or if you have had breast nodules or an abnormal mammogram.
Women who currently have or have had breast cancer should not use oral
contraceptives because breast cancer is usually a hormone-sensitive tumor.
Some studies have found an increase in the incidence of cancer of the cervix in
women who use oral contraceptives. However, this finding may be related to factors
other than the use of oral contraceptives. There is insufficient evidence to rule out
the possibility that the pill may cause such cancers.
Taking the combination pill provides some important non-contraceptive benefits.
These include less painful menstruation, less menstrual blood loss and anemia,
fewer pelvic infections, and fewer cancers of the ovary and the lining of the uterus.
Be sure to discuss any medical condition you may have with your healthcare
professional. Your healthcare professional will take a medical and family history before
prescribing oral contraceptives and will examine you. The physical examination may
be delayed to another time if you request it and the healthcare professional believes
that it is a good medical practice to postpone it. You should be reexamined at least
once a year while taking oral contraceptives. Your pharmacist should have given you
the detailed patient information labeling which gives you further information which you
should read and discuss with your healthcare professional.
HOW TO TAKE THE PILL
IMPORTANT POINTS TO REMEMBER
BEFORE YOU START TAKING YOUR PILLS:
1. BE SURE TO READ THESE DIRECTIONS:
Before you start taking your pills.
Anytime you are not sure what to do.
2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT
THE SAME TIME.
If you miss pills you could get pregnant. This includes starting the pack late.
The more pills you miss, the more likely you are to get pregnant.
3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK
TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you feel
sick to your stomach or have spotting or light bleeding, do not stop taking the pill.
The problem will usually go away. If it doesn't go away, check with your
healthcare professional.
4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even
when you make up these missed pills.
On the days you take 2 pills to make up for missed pills, you could also feel a
little sick to your stomach.
5. IF YOU HAVE VOMITING OR DIARRHEA, OR IF YOU TAKE SOME MEDICINES,
including some antibiotics, your pills may not work as well.
Use a back-up method (such as condoms or spermicide) until you check with
your healthcare professional.
6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your
healthcare professional about how to make pill-taking easier or about using
another method of birth control.
7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE
INFORMATION IN THIS LEAFLET, call your healthcare professional.
BEFOREYOU START TAKING YOUR PILLS
1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.
It is important to take it at about the same time every day.
2. LOOK AT YOUR PILL PACK
The pill pack has 21 “active” pills (with hormones) to take for 3 weeks. This is
followed by 1 week of “reminder” dark green pills (without hormones).
ORTHO TRI-CYCLEN®: There are 7 white “active” pills, 7 light blue “active” pills,
7 blue “active” pills, and 7 dark green “reminder” pills.
ORTHO-CYCLEN®: There are 21 blue “active" pills, and 7 dark green “reminder”
pills.
3. ALSO FIND:
1) where on the pack to start taking pills,
2) in what order to take the pills.
4. BE SURE YOU HAVE READY AT ALL TIMES:
ANOTHER KIND OF BIRTH CONTROL (such as condoms or spermicide) to use
as a back-up method in case you miss pills.
AN EXTRA, FULL PILL PACK.
WHEN TO START THE FIRST PACK OF PILLS
You have a choice of which day to start taking your first pack of pills. ORTHO TRI
CYCLEN® and ORTHO-CYCLEN® are available in the DIALPAK® Tablet Dispenser
which is preset for a Sunday Start. Day 1 Start is also provided. Decide with your
healthcare professional which is the best day for you. Pick a time of day which will
be easy to remember.
Sunday Start:
ORTHO TRI-CYCLEN®: Take the first white “active” pill of the first pack on the
Sunday after your period starts, even if you are still bleeding. If your period begins
on Sunday, start the pack that same day.
ORTHO-CYCLEN®: Take the first blue “active” pill of the first pack on the Sunday
after your period starts, even if you are still bleeding. If your period begins on
Sunday, start the pack that same day.
Use another method of birth control such as condoms or spermicide as a back-up
method if you have sex anytime from the Sunday you start your first pack until the
next Sunday (7 days).
Day 1 Start:
ORTHO TRI-CYCLEN®: Take the first white “active” pill of the first pack during the
first 24 hours of your period.
ORTHO-CYCLEN®: Take the first blue “active” pill of the first pack during the first 24
hours of your period.
You will not need to use a back-up method of birth control, since you are starting the
pill at the beginning of your period.
WHAT TO DO DURING THE MONTH
1. TAKE ONE PILL AT THE SAME TIME EVERY DAY UNTIL THE PACK IS
EMPTY.
Do not skip pills even if you are spotting or bleeding between monthly periods or
feel sick to your stomach (nausea).
Do not skip pills even if you do not have sex very often.
2. WHEN YOU FINISH A PACK OR SWITCH YOUR BRAND OF PILLS:
Start the next pack on the day after your last “reminder” pill. Do not wait any days
between packs.
WHAT TO DO IF YOU MISS PILLS
ORTHO TRI-CYCLEN®:
If you MISS 1 white, light blue or blue “active” pill:
1. Take it as soon as you remember. Take the next pill at your regular time. This
means you may take 2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 white or light blue “active” pills in a row in WEEK 1 OR WEEK 2 of
your pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss
pills.You MUST use another birth control method (such as condoms or
spermicide) as a back-up method for those 7 days.
If you MISS 2 blue “active” pills in a row in THE 3RD WEEK:
1. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of
the pack and start a new pack of pills that same day.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you
miss your period 2 months in a row, call your healthcare professional because
you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss
pills.You MUST use another birth control method (such as condoms or
spermicide) as a back-up method for those 7 days.
If you MISS 3 OR MORE white, light blue or blue “active” pills in a row (during the
first 3 weeks):
1. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of
the pack and start a new pack of pills that same day.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you
miss your period 2 months in a row, call your healthcare professional because
you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss
pills.You MUST use another birth control method (such as condoms or
spermicide) as a back-up method for those 7 days.
ORTHO-CYCLEN®:
If you MISS 1 blue “active” pill:
1. Take it as soon as you remember. Take the next pill at your regular time. This
means you may take 2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 blue “active” pills in a row in WEEK 1 OR WEEK 2 of your pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss
pills.You MUST use another birth control method (such as condoms or
spermicide) as a back-up method for those 7 days.
If you MISS 2 blue “active” pills in a row in THE 3RD WEEK:
1. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of
the pack and start a new pack of pills that same day.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you
miss your period 2 months in a row, call your healthcare professional because
you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss
pills.You MUST use another birth control method (such as condoms or
spermicide) as a back-up method for those 7 days.
If you MISS 3 OR MORE blue “active” pills in a row (during the first 3 weeks):
1. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of
the pack and start a new pack of pills that same day.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you
miss your period 2 months in a row, call your healthcare professional because
you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss
pills.You MUST use another birth control method (such as condoms or
spermicide) as a back-up method for those 7 days.
A REMINDER:
If you forget any of the 7 dark green “reminder” pills in Week 4:
THROW AWAY the pills you missed.
Keep taking 1 pill each day until the pack is empty.
You do not need a back-up method.
FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU
HAVE MISSED:
Use a BACK-UP METHOD anytime you have sex.
KEEP TAKING ONE “ACTIVE” PILL EACH DAY until you can reach your healthcare
professional.
INSTRUCTIONS FOR USING YOUR DIALPAK®TABLET DISPENSER
PLEASE READ ME! Sunday or Day 1 Start
Sunday Start
or
Day 1 Start
There are two ways to start taking birth control pills,
Sunday Start or Day 1 Start.
Your healthcare professional will tell you which to use.
woman, sunday
start, day
1 start, advancing dialpak
SAVE THESE INSTRUCTIONS.
1. If this is the first time you are taking birth control pills,
or if you have not taken birth control pills for 10 days or
more, your first step is to wait until the first day you get
your menstrual period. Then, follow these instructions for
either Sunday Start or Day 1 Start.
2.When you get your period:
• You will use a Sunday Start if your doctor told you to take
your first pill on a Sunday. Take pill “1” on the Sunday after
your period starts.
If your period starts on a Sunday, take pill “1” that day.
• You will use a Day 1 Start if your doctor told you to take
pill “1” on the first day of your period.
3. SET THE DAY:
Sunday Start: the arrow on your empty Dialpak should
point to SU (Sunday).
Day 1 Start: turn the dial on your empty Dialpak until the
arrow points to the first day of your period (if your period
starts on Tuesday, the arrow will point to TU).
4. Insert the new refill by lining up the “V” shape on the
refill with the “V” shape at the top of your Dialpak. Snap the
refill in place.You are ready to take pill “1.”You should
always begin your pill cycle with pill “1,” as shown on the
inner part of the refill ring.
5. Remove pill “1” by pushing down on the pill. The pill will
come out through a hole in the back of the Dialpak. women swalling pill, dialpak, and alarm clock
6. Swallow the pill. You will take one pill each day. If you
use a Sunday Start and you are taking the pill for the FIRST
TIME, YOU MUST USE A BACK-UP METHOD OF BIRTH
CONTROL FOR THE FIRST 7 DAYS. If you use a Day 1
Start, you are protected from becoming pregnant as soon
as you take your first pill.
7. Wait 24 hours to take your next pill. To take pill “2,” turn
the dial on your Dialpak to the next day. Continue to take
one pill each day until all the pills have been taken.
8.Take your pill at the same time every day. It is
important to take the correct pill each day and not miss any
pills. To help you remember, take your pill at the same time
as another daily activity, like turning off your alarm clock or
brushing your teeth.
9.When your refill is empty, keep your Dialpak case. You
will start a new refill on the day after pill “28.” dialpak
10.Turn the dial to the pill “1” position to remove the
empty refill and insert a new refill.THE FIRST PILL IN
EVERY REFILL WILL ALWAYS BE TAKEN ON THE SAME
DAY OF THE WEEK, NO MATTER WHEN YOUR NEXT
PERIOD STARTS.
DETAILED PATIENT LABELING
PLEASE NOTE: This labeling is revised from time to time as important new
medical information becomes available. Therefore, please review this labeling
carefully.
This product (like all oral contraceptives) does not protect against HIV
infection (AIDS) and other sexually transmitted diseases.
ORTHO TRI-CYCLEN® Regimen
Each white tablet contains 0.180 mg norgestimate and 0.035 mg ethinyl estradiol.
Each light blue tablet contains 0.215 mg norgestimate and 0.035 mg ethinyl
estradiol. Each blue tablet contains 0.250 mg norgestimate and 0.035 mg ethinyl
estradiol. Each dark green tablet contains inert ingredients.
ORTHO-CYCLEN® Regimen
Each blue tablet contains 0.250 mg norgestimate and 0.035 mg ethinyl estradiol.
Each dark green tablet contains inert ingredients.
INTRODUCTION
Any woman who considers using oral contraceptives (the birth control pill or the pill)
should understand the benefits and risks of using this form of birth control. This
patient labeling will give you much of the information you will need to make this
decision and will also help you determine if you are at risk of developing any of the
serious side effects of the pill. It will tell you how to use the pill properly so that it will
be as effective as possible. However, this labeling is not a replacement for a careful
discussion between you and your healthcare professional. You should discuss the
information provided in this labeling with him or her, both when you first start taking
the pill and during your revisits.You should also follow your healthcare professional’s
advice with regard to regular check-ups while you are on the pill.
EFFECTIVENESS OF ORAL CONTRACEPTIVES FOR CONTRACEPTION
Oral contraceptives or “birth control pills” or “the pill” are used to prevent pregnancy and
are more effective than most other non-surgical methods of birth control. When they are
taken correctly without missing any pills, the chance of becoming pregnant is
approximately 1% per year (1 pregnancy per 100 women per year of use). Typical failure
rates, including women who do not always take the pill correctly, are approximately 5%
per year (5 pregnancies per 100 women per year of use). The chance of becoming
pregnant increases with each missed pill during a menstrual cycle.
In comparison, typical failure rates for other non-surgical methods of birth control
during the first year of use are as follows:
Implant: <1%
Male sterilization: <1%
Injection: <1%
Cervical Cap with spermicides: 20 to 40%
IUD: 1 to 2%
Condom alone (male): 14%
Diaphragm with spermicides: 20%
Condom alone (female): 21%
Spermicides alone: 26%
Periodic abstinence: 25%
Vaginal sponge: 20 to 40%
Withdrawal: 19%
Female sterilization: <1%
No methods: 85%
ORTHO TRI-CYCLEN® may also be taken to treat moderate acne if all of the
following are true:
• You have started having menstrual cycles
• You are at least 15 years old
• Your healthcare professional says it is safe for you to use the pill
• You want to use the pill for birth control
WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES
Cigarette smoking increases the risk of serious cardiovascular side
effects from oral contraceptive use. This risk increases with age and
with heavy smoking (15 or more cigarettes per day) and is quite
marked in women over 35 years of age. Women who use oral
contraceptives are strongly advised not to smoke.
Some women should not use the pill. For example, you should not take the pill if you
have any of the following conditions:
• A history of heart attack or stroke
• Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes
• A history of blood clots in the deep veins of your legs
• Chest pain (angina pectoris)
• Known or suspected breast cancer or cancer of the lining of the uterus, cervix or
vagina
• Unexplained vaginal bleeding (until a diagnosis is reached by your healthcare
professional)
• Yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or
during previous use of the pill
• Liver tumor (benign or cancerous) or active liver disease
• Known or suspected pregnancy
• Valvular heart disease with complications
• Severe hypertension
• Diabetes with vascular involvement
• Headaches with focal neurological symptoms
• Major surgery with prolonged immobilization
• Hypersensitivity to any component of this product
Tell your healthcare professional if you have had any of these conditions. Your
healthcare professional can recommend a safer method of birth control.
OTHER CONSIDERATIONS BEFORE TAKING ORAL CONTRACEPTIVES
Tell your healthcare professional if you have or have had:
• Breast nodules, fibrocystic disease of the breast, an abnormal breast x-ray or
mammogram
• Diabetes
• Elevated cholesterol or triglycerides
• High blood pressure
• Migraine or other headaches or epilepsy
• Mental depression
• Gallbladder, liver, heart or kidney disease
• History of scanty or irregular menstrual periods
Women with any of these conditions should be checked often by their healthcare
professional if they choose to use oral contraceptives.
Also, be sure to inform your healthcare professional if you smoke or are on any
medications.
RISKS OF TAKING ORAL CONTRACEPTIVES
1. Risk of Developing Blood Clots
Blood clots and blockage of blood vessels are one of the most serious side effects of
taking oral contraceptives and can cause death or serious disability. In particular, a clot in
the legs can cause thrombophlebitis and a clot that travels to the lungs can cause a
sudden blocking of the vessel carrying blood to the lungs. Rarely, clots occur in the blood
vessels of the eye and may cause blindness, double vision, or impaired vision.
If you take oral contraceptives and need elective surgery, need to stay in bed for a
prolonged illness or injury or have recently delivered a baby, you may be at risk of
developing blood clots. You should consult your healthcare professional about
stopping oral contraceptives four weeks before surgery and not taking oral
contraceptives for two weeks after surgery or during bed rest. You should also not
take oral contraceptives soon after delivery of a baby. It is advisable to wait for at
least four weeks after delivery if you are not breast feeding. If you are breast
feeding, you should wait until you have weaned your child before using the pill. (See
also the section on Breast Feeding in General Precautions.)
The risk of circulatory disease in oral contraceptive users may be higher in users of
high-dose pills and may be greater with longer duration of oral contraceptive use. In
addition, some of these increased risks may continue for a number of years after
stopping oral contraceptives. The risk of abnormal blood clotting increases with age
in both users and nonusers of oral contraceptives, but the increased risk from the
oral contraceptive appears to be present at all ages. For women aged 20 to 44 it is
estimated that about 1 in 2,000 using oral contraceptives will be hospitalized each
year because of abnormal clotting. Among nonusers in the same age group, about 1
in 20,000 would be hospitalized each year. For oral contraceptive users in general, it
has been estimated that in women between the ages of 15 and 34 the risk of death
due to a circulatory disorder is about 1 in 12,000 per year, whereas for nonusers the
rate is about 1 in 50,000 per year. In the age group 35 to 44, the risk is estimated to
be about 1 in 2,500 per year for oral contraceptive users and about 1 in 10,000 per
year for nonusers.
2. Heart Attacks and Strokes
Oral contraceptives may increase the tendency to develop strokes (stoppage or
rupture of blood vessels in the brain) and angina pectoris and heart attacks
(blockage of blood vessels in the heart). Any of these conditions can cause death or
serious disability.
Smoking greatly increases the possibility of suffering heart attacks and strokes.
Furthermore, smoking and the use of oral contraceptives greatly increase the
chances of developing and dying of heart disease.
3. Gallbladder Disease
Oral contraceptive users probably have a greater risk than nonusers of having gallbladder
disease, although this risk may be related to pills containing high doses of estrogens.
4. Liver Tumors
In rare cases, oral contraceptives can cause benign but dangerous liver tumors.
These benign liver tumors can rupture and cause fatal internal bleeding. In addition,
some studies report an increased risk of developing liver cancer. However, liver
cancers are rare.
5. Cancer of the Reproductive Organs and Breasts
Various studies give conflicting reports on the relationship between breast cancer
and oral contraceptive use. Oral contraceptive use may slightly increase your
chance of having breast cancer diagnosed, particularly after using hormonal
contraceptives at a younger age. After you stop using hormonal contraceptives, the
chances of having breast cancer diagnosed begin to go back down.You should have
regular breast examinations by a healthcare professional and examine your own
breasts monthly. Tell your healthcare professional if you have a family history of
breast cancer or if you have had breast nodules or an abnormal mammogram.
Women who currently have or have had breast cancer should not use oral
contraceptives because breast cancer is usually a hormone-sensitive tumor.
Some studies have found an increase in the incidence of cancer of the cervix in
women who use oral contraceptives. However, this finding may be related to factors
other than the use of oral contraceptives. There is insufficient evidence to rule out
the possibility that the pill may cause such cancers.
ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD OR
PREGNANCY
All methods of birth control and pregnancy are associated with a risk of developing
certain diseases which may lead to disability or death. An estimate of the number of
deaths associated with different methods of birth control and pregnancy has been
calculated and is shown in the following table.
Annual Number of Birth-Related or Method-Related Deaths Associated With
Control of Fertility Per 100,000 Nonsterile Women, by Fertility Control Method
According To Age
Method of control
15-19
20-24
25-29
30-34
35-39
40-44
and outcome
No fertility
7.0
7.4
9.1
14.8
25.7
28.2
control methods*
Oral contraceptives
0.3
0.5
0.9
1.9
13.8
31.6
non-smoker**
Oral contraceptives
2.2
3.4
6.6
13.5
51.1
117.2
smoker**
IUD**
0.8
0.8
1.0
1.0
1.4
1.4
Condom*
1.1
1.6
0.7
0.2
0.3
0.4
Diaphragm/spermicide*
1.9
1.2
1.2
1.3
2.2
2.8
Periodic abstinence*
2.5
1.6
1.6
1.7
2.9
3.6
*Deaths are birth-related
**Deaths are method-related
Adapted from H.W. Ory, ref. #35.
In the above table, the risk of death from any birth control method is less than the risk
of childbirth, except for oral contraceptive users over the age of 35 who smoke and pill
users over the age of 40 even if they do not smoke. It can be seen in the table that for
women aged 15 to 39, the risk of death was highest with pregnancy (7 to 26 deaths
per 100,000 women, depending on age). Among pill users who do not smoke, the risk
of death was always lower than that associated with pregnancy for any age group less
than 40. Over the age of 40, the risk increases to 32 deaths per 100,000 women,
compared to 28 associated with pregnancy in that age group. However, for pill users
who smoke and are over the age of 35, the estimated number of deaths exceeds
those for other methods of birth control. If a woman is over the age of 40 and smokes,
her estimated risk of death is four times higher (117/100,000 women) than the
estimated risk associated with pregnancy (28/100,000 women) in that age group.
The suggestion that women over 40 who do not smoke should not take oral
contraceptives is based on information from older, higher-dose pills. An Advisory
Committee of the FDA discussed this issue in 1989 and recommended that the
benefits of low-dose oral contraceptive use by healthy, non-smoking women over 40
years of age may outweigh the possible risks. Older women, as all women, who take
oral contraceptives, should take an oral contraceptive which contains the least amount
of estrogen and progestogen that is compatible with the individual patient needs.
WARNING SIGNALS
If any of these adverse effects occur while you are taking oral contraceptives, call
your healthcare professional immediately:
• Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a
possible clot in the lung)
• Pain in the calf (indicating a possible clot in the leg)
• Crushing chest pain or heaviness in the chest (indicating a possible heart attack)
• Sudden severe headache or vomiting, dizziness or fainting, disturbances of
vision or speech, weakness, or numbness in an arm or leg (indicating a possible
stroke)
• Sudden partial or complete loss of vision (indicating a possible clot in the eye)
• Breast lumps (indicating possible breast cancer or fibrocystic disease of the
breast; ask your healthcare professional to show you how to examine your
breasts)
• Severe pain or tenderness in the stomach area (indicating a possibly ruptured
liver tumor)
• Difficulty in sleeping, weakness, lack of energy, fatigue, or change in mood
(possibly indicating severe depression)
• Jaundice or a yellowing of the skin or eyeballs, accompanied frequently by fever,
fatigue, loss of appetite, dark colored urine, or light colored bowel movements
(indicating possible liver problems)
SIDE EFFECTS OF ORAL CONTRACEPTIVES
In addition to the risks and more serious side effects discussed above, the following
may also occur:
1. Irregular vaginal bleeding
Irregular vaginal bleeding or spotting may occur while you are taking the pills.
Irregular bleeding may vary from slight staining between menstrual periods to
breakthrough bleeding which is a flow much like a regular period. Irregular bleeding
occurs most often during the first few months of oral contraceptive use, but may also
occur after you have been taking the pill for some time. Such bleeding may be
temporary and usually does not indicate any serious problems. It is important to
continue taking your pills on schedule. If the bleeding occurs in more than one cycle
or lasts for more than a few days, talk to your healthcare professional.
2. Contact Lenses
If you wear contact lenses and notice a change in vision or an inability to wear your
lenses, contact your healthcare professional.
3. Fluid Retention
Oral contraceptives may cause edema (fluid retention) with swelling of the fingers or
ankles and may raise your blood pressure. If you experience fluid retention, contact
your healthcare professional.
4. Melasma
A spotty darkening of the skin is possible, particularly of the face, which may persist.
5. Other Side Effects
Other side effects may include nausea and vomiting, change in appetite, headache,
nervousness, depression, dizziness, loss of scalp hair, rash, vaginal infections, and
allergic reactions.
If any of these side effects bother you, call your healthcare professional.
GENERAL PRECAUTIONS
1. Missed Periods and Use of Oral Contraceptives Before or During Early
Pregnancy
There may be times when you may not menstruate regularly after you have
completed taking a cycle of pills. If you have taken your pills regularly and miss one
menstrual period, continue taking your pills for the next cycle but be sure to inform
your healthcare professional. If you have not taken the pills daily as instructed and
missed a menstrual period, or if you missed two consecutive menstrual periods, you
may be pregnant. Check with your healthcare professional immediately to determine
whether you are pregnant. Stop taking your pills if you are pregnant.
There is no conclusive evidence that oral contraceptive use is associated with an
increase in birth defects, when taken inadvertently during early pregnancy.
Previously, a few studies had reported that oral contraceptives might be associated
with birth defects, but these findings have not been seen in more recent studies.
Nevertheless, oral contraceptives should not be used during pregnancy. You should
check with your healthcare professional about risks to your unborn child of any
medication taken during pregnancy.
2. While Breast Feeding
If you are breast feeding, consult your healthcare professional before starting oral
contraceptives. Some of the drug will be passed on to the child in the milk. A few
adverse effects on the child have been reported, including yellowing of the skin
(jaundice) and breast enlargement. In addition, combination oral contraceptives may
decrease the amount and quality of your milk. If possible, do not use combination
oral contraceptives while breast feeding. You should use another method of
contraception since breast feeding provides only partial protection from becoming
pregnant and this partial protection decreases significantly as you breast feed for
longer periods of time. You should consider starting combination oral contraceptives
only after you have weaned your child completely.
3. Laboratory Tests
If you are scheduled for any laboratory tests, tell your healthcare professional you are
taking birth control pills. Certain blood tests may be affected by birth control pills.
4. Drug Interactions
Certain drugs may interact with birth control pills to make them less effective in
preventing pregnancy or cause an increase in breakthrough bleeding. Such drugs
include rifampin, drugs used for epilepsy such as barbiturates (for example,
phenobarbital), topiramate (Topamax®), carbamazepine (Tegretol® is one brand of
this drug), or phenytoin (Dilantin® is one brand of this drug), phenylbutazone
(Butazolidin® is one brand), certain drugs used in the treatment of HIV or AIDS, and
possibly certain antibiotics. Medicine for pulmonary hypertension, such as bosentan
(Tracleer®). Pregnancies and breakthrough bleeding have been reported by women
who also used some form of the herbal supplement St. John’s Wort while using
combined hormonal contraceptives. Hormonal contraceptives may interact with
lamotrigine (LAMICTAL®), an anticonvulsant used for epilepsy. This may increase
the risk of seizures so your healthcare professional may need to adjust the dose of
lamotrigine. You may need to use additional contraception when you take drugs
which can make oral contraceptives less effective. Be sure to tell your healthcare
professional if you are taking or start taking any medications while taking birth
control pills.
5. Sexually Transmitted Diseases
ORTHO-CYCLEN® and ORTHO TRI-CYCLEN® (like all oral contraceptives) are
intended to prevent pregnancy. Oral contraceptives do not protect against
transmission of HIV (AIDS) and other sexually transmitted diseases such as
chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.
HOW TO TAKE THE PILL
IMPORTANT POINTS TO REMEMBER
BEFORE YOU START TAKING YOUR PILLS:
1. BE SURE TO READ THESE DIRECTIONS:
Before you start taking your pills.
Anytime you are not sure what to do.
2. THE RIGHT WAY TO TAKE THE PILL IS TO TAKE ONE PILL EVERY DAY AT
THE SAME TIME.
If you miss pills you could get pregnant. This includes starting the pack late. The
more pills you miss, the more likely you are to get pregnant.
3. MANY WOMEN HAVE SPOTTING OR LIGHT BLEEDING, OR MAY FEEL SICK
TO THEIR STOMACH DURING THE FIRST 1-3 PACKS OF PILLS. If you feel
sick to your stomach or have spotting or light bleeding, do not stop taking the pill.
The problem will usually go away. If it doesn't go away, check with your
healthcare professional.
4. MISSING PILLS CAN ALSO CAUSE SPOTTING OR LIGHT BLEEDING, even
when you make up these missed pills.
On the days you take 2 pills to make up for missed pills, you could also feel a
little sick to your stomach.
5. IF YOU HAVE VOMITING OR DIARRHEA, OR IF YOU TAKE SOME
MEDICINES, including some antibiotics, your pills may not work as well.
Use a back-up method (such as condoms or spermicide) until you check with
your healthcare professional.
6. IF YOU HAVE TROUBLE REMEMBERING TO TAKE THE PILL, talk to your
healthcare professional about how to make pill-taking easier or about using
another method of birth control.
7. IF YOU HAVE ANY QUESTIONS OR ARE UNSURE ABOUT THE
INFORMATION IN THIS LEAFLET, call your healthcare professional.
BEFORE YOU START TAKING YOUR PILLS
1. DECIDE WHAT TIME OF DAY YOU WANT TO TAKE YOUR PILL.
It is important to take it at about the same time every day.
2. LOOK AT YOUR PILL PACK
The pill pack has 21 “active” pills (with hormones) to take for 3 weeks. This is
followed by 1 week of “reminder” dark green pills (without hormones).
ORTHO TRI-CYCLEN®: There are 7 white “active” pills, 7 light blue “active” pills, 7
blue “active” pills, and 7 dark green “reminder” pills.
ORTHO-CYCLEN®: There are 21 blue “active” pills and 7 dark green “reminder”
pills.
3. ALSO FIND:
1) where on the pack to start taking pills,
2) in what order to take the pills.
CHECK PICTURE OF PILL PACK AND ADDITIONAL INSTRUCTIONS FOR
USING THIS PACKAGE IN THE BRIEF SUMMARY PATIENT PACKAGE INSERT.
4. BE SURE YOU HAVE READY AT ALL TIMES:
ANOTHER KIND OF BIRTH CONTROL (such as condoms or spermicide) to use
as a back-up method in case you miss pills.
AN EXTRA, FULL PILL PACK.
WHEN TO START THE FIRST PACK OF PILLS
You have a choice of which day to start taking your first pack of pills. ORTHO
TRI-CYCLEN® and ORTHO-CYCLEN® are available in the DIALPAK® Tablet
Dispenser which is preset for a Sunday Start. Day 1 Start is also provided. Decide
with your healthcare professional which is the best day for you. Pick a time of day
which will be easy to remember.
Sunday Start:
ORTHO TRI-CYCLEN®: Take the first white "active" pill of the first pack on the
Sunday after your period starts, even if you are still bleeding. If your period begins
on Sunday, start the pack that same day.
ORTHO-CYCLEN®: Take the first blue "active" pill of the first pack on the Sunday
after your period starts, even if you are still bleeding. If your period begins on
Sunday, start the pack that same day.
Use another method of birth control such as condoms or spermicide as a back-up
method if you have sex anytime from the Sunday you start your first pack until the
next Sunday (7 days).
Day 1 Start:
ORTHO TRI-CYCLEN®: Take the first white "active" pill of the first pack during the
first 24 hours of your period.
ORTHO-CYCLEN®: Take the first blue "active" pill of the first pack during the first 24
hours of your period.
You will not need to use a back-up method of birth control, since you are starting the
pill at the beginning of your period.
WHAT TO DO DURING THE MONTH
1. Take One Pill at the Same Time Every Day Until the Pack is Empty.
Do not skip pills even if you are spotting or bleeding between monthly periods or
feel sick to your stomach (nausea).
Do not skip pills even if you do not have sex very often.
2. When You Finish a Pack or Switch Your Brand of Pills:
Start the next pack on the day after your last “reminder” pill. Do not wait any days
between packs.
WHAT TO DO IF YOU MISS PILLS
ORTHO TRI-CYCLEN®:
If you MISS 1 white, light blue, or blue “active” pill:
1. Take it as soon as you remember. Take the next pill at your regular time. This
means you may take 2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 white or light blue “active” pills in a row in WEEK 1 OR WEEK 2 of
your pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss
pills. You MUST use another birth control method (such as condoms or
spermicide) as a back-up method for those 7 days.
If you MISS 2 blue “active” pills in a row in THE 3RD WEEK:
1. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of
the pack and start a new pack of pills that same day.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you
miss your period 2 months in a row, call your healthcare professional because
you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss
pills. You MUST use another birth control method (such as condoms or
spermicide) as a back-up method for those 7 days.
If you MISS 3 OR MORE white, light blue or blue “active” pills in a row (during the
first 3 weeks):
1. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of
the pack and start a new pack of pills that same day.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you
miss your period 2 months in a row, call your healthcare professional because
you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss
pills. You MUST use another birth control method (such as condoms or
spermicide) as a back-up method for those 7 days.
ORTHO-CYCLEN®:
If you MISS 1 blue “active” pill:
1. Take it as soon as you remember. Take the next pill at your regular time. This
means you may take 2 pills in 1 day.
2. You do not need to use a back-up birth control method if you have sex.
If you MISS 2 blue “active” pills in a row in WEEK 1 OR WEEK 2 of your pack:
1. Take 2 pills on the day you remember and 2 pills the next day.
2. Then take 1 pill a day until you finish the pack.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss
pills. You MUST use another birth control method (such as condoms or
spermicide) as a back-up method for those 7 days.
If you MISS 2 blue “active” pills in a row in THE 3RD WEEK:
1. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of
the pack and start a new pack of pills that same day.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you
miss your period 2 months in a row, call your healthcare professional because
you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss
pills. You MUST use another birth control method (such as condoms or
spermicide) as a back-up method for those 7 days.
If you MISS 3 OR MORE blue “active” pills in a row (during the first 3 weeks):
1. If you are a Sunday Starter:
Keep taking 1 pill every day until Sunday. On Sunday, THROW OUT the rest of
the pack and start a new pack of pills that same day.
If you are a Day 1 Starter:
THROW OUT the rest of the pill pack and start a new pack that same day.
2. You may not have your period this month but this is expected. However, if you
miss your period 2 months in a row, call your healthcare professional because
you might be pregnant.
3. You COULD BECOME PREGNANT if you have sex in the 7 days after you miss
pills. You MUST use another birth control method (such as condoms or
spermicide) as a back-up method for those 7 days.
A REMINDER:
If you forget any of the 7 dark green “reminder” pills in Week 4:
THROW AWAY the pills you missed.
Keep taking 1 pill each day until the pack is empty.
You do not need a back-up method.
FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU
HAVE MISSED:
Use a BACK-UP METHOD anytime you have sex.
KEEP TAKING ONE “ACTIVE” PILL EACH DAY until you can reach your healthcare
professional.
PREGNANCY DUE TO PILL FAILURE
The incidence of pill failure resulting in pregnancy is approximately 5%, including
women who do not always take the pills exactly as directed. If failure does occur, the
risk to the fetus is minimal.
PREGNANCY AFTER STOPPING THE PILL
There may be some delay in becoming pregnant after you stop using oral
contraceptives, especially if you had irregular menstrual cycles before you used oral
contraceptives. It may be advisable to postpone conception until you begin
menstruating regularly once you have stopped taking the pill and desire pregnancy.
There does not appear to be any increase in birth defects in newborn babies when
pregnancy occurs soon after stopping the pill.
OVERDOSAGE
Serious ill effects have not been reported following ingestion of
large doses of oral contraceptives by young children.
Overdosage may cause nausea and withdrawal bleeding in
females. In case of overdosage, contact your healthcare
professional or pharmacist.
OTHER INFORMATION
Your healthcare professional will take a medical and family
history before prescribing oral contraceptives and will examine
you. The physical examination may be delayed to another time if
you request it and the healthcare professional believes that it is a
good medical practice to postpone it. You should be reexamined
at least once a year. Be sure to inform your healthcare
professional if there is a family history of any of the conditions
listed previously in this leaflet. Be sure to keep all appointments
FnL1 02 0052
01 BEdQR1MEU2VhbgBIwOlGAjEyAzEwMAEz
02 CkNvZGUgMTI4IEMA/w==
with your healthcare professional, because this is a time to
determine if there are early signs of side effects of oral
contraceptive use.
Do not use the drug for any condition other than the one for which it was prescribed.
This drug has been prescribed specifically for you; do not give it to others who may
want birth control pills.
HEALTH BENEFITS FROM ORAL CONTRACEPTIVES
In addition to preventing pregnancy, use of combination oral contraceptives may
provide certain benefits. They are:
• menstrual cycles may become more regular
• blood flow during menstruation may be lighter and less iron may be lost.
Therefore, anemia due to iron deficiency is less likely to occur
• pain or other symptoms during menstruation may be encountered less frequently
• ectopic (tubal) pregnancy may occur less frequently
• noncancerous cysts or lumps in the breast may occur less frequently
• acute pelvic inflammatory disease may occur less frequently
• oral contraceptive use may provide some protection against developing two forms
of cancer: cancer of the ovaries and cancer of the lining of the uterus.
If you want more information about birth control pills, ask your healthcare
professional or pharmacist. They have a more technical leaflet called the
Professional Labeling, which you may wish to read. The professional labeling is also
published in a book entitled Physicians’ Desk Reference, available in many book
stores and public libraries.
Keep out of reach of children.
Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F).
Protect from light. logo
Mfd. for:
Mfd. by:
Ortho Women’s Health & Urology,
Janssen Ortho, LLC
Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.
Manati, Puerto Rico 00674
Raritan, New Jersey 08869
© Ortho-McNeil-Janssen Pharmaceuticals, Inc. 1998
Revised August 2008
10305001
Printed in U.S.A.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:38.447760
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019653s048lbl.pdf', 'application_number': 19653, 'submission_type': 'SUPPL ', 'submission_number': 48}
|
11,605
|
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
1
PRODUCT INFORMATION
1
RETROVIR® (zidovudine) Tablets
2
RETROVIR® (zidovudine) Capsules
3
RETROVIR® (zidovudine) Syrup
4
5
WARNING: RETROVIR (ZIDOVUDINE) MAY BE ASSOCIATED WITH
6
HEMATOLOGIC TOXICITY INCLUDING GRANULOCYTOPENIA AND SEVERE
7
ANEMIA PARTICULARLY IN PATIENTS WITH ADVANCED HIV DISEASE (SEE
8
WARNINGS). PROLONGED USE OF RETROVIR HAS BEEN ASSOCIATED WITH
9
SYMPTOMATIC MYOPATHY SIMILAR TO THAT PRODUCED BY HUMAN
10
IMMUNODEFICIENCY VIRUS.
11
RARE OCCURRENCES OF POTENTIALLY FATAL LACTIC ACIDOSIS IN THE ABSENCE OF
12
HYPOXEMIA, AND SEVERE HEPATOMEGALY WITH STEATOSIS HAVE BEEN REPORTED
13
WITH THE USE OF CERTAIN ANTIRETROVIRAL NUCLEOSIDE ANALOGUES (SEE
14
WARNINGS).
15
16
DESCRIPTION: RETROVIR is the brand name for zidovudine (formerly called azidothymidine [AZT]),
17
a pyrimidine nucleoside analogue active against human immunodeficiency virus (HIV).
18
Tablets: RETROVIR Tablets are for oral administration. Each film-coated tablet contains 300 mg of
19
zidovudine and the inactive ingredients hydroxypropyl methylcellulose, magnesium stearate,
20
microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide.
21
Capsules: RETROVIR Capsules are for oral administration. Each capsule contains 100 mg of
22
zidovudine and the inactive ingredients corn starch, magnesium stearate, microcrystalline cellulose,
23
and sodium starch glycolate. The 100-mg empty hard gelatin capsule, printed with edible black ink,
24
consists of black iron oxide, dimethylpolysiloxane, gelatin, pharmaceutical shellac, soya lecithin, and
25
titanium dioxide. The blue band around the capsule consists of gelatin and FD&C Blue No. 2.
26
Syrup: RETROVIR Syrup is for oral administration. Each teaspoonful (5 mL) of RETROVIR Syrup
27
contains 50 mg of zidovudine and the inactive ingredients sodium benzoate 0.2% (added as a
28
preservative), citric acid, flavors, glycerin, and liquid sucrose. Sodium hydroxide may be added to
29
adjust pH.
30
The chemical name of zidovudine is 3′-azido-3′-deoxythymidine; it has the following structural
31
formula:
32
33
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
2
34
35
Zidovudine is a white to beige, odorless, crystalline solid with a molecular weight of 267.24 and a
36
solubility of 20.1 mg/mL in water at 25°C. The molecular formula is C10H13N5O4.
37
38
MICROBIOLOGY: Mechanism of Action: Zidovudine is a synthetic nucleoside analogue of the
39
naturally occurring nucleoside, thymidine, in which the 3′-hydroxy (-OH) group is replaced by an azido
40
(-N3) group. Within cells, zidovudine is converted to the active metabolite, zidovudine 5′-triphosphate
41
(AztTP), by the sequential action of the cellular enzymes. Zidovudine 5′-triphosphate inhibits the
42
activity of the HIV reverse transcriptase both by competing for utilization with the natural substrate,
43
deoxythymidine 5′-triphosphate (dTTP), and by its incorporation into viral DNA. The lack of a 3′- OH
44
group in the incorporated nucleoside analogue prevents the formation of the 5′ to 3′ phosphodiester
45
linkage essential for DNA chain elongation and, therefore, the viral DNA growth is terminated. The
46
active metabolite AztTP is also a weak inhibitor of the cellular DNA polymerase-alpha and
47
mitochondrial polymerase-gamma and has been reported to be incorporated into the DNA of cells in
48
culture.
49
In Vitro HIV Susceptibility: The in vitro anti-HIV activity of zidovudine was assessed by infecting cell
50
lines of lymphoblastic and monocytic origin and peripheral blood lymphocytes with laboratory and
51
clinical isolates of HIV. The IC50 and IC90 values (50% and 90% inhibitory concentrations) were 0.003
52
to 0.013 and 0.03 to 0.13 mcg/mL, respectively (1 nM = 0.27 ng/mL).The IC50 and IC90 values of HIV
53
isolates recovered from 18 untreated AIDS/ARC patients were in the range of 0.003 to 0.013 mcg/mL
54
and 0.03 to 0.3 mcg/mL, respectively. Zidovudine showed antiviral activity in all acutely infected cell
55
lines; however, activity was substantially less in chronically infected cell lines. In drug combination
56
studies with zalcitabine, didanosine, lamivudine, saquinavir, indinavir, ritonavir, nevirapine,
57
delavirdine, or interferon-alpha, zidovudine showed additive to synergistic activity in cell culture. The
58
relationship between the in vitro susceptibility of HIV to reverse transcriptase inhibitors and the
59
inhibition of HIV replication in humans has not been established.
60
Drug Resistance: HIV isolates with reduced sensitivity to zidovudine have been selected in vitro and
61
were also recovered from patients treated with RETROVIR. Genetic analysis of the isolates showed
62
mutations which result in five amino acid substitutions (Met41→Leu, A67→Asn, Lys70→Arg,
63
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
3
Thr215→Tyr or Phe, and Lys219→Gln) in the viral reverse transcriptase. In general, higher levels of
64
resistance were associated with greater number of mutations with 215 mutation being the most
65
significant.
66
Cross-Resistance: The potential for cross-resistance between HIV reverse transcriptase inhibitors
67
and protease inhibitors is low because of the different enzyme targets involved. Combination therapy
68
with zidovudine plus zalcitabine or didanosine does not appear to prevent the emergence of
69
zidovudine-resistant isolates. Combination therapy with RETROVIR plus EPIVIR delayed the
70
emergence of mutations conferring resistance to zidovudine. In some patients harboring
71
zidovudine-resistant virus, combination therapy with RETROVIR plus EPIVIR restored phenotypic
72
sensitivity to zidovudine by 12 weeks of treatment. HIV isolates with multidrug resistance to
73
zidovudine, didanosine, zalcitabine, stavudine, and lamivudine were recovered from a small number
74
of patients treated for ≥1 year with the combination of zidovudine and didanosine or zalcitabine. The
75
pattern of resistant mutations in the combination therapy was different (Ala62→Val, Val75→Ile,
76
Phe77→116Tyr, and Gln→151Met) from monotherapy, with mutation 151 being most significant for
77
multidrug resistance. Site-directed mutagenesis studies showed that these mutations could also
78
result in resistance to zalcitabine, lamivudine, and stavudine.
79
80
CLINICAL PHARMACOLOGY:
81
Pharmacokinetics: Adults: The pharmacokinetics of zidovudine has been evaluated in 22 adult
82
HIV-infected patients in a Phase 1 dose-escalation study. After oral dosing (capsules), zidovudine
83
was rapidly absorbed from the gastrointestinal tract with peak serum concentrations occurring within
84
0.5 to 1.5 hours. Dose-independent kinetics was observed over the range of 2 mg/kg every 8 hours to
85
10 mg/kg every 4 hours. The mean zidovudine half-life was approximately 1 hour and ranged from
86
0.78 to 1.93 hours following oral dosing.
87
Zidovudine is rapidly metabolized to 3′-azido-3′-deoxy-5′-O-β-D-glucopyranuronosylthymidine
88
(GZDV) which has an apparent elimination half-life of 1 hour (range 0.61 to 1.73 hours). Following
89
oral administration, urinary recovery of zidovudine and GZDV accounted for 14% and 74% of the
90
dose, respectively, and the total urinary recovery averaged 90% (range 63% to 95%), indicating a
91
high degree of absorption. However, as a result of first-pass metabolism, the average oral capsule
92
bioavailability of zidovudine is 65% (range 52% to 75%). A second metabolite, 3′-amino-3′-
93
deoxythymidine (AMT), has been identified in the plasma following single-dose intravenous (IV)
94
administration of zidovudine. AMT area-under-the-curve (AUC) was one fifth of the AUC of
95
zidovudine and had a half-life of 2.7 ± 0.7 hours. In comparison, GZDV AUC was about threefold
96
greater than the AUC of zidovudine.
97
Additional pharmacokinetic data following intravenous dosing indicated dose-independent kinetics
98
over the range of 1 to 5 mg/kg with a mean zidovudine half-life of 1.1 hours (range 0.48 to
99
2.86 hours). Total body clearance averaged 1900 mL/min per 70 kg and the apparent volume of
100
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
4
distribution was 1.6 L/kg. Renal clearance is estimated to be 400 mL/min per 70 kg, indicating
101
glomerular filtration and active tubular secretion by the kidneys. Zidovudine plasma protein binding is
102
34% to 38%, indicating that drug interactions involving binding site displacement are not anticipated.
103
The zidovudine cerebrospinal fluid (CSF)/plasma concentration ratio was determined in
104
39 patients receiving chronic therapy with RETROVIR. The median ratio measured in 50 paired
105
samples drawn 1 to 8 hours after the last dose of RETROVIR was 0.6.
106
Adults with Impaired Renal Function: The pharmacokinetics of zidovudine has been evaluated
107
in patients with impaired renal function following a single 200-mg oral dose. In 14 patients (mean
108
creatinine clearance 18 ± 2 mL/min) the half-life of zidovudine was 1.4 hours compared to 1.0 hour
109
for control subjects with normal renal function; AUC values were approximately twice those of
110
controls. Additionally, GZDV half-life in these patients was 8.0 hours (vs 0.9 hours for control) and
111
AUC was 17 times higher than for control subjects. The pharmacokinetics and tolerance were
112
evaluated in a multiple-dose study in patients undergoing hemodialysis (n = 5) or peritoneal dialysis
113
(n = 6). Patients received escalating doses of zidovudine up to 200 mg five times daily for 8 weeks.
114
Daily doses of 500 mg or less were well tolerated despite significantly elevated plasma levels of
115
GZDV. Apparent oral clearance of zidovudine was approximately 50% of that reported in patients with
116
normal renal function. The plasma concentrations of AMT are not known in patients with renal
117
insufficiency. Daily doses of 300 to 400 mg should be appropriate in HIV-infected patients with severe
118
renal dysfunction (see DOSAGE AND ADMINISTRATION: Dose Adjustment). Hemodialysis and
119
peritoneal dialysis appear to have a negligible effect on the removal of zidovudine, whereas GZDV
120
elimination is enhanced.
121
Pediatrics: The pharmacokinetics and bioavailability of zidovudine have been evaluated in
122
21 HIV-infected pediatric patients, aged 6 months through 12 years, following intravenous doses
123
administered over the range of 80 to 160 mg/m2 every 6 hours, and following oral doses of the IV
124
solution administered over the range of 90 to 240 mg/m2 every 6 hours. After discontinuation of the IV
125
infusion, zidovudine plasma concentrations decayed biexponentially, consistent with
126
two-compartment pharmacokinetics. Proportional increases in AUC and in zidovudine concentrations
127
were observed with increasing dose, consistent with dose-independent kinetics over the dose range
128
studied. The mean terminal half-life and total body clearance across all dose levels administered
129
were 1.5 hours and 30.9 mL/min per kg, respectively. These values compare to mean half-life and
130
total body clearance in adults of 1.1 hours and 27.1 mL/min per kg.
131
The mean oral bioavailability of 65% was independent of dose. This value is the same as the
132
bioavailability in adults. Doses of 180 mg/m2 four times daily in pediatric patients produced similar
133
systemic exposure (24-hour AUC 10.7 hr•mcg/mL) as doses of 200 mg six times daily in adult
134
patients (10.9 hr•mcg/mL).
135
The pharmacokinetics of zidovudine have been studied in pediatric patients from birth to 3 months
136
of life. In one study of the pharmacokinetics of zidovudine in women during the last trimester of
137
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
5
pregnancy, zidovudine elimination was determined immediately after birth in eight neonates who were
138
exposed to zidovudine in utero. The half-life was 13.0 ± 5.8 hours. In another study, the
139
pharmacokinetics of zidovudine were evaluated in pediatric patients (ranging in age of 1 day to
140
3 months) of normal birth weight for gestational age and with normal renal and hepatic function. In
141
neonates less than or equal to 14 days old, mean ± SD total body clearance was 10.9 ± 4.8 mL/min
142
per kg (n = 18) and half-life was 3.1 ± 1.2 hours (n = 21). In neonates and infants greater than
143
14 days old, total body clearance was 19.0 ± 4.0 mL/min per kg (n = 16) and half-life was
144
1.9 ± 0.7 hours (n = 18). Bioavailability was 89% ± 19% (n = 15) in the younger age group and
145
decreased to 61% ± 19% (n = 17) in patients older than 14 days.
146
Concentrations of zidovudine in cerebrospinal fluid were measured after both intermittent oral and
147
IV drug administration in 21 pediatric patients during Phase 1 and Phase 2 studies. The mean
148
zidovudine CSF/plasma concentration ratio measured at an average time of 2.2 hours postdose at
149
oral doses of 120 to 240 mg/m2 was 0.52 ± 0.44 (n = 28); after an IV infusion of doses of 80 to
150
160 mg/m2 over 1 hour, the mean CSF/plasma concentration ratio was 0.87 ± 0.66 (n = 23) at
151
3.2 hours after the start of the infusion. During continuous IV infusion, mean steady-state
152
CSF/plasma ratio was 0.26 ± 0.17 (n = 28).
153
As in adult patients, the major route of elimination in pediatric patients was by metabolism to
154
GZDV. After IV dosing, about 29% of the dose was excreted in the urine unchanged and about 45%
155
of the dose was excreted as GZDV. Overall, the pharmacokinetics of zidovudine in pediatric patients
156
greater than 3 months of age are similar to that of zidovudine in adult patients.
157
Pregnancy: The pharmacokinetics of zidovudine have been studied in a Phase 1 study of eight
158
women during the last trimester of pregnancy. As pregnancy progressed, there was no evidence of
159
drug accumulation. The pharmacokinetics of zidovudine were similar to that of nonpregnant adults.
160
Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in
161
infant plasma at birth were essentially equal to those in maternal plasma at delivery. Although data
162
are limited, methadone maintenance therapy in five pregnant women did not appear to alter
163
zidovudine pharmacokinetics. However, in another patient population, a potential for interaction has
164
been identified (see PRECAUTIONS).
165
Nursing Mothers: The U.S. Public Health Service Centers for Disease Control and Prevention
166
advises HIV-infected women not to breastfeed to avoid postnatal transmission of HIV to a child who
167
may not yet be infected. After administration of a single dose of 200 mg zidovudine to 13 HIV-infected
168
women, the mean concentration of zidovudine was similar in human milk and serum (see
169
PRECAUTIONS: Nursing Mothers).
170
Effect of Food on Absorption: Administration of RETROVIR Capsules with food decreased
171
peak plasma concentrations by greater than 50%; however, bioavailability as determined by AUC
172
may not be affected.
173
The effect of food on the absorption of zidovudine from the tablet formulation is not known.
174
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
6
Tablets: In a single-dose study of 23 healthy volunteers, the mean ± SD relative bioavailability of
175
the RETROVIR 300-mg Tablet relative to three 100-mg RETROVIR Capsules was 110 ± 18%. After
176
administration of the 300-mg RETROVIR Tablet or three 100-mg RETROVIR Capsules, the mean
177
± SD Cmax values were 1.81 ± 0.52 and 1.50 ± 0.46 mcg/mL, respectively.
178
Syrup: In a multiple-dose bioavailability study conducted in 12 HIV-infected adults receiving doses
179
of 100 or 200 mg every 4 hours, RETROVIR Syrup was demonstrated to be bioequivalent to
180
RETROVIR Capsules with respect to area under the zidovudine plasma concentration-time curve
181
(AUC). The rate of absorption of RETROVIR Syrup was greater than that of RETROVIR Capsules,
182
as indicated by mean times to peak concentration of 0.5 and 0.8 hours, respectively. Mean values for
183
steady-state peak concentration (dose-normalized to 200 mg) were 1.5 and 1.2 mcg/mL for syrup
184
and capsules, respectively.
185
186
INDICATIONS AND USAGE: RETROVIR is indicated for the treatment of HIV infection when
187
antiretroviral therapy is warranted (see Description of Clinical Studies).
188
The duration of clinical benefit from antiretroviral therapy may be limited. Alterations in
189
antiretroviral therapy should be considered if disease progression occurs during treatment.
190
Maternal-Fetal HIV Transmission: RETROVIR is also indicated for the prevention of maternal-fetal
191
HIV transmission as part of a regimen that includes oral RETROVIR beginning between 14 and
192
34 weeks of gestation, intravenous RETROVIR during labor, and administration of RETROVIR Syrup
193
to the neonate after birth. The efficacy of this regimen for preventing HIV transmission in women who
194
have received RETROVIR for a prolonged period before pregnancy has not been evaluated. The
195
safety of RETROVIR for the mother or fetus during the first trimester of pregnancy has not been
196
assessed (see Description of Clinical Studies).
197
Description of Clinical Studies: Therapy with RETROVIR has been shown to prolong survival and
198
decrease the incidence of opportunistic infections in patients with advanced HIV disease at the
199
initiation of therapy and to delay disease progression in asymptomatic HIV-infected patients.
200
Other randomized studies suggest that the duration of the clinical benefit of monotherapy with
201
RETROVIR is time-limited.
202
Combination Therapy-Adults: ACTG175 was a randomized, double-blind, controlled trial that
203
compared RETROVIR 200 mg t.i.d.; didanosine 200 mg b.i.d.; RETROVIR plus didanosine; and
204
RETROVIR plus zalcitabine 0.75 mg t.i.d. A total of 2467 HIV-infected adults with baseline CD4
205
counts of 200 to 500 cells/mm3 (mean = 352) and no prior AIDS-defining event enrolled with the
206
following demographics: male (82%), Caucasian (70%), mean age of 35 years, asymptomatic HIV
207
infection (81%), and prior antiretroviral use (57%, mean duration = 89.5 weeks). The overall median
208
duration of study treatment was 118 weeks. The incidence of AIDS-defining events or death is shown
209
in Table 1.
210
211
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
7
Table 1
212
First AIDS-Defining Event or Death and Death Only
213
by Study Arm and Antiretroviral Experience
214
215
Treatment
Antiretroviral
Experience
Event
RETROVIR
Didanosine
RETROVIR
plus
Didanosine
RETROVIR
plus Zalcitabine
No. of Patients
619
620
613
615
Overall
AIDS/Death
96 (16%)
71 (11%)
66 (11%)
76 (12%)
Death Only
54 (9%)
29 (5%)
31 (5%)
40 (7%)
No. of Patients
269
268
263
267
Naive
AIDS/Death
32 (12%)
23 (9%)
20 (8%)
16 (6%)
Death Only
18 (7%)
11 (4%)
11 (4%)
9 (3%)
No. of Patients
350
352
350
348
Experienced
AIDS/Death
64 (18%)
48 (14%)
45 (13%)
60 (17%)
Death Only
36 (10%)
18 (5%)
20 (6%)
31 (9%)
216
RETROVIR in combination with certain antiretroviral agents has been shown to be superior to
217
monotherapy in one or more of the following: delaying death, delaying development of AIDS,
218
increasing CD4 cell counts, and decreasing plasma HIV RNA. Use of RETROVIR in some
219
combinations is based on surrogate marker data. The complete prescribing information for each drug
220
should be consulted before combination therapy which includes RETROVIR is initiated.
221
Pregnant Women and Their Neonates: The utility of RETROVIR for the prevention of
222
maternal-fetal HIV transmission was demonstrated in a randomized, double-blind, placebo-controlled
223
trial (ACTG 076) conducted in HIV-infected pregnant women with CD4 cell counts of 200
224
to1818 cells/mm3 (median in the treated group: 560 cells/mm3) who had little or no previous exposure
225
to RETROVIR. Oral RETROVIR was initiated between 14 and 34 weeks of gestation (median
226
11 weeks of therapy) followed by IV administration of RETROVIR during labor and delivery. After
227
birth, neonates received oral RETROVIR Syrup for 6 weeks. The study showed a statistically
228
significant difference in the incidence of HIV infection in the neonates (based on viral culture from
229
peripheral blood) between the group receiving RETROVIR and the group receiving placebo. Of
230
363 neonates evaluated in the study, the estimated risk of HIV infection was 7.8% in the group
231
receiving RETROVIR and 24.9% in the placebo group, a relative reduction in transmission risk of
232
68.7%. RETROVIR was well tolerated by mothers and infants. There was no difference in
233
pregnancy-related adverse events between the treatment groups.
234
Dose-Frequency Study: A randomized, double-blind, dose-frequency study of RETROVIR in
235
320 patients with AIDS or advanced ARC was conducted to assess the safety and tolerability of
236
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
8
600 mg RETROVIR per day given as either 100 mg every 4 hours or as 300 mg every 12 hours for
237
48 weeks. No significant difference was detected between the two dose frequencies with regard to
238
adverse experiences or hematologic abnormalities. Although this study was not designed to
239
determine efficacy, no differences in the frequency of or time to opportunistic infections, neoplasms,
240
or death were noted between treatment groups. Changes in CD4 cell counts and β2-microglobulin
241
levels were similar between treatment groups.
242
243
CONTRAINDICATIONS: RETROVIR Tablets, Capsules, and Syrup are contraindicated for patients
244
who have potentially life-threatening allergic reactions to any of the components of the formulations.
245
246
WARNINGS: Before combination therapy with RETROVIR is initiated, consult the complete
247
prescribing information for each drug. The safety profile of RETROVIR plus other antiretroviral agents
248
reflects the individual safety profiles of each component.
249
The incidence of adverse reactions appears to increase with disease progression, and patients
250
should be monitored carefully, especially as disease progression occurs.
251
Bone Marrow Suppression: RETROVIR should be used with caution in patients who have bone
252
marrow compromise evidenced by granulocyte count <1000 cells/mm3 or hemoglobin <9.5 g/dL. In
253
patients with advanced symptomatic HIV disease, anemia and neutropenia were the most significant
254
adverse events observed (see ADVERSE REACTIONS). There have been reports of pancytopenia
255
associated with the use of RETROVIR, which was reversible in most instances after discontinuance
256
of the drug. However, significant anemia, in many cases requiring dose adjustment, discontinuation
257
of RETROVIR, and/or blood transfusions has occurred during treatment with RETROVIR alone or in
258
combination with other antiretrovirals.
259
Frequent blood counts are strongly recommended in patients with advanced HIV disease who are
260
treated with RETROVIR. For HIV-infected individuals and patients with asymptomatic or early HIV
261
disease, periodic blood counts are recommended. If anemia or neutropenia develops, dosage
262
adjustments may be necessary (see DOSAGE AND ADMINISTRATION).
263
Myopathy: Myopathy and myositis with pathological changes, similar to that produced by HIV
264
disease, have been associated with prolonged use of RETROVIR.
265
Lactic Acidosis/Severe Hepatomegaly with Steatosis: Rare occurrences of potentially fatal lactic
266
acidosis in the absence of hypoxemia, and severe hepatomegaly with steatosis have been reported
267
with the use of certain antiretroviral nucleoside analogues. Lactic acidosis should be considered
268
whenever a patient receiving therapy with RETROVIR develops unexplained tachypnea, dyspnea, or
269
fall in serum bicarbonate level. Under these circumstances, therapy with RETROVIR should be
270
suspended until the diagnosis of lactic acidosis has been excluded. Caution should be exercised
271
when administering RETROVIR to any patient, particularly obese women, with hepatomegaly,
272
hepatitis, or other known risk factor for liver disease. These patients should be followed closely while
273
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
9
on therapy with RETROVIR. The significance of elevated aminotransferase levels suggesting hepatic
274
injury in HIV-infected patients prior to starting RETROVIR or while on RETROVIR is unclear.
275
Treatment with RETROVIR should be suspended in the setting of rapidly elevating aminotransferase
276
levels, progressive hepatomegaly, or metabolic/lactic acidosis of unknown etiology.
277
Other Serious Adverse Reactions: Several serious adverse events have been reported with use of
278
RETROVIR in clinical practice. Reports of pancreatitis, sensitization reactions (including anaphylaxis
279
in one patient), vasculitis, and seizures have been rare. These adverse events, except for
280
sensitization, have also been associated with HIV disease. Changes in skin and nail pigmentation
281
have been associated with the use of RETROVIR.
282
283
PRECAUTIONS:
284
General: Zidovudine is eliminated from the body primarily by renal excretion following metabolism in
285
the liver (glucuronidation). In patients with severely impaired renal function, dosage reduction is
286
recommended (see CLINICAL PHARMACOLOGY: Pharmacokinetics and DOSAGE AND
287
ADMINISTRATION). Although very little data are available, patients with severely impaired hepatic
288
function may be at greater risk of toxicity.
289
Information for Patients: RETROVIR is not a cure for HIV infection, and patients may continue to
290
acquire illnesses associated with HIV infection, including opportunistic infections. Therefore, patients
291
should be advised to seek medical care for any significant change in their health status.
292
The safety and efficacy of RETROVIR in women, intravenous drug users, and racial minorities is
293
not significantly different than that observed in white males.
294
Patients should be informed that the major toxicities of RETROVIR are neutropenia and/or
295
anemia. The frequency and severity of these toxicities are greater in patients with more advanced
296
disease and in those who initiate therapy later in the course of their infection. They should be told that
297
if toxicity develops, they may require transfusions or dose modifications including possible
298
discontinuation. They should be told of the extreme importance of having their blood counts followed
299
closely while on therapy, especially for patients with advanced symptomatic HIV disease. They
300
should be cautioned about the use of other medications, including ganciclovir and interferon-alpha,
301
that may exacerbate the toxicity of RETROVIR (see PRECAUTIONS: Drug Interactions). Patients
302
should be informed that other adverse effects of RETROVIR include nausea and vomiting. Patients
303
should also be encouraged to contact their physician if they experience muscle weakness, shortness
304
of breath, symptoms of hepatitis or pancreatitis, or any other unexpected adverse events while being
305
treated with RETROVIR.
306
RETROVIR Tablets, Capsules, and Syrup are for oral ingestion only. Patients should be told of the
307
importance of taking RETROVIR exactly as prescribed. They should be told not to share medication
308
and not to exceed the recommended dose. Patients should be told that the long-term effects of
309
RETROVIR are unknown at this time.
310
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
10
Pregnant women considering the use of RETROVIR during pregnancy for prevention of
311
HIV-transmission to their infants should be advised that transmission may still occur in some cases
312
despite therapy. The long-term consequences of in utero and infant exposure to RETROVIR are
313
unknown, including the possible risk of cancer.
314
HIV-infected pregnant women should be advised not to breastfeed to avoid postnatal transmission
315
of HIV to a child who may not yet be infected.
316
Patients should be advised that therapy with RETROVIR has not been shown to reduce the risk of
317
transmission of HIV to others through sexual contact or blood contamination.
318
Drug Interactions: Ganciclovir: Use of RETROVIR in combination with ganciclovir increases the
319
risk of hematologic toxicities in some patients with advanced HIV disease. Should the use of this
320
combination become necessary in the treatment of patients with HIV disease, dose reduction or
321
interruption of one or both agents may be necessary to minimize hematologic toxicity. Hematologic
322
parameters, including hemoglobin, hematocrit, and white blood cell count with differential, should be
323
monitored frequently in all patients receiving this combination.
324
Interferon-alpha: Hematologic toxicities have also been seen when RETROVIR is used
325
concomitantly with interferon-alpha. As with the concomitant use of RETROVIR and ganciclovir, dose
326
reduction or interruption of one or both agents may be necessary, and hematologic parameters
327
should be monitored frequently.
328
Bone Marrow Suppressive Agents/Cytotoxic Agents: Coadministration of RETROVIR with
329
drugs that are cytotoxic or which interfere with RBC/WBC number or function (e.g., dapsone,
330
flucytosine, vincristine, vinblastine, or adriamycin) may increase the risk of hematologic toxicity.
331
Probenecid: Limited data suggest that probenecid may increase zidovudine levels by inhibiting
332
glucuronidation and/or by reducing renal excretion of zidovudine. Some patients who have used
333
RETROVIR concomitantly with probenecid have developed flu-like symptoms consisting of myalgia,
334
malaise, and/or fever and maculopapular rash.
335
Phenytoin: Phenytoin plasma levels have been reported to be low in some patients receiving
336
RETROVIR, while in one case a high level was documented. However, in a pharmacokinetic
337
interaction study in which 12 HIV-positive volunteers received a single 300-mg phenytoin dose alone
338
and during steady-state zidovudine conditions (200 mg every 4 hours), no change in phenytoin
339
kinetics was observed. Although not designed to optimally assess the effect of phenytoin on
340
zidovudine kinetics, a 30% decrease in oral zidovudine clearance was observed with phenytoin.
341
Methadone: In a pharmacokinetic study of nine HIV-positive patients receiving
342
methadone-maintenance (30 to 90 mg daily) concurrent with 200 mg of RETROVIR every 4 hours,
343
no changes were observed in the pharmacokinetics of methadone upon initiation of therapy with
344
RETROVIR and after 14 days of treatment with RETROVIR. No adjustments in
345
methadone-maintenance requirements were reported. For four patients, the mean zidovudine AUC
346
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
11
was elevated twofold, while for five patients, the value was equal to that of control patients. The exact
347
mechanism and clinical significance of these data are unknown.
348
Fluconazole: The coadministration of fluconazole with RETROVIR has been reported to interfere
349
with the oral clearance and metabolism of RETROVIR. In a pharmacokinetic interaction study in
350
which 12 HIV-positive men received RETROVIR 200 mg every 8 hours alone and in combination with
351
fluconazole 400 mg daily, fluconazole increased the zidovudine AUC (74%; range 28% to 173%) and
352
the zidovudine half-life (128%; range -4% to 189%) at steady state. The clinical significance of this
353
interaction is unknown.
354
Atovaquone: Data from 14 HIV-infected volunteers who were given atovaquone tablets 750 mg
355
every 12 hours with zidovudine 200 mg every 8 hours showed a 24% ± 12% decrease in zidovudine
356
oral clearance, leading to a 35% ± 23% increase in plasma zidovudine AUC. The glucuronide
357
metabolite:parent ratio decreased from a mean of 4.5 when zidovudine was administered alone to 3.1
358
when zidovudine was administered with atovaquone tablets. Zidovudine had no effect on atovaquone
359
pharmacokinetics.
360
Valproic Acid: The concomitant administration of valproic acid 250 mg (n = 5) or 500 mg (n = 1)
361
every 8 hours and zidovudine 100 mg orally every 8 hours for 4 days to six HIV-infected,
362
asymptomatic male volunteers resulted in a 79% ± 61% (mean ± SD) increase in the plasma
363
zidovudine AUC and a 22% ± 10% decrease in the plasma GZDV AUC as compared to the
364
administration of zidovudine in the absence of valproic acid. The GZDV/zidovudine urinary excretion
365
ratio decreased 58% ± 12%. Because no change in the zidovudine plasma half-life occurred, these
366
results suggest that valproic acid may increase the oral bioavailability of zidovudine through inhibition
367
of first-pass metabolism. Although the clinical significance of this interaction is unknown, patients
368
should be monitored more closely for a possible increase in zidovudine-related adverse effects. The
369
effect of zidovudine on the pharmacokinetics of valproic acid was not evaluated.
370
Lamivudine: RETROVIR and lamivudine were coadministered to 12 asymptomatic HIV-positive
371
patients in a single-center, open-label, randomized, crossover study. No significant differences were
372
observed in AUC∞ or total clearance for lamivudine or zidovudine when the two drugs were
373
administered together. Coadministration of RETROVIR with lamivudine resulted in an increase of
374
39% ± 62% (mean ± SD) in Cmax of zidovudine.
375
Other Agents: Preliminary data from a drug interaction study (n = 10) suggest that
376
coadministration of 200 mg RETROVIR and 600 mg rifampin decreases the area under the plasma
377
concentration curve by an average of 48% ± 34%. However, the effect of once-daily dosing of
378
rifampin on multiple daily doses of RETROVIR is unknown. Some nucleoside analogues affecting
379
DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of RETROVIR against HIV;
380
concomitant use of such drugs should be avoided.
381
Carcinogenesis, Mutagenesis, Impairment of Fertility: Zidovudine was administered orally at
382
three dosage levels to separate groups of mice and rats (60 females and 60 males in each group).
383
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
12
Initial single daily doses were 30, 60, and 120 mg/kg per day in mice and 80, 220, and 600 mg/kg per
384
day in rats. The doses in mice were reduced to 20, 30, and 40 mg/kg per day after day 90 because of
385
treatment-related anemia, whereas in rats only the high dose was reduced to 450 mg/kg per day on
386
day 91 and then to 300 mg/kg per day on day 279.
387
In mice, seven late-appearing (after 19 months) vaginal neoplasms (five nonmetastasizing
388
squamous cell carcinomas, one squamous cell papilloma, and one squamous polyp) occurred in
389
animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina
390
of a middle-dose animal. No vaginal tumors were found at the lowest dose.
391
In rats, two late-appearing (after 20 months), nonmetastasizing vaginal squamous cell carcinomas
392
occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in
393
rats. No other drug-related tumors were observed in either sex of either species.
394
At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by
395
AUC) was approximately three times (mouse) and 24 times (rat) the estimated human exposure at
396
the recommended therapeutic dose of 100 mg every 4 hours.
397
Two transplacental carcinogenicity studies were conducted in mice. One study administered
398
zidovudine at doses of 20 mg/kg per day or 40 mg/kg per day from gestation day 10 through
399
parturition and lactation with dosing continuing in offspring for 24 months postnatally. The doses of
400
zidovudine employed in this study produced zidovudine exposures approximately three times the
401
estimated human exposure at recommended doses. After 24 months, an increase in incidence of
402
vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in either
403
gender. These findings are consistent with results of the standard oral carcinogenicity study in mice,
404
as described earlier. A second study administered zidovudine at maximum tolerated doses of
405
12.5 mg/day or 25 mg/day (∼1000 mg/kg nonpregnant body weight or ∼450 mg/kg of term body
406
weight) to pregnant mice from days 12 through 18 of gestation. There was an increase in the number
407
of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher
408
dose level of zidovudine.
409
It is not known how predictive the results of rodent carcinogenicity studies may be for humans.
410
Zidovudine was mutagenic in a 5178Y/TK+/- mouse lymphoma assay, positive in an in vitro cell
411
transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes, and
412
positive in mouse and rat micronucleus tests after repeated doses. It was negative in a cytogenetic
413
study in rats given a single dose.
414
Zidovudine, administered to male and female rats at doses up to seven times the usual adult dose
415
based on body surface area considerations, had no effect on fertility judged by conception rates.
416
Pregnancy: Pregnancy Category C. Oral teratology studies in the rat and in the rabbit at doses up to
417
500 mg/kg per day revealed no evidence of teratogenicity with zidovudine. Zidovudine treatment
418
resulted in embryo/fetal toxicity as evidenced by an increase in the incidence of fetal resorptions in
419
rats given 150 or 450 mg/kg per day and rabbits given 500 mg/kg per day. The doses used in the
420
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
13
teratology studies resulted in peak zidovudine plasma concentrations (after one half of the daily dose)
421
in rats 66 to 226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma
422
concentrations (after one sixth of the daily dose) achieved with the recommended daily dose (100 mg
423
every 4 hours). In an in vitro experiment with fertilized mouse oocytes, zidovudine exposure resulted
424
in a dose-dependent reduction in blastocyst formation. In an additional teratology study in rats, a dose
425
of 3000 mg/kg per day (very near the oral median lethal dose in rats of 3683 mg/kg) caused marked
426
maternal toxicity and an increase in the incidence of fetal malformations. This dose resulted in peak
427
zidovudine plasma concentrations 350 times peak human plasma concentrations. (Estimated
428
area-under-the-curve [AUC] in rats at this dose level was 300 times the daily AUC in humans given
429
600 mg per day.) No evidence of teratogenicity was seen in this experiment at doses of 600 mg/kg
430
per day or less.
431
Two rodent transplacental carcinogenicity studies were conducted (see Carcinogenesis,
432
Mutagenesis, Impairment of Fertility).
433
A randomized, double-blind, placebo-controlled trial was conducted in HIV-infected pregnant
434
women to determine the utility of RETROVIR for the prevention of maternal-fetal HIV-transmission
435
(see INDICATIONS AND USAGE: Description of Clinical Studies). Congenital abnormalities occurred
436
with similar frequency between neonates born to mothers who received RETROVIR and neonates
437
born to mothers who received placebo. Abnormalities were either problems in embryogenesis (prior
438
to 14 weeks) or were recognized on ultrasound before or immediately after initiation of study drug.
439
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women
440
exposed to RETROVIR, an Antiretroviral Pregnancy Registry has been established. Physicians are
441
encouraged to register patients by calling 1-800-258-4263.
442
Nursing Mothers: The U.S. Public Health Service Centers for Disease Control and Prevention
443
advises HIV-infected women not to breastfeed to avoid postnatal transmission of HIV to a child who
444
may not yet be infected. Zidovudine is excreted in human milk (see Pharmacokinetics).
445
Pediatric Use: RETROVIR has been studied in HIV-infected pediatric patients over 3 months of age
446
who have HIV-related symptoms or who are asymptomatic with abnormal laboratory values indicating
447
significant HIV-related immunosuppression (see ADVERSE REACTIONS, DOSAGE AND
448
ADMINISTRATION, and INDICATIONS AND USAGE: Description of Clinical Studies, and
449
Pharmacokinetics).
450
Geriatric Use: Clinical studies of RETROVIR did not include sufficient numbers of subjects aged 65
451
and over to determine whether they respond differently from younger subjects. Other reported clinical
452
experience has not identified differences in responses between the elderly and younger patients. In
453
general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of
454
decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
455
456
ADVERSE REACTIONS:
457
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
14
Monotherapy: Adults: The frequency and severity of adverse events associated with the use of
458
RETROVIR in adults are greater in patients with more advanced infection at the time of initiation of
459
therapy. The following table summarizes the relative incidence of hematologic adverse events
460
observed in clinical studies by severity of HIV disease present at the start of treatment:
461
462
Table 2
463
464
Stage of
Disease
RETROVIR
Daily Dose* (mg)
Granulocytopenia
(<750 cells/mm3)
Anemia
(Hgb <8.0 g/dL)
Asymptomatic
ACTG 019
500
1.8%†
1.1%†
Early HIV Disease
(CD4 >200 cells/mm3)
ACTG 016
1200
4%
4%
Advanced HIV Disease
(CD4 >200 cells/mm3)
BW 02
(CD4 ≤200 cells/mm3)
ACTG 002
BW 02
1500
600
1500
10%†
37%
47%
3%†‡
29%
29%‡
* The currently recommended dose is 500 to 600 mg daily.
465
† Not statistically significant compared to placebo.
466
‡ Anemia = Hgb <7.5 g/dL.
467
468
The anemia reported in patients with advanced HIV disease receiving RETROVIR appeared to be
469
the result of impaired erythrocyte maturation as evidenced by macrocytosis while on drug. Although
470
mean platelet counts in patients receiving RETROVIR were significantly increased compared to
471
mean baseline values, thrombocytopenia did occur in some of these patients with advanced disease.
472
Twelve percent of patients receiving RETROVIR compared to 5% of patients receiving placebo had
473
>50% decreases from baseline platelet count. Mild drug-associated elevations in total bilirubin levels
474
have been reported as an uncommon occurrence in patients treated for asymptomatic HIV infection.
475
The HIV-infected adults participating in these clinical trials often had baseline symptoms and signs
476
of HIV disease and/or experienced adverse events at some time during study. It was often difficult to
477
distinguish adverse events possibly associated with administration of RETROVIR from underlying
478
signs of HIV disease or intercurrent illnesses. The following table summarizes clinical adverse events
479
or symptoms which occurred in at least 5% of all patients with advanced HIV disease treated with
480
1500 mg/day of RETROVIR in the original placebo-controlled study. Of the items listed in the table,
481
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
15
only severe headache, nausea, insomnia, and myalgia were reported at a significantly greater rate in
482
patients receiving RETROVIR.
483
484
Table 3
485
Percentage (%) of Patients with Clinical Events in Advanced HIV Disease (BW 02)
486
487
Adverse Event
RETROVIR
1500 mg/day*
(n = 144) %
Placebo
(n = 137) %
BODY AS A WHOLE
Asthenia
Diaphoresis
Fever
Headache
Malaise
19
5
16
42
8
18
4
12
37
7
GASTROINTESTINAL
Anorexia
Diarrhea
Dyspepsia
GI Pain
Nausea
Vomiting
11
12
5
20
46
6
8
18
4
19
18
3
MUSCULOSKELETAL
Myalgia
8
2
NERVOUS
Dizziness
Insomnia
Paresthesia
Somnolence
6
5
6
8
4
1
3
9
RESPIRATORY
Dyspnea
5
3
SKIN
Rash
17
15
SPECIAL SENSES
Taste Perversion
5
8
* The currently recommended dose is 500 to 600 mg daily.
488
489
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
16
All events of a severe or life-threatening nature were monitored for adults in the placebo-controlled
490
studies in early HIV disease and asymptomatic HIV infection. Data concerning the occurrence of
491
additional signs or symptoms were also collected. No distinction was made in reporting events
492
between those possibly associated with the administration of the study medication and those due to
493
the underlying disease. The following tables summarize all those events reported at a statistically
494
significant greater incidence for patients receiving RETROVIR in these studies:
495
496
Table 4
497
Percentage (%) of Patients with Adverse Events in Early HIV Disease (ACTG 016)
498
499
Adverse Event
RETROVIR
1200 mg/day*
(n = 361) %
Placebo
(n = 352) %
BODY AS A WHOLE
Asthenia
69
62
GASTROINTESTINAL
Dyspepsia
Nausea
Vomiting
6
61
25
1
41
13
* The currently recommended dose is 500 to 600 mg daily.
500
501
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
17
Table 5
502
Percentage (%) of Patients with Adverse Events* in Asymptomatic HIV Infection (ACTG
503
019)
504
505
Adverse Event
RETROVIR
500 mg/day
(n = 453) %
Placebo
(n = 428) %
BODY AS A WHOLE
Asthenia
Headache
Malaise
8.6†
62.5
53.2
5.8
52.6
44.9
GASTROINTESTINAL
Anorexia
Constipation
Nausea
Vomiting
20.1
6.4†
51.4
17.2
10.5
3.5
29.9
9.8
NERVOUS
Dizziness
17.9†
15.2
* Reported in ≥5% of study population.
506
† Not statistically significant versus placebo.
507
508
Several serious adverse events have been reported with the use of RETROVIR in clinical practice.
509
Myopathy and myositis with pathological changes, similar to that produced by HIV disease, have
510
been associated with prolonged use of RETROVIR. Reports of hepatomegaly with steatosis,
511
hepatitis, pancreatitis, lactic acidosis, sensitization reactions (including anaphylaxis in one patient),
512
hyperbilirubinemia, vasculitis, and seizures have been rare. These adverse events, except for
513
sensitization, have also been associated with HIV disease. A single case of macular edema has been
514
reported with the use of RETROVIR.
515
Additional adverse events reported in clinical trials at a rate not significantly different from placebo
516
are listed below. Selected events from post-marketing clinical experience with RETROVIR are also
517
included. Many of these events may also occur as part of HIV disease. The clinical significance of the
518
association between treatment with RETROVIR and these events is unknown.
519
Body as a Whole: Abdominal pain, back pain, body odor, chest pain, chills, edema of the lip,
520
fever, flu syndrome, hyperalgesia.
521
Cardiovascular: Syncope, vasodilation.
522
Gastrointestinal: Bleeding gums, constipation, diarrhea, dysphagia, edema of the tongue,
523
eructation, flatulence, mouth ulcer, rectal hemorrhage.
524
Hemic and Lymphatic: Lymphadenopathy.
525
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
18
Musculoskeletal: Arthralgia, muscle spasm, tremor, twitch.
526
Nervous: Anxiety, confusion, depression, dizziness, emotional lability, loss of mental acuity,
527
nervousness, paresthesia, somnolence, vertigo.
528
Respiratory: Cough, dyspnea, epistaxis, hoarseness, pharyngitis, rhinitis, sinusitis.
529
Skin: Acne, changes in skin and nail pigmentation, pruritus, rash, sweat, urticaria.
530
Special senses: Amblyopia, hearing loss, photophobia, taste perversion.
531
Urogenital: Dysuria, polyuria, urinary frequency, urinary hesitancy.
532
Pediatrics: Anemia and granulocytopenia among pediatric patients with advanced HIV disease
533
receiving RETROVIR occurred with similar incidence to that reported for adults with AIDS or
534
advanced ARC (see above). Management of neutropenia and anemia included, in some cases, dose
535
modification and/or blood product transfusions. In the open-label studies, 17% had their dose
536
modified (generally a reduction in dose by 30%) due to anemia and 25% had their dose modified
537
(temporary discontinuation or dose reduction by 30%) for neutropenia. Four pediatric patients had
538
RETROVIR permanently discontinued for neutropenia. The following table summarizes the
539
occurrence of anemia (Hgb <7.5 g/dL) and granulocytopenia (<750 cells/mm3) among 124 pediatric
540
patients receiving RETROVIR for a mean of 267 days (range 3 to 855 days):
541
542
Table 6
543
544
Advanced
Pediatric
Granulocytopenia
(<750 cells/mm3)
Anemia
(Hgb <7.5 g/dL)
HIV Disease
n
%
n
%
(n = 124)
48
39
28*
23
* Twenty-two pediatric patients received one or more transfusions due to a decline in hemoglobin to
545
<7.5 g/dL; an additional 15 pediatric patients were transfused for hemoglobin levels >7.5 g/dL.
546
Fifty-nine percent of the patients transfused had a prestudy history of anemia or transfusion
547
requirement.
548
549
Macrocytosis was observed among the majority of pediatric patients enrolled in the studies.
550
In the open-label studies involving 124 pediatric patients, 16 clinical adverse events were reported
551
by 24 pediatric patients. No event was reported by more than 5.6% of the study populations. Due to
552
the open-label design of the studies, it was difficult to determine possible events related to the use of
553
RETROVIR versus disease-related events. Therefore, all clinical events reported as associated with
554
therapy with RETROVIR or of unknown relationship to therapy with RETROVIR are presented in the
555
following table:
556
557
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
19
Table 7
558
Percentage (%) of Pediatric Patients with Clinical Events in Open-Label Studies
559
560
Adverse Event
n
%
BODY AS A WHOLE
Fever
Phlebitis*/Bacteremia
Headache
4
2
2
3.2
1.6
1.6
GASTROINTESTINAL
Nausea
Vomiting
Abdominal Pain
Diarrhea
Weight Loss
1
6
4
1
1
0.8
4.8
3.2
0.8
0.8
NERVOUS
Insomnia
Nervousness/Irritability
Decreased Reflexes
Seizure
3
2
7
1
2.4
1.6
5.6
0.8
CARDIOVASCULAR
Left Ventricular Dilation
Cardiomyopathy
S3 Gallop
Congestive Heart Failure
Generalized Edema
ECG Abnormality
1
1
1
1
1
3
0.8
0.8
0.8
0.8
0.8
2.4
UROGENITAL
Hematuria/Viral Cystitis
1
0.8
* Peripheral vein IV catheter site.
561
562
The clinical adverse events reported among adult recipients of RETROVIR may also occur in
563
pediatric patients.
564
Use for the Prevention of Maternal-Fetal Transmission of HIV: In a randomized, double-blind,
565
placebo-controlled trial in HIV-infected women and their neonates conducted to determine the utility
566
of RETROVIR for the prevention of maternal-fetal HIV transmission, RETROVIR Syrup at 2 mg/kg
567
was administered every 6 hours for 6 weeks to neonates beginning within 12 hours after birth. The
568
most commonly reported adverse experiences were anemia (hemoglobin <9.0 g/dL) and neutropenia
569
(<1000 cells/mm3). Anemia occurred in 22% of the neonates who received RETROVIR and in 12% of
570
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
20
the neonates who received placebo. The mean difference in hemoglobin values was less than
571
1.0 g/dL for neonates receiving RETROVIR compared to neonates receiving placebo. No neonates
572
with anemia required transfusion and all hemoglobin values spontaneously returned to normal within
573
6 weeks after completion of therapy with RETROVIR. Neutropenia was reported with similar
574
frequency in the group that received RETROVIR (21%) and in the group that received placebo (27%).
575
The long-term consequences of in utero and infant exposure to RETROVIR are unknown.
576
577
OVERDOSAGE: Cases of acute overdoses in both pediatric patients and adults have been reported
578
with doses up to 50 grams. None were fatal. The only consistent finding in these cases of overdose
579
was spontaneous or induced nausea and vomiting. Hematologic changes were transient and not
580
severe. Some patients experienced nonspecific CNS symptoms such as headache, dizziness,
581
drowsiness, lethargy, and confusion. One report of a grand mal seizure possibly attributable to
582
RETROVIR occurred in a 35-year-old male 3 hours after ingesting 36 grams of RETROVIR. No other
583
cause could be identified. All patients recovered without permanent sequelae. Hemodialysis and
584
peritoneal dialysis appear to have a negligible effect on the removal of zidovudine while elimination of
585
its primary metabolite, GZDV, is enhanced.
586
587
DOSAGE AND ADMINISTRATION:
588
Adults: The recommended total oral daily dose of RETROVIR is 600 mg per day in divided doses in
589
combination with other antiretroviral agents and 500 mg (100 mg every 4 hours while awake) or
590
600 mg per day in divided doses for monotherapy. The effectiveness of this dose compared to higher
591
dosing regimens in improving the neurologic dysfunction associated with HIV disease is unknown. A
592
small randomized study found a greater effect of higher doses of RETROVIR on improvement of
593
neurological symptoms in patients with pre-existing neurological disease.
594
Pediatrics: The recommended dose in pediatric patients 3 months to 12 years of age is 180 mg/m2
595
every 6 hours (720 mg/m2 per day), not to exceed 200 mg every 6 hours.
596
Maternal-Fetal HIV Transmission: The recommended dosing regimen for administration to
597
pregnant women (>14 weeks of pregnancy) and their neonates is:
598
Maternal Dosing: 100 mg orally five times per day until the start of labor (see INDICATIONS AND
599
USAGE: Description of Clinical Studies). During labor and delivery, intravenous RETROVIR
600
should be administered at 2 mg/kg (total body weight) over 1 hour followed by a continuous
601
intravenous infusion of 1 mg/kg per hour (total body weight) until clamping of the umbilical cord.
602
Neonatal Dosing: 2 mg/kg orally every 6 hours starting within 12 hours after birth and continuing
603
through 6 weeks of age. Neonates unable to receive oral dosing may be administered RETROVIR
604
intravenously at 1.5 mg/kg, infused over 30 minutes, every 6 hours. (See PRECAUTIONS if
605
hepatic disease or renal insufficiency is present.)
606
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
21
Monitoring of Patients: Hematologic toxicities appear to be related to pretreatment bone marrow
607
reserve and to dose and duration of therapy. In patients with poor bone marrow reserve, particularly
608
in patients with advanced symptomatic HIV disease, frequent monitoring of hematologic indices is
609
recommended to detect serious anemia or neutropenia (see WARNINGS). In patients who
610
experience hematologic toxicity, reduction in hemoglobin may occur as early as 2 to 4 weeks, and
611
neutropenia usually occurs after 6 to 8 weeks.
612
Dose Adjustment: Significant anemia (hemoglobin of <7.5 g/dL or reduction of >25% of baseline)
613
and/or significant neutropenia (granulocyte count of <750 cells/mm3 or reduction of >50% from
614
baseline) may require a dose interruption until evidence of marrow recovery is observed (see
615
WARNINGS). For less severe anemia or neutropenia, a reduction in daily dose may be adequate. In
616
patients who develop significant anemia, dose modification does not necessarily eliminate the need
617
for transfusion. If marrow recovery occurs following dose modification, gradual increases in dose may
618
be appropriate depending on hematologic indices and patient tolerance.
619
In end-stage renal disease patients maintained on hemodialysis or peritoneal dialysis,
620
recommended dosing is 100 mg every 6 to 8 hours (see CLINICAL PHARMACOLOGY:
621
Pharmacokinetics).
622
There are insufficient data to recommend dose adjustment of RETROVIR in patients with
623
impaired hepatic function.
624
625
HOW SUPPLIED: RETROVIR Tablets 300 mg (biconvex, white, round, film-coated) containing
626
300 mg zidovudine, one side engraved “GX CW3” and “300” on the other side. Bottle of 60 (NDC
627
0173-0501-00).
628
Store at 15° to 25°C (59° to 77°F).
629
630
RETROVIR Capsules 100 mg (white, opaque cap and body with a dark blue band) containing
631
100 mg zidovudine and printed with “Wellcome” and unicorn logo on cap and “Y9C” and “100” on
632
body. Bottles of 100 (NDC 0173-0108-55) and Unit Dose Pack of 100 (NDC 0173-0108-56).
633
Store at 15° to 25°C (59° to 77°F) and protect from moisture.
634
635
RETROVIR Syrup (colorless to pale yellow, strawberry-flavored) containing 50 mg zidovudine in
636
each teaspoonful (5 mL). Bottle of 240 mL (NDC 0173-0113-18) with child-resistant cap.
637
Store at 15° to 25°C (59° to 77°F).
638
639
US Patent Nos. 4,818,538 and 4,828,838 (Product Patents); 4,724,232; 4,833,130; and 4,837,208
640
(Use Patents)
641
642
643
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
22
644
Glaxo Wellcome Inc.
645
Research Triangle Park, NC 27709
646
647
Copyright 1996, 2000, Glaxo Wellcome Inc. All rights reserved.
648
649
Date of Issue
RL-
650
651
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/
---------------------
Debra Birnkrant
10/5/01 03:55:05 PM
NDA 19-910 SLR 024
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:38.638931
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/19655s36lbl.pdf', 'application_number': 19655, 'submission_type': 'SUPPL ', 'submission_number': 36}
|
11,604
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
ORTHO-CYCLEN or ORTHO TRI-CYCLEN safely and effectively. See
full prescribing information for ORTHO-CYCLEN and ORTHO TRI
CYCLEN.
ORTHO-CYCLEN® and ORTHO TRI-CYCLEN® (norgestimate/ethinyl
estradiol) tablets, for oral use
Initial U.S. Approval: 1989
WARNING: CIGARETTE SMOKING AND SERIOUS
CARDIOVASCULAR EVENTS
See full prescribing information for complete boxed warning.
• ORTHO-CYCLEN or ORTHO TRI-CYCLEN is contraindicated in
women over 35 years old who smoke. (4)
• Cigarette smoking increases the risk of serious cardiovascular events
from combination oral contraceptives (COC) use. (4)
----------------------------INDICATIONS AND USAGE---------------------------
ORTHO-CYCLEN and ORTHO TRI-CYCLEN are estrogen/progestin COCs,
indicated for use by women to prevent pregnancy. (1.1)
ORTHO TRI-CYCLEN is also indicated for the treatment of moderate acne
vulgaris in females at least 15 years of age, who have no known
contraindications to oral contraceptive therapy and have achieved menarche.
ORTHO TRI-CYCLEN should be used for the treatment of acne only if the
patient desires an oral contraceptive for birth control. (1.2)
-----------------------DOSAGE AND ADMINISTRATION----------------------
•
Take one tablet daily by mouth at the same time every day. (2.2)
•
Take tablets in the order directed on the blister pack. (2.2)
•
Do not skip or delay tablet intake. (2.2)
----------------------DOSAGE FORMS AND STRENGTHS--------------------
ORTHO-CYCLEN consists of 28 round, biconvex, coated tablets in the
following order (3):
•
21 blue tablets each containing 0.250 mg norgestimate and 0.035 mg
ethinyl estradiol
•
7 dark green tablets (inert)
ORTHO TRI-CYCLEN consists of 28 round, biconvex, coated tablets in the
following order (3):
•
7 white tablets each containing 0.180 mg norgestimate and 0.035 mg
ethinyl estradiol
•
7 light blue tablets each containing 0.215 mg norgestimate and 0.035 mg
ethinyl estradiol
•
7 blue tablets each containing 0.250 mg norgestimate and 0.035 mg
ethinyl estradiol
•
7 dark green tablets (inert)
-------------------------------CONTRAINDICATIONS------------------------------
•
A high risk of arterial or venous thrombotic diseases (4)
•
Liver tumors or liver disease (4)
•
Undiagnosed abnormal uterine bleeding (4)
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNINGS: CIGARETTE SMOKING AND SERIOUS
CARDIOVASCULAR EVENTS
1
INDICATIONS AND USAGE
1.1
Oral Contraceptive
1.2
Acne
2
DOSAGE AND ADMINISTRATION
2.1
How to Start ORTHO-CYCLEN or ORTHO TRI
CYCLEN
2.2
How to Take ORTHO-CYCLEN or ORTHO TRI
CYCLEN
2.3
Missed Tablets
2.4
Advice in Case of Gastrointestinal Disturbances
2.5
ORTHO-TRICYCLEN Use for Acne
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Thromboembolic Disorders and Other Vascular
Problems
5.2
Liver Disease
•
Pregnancy (4)
•
Breast cancer or other estrogen- or progestin-sensitive cancer (4)
------------------------WARNINGS AND PRECAUTIONS----------------------
•
Thromboembolic Disorders and Other Vascular Problems: Stop
ORTHO-CYCLEN or ORTHO TRI-CYCLEN if a thrombotic event
occurs. Stop at least 4 weeks before and through 2 weeks after major
surgery. Start no earlier than 4 weeks after delivery, in women who are
not breastfeeding. (5.1)
•
Liver disease: Discontinue ORTHO-CYCLEN or
ORTHO TRI-CYCLEN if jaundice occurs. (5.2)
•
High blood pressure: If used in women with well-controlled
hypertension, monitor blood pressure and stop ORTHO-CYCLEN or
ORTHO TRI-CYCLEN if blood pressure rises significantly. (5.3)
•
Carbohydrate and lipid metabolic effects: Monitor prediabetic and
diabetic women taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN.
Consider an alternate contraceptive method for women with
uncontrolled dyslipidemia. (5.5)
•
Headache: Evaluate significant change in headaches and discontinue
ORTHO-CYCLEN or ORTHO TRI-CYCLEN if indicated. (5.6)
•
Bleeding Irregularities and Amenorrhea: Evaluate irregular bleeding or
amenorrhea. (5.7)
------------------------------ADVERSE REACTIONS------------------------------
The most common adverse reactions reported during clinical trials (≥2%)
were:
ORTHO-CYCLEN: headache/migraine, abdominal/gastrointestinal pain,
vaginal infection, genital discharge, breast issues (including breast pain,
discharge, and enlargement), mood disorders (including depression and mood
altered), flatulence, nervousness, rash. (6.1)
ORTHO TRI-CYCLEN: headache/migraine, breast issues (including breast
pain, enlargement, and discharge), vaginal infection,
abdominal/gastrointestinal pain, mood disorders (including mood alteration
and depression), genital discharge, changes in weight (including weight
increased or decreased). (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Janssen
Pharmaceutical, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at
1-800-FDA-1088 or www.fda.gov/medwatch.
-------------------------------DRUG INTERACTIONS------------------------------
Drugs or herbal products that induce certain enzymes including CYP3A4,
may decrease the effectiveness of COCs or increase breakthrough bleeding.
Counsel patients to use a back-up or alternative method of contraception when
enzyme inducers are used with COCs. (7.1)
-----------------------USE IN SPECIFIC POPULATIONS-----------------------
Nursing mothers: Not recommended; can decrease milk production. (8.3)
See 17 for PATIENT COUNSELING INFORMATION and
FDA-approved patient labeling.
Revised: 04/2015
5.3
High Blood Pressure
5.4
Gallbladder Disease
5.5
Carbohydrate and Lipid Metabolic Effects
5.6
Headache
5.7
Bleeding Irregularities and Amenorrhea
5.8
COC Use Before or During Early Pregnancy
5.9
Depression
5.10 Carcinoma of Breast and Cervix
5.11 Effect on Binding Globulins
5.12 Monitoring
5.13 Hereditary Angioedema
5.14 Chloasma
6
ADVERSE REACTIONS
6.1
Clinical Trial Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Effects of Other Drugs on Combined Oral
Contraceptives
7.2
Effects of Combined Oral Contraceptives on
Other Drugs
7.3
Interference with Laboratory Tests
Reference ID: 3745081
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Hepatic Impairment
8.7
Renal Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of
Fertility
14 CLINICAL STUDIES
14.1 Contraception
14.2 Acne
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Storage Conditions
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed
Reference ID: 3745081
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
FULL PRESCRIBING INFORMATION
WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS
Cigarette smoking increases the risk of serious cardiovascular events from combination
oral contraceptive (COC) use. This risk increases with age, particularly in women over 35
years of age, and with the number of cigarettes smoked. For this reason, COCs are
contraindicated in women who are over 35 years of age and smoke [see Contraindications
(4)].
1
INDICATIONS AND USAGE
1.1 Oral Contraceptive
ORTHO-CYCLEN and ORTHO TRI-CYCLEN Tablets are indicated for use by females of
reproductive potential to prevent pregnancy [see Clinical Studies (14)].
1.2 Acne
ORTHO TRI-CYCLEN is indicated for the treatment of moderate acne vulgaris in females at
least 15 years of age, who have no known contraindications to oral contraceptive therapy and
have achieved menarche. ORTHO TRI-CYCLEN should be used for the treatment of acne only
if the patient desires an oral contraceptive for birth control [see Clinical Studies (14)].
2
DOSAGE AND ADMINISTRATION
2.1 How to Start ORTHO-CYCLEN or ORTHO TRI-CYCLEN
ORTHO-CYCLEN and ORTHO TRI-CYCLEN are dispensed in either a DIALPAK Tablet
dispenser or a VERIDATE Tablet Dispenser [see How Supplied/Storage and Handling (16)].
ORTHO-CYCLEN and ORTHO TRI-CYCLEN may be started using either a Day 1 start or a
Sunday start (see Table 1). For the first cycle of a Sunday Start regimen, an additional method of
contraception should be used until after the first 7 consecutive days of administration.
Reference ID: 3745081
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.2 How to Take ORTHO-CYCLEN or ORTHO TRI-CYCLEN
Table 1:
Instructions for Administration of ORTHO-CYCLEN or ORTHO TRI-CYCLEN
Starting COCs in women not currently using
hormonal contraception (Day 1 Start or
Sunday Start)
Important:
Consider the possibility of ovulation and
conception prior to initiation of this product.
Tablet Color:
•
ORTHO-CYCLEN active tablets are blue
(Day 1 to Day 21).
•
ORTHO TRI-CYCLEN active tablets are
white (Day 1 to Day 7), light blue (Day 8 to
Day 15) and blue (Day 16 to Day 21).
•
ORTHO-CYCLEN and ORTHO
TRI-CYCLEN both have dark green
inactive tablets (Day 22 to Day 28).
Day 1 Start:
•
Take first active tablet without regard to
meals on the first day of menses.
•
Take subsequent active tablets once daily
at the same time each day for a total of 21
days.
•
Take one dark green inactive tablet daily
for 7 days and at the same time of day that
active tablets were taken.
•
Begin each subsequent pack on the same
day of the week as the first cycle pack (i.e.,
on the day after taking the last inactive
tablet)
Sunday Start:
•
Take first active tablet without regard to
meals on the first Sunday after the onset of
menses. Due to the potential risk of
becoming pregnant, use additional non-
hormonal contraception (such as
condoms and spermicide) for the first
seven days of the patient’s first cycle
pack of ORTHO-CYCLEN or ORTHO TRI
CYCLEN.
•
Take subsequent active tablets once daily
at the same time each day for a total of
21 days.
•
Take one dark green inactive tablet daily
for the following 7 days and at the same
time of day that active tablets were taken.
•
Begin each subsequent pack on the same
day of the week as the first cycle pack (i.e.,
on the Sunday after taking the last inactive
tablet) and additional non-hormonal
contraceptive is not needed.
Switching to ORTHO-CYCLEN or ORTHO
TRI-CYCLEN from another oral
contraceptive
Start on the same day that a new pack of the
previous oral contraceptive would have started.
Switching from another contraceptive
method to ORTHO-CYCLEN or ORTHO TRI
CYCLEN
Start ORTHO-CYCLEN or ORTHO TRI
CYCLEN:
•
Transdermal patch
•
On the day when next application would
have been scheduled
•
Vaginal ring
•
On the day when next insertion would have
been scheduled
•
Injection
•
On the day when next injection would have
been scheduled
•
Intrauterine contraceptive
•
On the day of removal
•
If the IUD is not removed on first day of the
Reference ID: 3745081
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
patient’s menstrual cycle, additional non-
hormonal contraceptive (such as condoms
and spermicide) is needed for the first
seven days of the first cycle pack.
•
Implant
•
On the day of removal
Complete instructions to facilitate patient counseling on proper tablet usage are located in
the FDA-Approved Patient Labeling.
Starting ORTHO-CYCLEN or ORTHO TRI-CYCLEN after Abortion or Miscarriage
First-trimester
• After a first-trimester abortion or miscarriage, ORTHO-CYCLEN or ORTHO TRI
CYCLEN may be started immediately. An additional method of contraception is not
needed if ORTHO-CYCLEN or ORTHO TRI-CYCLEN is started immediately.
• If ORTHO-CYCLEN or ORTHO TRI-CYCLEN is not started within 5 days after
termination of the pregnancy, the patient should use additional non-hormonal
contraception (such as condoms and spermicide) for the first seven days of her first cycle
pack of ORTHO-CYCLEN or ORTHO TRI-CYCLEN.
Second-trimester
• Do not start until 4 weeks after a second-trimester abortion or miscarriage, due to the
increased risk of thromboembolic disease. Start ORTHO-CYCLEN or ORTHO TRI
CYCLEN, following the instructions in Table 1 for Day 1 or Sunday start, as desired. If
using Sunday start, use additional non-hormonal contraception (such as condoms and
spermicide) for the first seven days of the patient’s first cycle pack of ORTHO-CYCLEN
or ORTHO TRI-CYCLEN. [See Contraindications (4), Warnings and Precautions (5.1),
and FDA-Approved Patient Labeling.]
Starting ORTHO-CYCLEN or ORTHO TRI-CYCLEN after Childbirth
• Do not start until 4 weeks after delivery, due to the increased risk of thromboembolic
disease. Start contraceptive therapy with ORTHO-CYCLEN or ORTHO TRI-CYCLEN
following the instructions in Table 1 for women not currently using hormonal
contraception.
• ORTHO-CYCLEN or ORTHO TRI-CYCLEN are not recommended for use in lactating
women [see Use in Specific Populations (8.3)].
• If the woman has not yet had a period postpartum, consider the possibility of ovulation
and conception occurring prior to use of ORTHO-CYCLEN or ORTHO TRI-CYCLEN.
[See Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations
(8.1 and 8.3), and FDA-Approved Patient Labeling].
Reference ID: 3745081
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
DIALPAK® Tablet Dispenser:
SET THE DAY:
□
Day 1 Start: turn the dial on the empty DIALPAK
until the arrow points to the first day of the patient's
period.
□
Sunday Start: the arrow on the empty DIALPAK
should point to SU (Sunday). usage illustration
Insert the new refill by lining up the “V” shape on the refill
with the “V” shape at the top of the DIALPAK. Snap the
refill in place. Pill “1” is ready to be taken. Always begin
the pill cycle with pill “1,” as shown on the inner part of the
refill ring.
Remove pill “1” by pushing down on the pill. The pill will
come out through a hole in the back of the DIALPAK.
The patient should wait 24 hours to take the next pill. To
take pill “2,” turn the dial on the DIALPAK in a clockwise
direction to the next day. Continue to take one pill each
day until all the pills have been taken.
Turn the dial to the pill “1” position to remove the empty
refill and insert a new refill. The first pill in every refill will
always be taken on the same day of the week, no matter
when the patient’s next period starts.
Reference ID: 3745081
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
VERIDATE® Tablet Dispenser
• Place the refill in the VERIDATE Tablet Dispenser so that the V notch in the refill is at the
top of the dispenser. Press the refill down so that it fits firmly under all the nibs (see
illustration below).
• If the patient starts pill-taking on Sunday, the first active pill should be taken on the first
Sunday after the patient’s menstrual period begins. Remove the first active pill at the top of
the dispenser (Sunday) by pressing the pill through the hole in the bottom of the dispenser. usage illustration
ORTHO-CYCLEN:
• If the patient will start pill-taking on “Day 1,” choose a blue pill that corresponds with the
day of the week the patient will take the first pill. Remove that blue pill by pressing the pill
through the hole in the bottom of the dispenser.
ORTHO TRI-CYCLEN:
• If the patient will start pill-taking on a day other than Sunday, a calendar label has been
provided and should be placed over the calendar in the center of the VERIDATE. To place
the label correctly, identify the correct starting day, locate that day printed in blue on the
label, and line that day up with the first white pill directly under the V notch at the top of the
dispenser. Remove the label from the backing. Press the center of the label down onto the
center of the printed calendar. Remove that white pill by pressing the pill through the hole in
the bottom of the dispenser.
• After all the dark green pills have been taken, insert a new refill into the VERIDATE. The
patient should take the first pill on the next day, even if the patient’s period is not over yet.
To Insert New Refill (ORTHO-CYCLEN or ORTHO TRI-CYCLEN):
• Lift the empty refill out of the VERIDATE Tablet Dispenser.
• Insert the new refill so that the V notch in the refill is at the top of the dispenser. Press the
refill down so that it fits firmly under the nibs.
Reference ID: 3745081
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
2.3 Missed Tablets
Table 2:
Instructions for Missed ORTHO-CYCLEN or ORTHO TRI-CYCLEN Tablets
•
If one active tablet is missed in W eeks 1, 2,
or 3
Take the tablet as soon as possible. Continue
taking one tablet a day until the pack is
finished.
•
If two active tablets are missed in W eek 1
or Week 2
Take the two missed tablets as soon as
possible and the next two active tablets the
next day. Continue taking one tablet a day until
the pack is finished. Additional non-hormonal
contraception (such as condoms and
spermicide) should be used as back-up if
the patient has sex within 7 days after
missing tablets.
•
If two active tablets are missed in the third
Day 1 start: Throw out the rest of the pack and
week or three or more active tablets are
start a new pack that same day.
missed in a row in Weeks 1, 2, or 3
Sunday start: Continue taking one tablet a day
until Sunday, then throw out the rest of the
pack and start a new pack that same day.
Additional
non-hormonal
contraception
(such as condoms and spermicide) should
be used as back-up if the patient has sex
within 7 days after missing tablets.
2.4 Advice in Case of Gastrointestinal Disturbances
In case of severe vomiting or diarrhea, absorption may not be complete and additional
contraceptive measures should be taken. If vomiting or diarrhea occurs within 3 to 4 hours after
taking an active tablet, handle this as a missed tablet [see FDA-Approved Patient Labeling].
2.5 ORTHO-TRICYCLEN Use for Acne
The timing of initiation of dosing with ORTHO TRI-CYCLEN for acne should follow the
guidelines for use of ORTHO TRI-CYCLEN as an oral contraceptive. Consult the DOSAGE
AND ADMINISTRATION section (2.1) for instructions.
3
DOSAGE FORMS AND STRENGTHS
ORTHO-CYCLEN:
ORTHO-CYCLEN Tablets are available in blister cards. Each blister card contains 28 tablets in
the following order:
• 21 blue, round, biconvex, coated tablet imprinted “O 250” on one side and “35” on the other
side of the tablet contains 0.250 mg norgestimate and 0.035 mg ethinyl estradiol
• 7 dark green round, biconvex, coated tablet (non-hormonal placebo) imprinted “O-M” on one
side and “P” on the other side contains inert ingredients
Reference ID: 3745081
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ORTHO TRI-CYCLEN:
ORTHO TRI-CYCLEN Tablets are available in blister cards. Each blister card contains
28 tablets in the following order:
• 7 white, round, biconvex, coated tablet imprinted “O 180” on one side and “35” on the other
side of the tablet contains 0.180 mg norgestimate and 0.035 mg ethinyl estradiol
• 7 light blue, round, biconvex, coated tablet imprinted “O 215” on one side and “35” on the
other side of the tablet contains 0.215 mg norgestimate and 0.035 mg ethinyl estradiol
• 7 blue, round, biconvex, coated tablet imprinted “O 250” on one side and “35” on the other
side of the tablet contains 0.250 mg norgestimate and 0.035 mg ethinyl estradiol
• 7 dark green round, biconvex, coated tablet (non-hormonal placebo) imprinted “O-M” on one
side and “P” on the other side contains inert ingredients
4
CONTRAINDICATIONS
Do not prescribe ORTHO-CYCLEN or ORTHO TRI-CYCLEN to women who are known to
have the following conditions:
• A high risk of arterial or venous thrombotic diseases. Examples include women who are
known to:
o Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions (5.1)]
o Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings
and Precautions (5.1)]
o Have inherited or acquired hypercoagulopathies [see Warnings and Precautions (5.1)]
o Have cerebrovascular disease [see Warnings and Precautions (5.1)]
o Have coronary artery disease [see Warnings and Precautions (5.1)]
o Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example,
subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings
and Precautions (5.1)]
o Have uncontrolled hypertension [see Warnings and Precautions (5.3)]
o Have diabetes mellitus with vascular disease [see Warnings and Precautions (5.5)]
o Have headaches with focal neurological symptoms or migraine headaches with aura [see
Warnings and Precautions (5.6)]
•
Women over age 35 with any migraine headaches [see Warnings and
Precautions (5.6)]
• Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions (5.2)]
• Undiagnosed abnormal uterine bleeding [see Warnings and Precautions (5.7)]
• Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and
Precautions (5.8) and Use in Specific Populations (8.1)]
Reference ID: 3745081
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past
[see Warnings and Precautions (5.10)]
5 WARNINGS AND PRECAUTIONS
5.1 Thromboembolic Disorders and Other Vascular Problems
• Stop ORTHO-CYCLEN or ORTHO TRI-CYCLEN if an arterial thrombotic event or
venous thromboembolic (VTE) event occurs.
• Stop ORTHO-CYCLEN or ORTHO TRI-CYCLEN if there is unexplained loss of vision,
proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein
thrombosis immediately [see Adverse Reactions (6.2)].
• If feasible, stop ORTHO-CYCLEN or ORTHO TRI-CYCLEN at least 4 weeks before
and through 2 weeks after major surgery or other surgeries known to have an elevated
risk of VTE as well as during and following prolonged immobilization.
• Start ORTHO-CYCLEN or ORTHO TRI-CYCLEN no earlier than 4 weeks after
delivery, in women who are not breastfeeding. The risk of postpartum VTE decreases
after the third postpartum week, whereas the risk of ovulation increases after the third
postpartum week.
• The use of COCs increases the risk of VTE. However, pregnancy increases the risk of
VTE as much or more than the use of COCs. The risk of VTE in women using COCs is 3
to 9 cases per 10,000 woman-years. The risk of VTE is highest during the first year of
use of COCs and when restarting hormonal contraception after a break of 4 weeks or
longer. The risk of thromboembolic disease due to COCs gradually disappears after use is
discontinued.
• Use of COCs also increases the risk of arterial thromboses such as strokes and
myocardial infarctions, especially in women with other risk factors for these events.
COCs have been shown to increase both the relative and attributable risks of
cerebrovascular events (thrombotic and hemorrhagic strokes). This risk increases with
age, particularly in women over 35 years of age who smoke.
• Use COCs with caution in women with cardiovascular disease risk factors.
5.2 Liver Disease
Impaired Liver Function
Do not use ORTHO-CYCLEN or ORTHO TRI-CYCLEN in women with liver disease, such as
acute viral hepatitis or severe (decompensated) cirrhosis of liver [see Contraindications (4)].
Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use
until markers of liver function return to normal and COC causation has been excluded.
Discontinue ORTHO-CYCLEN or ORTHO TRI-CYCLEN if jaundice develops.
Reference ID: 3745081
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Liver Tumors
ORTHO-CYCLEN and ORTHO TRI-CYCLEN are contraindicated in women with benign and
malignant liver tumors [see Contraindications (4)]. Hepatic adenomas are associated with COC
use. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic
adenomas may cause death through intra-abdominal hemorrhage.
Studies have shown an increased risk of developing hepatocellular carcinoma in long-term
(>8 years) COC users. However, the risk of liver cancers in COC users is less than one case per
million users.
5.3 High Blood Pressure
ORTHO-CYCLEN and ORTHO TRI-CYCLEN are contraindicated in women with uncontrolled
hypertension or hypertension with vascular disease [see Contraindications (4)]. For women with
well-controlled hypertension, monitor blood pressure and stop ORTHO-CYCLEN and ORTHO
TRI-CYCLEN if blood pressure rises significantly.
An increase in blood pressure has been reported in women taking COCs, and this increase is
more likely in older women with extended duration of use. The incidence of hypertension
increases with increasing concentrations of progestin.
5.4 Gallbladder Disease
Studies suggest a small increased relative risk of developing gallbladder disease among COC
users. Use of COCs may worsen existing gallbladder disease. A past history of COC-related
cholestasis predicts an increased risk with subsequent COC use. Women with a history of
pregnancy-related cholestasis may be at an increased risk for COC related cholestasis.
5.5 Carbohydrate and Lipid Metabolic Effects
Carefully monitor prediabetic and diabetic women who take ORTHO-CYCLEN or ORTHO TRI
CYCLEN. COCs may decrease glucose tolerance.
Consider alternative contraception for women with uncontrolled dyslipidemia. A small
proportion of women will have adverse lipid changes while on COCs.
Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of
pancreatitis when using COCs.
5.6 Headache
If a woman taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN develops new headaches that
are recurrent, persistent, or severe, evaluate the cause and discontinue ORTHO-CYCLEN or
ORTHO TRI-CYCLEN if indicated.
Reference ID: 3745081
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Consider discontinuation of ORTHO-CYCLEN or ORTHO TRI-CYCLEN in the case of
increased frequency or severity of migraine during COC use (which may be prodromal of a
cerebrovascular event).
5.7 Bleeding Irregularities and Amenorrhea
Unscheduled Bleeding and Spotting
Unscheduled (breakthrough or intracyclic) bleeding and spotting sometimes occur in patients on
COCs, especially during the first three months of use. If bleeding persists or occurs after
previously regular cycles, check for causes such as pregnancy or malignancy. If pathology and
pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a
different contraceptive product.
In clinical trials of ORTHO-CYCLEN and ORTHO TRI-CYCLEN, the frequency and duration
of breakthrough bleeding and/or spotting was assessed in 1,647 patients (21,275 evaluable
cycles) and 4,826 patients (35,546 evaluable cycles), respectively. A total of 100 (7.5%) women
discontinued ORTHO-CYCLEN and 231 (4.8%) women discontinued ORTHO TRI-CYCLEN,
at least in part, due to bleeding or spotting. Based on data from the clinical trials, 14-34% of
women using ORTHO-CYCLEN experienced unscheduled bleeding per cycle in the first year;
for ORTHO TRI-CYCLEN, the respective numbers were 13-38%. The percent of women who
experienced breakthrough/unscheduled bleeding tended to decrease over time.
Amenorrhea and Oligomenorrhea
Women who use ORTHO-CYCLEN or ORTHO TRI-CYCLEN may experience amenorrhea.
Some women may experience amenorrhea or oligomenorrhea after discontinuation of COCs,
especially when such a condition was pre-existent.
If scheduled (withdrawal) bleeding does not occur, consider the possibility of pregnancy. If the
patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or
started taking them on a day later than she should have), consider the possibility of pregnancy at
the time of the first missed period and take appropriate diagnostic measures. If the patient has
adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy.
5.8 COC Use Before or During Early Pregnancy
Extensive epidemiological studies have revealed no increased risk of birth defects in women who
have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect,
particularly in so far as cardiac anomalies and limb reduction defects are concerned, when oral
contraceptives are taken inadvertently during early pregnancy. Discontinue ORTHO-CYCLEN
or ORTHO TRI-CYCLEN use if pregnancy is confirmed.
Administration of COCs to induce withdrawal bleeding should not be used as a test for
pregnancy [see Use in Specific Populations (8.1)].
Reference ID: 3745081
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.9 Depression
Carefully observe women with a history of depression and discontinue ORTHO-CYCLEN or
ORTHO TRI-CYCLEN if depression recurs to a serious degree.
5.10 Carcinoma of Breast and Cervix
• ORTHO-CYCLEN and ORTHO TRI-CYCLEN are contraindicated in women who
currently have or have had breast cancer because breast cancer may be hormonally
sensitive [see Contraindications (4)].
There is substantial evidence that COCs do not increase the incidence of breast cancer.
Although some past studies have suggested that COCs might increase the incidence of
breast cancer, more recent studies have not confirmed such findings.
• Some studies suggest that COC use has been associated with an increase in the risk of
cervical cancer or intraepithelial neoplasia. However, there continues to be controversy
about the extent to which such findings may be due to differences in sexual behavior and
other factors.
5.11 Effect on Binding Globulins
The estrogen component of COCs may raise the serum concentrations of thyroxine-binding
globulin, sex hormone-binding globulin, and cortisol-binding globulin. The dose of replacement
thyroid hormone or cortisol therapy may need to be increased.
5.12 Monitoring
A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood
pressure check and for other indicated healthcare.
5.13 Hereditary Angioedema
In women with hereditary angioedema, exogenous estrogens may induce or exacerbate
symptoms of angioedema.
5.14 Chloasma
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum.
Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation
while taking ORTHO TRI-CYCLEN or ORTHO-CYCLEN.
6 ADVERSE REACTIONS
The following serious adverse reactions with the use of COCs are discussed elsewhere in
labeling:
• Serious cardiovascular events and stroke [see Boxed Warning and Warnings and Precautions
(5.1)]
Reference ID: 3745081
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Vascular events [see Warnings and Precautions (5.1)]
• Liver disease [see Warnings and Precautions (5.2)]
Adverse reactions commonly reported by COC users are:
• Irregular uterine bleeding
• Nausea
• Breast tenderness
• Headache
6.1 Clinical Trial 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 to rates in the clinical trials
of another drug and may not reflect the rates observed in clinical practice.
ORTHO-CYCLEN
The safety of ORTHO-CYCLEN was evaluated in 1,647 healthy women of child-bearing
potential who participated in 3 clinical trials and received at least 1 dose of ORTHO-CYCLEN
for contraception. Two trials were randomized active-controlled trials and 1 was an uncontrolled
open-label trial. In all 3 trials, subjects were followed for up to 24 cycles.
Common Adverse Reactions (≥ 2% of subjects): The most common adverse reactions reported
by at least 2% of the 1,647 women were the following in order of decreasing incidence:
headache/migraine (32.9%), abdominal/gastrointestinal pain (7.8%), vaginal infection (8.4%),
genital discharge (6.8%), breast issues (including breast pain, discharge, and enlargement)
(6.3%), mood disorders (including depression and mood altered) (5.0%), flatulence (3.2%),
nervousness (2.9%), and rash (2.6%).
Adverse Reactions Leading to Study Discontinuation: Over the three trials, between 11 to 21% of
subjects discontinued the trial due to an adverse reaction. The most common adverse reactions
(≥1%) leading to discontinuation were: metrorrhagia (6.9%), nausea/vomiting (5.0%), headache
(4.1%), mood disorders (including depression and mood altered) (2.4%), premenstrual syndrome
(1.7%), hypertension (1.4%), breast pain (1.4%), nervousness (1.3%), amenorrhea (1.1%),
dysmenorrhea (1.1%), weight increased (1.1%), and flatulence (1.1%).
Serious Adverse Reactions: breast cancer (1 subject), mood disorders including depression,
irritability, and mood swings (1 subject), myocardial infarction (1 subject), and venous
thromboembolic events including pulmonary embolism (1 subject) and deep vein thrombosis
(DVT) (1 subject).
Reference ID: 3745081
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ORTHO TRI-CYCLEN
The safety of ORTHO TRI-CYCLEN was evaluated in 4,826 healthy women of child-bearing
potential who participated in 6 clinical trials and received at least 1 dose of
ORTHO TRI-CYCLEN for contraception. Two trials were randomized active-controlled trials
and 4 were uncontrolled open-label trials. In 3 trials, subjects were followed for up to 24 cycles;
in 2 trials, subjects were followed for up to 12 cycles; and in 1 trial, subjects were followed for
up to 6 cycles.
Common Adverse Reactions (≥ 2% of subjects): The most common adverse reactions reported
by at least 2% of the 4,826 women were the following in order of decreasing incidence:
headache/migraine (33.6%), breast issues (including breast pain, enlargement, and discharge)
(8.0%), vaginal infection (7.1%), abdominal/gastrointestinal pain (5.6%), mood disorders
(including mood alteration and depression) (3.8%), genital discharge (3.2%), and changes in
weight (including weight fluctuation, increased or decreased) (2.5%).
Adverse Reactions Leading to Study Discontinuation: Over the trials, between 9 to 27% of
subjects discontinued the trial due to an adverse reaction. The most common adverse reactions
(≥1%) leading to discontinuation were: metrorrhagia (4.3%), nausea/vomiting (2.8%),
headache/migraine (2.4%), mood disorders (including depression and mood altered) (1.1%), and
weight increased (1.1%).
Serious Adverse Reactions: breast cancer (1 subject), carcinoma of the cervix in situ (1 subject),
hypertension (1 subject), and migraine (2 subjects).
Reference ID: 3745081
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
6.2 Postmarketing Experience
The following additional adverse drug reactions have been reported from worldwide
postmarketing experience with norgestimate/ethinyl estradiol. 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.
Infections and Infestations: Urinary tract infection;
Neoplasms Benign, Malignant and Unspecified (Incl. Cysts and Polyps): Breast cancer, benign
breast neoplasm, hepatic adenoma, focal nodular hyperplasia, breast cyst;
Immune System Disorders: Hypersensitivity;
Metabolism and Nutrition Disorders: Dyslipidemia;
Psychiatric Disorders: Anxiety, insomnia;
Nervous System Disorders: Syncope, convulsion, paresthesia, dizziness;
Eye Disorders: Visual impairment, dry eye, contact lens intolerance;
Ear and Labyrinth Disorders: Vertigo;
Cardiac Disorders: Tachycardia, palpitations;
Vascular Events: Deep vein thrombosis, pulmonary embolism, retinal vascular thrombosis, hot
flush;
Arterial Events: Arterial thromboembolism, myocardial infarction, cerebrovascular accident;
Respiratory, Thoracic and Mediastinal Disorders: Dyspnea;
Gastrointestinal Disorders: Pancreatitis, abdominal distension, diarrhea, constipation;
Hepatobiliary Disorders: Hepatitis;
Skin and Subcutaneous Tissue Disorders: Angioedema, erythema nodosum, hirsutism, night
sweats, hyperhidrosis, photosensitivity reaction, urticaria, pruritus, acne;
Musculoskeletal, Connective Tissue, and Bone Disorders: Muscle spasms, pain in extremity,
myalgia, back pain;
Reproductive System and Breast Disorders: Ovarian cyst, suppressed lactation, vulvovaginal
dryness;
General Disorders and Administration Site Conditions: Chest pain, asthenic conditions.
Reference ID: 3745081
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7
DRUG INTERACTIONS
Consult the labeling of concurrently used drugs to obtain further information about interactions
with hormonal contraceptives or the potential for enzyme alterations.
No
drug-drug
interaction
studies
were
conducted
with
ORTHO-CYCLEN
or
ORTHO TRI-CYCLEN.
7.1 Effects of Other Drugs on Combined Oral Contraceptives
Substances decreasing the plasma concentrations of COCs:
Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4
(CYP3A4), may decrease the plasma concentrations of COCs and potentially diminish the
effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that
may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates,
carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate,
rifabutin, rufinamide, aprepitant, and products containing St. John’s wort. Interactions between
hormonal contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive
failure. Counsel women to use an alternative method of contraception or a back-up method when
enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after
discontinuing the enzyme inducer to ensure contraceptive reliability.
Colesevelam: Colesevelam, a bile acid sequestrant, given together with a COC, has been shown
to significantly decrease the AUC of EE. The drug interaction between the contraceptive and
colesevelam was decreased when the two drug products were given 4 hours apart.
Substances increasing the plasma concentrations of COCs:
Co-administration of atorvastatin or rosuvastatin and certain COCs containing ethinyl estradiol
(EE) increase AUC values for EE by approximately 20-25%. Ascorbic acid and acetaminophen
may increase plasma EE concentrations, possibly by inhibition of conjugation. CYP3A4
inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may
increase plasma hormone concentrations.
Human immunodeficiency virus (HIV)/Hepatitis C virus (HCV) protease inhibitors and
non-nucleoside reverse transcriptase inhibitors:
Significant changes (increase or decrease) in the plasma concentrations of estrogen and/or
progestin have been noted in some cases of co-administration with HIV protease inhibitors
(decrease
[e.g.,
nelfinavir,
ritonavir,
darunavir/ritonavir,
(fos)amprenavir/ritonavir,
lopinavir/ritonavir,
and
tipranavir/ritonavir]
or
increase
[e.g.,
indinavir
and
atazanavir/ritonavir])/HCV protease inhibitors (decrease [e.g., boceprevir and telaprevir]) or with
non-nucleoside reverse transcriptase inhibitors (decrease [e.g., nevirapine] or increase [e.g.,
etravirine]).
Reference ID: 3745081
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
7.2 Effects of Combined Oral Contraceptives on Other Drugs
• COCs containing EE may inhibit the metabolism of other compounds (e.g., cyclosporine,
prednisolone, theophylline, tizanidine, and voriconazole) and increase their plasma
concentrations.
• COCs have been shown to decrease plasma concentrations of acetaminophen, clofibric
acid, morphine, salicylic acid, temazepam and lamotrigine. Significant decrease in
plasma concentration of lamotrigine has been shown, likely due to induction of
lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage
adjustments of lamotrigine may be necessary.
Women on thyroid hormone replacement therapy may need increased doses of thyroid
hormone because the serum concentration of thyroid-binding globulin increases with use
of COCs.
7.3 Interference with Laboratory Tests
The use of contraceptive steroids may influence the results of certain laboratory tests, such as
coagulation factors, lipids, glucose tolerance, and binding proteins.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
There is little or no increased risk of birth defects in women who inadvertently use COCs during
early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of
genital or non-genital birth defects (including cardiac anomalies and limb reduction defects)
following exposure to low dose COCs prior to conception or during early pregnancy.
Do not administer COCs to induce withdrawal bleeding as a test for pregnancy. Do not use
COCs during pregnancy to treat threatened or habitual abortion.
8.3 Nursing Mothers
Advise the nursing mother to use other forms of contraception, when possible, until she has
weaned her child. COCs can reduce milk production in breastfeeding mothers. This is less likely
to occur once breastfeeding is well-established; however, it can occur at any time in some
women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast
milk.
8.4 Pediatric Use
Safety and efficacy of ORTHO-CYCLEN Tablets and ORTHO TRI-CYCLEN Tablets have
been established in women of reproductive age. Efficacy is expected to be the same for post
pubertal adolescents under the age of 18 and for users 18 years and older. Use of this product
before menarche is not indicated.
Reference ID: 3745081
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
There was no significant difference between ORTHO TRI-CYCLEN Tablets and placebo in
mean change in total lumbar spine (L1-L4) and total hip bone mineral density between baseline
and Cycle 13 in 123 adolescent females with anorexia nervosa in a double-blind,
placebo-controlled, multicenter, one-year treatment duration clinical trial for the Intent To Treat
(ITT) population.
8.5 Geriatric Use
ORTHO-CYCLEN and ORTHO TRI-CYCLEN have not been studied in postmenopausal
women and are not indicated in this population.
8.6 Hepatic Impairment
The pharmacokinetics of ORTHO-CYCLEN and ORTHO TRI-CYCLEN have not been studied
in subjects with hepatic impairment. However, steroid hormones may be poorly metabolized in
patients with hepatic impairment. Acute or chronic disturbances of liver function may necessitate
the discontinuation of COC use until markers of liver function return to normal and COC
causation has been excluded. [See Contraindications (4) and Warnings and Precautions (5.2).]
8.7 Renal Impairment
The pharmacokinetics of ORTHO-CYCLEN and ORTHO TRI-CYCLEN have not been studied
in women with renal impairment.
10 OVERDOSAGE
There have been no reports of serious ill effects from overdosage of oral contraceptives,
including ingestion by children. Overdosage may cause withdrawal bleeding in females and
nausea.
11 DESCRIPTION
Each of the following products is a combination oral contraceptive containing the progestational
compound norgestimate and the estrogenic compound ethinyl estradiol. Norgestimate is
designated as (18,19-Dinor-17-pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-, oxime,(17α)
(+)-) and ethinyl estradiol is designated as (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol).
ORTHO-CYCLEN
• Each active blue tablet contains 0.250 mg of norgestimate and 0.035 mg of ethinyl estradiol.
Inactive ingredients include carnauba wax, croscarmellose sodium, FD & C Blue No. 2
Aluminum Lake, hypromellose, lactose, magnesium stearate, microcrystalline cellulose,
polyethylene glycol, polysorbate 80, purified water, and titanium dioxide.
• Each dark green placebo tablet containing only inert ingredients, as follows: FD & C Blue
No. 2 Aluminum Lake, ferric oxide, lactose, magnesium stearate, polyethylene glycol,
pregelatinized corn starch, purified water, polyvinyl alcohol, talc, and titanium dioxide.
Reference ID: 3745081
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
ORTHO TRI-CYCLEN
• Each active white tablet contains 0.180 mg of norgestimate and 0.035 mg of ethinyl
estradiol. Inactive ingredients include carnauba wax, croscarmellose sodium,
hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene
glycol, purified water, and titanium dioxide.
• Each active light blue tablet contains 0.215 mg of norgestimate and 0.035 mg of ethinyl
estradiol. Inactive ingredients include carnauba wax, croscarmellose sodium, FD & C
Blue No. 2 Aluminum Lake, hypromellose, lactose, magnesium stearate, microcrystalline
cellulose, polyethylene glycol, purified water, and titanium dioxide.
• Each active blue tablet contains 0.250 mg of norgestimate and 0.035 mg of ethinyl
estradiol. Inactive ingredients include carnauba wax, croscarmellose sodium, FD & C
Blue No. 2 Aluminum Lake, hypromellose, lactose, magnesium stearate, microcrystalline
cellulose, polyethylene glycol, polysorbate 80, purified water, and titanium dioxide.
• Each dark green placebo tablet contains only inert ingredients, as follows: FD & C Blue
No. 2 Aluminum Lake, ferric oxide, lactose, magnesium stearate, polyethylene glycol,
pregelatinized corn starch, purified water, polyvinyl alcohol, talc, and titanium dioxide. structural formula
Reference ID: 3745081
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
• Oral Contraception
COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other
possible mechanisms may include cervical mucus changes that inhibit sperm penetration
and endometrial changes that reduce the likelihood of implantation.
• Acne
Acne is a skin condition with a multifactorial etiology, including androgen stimulation of
sebum production. While the combination of ethinyl estradiol and norgestimate increases
sex hormone-binding globulin (SHBG) and decreases free testosterone, the relationship
between these changes and a decrease in the severity of facial acne in otherwise healthy
women with this skin condition has not been established.
12.2 Pharmacodynamics
No specific pharmacodynamic studies were conducted with ORTHO-CYCLEN or ORTHO TRI
CYCLEN.
12.3 Pharmacokinetics
Absorption
Norgestimate (NGM) and EE are rapidly absorbed following oral administration. NGM is
rapidly and completely metabolized by first pass (intestinal and/or hepatic) mechanisms to
norelgestromin (NGMN) and norgestrel (NG), which are the major active metabolites of
norgestimate.
Peak serum concentrations of NGMN and EE are generally reached by 2 hours after
administration of ORTHO-CYCLEN or ORTHO TRI-CYCLEN. Accumulation following
multiple dosing of the 250 mcg NGM / 35 mcg EE dose is approximately 2-fold for NGMN and
EE compared with single dose administration. The pharmacokinetics of NGMN is
dose-proportional following NGM doses of 180 mcg to 250 mcg. Steady-state concentration of
EE is achieved by Day 7 of each dosing cycle. Steady-state concentrations of NGMN and NG
are achieved by Day 21. Non-linear accumulation (approximately 8 fold) of NG is observed as a
result of high-affinity binding to SHBG, which limits its biological activity (Table 3).
Reference ID: 3745081
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 3:
Summary of NGMN, NG and EE pharmacokinetic parameters.
Mean (SD) Pharmacokinetic Parameters of ORTHO TRI-CYCLEN During a Three Cycle
Study
Analyte
Cycle
Day
Cmax
tmax (h)
AUC0-24h
t1/2 (h)
NGMN
3
7
1.80 (0.46)
1.42 (0.73)
15.0 (3.88)
NC
14
2.12 (0.56)
1.21 (0.26)
16.1 (4.97)
NC
21
2.66 (0.47)
1.29 (0.26)
21.4 (3.46)
22.3 (6.54)
NG
3
7
1.94 (0.82)
3.15 (4.05)
34.8 (16.5)
NC
14
3.00 (1.04)
2.21 (2.03)
55.2 (23.5)
NC
21
3.66 (1.15)
2.58 (2.97)
69.3 (23.8)
40.2 (15.4)
EE
3
7
124 (39.5)
1.27 (0.26)
1130 (420)
NC
14
128 (38.4)
1.32 (0.25)
1130 (324)
NC
21
126 (34.7)
1.31 (0.56)
1090 (359)
15.9 (4.39)
Mean (SD) Pharmacokinetic Parameters of ORTHO-CYCLEN During a Three Cycle
Study
Analyte
Cycle
Day
Cmax
tmax (h)
AUC0-24h
t1/2 (h)
NGMN
1
1
1.78 (0.397)
1.19 (0.250)
9.90 (3.25)
18.4 (5.91)
3
21
2.19 (0.655)
1.43 (0.680)
18.1 (5.53)
24.9 (9.04)
NG
1
1
0.649 (0.49)
1.42 (0.69)
6.22 (2.46)
37.8 (14.0)
3
21
2.65 (1.11)
1.67 (1.32)
48.2 (20.5)
45.0 (20.4)
EE
1
1
92.2 (24.5)
1.2 (0.26)
629 (138)
10.1 (1.90)
3
21
147 (41.5)
1.13 (0.23)
1210 (294)
15.0 (2.36)
Cmax = peak serum concentration, tmax = time to reach peak serum concentration, AUC0-24h = area
under serum concentration vs time curve from 0 to 24 hours, t1/2 = elimination half-life, NC =
not calculated.
NGMN and NG: Cmax = ng/mL, AUC0-24h = h•ng/mL
EE: Cmax = pg/mL, AUC0-24h = h•pg/mL
Food Effect
The effect of food on the pharmacokinetics of ORTHO-CYCLEN or ORTHO TRI-CYCLEN has
not been studied.
Distribution
NGMN and NG are highly bound (>97%) to serum proteins. NGMN is bound to albumin and not
to SHBG, while NG is bound primarily to SHBG. EE is extensively bound (>97%) to serum
albumin and induces an increase in the serum concentrations of SHBG.
Metabolism
NGM is extensively metabolized by first-pass mechanisms in the gastrointestinal tract and/or
liver. NGM’s primary active metabolite is NGMN. Subsequent hepatic metabolism of NGMN
occurs and metabolites include NG, which is also active, and various hydroxylated and
conjugated metabolites. Although NGMN and its metabolites inhibit a variety of P450 enzymes
in human liver microsomes, under the recommended dosing regimen, the in vivo concentrations
of NGMN and its metabolites, even at the peak serum levels, are relatively low compared to the
inhibitory constant (Ki). EE is also metabolized to various hydroxylated products and their
glucuronide and sulfate conjugates.
Reference ID: 3745081
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Excretion
The metabolites of NGMN and EE are eliminated by renal and fecal pathways. Following
administration of 14C-norgestimate, 47% (45-49%) and 37% (16-49%) of the administered
radioactivity was eliminated in the urine and feces, respectively. Unchanged NGM was not
detected in the urine. In addition to 17-deacetyl norgestimate, a number of metabolites of NGM
have been identified in human urine following administration of radiolabeled NGM. These
include 18, 19-Dinor-17-pregn-4-en-20-yn-3-one,17-hydroxy-13-ethyl,(17α)-(-);18,19-Dinor-5β
17-pregnan-20-yn,3α,17β-dihydroxy-13-ethyl,(17α), various hydroxylated metabolites and
conjugates of these metabolites.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
[See Warnings and Precautions (5.2, 5.10) and Use in Specific Populations (8.1).]
14 CLINICAL STUDIES
14.1 Contraception
In three US clinical trials with ORTHO-CYCLEN, 1,651 women aged 18 to 38 years were
studied for up to 24 cycles, proving a total of 24,272 cycles of exposure. The racial demographic
was about 73-86% Caucasian, 8-13% African-American, 6-14% Hispanic with the remainder
Asian or Other (≤1%). There were no exclusions on the basis of weight; the weight range for
women treated was 82-303 lbs, with a mean weight of about 135 lbs. The pregnancy rate was
approximately 1 pregnancy per 100 women-years.
In four clinical trials with ORTHO TRI-CYCLEN, 4,756 women aged 15 to 41 years were
studied for 24 cycles, providing a total of 45,244 cycles of exposure. The racial demographic was
about 87-90% Caucasian, 6-10% African-American, with the remainder Asian (≤1%) or Other
(2-5%). There were no exclusions on the basis of weight; the weight range for women treated
was 80-310 lbs, with a mean weight of about 132 lbs. The pregnancy rate was approximately 1
pregnancy per 100 women-years.
14.2 Acne
ORTHO TRI-CYCLEN was evaluated for the treatment of acne vulgaris in two randomized,
double-blind, placebo-controlled, multicenter, six- (28 day) cycle studies. Two hundred twenty-
one patients received ORTHO TRI-CYCLEN and 234 patients received placebo. Mean age at
enrollment for both groups was 28 years. At the end of 6 months, the mean total lesion count
changed from 55 to 31 (42% reduction) in patients treated with ORTHO TRI-CYCLEN and from
54 to 38 (27% reduction) in patients similarly treated with placebo. Table 4 summarizes the
changes in lesion count for each type of lesion. Based on the investigator’s global assessment
conducted at the final visit, patients treated with ORTHO TRI-CYCLEN showed a statistically
significant improvement in total lesions compared to those treated with placebo.
Reference ID: 3745081
23
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 4:
Acne Vulgaris Indication. Combined Results: Two Multicenter, Placebo-Controlled Trials.
Observed Means at Six Months (LOCF)* and at Baseline. Intent-to-Treat Population.
Difference in Counts
between ORTHO TRI
ORTHO TRI-CYCLEN
Placebo
CYCLEN and Placebo at
(N=221)
(N=234)
6 Months
# of Lesions
Counts
% Reduction
Counts
% Reduction
INFLAMMATORY
LESIONS
Baseline Mean
19
19
Sixth Month Mean
10
48%
13
30%
3 (95% CI: -1.2, 5.1)
NON
INFLAMMATORY
LESIONS
Baseline Mean
36
35
Sixth Month Mean
22
34%
25
21%
3 (95% CI: -0.2, 7.8)
TOTAL LESIONS
Baseline Mean
55
54
7 (95% CI: 2.0, 11.9)
Sixth Month Mean
31
42%
38
27%
*LOCF: Last Observation Carried Forward
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
ORTHO-CYCLEN
ORTHO-CYCLEN Tablets are available in a blister card with a DIALPAK Tablet Dispenser
(unfilled): (NDC 50458-197-00)
Each blister card (28 tablets) contains in the following order:
• 21 blue, round, biconvex, coated tablet imprinted “O 250” on one side and “35” on the other
side of the tablet contains 0.250 mg norgestimate and 0.035 mg ethinyl estradiol
• 7 dark green round, biconvex, coated tablet (non-hormonal placebo) imprinted “O-M” on one
side and “P” on the other side contains inert ingredients
ORTHO-CYCLEN Tablets are packaged in a carton (NDC 50458-197-15) containing 6 blister
cards and 6 unfilled DIALPAK Tablet Dispensers.
ORTHO-CYCLEN Tablets are available for clinic usage in a VERIDATE Tablet Dispenser
(unfilled) and VERIDATE refills (NDC 50458-197-20).
ORTHO TRI-CYCLEN
ORTHO TRI-CYCLEN Tablets are available in a blister card with a DIALPAK Tablet
Dispenser (unfilled): (NDC 50458-191-00)
Each blister card (28 tablets) contains in the following order:
Reference ID: 3745081
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• 7 white, round, biconvex, coated tablet imprinted “O 180” on one side and “35” on the other
side of the tablet contains 0.180 mg norgestimate and 0.035 mg ethinyl estradiol
• 7 light blue, round, biconvex, coated tablet imprinted “O 215” on one side and “35” on the
other side of the tablet contains 0.215 mg norgestimate and 0.035 mg ethinyl estradiol
• 7 blue, round, biconvex, coated tablet imprinted “O 250” on one side and “35” on the other
side of the tablet contains 0.250 mg norgestimate and 0.035 mg ethinyl estradiol
• 7 dark green round, biconvex, coated tablet (non-hormonal placebo) imprinted “O-M” on one
side and “P” on the other side contains inert ingredients
ORTHO TRI-CYCLEN Tablets are packaged in a carton containing 6 blister cards and 6 unfilled
DIALPAK Tablet dispensers: (NDC 50458-191-15)
ORTHO TRI-CYCLEN Tablets are available for clinic usage in a VERIDATE Tablet Dispenser
(unfilled) and VERIDATE refills (NDC 50458-191-20).
Keep out of reach of children.
16.2 Storage Conditions
• Store at 20-25°C (68-77°F); excursions permitted to 15° to 30°C (59° to 86°F).
• Protect from light.
17 PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Patient Information and Instructions for Use).
Counsel patients about the following information:
• Cigarette smoking increases the risk of serious cardiovascular events from COC use, and that
women who are over 35 years old and smoke should not use COCs [see Boxed Warning].
• Increased risk of VTE compared to non-users of COCs is greatest after initially starting a
COC or restarting (following a 4-week or greater pill-free interval) the same or a different
COC [see Warnings and Precautions (5.1)].
• ORTHO-CYCLEN and ORTHO TRI-CYCLEN do not protect against HIV infection (AIDS)
and other sexually transmitted infections.
• ORTHO-CYCLEN and ORTHO TRI-CYCLEN are not to be used during pregnancy; if
pregnancy occurs during use of ORTHO-CYCLEN or ORTHO TRI-CYCLEN instruct the
patient to stop further use [see Warnings and Precautions (5.8)].
• Take one tablet daily by mouth at the same time every day. Instruct patients what to do in the
event tablets are missed [see Dosage and Administration (2.2)].
• Use a back-up or alternative method of contraception when enzyme inducers are used with
ORTHO-CYCLEN or ORTHO TRI-CYCLEN [see Drug Interactions (7.1)].
Reference ID: 3745081
25
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• COCs may reduce breast milk production; this is less likely to occur if breastfeeding is well
established [see Use in Specific Populations (8.3)].
• Women who start COCs postpartum, and who have not yet had a period, should use an
additional method of contraception until they have taken an active tablet for 7 consecutive
days [see Dosage and Administration (2.2)].
• Amenorrhea may occur. Consider pregnancy in the event of amenorrhea at the time of the
first missed period. Rule out pregnancy in the event of amenorrhea in two or more
consecutive cycles [see Warnings and Precautions (5.7)].
Mfd. by:
Janssen Ortho, LLC
Manati, Puerto Rico 00674
Mfd. for:
Janssen Pharmaceuticals, Inc.
Titusville, New Jersey 08560
© Janssen Pharmaceuticals, Inc. 1998
Revised April 2015
Reference ID: 3745081
26
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patient Information
ORTHO-CYCLEN [OR-tho sī-klin]
ORTHO TRI-CYCLEN [OR-tho trī-sī-klin]
(norgestimate and ethinyl estradiol)
Tablets
What is the most important information I should know about ORTHO
CYCLEN or ORTHO TRI-CYCLEN?
Do not use ORTHO-CYCLEN or ORTHO TRI-CYCLEN if you smoke cigarettes
and are over 35 years old. Smoking increases your risk of serious cardiovascular
side effects from hormonal birth control pills, including death from heart attack,
blood clots or stroke. This risk increases with age and the number of cigarettes you
smoke.
What is ORTHO-CYCLEN or ORTHO TRI-CYCLEN?
ORTHO-CYCLEN or ORTHO TRI-CYCLEN is a birth control pill (oral contraceptive)
used by women to prevent pregnancy.
ORTHO TRI-CYCLEN is also used to treat moderate acne vulgaris in females 15
years of age and older, who have no known history of allergies or problems taking
birth control pills, and have started their menstrual cycle (“period”). ORTHO TRI
CYCLEN should only be used to treat acne in women who want to take birth control
pills to prevent pregnancy.
How does ORTHO-CYCLEN or ORTHO TRI-CYCLEN work for contraception?
Your chance of getting pregnant depends on how well you follow the directions for
taking your birth control pills. The better you follow the directions, the less chance
you have of getting pregnant.
Based on the results of clinical studies, about 1 out of 100 women may get
pregnant during the first year they use ORTHO-CYCLEN or ORTHO TRI-CYCLEN.
The following chart shows the chance of getting pregnant for women who use
different methods of birth control. Each box on the chart contains a list of birth
control methods that are similar in effectiveness. The most effective methods are at
the top of the chart. The box on the bottom of the chart shows the chance of
getting pregnant for women who do not use birth control and are trying to get
pregnant.
Reference ID: 3745081
27
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
flow chart
Who should not take ORTHO-CYCLEN or ORTHO TRI-CYCLEN?
Do not take ORTHO-CYCLEN or ORTHO TRI-CYCLEN if you:
• smoke and are over 35 years of age
• had blood clots in your arms, legs, lungs, or eyes
• had a problem with your blood that makes it clot more than normal
• have certain heart valve problems or irregular heart beat that increases your
risk of having blood clots
• had a stroke
Reference ID: 3745081
28
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• had a heart attack
• have high blood pressure that cannot be controlled by medicine
• have diabetes with kidney, eye, nerve, or blood vessel damage
• have certain kinds of severe migraine headaches with aura, numbness,
weakness or changes in vision, or any migraine headaches if you are over 35
years of age
• have liver problems, including liver tumors
• have any unexplained vaginal bleeding
• are pregnant
• had breast cancer or any cancer that is sensitive to female hormones
If any of these conditions happen while you are taking ORTHO-CYCLEN or
ORTHO TRI-CYCLEN, stop taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN
right away and talk to your healthcare provider. Use non-hormonal
contraception when you stop taking ORTHO-CYCLEN or ORTHO TRI
CYCLEN.
What should I tell my healthcare provider before taking ORTHO-CYCLEN or
ORTHO TRI-CYCLEN?
Tell your healthcare provider if you:
• are pregnant or think you may be pregnant
• are depressed now or have been depressed in the past
• had yellowing of your skin or eyes (jaundice) caused by pregnancy
(cholestasis of pregnancy)
• are breastfeeding or plan to breastfeed. ORTHO-CYCLEN or ORTHO TRI
CYCLEN may decrease the amount of breast milk you make. A small amount
of the hormones in ORTHO-CYCLEN or ORTHO TRI-CYCLEN may pass into
your breast milk.
Talk to your healthcare provider about the best birth
control method for you while breastfeeding.
Reference ID: 3745081
29
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Tell your healthcare provider about all the medicines you take, including
prescription and over-the-counter medicines, vitamins and herbal supplements.
ORTHO-CYCLEN or ORTHO TRI-CYCLEN may affect the way other medicines work,
and other medicines may affect how well ORTHO-CYCLEN or ORTHO TRI-CYCLEN
works.
Know the medicines you take. Keep a list of them to show your healthcare provider
and pharmacist when you get a new medicine.
How should I take ORTHO-CYCLEN or ORTHO TRI-CYCLEN?
Read the Instructions for Use at the end of this Patient Information.
What are the possible serious side effects of ORTHO-CYCLEN or ORTHO
TRI-CYCLEN?
• Like pregnancy, ORTHO-CYCLEN or ORTHO TRI-CYCLEN may cause
serious side effects, including blood clots in your lungs, heart attack, or
a stroke that may lead to death. Some other examples of serious blood
clots include blood clots in the legs or eyes.
Serious blood clots can happen especially if you smoke, are obese, or are older than
35 years of age. Serious blood clots are more likely to happen when you:
• first start taking birth control pills
• restart the same or different birth control pills after not using them for a month
or more
Call your healthcare provider or go to a hospital emergency room right
away if you have:
Reference ID: 3745081
30
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
O leg pain that will not go away
O a sudden, severe headache
unlike your usual headaches
O sudden severe shortness of
breath
O weakness or numbness in your
arm or leg
O sudden change in vision or
blindness
o trouble speaking
O chest pain
Other serious side effects include:
• liver problems, including:
O rare liver tumors
O jaundice (cholestasis), especially if you previously had cholestasis of
pregnancy. Call your healthcare provider if you have yellowing of your skin or
eyes.
• high blood pressure. You should see your healthcare provider for a yearly
check of your blood pressure.
• gallbladder problems
• changes in the sugar and fat (cholesterol and triglycerides) levels in
your blood
• new or worsening headaches including migraine headaches
• irregular or unusual vaginal bleeding and spotting between your
menstrual periods, especially during the first 3 months of taking
ORTHO-CYCLEN or ORTHO TRI-CYCLEN.
• depression
• possible cancer in your breast and cervix
• swelling of your skin especially around your mouth, eyes, and in your
throat (angioedema). Call your healthcare provider if you have a swollen face,
lips, mouth tongue or throat, which may lead to difficulty swallowing or
breathing. Your chance of having angioedema is higher is you have a history of
angioedema.
• dark patches of skin around your forehead, nose, cheeks and around
your mouth, especially during pregnancy (chloasma). Women who tend to
get chloasma should avoid spending a long time in sunlight, tanning booths, and
Reference ID: 3745081
31
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
under sun lamps while taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN. Use
sunscreen if you have to be in the sunlight.
What are the most common side effects of ORTHO-CYCLEN or ORTHO TRI
CYCLEN?
• headache (migraine)
• breast pain or tenderness,
enlargement or discharge
• stomach pain, discomfort, and
gas
• vaginal infections and discharge
• mood changes, including
depression
• nervousness
• changes in weight
• skin rash
Reference ID: 3745081
32
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 ORTHO-CYCLEN or
ORTHO TRI-CYCLEN. For more information, ask your healthcare provider or
pharmacist.
You may report side effects to the FDA at 1-800-FDA-1088.
What else should I know about taking ORTHO-CYCLEN or ORTHO
TRI-CYCLEN?
• If you are scheduled for any lab tests, tell your healthcare provider
you are taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN. Certain blood
tests may be affected by ORTHO-CYCLEN or ORTHO TRI-CYCLEN.
• ORTHO-CYCLEN or ORTHO TRI-CYCLEN does not protect against HIV
infection (AIDS) and other sexually transmitted infections.
How should I store ORTHO-CYCLEN or ORTHO TRI-CYCLEN?
• Store ORTHO-CYCLEN or ORTHO TRI-CYCLEN at room temperature
between 68°F to 77°F (20°C to 25°C).
• Keep ORTHO-CYCLEN or ORTHO TRI-CYCLEN and all medicines out of
the reach of children.
• Store away from light.
General information about the safe and effective use of ORTHO
CYCLEN or ORTHO TRI-CYCLEN.
Medicines are sometimes prescribed for purposes other than those listed in a
Patient Information leaflet. Do not use ORTHO-CYCLEN or ORTHO
TRI-CYCLEN for a condition for which it was not prescribed. Do not give
ORTHO-CYCLEN or ORTHO TRI-CYCLEN to other people, even if they have
the same symptoms that you have.
This Patient Information summarizes the most important information about
ORTHO-CYCLEN or ORTHO TRI-CYCLEN. You can ask your pharmacist or
healthcare provider for information about ORTHO-CYCLEN or ORTHO
TRI-CYCLEN that is written for health professionals.
For more information, call 1-800-JANSSEN (1-800-526-7736).
Do birth control pills cause cancer?
Birth control pills do not seem to cause breast cancer. However, if you have
breast cancer now, or have had it in the past, do not use birth control pills
Reference ID: 3745081
33
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
because some breast cancers are sensitive to hormones.
Women who use birth control pills may have a slightly higher chance of
getting cervical cancer. However, this may be due to other reasons such as
having more sexual partners.
What if I want to become pregnant?
You may stop taking the pill whenever you wish. Consider a visit with your
healthcare provider for a pre-pregnancy checkup before you stop taking the
pill.
What should I know about my period when taking ORTHO-CYCLEN or
ORTHO TRI-CYCLEN?
Your periods may be lighter and shorter than usual. Some women may miss
a period. Irregular vaginal bleeding or spotting may happen while you are
taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN, especially during the first few
months of use. This usually is not a serious problem. It is important to
continue taking your pills on a regular schedule to prevent a pregnancy.
What are the ingredients in ORTHO-CYCLEN or ORTHO TRI-CYCLEN?
ORTHO-CYCLEN:
Active ingredients: Each blue pill contains norgestimate and ethinyl
estradiol.
Inactive ingredients:
Blue pills: carnauba wax, croscarmellose sodium, FD & C Blue No. 2
Aluminum Lake, hypromellose, lactose, magnesium stearate, microcrystalline
cellulose, polyethylene glycol, polysorbate 80, purified water, and titanium
dioxide.
Dark-green pills: FD & C Blue No. 2 Aluminum Lake, ferric oxide, lactose,
magnesium stearate, polyethylene glycol, pregelatinized corn starch, purified
water, polyvinyl alcohol, talc, and titanium dioxide.
ORTHO TRI-CYCLEN:
Active ingredients: Each white, light-blue, and blue pill contains
norgestimate and ethinyl estradiol.
Inactive ingredients:
Reference ID: 3745081
34
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
White pills: carnauba wax, croscarmellose sodium, hypromellose, lactose,
magnesium stearate, microcrystalline cellulose, polyethylene glycol, purified
water, and titanium dioxide.
Light-blue pills: carnauba wax, croscarmellose sodium, FD & C Blue No. 2
Aluminum Lake, hypromellose, lactose, magnesium stearate, microcrystalline
cellulose, polyethylene glycol, purified water, and titanium dioxide.
Blue pills: carnauba wax, croscarmellose sodium, FD & C Blue No. 2
Aluminum Lake, hypromellose, lactose, magnesium stearate, microcrystalline
cellulose, polyethylene glycol, polysorbate 80, purified water, and titanium
dioxide.
Dark-green pills: FD & C Blue No. 2 Aluminum Lake, ferric oxide, lactose,
magnesium stearate, polyethylene glycol, pregelatinized corn starch, purified
water, polyvinyl alcohol, talc, and titanium dioxide.
Reference ID: 3745081
35
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Instructions For Use
ORTHO-CYCLEN [OR-tho sī-klin]
ORTHO TRI-CYCLEN [OR-tho trī-sī-klin]
(norgestimate and ethinyl estradiol)
Tablets
Important Information about taking ORTHO-CYCLEN or
ORTHO TRI-CYCLEN
• Take 1 pill every day at the same time. Take the pills in the order directed
on your pill dispenser.
• Do not skip your pills, even if you do not have sex often. If you miss pills
(including starting the pack late) you could get pregnant. The more
pills you miss, the more likely you are to get pregnant.
• If you have trouble remembering to take ORTHO-CYCLEN or
ORTHO TRI-CYCLEN, talk to your healthcare provider. When you first start
taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN, spotting or light bleeding
in between your periods may occur. Contact your healthcare provider if
this does not go away after a few months.
• You may feel sick to your stomach (nauseous), especially during the first
few months of taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN. If you feel
sick to your stomach, do not stop taking the pill. The problem will usually
go away. If your nausea does not go away, call your healthcare provider.
• Missing pills can also cause spotting or light bleeding, even when you take
the missed pills later. On the days you take 2 pills to make up for missed
pills (see What should I do if I miss any ORTHO-CYCLEN or ORTHO
TRI-CYCLEN pills? below), you could also feel a little sick to your
stomach.
• It is not uncommon to miss a period. However, if you miss a period and
have not taken ORTHO-CYCLEN or ORTHO TRI-CYCLEN according to
directions, or miss 2 periods in a row, or feel like you may be pregnant,
call your healthcare provider. If you have a positive pregnancy test, you
should stop taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN.
• If you have vomiting or diarrhea within 3-4 hours of taking your pill, take
another pill of the same color from your extra pill dispenser. If you do not
Reference ID: 3745081
36
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
have an extra pill dispenser, take the next pill in your pill dispenser.
Continue taking all your remaining pills in order. Start the first pill of your
next pill dispenser the day after finishing your current pill dispenser. This
will be 1 day earlier than originally scheduled. Continue on your new
schedule.
• If you have vomiting or diarrhea for more than 1 day, your birth control
pills may not work as well. Use an additional birth control method, like
condoms and a spermicide, until you check with your healthcare provider.
• Stop taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN at least 4 weeks
before you have major surgery and do not restart after the surgery
without asking your healthcare provider. Be sure to use other forms of
contraception (like condoms and spermicide) during this time period.
Before you start taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN:
• Decide what time of day you want to take your pill. It is important to take
it at the same time every day and in the order as directed on your pill
dispenser.
• Have backup contraception (condoms and spermicide) available and if
possible, an extra full pack of pills as needed.
When should I start taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN?
If you start taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN and you
have not used a hormonal birth control method before:
• There are 2 ways to start taking your birth control pills. You can either
start on a Sunday (Sunday Start) or on the first day (Day 1) of your
natural menstrual period (Day 1 Start). Your healthcare provider should
tell you when to start taking your birth control pill.
• If you use the Sunday Start, use non-hormonal back-up contraception
such as condoms and spermicide for the first 7 days that you take
ORTHO-CYCLEN or ORTHO TRI-CYCLEN. You do not need back-up
contraception if you use the Day 1 Start.
If you start taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN and you
are switching from another birth control pill:
• Start your new ORTHO-CYCLEN or ORTHO TRI-CYCLEN pack on the same
day that you would start the next pack of your previous birth control
method.
Reference ID: 3745081
37
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
• Do not continue taking the pills from your previous birth control pack.
If you start taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN and
previously used a vaginal ring or transdermal patch:
• Start using ORTHO-CYCLEN or ORTHO TRI-CYCLEN on the day you would
have reapplied the next ring or patch.
If you start taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN and you
are switching from a progestin-only method such as an implant or
injection:
• Start taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN on the day of
removal of your implant or on the day when you would have had your
next injection.
If you start taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN and you
are switching from an intrauterine device or system (IUD or IUS):
• Start taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN on the day of
removal of your IUD or IUS.
• You do not need back-up contraception if your IUD or IUS is removed on
the first day (Day 1) of your period. If your IUD or IUS is removed on
any other day, use non-hormonal back-up contraception such as condoms
and spermicide for the first 7 days that you take ORTHO-CYCLEN or
ORTHO TRI-CYCLEN.
Keep a calendar to track your period:
If this is the first time you are taking birth control pills, read, “When
should I start taking ORTHO-CYCLEN or ORTHO TRI-CYCLEN?” above.
Follow these instructions for either a Sunday Start or a Day 1 Start.
Sunday Start:
You will use a Sunday Start if your healthcare provider told you to take your
first pill on a Sunday.
• Take pill 1 on the Sunday after your period starts.
• If your period starts on a Sunday, take pill “1” that day and refer to Day 1
Start instructions below.
• Take 1 pill every day in the order on the pill dispenser at the same time
each day for 28 days.
• After taking the last pill on Day 28 from the pill dispenser, start taking
the first pill from a new pack, on the same day of the week as the first
pack (Sunday). Take the first pill in the new pack whether or not you are
having your period.
• Use non-hormonal back-up contraception such as condoms and
Reference ID: 3745081
38
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
spermicide for the first 7 days of the first cycle that you take ORTHO
CYCLEN or ORTHO TRI-CYCLEN.
Day 1 Start:
You will use a Day 1 Start if your doctor told you to take your first pill (Day
1) on the first day of your period.
• Take 1 pill every day in the order of the pill dispenser dial pack, at the
same time each day, for 28 days.
• After taking the last pill on Day 28 from the pill dispenser, start taking
the first pill from a new pack, on the same day of the week as the first
pack. Take the first pill in the new pack whether or not you are having
your period.
ORTHO-CYCLEN or ORTHO TRI-CYCLEN comes in either a DIALPAK
pill dispenser or a VERIDATE pill dispenser. Read the instructions
below for using your DIALPAK pill dispenser or your VERIDATE pill
dispenser.
Instructions for using your DIALPAK pill dispenser:
• Each DIALPAK pill dispenser has 28
pills.
o ORTHO-CYCLEN
•
21 blue pills with hormones,
for Days 1 to 21.
•
7 dark green pills (without
hormones), for Days 22 to
28.
usage illustration
Reference ID: 3745081
39
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
usage illustration
ORTHO TRI-CYCLEN
o ORTHO TRI-CYCLEN
•
7 white pills with hormone, for
Days 1 to 7
•
7 light-blue pills with hormone,
for Days 8 to 14
•
7 blue pills with hormones, for
Days 15 to 21
•
7 dark green pills (without
hormones), for Days 22 to
28. usage illustration
Figure A usage illustration
Figure B usage illustration
Figure C
Step 1. SET THE DAY on your DIALPAK
Sunday Start: The arrow on your empty
DIALPAK should point to SU (Sunday).
Day 1 Start: Turn the dial on your empty
DIALPAK in a clockwise direction until the
arrow points to the first day of your period (if
your period starts on Tuesday, the arrow will
point to TU). See Figure A.
Step 2. Insert the new refill by lining up
the “V” shape on the refill with the “V”
shape at the top of your DIALPAK.
Press the refill down so that it fits firmly. See
Figure B. Snap the refill in place. You are
ready to take pill “1”. You should always begin
your pill cycle with pill “1”, as shown on the
inner part of the refill ring.
Step 3. Remove pill “1” by pushing down
on the pill. The pill will come out through a
hole in the back of the DIALPAK. See Figure
C.
Step 4. Swallow the pill. You will take 1 pill
every day, at the same time each day.
Reference ID: 3745081
40
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
usage illustration
Figure D usage illustration
Figure E usage illustration
Step 5. Wait 24 hours to take your next
pill.
To take pill “2,” turn the dial on your DIALPAK
in a clockwise direction to the next day. See
Figure D. Continue to take 1 pill each day
until all the pills have been taken.
Step 6. Take your pill at the same time
every day. It is important to take the correct
pill each day and not miss any pills.
To help you remember, take your pill at the
same time as another daily activity, like
turning off your alarm clock or brushing your
teeth.
Step 7. Remove your empty pack. See
Figure E. You will start a new refill on the first
day after pill “28”. Turn the dial to the pill “1”
position to remove the empty refill pack.
When your refill is empty, keep your
DIALPAK case.
Step 8. Insert a new refill pack. See
Figure F. Insert a new refill pack. Remember
to take your first pill in every refill on the same
day of the week, no matter when your next
period starts.
Figure F
Reference ID: 3745081
41
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Instructions for using your VERIDATE pill dispenser:
• Each VERIDATE pill dispenser has 28 pills. See Figure A.
ORTHO-CYCLEN
o 21 blue pills with hormones, for Days 1 to 21
o 7 dark green pills (without hormones), for Days 22 to 28
ORTHO TRI-CYCLEN
o 7 white pills with hormone, for Days 1 to 7
o 7 light-blue pills with hormone, for Days 8 to 14
o 7 blue pills with hormones, for Days 15 to 21
o 7 dark green pills (without hormones), for Days 22 to 28 usage illustrationusage illustration
Figure B
Figure A
Step 1. Place the refill in the VERIDATE Pill
Dispenser so that the “V” notch in the refill is
at the top of the dispenser. Press the refill
down so that it fits firmly under all the nibs.
See Figure B.
Reference ID: 3745081
42
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
usage illustration
Figure C
Step 2. Starting your pills.
Sunday Start: Remove the first pill at the top
of the dispenser (Sunday) by pressing the pill
through the hole in the bottom of the
dispenser. See Figure C.
• If your healthcare provider tells you to start
taking your pill on Sunday, take your first
pill on the first Sunday after your period
begins.
• If your period begins on Sunday, take your
first pill that day. usage illustration
Figure D
Day 1 Start:
If you take ORTHO-CYCLEN:
• If your healthcare provider tells you to start
taking your pill on “Day 1,” choose a blue
pill that corresponds with the day of the
week on which you are taking the first pill.
• Remove that blue pill by pressing the pill
through the hole in the bottom of the
dispenser. See Figure D. usage illustration
Figure E
If you take ORTHO TRI-CYCLEN:
• If your healthcare provider tells you to start
taking your pill on a day other than Sunday,
you will need the calendar label found in
your pill package and place it over the
calendar in the center of the VERIDATE.
See Figure E.
• To correctly place the calendar label on the
VERIDATE:
o find your correct starting day
o find that day printed in blue on the label
o line your blue starting day up with the
Reference ID: 3745081
43
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
usage illustration
Figure F
first white pill which is directly under the
V notch at the top of the dispenser.
• Remove the label from the backing. Press
the center of the label down onto the center
of the printed calendar.
• Remove that white pill by pressing the pill
through the hole in the bottom of the
dispenser. See Figure F. usage illustration
Figure G
Step 3. Continue taking 1 pill every day
from the VERIDATE in a clockwise
direction until no pills remain in the outer
ring. See Figure G.
Reference ID: 3745081
44
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
usage illustration
Figure H
Step 4. The next day take a dark green pill
from the inner ring. See Figure H.
• Continue to take a dark green pill each day
until all 7 pills are taken.
• During this time your period should begin. usage illustration
Figure I
Step 5. Insert a new refill:
• After you have taken all the dark green
pills, insert a new refill into the VERIDATE
and take the first pill on the next day, even
if your period is not yet over.
• Lift the empty refill out of the VERIDATE Pill
Dispenser. See Figure I.
• Follow the instructions in Step 1 to replace
the new refill.
What should I do if I miss any ORTHO-CYCLEN or ORTHO TRI-CYCLEN
pills?
If you miss 1 pill in Weeks 1, 2, or 3, follow these steps:
• Take it as soon as you remember. Take the next pill at your regular time.
This means you may take 2 pills in 1 day.
• Then continue taking 1 pill every day until you finish the pack.
• You do not need to use a back-up birth control method if you have sex.
Reference ID: 3745081
45
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
If you miss 2 pills in Week 1 or Week 2 of your pack, follow these
steps:
• Take the 2 missed pills as soon as possible and the next 2 pills the
next day.
• Then continue to take 1 pill every day until you finish the pack.
• Use a non-hormonal birth control method (such as a condom and
spermicide) as a back-up if you have sex during the first 7 days
after missing your pills.
If you miss 2 pills in a row in Week 3, or you miss 3 or more pills in a
row during Weeks 1, 2, or 3 of the pack, follow these steps:
• If you are a Day 1 Starter:
o Throw out the rest of the pill pack and start a new pack that
same day.
o You may not have your period this month but this is expected.
However, if you miss your period 2 months in a row, call your
healthcare provider because you might be pregnant.
o You could become pregnant if you have sex during the first 7
days after you restart your pills. You MUST use a non-hormonal
birth control method (such as a condom and spermicide) as a
back-up if you have sex during the first 7 days after you restart
your pills.
• If you are a Sunday Starter:
o Keep taking 1 pill every day until Sunday. On Sunday, throw out
the rest of the pack and start a new pack of pills that same day.
o Use a non-hormonal birth control method (such as a condom
and spermicide) as a back-up if you have sex during the first 7
days after you restart your pills.
If you have any questions or are unsure about the information in this
leaflet, call your healthcare provider.
Mfd. by:
Janssen Ortho, LLC
Manati, Puerto Rico 00674
Reference ID: 3745081
46
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Mfd. for:
Janssen Pharmaceuticals, Inc.
Titusville, New Jersey 08560
© Janssen Pharmaceuticals, Inc. 1998
This Patient Information and Instructions for Use has been approved by the
U.S. Food and Drug Administration.
Revised April 2015
Reference ID: 3745081
47
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:38.802410
|
{'url': 'https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019653s056,019697s052,021690s001lbl.pdf', 'application_number': 19653, 'submission_type': 'SUPPL ', 'submission_number': 56}
|
11,607
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
RETROVIR safely and effectively. See full prescribing information for
RETROVIR.
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup
Initial U.S. Approval: 1987
WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY,
LACTIC ACIDOSIS.
See full prescribing information for complete boxed warning.
• Hematologic toxicity including neutropenia and severe anemia have
been associated with the use of zidovudine. (5.1)
• Symptomatic myopathy associated with prolonged use of zidovudine.
(5.2)
• Lactic acidosis and severe hepatomegaly with steatosis, including fatal
cases, have been reported with the use of nucleoside analogues
including RETROVIR. Suspend treatment if clinical or laboratory
findings suggestive of lactic acidosis or pronounced hepatotoxicity
occur. (5.3)
---------------------------RECENT MAJOR CHANGES -------------------
Dosage and Administration, Pediatric Patients (2.1)
September 2008
----------------------------INDICATIONS AND USAGE--------------------
RETROVIR is a nucleoside analogue reverse transcriptase inhibitor indicated for:
• Treatment of Human Immunodeficiency Virus (HIV-1) infection in
combination with other antiretroviral agents. (1.1)
• Prevention of maternal-fetal HIV-1 transmission. (1.2)
----------------------- DOSAGE AND ADMINISTRATION ---------------
• Treatment of HIV-1 infection:
Adults: 600 mg/day in divided doses with other antiretroviral agents.
Pediatric patients (6 weeks to <18 years of age): Dosage should be
calculated based on body weight not to exceed adult dose. (2.1)
• Prevention of maternal-fetal HIV-1 transmission:
Specific dosage instructions for mother and infant. (2.2)
• Patients with severe anemia and/or neutropenia:
Dosage interruption may be necessary. (2.3)
• Renal Impairment – Recommended dosage in hemodialysis or peritoneal
dialysis patients is 100 mg every 6 to 8 hours. (2.4)
---------------------DOSAGE FORMS AND STRENGTHS -------------
Tablets: 300 mg (3)
Capsules: 100 mg (3)
Syrup: 50 mg/5 mL (3)
-------------------------------CONTRAINDICATIONS-----------------------
Hypersensitivity to zidovudine (e.g., anaphylaxis, Stevens-Johnson
syndrome). (4)
----------------------- WARNINGS AND PRECAUTIONS ---------------
• Hematologic toxicity/bone marrow suppression including neutropenia and
severe anemia have been associated with the use of zidovudine. (5.1)
• Symptomatic myopathy associated with prolonged use of zidovudine. (5.2)
• Lactic acidosis and severe hepatomegaly with steatosis, including fatal
cases, have been reported with the use of nucleoside analogues including
RETROVIR. Suspend treatment if clinical or laboratory findings
suggestive of lactic acidosis or pronounced hepatotoxicity occur. (5.3)
• Exacerbation of anemia has been reported in HIV-1/HCV co-infected
patients receiving ribavirin and zidovudine. Coadministration of ribavirin
and zidovudine is not advised. (5.4)
• Hepatic decompensation, (some fatal), has occurred in HIV-1/HCV
co-infected patients receiving combination antiretroviral therapy and
interferon alfa with/without ribavirin. Discontinue zidovudine as medically
appropriate and consider dose reduction or discontinuation of interferon
alfa, ribavirin, or both. (5.4)
• RETROVIR should not be administered with other zidovudine-containing
combination products. (5.5)
• Immune reconstitution syndrome (5.6) and redistribution/accumulation of
body fat (5.7) have been reported in patients treated with combination
antiretroviral therapy.
------------------------------ ADVERSE REACTIONS ----------------------
• The most commonly reported adverse reactions (incidence ≥15%) in adult
HIV-1 clinical studies were headache, malaise, nausea, anorexia, and
vomiting. (6.1)
• The most commonly reported adverse reactions (incidence ≥15%) in
pediatric HIV-1 clinical studies were fever, cough, and digestive disorders.
(6.1)
• The most commonly reported adverse reactions in neonates (incidence
≥15%) in the prevention of maternal-fetal transmission of HIV-1 clinical
trial were anemia and neutropenia. (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-----------------------
• Stavudine: Concomitant use with zidovudine should be avoided. (7.1)
• Doxorubicin: Use with zidovudine should be avoided. (7.2)
• Bone marrow suppressive/cytotoxic agents: May increase the hematologic
toxicity of zidovudine. (7.3)
----------------------- USE IN SPECIFIC POPULATIONS ---------------
Pregnancy: Physicians are encouraged to register patients in the Antiretroviral
Pregnancy Registry by calling 1-800-258-4263. (8.1)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: September 2008
Version No.
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY,
LACTIC ACIDOSIS
1
INDICATIONS AND USAGE
1.1
Treatment of HIV-1
1.2
Prevention of Maternal-Fetal HIV-1 Transmission
2
DOSAGE AND ADMINISTRATION
2.1
Treatment of HIV-1 Infection
2.2
Prevention of Maternal-Fetal HIV-1 Transmission
2.3
Patients With Severe Anemia and/or Neutropenia
2.4
Patients With Renal Impairment:
2.5
Patients With Hepatic Impairment:
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Hematologic Toxicity/Bone Marrow Suppression
5.2
Myopathy
5.3
Lactic Acidosis/Severe Hepatomegaly With Steatosis
5.4
Use With Interferon- and Ribavirin-Based Regimens in
HIV-1/HCV Co-Infected Patients
5.5
Use With Other Zidovudine-Containing Products
5.6
Immune Reconstitution Syndrome
5.7
Fat Redistribution
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Antiretroviral Agents
7.2
Doxorubicin
7.3
Hematologic/Bone Marrow Suppressive/Cytotoxic
Agents
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
8.7
Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Reproductive and Developmental Toxicology Studies
14 CLINICAL STUDIES
14.1 Adults
14.2 Pediatric Patients
14.3 Prevention of Maternal-Fetal HIV-1 Transmission
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16 HOW SUPPLIED/STORAGE AND HANDLING
17.1 Information About Therapy With RETROVIR
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not listed.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1
______________________________________________________________________
2
FULL PRESCRIBING INFORMATION
3
WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY, LACTIC
4
ACIDOSIS
5
RETROVIR (zidovudine) has been associated with hematologic toxicity including
6
neutropenia and severe anemia, particularly in patients with advanced HIV-1 disease [see
7
Warnings and Precautions (5.1)].
8
Prolonged use of RETROVIR has been associated with symptomatic myopathy [see
9
Warnings and Precautions (5.2)].
10
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have
11
been reported with the use of nucleoside analogues alone or in combination, including
12
RETROVIR and other antiretrovirals. Suspend treatment if clinical or laboratory findings
13
suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and
14
Precautions (5.3)].
15
1
INDICATIONS AND USAGE
16
1.1
Treatment of HIV-1
17
RETROVIR, a nucleoside reverse transcriptase inhibitor, is indicated in combination with
18
other antiretroviral agents for the treatment of HIV-1 infection.
19
1.2
Prevention of Maternal-Fetal HIV-1 Transmission
20
RETROVIR is indicated for the prevention of maternal-fetal HIV-1 transmission [see
21
Dosage and Administration (2.2)]. The indication is based on a dosing regimen that included
22
3 components:
23
1.
antepartum therapy of HIV-1 infected mothers
24
2.
intrapartum therapy of HIV-1 infected mothers
25
3.
post-partum therapy of HIV-1 exposed neonate.
26
Points to consider prior to initiating RETROVIR in pregnant women for the prevention of
27
maternal-fetal HIV-1 transmission include:
28
• In most cases, RETROVIR for prevention of maternal-fetal HIV-1 transmission should be
29
given in combination with other antiretroviral drugs.
30
• Prevention of HIV-1 transmission in women who have received RETROVIR for a
31
prolonged period before pregnancy has not been evaluated.
32
• Because the fetus is most susceptible to the potential teratogenic effects of drugs during the
33
first 10 weeks of gestation and the risks of therapy with RETROVIR during that period are
34
not fully known, women in the first trimester of pregnancy who do not require immediate
35
initiation of antiretroviral therapy for their own health may consider delaying use; this
36
indication is based on use after 14 weeks gestation.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
37
2
DOSAGE AND ADMINISTRATION
38
2.1
Treatment of HIV-1 Infection
39
Adults: The recommended oral dose of RETROVIR is 600 mg/day in divided doses in
40
combination with other antiretroviral agents.
41
Pediatric Patients (6 weeks to <18 years of age): Healthcare professionals should
42
pay special attention to accurate calculation of the dose of RETROVIR, transcription of the
43
medication order, dispensing information, and dosing instructions to minimize risk for
44
medication dosing errors.
45
Prescribers should calculate the appropriate dose of RETROVIR for each child based on
46
body weight (kg) and should not exceed the recommended adult dose.
47
Before prescribing RETROVIR capsules or tablets, children should be assessed for the
48
ability to swallow capsules or tablets. If a child is unable to reliably swallow a RETROVIR
49
capsule or tablet, the RETROVIR syrup formulation should be prescribed.
50
The recommended dosage in pediatric patients 6 weeks of age and older and weighing
51
≥4 kg is provided in Table 1. RETROVIR Syrup should be used to provide accurate dosage
52
when whole tablets or capsules are not appropriate.
53
54
Table 1: Recommended Pediatric Dosage of RETROVIR
Body
Weight
(kg)
Total Daily
Dose
Dosage Regimen and Dose
b.i.d.
t.i.d.
4 to <9
24 mg/kg/day
12 mg/kg
8 mg/kg
≥9 to <30
18 mg/kg/day
9 mg/kg
6 mg/kg
≥30
600 mg/day
300 mg
200 mg
55
56
Alternatively, dosing for RETROVIR can be based on body surface area (BSA) for each
57
child. The recommended oral dose of RETROVIR is 480 mg/m2/day in divided doses
58
(240 mg/m2 twice daily or 160 mg/m2 three times daily). In some cases the dose calculated by
59
mg/kg will not be the same as that calculated by BSA.
60
2.2
Prevention of Maternal-Fetal HIV-1 Transmission
61
The recommended dosage regimen for administration to pregnant women (>14 weeks of
62
pregnancy) and their neonates is:
63
Maternal Dosing: 100 mg orally 5 times per day until the start of labor [see Clinical
64
Studies (14.3)]. During labor and delivery, intravenous RETROVIR should be administered at
65
2 mg/kg (total body weight) over 1 hour followed by a continuous intravenous infusion of
66
1 mg/kg/hour (total body weight) until clamping of the umbilical cord.
67
Neonatal Dosing: 2 mg/kg orally every 6 hours starting within 12 hours after birth and
68
continuing through 6 weeks of age. Neonates unable to receive oral dosing may be administered
69
RETROVIR intravenously at 1.5 mg/kg, infused over 30 minutes, every 6 hours.
70
2.3
Patients With Severe Anemia and/or Neutropenia
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
71
Significant anemia (hemoglobin <7.5 g/dL or reduction >25% of baseline) and/or
72
significant neutropenia (granulocyte count <750 cells/mm3 or reduction >50% from baseline)
73
may require a dose interruption until evidence of marrow recovery is observed [see Warnings
74
and Precautions (5.1)]. In patients who develop significant anemia, dose interruption does not
75
necessarily eliminate the need for transfusion. If marrow recovery occurs following dose
76
interruption, resumption in dose may be appropriate using adjunctive measures such as epoetin
77
alfa at recommended doses, depending on hematologic indices such as serum erythropoetin level
78
and patient tolerance.
79
2.4
Patients With Renal Impairment:
80
End-Stage Renal Disease: In patients maintained on hemodialysis or peritoneal
81
dialysis, the recommended dosage is 100 mg every 6 to 8 hours [see Clinical Pharmacology
82
(12.3)].
83
2.5
Patients With Hepatic Impairment:
84
There are insufficient data to recommend dose adjustment of RETROVIR in patients with
85
mild to moderate impaired hepatic function or liver cirrhosis.
86
3
DOSAGE FORMS AND STRENGTHS
87
RETROVIR Tablets 300 mg (biconvex, white, round, film-coated) containing 300 mg
88
zidovudine, one side engraved “GX CW3” and “300” on the other side.
89
RETROVIR Capsules 100 mg (white, opaque cap and body) containing 100 mg
90
zidovudine and printed with “Wellcome” and unicorn logo on cap and “Y9C” and “100” on
91
body.
92
RETROVIR Syrup (colorless to pale yellow, strawberry-flavored) containing 50 mg
93
zidovudine in each teaspoonful (5 mL).
94
4
CONTRAINDICATIONS
95
RETROVIR Tablets, Capsules, and Syrup are contraindicated in patients who have had
96
potentially life-threatening allergic reactions (e.g., anaphylaxis, Stevens-Johnson syndrome) to
97
any of the components of the formulations.
98
5
WARNINGS AND PRECAUTIONS
99
5.1
Hematologic Toxicity/Bone Marrow Suppression
100
RETROVIR should be used with caution in patients who have bone marrow compromise
101
evidenced by granulocyte count <1,000 cells/mm3 or hemoglobin <9.5 g/dL. Hematologic
102
toxicities appear to be related to pretreatment bone marrow reserve and to dose and duration of
103
therapy. In patients with advanced symptomatic HIV-1 disease, anemia and neutropenia were the
104
most significant adverse events observed. In patients who experience hematologic toxicity, a
105
reduction in hemoglobin may occur as early as 2 to 4 weeks, and neutropenia usually occurs after
106
6 to 8 weeks. There have been reports of pancytopenia associated with the use of RETROVIR,
107
which was reversible in most instances after discontinuance of the drug. However, significant
108
anemia, in many cases requiring dose adjustment, discontinuation of RETROVIR, and/or blood
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
109
transfusions, has occurred during treatment with RETROVIR alone or in combination with other
110
antiretrovirals.
111
Frequent blood counts are strongly recommended to detect severe anemia or neutropenia
112
in patients with poor bone marrow reserve, particularly in patients with advanced HIV-1 disease
113
who are treated with RETROVIR. For HIV-1-infected individuals and patients with
114
asymptomatic or early HIV-1 disease, periodic blood counts are recommended. If anemia or
115
neutropenia develops, dosage interruption may be needed [see Dosage and Administration
116
(2.3)].
117
5.2
Myopathy
118
Myopathy and myositis with pathological changes, similar to that produced by HIV-1
119
disease, have been associated with prolonged use of RETROVIR.
120
5.3
Lactic Acidosis/Severe Hepatomegaly With Steatosis
121
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been
122
reported with the use of nucleoside analogues alone or in combination, including zidovudine and
123
other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged
124
exposure to antiretroviral nucleoside analogues may be risk factors. Particular caution should be
125
exercised when administering RETROVIR to any patient with known risk factors for liver
126
disease; however, cases have also been reported in patients with no known risk factors.
127
Treatment with RETROVIR should be suspended in any patient who develops clinical or
128
laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may
129
include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
130
5.4
Use With Interferon- and Ribavirin-Based Regimens in HIV-1/HCV
131
Co-Infected Patients
132
In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine
133
nucleoside analogues such as zidovudine. Although no evidence of a pharmacokinetic or
134
pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when
135
ribavirin was coadministered with zidovudine in HIV-1/HCV co-infected patients [see Clinical
136
Pharmacology (12.3)], exacerbation of anemia due to ribavirin has been reported when
137
zidovudine is part of the HIV regimen. Coadministration of ribavirin and zidovudine is not
138
advised. Consideration should be given to replacing zidovudine in established combination
139
HIV-1/HCV therapy, especially in patients with a known history of zidovudine-induced anemia.
140
Hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients
141
receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without
142
ribavirin. Patients receiving interferon alfa with or without ribavirin and zidovudine should be
143
closely monitored for treatment-associated toxicities, especially hepatic decompensation,
144
neutropenia, and anemia.
145
Discontinuation of zidovudine should be considered as medically appropriate. Dose
146
reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if
147
worsening clinical toxicities are observed, including hepatic decompensation (e.g., Childs Pugh
148
>6) (see the complete prescribing information for interferon and ribavirin).
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
149
5.5
Use With Other Zidovudine-Containing Products
150
RETROVIR should not be administered with combination products that contain
151
zidovudine as one of their components (e.g., COMBIVIR® or TRIZIVIR®).
152
5.6
Immune Reconstitution Syndrome
153
Immune reconstitution syndrome has been reported in patients treated with combination
154
antiretroviral therapy, including RETROVIR. During the initial phase of combination
155
antiretroviral treatment, patients whose immune systems respond may develop an inflammatory
156
response to indolent or residual opportunistic infections (such as Mycobacterium avium
157
infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which
158
may necessitate further evaluation and treatment.
159
5.7
Fat Redistribution
160
Redistribution/accumulation of body fat, including central obesity, dorsocervical fat
161
enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and
162
“cushingoid appearance,” have been observed in patients receiving antiretroviral therapy. The
163
mechanism and long-term consequences of these events are currently unknown. A causal
164
relationship has not been established.
165
6
ADVERSE REACTIONS
166
6.1
Clinical Trials Experience
167
The following adverse reactions are discussed in greater detail in other sections of the
168
labeling:
169
• Hematologic toxicity, including neutropenia and anemia [see Boxed Warning, Warnings and
170
Precautions (5.1)].
171
• Symptomatic myopathy [see Boxed Warning, Warnings and Precautions (5.2)].
172
• Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and
173
Precautions (5.3)].
174
• Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [see Warnings
175
and Precautions (5.4)].
176
Because clinical trials are conducted under widely varying conditions, adverse reaction
177
rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical
178
trials of another drug and may not reflect the rates observed in practice.
179
Adults: The frequency and severity of adverse reactions associated with the use of
180
RETROVIR are greater in patients with more advanced infection at the time of initiation of
181
therapy.
182
Table 2 summarizes events reported at a statistically significant greater incidence for
183
patients receiving RETROVIR in a monotherapy study.
184
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
185
Table 2. Percentage (%) of Patients With Adverse Reactions* in Asymptomatic HIV-1
186
Infection (ACTG 019)
Adverse Reaction
RETROVIR 500 mg/day
(n = 453)
Placebo
(n = 428)
Body as a whole
Asthenia
Headache
Malaise
Gastrointestinal
Anorexia
Constipation
Nausea
Vomiting
9%
†
63%
53%
20%
6%†
51%
17%
6%
53%
45%
11%
4%
30%
10%
187
*Reported in ≥5% of study population.
188
†Not statistically significant versus placebo.
189
190
In addition to the adverse reactions listed in Table 2, adverse reactions observed at an
191
incidence of ≥5% in any treatment arm in clinical studies (NUCA3001, NUCA3002,
192
NUCB3001, and NUCB3002) were abdominal cramps, abdominal pain, arthralgia, chills,
193
dyspepsia, fatigue, insomnia, musculoskeletal pain, myalgia, and neuropathy. Additionally, in
194
these studies hyperbilirubinemia was reported at an incidence of ≤0.8%.
195
Selected laboratory abnormalities observed during a clinical study of monotherapy with
196
RETROVIR are shown in Table 3.
197
198
Table 3. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Patients With
199
Asymptomatic HIV-1 Infection (ACTG 019)
Test
(Abnormal Level)
RETROVIR 500 mg/day
(n = 453)
Placebo
(n = 428)
Anemia (Hgb<8 g/dL)
Granulocytopenia (<750 cells/mm3)
Thrombocytopenia (platelets<50,000/mm3)
ALT (>5 x ULN)
AST (>5 x ULN)
1%
2%
0%
3%
1%
<1%
2%
<1%
3%
2%
200
ULN = Upper limit of normal.
201
202
Pediatrics: The clinical adverse reactions reported among adult recipients of
203
RETROVIR may also occur in pediatric patients.
204
Study ACTG300: Selected clinical adverse reactions and physical findings with a
205
≥5% frequency during therapy with EPIVIR 4 mg/kg twice daily plus RETROVIR 160 mg/m2
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
206
3 times daily compared with didanosine in therapy-naive (≤56 days of antiretroviral therapy)
207
pediatric patients are listed in Table 4.
208
209
Table 4. Selected Clinical Adverse Reactions and Physical Findings (≥5% Frequency) in
210
Pediatric Patients in Study ACTG300
Adverse Reaction
EPIVIR plus
RETROVIR
(n = 236)
Didanosine
(n = 235)
Body as a whole
Fever
Digestive
25%
32%
Hepatomegaly
11%
11%
Nausea & vomiting
8%
7%
Diarrhea
8%
6%
Stomatitis
6%
12%
Splenomegaly
Respiratory
5%
8%
Cough
15%
18%
Abnormal breath sounds/wheezing
Ear, Nose, and Throat
7%
9%
Signs or symptoms of ears*
7%
6%
Nasal discharge or congestion
Other
8%
11%
Skin rashes
12%
14%
Lymphadenopathy
9%
11%
211
*Includes pain, discharge, erythema, or swelling of an ear.
212
213
Selected laboratory abnormalities experienced by therapy-naive (≤56 days of
214
antiretroviral therapy) pediatric patients are listed in Table 5.
215
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
216
Table 5. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Pediatric
217
Patients in Study ACTG300
Test
(Abnormal Level)
EPIVIR plus
RETROVIR
Didanosine
Neutropenia (ANC<400 cells/mm3)
Anemia (Hgb<7.0 g/dL)
Thrombocytopenia (platelets<50,000/mm3)
ALT (>10 x ULN)
AST (>10 x ULN)
Lipase (>2.5 x ULN)
Total amylase (>2.5 x ULN)
8%
4%
1%
1%
2%
3%
3%
3%
2%
3%
3%
4%
3%
3%
218
ULN = Upper limit of normal.
219
ANC = Absolute neutrophil count.
220
221
Macrocytosis was reported in the majority of pediatric patients receiving RETROVIR
222
180 mg/m2 every 6 hours in open-label studies. Additionally, adverse reactions reported at an
223
incidence of <6% in these studies were congestive heart failure, decreased reflexes, ECG
224
abnormality, edema, hematuria, left ventricular dilation, nervousness/irritability, and weight loss.
225
Use for the Prevention of Maternal-Fetal Transmission of HIV-1: In a randomized,
226
double-blind, placebo-controlled trial in HIV-1-infected women and their neonates conducted to
227
determine the utility of RETROVIR for the prevention of maternal-fetal HIV-1 transmission,
228
RETROVIR Syrup at 2 mg/kg was administered every 6 hours for 6 weeks to neonates
229
beginning within 12 hours following birth. The most commonly reported adverse reactions were
230
anemia (hemoglobin <9.0 g/dL) and neutropenia (<1,000 cells/mm3). Anemia occurred in 22%
231
of the neonates who received RETROVIR and in 12% of the neonates who received placebo.
232
The mean difference in hemoglobin values was less than 1.0 g/dL for neonates receiving
233
RETROVIR compared with neonates receiving placebo. No neonates with anemia required
234
transfusion and all hemoglobin values spontaneously returned to normal within 6 weeks after
235
completion of therapy with RETROVIR. Neutropenia in neonates was reported with similar
236
frequency in the group that received RETROVIR (21%) and in the group that received placebo
237
(27%). The long-term consequences of in utero and infant exposure to RETROVIR are
238
unknown.
239
6.2
Postmarketing Experience
240
In addition to adverse reactions reported from clinical trials, the following reactions have
241
been identified during postmarketing use of RETROVIR. Because they are reported voluntarily
242
from a population of unknown size, estimates of frequency cannot be made. These reactions have
243
been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or
244
potential causal connection to RETROVIR.
245
Body as a Whole: Back pain, chest pain, flu-like syndrome, generalized pain,
246
redistribution/accumulation of body fat [see Warnings and Precautions (5.6)].
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
247
Cardiovascular: Cardiomyopathy, syncope.
248
Endocrine: Gynecomastia.
249
Eye: Macular edema.
250
Gastrointestinal: Dysphagia, flatulence, oral mucosa pigmentation, mouth ulcer.
251
General: Sensitization reactions including anaphylaxis and angioedema, vasculitis.
252
Hemic and Lymphatic: Aplastic anemia, hemolytic anemia, leukopenia,
253
lymphadenopathy, pancytopenia with marrow hypoplasia, pure red cell aplasia.
254
Hepatobiliary Tract and Pancreas: Hepatitis, hepatomegaly with steatosis, jaundice,
255
lactic acidosis, pancreatitis.
256
Musculoskeletal: Increased CPK, increased LDH, muscle spasm, myopathy and
257
myositis with pathological changes (similar to that produced by HIV-1 disease), rhabdomyolysis,
258
tremor.
259
Nervous: Anxiety, confusion, depression, dizziness, loss of mental acuity, mania,
260
paresthesia, seizures, somnolence, vertigo.
261
Respiratory: Dyspnea, rhinitis, sinusitis.
262
Skin: Changes in skin and nail pigmentation, pruritus, Stevens-Johnson syndrome, toxic
263
epidermal necrolysis, sweat, urticaria.
264
Special Senses: Amblyopia, hearing loss, photophobia, taste perversion.
265
Urogenital: Urinary frequency, urinary hesitancy.
266
7
DRUG INTERACTIONS
267
7.1
Antiretroviral Agents
268
Stavudine: Concomitant use of zidovudine with stavudine should be avoided since an
269
antagonistic relationship has been demonstrated in vitro.
270
Nucleoside Analogues Affecting DNA Replication: Some nucleoside analogues
271
affecting DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of
272
RETROVIR against HIV-1; concomitant use of such drugs should be avoided.
273
7.2
Doxorubicin
274
Concomitant use of zidovudine with doxorubicin should be avoided since an antagonistic
275
relationship has been demonstrated in vitro.
276
7.3
Hematologic/Bone Marrow Suppressive/Cytotoxic Agents
277
Coadministration of ganciclovir, interferon alfa, ribavirin, and other bone marrow
278
suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine.
279
8
USE IN SPECIFIC POPULATIONS
280
8.1
Pregnancy
281
Pregnancy Category C.
282
In humans, treatment with RETROVIR during pregnancy reduced the rate of
283
maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to
284
7.8% for infants born to mothers treated with RETROVIR [see Clinical Studies (14.3)]. There
285
were no differences in pregnancy-related adverse events between the treatment groups. Animal
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
286
reproduction studies in rats and rabbits showed evidence of embryotoxicity and increased fetal
287
malformations.
288
A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected
289
pregnant women to determine the utility of RETROVIR for the prevention of maternal-fetal
290
HIV-1-transmission [see Clinical Studies (14.3)]. Congenital abnormalities occurred with similar
291
frequency between neonates born to mothers who received RETROVIR and neonates born to
292
mothers who received placebo. The observed abnormalities included problems in embryogenesis
293
(prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of
294
study drug.
295
Increased fetal resorptions occurred in pregnant rats and rabbits treated with doses of
296
zidovudine that produced drug plasma concentrations 66 to 226 times (rats) and 12 to 87 times
297
(rabbits) the mean steady-state peak human plasma concentration following a single 100-mg
298
dose of zidovudine. There were no other reported developmental anomalies. In another
299
developmental toxicity study, pregnant rats received zidovudine up to near-lethal doses that
300
produced peak plasma concentrations 350 times peak human plasma concentrations (300 times
301
the daily AUC in humans given 600 mg/day zidovudine). This dose was associated with marked
302
maternal toxicity and an increased incidence of fetal malformations. However, there were no
303
signs of teratogenicity at doses up to one fifth the lethal dose [see Nonclinical Toxicology
304
(13.2)].
305
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant
306
women exposed to RETROVIR, an Antiretroviral Pregnancy Registry has been established.
307
Physicians are encouraged to register patients by calling 1-800-258-4263.
308
8.3
Nursing Mothers
309
Zidovudine is excreted in human milk [see Clinical Pharmacology (12.3)].
310
The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers
311
in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1
312
infection. Because of both the potential for HIV-1 transmission and the potential for serious
313
adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are
314
receiving RETROVIR.
315
8.4
Pediatric Use
316
RETROVIR has been studied in HIV-1-infected pediatric patients ≥6 weeks of age who
317
had HIV-1-related symptoms or who were asymptomatic with abnormal laboratory values
318
indicating significant HIV-1-related immunosuppression. RETROVIR has also been studied in
319
neonates perinatally exposed to HIV-1 [see Dosage and Administration (2.1), Adverse Reactions
320
(6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2), (14.3)].
321
8.5
Geriatric Use
322
Clinical studies of RETROVIR did not include sufficient numbers of subjects aged 65
323
and over to determine whether they respond differently from younger subjects. Other reported
324
clinical experience has not identified differences in responses between the elderly and younger
325
patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
326
frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other
327
drug therapy.
328
8.6
Renal Impairment
329
In patients with severely impaired renal function (CrCl<15 mL/min), dosage reduction is
330
recommended [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
331
8.7
Hepatic Impairment
332
Zidovudine is eliminated from the body primarily by renal excretion following
333
metabolism in the liver (glucuronidation). Although the data are limited, zidovudine
334
concentrations appear to be increased in patients with severely impaired hepatic function which
335
may increase the risk of hematologic toxicity [see Dosage and Administration (2.5), Clinical
336
Pharmacology (12.3)].
337
10
OVERDOSAGE
338
Acute overdoses of zidovudine have been reported in pediatric patients and adults. These
339
involved exposures up to 50 grams. No specific symptoms or signs have been identified
340
following acute overdosage with zidovudine apart from those listed as adverse events such as
341
fatigue, headache, vomiting, and occasional reports of hematological disturbances. All patients
342
recovered without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a
343
negligible effect on the removal of zidovudine while elimination of its primary metabolite, 3′
344
azido-3′-deoxy-5′-O-β-D-glucopyranuronosylthymidine (GZDV), is enhanced.
345
11
DESCRIPTION
346
RETROVIR is the brand name for zidovudine (formerly called azidothymidine [AZT]), a
347
pyrimidine nucleoside analogue active against HIV-1. The chemical name of zidovudine is 3′
348
349
350
Zidovudine is a white to beige, odorless, crystalline solid with a molecular weight of
351
267.24 and a solubility of 20.1 mg/mL in water at 25°C. The molecular formula is C10H13N5O4.
352
RETROVIR Tablets are for oral administration. Each film-coated tablet contains 300 mg
353
of zidovudine and the inactive ingredients hypromellose, magnesium stearate, microcrystalline
354
cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide.
355
RETROVIR Capsules are for oral administration. Each capsule contains 100 mg of
356
zidovudine and the inactive ingredients corn starch, magnesium stearate, microcrystalline
357
cellulose, and sodium starch glycolate. The 100-mg empty hard gelatin capsule, printed with
Chemical Structure
12
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
358
edible black ink, consists of black iron oxide, dimethylpolysiloxane, gelatin, pharmaceutical
359
shellac, soya lecithin, and titanium dioxide.
360
RETROVIR Syrup is for oral administration. Each teaspoonful (5 mL) of RETROVIR
361
Syrup contains 50 mg of zidovudine and the inactive ingredients sodium benzoate 0.2% (added
362
as a preservative), citric acid, flavors, glycerin, and liquid sucrose. Sodium hydroxide may be
363
added to adjust pH.
364
12
CLINICAL PHARMACOLOGY
365
12.1 Mechanism of Action
366
Zidovudine is an antiviral agent [see Clinical Pharmacology (12.4)].
367
12.3 Pharmacokinetics
368
Absorption and Bioavailability: In adults, following oral administration, zidovudine is
369
rapidly absorbed and extensively distributed, with peak serum concentrations occurring within
370
0.5 to 1.5 hours. The extent of absorption (AUC) was equivalent when zidovudine was
371
administered as RETROVIR Tablets or Syrup compared with RETROVIR Capsules. The
372
pharmacokinetic properties of zidovudine in fasting adult patients are summarized in Table 6.
373
374
Table 6. Zidovudine Pharmacokinetic Parameters in Fasting Adult Patients
Parameter
Mean ± SD
(except where noted)
Oral bioavailability (%)
64 ± 10
(n = 5)
Apparent volume of distribution (L/kg)
1.6 ± 0.6
(n = 8)
Plasma protein binding (%)
<38
CSF:plasma ratio*
0.6 [0.04 to 2.62]
(n = 39)
Systemic clearance (L/hr/kg)
1.6 ± 0.6
(n = 6)
Renal clearance (L/hr/kg)
0.34 ± 0.05
(n = 9)
Elimination half-life (hr)†
0.5 to 3
(n = 19)
375
*Median [range].
376
†Approximate range.
377
378
Distribution: The apparent volume of distribution of zidovudine, following oral
379
administration, is 1.6 ± 0.6 L/kg; and binding to plasma protein is low, <38% (Table 6).
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
380
Metabolism and Elimination: Zidovudine is primarily eliminated by hepatic
381
metabolism. The major metabolite of zidovudine is GZDV. GZDV AUC is about 3-fold greater
382
than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and
383
74%, respectively, of the dose following oral administration. A second metabolite, 3′-amino-3′
384
deoxythymidine (AMT), has been identified in the plasma following single-dose intravenous
385
(IV) administration of zidovudine. The AMT AUC was one fifth of the zidovudine AUC.
386
Pharmacokinetics of zidovudine were dose independent at oral dosing regimens ranging from
387
2 mg/kg every 8 hours to 10 mg/kg every 4 hours.
388
Effect of Food on Absorption: RETROVIR may be administered with or without food.
389
The extent of zidovudine absorption (AUC) was similar when a single dose of zidovudine was
390
administered with food.
391
Special Populations: Renal Impairment: Zidovudine clearance was decreased
392
resulting in increased zidovudine and GZDV half-life and AUC in patients with impaired renal
393
function (n = 14) following a single 200-mg oral dose (Table 7). Plasma concentrations of AMT
394
were not determined. A dose adjustment should not be necessary for patients with creatinine
395
clearance (CrCl) ≥15 mL/min.
396
397
Table 7. Zidovudine Pharmacokinetic Parameters in Patients With Severe Renal
398
Impairment*
Parameter
Control Subjects
(Normal Renal Function)
(n = 6)
Patients With Renal
Impairment
(n = 14)
CrCl (mL/min)
120 ± 8
18 ± 2
Zidovudine AUC (ng•hr/mL)
1,400 ± 200
3,100 ± 300
Zidovudine half-life (hr)
1.0 ± 0.2
1.4 ± 0.1
399
*Data are expressed as mean ± standard deviation.
400
401
Hemodialysis and Peritoneal Dialysis: The pharmacokinetics and tolerance of
402
zidovudine were evaluated in a multiple-dose study in patients undergoing hemodialysis (n = 5)
403
or peritoneal dialysis (n = 6) receiving escalating doses up to 200 mg 5 times daily for 8 weeks.
404
Daily doses of 500 mg or less were well tolerated despite significantly elevated GZDV plasma
405
concentrations. Apparent zidovudine oral clearance was approximately 50% of that reported in
406
patients with normal renal function. Hemodialysis and peritoneal dialysis appeared to have a
407
negligible effect on the removal of zidovudine, whereas GZDV elimination was enhanced. A
408
dosage adjustment is recommended for patients undergoing hemodialysis or peritoneal dialysis
409
[see Dosage and Administration (2.4)].
410
Hepatic Impairment: Data describing the effect of hepatic impairment on the
411
pharmacokinetics of zidovudine are limited. However, because zidovudine is eliminated
412
primarily by hepatic metabolism, it is expected that zidovudine clearance would be decreased
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
413
and plasma concentrations would be increased following administration of the recommended
414
adult doses to patients with hepatic impairment [see Dosage and Administration (2.5)].
415
Pediatric Patients: Zidovudine pharmacokinetics have been evaluated in
416
HIV-1-infected pediatric patients (Table 8).
417
Patients 3 Months to 12 Years of Age: Overall, zidovudine pharmacokinetics in
418
pediatric patients greater than 3 months of age are similar to those in adult patients. Proportional
419
increases in plasma zidovudine concentrations were observed following administration of oral
420
solution from 90 to 240 mg/m2 every 6 hours. Oral bioavailability, terminal half-life, and oral
421
clearance were comparable to adult values. As in adult patients, the major route of elimination
422
was by metabolism to GZDV. After intravenous dosing, about 29% of the dose was excreted in
423
the urine unchanged, and about 45% of the dose was excreted as GZDV [see Dosage and
424
Administration (2.1)].
425
Patients <3 Months of Age: Zidovudine pharmacokinetics have been evaluated in
426
pediatric patients from birth to 3 months of life. Zidovudine elimination was determined
427
immediately following birth in 8 neonates who were exposed to zidovudine in utero. The
428
half-life was 13.0 ± 5.8 hours. In neonates ≤14 days old, bioavailability was greater, total body
429
clearance was slower, and half-life was longer than in pediatric patients >14 days old. For dose
430
recommendations for neonates [see Dosage and Administration (2.2)].
431
432
Table 8. Zidovudine Pharmacokinetic Parameters in Pediatric Patients*
Parameter
Birth to 14 Days of
Age
14 Days to 3 Months
of Age
3 Months to 12 Years
of Age
Oral bioavailability (%)
89 ± 19
(n = 15)
61 ± 19
(n = 17)
65 ± 24
(n = 18)
CSF:plasma ratio
no data
no data
0.68 [0.03 to 3.25]†
(n = 38)
CL (L/hr/kg)
0.65 ± 0.29
(n = 18)
1.14 ± 0.24
(n = 16)
1.85 ± 0.47
(n = 20)
Elimination half-life (hr)
3.1 ± 1.2
(n = 21)
1.9 ± 0.7
(n = 18)
1.5 ± 0.7
(n = 21)
433
*Data presented as mean ± standard deviation except where noted.
434
†Median [range].
435
436
Pregnancy: Zidovudine pharmacokinetics have been studied in a Phase I study of
437
8 women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to
438
those of nonpregnant adults. Consistent with passive transmission of the drug across the
439
placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in
440
maternal plasma at delivery [see Use in Specific Populations (8.1)].
441
Although data are limited, methadone maintenance therapy in 5 pregnant women did not
442
appear to alter zidovudine pharmacokinetics.
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
443
Nursing Mothers: The Centers for Disease Control and Prevention recommend that
444
HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of
445
HIV-1. After administration of a single dose of 200 mg zidovudine to 13 HIV-1-infected women,
446
the mean concentration of zidovudine was similar in human milk and serum [see Use In Specific
447
Populations (8.3)].
448
Geriatric Patients: Zidovudine pharmacokinetics have not been studied in patients
449
over 65 years of age.
450
Gender: A pharmacokinetic study in healthy male (n = 12) and female (n = 12)
451
subjects showed no differences in zidovudine exposure (AUC) when a single dose of zidovudine
452
was administered as the 300-mg RETROVIR Tablet.
453
Drug Interactions: [See Drug Interactions (7)].
454
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
455
Table 9. Effect of Coadministered Drugs on Zidovudine AUC*
Note: ROUTINE DOSE MODIFICATION OF ZIDOVUDINE IS NOT WARRANTED
WITH COADMINISTRATION OF THE FOLLOWING DRUGS.
Coadministered
Drug and Dose
Zidovudine
Dose
n
Zidovudine
Concentrations
Concentration
of
Coadministered
Drug
AUC
Variability
Atovaquone
750 mg q 12 hr
with food
200 mg q 8 hr
14
↑AUC
31%
Range
23% to 78%†
↔
Fluconazole
400 mg daily
200 mg q 8 hr
12
↑AUC
74%
95% CI:
54% to 98%
Not Reported
Lamivudine
300 mg q 12 hr
single 200 mg
12
↑AUC
13%
90% CI:
2% to 27%
↔
Methadone
30 to 90 mg daily
200 mg q 4 hr
9
↑AUC
43%
Range
16% to 64%†
↔
Nelfinavir
750 mg q 8 hr x
7 to 10 days
single 200 mg
11
↓AUC
35%
Range
28% to 41%
↔
Probenecid
500 mg q 6 hr x
2 days
2 mg/kg q 8 hr
x 3 days
3
↑AUC
106%
Range
100% to
170%†
Not Assessed
Rifampin
600 mg daily x
14 days
200 mg q 8 hr
x 14 days
8
↓AUC
47%
90% CI:
41% to 53%
Not Assessed
Ritonavir
300 mg q 6 hr x
4 days
200 mg q 8 hr
x 4 days
9
↓AUC
25%
95% CI:
15% to 34%
↔
Valproic acid
250 mg or 500 mg
q 8 hr x 4 days
100 mg q 8 hr
x 4 days
6
↑AUC
80%
Range
64% to
130%†
Not Assessed
456
↑ = Increase; ↓ = Decrease; ↔ = no significant change; AUC = area under the concentration
457
versus time curve; CI = confidence interval.
458
*This table is not all inclusive.
459
†Estimated range of percent difference.
460
461
Phenytoin: Phenytoin plasma levels have been reported to be low in some patients
462
receiving RETROVIR, while in one case a high level was documented. However, in a
463
pharmacokinetic interaction study in which 12 HIV-1-positive volunteers received a single
464
300-mg phenytoin dose alone and during steady-state zidovudine conditions (200 mg every
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
465
4 hours), no change in phenytoin kinetics was observed. Although not designed to optimally
466
assess the effect of phenytoin on zidovudine kinetics, a 30% decrease in oral zidovudine
467
clearance was observed with phenytoin.
468
Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine,
469
stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or
470
intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss
471
of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine
472
(n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug
473
regimen to HIV-1/HCV co-infected patients [see Warnings and Precautions (5.4)].
474
12.4 Microbiology
475
Mechanism of Action: Zidovudine is a synthetic nucleoside analogue. Intracellularly,
476
zidovudine is phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate
477
(ZDV-TP). The principal mode of action of ZDV-TP is inhibition of reverse transcriptase (RT)
478
via DNA chain termination after incorporation of the nucleotide analogue. ZDV-TP is a weak
479
inhibitor of the cellular DNA polymerases α and γ and has been reported to be incorporated into
480
the DNA of cells in culture.
481
Antiviral Activity: The antiviral activity of zidovudine against HIV-1 was assessed in a
482
number of cell lines (including monocytes and fresh human peripheral blood lymphocytes). The
483
EC50 and EC90 values for zidovudine were 0.01 to 0.49 µM (1 μM = 0.27 mcg/mL) and 0.1 to
484
9 μM, respectively. HIV-1 from therapy-naive subjects with no mutations associated with
485
resistance gave median EC50 values of 0.011 µM (range: 0.005 to 0.110 µM) from Virco (n = 92
486
baseline samples from COLA40263) and 0.0017 µM (0.006 to 0.0340 µM) from Monogram
487
Biosciences (n = 135 baseline samples from ESS30009). The EC50 values of zidovudine against
488
different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 μM, and against HIV-2 isolates from
489
0.00049 to 0.004 μM. In cell culture drug combination studies, zidovudine demonstrates
490
synergistic activity with the nucleoside reverse transcriptase inhibitors abacavir, didanosine, and
491
lamivudine; the non-nucleoside reverse transcriptase inhibitors delavirdine and nevirapine; and
492
the protease inhibitors indinavir, nelfinavir, ritonavir, and saquinavir; and additive activity with
493
interferon alfa. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell
494
culture.
495
Resistance: Genotypic analyses of the isolates selected in cell culture and recovered
496
from zidovudine-treated patients showed mutations in the HIV-1 RT gene resulting in 6 amino
497
acid substitutions (M41L, D67N, K70R, L210W, T215Y or F, and K219Q) that confer
498
zidovudine resistance. In general, higher levels of resistance were associated with greater number
499
of amino acid substitutions. In some patients harboring zidovudine-resistant virus at baseline,
500
phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and
501
zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of
502
substitutions conferring resistance to zidovudine.
503
Cross-Resistance: In a study of 167 HIV-1-infected patients, isolates (n = 2) with
504
multi-drug resistance to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine were
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
505
recovered from patients treated for ≥1 year with zidovudine plus didanosine or zidovudine plus
506
zalcitabine. The pattern of resistance-associated amino acid substitutions with such combination
507
therapies was different (A62V, V75I, F77L, F116Y, Q151M) from the pattern with zidovudine
508
monotherapy, with the Q151M substitution being most commonly associated with multi-drug
509
resistance. The substitution at codon 151 in combination with substitutions at 62, 75, 77, and 116
510
results in a virus with reduced susceptibility to didanosine, lamivudine, stavudine, zalcitabine,
511
and zidovudine. Thymidine analogue mutations (TAMs) are selected by zidovudine and confer
512
cross-resistance to abacavir, didanosine, stavudine, tenofovir, and zalcitabine.
513
13
NONCLINICAL TOXICOLOGY
514
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
515
Zidovudine was administered orally at 3 dosage levels to separate groups of mice and rats
516
(60 females and 60 males in each group). Initial single daily doses were 30, 60, and
517
120 mg/kg/day in mice and 80, 220, and 600 mg/kg/day in rats. The doses in mice were reduced
518
to 20, 30, and 40 mg/kg/day after day 90 because of treatment-related anemia, whereas in rats
519
only the high dose was reduced to 450 mg/kg/day on day 91 and then to 300 mg/kg/day on
520
day 279.
521
In mice, 7 late-appearing (after 19 months) vaginal neoplasms (5 nonmetastasizing
522
squamous cell carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in
523
animals given the highest dose. One late-appearing squamous cell papilloma occurred in the
524
vagina of a middle-dose animal. No vaginal tumors were found at the lowest dose.
525
In rats, 2 late-appearing (after 20 months), nonmetastasizing vaginal squamous cell
526
carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or
527
middle dose in rats. No other drug-related tumors were observed in either sex of either species.
528
At doses that produced tumors in mice and rats, the estimated drug exposure (as
529
measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human
530
exposure at the recommended therapeutic dose of 100 mg every 4 hours.
531
It is not known how predictive the results of rodent carcinogenicity studies may be for
532
humans.
533
Zidovudine was mutagenic in a 5178Y/TK+/- mouse lymphoma assay, positive in an in
534
vitro cell transformation assay, clastogenic in a cytogenetic assay using cultured human
535
lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was
536
negative in a cytogenetic study in rats given a single dose.
537
Zidovudine, administered to male and female rats at doses up to 7 times the usual adult
538
dose based on body surface area, had no effect on fertility judged by conception rates.
539
Two transplacental carcinogenicity studies were conducted in mice. One study
540
administered zidovudine at doses of 20 mg/kg/day or 40 mg/kg/day from gestation day 10
541
through parturition and lactation with dosing continuing in offspring for 24 months postnatally.
542
The doses of zidovudine administered in this study produced zidovudine exposures
543
approximately 3 times the estimated human exposure at recommended doses. After 24 months,
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
544
an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or
545
lung or any other organ in either gender. These findings are consistent with results of the
546
standard oral carcinogenicity study in mice, as described earlier. A second study administered
547
zidovudine at maximum tolerated doses of 12.5 mg/day or 25 mg/day (∼1,000 mg/kg
548
nonpregnant body weight or ∼450 mg/kg of term body weight) to pregnant mice from days 12
549
through 18 of gestation. There was an increase in the number of tumors in the lung, liver, and
550
female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine.
551
13.2 Reproductive and Developmental Toxicology Studies
552
Oral teratology studies in the rat and in the rabbit at doses up to 500 mg/kg/day revealed
553
no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted in embryo/fetal
554
toxicity as evidenced by an increase in the incidence of fetal resorptions in rats given 150 or
555
450 mg/kg/day and rabbits given 500 mg/kg/day. The doses used in the teratology studies
556
resulted in peak zidovudine plasma concentrations (after one half of the daily dose) in rats 66 to
557
226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma concentrations
558
(after one sixth of the daily dose) achieved with the recommended daily dose (100 mg every
559
4 hours). In an in vitro experiment with fertilized mouse oocytes, zidovudine exposure resulted
560
in a dose-dependent reduction in blastocyst formation. In an additional teratology study in rats, a
561
dose of 3,000 mg/kg/day (very near the oral median lethal dose in rats of 3,683 mg/kg) caused
562
marked maternal toxicity and an increase in the incidence of fetal malformations. This dose
563
resulted in peak zidovudine plasma concentrations 350 times peak human plasma concentrations.
564
(Estimated area under the curve [AUC] in rats at this dose level was 300 times the daily AUC in
565
humans given 600 mg/day.) No evidence of teratogenicity was seen in this experiment at doses
566
of 600 mg/kg/day or less.
567
14
CLINICAL STUDIES
568
Therapy with RETROVIR has been shown to prolong survival and decrease the incidence
569
of opportunistic infections in patients with advanced HIV-1 disease and to delay disease
570
progression in asymptomatic HIV-1-infected patients.
571
14.1 Adults
572
Combination Therapy: RETROVIR in combination with other antiretroviral agents has
573
been shown to be superior to monotherapy for one or more of the following endpoints: delaying
574
death, delaying development of AIDS, increasing CD4+ cell counts, and decreasing plasma
575
HIV-1 RNA.
576
The clinical efficacy of a combination regimen that includes RETROVIR was
577
demonstrated in study ACTG320. This study was a multi-center, randomized, double-blind,
578
placebo-controlled trial that compared RETROVIR 600 mg/day plus EPIVIR® 300 mg/day to
579
RETROVIR plus EPIVIR plus indinavir 800 mg t.i.d. The incidence of AIDS-defining events or
580
death was lower in the triple-drug–containing arm compared with the 2-drug–containing arm
581
(6.1% versus 10.9%, respectively).
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
582
Monotherapy: In controlled studies of treatment-naive patients conducted between 1986
583
and 1989, monotherapy with RETROVIR, as compared with placebo, reduced the risk of HIV-1
584
disease progression, as assessed using endpoints that included the occurrence of HIV-1-related
585
illnesses, AIDS-defining events, or death. These studies enrolled patients with advanced disease
586
(BW002), and asymptomatic or mildly symptomatic disease in patients with CD4+ cell counts
587
between 200 and 500 cells/mm3 (ACTG016 and ACTG019). A survival benefit for monotherapy
588
with RETROVIR was not demonstrated in the latter 2 studies. Subsequent studies showed that
589
the clinical benefit of monotherapy with RETROVIR was time limited.
590
14.2 Pediatric Patients
591
ACTG300 was a multi-center, randomized, double-blind study that provided for
592
comparison of EPIVIR plus RETROVIR to didanosine monotherapy. A total of
593
471 symptomatic, HIV-1-infected therapy-naive pediatric patients were enrolled in these
594
2 treatment arms. The median age was 2.7 years (range 6 weeks to 14 years), the mean baseline
595
CD4+ cell count was 868 cells/mm3, and the mean baseline plasma HIV-1 RNA was
596
5.0 log10 copies/mL. The median duration that patients remained on study was approximately
597
10 months. Results are summarized in Table 10.
598
599
Table 10. Number of Patients (%) Reaching a Primary Clinical Endpoint (Disease
600
Progression or Death)
Endpoint
EPIVIR plus
RETROVIR
(n = 236)
Didanosine
(n = 235)
HIV disease progression or death (total)
15 (6.4%)
37 (15.7%)
Physical growth failure
7 (3.0%)
6 (2.6%)
Central nervous system deterioration
4 (1.7%)
12 (5.1%)
CDC Clinical Category C
2 (0.8%)
8 (3.4%)
Death
2 (0.8%)
11 (4.7%)
601
602
14.3 Prevention of Maternal-Fetal HIV-1 Transmission
603
The utility of RETROVIR for the prevention of maternal-fetal HIV-1 transmission was
604
demonstrated in a randomized, double-blind, placebo-controlled trial (ACTG076) conducted in
605
HIV-1-infected pregnant women with CD4+ cell counts of 200 to 1,818 cells/mm3 (median in
606
the treated group: 560 cells/mm3) who had little or no previous exposure to RETROVIR. Oral
607
RETROVIR was initiated between 14 and 34 weeks of gestation (median 11 weeks of therapy)
608
followed by IV administration of RETROVIR during labor and delivery. Following birth,
609
neonates received oral RETROVIR Syrup for 6 weeks. The study showed a statistically
610
significant difference in the incidence of HIV-1 infection in the neonates (based on viral culture
611
from peripheral blood) between the group receiving RETROVIR and the group receiving
612
placebo. Of 363 neonates evaluated in the study, the estimated risk of HIV-1 infection was 7.8%
613
in the group receiving RETROVIR and 24.9% in the placebo group, a relative reduction in
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
614
transmission risk of 68.7%. RETROVIR was well tolerated by mothers and infants. There was
615
no difference in pregnancy-related adverse events between the treatment groups.
616
16
HOW SUPPLIED/STORAGE AND HANDLING
617
RETROVIR Tablets 300 mg (biconvex, white, round, film-coated) containing 300 mg
618
zidovudine, one side engraved “GX CW3” and “300” on the other side.
619
Bottle of 60 (NDC 0173-0501-00).
620
Store at 15° to 25°C (59° to 77°F).
621
RETROVIR Capsules 100 mg (white, opaque cap and body) containing 100 mg
622
zidovudine and printed with “Wellcome” and unicorn logo on cap and “Y9C” and “100” on
623
body.
624
Bottles of 100 (NDC 0173-0108-55).
625
Unit Dose Pack of 100 (NDC 0173-0108-56).
626
Store at 15° to 25°C (59° to 77°F) and protect from moisture.
627
RETROVIR Syrup (colorless to pale yellow, strawberry-flavored) containing 50 mg
628
zidovudine in each teaspoonful (5 mL).
629
Bottle of 240 mL (NDC 0173-0113-18) with child-resistant cap.
630
Store at 15° to 25°C (59° to 77°F).
631
17
PATIENT COUNSELING INFORMATION
632
17.1 Information About Therapy With RETROVIR
633
Neutropenia and Anemia: The major toxicities of RETROVIR are neutropenia and/or
634
anemia. The frequency and severity of these toxicities are greater in patients with more advanced
635
disease and in those who initiate therapy later in the course of their infection. They should be
636
told that if toxicity develops, they may require transfusions or drug discontinuation. They should
637
be told of the extreme importance of having their blood counts followed closely while on
638
therapy, especially for patients with advanced symptomatic HIV-1 disease [see Boxed Warning,
639
Warnings and Precautions (5.1)].
640
Common Adverse Reactions: Other adverse effects of RETROVIR include nausea and
641
vomiting. Patients should also be encouraged to contact their physician if they experience muscle
642
weakness, shortness of breath, symptoms of hepatitis or pancreatitis, or any other unexpected
643
adverse events while being treated with RETROVIR [see Adverse Reactions (6)].
644
Drug Interactions: Patients should be cautioned about the use of other medications,
645
including ganciclovir, interferon alfa, and ribavirin, which may exacerbate the toxicity of
646
RETROVIR.
647
Redistribution/Accumulation of Body Fat: Redistribution or accumulation of body fat
648
may occur in patients receiving antiretroviral therapy and that the cause and long-term health
649
effects of these conditions are not known at this time [see Warnings and Precautions (5.6)].
650
Pregnancy: Pregnant women considering the use of RETROVIR during pregnancy for
651
prevention of HIV-1 transmission to their infants should be advised that transmission may still
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
652
occur in some cases despite therapy. The long-term consequences of in utero and infant exposure
653
to RETROVIR are unknown, including the possible risk of cancer.
654
HIV-1-infected pregnant women should be advised not to breastfeed to avoid postnatal
655
transmission of HIV to a child who may not yet be infected.
656
Information About Therapy With RETROVIR: RETROVIR is not a cure for HIV-1
657
infection, and patients may continue to acquire illnesses associated with HIV-1 infection,
658
including opportunistic infections. Therefore, patients should be advised to seek medical care for
659
any significant change in their health status.
660
Patients should be told of the importance of taking RETROVIR exactly as prescribed.
661
They should be told not to share medication and not to exceed the recommended dose. Patients
662
should be told that the long-term effects of RETROVIR are unknown at this time.
663
Therapy with RETROVIR has not been shown to reduce the risk of transmission of
664
HIV-1 to others through sexual contact or blood contamination.
665
666
RETROVIR, COMBIVIR, EPIVIR, and TRIZIVIR are registered trademarks of
667
GlaxoSmithKline.
668
669
GSK Logo
671
GlaxoSmithKline
672
Research Triangle Park, NC 27709
673
674
©2008, GlaxoSmithKline. All rights reserved.
675
23
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:38.989925
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019910s033,019655s046,020518s016lbl.pdf', 'application_number': 19655, 'submission_type': 'SUPPL ', 'submission_number': 46}
|
11,609
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
RETROVIR safely and effectively. See full prescribing information for
RETROVIR.
RETROVIR (zidovudine) Tablets, Capsules, and Syrup
Initial U.S. Approval: 1987
WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY,
LACTIC ACIDOSIS
See full prescribing information for complete boxed warning.
• Hematologic toxicity including neutropenia and severe anemia have
been associated with the use of zidovudine. (5.1)
• Symptomatic myopathy associated with prolonged use of zidovudine.
(5.2)
• Lactic acidosis and severe hepatomegaly with steatosis, including fatal
cases, have been reported with the use of nucleoside analogues
including RETROVIR. Suspend treatment if clinical or laboratory
findings suggestive of lactic acidosis or pronounced hepatotoxicity
occur. (5.3)
---------------------------RECENT MAJOR CHANGES -------------------
Warnings and Precautions, Immune Reconstitution -------------(11/2011)
Syndrome (5.6)
----------------------------INDICATIONS AND USAGE--------------------
RETROVIR is a nucleoside analogue reverse transcriptase inhibitor indicated for:
• Treatment of Human Immunodeficiency Virus (HIV-1) infection in
combination with other antiretroviral agents. (1.1)
• Prevention of maternal-fetal HIV-1 transmission. (1.2)
----------------------- DOSAGE AND ADMINISTRATION ---------------
• Treatment of HIV-1 infection:
Adults: 600 mg/day in divided doses with other antiretroviral agents.
Pediatric patients (aged 4 weeks to <18 years): Dosage should be
calculated based on body weight not to exceed adult dose. (2.1)
• Prevention of maternal-fetal HIV-1 transmission:
Specific dosage instructions for mother and infant. (2.2)
• Patients with severe anemia and/or neutropenia:
Dosage interruption may be necessary. (2.3)
• Renal impairment: Recommended dosage in hemodialysis or peritoneal
dialysis patients is 100 mg every 6 to 8 hours. (2.4)
---------------------DOSAGE FORMS AND STRENGTHS -------------
Tablets: 300 mg (3)
Capsules: 100 mg (3)
Syrup: 50 mg/5 mL (3)
-------------------------------CONTRAINDICATIONS-----------------------
Hypersensitivity to zidovudine (e.g., anaphylaxis, Stevens-Johnson
syndrome). (4)
----------------------- WARNINGS AND PRECAUTIONS ---------------
• See boxed warning for information about the following: hematologic
toxicity, myopathy, and lactic acidosis and severe hepatomegaly (5.1, 5.2,
5.3)
• Exacerbation of anemia has been reported in HIV-1/HCV co-infected
patients receiving ribavirin and zidovudine. Coadministration of ribavirin
and zidovudine is not advised. (5.4)
• Hepatic decompensation, (some fatal), has occurred in HIV-1/HCV
co-infected patients receiving combination antiretroviral therapy and
interferon alfa with/without ribavirin. Discontinue zidovudine as medically
appropriate and consider dose reduction or discontinuation of interferon
alfa, ribavirin, or both. (5.4)
• RETROVIR should not be administered with other zidovudine-containing
combination products. (5.5)
• Immune reconstitution syndrome (5.6) and redistribution/accumulation of
body fat (5.7) have been reported in patients treated with combination
antiretroviral therapy.
------------------------------ ADVERSE REACTIONS ----------------------
• Most commonly reported adverse reactions (incidence ≥15%) in adult
HIV-1 clinical studies were headache, malaise, nausea, anorexia, and
vomiting. (6.1)
• Most commonly reported adverse reactions (incidence ≥15%) in pediatric
HIV-1 clinical studies were fever, cough, and digestive disorders. (6.1)
• Most commonly reported adverse reactions in neonates (incidence ≥15%)
in the prevention of maternal-fetal transmission of HIV-1 clinical trial
were anemia and neutropenia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact ViiV
Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
-------------------------------DRUG INTERACTIONS-----------------------
• Stavudine: Concomitant use with zidovudine should be avoided. (7.1)
• Doxorubicin: Use with zidovudine should be avoided. (7.2)
• Bone marrow suppressive/cytotoxic agents: May increase the hematologic
toxicity of zidovudine. (7.3)
----------------------- USE IN SPECIFIC POPULATIONS ---------------
Pregnancy: Physicians are encouraged to register patients in the Antiretroviral
Pregnancy Registry by calling 1-800-258-4263. (8.1)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: November 2011
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY,
LACTIC ACIDOSIS
1
INDICATIONS AND USAGE
1.1
Treatment of HIV-1
1.2
Prevention of Maternal-Fetal HIV-1 Transmission
2
DOSAGE AND ADMINISTRATION
2.1
Treatment of HIV-1 Infection
2.2
Prevention of Maternal-Fetal HIV-1 Transmission
2.3
Patients With Severe Anemia and/or Neutropenia
2.4
Patients With Renal Impairment
2.5
Patients With Hepatic Impairment
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Hematologic Toxicity/Bone Marrow Suppression
5.2
Myopathy
5.3
Lactic Acidosis/Severe Hepatomegaly With Steatosis
5.4
Use With Interferon- and Ribavirin-Based Regimens in
HIV-1/HCV Co-Infected Patients
5.5
Use With Other Zidovudine-Containing Products
5.6
Immune Reconstitution Syndrome
5.7
Fat Redistribution
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Antiretroviral Agents
7.2
Doxorubicin
7.3
Hematologic/Bone Marrow Suppressive/Cytotoxic
Agents
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
8.7
Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Reproductive and Developmental Toxicology Studies
14 CLINICAL STUDIES
14.1 Adults
14.2 Pediatric Patients
14.3 Prevention of Maternal-Fetal HIV-1 Transmission
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Information About Therapy With RETROVIR
*Sections or subsections omitted from the full prescribing information are not listed.
1
Reference ID: 3047317
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
______________________________________________________________________
FULL PRESCRIBING INFORMATION
WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY, LACTIC
ACIDOSIS
Hematologic Toxicity: RETROVIR® (zidovudine) Tablets, Capsules, and Syrup have
been associated with hematologic toxicity including neutropenia and severe anemia,
particularly in patients with advanced HIV-1 disease [see Warnings and Precautions (5.1)].
Myopathy: Prolonged use of RETROVIR has been associated with symptomatic myopathy
[see Warnings and Precautions (5.2)].
Lactic Acidosis and Severe Hepatomegaly: Lactic acidosis and severe hepatomegaly
with steatosis, including fatal cases, have been reported with the use of nucleoside
analogues alone or in combination, including RETROVIR and other antiretrovirals.
Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or
pronounced hepatotoxicity occur [see Warnings and Precautions (5.3)].
1
INDICATIONS AND USAGE
1.1
Treatment of HIV-1
RETROVIR, a nucleoside reverse transcriptase inhibitor, is indicated in combination with
other antiretroviral agents for the treatment of HIV-1 infection.
1.2
Prevention of Maternal-Fetal HIV-1 Transmission
RETROVIR is indicated for the prevention of maternal-fetal HIV-1 transmission [see
Dosage and Administration (2.2)]. The indication is based on a dosing regimen that included
3 components:
1.
antepartum therapy of HIV-1 infected mothers
2.
intrapartum therapy of HIV-1 infected mothers
3.
post-partum therapy of HIV-1 exposed neonate.
Points to consider prior to initiating RETROVIR in pregnant women for the prevention of
maternal-fetal HIV-1 transmission include:
• In most cases, RETROVIR for prevention of maternal-fetal HIV-1 transmission should be
given in combination with other antiretroviral drugs.
• Prevention of HIV-1 transmission in women who have received RETROVIR for a prolonged
period before pregnancy has not been evaluated.
• Because the fetus is most susceptible to the potential teratogenic effects of drugs during the
first 10 weeks of gestation and the risks of therapy with RETROVIR during that period are
not fully known, women in the first trimester of pregnancy who do not require immediate
initiation of antiretroviral therapy for their own health may consider delaying use; this
indication is based on use after 14 weeks gestation.
Reference ID: 3047317
2
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
Treatment of HIV-1 Infection
Adults: The recommended oral dose of RETROVIR is 600 mg/day in divided doses in
combination with other antiretroviral agents.
Pediatric Patients (Aged 4 Weeks to <18 Years): Healthcare professionals should
pay special attention to accurate calculation of the dose of RETROVIR, transcription of the
medication order, dispensing information, and dosing instructions to minimize risk for
medication dosing errors.
Prescribers should calculate the appropriate dose of RETROVIR for each child based on
body weight (kg) and should not exceed the recommended adult dose.
Before prescribing RETROVIR Capsules or Tablets, children should be assessed for the
ability to swallow capsules or tablets. If a child is unable to reliably swallow a RETROVIR
Capsule or Tablet, the RETROVIR Syrup formulation should be prescribed.
The recommended dosage in pediatric patients 4 weeks of age and older and weighing
≥4 kg is provided in Table 1. RETROVIR Syrup should be used to provide accurate dosage
when whole tablets or capsules are not appropriate.
Table 1: Recommended Pediatric Dosage of RETROVIR
Body Weight
(kg)
Total Daily Dose
Dosage Regimen and Dose
Twice Daily
Three Times Daily
4 to <9
24 mg/kg/day
12 mg/kg
8 mg/kg
≥9 to <30
18 mg/kg/day
9 mg/kg
6 mg/kg
≥30
600 mg/day
300 mg
200 mg
Alternatively, dosing for RETROVIR can be based on body surface area (BSA) for each
child. The recommended oral dose of RETROVIR is 480 mg/m2/day in divided doses
(240 mg/m2 twice daily or 160 mg/m2 three times daily). In some cases the dose calculated by
mg/kg will not be the same as that calculated by BSA.
2.2
Prevention of Maternal-Fetal HIV-1 Transmission
The recommended dosage regimen for administration to pregnant women (>14 weeks of
pregnancy) and their neonates is:
Maternal Dosing: 100 mg orally 5 times per day until the start of labor [see Clinical
Studies (14.3)]. During labor and delivery, intravenous RETROVIR should be administered at
2 mg/kg (total body weight) over 1 hour followed by a continuous intravenous infusion of
1 mg/kg/hour (total body weight) until clamping of the umbilical cord.
Neonatal Dosing: 2 mg/kg orally every 6 hours starting within 12 hours after birth and
continuing through 6 weeks of age. Neonates unable to receive oral dosing may be administered
RETROVIR intravenously at 1.5 mg/kg, infused over 30 minutes, every 6 hours.
2.3
Patients With Severe Anemia and/or Neutropenia
3
Reference ID: 3047317
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Significant anemia (hemoglobin <7.5 g/dL or reduction >25% of baseline) and/or
significant neutropenia (granulocyte count <750 cells/mm3 or reduction >50% from baseline)
may require a dose interruption until evidence of marrow recovery is observed [see Warnings
and Precautions (5.1)]. In patients who develop significant anemia, dose interruption does not
necessarily eliminate the need for transfusion. If marrow recovery occurs following dose
interruption, resumption in dose may be appropriate using adjunctive measures such as epoetin
alfa at recommended doses, depending on hematologic indices such as serum erythropoetin level
and patient tolerance.
2.4
Patients With Renal Impairment
End-Stage Renal Disease: In patients maintained on hemodialysis or peritoneal
dialysis, the recommended dosage is 100 mg every 6 to 8 hours [see Clinical Pharmacology
(12.3)].
2.5
Patients With Hepatic Impairment
There are insufficient data to recommend dose adjustment of RETROVIR in patients with
mild to moderate impaired hepatic function or liver cirrhosis.
3
DOSAGE FORMS AND STRENGTHS
RETROVIR Tablets 300 mg (biconvex, white, round, film-coated) containing 300 mg
zidovudine, one side engraved “GX CW3” and “300” on the other side.
RETROVIR Capsules 100 mg (white, opaque cap and body) containing 100 mg
zidovudine and printed with “Wellcome” and unicorn logo on cap and “Y9C” and “100” on
body.
RETROVIR Syrup (colorless to pale yellow, strawberry-flavored) containing 50 mg
zidovudine in each teaspoonful (5 mL).
4
CONTRAINDICATIONS
RETROVIR Tablets, Capsules, and Syrup are contraindicated in patients who have had
potentially life-threatening allergic reactions (e.g., anaphylaxis, Stevens-Johnson syndrome) to
any of the components of the formulations.
5
WARNINGS AND PRECAUTIONS
5.1
Hematologic Toxicity/Bone Marrow Suppression
RETROVIR should be used with caution in patients who have bone marrow compromise
evidenced by granulocyte count <1,000 cells/mm3 or hemoglobin <9.5 g/dL. Hematologic
toxicities appear to be related to pretreatment bone marrow reserve and to dose and duration of
therapy. In patients with advanced symptomatic HIV-1 disease, anemia and neutropenia were the
most significant adverse events observed. In patients who experience hematologic toxicity, a
reduction in hemoglobin may occur as early as 2 to 4 weeks, and neutropenia usually occurs after
6 to 8 weeks. There have been reports of pancytopenia associated with the use of RETROVIR,
which was reversible in most instances after discontinuance of the drug. However, significant
anemia, in many cases requiring dose adjustment, discontinuation of RETROVIR, and/or blood
4
Reference ID: 3047317
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
transfusions, has occurred during treatment with RETROVIR alone or in combination with other
antiretrovirals.
Frequent blood counts are strongly recommended to detect severe anemia or neutropenia
in patients with poor bone marrow reserve, particularly in patients with advanced HIV-1 disease
who are treated with RETROVIR. For HIV-1-infected individuals and patients with
asymptomatic or early HIV-1 disease, periodic blood counts are recommended. If anemia or
neutropenia develops, dosage interruption may be needed [see Dosage and Administration
(2.3)].
5.2
Myopathy
Myopathy and myositis with pathological changes, similar to that produced by HIV-1
disease, have been associated with prolonged use of RETROVIR.
5.3
Lactic Acidosis/Severe Hepatomegaly With Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been
reported with the use of nucleoside analogues alone or in combination, including zidovudine and
other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged
exposure to antiretroviral nucleoside analogues may be risk factors. Particular caution should be
exercised when administering RETROVIR to any patient with known risk factors for liver
disease; however, cases have also been reported in patients with no known risk factors.
Treatment with RETROVIR should be suspended in any patient who develops clinical or
laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may
include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
5.4
Use With Interferon- and Ribavirin-Based Regimens in HIV-1/HCV
Co-Infected Patients
In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine
nucleoside analogues such as zidovudine. Although no evidence of a pharmacokinetic or
pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when
ribavirin was coadministered with zidovudine in HIV-1/HCV co-infected patients [see Clinical
Pharmacology (12.3)], exacerbation of anemia due to ribavirin has been reported when
zidovudine is part of the HIV regimen. Coadministration of ribavirin and zidovudine is not
advised. Consideration should be given to replacing zidovudine in established combination
HIV-1/HCV therapy, especially in patients with a known history of zidovudine-induced anemia.
Hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients
receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without
ribavirin. Patients receiving interferon alfa with or without ribavirin and zidovudine should be
closely monitored for treatment-associated toxicities, especially hepatic decompensation,
neutropenia, and anemia.
Discontinuation of zidovudine should be considered as medically appropriate. Dose
reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if
worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh
>6) (see the complete prescribing information for interferon and ribavirin).
Reference ID: 3047317
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
5.5
Use With Other Zidovudine-Containing Products
RETROVIR should not be administered with combination products that contain
zidovudine as one of their components (e.g., COMBIVIR® [lamivudine and zidovudine] Tablets
or TRIZIVIR® [abacavir sulfate, lamivudine, and zidovudine] Tablets).
5.6
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination
antiretroviral therapy, including RETROVIR. During the initial phase of combination
antiretroviral treatment, patients whose immune systems respond may develop an inflammatory
response to indolent or residual opportunistic infections (such as Mycobacterium avium
infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which
may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré
syndrome) have also been reported to occur in the setting of immune reconstitution, however, the
time to onset is more variable, and can occur many months after initiation of treatment.
5.7
Fat Redistribution
Redistribution/accumulation of body fat, including central obesity, dorsocervical fat
enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and
“cushingoid appearance,” have been observed in patients receiving antiretroviral therapy. The
mechanism and long-term consequences of these events are currently unknown. A causal
relationship has not been established.
6
ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the
labeling:
• Hematologic toxicity, including neutropenia and anemia [see Boxed Warning, Warnings and
Precautions (5.1)].
• Symptomatic myopathy [see Boxed Warning, Warnings and Precautions (5.2)].
• Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and
Precautions (5.3)].
• Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [see Warnings
and Precautions (5.4)].
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 to rates in the clinical
trials of another drug and may not reflect the rates observed in practice.
Adults: The frequency and severity of adverse reactions associated with the use of
RETROVIR are greater in patients with more advanced infection at the time of initiation of
therapy.
Table 2 summarizes events reported at a statistically significant greater incidence for
patients receiving RETROVIR in a monotherapy study.
Reference ID: 3047317
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 2. Percentage (%) of Patients With Adverse Reactionsa in Asymptomatic HIV-1
Infection (ACTG 019)
Adverse Reaction
RETROVIR 500 mg/day
(n = 453)
Placebo
(n = 428)
Body as a whole
Asthenia
Headache
Malaise
Gastrointestinal
Anorexia
Constipation
Nausea
Vomiting
9%
b
63%
53%
20%
6%
b
51%
17%
6%
53%
45%
11%
4%
30%
10%
a Reported in ≥5% of study population.
b Not statistically significant versus placebo.
In addition to the adverse reactions listed in Table 2, adverse reactions observed at an
incidence of ≥5% in any treatment arm in clinical studies (NUCA3001, NUCA3002,
NUCB3001, and NUCB3002) were abdominal cramps, abdominal pain, arthralgia, chills,
dyspepsia, fatigue, insomnia, musculoskeletal pain, myalgia, and neuropathy. Additionally, in
these studies hyperbilirubinemia was reported at an incidence of ≤0.8%.
Selected laboratory abnormalities observed during a clinical study of monotherapy with
RETROVIR are shown in Table 3.
Table 3. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Patients With
Asymptomatic HIV-1 Infection (ACTG 019)
Test
(Abnormal Level)
RETROVIR 500 mg/day
(n = 453)
Placebo
(n = 428)
Anemia (Hgb<8 g/dL)
Granulocytopenia (<750 cells/mm3)
Thrombocytopenia (platelets<50,000/mm3)
ALT (>5 x ULN)
AST (>5 x ULN)
1%
2%
0%
3%
1%
<1%
2%
<1%
3%
2%
ULN = Upper limit of normal.
Pediatrics: The clinical adverse reactions reported among adult recipients of
RETROVIR may also occur in pediatric patients.
Study ACTG 300: Selected clinical adverse reactions and physical findings with a
≥5% frequency during therapy with EPIVIR® (lamivudine) Oral Suspension 4 mg/kg twice daily
Reference ID: 3047317
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
plus RETROVIR 160 mg/m2 3 times daily compared with didanosine in therapy-naive (≤56 days
of antiretroviral therapy) pediatric patients are listed in Table 4.
Table 4. Selected Clinical Adverse Reactions and Physical Findings (≥5% Frequency) in
Pediatric Patients in Study ACTG 300
Adverse Reaction
EPIVIR plus
RETROVIR
(n = 236)
Didanosine
(n = 235)
Body as a whole
Fever
Digestive
25%
32%
Hepatomegaly
11%
11%
Nausea & vomiting
8%
7%
Diarrhea
8%
6%
Stomatitis
6%
12%
Splenomegaly
Respiratory
5%
8%
Cough
15%
18%
Abnormal breath sounds/wheezing
Ear, Nose, and Throat
7%
9%
Signs or symptoms of earsa
7%
6%
Nasal discharge or congestion
Other
8%
11%
Skin rashes
12%
14%
Lymphadenopathy
9%
11%
a Includes pain, discharge, erythema, or swelling of an ear.
Selected laboratory abnormalities experienced by therapy-naive (≤56 days of
antiretroviral therapy) pediatric patients are listed in Table 5.
8
Reference ID: 3047317
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 5. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Pediatric
Patients in Study ACTG 300
Test
(Abnormal Level)
EPIVIR plus
RETROVIR
Didanosine
Neutropenia (ANC<400 cells/mm3)
Anemia (Hgb<7.0 g/dL)
Thrombocytopenia (platelets<50,000/mm3)
ALT (>10 x ULN)
AST (>10 x ULN)
Lipase (>2.5 x ULN)
Total amylase (>2.5 x ULN)
8%
4%
1%
1%
2%
3%
3%
3%
2%
3%
3%
4%
3%
3%
ULN = Upper limit of normal.
ANC = Absolute neutrophil count.
Macrocytosis was reported in the majority of pediatric patients receiving RETROVIR
180 mg/m2 every 6 hours in open-label studies. Additionally, adverse reactions reported at an
incidence of <6% in these studies were congestive heart failure, decreased reflexes, ECG
abnormality, edema, hematuria, left ventricular dilation, nervousness/irritability, and weight loss.
Use for the Prevention of Maternal-Fetal Transmission of HIV-1: In a randomized,
double-blind, placebo-controlled trial in HIV-1-infected women and their neonates conducted to
determine the utility of RETROVIR for the prevention of maternal-fetal HIV-1 transmission,
RETROVIR Syrup at 2 mg/kg was administered every 6 hours for 6 weeks to neonates
beginning within 12 hours following birth. The most commonly reported adverse reactions were
anemia (hemoglobin <9.0 g/dL) and neutropenia (<1,000 cells/mm3). Anemia occurred in 22%
of the neonates who received RETROVIR and in 12% of the neonates who received placebo.
The mean difference in hemoglobin values was less than 1.0 g/dL for neonates receiving
RETROVIR compared with neonates receiving placebo. No neonates with anemia required
transfusion and all hemoglobin values spontaneously returned to normal within 6 weeks after
completion of therapy with RETROVIR. Neutropenia in neonates was reported with similar
frequency in the group that received RETROVIR (21%) and in the group that received placebo
(27%). The long-term consequences of in utero and infant exposure to RETROVIR are
unknown.
6.2
Postmarketing Experience
In addition to adverse reactions reported from clinical trials, the following reactions have
been identified during postmarketing use of RETROVIR. Because they are reported voluntarily
from a population of unknown size, estimates of frequency cannot be made. These reactions have
been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or
potential causal connection to RETROVIR.
Body as a Whole: Back pain, chest pain, flu-like syndrome, generalized pain,
redistribution/accumulation of body fat [see Warnings and Precautions (5.7)].
Reference ID: 3047317
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Cardiovascular: Cardiomyopathy, syncope.
Endocrine: Gynecomastia.
Eye: Macular edema.
Gastrointestinal: Dysphagia, flatulence, oral mucosa pigmentation, mouth ulcer.
General: Sensitization reactions including anaphylaxis and angioedema, vasculitis.
Hemic and Lymphatic: Aplastic anemia, hemolytic anemia, leukopenia,
lymphadenopathy, pancytopenia with marrow hypoplasia, pure red cell aplasia.
Hepatobiliary Tract and Pancreas: Hepatitis, hepatomegaly with steatosis, jaundice,
lactic acidosis, pancreatitis.
Musculoskeletal: Increased CPK, increased LDH, muscle spasm, myopathy and
myositis with pathological changes (similar to that produced by HIV-1 disease), rhabdomyolysis,
tremor.
Nervous: Anxiety, confusion, depression, dizziness, loss of mental acuity, mania,
paresthesia, seizures, somnolence, vertigo.
Respiratory: Dyspnea, rhinitis, sinusitis.
Skin: Changes in skin and nail pigmentation, pruritus, Stevens-Johnson syndrome, toxic
epidermal necrolysis, sweat, urticaria.
Special Senses: Amblyopia, hearing loss, photophobia, taste perversion.
Urogenital: Urinary frequency, urinary hesitancy.
7
DRUG INTERACTIONS
7.1
Antiretroviral Agents
Stavudine: Concomitant use of zidovudine with stavudine should be avoided since an
antagonistic relationship has been demonstrated in vitro.
Nucleoside Analogues Affecting DNA Replication: Some nucleoside analogues
affecting DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of
RETROVIR against HIV-1; concomitant use of such drugs should be avoided.
7.2
Doxorubicin
Concomitant use of zidovudine with doxorubicin should be avoided since an antagonistic
relationship has been demonstrated in vitro.
7.3
Hematologic/Bone Marrow Suppressive/Cytotoxic Agents
Coadministration of ganciclovir, interferon alfa, ribavirin, and other bone marrow
suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category C.
In humans, treatment with RETROVIR during pregnancy reduced the rate of
maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to
7.8% for infants born to mothers treated with RETROVIR [see Clinical Studies (14.3)]. There
were no differences in pregnancy-related adverse events between the treatment groups. Animal
10
Reference ID: 3047317
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
reproduction studies in rats and rabbits showed evidence of embryotoxicity and increased fetal
malformations.
A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected
pregnant women to determine the utility of RETROVIR for the prevention of maternal-fetal
HIV-1-transmission [see Clinical Studies (14.3)]. Congenital abnormalities occurred
with similar frequency between neonates born to mothers who received RETROVIR and
neonates born to mothers who received placebo. The observed abnormalities included problems
in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately
after initiation of study drug.
Increased fetal resorptions occurred in pregnant rats and rabbits treated with doses of
zidovudine that produced drug plasma concentrations 66 to 226 times (rats) and 12 to 87 times
(rabbits) the mean steady-state peak human plasma concentration following a single 100-mg
dose of zidovudine. There were no other reported developmental anomalies. In another
developmental toxicity study, pregnant rats received zidovudine up to near-lethal doses that
produced peak plasma concentrations 350 times peak human plasma concentrations (300 times
the daily exposure [AUC] in humans given 600 mg/day zidovudine). This dose was associated
with marked maternal toxicity and an increased incidence of fetal malformations. However, there
were no signs of teratogenicity at doses up to one-fifth the lethal dose [see Nonclinical
Toxicology (13.2)].
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant
women exposed to RETROVIR, an Antiretroviral Pregnancy Registry has been established.
Physicians are encouraged to register patients by calling 1-800-258-4263.
8.3
Nursing Mothers
Zidovudine is excreted in human milk [see Clinical Pharmacology (12.3)].
The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers
in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1
infection. Because of both the potential for HIV-1 transmission and the potential for serious
adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are
receiving RETROVIR.
8.4
Pediatric Use
RETROVIR has been studied in HIV-1-infected pediatric patients ≥6 weeks of age who
had HIV-1-related symptoms or who were asymptomatic with abnormal laboratory values
indicating significant HIV-1-related immunosuppression. RETROVIR has also been studied in
neonates perinatally exposed to HIV-1 [see Dosage and Administration (2.1), Adverse
Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2),
(14.3)].
8.5
Geriatric Use
Clinical studies of RETROVIR 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
11
Reference ID: 3047317
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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.
8.6
Renal Impairment
In patients with severely impaired renal function (CrCl<15 mL/min), dosage reduction is
recommended [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
8.7
Hepatic Impairment
Zidovudine is eliminated from the body primarily by renal excretion following
metabolism in the liver (glucuronidation). Although the data are limited, zidovudine
concentrations appear to be increased in patients with severely impaired hepatic function, which
may increase the risk of hematologic toxicity [see Dosage and Administration (2.5), Clinical
Pharmacology (12.3)].
10
OVERDOSAGE
Acute overdoses of zidovudine have been reported in pediatric patients and adults. These
involved exposures up to 50 grams. No specific symptoms or signs have been identified
following acute overdosage with zidovudine apart from those listed as adverse events such as
fatigue, headache, vomiting, and occasional reports of hematological disturbances. All patients
recovered without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a
negligible effect on the removal of zidovudine while elimination of its primary metabolite, 3′
azido-3′-deoxy-5′-O-β-D-glucopyranuronosylthymidine (GZDV), is enhanced.
11
DESCRIPTION
RETROVIR is the brand name for zidovudine (formerly called azidothymidine [AZT]), a
pyrimidine nucleoside analogue active against HIV-1. The chemical name of zidovudine is 3′
structural formula
Zidovudine is a white to beige, odorless, crystalline solid with a molecular weight of
267.24 and a solubility of 20.1 mg/mL in water at 25°C. The molecular formula is C10H13N5O4.
RETROVIR Tablets are for oral administration. Each film-coated tablet contains 300 mg
of zidovudine and the inactive ingredients hypromellose, magnesium stearate, microcrystalline
cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide.
RETROVIR Capsules are for oral administration. Each capsule contains 100 mg of
zidovudine and the inactive ingredients corn starch, magnesium stearate, microcrystalline
12
Reference ID: 3047317
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
cellulose, and sodium starch glycolate. The 100-mg empty hard gelatin capsule, printed with
edible black ink, consists of black iron oxide, dimethylpolysiloxane, gelatin, pharmaceutical
shellac, soya lecithin, and titanium dioxide.
RETROVIR Syrup is for oral administration. Each teaspoonful (5 mL) of RETROVIR
Syrup contains 50 mg of zidovudine and the inactive ingredients sodium benzoate 0.2% (added
as a preservative), citric acid, flavors, glycerin, and liquid sucrose. Sodium hydroxide may be
added to adjust pH.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Zidovudine is an antiviral agent [see Clinical Pharmacology (12.4)].
12.3 Pharmacokinetics
Absorption and Bioavailability: In adults, following oral administration, zidovudine is
rapidly absorbed and extensively distributed, with peak serum concentrations occurring within
0.5 to 1.5 hours. The AUC was equivalent when zidovudine was administered as RETROVIR
Tablets or Syrup compared with RETROVIR Capsules. The pharmacokinetic properties of
zidovudine in fasting adult patients are summarized in Table 6.
Table 6. Zidovudine Pharmacokinetic Parameters in Fasting Adult Patients
Parameter
Mean ± SD
(except where noted)
Oral bioavailability (%)
64 ± 10
(n = 5)
Apparent volume of distribution (L/kg)
1.6 ± 0.6
(n = 8)
Plasma protein binding (%)
<38
CSF:plasma ratioa
0.6 [0.04 to 2.62]
(n = 39)
Systemic clearance (L/hr/kg)
1.6 ± 0.6
(n = 6)
Renal clearance (L/hr/kg)
0.34 ± 0.05
(n = 9)
Elimination half-life (hr)b
0.5 to 3
(n = 19)
a Median [range].
b Approximate range.
Distribution: The apparent volume of distribution of zidovudine, following oral
administration, is 1.6 ± 0.6 L/kg; and binding to plasma protein is low, <38% (Table 6).
Reference ID: 3047317
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Metabolism and Elimination: Zidovudine is primarily eliminated by hepatic
metabolism. The major metabolite of zidovudine is GZDV. GZDV AUC is about 3-fold greater
than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and
74%, respectively, of the dose following oral administration. A second metabolite, 3′-amino-3′
deoxythymidine (AMT), has been identified in the plasma following single-dose intravenous
(IV) administration of zidovudine. The AMT AUC was one-fifth of the zidovudine AUC.
Pharmacokinetics of zidovudine were dose independent at oral dosing regimens ranging from
2 mg/kg every 8 hours to 10 mg/kg every 4 hours.
Effect of Food on Absorption: RETROVIR may be administered with or without food.
The zidovudine AUC was similar when a single dose of zidovudine was administered with food.
Special Populations: Renal Impairment: Zidovudine clearance was decreased
resulting in increased zidovudine and GZDV half-life and AUC in patients with impaired renal
function (n = 14) following a single 200-mg oral dose (Table 7). Plasma concentrations of AMT
were not determined. A dose adjustment should not be necessary for patients with creatinine
clearance (CrCl) ≥15 mL/min.
Table 7. Zidovudine Pharmacokinetic Parameters in Patients With Severe Renal
Impairmenta
Parameter
Control Subjects
(Normal Renal Function)
(n = 6)
Patients With Renal
Impairment
(n = 14)
CrCl (mL/min)
120 ± 8
18 ± 2
Zidovudine AUC (ng•hr/mL)
1,400 ± 200
3,100 ± 300
Zidovudine half-life (hr)
1.0 ± 0.2
1.4 ± 0.1
a Data are expressed as mean ± standard deviation.
Hemodialysis and Peritoneal Dialysis: The pharmacokinetics and tolerance of
zidovudine were evaluated in a multiple-dose study in patients undergoing hemodialysis (n = 5)
or peritoneal dialysis (n = 6) receiving escalating doses up to 200 mg 5 times daily for 8 weeks.
Daily doses of 500 mg or less were well tolerated despite significantly elevated GZDV plasma
concentrations. Apparent zidovudine oral clearance was approximately 50% of that reported in
patients with normal renal function. Hemodialysis and peritoneal dialysis appeared to have a
negligible effect on the removal of zidovudine, whereas GZDV elimination was enhanced. A
dosage adjustment is recommended for patients undergoing hemodialysis or peritoneal dialysis
[see Dosage and Administration (2.4)].
Hepatic Impairment: Data describing the effect of hepatic impairment on the
pharmacokinetics of zidovudine are limited. However, because zidovudine is eliminated
primarily by hepatic metabolism, it is expected that zidovudine clearance would be decreased
and plasma concentrations would be increased following administration of the recommended
adult doses to patients with hepatic impairment [see Dosage and Administration (2.5)].
14
Reference ID: 3047317
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pediatric Patients: Zidovudine pharmacokinetics have been evaluated in
HIV-1-infected pediatric patients (Table 8).
Patients Aged 3 Months to 12 Years: Overall, zidovudine pharmacokinetics in
pediatric patients greater than 3 months of age are similar to those in adult patients. Proportional
increases in plasma zidovudine concentrations were observed following administration of oral
solution from 90 to 240 mg/m2 every 6 hours. Oral bioavailability, terminal half-life, and oral
clearance were comparable to adult values. As in adult patients, the major route of elimination
was by metabolism to GZDV. After intravenous dosing, about 29% of the dose was excreted in
the urine unchanged, and about 45% of the dose was excreted as GZDV [see Dosage and
Administration (2.1)].
Patients Aged Less Than 3 Months: Zidovudine pharmacokinetics have been
evaluated in pediatric patients from birth to 3 months of life. Zidovudine elimination was
determined immediately following birth in 8 neonates who were exposed to zidovudine in utero.
The half-life was 13.0 ± 5.8 hours. In neonates ≤14 days old, bioavailability was greater, total
body clearance was slower, and half-life was longer than in pediatric patients >14 days old. For
dose recommendations for neonates [see Dosage and Administration (2.2)].
Table 8. Zidovudine Pharmacokinetic Parameters in Pediatric Patientsa
Parameter
Birth to 14 Days
Aged 14 Days to
3 Months
Aged 3 Months to
12 Years
Oral bioavailability (%)
89 ± 19
(n = 15)
61 ± 19
(n = 17)
65 ± 24
(n = 18)
CSF:plasma ratio
no data
no data
0.68 [0.03 to 3.25]b
(n = 38)
CL (L/hr/kg)
0.65 ± 0.29
(n = 18)
1.14 ± 0.24
(n = 16)
1.85 ± 0.47
(n = 20)
Elimination half-life (hr)
3.1 ± 1.2
(n = 21)
1.9 ± 0.7
(n = 18)
1.5 ± 0.7
(n = 21)
a Data presented as mean ± standard deviation except where noted.
b Median [range].
Pregnancy: Zidovudine pharmacokinetics have been studied in a Phase I study of
8 women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to
those of nonpregnant adults. Consistent with passive transmission of the drug across the
placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in
maternal plasma at delivery [see Use in Specific Populations (8.1)].
Although data are limited, methadone maintenance therapy in 5 pregnant women did not
appear to alter zidovudine pharmacokinetics.
Nursing Mothers: The Centers for Disease Control and Prevention recommend that
HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of
15
Reference ID: 3047317
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
HIV-1. After administration of a single dose of 200 mg zidovudine to 13 HIV-1-infected women,
the mean concentration of zidovudine was similar in human milk and serum [see Use in Specific
Populations (8.3)].
Geriatric Patients: Zidovudine pharmacokinetics have not been studied in patients
over 65 years of age.
Gender: A pharmacokinetic study in healthy male (n = 12) and female (n = 12)
subjects showed no differences in zidovudine AUC when a single dose of zidovudine was
administered as the 300-mg RETROVIR Tablet.
Drug Interactions: [See Drug Interactions (7)].
16
Reference ID: 3047317
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 9. Effect of Coadministered Drugs on Zidovudine AUCa
Note: ROUTINE DOSE MODIFICATION OF ZIDOVUDINE IS NOT WARRANTED
WITH COADMINISTRATION OF THE FOLLOWING DRUGS.
Coadministered
Drug and Dose
Zidovudine
Dose
n
Zidovudine
Concentrations
Concentration of
Coadministered
Drug
AUC
Variability
Atovaquone
750 mg q 12 hr
with food
200 mg q 8 hr
14
↑AUC
31%
Range
23% to 78%b
↔
Clarithromycin
500 mg twice daily
100 mg q 4 hr
x 7 days
4
↓AUC
12%
Range
↓34% to ↑14%
Not Reported
Fluconazole
400 mg daily
200 mg q 8 hr
12
↑AUC
74%
95% CI:
54% to 98%
Not Reported
Lamivudine
300 mg q 12 hr
single 200 mg
12
↑AUC
13%
90% CI:
2% to 27%
↔
Methadone
30 to 90 mg daily
200 mg q 4 hr
9
↑AUC
43%
Range
16% to 64%b
↔
Nelfinavir
750 mg q 8 hr x
7 to 10 days
single 200 mg
11
↓AUC
35%
Range
28% to 41%
↔
Probenecid
500 mg q 6 hr x
2 days
2 mg/kg q 8 hr
x 3 days
3
↑AUC
106%
Range
100% to 170%b
Not Assessed
Rifampin
600 mg daily x
14 days
200 mg q 8 hr
x 14 days
8
↓AUC
47%
90% CI:
41% to 53%
Not Assessed
Ritonavir
300 mg q 6 hr x
4 days
200 mg q 8 hr
x 4 days
9
↓AUC
25%
95% CI:
15% to 34%
↔
Valproic acid
250 mg or 500 mg
q 8 hr x 4 days
100 mg q 8 hr
x 4 days
6
↑AUC
80%
Range
64% to 130%b
Not Assessed
↑ = Increase; ↓ = Decrease; ↔ = no significant change; AUC = area under the concentration
versus time curve; CI = confidence interval.
a This table is not all inclusive.
b Estimated range of percent difference.
Phenytoin: Phenytoin plasma levels have been reported to be low in some patients
receiving RETROVIR, while in one case a high level was documented. However, in a
pharmacokinetic interaction study in which 12 HIV-1-positive volunteers received a single
17
Reference ID: 3047317
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
300-mg phenytoin dose alone and during steady-state zidovudine conditions (200 mg every
4 hours), no change in phenytoin kinetics was observed. Although not designed to optimally
assess the effect of phenytoin on zidovudine kinetics, a 30% decrease in oral zidovudine
clearance was observed with phenytoin.
Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine,
stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or
intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss
of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine
(n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug
regimen to HIV-1/HCV co-infected patients [see Warnings and Precautions (5.4)].
12.4 Microbiology
Mechanism of Action: Zidovudine is a synthetic nucleoside analogue. Intracellularly,
zidovudine is phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate
(ZDV-TP). The principal mode of action of ZDV-TP is inhibition of reverse transcriptase (RT)
via DNA chain termination after incorporation of the nucleotide analogue. ZDV-TP is a weak
inhibitor of the cellular DNA polymerases α and γ and has been reported to be incorporated into
the DNA of cells in culture.
Antiviral Activity: The antiviral activity of zidovudine against HIV-1 was assessed in a
number of cell lines (including monocytes and fresh human peripheral blood lymphocytes). The
EC50 and EC90 values for zidovudine were 0.01 to 0.49 µM (1 μM = 0.27 mcg/mL) and 0.1 to
9 μM, respectively. HIV-1 from therapy-naive subjects with no mutations associated with
resistance gave median EC50 values of 0.011 µM (range: 0.005 to 0.110 µM) from Virco
(n = 92 baseline samples from COL40263) and 0.0017 µM (0.006 to 0.0340 µM) from
Monogram Biosciences (n = 135 baseline samples from ESS30009). The EC50 values of
zidovudine against different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 μM, and against
HIV-2 isolates from 0.00049 to 0.004 μM. In cell culture drug combination studies, zidovudine
demonstrates synergistic activity with the nucleoside reverse transcriptase inhibitors abacavir,
didanosine, and lamivudine; the non-nucleoside reverse transcriptase inhibitors delavirdine and
nevirapine; and the protease inhibitors indinavir, nelfinavir, ritonavir, and saquinavir; and
additive activity with interferon alfa. Ribavirin has been found to inhibit the phosphorylation of
zidovudine in cell culture.
Resistance: Genotypic analyses of the isolates selected in cell culture and recovered
from zidovudine-treated patients showed mutations in the HIV-1 RT gene resulting in 6 amino
acid substitutions (M41L, D67N, K70R, L210W, T215Y or F, and K219Q) that confer
zidovudine resistance. In general, higher levels of resistance were associated with greater number
of amino acid substitutions. In some patients harboring zidovudine-resistant virus at baseline,
phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and
zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of
substitutions conferring resistance to zidovudine.
Reference ID: 3047317
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Cross-Resistance: In a study of 167 HIV-1-infected patients, isolates (n = 2) with
multi-drug resistance to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine were
recovered from patients treated for ≥1 year with zidovudine plus didanosine or zidovudine plus
zalcitabine. The pattern of resistance-associated amino acid substitutions with such combination
therapies was different (A62V, V75I, F77L, F116Y, Q151M) from the pattern with zidovudine
monotherapy, with the Q151M substitution being most commonly associated with multi-drug
resistance. The substitution at codon 151 in combination with substitutions at 62, 75, 77, and 116
results in a virus with reduced susceptibility to didanosine, lamivudine, stavudine, zalcitabine,
and zidovudine. Thymidine analogue mutations (TAMs) are selected by zidovudine and confer
cross-resistance to abacavir, didanosine, stavudine, tenofovir, and zalcitabine.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Zidovudine was administered orally at 3 dosage levels to separate groups of mice and rats
(60 females and 60 males in each group). Initial single daily doses were 30, 60, and
120 mg/kg/day in mice and 80, 220, and 600 mg/kg/day in rats. The doses in mice were reduced
to 20, 30, and 40 mg/kg/day after day 90 because of treatment-related anemia, whereas in rats
only the high dose was reduced to 450 mg/kg/day on day 91 and then to 300 mg/kg/day on
day 279.
In mice, 7 late-appearing (after 19 months) vaginal neoplasms (5 nonmetastasizing
squamous cell carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in
animals given the highest dose. One late-appearing squamous cell papilloma occurred in the
vagina of a middle-dose animal. No vaginal tumors were found at the lowest dose.
In rats, 2 late-appearing (after 20 months), nonmetastasizing vaginal squamous cell
carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or
middle dose in rats. No other drug-related tumors were observed in either sex of either species.
At doses that produced tumors in mice and rats, the estimated drug exposure (as
measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human
exposure at the recommended therapeutic dose of 100 mg every 4 hours.
It is not known how predictive the results of rodent carcinogenicity studies may be for
humans.
Zidovudine was mutagenic in a 5178Y/TK+/- mouse lymphoma assay, positive in an in
vitro cell transformation assay, clastogenic in a cytogenetic assay using cultured human
lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was
negative in a cytogenetic study in rats given a single dose.
Zidovudine, administered to male and female rats at doses up to 7 times the usual adult
dose based on body surface area, had no effect on fertility judged by conception rates.
Two transplacental carcinogenicity studies were conducted in mice. One study
administered zidovudine at doses of 20 mg/kg/day or 40 mg/kg/day from gestation day 10
through parturition and lactation with dosing continuing in offspring for 24 months postnatally.
19
Reference ID: 3047317
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The doses of zidovudine administered in this study produced zidovudine exposures
approximately 3 times the estimated human exposure at recommended doses. After 24 months,
an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or
lung or any other organ in either gender. These findings are consistent with results of the
standard oral carcinogenicity study in mice, as described earlier. A second study administered
zidovudine at maximum tolerated doses of 12.5 mg/day or 25 mg/day (∼1,000 mg/kg
nonpregnant body weight or ∼450 mg/kg of term body weight) to pregnant mice from days 12
through 18 of gestation. There was an increase in the number of tumors in the lung, liver, and
female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine.
13.2 Reproductive and Developmental Toxicology Studies
Oral teratology studies in the rat and in the rabbit at doses up to 500 mg/kg/day revealed
no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted in embryo/fetal
toxicity as evidenced by an increase in the incidence of fetal resorptions in rats given 150 or
450 mg/kg/day and rabbits given 500 mg/kg/day. The doses used in the teratology studies
resulted in peak zidovudine plasma concentrations (after one-half of the daily dose) in rats 66 to
226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma concentrations
(after one-sixth of the daily dose) achieved with the recommended daily dose (100 mg every
4 hours). In an in vitro experiment with fertilized mouse oocytes, zidovudine exposure resulted
in a dose-dependent reduction in blastocyst formation. In an additional teratology study in rats, a
dose of 3,000 mg/kg/day (very near the oral median lethal dose in rats of 3,683 mg/kg) caused
marked maternal toxicity and an increase in the incidence of fetal malformations. This dose
resulted in peak zidovudine plasma concentrations 350 times peak human plasma concentrations.
(Estimated AUC in rats at this dose level was 300 times the daily AUC in humans given
600 mg/day.) No evidence of teratogenicity was seen in this experiment at doses of
600 mg/kg/day or less.
14
CLINICAL STUDIES
Therapy with RETROVIR has been shown to prolong survival and decrease the incidence
of opportunistic infections in patients with advanced HIV-1 disease and to delay disease
progression in asymptomatic HIV-1-infected patients.
14.1 Adults
Combination Therapy: RETROVIR in combination with other antiretroviral agents has
been shown to be superior to monotherapy for one or more of the following endpoints: delaying
death, delaying development of AIDS, increasing CD4+ cell counts, and decreasing plasma
HIV-1 RNA.
The clinical efficacy of a combination regimen that includes RETROVIR was
demonstrated in study ACTG 320. This study was a multi-center, randomized, double-blind,
placebo-controlled trial that compared RETROVIR 600 mg/day plus EPIVIR 300 mg/day to
RETROVIR plus EPIVIR plus indinavir 800 mg three times daily. The incidence of AIDS-
20
Reference ID: 3047317
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
defining events or death was lower in the triple-drug–containing arm compared with the 2-drug–
containing arm (6.1% versus 10.9%, respectively).
Monotherapy: In controlled studies of treatment-naive patients conducted between 1986
and 1989, monotherapy with RETROVIR, as compared with placebo, reduced the risk of HIV-1
disease progression, as assessed using endpoints that included the occurrence of HIV-1-related
illnesses, AIDS-defining events, or death. These studies enrolled patients with advanced disease
(BW 002), and asymptomatic or mildly symptomatic disease in patients with CD4+ cell counts
between 200 and 500 cells/mm3 (ACTG 016 and ACTG 019). A survival benefit for
monotherapy with RETROVIR was not demonstrated in the latter 2 studies. Subsequent studies
showed that the clinical benefit of monotherapy with RETROVIR was time limited.
14.2 Pediatric Patients
ACTG 300 was a multi-center, randomized, double-blind study that provided for
comparison of EPIVIR plus RETROVIR to didanosine monotherapy. A total of
471 symptomatic, HIV-1-infected therapy-naive pediatric patients were enrolled in these
2 treatment arms. The median age was 2.7 years (range: 6 weeks to 14 years), the mean baseline
CD4+ cell count was 868 cells/mm3, and the mean baseline plasma HIV-1 RNA was
5.0 log10 copies/mL. The median duration that patients remained on study was approximately
10 months. Results are summarized in Table 10.
Table 10. Number of Patients (%) Reaching a Primary Clinical Endpoint (Disease
Progression or Death)
EPIVIR plus RETROVIR
Didanosine
Endpoint
(n = 236)
(n = 235)
HIV disease progression or death (total)
15 (6.4%)
37 (15.7%)
Physical growth failure
7 (3.0%)
6 (2.6%)
Central nervous system deterioration
4 (1.7%)
12 (5.1%)
CDC Clinical Category C
2 (0.8%)
8 (3.4%)
Death
2 (0.8%)
11 (4.7%)
14.3 Prevention of Maternal-Fetal HIV-1 Transmission
The utility of RETROVIR for the prevention of maternal-fetal HIV-1 transmission was
demonstrated in a randomized, double-blind, placebo-controlled trial (ACTG 076) conducted in
HIV-1-infected pregnant women with CD4+ cell counts of 200 to 1,818 cells/mm3 (median in
the treated group: 560 cells/mm3) who had little or no previous exposure to RETROVIR. Oral
RETROVIR was initiated between 14 and 34 weeks of gestation (median 11 weeks of therapy)
followed by IV administration of RETROVIR during labor and delivery. Following birth,
neonates received oral RETROVIR Syrup for 6 weeks. The study showed a statistically
significant difference in the incidence of HIV-1 infection in the neonates (based on viral culture
from peripheral blood) between the group receiving RETROVIR and the group receiving
placebo. Of 363 neonates evaluated in the study, the estimated risk of HIV-1 infection was 7.8%
21
Reference ID: 3047317
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
in the group receiving RETROVIR and 24.9% in the placebo group, a relative reduction in
transmission risk of 68.7%. RETROVIR was well tolerated by mothers and infants. There was
no difference in pregnancy-related adverse events between the treatment groups.
16
HOW SUPPLIED/STORAGE AND HANDLING
RETROVIR Tablets 300 mg (biconvex, white, round, film-coated) containing 300 mg
zidovudine, one side engraved “GX CW3” and “300” on the other side.
Bottle of 60 (NDC 49702-214-18).
Store at 15° to 25°C (59° to 77°F).
RETROVIR Capsules 100 mg (white, opaque cap and body) containing 100 mg
zidovudine and printed with “Wellcome” and unicorn logo on cap and “Y9C” and “100” on
body.
Bottles of 100 (NDC 49702-211-20).
Store at 15° to 25°C (59° to 77°F) and protect from moisture.
RETROVIR Syrup (colorless to pale yellow, strawberry-flavored) containing 50 mg
zidovudine in each teaspoonful (5 mL).
Bottle of 240 mL (NDC 49702-212-48) with child-resistant cap.
Store at 15° to 25°C (59° to 77°F).
17
PATIENT COUNSELING INFORMATION
17.1 Advice for the Patient
Neutropenia and Anemia: Patients should be informed that the major toxicities of
RETROVIR are neutropenia and/or anemia. The frequency and severity of these toxicities are
greater in patients with more advanced disease and in those who initiate therapy later in the
course of their infection. Patients should be informed that if toxicity develops, they may require
transfusions or drug discontinuation. Patients should be informed of the extreme importance of
having their blood counts followed closely while on therapy, especially for patients with
advanced symptomatic HIV-1 disease [see Boxed Warning, Warnings and Precautions (5.1)].
Myopathy: Patients should be informed that myopathy and myositis with pathological
changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of
RETROVIR [see Boxed Warning, Warnings and Precautions (5.2)].
Lactic Acidosis/Hepatomegaly: Patients should be informed that some HIV medicines,
including RETROVIR, can cause a rare, but serious condition called lactic acidosis with liver
enlargement (hepatomegaly) [see Boxed Warning, Warnings and Precautions (5.3)].
HIV-1/HCV Co-Infection: Patients with HIV-1/HCV co-infection should be informed
that hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients
receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without
ribavirin [see Warnings and Precautions (5.4)].
Use With Other Zidovudine-Containing Products: RETROVIR should not be
administered with combination products that contain zidovudine as one of their components
22
Reference ID: 3047317
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
(e.g., COMBIVIR [lamivudine and zidovudine] Tablets or TRIZIVIR [abacavir sulfate,
lamivudine, and zidovudine] Tablets) [see Warnings and Precautions (5.5)].
Redistribution/Accumulation of Body Fat: Patients should be informed that
redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy
and that the cause and long-term health effects of these conditions are not known at this time
[see Warnings and Precautions (5.7)].
Common Adverse Reactions: Patients should be informed that the most commonly
reported adverse reactions in adult patients being treated with RETROVIR were headache,
malaise, nausea, anorexia, and vomiting. The most commonly reported adverse reactions in
pediatric patients receiving RETROVIR were fever, cough, and digestive disorders. Patients also
should be encouraged to contact their physician if they experience muscle weakness, shortness of
breath, symptoms of hepatitis or pancreatitis, or any other unexpected adverse events while being
treated with RETROVIR [see Adverse Reactions (6)].
Drug Interactions: Patients should be cautioned about the use of other medications,
including ganciclovir, interferon alfa, and ribavirin, which may exacerbate the toxicity of
RETROVIR [see Drug Interactions (7)].
Pregnancy: Pregnant women considering the use of RETROVIR during pregnancy for
prevention of HIV-1 transmission to their infants should be informed that transmission may still
occur in some cases despite therapy. The long-term consequences of in utero and infant exposure
to RETROVIR are unknown, including the possible risk of cancer [see Use in Specific
Populations (8.1)].
HIV-1-infected pregnant women should be informed not to breastfeed to avoid postnatal
transmission of HIV to a child who may not yet be infected [see Use in Specific Populations
(8.3)].
Information About HIV-1 Infection: RETROVIR is not a cure for HIV-1 infection, and
patients may continue to experience illnesses associated with HIV-1 infection, including
opportunistic infections. Patients should remain under the care of a physician when using
RETROVIR. Patients should be advised to avoid doing things that can spread HIV-1 infection
to others.
• Do not share needles or other injection equipment.
• Do not share personal items that can have blood or body fluids on them, like
toothbrushes and razor blades.
• Do not have any kind of sex without protection. Always practice safe sex by using a
latex or polyurethane condom or other barrier method to lower the chance of sexual
contact with semen, vaginal secretions, or blood.
• Do not breastfeed. Zidovudine is excreted in human breast milk. Mothers with HIV-1
should not breastfeed because HIV-1 can be passed to the baby in the breast milk.
Patients should be informed to take all HIV medications exactly as prescribed.
23
Reference ID: 3047317
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
RETROVIR, COMBIVIR, EPIVIR, and TRIZIVIR are registered trademarks of ViiV
Healthcare.
company logo
Research Triangle Park, NC 27709
comp
any logo
Research Triangle Park, NC 27709
©2011, ViiV Healthcare. All rights reserved.
November 2011
RTT:PI
24
Reference ID: 3047317
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:39.215725
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019655s052,019910s039,020518s022lbl.pdf', 'application_number': 19655, 'submission_type': 'SUPPL ', 'submission_number': 52}
|
11,606
|
NDA 19-655/S-041
NDA 19-910/S-029
NDA 20-518/S-013
Page 3
PRESCRIBING INFORMATION
RETROVIR®
FINAL AGREED-UPON PI 05/08/2006
(zidovudine)
Tablets
RETROVIR®
(zidovudine)
Capsules
RETROVIR®
(zidovudine)
Syrup
WARNING
RETROVIR (ZIDOVUDINE) HAS BEEN ASSOCIATED WITH HEMATOLOGIC
TOXICITY INCLUDING NEUTROPENIA AND SEVERE ANEMIA PARTICULARLY IN
PATIENTS WITH ADVANCED HUMAN IMMUNODEFICIENCY VIRUS (HIV) DISEASE
(SEE WARNINGS). PROLONGED USE OF RETROVIR HAS BEEN ASSOCIATED WITH
SYMPTOMATIC MYOPATHY.
LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS,
INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE
ANALOGUES ALONE OR IN COMBINATION, INCLUDING RETROVIR AND OTHER
ANTIRETROVIRALS (SEE WARNINGS).
DESCRIPTION
RETROVIR is the brand name for zidovudine (formerly called azidothymidine [AZT]), a
pyrimidine nucleoside analogue active against HIV.
Tablets: RETROVIR Tablets are for oral administration. Each film-coated tablet contains 300 mg of
zidovudine and the inactive ingredients hypromellose, magnesium stearate, microcrystalline cellulose,
polyethylene glycol, sodium starch glycolate, and titanium dioxide.
Capsules: RETROVIR Capsules are for oral administration. Each capsule contains 100 mg of
zidovudine and the inactive ingredients corn starch, magnesium stearate, microcrystalline cellulose,
and sodium starch glycolate. The 100-mg empty hard gelatin capsule, printed with edible black ink,
consists of black iron oxide, dimethylpolysiloxane, gelatin, pharmaceutical shellac, soya lecithin, and
titanium dioxide. The blue band around the capsule consists of gelatin and FD&C Blue No. 2.
Syrup: RETROVIR Syrup is for oral administration. Each teaspoonful (5 mL) of RETROVIR Syrup
contains 50 mg of zidovudine and the inactive ingredients sodium benzoate 0.2% (added as a
preservative), citric acid, flavors, glycerin, and liquid sucrose. Sodium hydroxide may be added to
adjust pH.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-655/S-041
NDA 19-910/S-029
NDA 20-518/S-013
Page 4
The chemical name of zidovudine is 3′-azido-3′-deoxythymidine; it has the following structural
formula:
Zidovudine is a white to beige, odorless, crystalline solid with a molecular weight of 267.24 and a
solubility of 20.1 mg/mL in water at 25°C. The molecular formula is C10H13N5O4.
MICROBIOLOGY
Mechanism of Action: Zidovudine is a synthetic nucleoside analogue. Intracellularly, zidovudine is
phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The
principal mode of action of ZDV-TP is inhibition of RT via DNA chain termination after incorporation
of the nucleotide analogue. ZDV-TP is a weak inhibitor of the cellular DNA polymerases α and γ and
has been reported to be incorporated into the DNA of cells in culture.
Antiviral Activity: In vitro activity of zidovudine against HIV-1 was assessed in a number of cell
lines (including monocytes and fresh human peripheral blood lymphocytes). The IC50 and IC90 values
for zidovudine were 0.01 to 0.49 µM (1 µM = 0.27 mcg/mL) and 0.1 to 9 µM, respectively.
Zidovudine had anti–HIV-1 activity in all acute virus-cell infections tested. However, zidovudine
activity was substantially less in chronically infected cell lines. The IC50 values of zidovudine against
different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 µM, and against HIV-2 isolates from
0.00049 to 0.004 µM. In cell culture drug combination studies, zidovudine demonstrates synergistic
activity with the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, didanosine, lamivudine,
and zalcitabine; the non-nucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine and
nevirapine; and the protease inhibitors (PIs) indinavir, nelfinavir, ritonavir, and saquinavir; and
additive activity with interferon alfa. Ribavirin has been found to inhibit the phosphorylation of
zidovudine in vitro.
Resistance: Genotypic analyses of the isolates selected in vitro and recovered from
zidovudine-treated patients showed mutations in the HIV-1 RT gene resulting in 6 amino acid
substitutions (M41L, D67N, K70R, L210W, T215Y or F, and K219Q) that confer zidovudine
resistance. In general, higher levels of resistance were associated with greater number of mutations. In
some patients harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine
was restored by 12 weeks of treatment with lamivudine and zidovudine. Combination therapy with
lamivudine plus zidovudine delayed the emergence of mutations conferring resistance to zidovudine.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-655/S-041
NDA 19-910/S-029
NDA 20-518/S-013
Page 5
Cross-Resistance: In a study of 167 HIV-infected patients, isolates (n = 2) with multi-drug
resistance to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine were recovered from
patients treated for ≥1 year with zidovudine plus didanosine or zidovudine plus zalcitabine. The pattern
of resistance-associated mutations with such combination therapies was different (A62V, V75I, F77L,
F116Y, Q151M) from the pattern with zidovudine monotherapy, with the Q151M mutation being most
commonly associated with multi-drug resistance. The mutation at codon 151 in combination with
mutations at 62, 75, 77, and 116 results in a virus with reduced susceptibility to didanosine,
lamivudine, stavudine, zalcitabine, and zidovudine. Thymidine analogue mutations (TAMs) are
selected by zidovudine and confer cross-resistance to abacavir, didanosine, stavudine, tenofovir, and
zalcitabine.
CLINICAL PHARMACOLOGY
Pharmacokinetics: Adults: The pharmacokinetic properties of zidovudine in fasting patients are
summarized in Table 1. Following oral administration, zidovudine is rapidly absorbed and extensively
distributed, with peak serum concentrations occurring within 0.5 to 1.5 hours. Binding to plasma
protein is low. Zidovudine is primarily eliminated by hepatic metabolism. The major metabolite of
zidovudine is 3′-azido-3′-deoxy-5′-O-β-D-glucopyranuronosylthymidine (GZDV). GZDV area under
the curve (AUC) is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and
GZDV accounts for 14% and 74%, respectively, of the dose following oral administration. A second
metabolite, 3′-amino-3′-deoxythymidine (AMT), has been identified in the plasma following
single-dose intravenous (IV) administration of zidovudine. The AMT AUC was one fifth of the
zidovudine AUC. Pharmacokinetics of zidovudine were dose independent at oral dosing regimens
ranging from 2 mg/kg every 8 hours to 10 mg/kg every 4 hours.
The extent of absorption (AUC) was equivalent when zidovudine was administered as RETROVIR
Tablets or Syrup compared to RETROVIR Capsules.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-655/S-041
NDA 19-910/S-029
NDA 20-518/S-013
Page 6
Table 1. Zidovudine Pharmacokinetic Parameters in Fasting Adult Patients
Parameter
Mean ± SD
(except where noted)
Oral bioavailability (%)
64 ± 10
(n = 5)
Apparent volume of distribution (L/kg)
1.6 ± 0.6
(n = 8)
Plasma protein binding (%)
<38
CSF:plasma ratio*
0.6 [0.04 to 2.62]
(n = 39)
Systemic clearance (L/hr/kg)
1.6 ± 0.6
(n = 6)
Renal clearance (L/hr/kg)
0.34 ± 0.05
(n = 9)
Elimination half-life (hr)†
0.5 to 3
(n = 19)
*Median [range].
†Approximate range.
Adults With Impaired Renal Function: Zidovudine clearance was decreased resulting in
increased zidovudine and GZDV half-life and AUC in patients with impaired renal function (n = 14)
following a single 200-mg oral dose (Table 2). Plasma concentrations of AMT were not determined. A
dose adjustment should not be necessary for patients with creatinine clearance (CrCl) ≥15 mL/min.
Table 2. Zidovudine Pharmacokinetic Parameters in Patients With Severe Renal Impairment*
Parameter
Control Subjects
(Normal Renal Function)
(n = 6)
Patients With Renal
Impairment
(n = 14)
CrCl (mL/min)
120 ± 8
18 ± 2
Zidovudine AUC (ng•hr/mL)
1,400 ± 200
3,100 ± 300
Zidovudine half-life (hr)
1.0 ± 0.2
1.4 ± 0.1
*Data are expressed as mean ± standard deviation.
The pharmacokinetics and tolerance of zidovudine were evaluated in a multiple-dose study in patients
undergoing hemodialysis (n = 5) or peritoneal dialysis (n = 6) receiving escalating doses up to 200 mg
5 times daily for 8 weeks. Daily doses of 500 mg or less were well tolerated despite significantly
elevated GZDV plasma concentrations. Apparent zidovudine oral clearance was approximately 50% of
that reported in patients with normal renal function. Hemodialysis and peritoneal dialysis appeared to
have a negligible effect on the removal of zidovudine, whereas GZDV elimination was enhanced. A
dosage adjustment is recommended for patients undergoing hemodialysis or peritoneal dialysis (see
DOSAGE AND ADMINISTRATION: Dose Adjustment).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-655/S-041
NDA 19-910/S-029
NDA 20-518/S-013
Page 7
Adults With Impaired Hepatic Function: Data describing the effect of hepatic impairment on
the pharmacokinetics of zidovudine are limited. However, because zidovudine is eliminated primarily
by hepatic metabolism, it is expected that zidovudine clearance would be decreased and plasma
concentrations would be increased following administration of the recommended adult doses to
patients with hepatic impairment (see DOSAGE AND ADMINISTRATION: Dose Adjustment).
Pediatrics: Zidovudine pharmacokinetics have been evaluated in HIV-infected pediatric patients
(Table 3).
Patients From 3 Months to 12 Years of Age: Overall, zidovudine pharmacokinetics in
pediatric patients greater than 3 months of age are similar to those in adult patients. Proportional
increases in plasma zidovudine concentrations were observed following administration of oral solution
from 90 to 240 mg/m2 every 6 hours. Oral bioavailability, terminal half-life, and oral clearance were
comparable to adult values. As in adult patients, the major route of elimination was by metabolism to
GZDV. After intravenous dosing, about 29% of the dose was excreted in the urine unchanged, and
about 45% of the dose was excreted as GZDV (see DOSAGE AND ADMINISTRATION: Pediatrics).
Patients Younger Than 3 Months of Age: Zidovudine pharmacokinetics have been
evaluated in pediatric patients from birth to 3 months of life. Zidovudine elimination was determined
immediately following birth in 8 neonates who were exposed to zidovudine in utero. The half-life was
13.0 ± 5.8 hours. In neonates ≤14 days old, bioavailability was greater, total body clearance was
slower, and half-life was longer than in pediatric patients >14 days old. For dose recommendations for
neonates, see DOSAGE AND ADMINISTRATION: Neonatal Dosing.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-655/S-041
NDA 19-910/S-029
NDA 20-518/S-013
Page 8
Table 3. Zidovudine Pharmacokinetic Parameters in Pediatric Patients*
Parameter
Birth to 14 Days of
Age
14 Days to 3 Months
of Age
3 Months to 12 Years
of Age
Oral bioavailability (%)
89 ± 19
(n = 15)
61 ± 19
(n = 17)
65 ± 24
(n = 18)
CSF:plasma ratio
no data
no data
0.68 [0.03 to 3.25]†
(n = 38)
CL (L/hr/kg)
0.65 ± 0.29
(n = 18)
1.14 ± 0.24
(n = 16)
1.85 ± 0.47
(n = 20)
Elimination half-life
(hr)
3.1 ± 1.2
(n = 21)
1.9 ± 0.7
(n = 18)
1.5 ± 0.7
(n = 21)
*Data presented as mean ± standard deviation except where noted.
†Median [range].
Pregnancy: Zidovudine pharmacokinetics have been studied in a Phase 1 study of 8 women during
the last trimester of pregnancy. As pregnancy progressed, there was no evidence of drug accumulation.
Zidovudine pharmacokinetics were similar to those of nonpregnant adults. Consistent with passive
transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth
were essentially equal to those in maternal plasma at delivery. Although data are limited, methadone
maintenance therapy in 5 pregnant women did not appear to alter zidovudine pharmacokinetics.
However, in another patient population, a potential for interaction has been identified (see
PRECAUTIONS).
Nursing Mothers: The Centers for Disease Control and Prevention recommend that
HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of
HIV. After administration of a single dose of 200 mg zidovudine to 13 HIV-infected women, the mean
concentration of zidovudine was similar in human milk and serum (see PRECAUTIONS: Nursing
Mothers).
Geriatric Patients: Zidovudine pharmacokinetics have not been studied in patients over 65 years
of age.
Gender: A pharmacokinetic study in healthy male (n = 12) and female (n = 12) subjects showed no
differences in zidovudine exposure (AUC) when a single dose of zidovudine was administered as the
300-mg RETROVIR Tablet.
Effect of Food on Absorption: RETROVIR may be administered with or without food. The
extent of zidovudine absorption (AUC) was similar when a single dose of zidovudine was administered
with food.
Drug Interactions: See Table 4 and PRECAUTIONS: Drug Interactions.
Zidovudine Plus Lamivudine: No clinically significant alterations in lamivudine or zidovudine
pharmacokinetics were observed in 12 asymptomatic HIV-infected adult patients given a single dose
of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-655/S-041
NDA 19-910/S-029
NDA 20-518/S-013
Page 9
Table 4. Effect of Coadministered Drugs on Zidovudine AUC*
Note: ROUTINE DOSE MODIFICATION OF ZIDOVUDINE IS NOT WARRANTED WITH
COADMINISTRATION OF THE FOLLOWING DRUGS.
Coadministered
Zidovudine
Zidovudine
Concentrations
Concentration
of
Coadministered
Drug and Dose
Dose
n
AUC
Variability
Drug
Atovaquone
750 mg q 12 hr
with food
200 mg q 8 hr
14
↑AUC
31%
Range
23% to 78%†
↔
Fluconazole
400 mg daily
200 mg q 8 hr
12
↑AUC
74%
95% CI:
54% to 98%
Not Reported
Methadone
30 to 90 mg daily
200 mg q 4 hr
9
↑AUC
43%
Range
16% to 64%†
↔
Nelfinavir
750 mg q 8 hr x 7
to 10 days
single 200 mg
11
↓AUC
35%
Range
28% to 41%
↔
Probenecid
500 mg q 6 hr x
2 days
2 mg/kg q 8 hr
x 3 days
3
↑AUC
106%
Range
100% to
170%†
Not Assessed
Rifampin
600 mg daily x
14 days
200 mg q 8 hr
x 14 days
8
↓AUC
47%
90% CI:
41% to 53%
Not Assessed
Ritonavir
300 mg q 6 hr x
4 days
200 mg q 8 hr
x 4 days
9
↓AUC
25%
95% CI:
15% to 34%
↔
Valproic acid
250 mg or 500 mg
q 8 hr x 4 days
100 mg q 8 hr
x 4 days
6
↑AUC
80%
Range
64% to
130%†
Not Assessed
↑ = Increase; ↓ = Decrease; ↔ = no significant change; AUC = area under the concentration versus
time curve; CI = confidence interval.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-655/S-041
NDA 19-910/S-029
NDA 20-518/S-013
Page 10
*This table is not all inclusive.
†Estimated range of percent difference.
Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and
zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular
triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV
virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine
(n = 10), or zidovudine (n = 6) were co-administered as part of a multi-drug regimen to HIV/HCV
co-infected patients (see WARNINGS).
INDICATIONS AND USAGE
RETROVIR in combination with other antiretroviral agents is indicated for the treatment of HIV
infection.
Maternal-Fetal HIV Transmission: RETROVIR is also indicated for the prevention of
maternal-fetal HIV transmission as part of a regimen that includes oral RETROVIR beginning between
14 and 34 weeks of gestation, intravenous RETROVIR during labor, and administration of
RETROVIR Syrup to the neonate after birth. The efficacy of this regimen for preventing HIV
transmission in women who have received RETROVIR for a prolonged period before pregnancy has
not been evaluated. The safety of RETROVIR for the mother or fetus during the first trimester of
pregnancy has not been assessed (see Description of Clinical Studies).
Description of Clinical Studies: Therapy with RETROVIR has been shown to prolong survival
and decrease the incidence of opportunistic infections in patients with advanced HIV disease and to
delay disease progression in asymptomatic HIV-infected patients.
Combination Therapy in Adults: RETROVIR in combination with other antiretroviral agents
has been shown to be superior to monotherapy for one or more of the following endpoints: delaying
death, delaying development of AIDS, increasing CD4+ cell counts, and decreasing plasma HIV-1
RNA. The clinical efficacy of a combination regimen that includes RETROVIR was demonstrated in
study ACTG320. This study was a multi-center, randomized, double-blind, placebo-controlled trial
that compared RETROVIR 600 mg/day plus EPIVIR 300 mg/day to RETROVIR plus EPIVIR plus
indinavir 800 mg t.i.d. The incidence of AIDS-defining events or death was lower in the triple-drug–
containing arm compared to the 2-drug–containing arm (6.1% versus 10.9%, respectively).
The complete prescribing information for each drug should be consulted before combination
therapy that includes RETROVIR is initiated.
Monotherapy in Adults: In controlled studies of treatment-naive patients conducted between
1986 and 1989, monotherapy with RETROVIR, as compared to placebo, reduced the risk of HIV
disease progression, as assessed using endpoints that included the occurrence of HIV-related illnesses,
AIDS-defining events, or death. These studies enrolled patients with advanced disease (BW002), and
asymptomatic or mildly symptomatic disease in patients with CD4+ cell counts between 200 and
500 cells/mm3 (ACTG016 and ACTG019). A survival benefit for monotherapy with RETROVIR was
not demonstrated in the latter 2 studies.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-655/S-041
NDA 19-910/S-029
NDA 20-518/S-013
Page 11
Subsequent studies showed that the clinical benefit of monotherapy with RETROVIR was time
limited.
Pediatric Patients: ACTG300 was a multi-center, randomized, double-blind study that provided
for comparison of EPIVIR plus RETROVIR to didanosine monotherapy. A total of 471 symptomatic,
HIV-infected therapy-naive pediatric patients were enrolled in these 2 treatment arms. The median age
was 2.7 years (range 6 weeks to 14 years), the mean baseline CD4+ cell count was 868 cells/mm3, and
the mean baseline plasma HIV-1 RNA was 5.0 log10 copies/mL. The median duration that patients
remained on study was approximately 10 months. Results are summarized in Table 5.
Table 5. Number of Patients (%) Reaching a Primary Clinical Endpoint (Disease Progression or
Death)
Endpoint
EPIVIR plus
RETROVIR
(n = 236)
Didanosine
(n = 235)
HIV disease progression or death (total)
15 (6.4%)
37 (15.7%)
Physical growth failure
7 (3.0%)
6 (2.6%)
Central nervous system deterioration
4 (1.7%)
12 (5.1%)
CDC Clinical Category C
2 (0.8%)
8 (3.4%)
Death
2 (0.8%)
11 (4.7%)
Pregnant Women and Their Neonates: The utility of RETROVIR for the prevention of
maternal-fetal HIV transmission was demonstrated in a randomized, double-blind, placebo-controlled
trial (ACTG076) conducted in HIV-infected pregnant women with CD4+ cell counts of 200 to
1,818 cells/mm3 (median in the treated group: 560 cells/mm3) who had little or no previous exposure to
RETROVIR. Oral RETROVIR was initiated between 14 and 34 weeks of gestation (median 11 weeks
of therapy) followed by IV administration of RETROVIR during labor and delivery. Following birth,
neonates received oral RETROVIR Syrup for 6 weeks. The study showed a statistically significant
difference in the incidence of HIV infection in the neonates (based on viral culture from peripheral
blood) between the group receiving RETROVIR and the group receiving placebo. Of 363 neonates
evaluated in the study, the estimated risk of HIV infection was 7.8% in the group receiving
RETROVIR and 24.9% in the placebo group, a relative reduction in transmission risk of 68.7%.
RETROVIR was well tolerated by mothers and infants. There was no difference in pregnancy-related
adverse events between the treatment groups.
CONTRAINDICATIONS
RETROVIR Tablets, Capsules, and Syrup are contraindicated for patients who have potentially
life-threatening allergic reactions to any of the components of the formulations.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-655/S-041
NDA 19-910/S-029
NDA 20-518/S-013
Page 12
WARNINGS
COMBIVIR and TRIZIVIR are combination product tablets that contain zidovudine as one of
their components. RETROVIR should not be administered concomitantly with COMBIVIR or
TRIZIVIR.
The incidence of adverse reactions appears to increase with disease progression; patients should
be monitored carefully, especially as disease progression occurs.
Bone Marrow Suppression: RETROVIR should be used with caution in patients who have bone
marrow compromise evidenced by granulocyte count <1,000 cells/mm3 or hemoglobin <9.5 g/dL. In
patients with advanced symptomatic HIV disease, anemia and neutropenia were the most significant
adverse events observed. There have been reports of pancytopenia associated with the use of
RETROVIR, which was reversible in most instances after discontinuance of the drug. However,
significant anemia, in many cases requiring dose adjustment, discontinuation of RETROVIR, and/or
blood transfusions, has occurred during treatment with RETROVIR alone or in combination with other
antiretrovirals.
Frequent blood counts are strongly recommended in patients with advanced HIV disease who are
treated with RETROVIR. For HIV-infected individuals and patients with asymptomatic or early HIV
disease, periodic blood counts are recommended. If anemia or neutropenia develops, dosage
adjustments may be necessary (see DOSAGE AND ADMINISTRATION).
Myopathy: Myopathy and myositis with pathological changes, similar to that produced by HIV
disease, have been associated with prolonged use of RETROVIR.
Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis and severe
hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside
analogues alone or in combination, including zidovudine and other antiretrovirals. A majority of these
cases have been in women. Obesity and prolonged exposure to antiretroviral nucleoside analogues may
be risk factors. Particular caution should be exercised when administering RETROVIR to any patient
with known risk factors for liver disease; however, cases have also been reported in patients with no
known risk factors. Treatment with RETROVIR should be suspended in any patient who develops
clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may
include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-655/S-041
NDA 19-910/S-029
NDA 20-518/S-013
Page 13
Use With Interferon- and Ribavirin-Based Regimens: In vitro studies have shown ribavirin
can reduce the phosphorylation of pyrimidine nucleoside analogues such as zidovudine. Although no
evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV/HCV virologic
suppression) was seen when ribavirin was coadministered with zidovudine in HIV/HCV co-infected
patients (see CLINICAL PHARMACOLOGY: Drug Interactions), hepatic decompensation (some
fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral
therapy for HIV and interferon alfa with or without ribavirin. Patients receiving interferon alfa
with or without ribavirin and RETROVIR should be closely monitored for treatment-associated
toxicities, especially hepatic decompensation, neutropenia, and anemia. Discontinuation of
RETROVIR should be considered as medically appropriate. Dose reduction or discontinuation of
interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are
observed, including hepatic decompensation (e.g., Childs Pugh >6) (see the complete prescribing
information for interferon and ribavirin).
PRECAUTIONS
General: Zidovudine is eliminated from the body primarily by renal excretion following metabolism
in the liver (glucuronidation). In patients with severely impaired renal function (CrCl<15 mL/min),
dosage reduction is recommended. Although the data are limited, zidovudine concentrations appear to
be increased in patients with severely impaired hepatic function which may increase the risk of
hematologic toxicity (see CLINICAL PHARMACOLOGY: Pharmacokinetics and DOSAGE AND
ADMINISTRATION).
Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in
patients treated with combination antiretroviral therapy, including RETROVIR. During the initial
phase of combination antiretroviral treatment, patients whose immune system responds may develop
an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium
avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which
may necessitate further evaluation and treatment.
Fat Redistribution: Redistribution/accumulation of body fat, including central obesity,
dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement,
and “cushingoid appearance,” have been observed in patients receiving antiretroviral therapy. The
mechanism and long-term consequences of these events are currently unknown. A causal relationship
has not been established.
Information for Patients: RETROVIR is not a cure for HIV infection, and patients may continue to
acquire illnesses associated with HIV infection, including opportunistic infections. Therefore, patients
should be advised to seek medical care for any significant change in their health status.
The safety and efficacy of RETROVIR in women, intravenous drug users, and racial minorities is
not significantly different than that observed in white males.
Patients should be informed that the major toxicities of RETROVIR are neutropenia and/or anemia.
The frequency and severity of these toxicities are greater in patients with more advanced
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-655/S-041
NDA 19-910/S-029
NDA 20-518/S-013
Page 14
disease and in those who initiate therapy later in the course of their infection. They should be told that
if toxicity develops, they may require transfusions or drug discontinuation. They should be told of the
extreme importance of having their blood counts followed closely while on therapy, especially for
patients with advanced symptomatic HIV disease. They should be cautioned about the use of other
medications, including ganciclovir and interferon alfa, which may exacerbate the toxicity of
RETROVIR (see PRECAUTIONS: Drug Interactions). Patients should be informed that other adverse
effects of RETROVIR include nausea and vomiting. Patients should also be encouraged to contact
their physician if they experience muscle weakness, shortness of breath, symptoms of hepatitis or
pancreatitis, or any other unexpected adverse events while being treated with RETROVIR.
RETROVIR Tablets, Capsules, and Syrup are for oral ingestion only. Patients should be told of the
importance of taking RETROVIR exactly as prescribed. They should be told not to share medication
and not to exceed the recommended dose. Patients should be told that the long-term effects of
RETROVIR are unknown at this time.
Pregnant women considering the use of RETROVIR during pregnancy for prevention of HIV
transmission to their infants should be advised that transmission may still occur in some cases despite
therapy. The long-term consequences of in utero and infant exposure to RETROVIR are unknown,
including the possible risk of cancer.
HIV-infected pregnant women should be advised not to breastfeed to avoid postnatal transmission
of HIV to a child who may not yet be infected.
Patients should be advised that therapy with RETROVIR has not been shown to reduce the risk of
transmission of HIV to others through sexual contact or blood contamination.
Patients should be informed that redistribution or accumulation of body fat may occur in patients
receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are
not known at this time.
Drug Interactions: See CLINICAL PHARMACOLOGY section (Table 4) for information on
zidovudine concentrations when coadministered with other drugs. For patients experiencing
pronounced anemia or other severe zidovudine-associated events while receiving chronic
administration of zidovudine and some of the drugs (e.g., fluconazole, valproic acid) listed in Table 4,
zidovudine dose reduction may be considered.
Antiretroviral Agents: Concomitant use of zidovudine with stavudine should be avoided since an
antagonistic relationship has been demonstrated in vitro.
Some nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the in vitro
antiviral activity of RETROVIR against HIV; concomitant use of such drugs should be avoided.
Doxorubicin: Concomitant use of zidovudine with doxorubicin should be avoided since an
antagonistic relationship has been demonstrated in vitro (see CLINICAL PHARMACOLOGY for
additional drug interactions).
Phenytoin: Phenytoin plasma levels have been reported to be low in some patients receiving
RETROVIR, while in one case a high level was documented. However, in a pharmacokinetic
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-655/S-041
NDA 19-910/S-029
NDA 20-518/S-013
Page 15
interaction study in which 12 HIV-positive volunteers received a single 300-mg phenytoin dose alone
and during steady-state zidovudine conditions (200 mg every 4 hours), no change in phenytoin kinetics
was observed. Although not designed to optimally assess the effect of phenytoin on zidovudine
kinetics, a 30% decrease in oral zidovudine clearance was observed with phenytoin.
Overlapping Toxicities: Coadministration of ganciclovir, interferon alfa, and other bone marrow
suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Zidovudine was administered orally at
3 dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial
single daily doses were 30, 60, and 120 mg/kg/day in mice and 80, 220, and 600 mg/kg/day in rats.
The doses in mice were reduced to 20, 30, and 40 mg/kg/day after day 90 because of treatment-related
anemia, whereas in rats only the high dose was reduced to 450 mg/kg/day on day 91 and then to
300 mg/kg/day on day 279.
In mice, 7 late-appearing (after 19 months) vaginal neoplasms (5 nonmetastasizing squamous cell
carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in animals given the highest
dose. One late-appearing squamous cell papilloma occurred in the vagina of a middle-dose animal. No
vaginal tumors were found at the lowest dose.
In rats, 2 late-appearing (after 20 months), nonmetastasizing vaginal squamous cell carcinomas
occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in
rats. No other drug-related tumors were observed in either sex of either species.
At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC)
was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the
recommended therapeutic dose of 100 mg every 4 hours.
Two transplacental carcinogenicity studies were conducted in mice. One study administered
zidovudine at doses of 20 mg/kg/day or 40 mg/kg/day from gestation day 10 through parturition and
lactation with dosing continuing in offspring for 24 months postnatally. The doses of zidovudine
employed in this study produced zidovudine exposures approximately 3 times the estimated human
exposure at recommended doses. After 24 months, an increase in incidence of vaginal tumors was
noted with no increase in tumors in the liver or lung or any other organ in either gender. These findings
are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. A
second study administered zidovudine at maximum tolerated doses of 12.5 mg/day or 25 mg/day
(∼1,000 mg/kg nonpregnant body weight or ∼450 mg/kg of term body weight) to pregnant mice from
days 12 through 18 of gestation. There was an increase in the number of tumors in the lung, liver, and
female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine.
It is not known how predictive the results of rodent carcinogenicity studies may be for humans.
Zidovudine was mutagenic in a 5178Y/TK+/- mouse lymphoma assay, positive in an in vitro cell
transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-655/S-041
NDA 19-910/S-029
NDA 20-518/S-013
Page 16
and positive in mouse and rat micronucleus tests after repeated doses. It was negative in a cytogenetic
study in rats given a single dose.
Zidovudine, administered to male and female rats at doses up to 7 times the usual adult dose based
on body surface area considerations, had no effect on fertility judged by conception rates.
Pregnancy: Pregnancy Category C. Oral teratology studies in the rat and in the rabbit at doses up to
500 mg/kg/day revealed no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted
in embryo/fetal toxicity as evidenced by an increase in the incidence of fetal resorptions in rats given
150 or 450 mg/kg/day and rabbits given 500 mg/kg/day. The doses used in the teratology studies
resulted in peak zidovudine plasma concentrations (after one half of the daily dose) in rats 66 to
226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma concentrations (after
one sixth of the daily dose) achieved with the recommended daily dose (100 mg every 4 hours). In an
in vitro experiment with fertilized mouse oocytes, zidovudine exposure resulted in a dose-dependent
reduction in blastocyst formation. In an additional teratology study in rats, a dose of 3,000 mg/kg/day
(very near the oral median lethal dose in rats of 3,683 mg/kg) caused marked maternal toxicity and an
increase in the incidence of fetal malformations. This dose resulted in peak zidovudine plasma
concentrations 350 times peak human plasma concentrations. (Estimated area under the curve [AUC]
in rats at this dose level was 300 times the daily AUC in humans given 600 mg/day.) No evidence of
teratogenicity was seen in this experiment at doses of 600 mg/kg/day or less.
Two rodent transplacental carcinogenicity studies were conducted (see Carcinogenesis,
Mutagenesis, Impairment of Fertility).
A randomized, double-blind, placebo-controlled trial was conducted in HIV-infected pregnant
women to determine the utility of RETROVIR for the prevention of maternal-fetal HIV-transmission
(see INDICATIONS AND USAGE: Description of Clinical Studies). Congenital abnormalities
occurred with similar frequency between neonates born to mothers who received RETROVIR and
neonates born to mothers who received placebo. Abnormalities were either problems in embryogenesis
(prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of study
drug.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women
exposed to RETROVIR, an Antiretroviral Pregnancy Registry has been established. Physicians are
encouraged to register patients by calling 1-800-258-4263.
Nursing Mothers: The Centers for Disease Control and Prevention recommend that
HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of
HIV. Zidovudine is excreted in human milk (see CLINICAL PHARMACOLOGY: Pharmacokinetics:
Nursing Mothers). Because of both the potential for HIV transmission and the potential for serious
adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are
receiving RETROVIR (see Pediatric Use and INDICATIONS AND USAGE: Maternal-Fetal HIV
Transmission).
Pediatric Use: RETROVIR has been studied in HIV-infected pediatric patients over 3 months of age
who had HIV-related symptoms or who were asymptomatic with abnormal laboratory
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-655/S-041
NDA 19-910/S-029
NDA 20-518/S-013
Page 17
values indicating significant HIV-related immunosuppression. RETROVIR has also been studied in
neonates perinatally exposed to HIV (see ADVERSE REACTIONS, DOSAGE AND
ADMINISTRATION, INDICATIONS AND USAGE: Description of Clinical Studies, and CLINICAL
PHARMACOLOGY: Pharmacokinetics).
Geriatric Use: Clinical studies of RETROVIR 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
Adults: The frequency and severity of adverse events associated with the use of RETROVIR are
greater in patients with more advanced infection at the time of initiation of therapy.
Table 6 summarizes events reported at a statistically significant greater incidence for patients
receiving RETROVIR in a monotherapy study:
Table 6. Percentage (%) of Patients with Adverse Events* in Asymptomatic HIV Infection
(ACTG019)
Adverse Event
RETROVIR 500 mg/day
(n = 453)
Placebo
(n = 428)
Body as a whole
Asthenia
8.6%†
5.8%
Headache
62.5%
52.6%
Malaise
53.2%
44.9%
Gastrointestinal
Anorexia
20.1%
10.5%
Constipation
6.4%†
3.5%
Nausea
51.4%
29.9%
Vomiting
17.2%
9.8%
*Reported in ≥5% of study population.
†Not statistically significant versus placebo.
In addition to the adverse events listed in Table 6, other adverse events observed in clinical studies
were abdominal cramps, abdominal pain, arthralgia, chills, dyspepsia, fatigue, hyperbilirubinemia,
insomnia, musculoskeletal pain, myalgia, and neuropathy.
Selected laboratory abnormalities observed during a clinical study of monotherapy with
RETROVIR are shown in Table 7.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-655/S-041
NDA 19-910/S-029
NDA 20-518/S-013
Page 18
Table 7. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Patients with
Asymptomatic HIV Infection (ACTG019)
Adverse Event
RETROVIR 500 mg/day
(n = 453)
Placebo
(n = 428)
Anemia (Hgb<8 g/dL)
1.1%
0.2%
Granulocytopenia (<750 cells/mm3)
1.8%
1.6%
Thrombocytopenia (platelets<50,000/mm3)
0%
0.5%
ALT (>5 x ULN)
3.1%
2.6%
AST (>5 x ULN)
0.9%
1.6%
Alkaline phosphatase (>5 x ULN)
0%
0%
ULN = Upper limit of normal.
Pediatrics: Study ACTG300: Selected clinical adverse events and physical findings with a ≥5%
frequency during therapy with EPIVIR 4 mg/kg twice daily plus RETROVIR 160 mg/m2 3 times daily
compared with didanosine in therapy-naive (≤56 days of antiretroviral therapy) pediatric patients are
listed in Table 8.
Table 8. Selected Clinical Adverse Events and Physical Findings (≥5% Frequency) in Pediatric
Patients in Study ACTG300
Adverse Event
EPIVIR plus
RETROVIR
(n = 236)
Didanosine
(n = 235)
Body as a whole
Fever
25%
32%
Digestive
Hepatomegaly
11%
11%
Nausea & vomiting
8%
7%
Diarrhea
8%
6%
Stomatitis
6%
12%
Splenomegaly
5%
8%
Respiratory
Cough
15%
18%
Abnormal breath sounds/wheezing
7%
9%
Ear, Nose, and Throat
Signs or symptoms of ears*
7%
6%
Nasal discharge or congestion
8%
11%
Other
Skin rashes
12%
14%
Lymphadenopathy
9%
11%
*Includes pain, discharge, erythema, or swelling of an ear.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-655/S-041
NDA 19-910/S-029
NDA 20-518/S-013
Page 19
Selected laboratory abnormalities experienced by therapy-naive (≤56 days of antiretroviral therapy)
pediatric patients are listed in Table 9.
Table 9. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Pediatric Patients in
Study ACTG300
Test
(Abnormal Level)
EPIVIR plus
RETROVIR
Didanosine
Neutropenia (ANC<400 cells/mm3)
8%
3%
Anemia (Hgb<7.0 g/dL)
4%
2%
Thrombocytopenia (platelets<50,000/mm3)
1%
3%
ALT (>10 x ULN)
1%
3%
AST (>10 x ULN)
2%
4%
Lipase (>2.5 x ULN)
3%
3%
Total amylase (>2.5 x ULN)
3%
3%
ULN = Upper limit of normal.
ANC = Absolute neutrophil count.
Additional adverse events reported in open-label studies in pediatric patients receiving RETROVIR
180 mg/m2 every 6 hours were congestive heart failure, decreased reflexes, ECG abnormality, edema,
hematuria, left ventricular dilation, macrocytosis, nervousness/irritability, and weight loss.
The clinical adverse events reported among adult recipients of RETROVIR may also occur in
pediatric patients.
Use for the Prevention of Maternal-Fetal Transmission of HIV: In a randomized,
double-blind, placebo-controlled trial in HIV-infected women and their neonates conducted to
determine the utility of RETROVIR for the prevention of maternal-fetal HIV transmission,
RETROVIR Syrup at 2 mg/kg was administered every 6 hours for 6 weeks to neonates beginning
within 12 hours following birth. The most commonly reported adverse experiences were anemia
(hemoglobin <9.0 g/dL) and neutropenia (<1,000 cells/mm3). Anemia occurred in 22% of the neonates
who received RETROVIR and in 12% of the neonates who received placebo. The mean difference in
hemoglobin values was less than 1.0 g/dL for neonates receiving RETROVIR compared to neonates
receiving placebo. No neonates with anemia required transfusion and all hemoglobin values
spontaneously returned to normal within 6 weeks after completion of therapy with RETROVIR.
Neutropenia was reported with similar frequency in the group that received RETROVIR (21%) and in
the group that received placebo (27%). The long-term consequences of in utero and infant exposure to
RETROVIR are unknown.
Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the
following events have been identified during use of RETROVIR in clinical practice. Because they are
reported voluntarily from a population of unknown size, estimates of frequency
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-655/S-041
NDA 19-910/S-029
NDA 20-518/S-013
Page 20
cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency
of reporting, potential causal connection to RETROVIR, or a combination of these factors.
Body as a Whole: Back pain, chest pain, flu-like syndrome, generalized pain,
redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution).
Cardiovascular: Cardiomyopathy, syncope.
Endocrine: Gynecomastia.
Eye: Macular edema.
Gastrointestinal: Constipation, dysphagia, flatulence, oral mucosa pigmentation, mouth ulcer.
General: Sensitization reactions including anaphylaxis and angioedema, vasculitis.
Hemic and Lymphatic: Aplastic anemia, hemolytic anemia, leukopenia, lymphadenopathy,
pancytopenia with marrow hypoplasia, pure red cell aplasia.
Hepatobiliary Tract and Pancreas: Hepatitis, hepatomegaly with steatosis, jaundice, lactic
acidosis, pancreatitis.
Musculoskeletal: Increased CPK, increased LDH, muscle spasm, myopathy and myositis with
pathological changes (similar to that produced by HIV disease), rhabdomyolysis, tremor.
Nervous: Anxiety, confusion, depression, dizziness, loss of mental acuity, mania, paresthesia,
seizures, somnolence, vertigo.
Respiratory: Cough, dyspnea, rhinitis, sinusitis.
Skin: Changes in skin and nail pigmentation, pruritus, rash, Stevens-Johnson syndrome, toxic
epidermal necrolysis, sweat, urticaria.
Special Senses: Amblyopia, hearing loss, photophobia, taste perversion.
Urogenital: Urinary frequency, urinary hesitancy.
OVERDOSAGE
Acute overdoses of zidovudine have been reported in pediatric patients and adults. These involved
exposures up to 50 grams. No specific symptoms or signs have been identified following acute
overdosage with zidovudine apart from those listed as adverse events such as fatigue, headache,
vomiting, and occasional reports of hematological disturbances. All patients recovered without
permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the
removal of zidovudine while elimination of its primary metabolite, GZDV, is enhanced.
DOSAGE AND ADMINISTRATION
Adults: The recommended oral dose of RETROVIR is 600 mg per day in divided doses in
combination with other antiretroviral agents.
Pediatrics: The recommended dose in pediatric patients 6 weeks to 12 years of age is 160 mg/m2
every 8 hours (480 mg/m2/day up to a maximum of 200 mg every 8 hours) in combination with other
antiretroviral agents.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-655/S-041
NDA 19-910/S-029
NDA 20-518/S-013
Page 21
Maternal-Fetal HIV Transmission: The recommended dosing regimen for administration to
pregnant women (>14 weeks of pregnancy) and their neonates is:
Maternal Dosing: 100 mg orally 5 times per day until the start of labor (see INDICATIONS AND
USAGE: Description of Clinical Studies). During labor and delivery, intravenous RETROVIR should
be administered at 2 mg/kg (total body weight) over 1 hour followed by a continuous intravenous
infusion of 1 mg/kg/hour (total body weight) until clamping of the umbilical cord.
Neonatal Dosing: 2 mg/kg orally every 6 hours starting within 12 hours after birth and
continuing through 6 weeks of age. Neonates unable to receive oral dosing may be administered
RETROVIR intravenously at 1.5 mg/kg, infused over 30 minutes, every 6 hours. (See
PRECAUTIONS if hepatic disease or renal insufficiency is present.)
Monitoring of Patients: Hematologic toxicities appear to be related to pretreatment bone marrow
reserve and to dose and duration of therapy. In patients with poor bone marrow reserve, particularly in
patients with advanced symptomatic HIV disease, frequent monitoring of hematologic indices is
recommended to detect serious anemia or neutropenia (see WARNINGS). In patients who experience
hematologic toxicity, reduction in hemoglobin may occur as early as 2 to 4 weeks, and neutropenia
usually occurs after 6 to 8 weeks.
Dose Adjustment: Anemia: Significant anemia (hemoglobin of <7.5 g/dL or reduction of >25% of
baseline) and/or significant neutropenia (granulocyte count of <750 cells/mm3 or reduction of >50%
from baseline) may require a dose interruption until evidence of marrow recovery is observed (see
WARNINGS). In patients who develop significant anemia, dose interruption does not necessarily
eliminate the need for transfusion. If marrow recovery occurs following dose interruption, resumption
in dose may be appropriate using adjunctive measures such as epoetin alfa at recommended doses,
depending on hematologic indices such as serum erythropoetin level and patient tolerance.
For patients experiencing pronounced anemia while receiving chronic coadministration of
zidovudine and some of the drugs (e.g., fluconazole, valproic acid) listed in Table 4, zidovudine dose
reduction may be considered.
End-Stage Renal Disease: In patients maintained on hemodialysis or peritoneal dialysis,
recommended dosing is 100 mg every 6 to 8 hours (see CLINICAL PHARMACOLOGY:
Pharmacokinetics).
Hepatic Impairment: There are insufficient data to recommend dose adjustment of RETROVIR
in patients with mild to moderate impaired hepatic function or liver cirrhosis. Since RETROVIR is
primarily eliminated by hepatic metabolism, a reduction in the daily dose may be necessary in these
patients. Frequent monitoring for hematologic toxicities is advised (see CLINICAL
PHARMACOLOGY: Pharmacokinetics and PRECAUTIONS: General).
HOW SUPPLIED
RETROVIR Tablets 300 mg (biconvex, white, round, film-coated) containing 300 mg zidovudine,
one side engraved “GX CW3” and “300” on the other side.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
NDA 19-655/S-041
NDA 19-910/S-029
NDA 20-518/S-013
Page 22
Bottle of 60 (NDC 0173-0501-00).
Store at 15° to 25°C (59° to 77°F).
RETROVIR Capsules 100 mg (white, opaque cap and body with a dark blue band) containing
100 mg zidovudine and printed with “Wellcome” and unicorn logo on cap and “Y9C” and “100” on
body.
Bottles of 100 (NDC 0173-0108-55).
Unit Dose Pack of 100 (NDC 0173-0108-56).
Store at 15° to 25°C (59° to 77°F) and protect from moisture.
RETROVIR Syrup (colorless to pale yellow, strawberry-flavored) containing 50 mg zidovudine in
each teaspoonful (5 mL).
Bottle of 240 mL (NDC 0173-0113-18) with child-resistant cap.
Store at 15° to 25°C (59° to 77°F).
GlaxoSmithKline
Research Triangle Park, NC 27709
©2006, GlaxoSmithKline. All rights reserved.
April 2006
RL-2273
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:39.326229
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/019655s41,019910s29,020518s13lbl.pdf', 'application_number': 19655, 'submission_type': 'SUPPL ', 'submission_number': 41}
|
11,608
|
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
RETROVIR safely and effectively. See full prescribing information for
RETROVIR.
RETROVIR (zidovudine) Tablets, Capsules, and Syrup
Initial U.S. Approval: 1987
WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY,
LACTIC ACIDOSIS
See full prescribing information for complete boxed warning.
• Hematologic toxicity including neutropenia and severe anemia have
been associated with the use of zidovudine. (5.1)
• Symptomatic myopathy associated with prolonged use of zidovudine.
(5.2)
• Lactic acidosis and severe hepatomegaly with steatosis, including fatal
cases, have been reported with the use of nucleoside analogues
including RETROVIR. Suspend treatment if clinical or laboratory
findings suggestive of lactic acidosis or pronounced hepatotoxicity
occur. (5.3)
---------------------------RECENT MAJOR CHANGES -------------------
Dosage and Administration, Pediatric Patients (2.1)
November 2009
----------------------------INDICATIONS AND USAGE--------------------
RETROVIR is a nucleoside analogue reverse transcriptase inhibitor indicated for:
• Treatment of Human Immunodeficiency Virus (HIV-1) infection in
combination with other antiretroviral agents. (1.1)
• Prevention of maternal-fetal HIV-1 transmission. (1.2)
----------------------- DOSAGE AND ADMINISTRATION ---------------
• Treatment of HIV-1 infection:
Adults: 600 mg/day in divided doses with other antiretroviral agents.
Pediatric patients (4 weeks to <18 years of age): Dosage should be
calculated based on body weight not to exceed adult dose. (2.1)
• Prevention of maternal-fetal HIV-1 transmission:
Specific dosage instructions for mother and infant. (2.2)
• Patients with severe anemia and/or neutropenia:
Dosage interruption may be necessary. (2.3)
• Renal Impairment: Recommended dosage in hemodialysis or peritoneal
dialysis patients is 100 mg every 6 to 8 hours. (2.4)
---------------------DOSAGE FORMS AND STRENGTHS -------------
Tablets: 300 mg (3)
Capsules: 100 mg (3)
Syrup: 50 mg/5 mL (3)
-------------------------------CONTRAINDICATIONS-----------------------
Hypersensitivity to zidovudine (e.g., anaphylaxis, Stevens-Johnson
syndrome). (4)
----------------------- WARNINGS AND PRECAUTIONS ---------------
• Hematologic toxicity/bone marrow suppression including neutropenia and
severe anemia have been associated with the use of zidovudine. (5.1)
• Symptomatic myopathy associated with prolonged use of zidovudine. (5.2)
• Lactic acidosis and severe hepatomegaly with steatosis, including fatal
cases, have been reported with the use of nucleoside analogues including
RETROVIR. Suspend treatment if clinical or laboratory findings
suggestive of lactic acidosis or pronounced hepatotoxicity occur. (5.3)
• Exacerbation of anemia has been reported in HIV-1/HCV co-infected
patients receiving ribavirin and zidovudine. Coadministration of ribavirin
and zidovudine is not advised. (5.4)
• Hepatic decompensation, (some fatal), has occurred in HIV-1/HCV
co-infected patients receiving combination antiretroviral therapy and
interferon alfa with/without ribavirin. Discontinue zidovudine as medically
appropriate and consider dose reduction or discontinuation of interferon
alfa, ribavirin, or both. (5.4)
• RETROVIR should not be administered with other zidovudine-containing
combination products. (5.5)
• Immune reconstitution syndrome (5.6) and redistribution/accumulation of
body fat (5.7) have been reported in patients treated with combination
antiretroviral therapy.
------------------------------ ADVERSE REACTIONS ----------------------
• Most commonly reported adverse reactions (incidence ≥15%) in adult
HIV-1 clinical studies were headache, malaise, nausea, anorexia, and
vomiting. (6.1)
• Most commonly reported adverse reactions (incidence ≥15%) in pediatric
HIV-1 clinical studies were fever, cough, and digestive disorders. (6.1)
• Most commonly reported adverse reactions in neonates (incidence ≥15%)
in the prevention of maternal-fetal transmission of HIV-1 clinical trial
were anemia and neutropenia. (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-----------------------
• Stavudine: Concomitant use with zidovudine should be avoided. (7.1)
• Doxorubicin: Use with zidovudine should be avoided. (7.2)
• Bone marrow suppressive/cytotoxic agents: May increase the hematologic
toxicity of zidovudine. (7.3)
----------------------- USE IN SPECIFIC POPULATIONS ---------------
Pregnancy: Physicians are encouraged to register patients in the Antiretroviral
Pregnancy Registry by calling 1-800-258-4263. (8.1)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: May 2010
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY,
LACTIC ACIDOSIS
1
INDICATIONS AND USAGE
1.1
Treatment of HIV-1
1.2
Prevention of Maternal-Fetal HIV-1 Transmission
2
DOSAGE AND ADMINISTRATION
2.1
Treatment of HIV-1 Infection
2.2
Prevention of Maternal-Fetal HIV-1 Transmission
2.3
Patients With Severe Anemia and/or Neutropenia
2.4
Patients With Renal Impairment
2.5
Patients With Hepatic Impairment
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Hematologic Toxicity/Bone Marrow Suppression
5.2
Myopathy
5.3
Lactic Acidosis/Severe Hepatomegaly With Steatosis
5.4
Use With Interferon- and Ribavirin-Based Regimens in
HIV-1/HCV Co-Infected Patients
5.5
Use With Other Zidovudine-Containing Products
5.6
Immune Reconstitution Syndrome
5.7
Fat Redistribution
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Antiretroviral Agents
7.2
Doxorubicin
7.3
Hematologic/Bone Marrow Suppressive/Cytotoxic
Agents
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Renal Impairment
8.7
Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Reproductive and Developmental Toxicology Studies
14 CLINICAL STUDIES
14.1 Adults
14.2 Pediatric Patients
14.3 Prevention of Maternal-Fetal HIV-1 Transmission
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
16 HOW SUPPLIED/STORAGE AND HANDLING
17.1 Information About Therapy With RETROVIR
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not listed.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
______________________________________________________________________
1
FULL PRESCRIBING INFORMATION
2
WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY, LACTIC
3
ACIDOSIS
4
RETROVIR® (zidovudine) Tablets, Capsules, and Syrup have been associated with
5
hematologic toxicity including neutropenia and severe anemia, particularly in patients with
6
advanced HIV-1 disease [see Warnings and Precautions (5.1)].
7
Prolonged use of RETROVIR has been associated with symptomatic myopathy [see
8
Warnings and Precautions (5.2)].
9
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have
10
been reported with the use of nucleoside analogues alone or in combination, including
11
RETROVIR and other antiretrovirals. Suspend treatment if clinical or laboratory findings
12
suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and
13
Precautions (5.3)].
14
1
INDICATIONS AND USAGE
15
1.1
Treatment of HIV-1
16
RETROVIR, a nucleoside reverse transcriptase inhibitor, is indicated in combination with
17
other antiretroviral agents for the treatment of HIV-1 infection.
18
1.2
Prevention of Maternal-Fetal HIV-1 Transmission
19
RETROVIR is indicated for the prevention of maternal-fetal HIV-1 transmission [see
20
Dosage and Administration (2.2)]. The indication is based on a dosing regimen that included
21
3 components:
22
1.
antepartum therapy of HIV-1 infected mothers
23
2.
intrapartum therapy of HIV-1 infected mothers
24
3.
post-partum therapy of HIV-1 exposed neonate.
25
Points to consider prior to initiating RETROVIR in pregnant women for the prevention of
26
maternal-fetal HIV-1 transmission include:
27
• In most cases, RETROVIR for prevention of maternal-fetal HIV-1 transmission should be
28
given in combination with other antiretroviral drugs.
29
• Prevention of HIV-1 transmission in women who have received RETROVIR for a prolonged
30
period before pregnancy has not been evaluated.
31
• Because the fetus is most susceptible to the potential teratogenic effects of drugs during the
32
first 10 weeks of gestation and the risks of therapy with RETROVIR during that period are
33
not fully known, women in the first trimester of pregnancy who do not require immediate
34
initiation of antiretroviral therapy for their own health may consider delaying use; this
35
indication is based on use after 14 weeks gestation.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
36
2
DOSAGE AND ADMINISTRATION
37
2.1
Treatment of HIV-1 Infection
38
Adults: The recommended oral dose of RETROVIR is 600 mg/day in divided doses in
39
combination with other antiretroviral agents.
40
Pediatric Patients (4 Weeks to <18 Years of Age): Healthcare professionals should
41
pay special attention to accurate calculation of the dose of RETROVIR, transcription of the
42
medication order, dispensing information, and dosing instructions to minimize risk for
43
medication dosing errors.
44
Prescribers should calculate the appropriate dose of RETROVIR for each child based on
45
body weight (kg) and should not exceed the recommended adult dose.
46
Before prescribing RETROVIR Capsules or Tablets, children should be assessed for the
47
ability to swallow capsules or tablets. If a child is unable to reliably swallow a RETROVIR
48
Capsule or Tablet, the RETROVIR Syrup formulation should be prescribed.
49
The recommended dosage in pediatric patients 4 weeks of age and older and weighing
50
≥4 kg is provided in Table 1. RETROVIR Syrup should be used to provide accurate dosage
51
when whole tablets or capsules are not appropriate.
52
53
Table 1: Recommended Pediatric Dosage of RETROVIR
Body Weight
(kg)
Total Daily Dose
Dosage Regimen and Dose
b.i.d.
t.i.d.
4 to <9
24 mg/kg/day
12 mg/kg
8 mg/kg
≥9 to <30
18 mg/kg/day
9 mg/kg
6 mg/kg
≥30
600 mg/day
300 mg
200 mg
54
55
Alternatively, dosing for RETROVIR can be based on body surface area (BSA) for each
56
child. The recommended oral dose of RETROVIR is 480 mg/m2/day in divided doses
57
(240 mg/m2 twice daily or 160 mg/m2 three times daily). In some cases the dose calculated by
58
mg/kg will not be the same as that calculated by BSA.
59
2.2
Prevention of Maternal-Fetal HIV-1 Transmission
60
The recommended dosage regimen for administration to pregnant women (>14 weeks of
61
pregnancy) and their neonates is:
62
Maternal Dosing: 100 mg orally 5 times per day until the start of labor [see Clinical
63
Studies (14.3)]. During labor and delivery, intravenous RETROVIR should be administered at
64
2 mg/kg (total body weight) over 1 hour followed by a continuous intravenous infusion of
65
1 mg/kg/hour (total body weight) until clamping of the umbilical cord.
66
Neonatal Dosing: 2 mg/kg orally every 6 hours starting within 12 hours after birth and
67
continuing through 6 weeks of age. Neonates unable to receive oral dosing may be administered
68
RETROVIR intravenously at 1.5 mg/kg, infused over 30 minutes, every 6 hours.
69
2.3
Patients With Severe Anemia and/or Neutropenia
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
70
Significant anemia (hemoglobin <7.5 g/dL or reduction >25% of baseline) and/or
71
significant neutropenia (granulocyte count <750 cells/mm3 or reduction >50% from baseline)
72
may require a dose interruption until evidence of marrow recovery is observed [see Warnings
73
and Precautions (5.1)]. In patients who develop significant anemia, dose interruption does not
74
necessarily eliminate the need for transfusion. If marrow recovery occurs following dose
75
interruption, resumption in dose may be appropriate using adjunctive measures such as epoetin
76
alfa at recommended doses, depending on hematologic indices such as serum erythropoetin level
77
and patient tolerance.
78
2.4
Patients With Renal Impairment
79
End-Stage Renal Disease: In patients maintained on hemodialysis or peritoneal
80
dialysis, the recommended dosage is 100 mg every 6 to 8 hours [see Clinical Pharmacology
81
(12.3)].
82
2.5
Patients With Hepatic Impairment
83
There are insufficient data to recommend dose adjustment of RETROVIR in patients with
84
mild to moderate impaired hepatic function or liver cirrhosis.
85
3
DOSAGE FORMS AND STRENGTHS
86
RETROVIR Tablets 300 mg (biconvex, white, round, film-coated) containing 300 mg
87
zidovudine, one side engraved “GX CW3” and “300” on the other side.
88
RETROVIR Capsules 100 mg (white, opaque cap and body) containing 100 mg
89
zidovudine and printed with “Wellcome” and unicorn logo on cap and “Y9C” and “100” on
90
body.
91
RETROVIR Syrup (colorless to pale yellow, strawberry-flavored) containing 50 mg
92
zidovudine in each teaspoonful (5 mL).
93
4
CONTRAINDICATIONS
94
RETROVIR Tablets, Capsules, and Syrup are contraindicated in patients who have had
95
potentially life-threatening allergic reactions (e.g., anaphylaxis, Stevens-Johnson syndrome) to
96
any of the components of the formulations.
97
5
WARNINGS AND PRECAUTIONS
98
5.1
Hematologic Toxicity/Bone Marrow Suppression
99
RETROVIR should be used with caution in patients who have bone marrow compromise
100
evidenced by granulocyte count <1,000 cells/mm3 or hemoglobin <9.5 g/dL. Hematologic
101
toxicities appear to be related to pretreatment bone marrow reserve and to dose and duration of
102
therapy. In patients with advanced symptomatic HIV-1 disease, anemia and neutropenia were the
103
most significant adverse events observed. In patients who experience hematologic toxicity, a
104
reduction in hemoglobin may occur as early as 2 to 4 weeks, and neutropenia usually occurs after
105
6 to 8 weeks. There have been reports of pancytopenia associated with the use of RETROVIR,
106
which was reversible in most instances after discontinuance of the drug. However, significant
107
anemia, in many cases requiring dose adjustment, discontinuation of RETROVIR, and/or blood
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
108
transfusions, has occurred during treatment with RETROVIR alone or in combination with other
109
antiretrovirals.
110
Frequent blood counts are strongly recommended to detect severe anemia or neutropenia
111
in patients with poor bone marrow reserve, particularly in patients with advanced HIV-1 disease
112
who are treated with RETROVIR. For HIV-1-infected individuals and patients with
113
asymptomatic or early HIV-1 disease, periodic blood counts are recommended. If anemia or
114
neutropenia develops, dosage interruption may be needed [see Dosage and Administration
115
(2.3)].
116
5.2
Myopathy
117
Myopathy and myositis with pathological changes, similar to that produced by HIV-1
118
disease, have been associated with prolonged use of RETROVIR.
119
5.3
Lactic Acidosis/Severe Hepatomegaly With Steatosis
120
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been
121
reported with the use of nucleoside analogues alone or in combination, including zidovudine and
122
other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged
123
exposure to antiretroviral nucleoside analogues may be risk factors. Particular caution should be
124
exercised when administering RETROVIR to any patient with known risk factors for liver
125
disease; however, cases have also been reported in patients with no known risk factors.
126
Treatment with RETROVIR should be suspended in any patient who develops clinical or
127
laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may
128
include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
129
5.4
Use With Interferon- and Ribavirin-Based Regimens in HIV-1/HCV
130
Co-Infected Patients
131
In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine
132
nucleoside analogues such as zidovudine. Although no evidence of a pharmacokinetic or
133
pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when
134
ribavirin was coadministered with zidovudine in HIV-1/HCV co-infected patients [see Clinical
135
Pharmacology (12.3)], exacerbation of anemia due to ribavirin has been reported when
136
zidovudine is part of the HIV regimen. Coadministration of ribavirin and zidovudine is not
137
advised. Consideration should be given to replacing zidovudine in established combination
138
HIV-1/HCV therapy, especially in patients with a known history of zidovudine-induced anemia.
139
Hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients
140
receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without
141
ribavirin. Patients receiving interferon alfa with or without ribavirin and zidovudine should be
142
closely monitored for treatment-associated toxicities, especially hepatic decompensation,
143
neutropenia, and anemia.
144
Discontinuation of zidovudine should be considered as medically appropriate. Dose
145
reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if
146
worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh
147
>6) (see the complete prescribing information for interferon and ribavirin).
5
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
148
5.5
Use With Other Zidovudine-Containing Products
149
RETROVIR should not be administered with combination products that contain
150
zidovudine as one of their components (e.g., COMBIVIR® [lamivudine and zidovudine] Tablets
151
or TRIZIVIR® [abacavir sulfate, lamivudine, and zidovudine] Tablets).
152
5.6
Immune Reconstitution Syndrome
153
Immune reconstitution syndrome has been reported in patients treated with combination
154
antiretroviral therapy, including RETROVIR. During the initial phase of combination
155
antiretroviral treatment, patients whose immune systems respond may develop an inflammatory
156
response to indolent or residual opportunistic infections (such as Mycobacterium avium
157
infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which
158
may necessitate further evaluation and treatment.
159
5.7
Fat Redistribution
160
Redistribution/accumulation of body fat, including central obesity, dorsocervical fat
161
enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and
162
“cushingoid appearance,” have been observed in patients receiving antiretroviral therapy. The
163
mechanism and long-term consequences of these events are currently unknown. A causal
164
relationship has not been established.
165
6
ADVERSE REACTIONS
166
6.1
Clinical Trials Experience
167
The following adverse reactions are discussed in greater detail in other sections of the
168
labeling:
169
• Hematologic toxicity, including neutropenia and anemia [see Boxed Warning, Warnings and
170
Precautions (5.1)].
171
• Symptomatic myopathy [see Boxed Warning, Warnings and Precautions (5.2)].
172
• Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and
173
Precautions (5.3)].
174
• Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [see Warnings
175
and Precautions (5.4)].
176
Because clinical trials are conducted under widely varying conditions, adverse reaction
177
rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical
178
trials of another drug and may not reflect the rates observed in practice.
179
Adults: The frequency and severity of adverse reactions associated with the use of
180
RETROVIR are greater in patients with more advanced infection at the time of initiation of
181
therapy.
182
Table 2 summarizes events reported at a statistically significant greater incidence for
183
patients receiving RETROVIR in a monotherapy study.
184
6
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
185
Table 2. Percentage (%) of Patients With Adverse Reactionsa in Asymptomatic HIV-1
186
Infection (ACTG 019)
Adverse Reaction
RETROVIR 500 mg/day
(n = 453)
Placebo
(n = 428)
Body as a whole
Asthenia
Headache
Malaise
Gastrointestinal
Anorexia
Constipation
Nausea
Vomiting
9%
b
63%
53%
20%
6%
b
51%
17%
6%
53%
45%
11%
4%
30%
10%
187
a Reported in ≥5% of study population.
188
b Not statistically significant versus placebo.
189
190
In addition to the adverse reactions listed in Table 2, adverse reactions observed at an
191
incidence of ≥5% in any treatment arm in clinical studies (NUCA3001, NUCA3002,
192
NUCB3001, and NUCB3002) were abdominal cramps, abdominal pain, arthralgia, chills,
193
dyspepsia, fatigue, insomnia, musculoskeletal pain, myalgia, and neuropathy. Additionally, in
194
these studies hyperbilirubinemia was reported at an incidence of ≤0.8%.
195
Selected laboratory abnormalities observed during a clinical study of monotherapy with
196
RETROVIR are shown in Table 3.
197
198
Table 3. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Patients With
199
Asymptomatic HIV-1 Infection (ACTG 019)
Test
(Abnormal Level)
RETROVIR 500 mg/day
(n = 453)
Placebo
(n = 428)
Anemia (Hgb<8 g/dL)
Granulocytopenia (<750 cells/mm3)
Thrombocytopenia (platelets<50,000/mm3)
ALT (>5 x ULN)
AST (>5 x ULN)
1%
2%
0%
3%
1%
<1%
2%
<1%
3%
2%
200
ULN = Upper limit of normal.
201
202
Pediatrics: The clinical adverse reactions reported among adult recipients of
203
RETROVIR may also occur in pediatric patients.
204
Study ACTG 300: Selected clinical adverse reactions and physical findings with a
205
≥5% frequency during therapy with EPIVIR® (lamivudine) Oral Suspension 4 mg/kg twice daily
7
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
206
plus RETROVIR 160 mg/m2 3 times daily compared with didanosine in therapy-naive (≤56 days
207
of antiretroviral therapy) pediatric patients are listed in Table 4.
208
209
Table 4. Selected Clinical Adverse Reactions and Physical Findings (≥5% Frequency) in
210
Pediatric Patients in Study ACTG 300
Adverse Reaction
EPIVIR plus
RETROVIR
(n = 236)
Didanosine
(n = 235)
Body as a whole
Fever
Digestive
25%
32%
Hepatomegaly
11%
11%
Nausea & vomiting
8%
7%
Diarrhea
8%
6%
Stomatitis
6%
12%
Splenomegaly
Respiratory
5%
8%
Cough
15%
18%
Abnormal breath sounds/wheezing
Ear, Nose, and Throat
7%
9%
Signs or symptoms of earsa
7%
6%
Nasal discharge or congestion
Other
8%
11%
Skin rashes
12%
14%
Lymphadenopathy
9%
11%
211
a Includes pain, discharge, erythema, or swelling of an ear.
212
213
Selected laboratory abnormalities experienced by therapy-naive (≤56 days of
214
antiretroviral therapy) pediatric patients are listed in Table 5.
215
8
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
216
Table 5. Frequencies of Selected (Grade 3/4) Laboratory Abnormalities in Pediatric
217
Patients in Study ACTG 300
Test
(Abnormal Level)
EPIVIR plus
RETROVIR
Didanosine
Neutropenia (ANC<400 cells/mm3)
Anemia (Hgb<7.0 g/dL)
Thrombocytopenia (platelets<50,000/mm3)
ALT (>10 x ULN)
AST (>10 x ULN)
Lipase (>2.5 x ULN)
Total amylase (>2.5 x ULN)
8%
4%
1%
1%
2%
3%
3%
3%
2%
3%
3%
4%
3%
3%
218
ULN = Upper limit of normal.
219
ANC = Absolute neutrophil count.
220
221
Macrocytosis was reported in the majority of pediatric patients receiving RETROVIR
222
180 mg/m2 every 6 hours in open-label studies. Additionally, adverse reactions reported at an
223
incidence of <6% in these studies were congestive heart failure, decreased reflexes, ECG
224
abnormality, edema, hematuria, left ventricular dilation, nervousness/irritability, and weight loss.
225
Use for the Prevention of Maternal-Fetal Transmission of HIV-1: In a randomized,
226
double-blind, placebo-controlled trial in HIV-1-infected women and their neonates conducted to
227
determine the utility of RETROVIR for the prevention of maternal-fetal HIV-1 transmission,
228
RETROVIR Syrup at 2 mg/kg was administered every 6 hours for 6 weeks to neonates
229
beginning within 12 hours following birth. The most commonly reported adverse reactions were
230
anemia (hemoglobin <9.0 g/dL) and neutropenia (<1,000 cells/mm3). Anemia occurred in 22%
231
of the neonates who received RETROVIR and in 12% of the neonates who received placebo.
232
The mean difference in hemoglobin values was less than 1.0 g/dL for neonates receiving
233
RETROVIR compared with neonates receiving placebo. No neonates with anemia required
234
transfusion and all hemoglobin values spontaneously returned to normal within 6 weeks after
235
completion of therapy with RETROVIR. Neutropenia in neonates was reported with similar
236
frequency in the group that received RETROVIR (21%) and in the group that received placebo
237
(27%). The long-term consequences of in utero and infant exposure to RETROVIR are
238
unknown.
239
6.2
Postmarketing Experience
240
In addition to adverse reactions reported from clinical trials, the following reactions have
241
been identified during postmarketing use of RETROVIR. Because they are reported voluntarily
242
from a population of unknown size, estimates of frequency cannot be made. These reactions have
243
been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or
244
potential causal connection to RETROVIR.
245
Body as a Whole: Back pain, chest pain, flu-like syndrome, generalized pain,
246
redistribution/accumulation of body fat [see Warnings and Precautions (5.7)].
9
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
247
Cardiovascular: Cardiomyopathy, syncope.
248
Endocrine: Gynecomastia.
249
Eye: Macular edema.
250
Gastrointestinal: Dysphagia, flatulence, oral mucosa pigmentation, mouth ulcer.
251
General: Sensitization reactions including anaphylaxis and angioedema, vasculitis.
252
Hemic and Lymphatic: Aplastic anemia, hemolytic anemia, leukopenia,
253
lymphadenopathy, pancytopenia with marrow hypoplasia, pure red cell aplasia.
254
Hepatobiliary Tract and Pancreas: Hepatitis, hepatomegaly with steatosis, jaundice,
255
lactic acidosis, pancreatitis.
256
Musculoskeletal: Increased CPK, increased LDH, muscle spasm, myopathy and
257
myositis with pathological changes (similar to that produced by HIV-1 disease), rhabdomyolysis,
258
tremor.
259
Nervous: Anxiety, confusion, depression, dizziness, loss of mental acuity, mania,
260
paresthesia, seizures, somnolence, vertigo.
261
Respiratory: Dyspnea, rhinitis, sinusitis.
262
Skin: Changes in skin and nail pigmentation, pruritus, Stevens-Johnson syndrome, toxic
263
epidermal necrolysis, sweat, urticaria.
264
Special Senses: Amblyopia, hearing loss, photophobia, taste perversion.
265
Urogenital: Urinary frequency, urinary hesitancy.
266
7
DRUG INTERACTIONS
267
7.1
Antiretroviral Agents
268
Stavudine: Concomitant use of zidovudine with stavudine should be avoided since an
269
antagonistic relationship has been demonstrated in vitro.
270
Nucleoside Analogues Affecting DNA Replication: Some nucleoside analogues
271
affecting DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of
272
RETROVIR against HIV-1; concomitant use of such drugs should be avoided.
273
7.2
Doxorubicin
274
Concomitant use of zidovudine with doxorubicin should be avoided since an antagonistic
275
relationship has been demonstrated in vitro.
276
7.3
Hematologic/Bone Marrow Suppressive/Cytotoxic Agents
277
Coadministration of ganciclovir, interferon alfa, ribavirin, and other bone marrow
278
suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine.
279
8
USE IN SPECIFIC POPULATIONS
280
8.1
Pregnancy
281
Pregnancy Category C.
282
In humans, treatment with RETROVIR during pregnancy reduced the rate of
283
maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to
284
7.8% for infants born to mothers treated with RETROVIR [see Clinical Studies (14.3)]. There
285
were no differences in pregnancy-related adverse events between the treatment groups. Animal
10
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
286
reproduction studies in rats and rabbits showed evidence of embryotoxicity and increased fetal
287
malformations.
288
A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected
289
pregnant women to determine the utility of RETROVIR for the prevention of maternal-fetal
290
HIV-1-transmission [see Clinical Studies (14.3)]. Congenital abnormalities occurred with similar
291
frequency between neonates born to mothers who received RETROVIR and neonates born to
292
mothers who received placebo. The observed abnormalities included problems in embryogenesis
293
(prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of
294
study drug.
295
Increased fetal resorptions occurred in pregnant rats and rabbits treated with doses of
296
zidovudine that produced drug plasma concentrations 66 to 226 times (rats) and 12 to 87 times
297
(rabbits) the mean steady-state peak human plasma concentration following a single 100-mg
298
dose of zidovudine. There were no other reported developmental anomalies. In another
299
developmental toxicity study, pregnant rats received zidovudine up to near-lethal doses that
300
produced peak plasma concentrations 350 times peak human plasma concentrations (300 times
301
the daily exposure [AUC] in humans given 600 mg/day zidovudine). This dose was associated
302
with marked maternal toxicity and an increased incidence of fetal malformations. However, there
303
were no signs of teratogenicity at doses up to one fifth the lethal dose [see Nonclinical
304
Toxicology (13.2)].
305
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant
306
women exposed to RETROVIR, an Antiretroviral Pregnancy Registry has been established.
307
Physicians are encouraged to register patients by calling 1-800-258-4263.
308
8.3
Nursing Mothers
309
Zidovudine is excreted in human milk [see Clinical Pharmacology (12.3)].
310
The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers
311
in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1
312
infection. Because of both the potential for HIV-1 transmission and the potential for serious
313
adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are
314
receiving RETROVIR.
315
8.4
Pediatric Use
316
RETROVIR has been studied in HIV-1-infected pediatric patients ≥6 weeks of age who
317
had HIV-1-related symptoms or who were asymptomatic with abnormal laboratory values
318
indicating significant HIV-1-related immunosuppression. RETROVIR has also been studied in
319
neonates perinatally exposed to HIV-1 [see Dosage and Administration (2.1), Adverse Reactions
320
(6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2), (14.3)].
321
8.5
Geriatric Use
322
Clinical studies of RETROVIR did not include sufficient numbers of subjects aged 65
323
and over to determine whether they respond differently from younger subjects. Other reported
324
clinical experience has not identified differences in responses between the elderly and younger
325
patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater
11
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
326
frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other
327
drug therapy.
328
8.6
Renal Impairment
329
In patients with severely impaired renal function (CrCl<15 mL/min), dosage reduction is
330
recommended [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
331
8.7
Hepatic Impairment
332
Zidovudine is eliminated from the body primarily by renal excretion following
333
metabolism in the liver (glucuronidation). Although the data are limited, zidovudine
334
concentrations appear to be increased in patients with severely impaired hepatic function, which
335
may increase the risk of hematologic toxicity [see Dosage and Administration (2.5), Clinical
336
Pharmacology (12.3)].
337
10
OVERDOSAGE
338
Acute overdoses of zidovudine have been reported in pediatric patients and adults. These
339
involved exposures up to 50 grams. No specific symptoms or signs have been identified
340
following acute overdosage with zidovudine apart from those listed as adverse events such as
341
fatigue, headache, vomiting, and occasional reports of hematological disturbances. All patients
342
recovered without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a
343
negligible effect on the removal of zidovudine while elimination of its primary metabolite, 3′
344
azido-3′-deoxy-5′-O-β-D-glucopyranuronosylthymidine (GZDV), is enhanced.
345
11
DESCRIPTION
346
RETROVIR is the brand name for zidovudine (formerly called azidothymidine [AZT]), a
347
pyrimidine nucleoside analogue active against HIV-1. The chemical name of zidovudine is 3′
348
Chemical structure of Retrovir
12
349
350
Zidovudine is a white to beige, odorless, crystalline solid with a molecular weight of
351
267.24 and a solubility of 20.1 mg/mL in water at 25°C. The molecular formula is C10H13N5O4.
352
RETROVIR Tablets are for oral administration. Each film-coated tablet contains 300 mg
353
of zidovudine and the inactive ingredients hypromellose, magnesium stearate, microcrystalline
354
cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide.
355
RETROVIR Capsules are for oral administration. Each capsule contains 100 mg of
356
zidovudine and the inactive ingredients corn starch, magnesium stearate, microcrystalline
357
cellulose, and sodium starch glycolate. The 100-mg empty hard gelatin capsule, printed with
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
358
edible black ink, consists of black iron oxide, dimethylpolysiloxane, gelatin, pharmaceutical
359
shellac, soya lecithin, and titanium dioxide.
360
RETROVIR Syrup is for oral administration. Each teaspoonful (5 mL) of RETROVIR
361
Syrup contains 50 mg of zidovudine and the inactive ingredients sodium benzoate 0.2% (added
362
as a preservative), citric acid, flavors, glycerin, and liquid sucrose. Sodium hydroxide may be
363
added to adjust pH.
364
12
CLINICAL PHARMACOLOGY
365
12.1 Mechanism of Action
366
Zidovudine is an antiviral agent [see Clinical Pharmacology (12.4)].
367
12.3 Pharmacokinetics
368
Absorption and Bioavailability: In adults, following oral administration, zidovudine is
369
rapidly absorbed and extensively distributed, with peak serum concentrations occurring within
370
0.5 to 1.5 hours. The AUC was equivalent when zidovudine was administered as RETROVIR
371
Tablets or Syrup compared with RETROVIR Capsules. The pharmacokinetic properties of
372
zidovudine in fasting adult patients are summarized in Table 6.
373
374
Table 6. Zidovudine Pharmacokinetic Parameters in Fasting Adult Patients
Parameter
Mean ± SD
(except where noted)
Oral bioavailability (%)
64 ± 10
(n = 5)
Apparent volume of distribution (L/kg)
1.6 ± 0.6
(n = 8)
Plasma protein binding (%)
<38
CSF:plasma ratioa
0.6 [0.04 to 2.62]
(n = 39)
Systemic clearance (L/hr/kg)
1.6 ± 0.6
(n = 6)
Renal clearance (L/hr/kg)
0.34 ± 0.05
(n = 9)
Elimination half-life (hr)b
0.5 to 3
(n = 19)
375
a Median [range].
376
b Approximate range.
377
378
Distribution: The apparent volume of distribution of zidovudine, following oral
379
administration, is 1.6 ± 0.6 L/kg; and binding to plasma protein is low, <38% (Table 6).
13
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
380
Metabolism and Elimination: Zidovudine is primarily eliminated by hepatic
381
metabolism. The major metabolite of zidovudine is GZDV. GZDV AUC is about 3-fold greater
382
than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and
383
74%, respectively, of the dose following oral administration. A second metabolite, 3′-amino-3′
384
deoxythymidine (AMT), has been identified in the plasma following single-dose intravenous
385
(IV) administration of zidovudine. The AMT AUC was one fifth of the zidovudine AUC.
386
Pharmacokinetics of zidovudine were dose independent at oral dosing regimens ranging from
387
2 mg/kg every 8 hours to 10 mg/kg every 4 hours.
388
Effect of Food on Absorption: RETROVIR may be administered with or without food.
389
The zidovudine AUC was similar when a single dose of zidovudine was administered with food.
390
Special Populations: Renal Impairment: Zidovudine clearance was decreased
391
resulting in increased zidovudine and GZDV half-life and AUC in patients with impaired renal
392
function (n = 14) following a single 200-mg oral dose (Table 7). Plasma concentrations of AMT
393
were not determined. A dose adjustment should not be necessary for patients with creatinine
394
clearance (CrCl) ≥15 mL/min.
395
396
Table 7. Zidovudine Pharmacokinetic Parameters in Patients With Severe Renal
397
Impairmenta
Parameter
Control Subjects
(Normal Renal Function)
(n = 6)
Patients With Renal
Impairment
(n = 14)
CrCl (mL/min)
120 ± 8
18 ± 2
Zidovudine AUC (ng•hr/mL)
1,400 ± 200
3,100 ± 300
Zidovudine half-life (hr)
1.0 ± 0.2
1.4 ± 0.1
398
a Data are expressed as mean ± standard deviation.
399
400
Hemodialysis and Peritoneal Dialysis: The pharmacokinetics and tolerance of
401
zidovudine were evaluated in a multiple-dose study in patients undergoing hemodialysis (n = 5)
402
or peritoneal dialysis (n = 6) receiving escalating doses up to 200 mg 5 times daily for 8 weeks.
403
Daily doses of 500 mg or less were well tolerated despite significantly elevated GZDV plasma
404
concentrations. Apparent zidovudine oral clearance was approximately 50% of that reported in
405
patients with normal renal function. Hemodialysis and peritoneal dialysis appeared to have a
406
negligible effect on the removal of zidovudine, whereas GZDV elimination was enhanced. A
407
dosage adjustment is recommended for patients undergoing hemodialysis or peritoneal dialysis
408
[see Dosage and Administration (2.4)].
409
Hepatic Impairment: Data describing the effect of hepatic impairment on the
410
pharmacokinetics of zidovudine are limited. However, because zidovudine is eliminated
411
primarily by hepatic metabolism, it is expected that zidovudine clearance would be decreased
412
and plasma concentrations would be increased following administration of the recommended
413
adult doses to patients with hepatic impairment [see Dosage and Administration (2.5)].
14
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
414
Pediatric Patients: Zidovudine pharmacokinetics have been evaluated in
415
HIV-1-infected pediatric patients (Table 8).
416
Patients 3 Months to 12 Years of Age: Overall, zidovudine pharmacokinetics in
417
pediatric patients greater than 3 months of age are similar to those in adult patients. Proportional
418
increases in plasma zidovudine concentrations were observed following administration of oral
419
solution from 90 to 240 mg/m2 every 6 hours. Oral bioavailability, terminal half-life, and oral
420
clearance were comparable to adult values. As in adult patients, the major route of elimination
421
was by metabolism to GZDV. After intravenous dosing, about 29% of the dose was excreted in
422
the urine unchanged, and about 45% of the dose was excreted as GZDV [see Dosage and
423
Administration (2.1)].
424
Patients <3 Months of Age: Zidovudine pharmacokinetics have been evaluated in
425
pediatric patients from birth to 3 months of life. Zidovudine elimination was determined
426
immediately following birth in 8 neonates who were exposed to zidovudine in utero. The
427
half-life was 13.0 ± 5.8 hours. In neonates ≤14 days old, bioavailability was greater, total body
428
clearance was slower, and half-life was longer than in pediatric patients >14 days old. For dose
429
recommendations for neonates [see Dosage and Administration (2.2)].
430
431
Table 8. Zidovudine Pharmacokinetic Parameters in Pediatric Patientsa
Parameter
Birth to 14 Days of
Age
14 Days to 3 Months
of Age
3 Months to 12 Years
of Age
Oral bioavailability (%)
89 ± 19
(n = 15)
61 ± 19
(n = 17)
65 ± 24
(n = 18)
CSF:plasma ratio
no data
no data
0.68 [0.03 to 3.25]b
(n = 38)
CL (L/hr/kg)
0.65 ± 0.29
(n = 18)
1.14 ± 0.24
(n = 16)
1.85 ± 0.47
(n = 20)
Elimination half-life (hr)
3.1 ± 1.2
(n = 21)
1.9 ± 0.7
(n = 18)
1.5 ± 0.7
(n = 21)
432
a Data presented as mean ± standard deviation except where noted.
433
b Median [range].
434
435
Pregnancy: Zidovudine pharmacokinetics have been studied in a Phase I study of
436
8 women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to
437
those of nonpregnant adults. Consistent with passive transmission of the drug across the
438
placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in
439
maternal plasma at delivery [see Use in Specific Populations (8.1)].
440
Although data are limited, methadone maintenance therapy in 5 pregnant women did not
441
appear to alter zidovudine pharmacokinetics.
442
Nursing Mothers: The Centers for Disease Control and Prevention recommend that
443
HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
444
HIV-1. After administration of a single dose of 200 mg zidovudine to 13 HIV-1-infected women,
445
the mean concentration of zidovudine was similar in human milk and serum [see Use in Specific
446
Populations (8.3)].
447
Geriatric Patients: Zidovudine pharmacokinetics have not been studied in patients
448
over 65 years of age.
449
Gender: A pharmacokinetic study in healthy male (n = 12) and female (n = 12)
450
subjects showed no differences in zidovudine AUC when a single dose of zidovudine was
451
administered as the 300-mg RETROVIR Tablet.
452
Drug Interactions: [See Drug Interactions (7)].
453
16
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
454
Table 9. Effect of Coadministered Drugs on Zidovudine AUCa
Note: ROUTINE DOSE MODIFICATION OF ZIDOVUDINE IS NOT WARRANTED
WITH COADMINISTRATION OF THE FOLLOWING DRUGS.
Coadministered
Drug and Dose
Zidovudine
Dose
n
Zidovudine
Concentrations
Concentration of
Coadministered
Drug
AUC
Variability
Atovaquone
750 mg q 12 hr
with food
200 mg q 8 hr
14
↑AUC
31%
Range
23% to 78%b
↔
Clarithromycin
500 mg twice daily
100 mg q 4 hr
x 7 days
4
↓AUC
12%
Range
↓34% to ↑14%
Not Reported
Fluconazole
400 mg daily
200 mg q 8 hr
12
↑AUC
74%
95% CI:
54% to 98%
Not Reported
Lamivudine
300 mg q 12 hr
single 200 mg
12
↑AUC
13%
90% CI:
2% to 27%
↔
Methadone
30 to 90 mg daily
200 mg q 4 hr
9
↑AUC
43%
Range
16% to 64%b
↔
Nelfinavir
750 mg q 8 hr x
7 to 10 days
single 200 mg
11
↓AUC
35%
Range
28% to 41%
↔
Probenecid
500 mg q 6 hr x
2 days
2 mg/kg q 8 hr
x 3 days
3
↑AUC
106%
Range
100% to 170%b
Not Assessed
Rifampin
600 mg daily x
14 days
200 mg q 8 hr
x 14 days
8
↓AUC
47%
90% CI:
41% to 53%
Not Assessed
Ritonavir
300 mg q 6 hr x
4 days
200 mg q 8 hr
x 4 days
9
↓AUC
25%
95% CI:
15% to 34%
↔
Valproic acid
250 mg or 500 mg
q 8 hr x 4 days
100 mg q 8 hr
x 4 days
6
↑AUC
80%
Range
64% to 130%b
Not Assessed
455
↑ = Increase; ↓ = Decrease; ↔ = no significant change; AUC = area under the concentration
456
versus time curve; CI = confidence interval.
457
a This table is not all inclusive.
458
b Estimated range of percent difference.
459
460
Phenytoin: Phenytoin plasma levels have been reported to be low in some patients
461
receiving RETROVIR, while in one case a high level was documented. However, in a
462
pharmacokinetic interaction study in which 12 HIV-1-positive volunteers received a single
17
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
463
300-mg phenytoin dose alone and during steady-state zidovudine conditions (200 mg every
464
4 hours), no change in phenytoin kinetics was observed. Although not designed to optimally
465
assess the effect of phenytoin on zidovudine kinetics, a 30% decrease in oral zidovudine
466
clearance was observed with phenytoin.
467
Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine,
468
stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or
469
intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss
470
of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine
471
(n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug
472
regimen to HIV-1/HCV co-infected patients [see Warnings and Precautions (5.4)].
473
12.4 Microbiology
474
Mechanism of Action: Zidovudine is a synthetic nucleoside analogue. Intracellularly,
475
zidovudine is phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate
476
(ZDV-TP). The principal mode of action of ZDV-TP is inhibition of reverse transcriptase (RT)
477
via DNA chain termination after incorporation of the nucleotide analogue. ZDV-TP is a weak
478
inhibitor of the cellular DNA polymerases α and γ and has been reported to be incorporated into
479
the DNA of cells in culture.
480
Antiviral Activity: The antiviral activity of zidovudine against HIV-1 was assessed in a
481
number of cell lines (including monocytes and fresh human peripheral blood lymphocytes). The
482
EC50 and EC90 values for zidovudine were 0.01 to 0.49 µM (1 μM = 0.27 mcg/mL) and 0.1 to
483
9 μM, respectively. HIV-1 from therapy-naive subjects with no mutations associated with
484
resistance gave median EC50 values of 0.011 µM (range: 0.005 to 0.110 µM) from Virco (n = 92
485
baseline samples from COL40263) and 0.0017 µM (0.006 to 0.0340 µM) from Monogram
486
Biosciences (n = 135 baseline samples from ESS30009). The EC50 values of zidovudine against
487
different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 μM, and against HIV-2 isolates from
488
0.00049 to 0.004 μM. In cell culture drug combination studies, zidovudine demonstrates
489
synergistic activity with the nucleoside reverse transcriptase inhibitors abacavir, didanosine, and
490
lamivudine; the non-nucleoside reverse transcriptase inhibitors delavirdine and nevirapine; and
491
the protease inhibitors indinavir, nelfinavir, ritonavir, and saquinavir; and additive activity with
492
interferon alfa. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell
493
culture.
494
Resistance: Genotypic analyses of the isolates selected in cell culture and recovered
495
from zidovudine-treated patients showed mutations in the HIV-1 RT gene resulting in 6 amino
496
acid substitutions (M41L, D67N, K70R, L210W, T215Y or F, and K219Q) that confer
497
zidovudine resistance. In general, higher levels of resistance were associated with greater number
498
of amino acid substitutions. In some patients harboring zidovudine-resistant virus at baseline,
499
phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and
500
zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of
501
substitutions conferring resistance to zidovudine.
18
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
502
Cross-Resistance: In a study of 167 HIV-1-infected patients, isolates (n = 2) with
503
multi-drug resistance to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine were
504
recovered from patients treated for ≥1 year with zidovudine plus didanosine or zidovudine plus
505
zalcitabine. The pattern of resistance-associated amino acid substitutions with such combination
506
therapies was different (A62V, V75I, F77L, F116Y, Q151M) from the pattern with zidovudine
507
monotherapy, with the Q151M substitution being most commonly associated with multi-drug
508
resistance. The substitution at codon 151 in combination with substitutions at 62, 75, 77, and 116
509
results in a virus with reduced susceptibility to didanosine, lamivudine, stavudine, zalcitabine,
510
and zidovudine. Thymidine analogue mutations (TAMs) are selected by zidovudine and confer
511
cross-resistance to abacavir, didanosine, stavudine, tenofovir, and zalcitabine.
512
13
NONCLINICAL TOXICOLOGY
513
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
514
Zidovudine was administered orally at 3 dosage levels to separate groups of mice and rats
515
(60 females and 60 males in each group). Initial single daily doses were 30, 60, and
516
120 mg/kg/day in mice and 80, 220, and 600 mg/kg/day in rats. The doses in mice were reduced
517
to 20, 30, and 40 mg/kg/day after day 90 because of treatment-related anemia, whereas in rats
518
only the high dose was reduced to 450 mg/kg/day on day 91 and then to 300 mg/kg/day on
519
day 279.
520
In mice, 7 late-appearing (after 19 months) vaginal neoplasms (5 nonmetastasizing
521
squamous cell carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in
522
animals given the highest dose. One late-appearing squamous cell papilloma occurred in the
523
vagina of a middle-dose animal. No vaginal tumors were found at the lowest dose.
524
In rats, 2 late-appearing (after 20 months), nonmetastasizing vaginal squamous cell
525
carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or
526
middle dose in rats. No other drug-related tumors were observed in either sex of either species.
527
At doses that produced tumors in mice and rats, the estimated drug exposure (as
528
measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human
529
exposure at the recommended therapeutic dose of 100 mg every 4 hours.
530
It is not known how predictive the results of rodent carcinogenicity studies may be for
531
humans.
532
Zidovudine was mutagenic in a 5178Y/TK+/- mouse lymphoma assay, positive in an in
533
vitro cell transformation assay, clastogenic in a cytogenetic assay using cultured human
534
lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was
535
negative in a cytogenetic study in rats given a single dose.
536
Zidovudine, administered to male and female rats at doses up to 7 times the usual adult
537
dose based on body surface area, had no effect on fertility judged by conception rates.
538
Two transplacental carcinogenicity studies were conducted in mice. One study
539
administered zidovudine at doses of 20 mg/kg/day or 40 mg/kg/day from gestation day 10
540
through parturition and lactation with dosing continuing in offspring for 24 months postnatally.
19
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
541
The doses of zidovudine administered in this study produced zidovudine exposures
542
approximately 3 times the estimated human exposure at recommended doses. After 24 months,
543
an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or
544
lung or any other organ in either gender. These findings are consistent with results of the
545
standard oral carcinogenicity study in mice, as described earlier. A second study administered
546
zidovudine at maximum tolerated doses of 12.5 mg/day or 25 mg/day (∼1,000 mg/kg
547
nonpregnant body weight or ∼450 mg/kg of term body weight) to pregnant mice from days 12
548
through 18 of gestation. There was an increase in the number of tumors in the lung, liver, and
549
female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine.
550
13.2 Reproductive and Developmental Toxicology Studies
551
Oral teratology studies in the rat and in the rabbit at doses up to 500 mg/kg/day revealed
552
no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted in embryo/fetal
553
toxicity as evidenced by an increase in the incidence of fetal resorptions in rats given 150 or
554
450 mg/kg/day and rabbits given 500 mg/kg/day. The doses used in the teratology studies
555
resulted in peak zidovudine plasma concentrations (after one half of the daily dose) in rats 66 to
556
226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma concentrations
557
(after one sixth of the daily dose) achieved with the recommended daily dose (100 mg every
558
4 hours). In an in vitro experiment with fertilized mouse oocytes, zidovudine exposure resulted
559
in a dose-dependent reduction in blastocyst formation. In an additional teratology study in rats, a
560
dose of 3,000 mg/kg/day (very near the oral median lethal dose in rats of 3,683 mg/kg) caused
561
marked maternal toxicity and an increase in the incidence of fetal malformations. This dose
562
resulted in peak zidovudine plasma concentrations 350 times peak human plasma concentrations.
563
(Estimated AUC in rats at this dose level was 300 times the daily AUC in humans given
564
600 mg/day.) No evidence of teratogenicity was seen in this experiment at doses of
565
600 mg/kg/day or less.
566
14
CLINICAL STUDIES
567
Therapy with RETROVIR has been shown to prolong survival and decrease the incidence
568
of opportunistic infections in patients with advanced HIV-1 disease and to delay disease
569
progression in asymptomatic HIV-1-infected patients.
570
14.1 Adults
571
Combination Therapy: RETROVIR in combination with other antiretroviral agents has
572
been shown to be superior to monotherapy for one or more of the following endpoints: delaying
573
death, delaying development of AIDS, increasing CD4+ cell counts, and decreasing plasma
574
HIV-1 RNA.
575
The clinical efficacy of a combination regimen that includes RETROVIR was
576
demonstrated in study ACTG 320. This study was a multi-center, randomized, double-blind,
577
placebo-controlled trial that compared RETROVIR 600 mg/day plus EPIVIR 300 mg/day to
578
RETROVIR plus EPIVIR plus indinavir 800 mg t.i.d. The incidence of AIDS-defining events or
20
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
579
death was lower in the triple-drug–containing arm compared with the 2-drug–containing arm
580
(6.1% versus 10.9%, respectively).
581
Monotherapy: In controlled studies of treatment-naive patients conducted between 1986
582
and 1989, monotherapy with RETROVIR, as compared with placebo, reduced the risk of HIV-1
583
disease progression, as assessed using endpoints that included the occurrence of HIV-1-related
584
illnesses, AIDS-defining events, or death. These studies enrolled patients with advanced disease
585
(BW 002), and asymptomatic or mildly symptomatic disease in patients with CD4+ cell counts
586
between 200 and 500 cells/mm3 (ACTG 016 and ACTG 019). A survival benefit for
587
monotherapy with RETROVIR was not demonstrated in the latter 2 studies. Subsequent studies
588
showed that the clinical benefit of monotherapy with RETROVIR was time limited.
589
14.2 Pediatric Patients
590
ACTG 300 was a multi-center, randomized, double-blind study that provided for
591
comparison of EPIVIR plus RETROVIR to didanosine monotherapy. A total of
592
471 symptomatic, HIV-1-infected therapy-naive pediatric patients were enrolled in these
593
2 treatment arms. The median age was 2.7 years (range: 6 weeks to 14 years), the mean baseline
594
CD4+ cell count was 868 cells/mm3, and the mean baseline plasma HIV-1 RNA was
595
5.0 log10 copies/mL. The median duration that patients remained on study was approximately
596
10 months. Results are summarized in Table 10.
597
598
Table 10. Number of Patients (%) Reaching a Primary Clinical Endpoint (Disease
599
Progression or Death)
EPIVIR plus RETROVIR
Didanosine
Endpoint
(n = 236)
(n = 235)
HIV disease progression or death (total)
15 (6.4%)
37 (15.7%)
Physical growth failure
7 (3.0%)
6 (2.6%)
Central nervous system deterioration
4 (1.7%)
12 (5.1%)
CDC Clinical Category C
2 (0.8%)
8 (3.4%)
Death
2 (0.8%)
11 (4.7%)
600
601
14.3 Prevention of Maternal-Fetal HIV-1 Transmission
602
The utility of RETROVIR for the prevention of maternal-fetal HIV-1 transmission was
603
demonstrated in a randomized, double-blind, placebo-controlled trial (ACTG 076) conducted in
604
HIV-1-infected pregnant women with CD4+ cell counts of 200 to 1,818 cells/mm3 (median in
605
the treated group: 560 cells/mm3) who had little or no previous exposure to RETROVIR. Oral
606
RETROVIR was initiated between 14 and 34 weeks of gestation (median 11 weeks of therapy)
607
followed by IV administration of RETROVIR during labor and delivery. Following birth,
608
neonates received oral RETROVIR Syrup for 6 weeks. The study showed a statistically
609
significant difference in the incidence of HIV-1 infection in the neonates (based on viral culture
610
from peripheral blood) between the group receiving RETROVIR and the group receiving
611
placebo. Of 363 neonates evaluated in the study, the estimated risk of HIV-1 infection was 7.8%
21
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
612
in the group receiving RETROVIR and 24.9% in the placebo group, a relative reduction in
613
transmission risk of 68.7%. RETROVIR was well tolerated by mothers and infants. There was
614
no difference in pregnancy-related adverse events between the treatment groups.
615
16
HOW SUPPLIED/STORAGE AND HANDLING
616
RETROVIR Tablets 300 mg (biconvex, white, round, film-coated) containing 300 mg
617
zidovudine, one side engraved “GX CW3” and “300” on the other side.
618
Bottle of 60 (NDC 0173-0501-00).
619
Store at 15° to 25°C (59° to 77°F).
620
RETROVIR Capsules 100 mg (white, opaque cap and body) containing 100 mg
621
zidovudine and printed with “Wellcome” and unicorn logo on cap and “Y9C” and “100” on
622
body.
623
Bottles of 100 (NDC 0173-0108-55).
624
Store at 15° to 25°C (59° to 77°F) and protect from moisture.
625
RETROVIR Syrup (colorless to pale yellow, strawberry-flavored) containing 50 mg
626
zidovudine in each teaspoonful (5 mL).
627
Bottle of 240 mL (NDC 0173-0113-18) with child-resistant cap.
628
Store at 15° to 25°C (59° to 77°F).
629
17
PATIENT COUNSELING INFORMATION
630
17.1 Information About Therapy With RETROVIR
631
Neutropenia and Anemia: Patients should be informed that the major toxicities of
632
RETROVIR are neutropenia and/or anemia. The frequency and severity of these toxicities are
633
greater in patients with more advanced disease and in those who initiate therapy later in the
634
course of their infection. Patients should be informed that if toxicity develops, they may require
635
transfusions or drug discontinuation. Patients should be informed of the extreme importance of
636
having their blood counts followed closely while on therapy, especially for patients with
637
advanced symptomatic HIV-1 disease [see Boxed Warning, Warnings and Precautions (5.1)].
638
Myopathy: Patients should be informed that myopathy and myositis with pathological
639
changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of
640
RETROVIR [see Boxed Warning, Warnings and Precautions (5.2)].
641
Lactic Acidosis/Hepatomegaly: Patients should be informed that some HIV medicines,
642
including RETROVIR, can cause a rare, but serious condition called lactic acidosis with liver
643
enlargement (hepatomegaly) [see Boxed Warning, Warnings and Precautions (5.3)].
644
HIV-1/HCV Co-Infection: Patients with HIV-1/HCV co-infection should be informed
645
that hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients
646
receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without
647
ribavirin [see Warnings and Precautions (5.4)].
648
Redistribution/Accumulation of Body Fat: Patients should be informed that
649
redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy
22
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
650
and that the cause and long-term health effects of these conditions are not known at this time
651
[see Warnings and Precautions (5.7)].
652
Common Adverse Reactions: Patients should be informed that the most commonly
653
reported adverse reactions in adult patients being treated with RETROVIR were headache,
654
malaise, nausea, anorexia, and vomiting. The most commonly reported adverse reactions in
655
pediatric patients receiving RETROVIR were fever, cough, and digestive disorders. Patients also
656
should be encouraged to contact their physician if they experience muscle weakness, shortness of
657
breath, symptoms of hepatitis or pancreatitis, or any other unexpected adverse events while being
658
treated with RETROVIR [see Adverse Reactions (6)].
659
Drug Interactions: Patients should be cautioned about the use of other medications,
660
including ganciclovir, interferon alfa, and ribavirin, which may exacerbate the toxicity of
661
RETROVIR [see Drug Interactions (7)].
662
Pregnancy: Pregnant women considering the use of RETROVIR during pregnancy for
663
prevention of HIV-1 transmission to their infants should be informed that transmission may still
664
occur in some cases despite therapy. The long-term consequences of in utero and infant exposure
665
to RETROVIR are unknown, including the possible risk of cancer [see Use in Specific
666
Populations (8.1)].
667
HIV-1-infected pregnant women should be informed not to breastfeed to avoid postnatal
668
transmission of HIV to a child who may not yet be infected [see Use in Specific Populations
669
(8.3)].
670
Information About Therapy With RETROVIR: RETROVIR is not a cure for HIV-1
671
infection, and patients may continue to acquire illnesses associated with HIV-1 infection,
672
including opportunistic infections. Therefore, patients should be informed to seek medical care
673
for any significant change in their health status.
674
Patients should be informed of the importance of taking RETROVIR exactly as
675
prescribed. They should be informed not to share medication and not to exceed the
676
recommended dose. Patients should be informed that the long-term effects of RETROVIR are
677
unknown at this time.
678
Patients should be informed that therapy with RETROVIR has not been shown to reduce
679
the risk of transmission of HIV-1 to others through sexual contact or blood contamination.
680
681
RETROVIR, COMBIVIR, EPIVIR, and TRIZIVIR are registered trademarks of
682
GlaxoSmithKline.
683
684
685
686
GlaxoSmithKline
687
Research Triangle Park, NC 27709
23
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
688
689
©2010, GlaxoSmithKline. All rights reserved.
690
691
May 2010
692
RTT:xPI
24
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:39.560349
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019655s049lbl.pdf', 'application_number': 19655, 'submission_type': 'SUPPL ', 'submission_number': 49}
|
11,612
|
Sandostatin®
octreotide acetate
Injection
Rx Only
T2002-XX
XXXXXXXX
as a clear sterile
inistration by deep
or intravenous injection. Octreotide acetate, known chemically as
-lysyl-L-
-(R*, R*)]
acetate salt, is a long-acting octapeptide with pharmacologic actions mimicking those of the
atostatin.
Sand
sterile 1 mL ampuls in 3 strengths,
conta
nd sterile 5 mL multi-dose vials in
2 stre
(as acetate).
........ 3.4 mg
......... 45 mg
pH 4.2 ± 0.3
... qs to 1 mL
id, USP ........................................................... 3.4 mg
mannitol, USP .............................................................. 45 mg
phenol, USP ................................................................ 5.0 mg
sodium
o pH 4.2 ± 0.3
water for injection, USP
qs to 1 mL
Lactic acid and sodium bicarbonate are added to provide a buffered solution, pH to 4.2 ± 0.3.
The molecular weight of octreotide acetate is 1019.3 (free peptide, C49H66N10O10S2) and its
amino acid sequence is:
xCH3COOH
where x = 1.4 to 2.5
DESCRIPTION
Sandostatin® (octreotide acetate) Injection, a cyclic octapeptide prepared
solution of octreotide, acetate salt, in a buffered lactic acid solution for adm
subcutaneous (intrafat)
L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L
threonyl-N-[2-hydroxy-1-(hydroxymethyl)propyl]-, cyclic (2→7)-disulfide; [R
natural hormone som
ostatin® (octreotide acetate) Injection is available as:
ining 50, 100, or 500 mcg octreotide (as acetate), a
ngths, containing 200 and 1000 mcg/mL of octreotide
Each ampul also contains:
lactic acid, USP....................................................
mannitol, USP .....................................................
sodium bicarbonate, USP.............................qs to
water for injection, USP .....................................
Each mL of the multi-dose vials also contains:
lactic ac
bicarbonate, USP ........................... qs t
........................................
H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol,
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 2
atural hormone,
gon, and insulin
in, it also suppresses LH response to GnRH, decreases
ntestinal peptide,
treotide acetate) has been used to
d diarrhea), and
ng adenomas (watery diarrhea).
e and/or IGF-I
Single doses of Sandostatin® (octreotide acetate) have been shown to inhibit gallbladder
lled clinical trials
gallstone or biliary sludge formation was markedly increased (See
ormone (TSH).
nd completely from the injection
urs after dosing.
ere found to be
ose proportional
s up to 500 mcg
and after subcutaneous multiple doses up to 500 mcg t.i.d. (1,500 mcg/day).
1/2 = 0.2 h), the
clearance ranged
as found to be
endent manner.
Binding was mainly to lipoprotein and, to a lesser extent, to albumin.
1.7 to 1.9 hours
of Sandostatin®
e type of tumor.
About 32% of the dose is excreted unchanged into the urine. In an elderly population, dose
adjustments may be necessary due to a significant increase in the half-life (46%) and a
significant decrease in the clearance (26%) of the drug.
In patients with acromegaly, the pharmacokinetics differ somewhat from those in healthy
volunteers. A mean peak concentration of 2.8 ng/mL (100 mcg dose) was reached in 0.7 hours
after subcutaneous dosing. The volume of distribution (Vdss) was estimated to be 21.6 ± 8.5 L
and the total body clearance was increased to 18 L/h. The mean percent of the drug bound was
41.2%. The disposition and elimination half-lives were similar to normals.
CLINICAL PHARMACOLOGY
Sandostatin® (octreotide acetate) exerts pharmacologic actions similar to the n
somatostatin. It is an even more potent inhibitor of growth hormone, gluca
than somatostatin. Like somatostat
splanchnic blood flow, and inhibits release of serotonin, gastrin, vasoactive i
secretin, motilin, and pancreatic polypeptide.
By virtue of these pharmacological actions, Sandostatin® (oc
treat the symptoms associated with metastatic carcinoid tumors (flushing an
Vasoactive Intestinal Peptide (VIP) secreti
Sandostatin® (octreotide acetate) substantially reduces growth hormon
(somatomedin C) levels in patients with acromegaly.
contractility and to decrease bile secretion in normal volunteers. In contro
the incidence of
WARNINGS).
Sandostatin® (octreotide acetate) suppresses secretion of thyroid stimulating h
Pharmacokinetics
After subcutaneous injection, octreotide is absorbed rapidly a
site. Peak concentrations of 5.2 ng/mL (100 mcg dose) were reached 0.4 ho
Using a specific radioimmunoassay, intravenous and subcutaneous doses w
bioequivalent. Peak concentrations and area under the curve values were d
after intravenous single doses up to 200 mcg and subcutaneous single dose
In healthy volunteers the distribution of octreotide from plasma was rapid (tα
volume of distribution (Vdss) was estimated to be 13.6 L, and the total body
from 7 L/hr to 10 L/hr.In blood, the distribution into the erythrocytes w
negligible and about 65% was bound in the plasma in a concentration-indep
The elimination of octreotide from plasma had an apparent half-life of
compared with 1-3 minutes with the natural hormone. The duration of action
(octreotide acetate) is variable but extends up to 12 hours depending upon th
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 3
a was prolonged
/min) octreotide
ent (ClCR 10-39
renally impaired
l body clearance
dy clearance was
/hr to 4.5 L/hr.).
Patients with liver cirrhosis showed prolonged elimination of drug, with octreotide t1/2
l body clearance decreasing to 5.9 L/hr, whereas patients with
1/2 increased to 3.4 hr and total body clearance of 8.2 L/hr.
th hormone and
response to or
tine mesylate at
rmone and IGF-I
patients with
tatin® (octreotide acetate) reduces growth hormone to within normal
ormal ranges in
me maximal for
th Sandostatin® (octreotide acetate) to reduce blood levels
e and IGF-I (somatomedin C) offers potential benefit before the effects of
irradiation are manifested.
e of growth were
erformed with Sandostatin® (octreotide acetate); these trials were
of patients with
ea and flushing
Sandostatin® (octreotide acetate) studies were not designed to show an effect on the size, rate
of growth or development of metastases.
Vasoactive Intestinal Peptide Tumors (VIPomas)
Sandostatin® (octreotide acetate) is indicated for the treatment of the profuse watery diarrhea
associated with VIP-secreting tumors. Sandostatin® (octreotide acetate) studies were not
designed to show an effect on the size, rate of growth or development of metastases.
In patients with renal impairment the elimination of octreotide from plasm
and total body clearance reduced. In mild renal impairment (ClCR 40-60 mL
t1/2 was 2.4 hours and total body clearance was 8.8 L/hr, in moderate impairm
mL/min) t1/2 was 3.0 hours and total body clearance 7.3 L/hr, and in severely
patients not requiring dialysis (ClCR <10 mL/min) t1/2 was 3.1 hours and tota
was 7.6 L/hr. In patients with severe renal failure requiring dialysis, total bo
reduced to about half that found in healthy subjects (from approximately 10 L
increasing to 3.7 hr and tota
fatty liver disease showed t
INDICATIONS AND USAGE
Acromegaly
Sandostatin® (octreotide acetate) is indicated to reduce blood levels of grow
IGF-I (somatomedin C) in acromegaly patients who have had inadequate
cannot be treated with surgical resection, pituitary irradiation, and bromocrip
maximally tolerated doses. The goal is to achieve normalization of growth ho
(somatomedin C) levels (See DOSAGE AND ADMINISTRATION). In
acromegaly, Sandos
ranges in 50% of patients and reduces IGF-I (somatomedin C) to within n
50%-60% of patients. Since the effects of pituitary irradiation may not beco
several years, adjunctive therapy wi
of growth hormon
Improvement in clinical signs and symptoms or reduction in tumor size or rat
not shown in clinical trials p
not optimally designed to detect such effects.
Carcinoid Tumors
®
Sandostatin (octreotide acetate) is indicated for the symptomatic treatment
metastatic carcinoid tumors where it suppresses or inhibits the severe diarrh
episodes associated with the disease.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 4
Sensitivity to this drug or any of its components.
hibit gallbladder
trials (primarily
alities was 63%
he incidence of
or 12 months or
tide acetate) for
ppear related to
al symptoms. The
symptoms were not specific for gallbladder disease. A few patients developed acute
cending cholangitis, biliary obstruction, cholestatic hepatitis, or pancreatitis
during Sandostatin® (octreotide acetate) therapy or following its withdrawal. One patient
ped ascending cholangitis during Sandostatin® (octreotide acetate) therapy and died.
latory hormones,
hyperglycemia.
lating hormone,
e also occurred
idence of these
adverse events during long-term therapy was determined vigorously only in acromegaly
they receive, are
thyroidism, and
s are related to
lycemic control,
acetate) therapy as
treotide acetate)
in overt diabetes mellitus or necessitate dose changes
in insulin or other hypoglycemic agents. Hypoglycemia and hyperglycemia occurred on
Sandostatin® (octreotide acetate) in 3% and 16% of acromegalic patients, respectively. Severe
hyperglycemia, subsequent pneumonia, and death following initiation of Sandostatin®
(octreotide acetate) therapy was reported in one patient with no history of hyperglycemia.
In acromegalic patients, 12% developed biochemical hypothyroidism only, 8% developed
goiter, and 4% required initiation of thyroid replacement therapy while receiving Sandostatin®
(octreotide acetate). Baseline and periodic assessment of thyroid function (TSH, total and/or
free T4) is recommended during chronic therapy.
CONTRAINDICATIONS
WARNINGS
Single doses of Sandostatin® (octreotide acetate) have been shown to in
contractility and decrease bile secretion in normal volunteers. In clinical
patients with acromegaly or psoriasis), the incidence of biliary tract abnorm
(27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). T
stones or sludge in patients who received Sandostatin® (octreotide acetate) f
longer was 52%. Less than 2% of patients treated with Sandostatin® (octreo
1 month or less developed gallstones. The incidence of gallstones did not a
age, sex or dose. Like patients without gallbladder abnormalities, the majority of patients
developing gallbladder abnormalities on ultrasound had gastrointestin
cholecystitis, as
develo
PRECAUTIONS
General
Sandostatin® (octreotide acetate) alters the balance between the counter-regu
insulin, glucagon and growth hormone, which may result in hypoglycemia or
Sandostatin® (octreotide acetate) also suppresses secretion of thyroid stimu
which may result in hypothyroidism. Cardiac conduction abnormalities hav
during treatment with Sandostatin® (octreotide acetate). However, the inc
patients who, due to their underlying disease and/or the subsequent treatment
at an increased risk for the development of diabetes mellitus, hypo
cardiovascular disease. Although the degree to which these abnormalitie
Sandostatin® (octreotide acetate) therapy is not clear, new abnormalities of g
thyroid function and ECG developed during Sandostatin® (octreotide
described below.
The hypoglycemia or hyperglycemia which occurs during Sandostatin® (oc
therapy is usually mild, but may result
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 5
n abnormalities
atin® (octreotide
axis shifts, early
se ECG changes
as beta-blockers
ient with severe
Sandostatin® (octreotide acetate) therapy resulted in
ation of a drug
btained with a positive rechallenge.
andostatin® (octreotide
®
atients.
tatin® (octreotide
ance dosage.
levels and abnormal Schilling’s tests have been observed in some
of vitamin B12
e) therapy.
or Patients
n to the patients
otide acetate) Injection.
Laboratory T
Laboratory test
g and following
patient respons
urement of the
following subst
ness to Sandostatin® (octreotide acetate) may be evaluated
ment of IGF-I
din C) level may be made two weeks after drug initiation or
dosage change.
asma serotonin,
VIPoma:
VIP (plasma vasoactive intestinal peptide)
Baseline and periodic total and/or free T4 measurements should be performed during chronic
therapy (see PRECAUTIONS — General).
Drug Interactions
Sandostatin® (octreotide acetate) has been associated with alterations in nutrient absorption,
so it may have an effect on absorption of orally administered drugs. Concomitant
In acromegalics, bradycardia (<50 bpm) developed in 25%; conductio
occurred in 10% and arrhythmias occurred in 9% of patients during Sandost
acetate) therapy. Other EKG changes observed included QT prolongation,
repolarization, low voltage, R/S transition, and early R wave progression. The
are not uncommon in acromegalic patients. Dose adjustments in drugs such
that have bradycardia effects may be necessary. In one acromegalic pat
congestive heart failure, initiation of
worsening of CHF with improvement when drug was discontinued. Confirm
effect was o
Several cases of pancreatitis have been reported in patients receiving S
acetate) therapy.
Sandostatin (octreotide acetate) may alter absorption of dietary fats in some p
In patients with severe renal failure requiring dialysis, the half-life of Sandos
acetate) may be increased, necessitating adjustment of the mainten
Depressed vitamin B12
patients receiving Sandostatin® (octreotide acetate) therapy, and monitoring
levels is recommended during chronic Sandostatin® (octreotide acetat
Information f
Careful instruction in sterile subcutaneous injection technique should be give
and to other persons who may administer Sandostatin® (octre
ests
s that may be helpful as biochemical markers in determinin
e depend on the specific tumor. Based on diagnosis, meas
ances may be useful in monitoring the progress of therapy:
Acromegaly: Growth Hormone, IGF-I (somatomedin C)
Responsive
by determining growth hormone levels at 1-4 hour intervals for 8-12
hours post dose. Alternatively, a single measure
(somatome
Carcinoid:
5-HIAA (urinary 5-hydroxyindole acetic acid), pl
plasma Substance P
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 6
acetate) with cyclosporine may decrease blood
ing insulin, oral hypoglycemic agents, beta blockers, calcium channel blockers,
or agents to control fluid and electrolyte balance, may require dose adjustments of these
oratory Test Interactions
tory tests, including amine or peptide
of Sandostatin®
for 85-99 weeks
rface area). In a
site sarcomas or
y, at the highest
y surface area)
reased incidence
sensitivity of the
s would prevent
mors in patients
treated with Sandostatin (octreotide acetate) for up to 5 years. There was also a 15%
ed to 7% in the
saline control females and 0% in the vehicle control females. The presence of endometritis
ce of corpora lutea, the reduction in mammary fibroadenomas, and the
d with estrogen
t doses up to
rface area.
Pregnancy Category B
to 16 times the
ence of impaired
rm to the fetus due to Sandostatin (octreotide acetate). 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 milk, caution should be exercised when Sandostatin® (octreotide acetate) is administered to
a nursing woman.
administration of Sandostatin® (octreotide
levels of cyclosporine and result in transplant rejection.
Patients receiv
therapeutic agents.
Drug Lab
No known interference exists with clinical labora
determinations.
Carcinogenesis/Mutagenesis/Impairment of Fertility
Studies in laboratory animals have demonstrated no mutagenic potential
(octreotide acetate).
No carcinogenic potential was demonstrated in mice treated subcutaneously
at doses up to 2000 mcg/kg/day (8x the human exposure based on body su
116-week subcutaneous study in rats, a 27% and 12% incidence of injection
squamous cell carcinomas was observed in males and females, respectivel
dose level of 1250 mcg/kg/day (10x the human exposure based on bod
compared to an incidence of 8%-10% in the vehicle control groups. The inc
of injection site tumors was most probably caused by irritation and the high
rat to repeated subcutaneous injections at the same site. Rotating injection site
chronic irritation in humans. There have been no reports of injection site tu
®
incidence of uterine adenocarcinomas in the 1250 mcg/kg/day females compar
coupled with the absen
presence of uterine dilatation suggest that the uterine tumors were associate
dominance in the aged female rats which does not occur in humans.
Sandostatin® (octreotide acetate) did not impair fertility in rats a
1000 mcg/kg/day, which represents 7x the human exposure based on body su
Reproduction studies have been performed in rats and rabbits at doses up
highest human dose based on body surface area and have revealed no evid
fertility or ha
®
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 7
tion is limited.
luate safety and
of neonates and
(HI), persistent
cemia of infancy (PHHI), or nesidioblastosis] who have received
fety information
atectomy and to
in this setting is
apy in pediatric
to diazoxide for
ved Sandostatin®
follow-up was
as replaced by
the remainder of
of patients who
oxide. Doses of
de effects were
each reported in
with resolution
hin 2-4 weeks.
plements. Poor
1-4.33 years. It
atients in whom
tients who were
rted in 32% of
ported in 35% (n = 17) of patients. Asymptomatic
as reported in one infant after one year of therapy and was treated
d. There has been a single report of an infant with nesidioblastosis
thought to be independent of Sandostatin® therapy. A single death
veloped sudden
d 8 hours after receiving a
single 100 mcg subcutaneous dose of Sandostatin .
ADVERSE REACTIONS
Gallbladder Abnormalities
Gallbladder abnormalities, especially stones and/or biliary sludge, frequently develop in
patients on chronic Sandostatin® (octreotide acetate) therapy (See WARNINGS).
Pediatric Use
Experience with Sandostatin® (octreotide acetate) in the pediatric popula
Although formal controlled clinical trials have not been performed to eva
effectiveness in this age group, there are reports of 49 cases in the literature
infants with congenital hyperinsulinism [also called familial hyperinsulinism
hyperinsulinemic hypogly
Sandostatin® as an inhibitor of insulin release. The following efficacy and sa
is derived from these 49 patients.
Sandostatin® has been used to stabilize plasma glucose levels prior to pancre
treat recurrent post-operative hypoglycemia. Although most use of octreotide
short-term, a few reports in the literature have documented longer-term ther
patients (2.2-5.5 years). Octreotide is an alternative medical treatment
control of hypoglycemia in this disorder. Of 31 pediatric patients who recei
as prescribed for congenital hyperinsulinism and for which long-term
available, octreotide obviated the need for surgery in 3 patients (10%) and w
diazoxide in 4 patients (13%) due to uncontrolled hypoglycemia. Although
these patients required surgery, there have been a few reports in the literature
have responded to octreotide after failing treatment with surgery and/or diaz
3-40 mcg/kg/day have been used. At these doses, the majority of si
gastrointestinal: diarrhea, steatorrhea, vomiting, and abdominal distension,
22-35% (n = 11-17) of patients. However, they were generally short-lived –
of vomiting and distention in 2-4 days, and diarrhea/steatorrhea, wit
Steatorrhea was controlled in most patients with pancreatic enzyme sup
growth was reported in 37% of patients (n = 7) who received Sandostatin® for
was associated with low serum growth hormone and/or IGF-1 levels in 4/6 p
these parameters were measured. Catch-up growth occurred in 3/3 pa
followed after Sandostatin® was discontinued. Poor weight gain was repo
patients (n = 6). Tachyphylaxis was re
gallstones with sludge w
with ursodeoxycholic aci
who experienced a seizure
has been reported in a 16-month-old male with enterocutaneous fistula who de
abdominal pain and increased nasogastric drainage and expire
®
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 8
on abnormalities
occurred in 10% and arrhythmias developed in 9% of patients during Sandostatin® (octreotide
(See PRECAUTIONS — General).
in 34%-61% of
acromegalic patients in US studies although only 2.6% of the patients discontinued therapy
ents with other
ot dose-related, but diarrhea and abdominal
resolved more quickly in patients treated with 300 mcg/day than in those
distention, and
Hypo/Hyperglycemia
and hyperglycemia occurred in 3% and 16% of acromegalic patients,
emia were noted
Hypothyroidism
In acromegalics, biochemical hypothyroidism alone occurred in 12% while goiter occurred in
— General). In
patients without acromegaly, hypothyroidism has only been reported in several isolated
n reported.
Pancreatitis was
also observed (See WARNINGS and PRECAUTIONS).
4% of patients,
infection, cold
, blurred vision,
Other Adverse Events <1%
Events reported in less than 1% of patients and for which relationship to drug is not
established are listed: Gastrointestinal: hepatitis, jaundice, increase in liver enzymes, GI
bleeding, hemorrhoids, appendicitis, gastric/peptic ulcer, gallbladder polyp; Integumentary:
rash, cellulitis, petechiae, urticaria, basal cell carcinoma; Musculoskeletal: arthritis, joint
effusion, muscle pain, Raynaud’s phenomenon; Cardiovascular: chest pain, shortness of
breath, thrombophlebitis, ischemia, congestive heart failure, hypertension, hypertensive
Cardiac
In acromegalics, sinus bradycardia (<50 bpm) developed in 25%; conducti
acetate) therapy
Gastrointestinal
Diarrhea, loose stools, nausea and abdominal discomfort were each seen
due to these symptoms. These symptoms were seen in 5%-10% of pati
disorders.
The frequency of these symptoms was n
discomfort generally
treated with 750 mcg/day. Vomiting, flatulence, abnormal stools, abdominal
constipation were each seen in less than 10% of patients.
Hypoglycemia
respectively, but only in about 1.5% of other patients. Symptoms of hypoglyc
in approximately 2% of patients.
6% during Sandostatin® (octreotide acetate) therapy (See PRECAUTIONS
patients and goiter has not bee
Other Adverse Events
Pain on injection was reported in 7.7%, headache in 6% and dizziness in 5%.
Other Adverse Events 1%-4%
Other events (relationship to drug not established), each observed in 1%-
included fatigue, weakness, pruritus, joint pain, backache, urinary tract
symptoms, flu symptoms, injection site hematoma, bruise, edema, flushing
pollakiuria, fat malabsorption, hair loss, visual disturbance and depression.
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 9
libido decrease,
lexy, increased
onary
betes insipidus,
orrhea,
oligomenorrhea,
vaginitis;
Urogenital:
Miscellaneous:
onstrate titers of
dy titers to Sandostatin® (octreotide
acetate) were subsequently reported in three patients and resulted in prolonged duration of
o patients. Anaphylactoid reactions, including anaphylactic shock, have been
®
doses of 1 mg
0 minutes and of
research patients have not resulted in serious ill
the treatment of overdose can often be obtained from a certified
Regional Poison Control Center. Telephone numbers of certified Regional Poison Control
iven 72 mg/kg and 18 mg/kg IV, respectively.
r drug abuse or
ous system are
DOSAGE AND ADMINISTRATION
r intravenously.
tin® (octreotide
y be reduced by
neous injections
at the same site within short periods of time should be avoided. Sites should be rotated in a
systematic manner.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration. Do not use if particulates and/or discoloration are observed.
Proper sterile technique should be used in the preparation of parenteral admixtures to
minimize the possibility of microbial contamination. Sandostatin® (octreotide acetate) is
not compatible in Total Parenteral Nutrition (TPN) solutions because of the formation
of a glycosyl octreotide conjugate which may decrease the efficacy of the product.
reaction, palpitations, orthostatic BP decrease, tachycardia; CNS: anxiety,
syncope, tremor, seizure, vertigo, Bell’s Palsy, paranoia, pituitary apop
intraocular pressure, amnesia, hearing loss, neuritis; Respiratory: pneumonia, pulm
nodule, status asthmaticus; Endocrine: galactorrhea, hypoadrenalism, dia
gynecomastia,
amenorrhea,
polymen
nephrolithiasis, hematuria; Hematologic: anemia, iron deficiency, epistaxis;
otitis, allergic reaction, increased CK, weight loss.
Evaluation of 20 patients treated for at least 6 months has failed to dem
antibodies exceeding background levels. However, antibo
drug action in tw
reported in several patients receiving Sandostatin (octreotide acetate).
OVERDOSAGE
No frank overdose has occurred in any patient to date. Intravenous bolus
(1000 mcg) given to healthy volunteers and of 30 mg (30,000 mcg) IV over 2
120 mg (120,000 mcg) IV over 8 hours to
effects.
Up-to-date information about
Centers are listed in the Physicians’ Desk Reference®.*
Mortality occurred in mice and rats g
Drug Abuse and Dependence
There is no indication that Sandostatin® (octreotide acetate) has potential fo
dependence. Sandostatin® (octreotide acetate) levels in the central nerv
negligible, even after doses up to 30,000 mcg.
Sandostatin® (octreotide acetate) may be administered subcutaneously o
Subcutaneous injection is the usual route of administration of Sandosta
acetate) for control of symptoms. Pain with subcutaneous administration ma
using the smallest volume that will deliver the desired dose. Multiple subcuta
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 10
tions or sterile
L
d by IV push over 3 minutes. In
The initial dosage is usually 50 mcg administered twice or three times daily. Upward dose
requently required. Dosage information for patients with specific tumors follows.
ermit adaptation
r doses. IGF-I
atively, multiple
) administration
levels less than
s than 2.2 U/mL
und to be effective is 100 mcg t.i.d., but some patients
an 300 mcg/day
fails to provide
growth hormone
d at 6 month intervals.
reotide acetate) should be withdrawn yearly for approximately 4 weeks from
ormone or IGF-I
atin® (octreotide
gested daily dosage of Sandostatin® (octreotide acetate) during the first 2 weeks of
ranges from 100-600 mcg/day in 2-4 divided doses (mean daily dosage is 300 mcg).
ly 450 mcg, but
ittle as 50 mcg,
doses up to 1500 mcg/day. However, experience with doses above
750 mcg/day is limited.
VIPomas
es of 200-300 mcg in 2-4 divided doses are recommended during the initial
2 weeks of therapy (range 150-750 mcg) to control symptoms of the disease. On an individual
basis, dosage may be adjusted to achieve a therapeutic response, but usually doses above
450 mcg/day are not required.
HOW SUPPLIED
Sandostatin® (octreotide acetate) Injection is available in 1 mL ampuls and 5 mL multi-dose
vials as follows:
Sandostatin® (octreotide acetate) is stable in sterile isotonic saline solu
solutions of dextrose 5% in water for 24 hours. It may be diluted in volumes of 50-200 m
and infused intravenously over 15-30 minutes or administere
emergency situations (e.g.: carcinoid crisis) it may be given by rapid bolus.
titration is f
Acromegaly
Dosage may be initiated at 50 mcg t.i.d. Beginning with this low dose may p
to adverse gastrointestinal effects for patients who will require highe
(somatomedin C) levels every 2 weeks can be used to guide titration. Altern
growth hormone levels at 0-8 hours after Sandostatin® (octreotide acetate
permit more rapid titration of dose. The goal is to achieve growth hormone
5 ng/mL or IGF-I (somatomedin C) levels less than 1.9 U/mL in males and les
in females. The dose most commonly fo
require up to 500 mcg t.i.d. for maximum effectiveness. Doses greater th
seldom result in additional biochemical benefit, and if an increase in dose
additional benefit, the dose should be reduced. IGF-I (somatomedin C) or
levels should be reevaluate
Sandostatin® (oct
patients who have received irradiation to assess disease activity. If growth h
(somatomedin C) levels increase and signs and symptoms recur, Sandost
acetate) therapy may be resumed.
Carcinoid Tumors
The sug
therapy
In the clinical studies, the median daily maintenance dosage was approximate
clinical and biochemical benefits were obtained in some patients with as l
while others required
Daily dosag
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 11
Package of 20 ampuls (NDC 0078-0180-03)
Package of 10 ampuls (NDC 0078-0180-01)
Package of 20 ampuls (NDC 0078-0181-03)
0078-0181-01)
500 mcg/mL octreotide (as acetate)
Package of 20 ampuls (NDC 0078-0182-03)
mpuls (NDC 0078-0182-01)
200 mcg/mL octreotide (as acetate)
one (NDC 0078-0183-25)
ge, Sandostatin® (octreotide acetate) ampuls and multi-dose vials should
be stored at refrigerated temperatures 2º-8ºC (36º-46ºF) and protected from light. At room
º-86ºF), Sandostatin® (octreotide acetate) is stable for 14 days if
protected from light. The solution can be allowed to come to room temperature prior to
administration. Do not warm artificially. After initial use, multiple dose vials should be
be opened just prior to administration and the
unused portion discarded.
Company, Inc.
ls are manufactured by:
Novartis Pharma Stein AG
Schaffhauserstrasse
CH-4332 Stein, Switzerland
Distributed by:
Novartis Pharmaceuticals Corporation
Ampuls
50 mcg/mL octreotide (as acetate)
100 mcg/mL octreotide (as acetate)
Package of 10 ampuls (NDC
Package of 10 a
Multi-Dose Vials
Box of
1000 mcg/mL octreotide (as acetate)
Box of one (NDC 0078-0184-25)
Storage
For prolonged stora
temperature, (20º-30ºC or 70
discarded within 14 days. Ampuls should
*Medical Economics
The ampuls and multi-dose via
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Page 12
East Hanover, New Jersey 07936
XXXXXXXX
Novartis Pharmaceuticals Corporation
r, New Jersey 07936
© 2002 Novartis
REV: 2002
PRINTED IN USA T2002-XX
East Hanove
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:39.651664
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/19667scm044_Sandostatin_lbl.pdf', 'application_number': 19667, 'submission_type': 'SUPPL ', 'submission_number': 44}
|
11,613
|
----------
Sandostatin®
Page 1 of 15
SANDOSTATIN - octreotide injection, solution
Novartis Pharmaceuticals Corporation
Sandostatin®
Rx Only
Prescribing Information
DESCRIPTION
Sandostatin® (octreotide acetate) Injection, a cyclic octapeptide prepared as a clear sterile
solution of octreotide, acetate salt, in a buffered lactic acid solution for administration by deep
subcutaneous (intrafat) or intravenous injection. Octreotide acetate, known chemically as L-
Cysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2
hydroxy-1-(hydroxymethyl)propyl]-, cyclic (2→7)-disulfide; [R-(R*, R*)] acetate salt, is a long-
acting octapeptide with pharmacologic actions mimicking those of the natural hormone
somatostatin.
Sandostatin Injection is available as: sterile 1-mL ampuls in 3 strengths, containing 50, 100, or
500 mcg octreotide (as acetate), and sterile 5-mL multi-dose vials in 2 strengths, containing
200 and 1000 mcg/mL of octreotide (as acetate).
Each ampul also contains:
lactic acid, USP
3.4 mg
mannitol, USP
45 mg
sodium bicarbonate, USP
qs to pH 4.2 ± 0.3
water for injection, USP
qs to 1 mL
Each mL of the multi-dose vials also contains:
lactic acid, USP
3.4 mg
mannitol, USP
45 mg
phenol, USP
5.0 mg
sodium bicarbonate, USP
qs to pH 4.2 ± 0.3
water for injection, USP
qs to 1 mL
Lactic acid and sodium bicarbonate are added to provide a buffered solution, pH to 4.2 ± 0.3.
The molecular weight of octreotide acetate is 1019.3 (free peptide, C H N O S ) and its
49
66
10 10
2
amino acid sequence is:
amino aci
d sequence
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Sandostatin®
Page 2 of 15
CLINICAL PHARMACOLOGY
Sandostatin® (octreotide acetate) exerts pharmacologic actions similar to the natural hormone,
somatostatin. It is an even more potent inhibitor of growth hormone, glucagon, and insulin than
somatostatin. Like somatostatin, it also suppresses LH response to GnRH, decreases
splanchnic blood flow, and inhibits release of serotonin, gastrin, vasoactive intestinal peptide,
secretin, motilin, and pancreatic polypeptide.
By virtue of these pharmacological actions, Sandostatin has been used to treat the symptoms
associated with metastatic carcinoid tumors (flushing and diarrhea), and Vasoactive Intestinal
Peptide (VIP) secreting adenomas (watery diarrhea).
Sandostatin substantially reduces growth hormone and/or IGF-I (somatomedin C) levels in
patients with acromegaly.
Single doses of Sandostatin have been shown to inhibit gallbladder contractility and to
decrease bile secretion in normal volunteers. In controlled clinical trials the incidence of
gallstone or biliary sludge formation was markedly increased (see WARNINGS).
Sandostatin suppresses secretion of thyroid stimulating hormone (TSH).
Pharmacokinetics
After subcutaneous injection, octreotide is absorbed rapidly and completely from the injection
site. Peak concentrations of 5.2 ng/mL (100-mcg dose) were reached 0.4 hours after dosing.
Using a specific radioimmunoassay, intravenous and subcutaneous doses were found to be
bioequivalent. Peak concentrations and area under the curve values were dose proportional
after intravenous single doses up to 200 mcg and subcutaneous single doses up to 500 mcg
and after subcutaneous multiple doses up to 500 mcg t.i.d. (1500 mcg/day).
In healthy volunteers the distribution of octreotide from plasma was rapid (tα1/2 = 0.2 h), the
volume of distribution (Vdss) was estimated to be 13.6 L, and the total body clearance ranged
from 7 L/hr to 10 L/hr. In blood, the distribution into the erythrocytes was found to be negligible
and about 65% was bound in the plasma in a concentration-independent manner. Binding was
mainly to lipoprotein and, to a lesser extent, to albumin.
The elimination of octreotide from plasma had an apparent half-life of 1.7 to 1.9 hours
compared with 1-3 minutes with the natural hormone. The duration of action of Sandostatin is
variable but extends up to 12 hours depending upon the type of tumor. About 32% of the dose
is excreted unchanged into the urine. In an elderly population, dose adjustments may be
necessary due to a significant increase in the half-life (46%) and a significant decrease in the
clearance (26%) of the drug.
In patients with acromegaly, the pharmacokinetics differ somewhat from those in healthy
volunteers. A mean peak concentration of 2.8 ng/mL (100-mcg dose) was reached in 0.7 hours
after subcutaneous dosing. The volume of distribution (Vdss) was estimated to be 21.6 ± 8.5 L
and the total body clearance was increased to 18 L/h. The mean percent of the drug bound
was 41.2%. The disposition and elimination half-lives were similar to normals.
In patients with renal impairment the elimination of octreotide from plasma was prolonged and
total body clearance reduced. In mild renal impairment (ClCR 40-60 mL/min) octreotide t 1/2 was
2.4 hours and total body clearance was 8.8 L/hr, in moderate impairment (ClCR 10-39 mL/min)
t1/2 was 3.0 hours and total body clearance 7.3 L/hr, and in severely renally impaired patients
file://\\Cdsesub1\evsprod\NDA019667\0003\m1\us\spl\proposed.xml
8/26/2008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Sandostatin®
Page 3 of 15
not requiring dialysis (Cl CR <10 mL/min) t 1/2 was 3.1 hours and total body clearance was 7.6
L/hr. In patients with severe renal failure requiring dialysis, total body clearance was reduced
to about half that found in healthy subjects (from approximately 10 L/hr to 4.5 L/hr).
Patients with liver cirrhosis showed prolonged elimination of drug, with octreotide t1/2
increasing to 3.7 hr and total body clearance decreasing to 5.9 L/hr, whereas patients with fatty
liver disease showed t1/2 increased to 3.4 hr and total body clearance of 8.2 L/hr.
INDICATIONS AND USAGE
Acromegaly
Sandostatin® (octreotide acetate) is indicated to reduce blood levels of growth hormone and
IGF-I (somatomedin C) in acromegaly patients who have had inadequate response to or
cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at
maximally tolerated doses. The goal is to achieve normalization of growth hormone and IGF-I
(somatomedin C) levels (see DOSAGE AND ADMINISTRATION). In patients with acromegaly,
Sandostatin reduces growth hormone to within normal ranges in 50% of patients and reduces
IGF-I (somatomedin C) to within normal ranges in 50%-60% of patients. Since the effects of
pituitary irradiation may not become maximal for several years, adjunctive therapy with
Sandostatin to reduce blood levels of growth hormone and IGF-I (somatomedin C) offers
potential benefit before the effects of irradiation are manifested.
Improvement in clinical signs and symptoms or reduction in tumor size or rate of growth were
not shown in clinical trials performed with Sandostatin; these trials were not optimally designed
to detect such effects.
Carcinoid Tumors
Sandostatin is indicated for the symptomatic treatment of patients with metastatic carcinoid
tumors where it suppresses or inhibits the severe diarrhea and flushing episodes associated
with the disease.
Sandostatin studies were not designed to show an effect on the size, rate of growth or
development of metastases.
Vasoactive Intestinal Peptide Tumors (VIPomas)
Sandostatin is indicated for the treatment of the profuse watery diarrhea associated with VIP-
secreting tumors. Sandostatin studies were not designed to show an effect on the size, rate of
growth or development of metastases.
CONTRAINDICATIONS
Sensitivity to this drug or any of its components.
WARNINGS
Single doses of Sandostatin® (octreotide acetate) have been shown to inhibit gallbladder
contractility and decrease bile secretion in normal volunteers. In clinical trials (primarily
patients with acromegaly or psoriasis), the incidence of biliary tract abnormalities was 63%
(27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). The incidence of
stones or sludge in patients who received Sandostatin for 12 months or longer was 52%. Less
file://\\Cdsesub1\evsprod\NDA019667\0003\m1\us\spl\proposed.xml
8/26/2008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Sandostatin®
Page 4 of 15
than 2% of patients treated with Sandostatin for 1 month or less developed gallstones. The
incidence of gallstones did not appear related to age, sex or dose. Like patients without
gallbladder abnormalities, the majority of patients developing gallbladder abnormalities on
ultrasound had gastrointestinal symptoms. The symptoms were not specific for gallbladder
disease. A few patients developed acute cholecystitis, ascending cholangitis, biliary
obstruction, cholestatic hepatitis, or pancreatitis during Sandostatin therapy or following its
withdrawal. One patient developed ascending cholangitis during Sandostatin therapy and died.
PRECAUTIONS
General
Sandostatin® (octreotide acetate) alters the balance between the counter-regulatory
hormones, insulin, glucagon and growth hormone, which may result in hypoglycemia or
hyperglycemia. Sandostatin also suppresses secretion of thyroid stimulating hormone, which
may result in hypothyroidism. Cardiac conduction abnormalities have also occurred during
treatment with Sandostatin. However, the incidence of these adverse events during long-term
therapy was determined vigorously only in acromegaly patients who, due to their underlying
disease and/or the subsequent treatment they receive, are at an increased risk for the
development of diabetes mellitus, hypothyroidism, and cardiovascular disease. Although the
degree to which these abnormalities are related to Sandostatin therapy is not clear, new
abnormalities of glycemic control, thyroid function and ECG developed during Sandostatin
therapy as described below.
Risk of Pregnancy with Normalization of IGF-1 and GH
Although acromegaly may lead to infertility, there are reports of pregnancy in acromegalic
women. In women with active acromegaly who have been unable to become pregnant,
normalization of GH and IGF-1 may restore fertility. Female patients of childbearing potential
should be advised to use adequate contraception during treatment with octreotide.
The hypoglycemia or hyperglycemia which occurs during Sandostatin therapy is usually mild,
but may result in overt diabetes mellitus or necessitate dose changes in insulin or other
hypoglycemic agents. Hypoglycemia and hyperglycemia occurred on Sandostatin in 3% and
16% of acromegalic patients, respectively. Severe hyperglycemia, subsequent pneumonia,
and death following initiation of Sandostatin therapy was reported in one patient with no history
of hyperglycemia.
In patients with concomitant Type I diabetes mellitus, Sandostatin Injection and Sandostatin
LAR® Depot (octreotide acetate for injectable suspension) are likely to affect glucose
regulation, and insulin requirements may be reduced. Symptomatic hypoglycemia, which may
be severe, has been reported in these patients. In non-diabetics and Type II diabetics with
partially intact insulin reserves, Sandostatin Injection or Sandostatin LAR Depot administration
may result in decreases in plasma insulin levels and hyperglycemia. It is therefore
recommended that glucose tolerance and antidiabetic treatment be periodically monitored
during therapy with these drugs.
In acromegalic patients, 12% developed biochemical hypothyroidism only, 8% developed
goiter, and 4% required initiation of thyroid replacement therapy while receiving Sandostatin.
Baseline and periodic assessment of thyroid function (TSH, total and/or free T ) is
4
recommended during chronic therapy.
In acromegalics, bradycardia (<50 bpm) developed in 25%; conduction abnormalities occurred
file://\\Cdsesub1\evsprod\NDA019667\0003\m1\us\spl\proposed.xml
8/26/2008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Sandostatin®
Page 5 of 15
in 10% and arrhythmias occurred in 9% of patients during Sandostatin therapy. Other EKG
changes observed included QT prolongation, axis shifts, early repolarization, low voltage, R/S
transition, and early R wave progression. These ECG changes are not uncommon in
acromegalic patients. Dose adjustments in drugs such as beta-blockers that have bradycardia
effects may be necessary. In one acromegalic patient with severe congestive heart failure,
initiation of Sandostatin therapy resulted in worsening of CHF with improvement when drug
was discontinued. Confirmation of a drug effect was obtained with a positive rechallenge.
Several cases of pancreatitis have been reported in patients receiving Sandostatin therapy.
Sandostatin may alter absorption of dietary fats in some patients.
In patients with severe renal failure requiring dialysis, the half-life of Sandostatin may be
increased, necessitating adjustment of the maintenance dosage.
Depressed vitamin B 12 levels and abnormal Schilling’s tests have been observed in some
patients receiving Sandostatin therapy, and monitoring of vitamin B12 levels is recommended
during chronic Sandostatin therapy.
Information for Patients
Careful instruction in sterile subcutaneous injection technique should be given to the patients
and to other persons who may administer Sandostatin Injection.
Laboratory Tests
Laboratory tests that may be helpful as biochemical markers in determining and following
patient response depend on the specific tumor. Based on diagnosis, measurement of the
following substances may be useful in monitoring the progress of therapy:
Acromegaly:
Growth Hormone, IGF-I (somatomedin C) Responsiveness to Sandostatin
may be evaluated by determining growth hormone levels at 1-4 hour intervals for 8-12 hours
post dose. Alternatively, a single measurement of IGF-I (somatomedin C) level may be made
two weeks after drug initiation or dosage change.
Carcinoid:
5-HIAA (urinary 5-hydroxyindole acetic acid), plasma serotonin, plasma
Substance P
VIPoma:
VIP (plasma vasoactive intestinal peptide)
Baseline and periodic total and/or free T 4 measurements should be performed during chronic
therapy (see PRECAUTIONS – General).
Drug Interactions
Sandostatin has been associated with alterations in nutrient absorption, so it may have an
effect on absorption of orally administered drugs. Concomitant administration of Sandostatin
with cyclosporine may decrease blood levels of cyclosporine and result in transplant rejection.
Patients receiving insulin, oral hypoglycemic agents, beta blockers, calcium channel blockers,
or agents to control fluid and electrolyte balance, may require dose adjustments of these
therapeutic agents.
Concomitant administration of octreotide and bromocriptine increases the availability of
bromocriptine. Limited published data indicate that somatostatin analogs might decrease the
file://\\Cdsesub1\evsprod\NDA019667\0003\m1\us\spl\proposed.xml
8/26/2008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Sandostatin®
Page 6 of 15
metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes,
which may be due to the suppression of growth hormones. Since it cannot be excluded that
octreotide may have this effect, other drugs mainly metabolized by CYP3A4 and which have a
low therapeutic index (e.g., quinidine, terfenadine) should therefore be used with caution.
Drug Laboratory Test Interactions
No known interference exists with clinical laboratory tests, including amine or peptide
determinations.
Carcinogenesis/Mutagenesis/Impairment of Fertility
Studies in laboratory animals have demonstrated no mutagenic potential of Sandostatin.
No carcinogenic potential was demonstrated in mice treated subcutaneously for 85-99 weeks
at doses up to 2000 mcg/kg/day (8x the human exposure based on body surface area). In a
116-week subcutaneous study in rats, a 27% and 12% incidence of injection site sarcomas or
squamous cell carcinomas was observed in males and females, respectively, at the highest
dose level of 1250 mcg/kg/day (10x the human exposure based on body surface area)
compared to an incidence of 8%-10% in the vehicle-control groups. The increased incidence of
injection site tumors was most probably caused by irritation and the high sensitivity of the rat to
repeated subcutaneous injections at the same site. Rotating injection sites would prevent
chronic irritation in humans. There have been no reports of injection site tumors in patients
treated with Sandostatin for up to 5 years. There was also a 15% incidence of uterine
adenocarcinomas in the 1250 mcg/kg/day females compared to 7% in the saline-control
females and 0% in the vehicle-control females. The presence of endometritis coupled with the
absence of corpora lutea, the reduction in mammary fibroadenomas, and the presence of
uterine dilatation suggest that the uterine tumors were associated with estrogen dominance in
the aged female rats which does not occur in humans.
Sandostatin did not impair fertility in rats at doses up to 1000 mcg/kg/day, which represents 7x
the human exposure based on body surface area.
Pregnancy Category B
There are no adequate and well-controlled studies of octreotide use in pregnant women.
Reproduction studies have been performed in rats and rabbits at doses up to 16 times the
highest recommended human dose based on body surface area and revealed no evidence of
harm to the fetus due to octreotide. However, because animal reproduction studies are not
always predictive of human response, this drug should be used during pregnancy only if clearly
needed.
In postmarketing data, a limited number of exposed pregnancies have been reported in
patients with acromegaly. Most women were exposed to octreotide during the first trimester of
pregnancy at doses ranging from 100-300 mcg/day of Sandostatin s.c. or 20-30 mg/month of
Sandostatin LAR, however some women elected to continue octreotide therapy throughout
pregnancy. In cases with a known outcome, no congenital malformations were reported.
Nursing Mothers
It is not known whether octreotide is excreted into human milk. Because many drugs are
excreted in human milk, caution should be exercised when octreotide is administered to a
nursing woman.
file://\\Cdsesub1\evsprod\NDA019667\0003\m1\us\spl\proposed.xml
8/26/2008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Sandostatin®
Page 7 of 15
Pediatric Use
Experience with Sandostatin in the pediatric population is limited. Although formal controlled
clinical trials have not been performed to evaluate safety and effectiveness in this age group,
there are reports of 49 cases in the literature of neonates and infants with congenital
hyperinsulinism [also called familial hyperinsulinism (HI), persistent hyperinsulinemic
hypoglycemia of infancy (PHHI), or nesidioblastosis] who have received Sandostatin as an
inhibitor of insulin release. The following efficacy and safety information is derived from these
49 patients.
Sandostatin has been used to stabilize plasma glucose levels prior to pancreatectomy and to
treat recurrent post-operative hypoglycemia. Although most use of octreotide in this setting is
short-term, a few reports in the literature have documented longer-term therapy in pediatric
patients (2.2-5.5 years). Octreotide is an alternative medical treatment to diazoxide for control
of hypoglycemia in this disorder. Of 31 pediatric patients who received Sandostatin as
prescribed for congenital hyperinsulinism and for which long-term follow-up was available,
octreotide obviated the need for surgery in 3 patients (10%) and was replaced by diazoxide in
4 patients (13%) due to uncontrolled hypoglycemia. Although the remainder of these patients
required surgery, there have been a few reports in the literature of patients who have
responded to octreotide after failing treatment with surgery and/or diazoxide. Doses of 3-40
mcg/kg/day have been used. At these doses, the majority of side effects were gastrointestinal:
diarrhea, steatorrhea, vomiting, and abdominal distention, each reported in 22%-35% (n = 11
17) of patients. However, they were generally short-lived – with resolution of vomiting and
distention in 2-4 days, and diarrhea/steatorrhea, within 2-4 weeks. Steatorrhea was controlled
in most patients with pancreatic enzyme supplements. Poor growth was reported in 37% of
patients (n = 7) who received Sandostatin for 1-4.33 years. It was associated with low serum
growth hormone and/or IGF-1 levels in 4/6 patients in whom these parameters were
measured. Catch-up growth occurred in 3/3 patients who were followed after Sandostatin was
discontinued. Poor weight gain was reported in 32% of patients (n = 6). Tachyphylaxis was
reported in 35% (n = 17) of patients. Asymptomatic gallstones with sludge was reported in one
infant after one year of therapy and was treated with ursodeoxycholic acid. There has been a
single report of an infant with nesidioblastosis who experienced a seizure thought to be
independent of Sandostatin therapy. A single death has been reported in a 16-month-old male
with enterocutaneous fistula who developed sudden abdominal pain and increased nasogastric
drainage and expired 8 hours after receiving a single 100 mcg subcutaneous dose of
Sandostatin.
Geriatric Use
Clinical studies of Sandostatin 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
Gallbladder Abnormalities
file://\\Cdsesub1\evsprod\NDA019667\0003\m1\us\spl\proposed.xml
8/26/2008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Sandostatin®
Page 8 of 15
Gallbladder abnormalities, especially stones and/or biliary sludge, frequently develop in
patients on chronic Sandostatin ® (octreotide acetate) therapy (see WARNINGS).
Cardiac
In acromegalics, sinus bradycardia (<50 bpm) developed in 25%; conduction abnormalities
occurred in 10% and arrhythmias developed in 9% of patients during Sandostatin therapy (see
PRECAUTIONS – General).
Gastrointestinal
Diarrhea, loose stools, nausea and abdominal discomfort were each seen in 34%-61% of
acromegalic patients in U.S. studies although only 2.6% of the patients discontinued therapy
due to these symptoms. These symptoms were seen in 5%-10% of patients with other
disorders.
The frequency of these symptoms was not dose-related, but diarrhea and abdominal
discomfort generally resolved more quickly in patients treated with 300 mcg/day than in those
treated with 750 mcg/day. Vomiting, flatulence, abnormal stools, abdominal distention, and
constipation were each seen in less than 10% of patients.
In rare instances, gastrointestinal side effects may resemble acute intestinal obstruction, with
progressive abdominal distension, severe epigastric pain, abdominal tenderness and guarding.
Hypo/Hyperglycemia
Hypoglycemia and hyperglycemia occurred in 3% and 16% of acromegalic patients,
respectively, but only in about 1.5% of other patients. Symptoms of hypoglycemia were noted
in approximately 2% of patients.
Hypothyroidism
In acromegalics, biochemical hypothyroidism alone occurred in 12% while goiter occurred in
6% during Sandostatin therapy (see PRECAUTIONS – General). In patients without
acromegaly, hypothyroidism has only been reported in several isolated patients and goiter has
not been reported.
Other Adverse Events
Pain on injection was reported in 7.7%, headache in 6% and dizziness in 5%. Pancreatitis was
also observed (see WARNINGS and PRECAUTIONS).
Other Adverse Events 1%-4%
Other events (relationship to drug not established), each observed in 1%-4% of patients,
included fatigue, weakness, pruritus, joint pain, backache, urinary tract infection, cold
symptoms, flu symptoms, injection site hematoma, bruise, edema, flushing, blurred vision,
pollakiuria, fat malabsorption, hair loss, visual disturbance and depression.
Other Adverse Events <1%
Events reported in less than 1% of patients and for which relationship to drug is not
file://\\Cdsesub1\evsprod\NDA019667\0003\m1\us\spl\proposed.xml
8/26/2008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Sandostatin®
Page 9 of 15
established are listed: Gastrointestinal: hepatitis, jaundice, increase in liver enzymes, GI
bleeding, hemorrhoids, appendicitis, gastric/peptic ulcer, gallbladder polyp; Integumentary:
rash, cellulitis, petechiae, urticaria, basal cell carcinoma; Musculoskeletal: arthritis, joint
effusion, muscle pain, Raynaud’s phenomenon; Cardiovascular: chest pain, shortness of
breath, thrombophlebitis, ischemia, congestive heart failure, hypertension, hypertensive
reaction, palpitations, orthostatic BP decrease, tachycardia; CNS: anxiety, libido decrease,
syncope, tremor, seizure, vertigo, Bell’s Palsy, paranoia, pituitary apoplexy, increased
intraocular pressure, amnesia, hearing loss, neuritis; Respiratory: pneumonia, pulmonary
nodule, status asthmaticus; Endocrine: galactorrhea, hypoadrenalism, diabetes insipidus,
gynecomastia, amenorrhea, polymenorrhea, oligomenorrhea, vaginitis; Urogenital:
nephrolithiasis, hematuria; Hematologic: anemia, iron deficiency, epistaxis; Miscellaneous:
otitis, allergic reaction, increased CK, weight loss.
Evaluation of 20 patients treated for at least 6 months has failed to demonstrate titers of
antibodies exceeding background levels. However, antibody titers to Sandostatin were
subsequently reported in three patients and resulted in prolonged duration of drug action in two
patients. Anaphylactoid reactions, including anaphylactic shock, have been reported in several
patients receiving Sandostatin.
OVERDOSAGE
A limited number of accidental overdoses of Sandostatin® in adults have been reported. In
adults, the doses ranged from 2,400–6,000 micrograms/day administered by continuous
infusion (100-250 micrograms/hour) or subcutaneously (1,500 micrograms t.i.d.). Adverse
events in some patients included arrhythmia, hypotension, cardiac arrest, brain hypoxia,
pancreatitis, hepatitis steatosis, hepatomegaly, lactic acidosis, flushing, diarrhea, lethargy,
weakness, and weight loss.
Sandostatin Injection given in intravenous boluses of 1 mg (1000 mcg) to healthy volunteers
did not result in serious ill effects, nor did doses of 30 mg (30,000 mcg) given intravenously
over 20 minutes and of 120 mg (120,000 mcg) given intravenously over 8 hours to research
patients.
If overdose occurs, symptomatic management is indicated. Up-to-date information about the
treatment of overdose can often be obtained from the National Poison Control Center at 1-800
222-1222.
Drug Abuse and Dependence
There is no indication that Sandostatin has potential for drug abuse or dependence.
Sandostatin levels in the central nervous system are negligible, even after doses up to 30,000
mcg.
DOSAGE AND ADMINISTRATION
Sandostatin® (octreotide acetate) may be administered subcutaneously or intravenously.
Subcutaneous injection is the usual route of administration of Sandostatin for control of
symptoms. Pain with subcutaneous administration may be reduced by using the smallest
volume that will deliver the desired dose. Multiple subcutaneous injections at the same site
within short periods of time should be avoided. Sites should be rotated in a systematic manner.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration. Do not use if particulates and/or discoloration are observed. Proper
file://\\Cdsesub1\evsprod\NDA019667\0003\m1\us\spl\proposed.xml
8/26/2008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Sandostatin®
Page 10 of 15
sterile technique should be used in the preparation of parenteral admixtures to minimize the
possibility of microbial contamination. Sandostatin is not compatible in Total Parenteral
Nutrition (TPN) solutions because of the formation of a glycosyl octreotide conjugate which
may decrease the efficacy of the product.
Sandostatin is stable in sterile isotonic saline solutions or sterile solutions of dextrose 5% in
water for 24 hours. It may be diluted in volumes of 50-200 mL and infused intravenously over
15-30 minutes or administered by IV push over 3 minutes. In emergency situations (e.g.,
carcinoid crisis) it may be given by rapid bolus.
The initial dosage is usually 50 mcg administered twice or three times daily. Upward dose
titration is frequently required. Dosage information for patients with specific tumors follows.
Acromegaly
Dosage may be initiated at 50 mcg t.i.d. Beginning with this low dose may permit adaptation to
adverse gastrointestinal effects for patients who will require higher doses. IGF-I (somatomedin
C) levels every 2 weeks can be used to guide titration. Alternatively, multiple growth hormone
levels at 0-8 hours after Sandostatin® (octreotide acetate) administration permit more rapid
titration of dose. The goal is to achieve growth hormone levels less than 5 ng/mL or IGF-I
(somatomedin C) levels less than 1.9 U/mL in males and less than 2.2 U/mL in females. The
dose most commonly found to be effective is 100 mcg t.i.d., but some patients require up to
500 mcg t.i.d. for maximum effectiveness. Doses greater than 300 mcg/day seldom result in
additional biochemical benefit, and if an increase in dose fails to provide additional benefit, the
dose should be reduced. IGF-I (somatomedin C) or growth hormone levels should be re
evaluated at 6-month intervals.
Sandostatin should be withdrawn yearly for approximately 4 weeks from patients who have
received irradiation to assess disease activity. If growth hormone or IGF-I (somatomedin C)
levels increase and signs and symptoms recur, Sandostatin therapy may be resumed.
Carcinoid Tumors
The suggested daily dosage of Sandostatin during the first 2 weeks of therapy ranges from
100-600 mcg/day in 2-4 divided doses (mean daily dosage is 300 mcg). In the clinical studies,
the median daily maintenance dosage was approximately 450 mcg, but clinical and
biochemical benefits were obtained in some patients with as little as 50 mcg, while others
required doses up to 1500 mcg/day. However, experience with doses above 750 mcg/day is
limited.
VIPomas
Daily dosages of 200-300 mcg in 2-4 divided doses are recommended during the initial 2
weeks of therapy (range 150-750 mcg) to control symptoms of the disease. On an individual
basis, dosage may be adjusted to achieve a therapeutic response, but usually doses above
450 mcg/day are not required.
HOW SUPPLIED
Sandostatin® (octreotide acetate) Injection is available in 1-mL ampuls and 5-mL multi-dose
vials as follows:
file://\\Cdsesub1\evsprod\NDA019667\0003\m1\us\spl\proposed.xml
8/26/2008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Sandostatin®
Page 11 of 15
Ampuls
50 mcg/mL octreotide (as acetate)
Package of 10 ampuls
NDC 0078-0180-01
100 mcg/mL octreotide (as acetate)
Package of 10 ampuls
NDC 0078-0181-01
500 mcg/mL octreotide (as acetate)
Package of 10 ampuls
NDC 0078-0182-01
Multi-Dose Vials
200 mcg/mL octreotide (as acetate)
Box of one
NDC 0078-0183-25
1000 mcg/mL octreotide (as acetate)
Box of one
NDC 0078-0184-25
Storage
For prolonged storage, Sandostatin ampuls and multi-dose vials should be stored at
refrigerated temperatures 2ºC-8ºC (36ºF-46ºF) and store in outer carton in order to
protect from light. At room temperature, (20ºC-30ºC or 70ºF-86ºF), Sandostatin is stable for 14
days if protected from light. The solution can be allowed to come to room temperature prior to
administration. Do not warm artificially. After initial use, multiple-dose vials should be discarded
within 14 days. Ampuls should be opened just prior to administration and the unused portion
discarded. Dispose unused product or waste properly.
*Thomson Healthcare, Inc.
REV: AUGUST 2008
T2008-81
Manufactured by:
Novartis Pharma Stein AG
Stein, Switzerland
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, NJ 07936
© Novartis
SANDOSTATIN
octreotide acetate injection, solution
8/26/2008
file://\\Cdsesub1\evsprod\NDA019667\0003\m1\us\spl\proposed.xml
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Product Information
Product Type
HUMAN PRESCRIPTION DRUG
NDC Product Code (Source)
0078-0180
Route of Administration
INTRAVENOUS, SUBCUTANEOUS
DEA Schedule
INGREDIENTS
Name (Active Moiety)
Type
Strength
octreotide (octreotide)
Active
50 MICROGRAM In 1 MILLILITER
lactic acid
Inactive
3.4 MILLIGRAM In 1 MILLILITER
mannitol
Inactive
45 MILLIGRAM In 1 MILLILITER
sodium bicarbonate
Inactive
1 ADJUST PH In 1 MILLILITER
water for injection
Inactive
1 QUANTITY SUFFICIENT In 1 MILLILITER
Product Characteristics
Color
Score
Shape
Size
Flavor
Imprint Code
Contains
Packaging
# NDC
Package Description
Multilevel Packaging
1 0078-0180-01
10 AMPULE In 1 PACKAGE
contains a AMPULE
1
1 mL (MILLILITER) In 1 AMPULE
This package is contained within the PACKAGE (0078-0180-01)
SANDOSTATIN
octreotide acetate injection, solution
Product Information
Product Type
HUMAN PRESCRIPTION DRUG
NDC Product Code (Source)
0078-0181
Route of Administration
INTRAVENOUS, SUBCUTANEOUS
DEA Schedule
INGREDIENTS
Name (Active Moiety)
Type
Strength
octreotide (octreotide)
Active
100 MICROGRAM In 1 MILLILITER
lactic acid
Inactive
3.4 MILLIGRAM In 1 MILLILITER
Sandostatin®
Page 12 of 15
file://\\Cdsesub1\evsprod\NDA019667\0003\m1\us\spl\proposed.xml
8/26/2008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Sandostatin®
Page 13 of 15
mannitol
Inactive
45 MILLIGRAM In 1 MILLILITER
sodium bicarbonate
Inactive
1 ADJUST PH In 1 MILLILITER
water for injection
Inactive
1 QUANTITY SUFFICIENT In 1 MILLILITER
Product Characteristics
Color
Score
Shape
Size
Flavor
Imprint Code
Contains
Packaging
# NDC
Package Description
Multilevel Packaging
1 0078-0181-01
10 AMPULE In 1 PACKAGE
contains a AMPULE
1
1 mL (MILLILITER) In 1 AMPULE
This package is contained within the PACKAGE (0078-0181-01)
SANDOSTATIN
octreotide acetate injection, solution
Product Information
Product Type
HUMAN PRESCRIPTION DRUG
NDC Product Code (Source)
0078-0182
Route of Administration
INTRAVENOUS, SUBCUTANEOUS
DEA Schedule
INGREDIENTS
Name (Active Moiety)
Type
Strength
octreotide (octreotide)
Active
500 MICROGRAM In 1 MILLILITER
lactic acid
Inactive
3.4 MILLIGRAM In 1 MILLILITER
mannitol
Inactive
45 MILLIGRAM In 1 MILLILITER
sodium bicarbonate
Inactive
1 ADJUST PH In 1 MILLILITER
water for injection
Inactive
1 QUANTITY SUFFICIENT In 1 MILLILITER
Product Characteristics
Color
Score
Shape
Size
Flavor
Imprint Code
file://\\Cdsesub1\evsprod\NDA019667\0003\m1\us\spl\proposed.xml
8/26/2008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Sandostatin®
Page 14 of 15
Contains
Packaging
# NDC
Package Description
Multilevel Packaging
1 0078-0182-01
10 AMPULE In 1 PACKAGE
contains a AMPULE
1
1 mL (MILLILITER) In 1 AMPULE
This package is contained within the PACKAGE (0078-0182-01)
SANDOSTATIN
octreotide acetate injection, solution
Product Information
Product Type
HUMAN PRESCRIPTION DRUG
NDC Product Code (Source)
0078-0183
Route of Administration
INTRAVENOUS, SUBCUTANEOUS
DEA Schedule
INGREDIENTS
Name (Active Moiety)
Type
Strength
octreotide (octreotide)
Active
200 MICROGRAM In 1 MILLILITER
lactic acid
Inactive
3.4 MILLIGRAM In 1 MILLILITER
mannitol
Inactive
45 MILLIGRAM In 1 MILLILITER
phenol
Inactive
5 MILLIGRAM In 1 MILLILITER
sodium bicarbonate
Inactive
1 ADJUST PH In 1 MILLILITER
water for injection
Inactive
1 QUANTITY SUFFICIENT In 1 MILLILITER
Product Characteristics
Color
Score
Shape
Size
Flavor
Imprint Code
Contains
Packaging
# NDC
Package Description
Multilevel Packaging
1 0078-0183-25
1 VIAL In 1 BOX
contains a VIAL, MULTI-DOSE
1
5 mL (MILLILITER) In 1 VIAL, MULTI-DOSE
This package is contained within the BOX (0078-0183-25)
file://\\Cdsesub1\evsprod\NDA019667\0003\m1\us\spl\proposed.xml
8/26/2008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Sandostatin®
Page 15 of 15
SANDOSTATIN
octreotide acetate injection, solution
Product Information
Product Type
HUMAN PRESCRIPTION DRUG
NDC Product Code (Source)
0078-0184
Route of Administration
INTRAVENOUS, SUBCUTANEOUS
DEA Schedule
INGREDIENTS
Name (Active Moiety)
Type
Strength
octreotide (octreotide)
Active
1000 MICROGRAM In 1 MILLILITER
lactic acid
Inactive
3.4 MILLIGRAM In 1 MILLILITER
mannitol
Inactive
45 MILLIGRAM In 1 MILLILITER
phenol
Inactive
5 MILLIGRAM In 1 MILLILITER
sodium bicarbonate
Inactive
1 ADJUST PH In 1 MILLILITER
water for injection
Inactive
1 QUANTITY SUFFICIENT In 1 MILLILITER
Product Characteristics
Color
Score
Shape
Size
Flavor
Imprint Code
Contains
Packaging
# NDC
Package Description
Multilevel Packaging
1 0078-0184-25
1 VIAL In 1 BOX
contains a VIAL, MULTI-DOSE
1
5 mL (MILLILITER) In 1 VIAL, MULTI-DOSE
This package is contained within the BOX (0078-0184-25)
Revised: 08/2008
Novartis Pharmaceuticals Corporation
file://\\Cdsesub1\evsprod\NDA019667\0003\m1\us\spl\proposed.xml
8/26/2008
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:39.943584
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019667s054lbl.pdf', 'application_number': 19667, 'submission_type': 'SUPPL ', 'submission_number': 54}
|
11,611
|
1
1
CYTOVENE-IV
2
(ganciclovir sodium for injection)
3
FOR INTRAVENOUS INFUSION ONLY
4
5
Rx only
6
WARNING
7
THE
CLINICAL
TOXICITY
OF
CYTOVENE-IV
INCLUDES
8
GRANULOCYTOPENIA, ANEMIA AND THROMBOCYTOPENIA. IN ANIMAL
9
STUDIES GANCICLOVIR WAS CARCINOGENIC, TERATOGENIC AND
10
CAUSED ASPERMATOGENESIS.
11
CYTOVENE-IV IS INDICATED FOR USE ONLY IN THE TREATMENT OF
12
CYTOMEGALOVIRUS (CMV) RETINITIS IN IMMUNOCOMPROMISED
13
PATIENTS AND FOR THE PREVENTION OF CMV DISEASE IN TRANSPLANT
14
PATIENTS AT RISK FOR CMV DISEASE (see INDICATIONS AND USAGE).
15
DESCRIPTION
16
Ganciclovir is a synthetic guanine derivative active against cytomegalovirus (CMV).
17
CYTOVENE-IV is the brand name for ganciclovir sodium for injection.
18
CYTOVENE-IV is available as sterile lyophilized powder in strength of 500 mg per vial
19
for intravenous administration only. Each vial of CYTOVENE-IV contains the equivalent
20
of 500 mg ganciclovir as the sodium salt (46 mg sodium). Reconstitution with 10 mL of
21
Sterile Water for Injection, USP, yields a solution with pH 11 and a ganciclovir
22
concentration of approximately 50 mg/mL. Further dilution in an appropriate intravenous
23
solution must be performed before infusion (see DOSAGE AND ADMINISTRATION).
24
Ganciclovir is a white to off-white crystalline powder with a molecular formula of
25
C9H13N504 and a molecular weight of 255.23. The chemical name for ganciclovir is 9-[[2-
26
hydroxy-1-(hydroxymethyl)-ethoxy]methyl]guanine. Ganciclovir is a polar hydrophilic
27
compound with a solubility of 2.6 mg/mL in water at 25°C and an n-octanol/water partition
28
coefficient of 0.022. The pKas for ganciclovir are 2.2 and 9.4.
29
Ganciclovir, when formulated as monosodium salt in the IV dosage form, is a white to off-
30
white lyophilized powder with the molecular formula of C9H12N5Na04, and a molecular
31
weight of 277.22. The chemical name for ganciclovir sodium is 9-[[2-hydroxy-1-
32
(hydroxymethyl)-ethoxy]methyl]guanine, monosodium salt. The lyophilized powder has an
33
aqueous solubility of greater than 50 mg/mL at 25°C. At physiological pH, ganciclovir
34
sodium exists as the un-ionized form with a solubility of approximately 6 mg/mL at 37°C.
35
The chemical structures of ganciclovir sodium and ganciclovir are:
36
2
37
ganciclovir sodium
ganciclovir
38
All doses in this insert are specified in terms of ganciclovir.
39
VIROLOGY
40
Mechanism of Action
41
Ganciclovir is an acyclic nucleoside analogue of 2'-deoxyguanosine that inhibits replication
42
of herpes viruses. Ganciclovir has been shown to be active against cytomegalovirus (CMV)
43
and herpes simplex virus (HSV) in human clinical studies.
44
To achieve anti-CMV activity, ganciclovir is phosphorylated first to the monophosphate
45
form by a CMV-encoded (UL97 gene) protein kinase homologue, then to the di- and
46
triphosphate forms by cellular kinases. Ganciclovir triphosphate concentrations may be
47
100-fold greater in CMV-infected than in uninfected cells, indicating preferential
48
phosphorylation in infected cells. Ganciclovir triphosphate, once formed, persists for days
49
in the CMV-infected cell. Ganciclovir triphosphate is believed to inhibit viral DNA
50
synthesis by (1) competitive inhibition of viral DNA polymerases; and (2) incorporation
51
into viral DNA, resulting in eventual termination of viral DNA elongation.
52
Antiviral Activity
53
The median concentration of ganciclovir that inhibits CMV replication (IC50) in vitro
54
(laboratory strains or clinical isolates) has ranged from 0.02 to 3.48 µg/mL. Ganciclovir
55
inhibits mammalian cell proliferation (CIC50) in vitro at higher concentrations ranging from
56
30 to 725 µg/mL. Bone marrow-derived colony-forming cells are more sensitive (CIC50
57
0.028 to 0.7 µg/mL). The relationship of in vitro sensitivity of CMV to ganciclovir and
58
clinical response has not been established.
59
Clinical Antiviral Effect of CYTOVENE-IV and Ganciclovir Capsules
60
CYTOVENE-IV
61
In a study of CYTOVENE-IV treatment of life- or sight-threatening CMV disease in
62
immunocompromised patients, 121 of 314 patients had CMV cultured within 7 days prior
63
to treatment and sequential posttreatment viral cultures of urine, blood, throat and/or
64
semen. As judged by conversion to culture negativity, or a greater than 100-fold decrease in
65
in vitro CMV titer, at least 83% of patients had a virologic response with a median response
66
time of 7 to 15 days.
67
Antiviral activity of CYTOVENE-IV was demonstrated in two randomized studies for the
68
prevention of CMV disease in transplant recipients (see Table 1).
69
3
Table 1
Patients With Positive CMV Cultures
70
Heart Allograft* (n = 147)
Bone Marrow Allograft (n = 72)
Time
CYTOVENE-IV†
Placebo
CYTOVENE-IV‡
Placebo
Pretreatment
1/67
(2%)
5/64
(8%)
37/37 (100%)
35/35 (100%)
Week 2
2/75
(3%)
11/67 (16%)
2/31
(6%)
19/28 (68%)
Week 4
3/66
(5%)
28/66 (43%)
0/24
(0%)
16/20 (80%)
* CMV seropositive or receiving graft from seropositive donor
71
† 5 mg/kg bid for 14 days followed by 6 mg/kg qd for 5 days/week for 14 days
72
‡ 5 mg/kg bid for 7 days followed by 5 mg/kg qd until day 100 posttransplant
73
Ganciclovir Capsules
74
In trials comparing CYTOVENE-IV with Ganciclovir capsules for the maintenance
75
treatment of CMV retinitis in patients with AIDS, serial urine cultures and other available
76
cultures (semen, biopsy specimens, blood and others) showed that a small proportion of
77
patients remained culture-positive during maintenance therapy with no statistically
78
significant differences in CMV isolation rates between treatment groups.
79
Viral Resistance
80
The current working definition of CMV resistance to ganciclovir in in vitro assays is IC50
81
>3.0 µg/mL (12.0 µM). CMV resistance to ganciclovir has been observed in individuals
82
with AIDS and CMV retinitis who have never received ganciclovir therapy. Viral resistance
83
has also been observed in patients receiving prolonged treatment for CMV retinitis with
84
CYTOVENE-IV. In a controlled study of oral ganciclovir for prevention of AIDS-
85
associated CMV disease, 364 individuals had one or more cultures performed after at least
86
90 days of ganciclovir treatment. Of these, 113 had at least one positive culture. The last
87
available isolate from each subject was tested for reduced sensitivity, and 2 of 40 were
88
found to be resistant to ganciclovir. These resistant isolates were associated with
89
subsequent treatment failure for retinitis.
90
The possibility of viral resistance should be considered in patients who show poor clinical
91
response or experience persistent viral excretion during therapy. The principal mechanism
92
of resistance to ganciclovir in CMV is the decreased ability to form the active triphosphate
93
moiety; resistant viruses have been described that contain mutations in the UL97 gene of
94
CMV that controls phosphorylation of ganciclovir. Mutations in the viral DNA polymerase
95
have also been reported to confer viral resistance to ganciclovir.
96
CLINICAL PHARMACOLOGY
97
Pharmacokinetics
98
BECAUSE THE MAJOR ELIMINATION PATHWAY FOR GANCICLOVIR IS
99
RENAL, DOSAGE REDUCTIONS ACCORDING TO CREATININE CLEARANCE
100
ARE REQUIRED FOR CYTOVENE-IV. FOR DOSING INSTRUCTIONS IN
101
PATIENTS WITH RENAL IMPAIRMENT, REFER TO DOSAGE AND
102
ADMINISTRATION.
103
4
Absorption
104
At the end of a 1-hour intravenous infusion of 5 mg/kg ganciclovir, total AUC ranged
105
between 22.1 ± 3.2 (n=16) and 26.8 ± 6.1 µg·hr/mL (n=16) and Cmax ranged between
106
8.27 ± 1.02 (n=16) and 9.0 ± 1.4 µg/mL (n=16).
107
Distribution
108
The steady-state volume of distribution of ganciclovir after intravenous administration was
109
0.74 ± 0.15 L/kg (n=98). Cerebrospinal fluid concentrations obtained 0.25 to 5.67 hours
110
postdose in 3 patients who received 2.5 mg/kg ganciclovir intravenously q8h or q12h
111
ranged from 0.31 to 0.68 µg/mL representing 24% to 70% of the respective plasma
112
concentrations. Binding to plasma proteins was 1% to 2% over ganciclovir concentrations
113
of 0.5 and 51 µg/mL.
114
Elimination
115
When administered intravenously, ganciclovir exhibits linear pharmacokinetics over the
116
range of 1.6 to 5.0 mg/kg and when administered orally, it exhibits linear kinetics up to a
117
total daily dose of 4 g/day. Renal excretion of unchanged drug by glomerular filtration and
118
active tubular secretion is the major route of elimination of ganciclovir. In patients with
119
normal renal function, 91.3 ± 5.0% (n=4) of intravenously administered ganciclovir was
120
recovered unmetabolized in the urine. Systemic clearance of intravenously administered
121
ganciclovir was 3.52 ± 0.80 mL/min/kg (n=98) while renal clearance was 3.20 ± 0.80
122
mL/min/kg (n=47), accounting for 91 ± 11% of the systemic clearance (n=47). Half-life
123
was 3.5 ± 0.9 hours (n=98) following IV administration and 4.8 ± 0.9 hours (n=39)
124
following oral administration.
125
Special Populations
126
Renal Impairment
127
The pharmacokinetics following intravenous administration of CYTOVENE-IV solution
128
were evaluated in 10 immunocompromised patients with renal impairment who received
129
doses ranging from 1.25 to 5.0 mg/kg.
130
Table 2
Pharmacokinetics of Patients with Renal Impairment
131
Estimated
Creatinine
Clearance
(mL/min)
n
Dose
Clearance
(mL/min)
Mean ± SD
Half-life
(hours)
Mean ± SD
50-79
4
3.2-5 mg/kg
128 + 63
4.6 ± 1.4
25-49
3
3-5 mg/kg
57 + 8
4.4 + 0.4
<25
3
1.25-5 mg/kg
30 + 13
10.7 + 5.7
Based on these observations, it is necessary to modify the dosage of ganciclovir in patients
132
with renal impairment (see DOSAGE AND ADMINISTRATION).
133
Hemodialysis reduces plasma concentrations of ganciclovir by about 50% after intravenous
134
administration.
135
5
Race/Ethnicity and Gender
136
The effects of race/ethnicity and gender were studied in subjects receiving a dose regimen
137
of 1000 mg every 8 hours. Although the numbers of blacks (16%) and Hispanics (20%)
138
were small, there appeared to be a trend towards a lower steady-state Cmax and AUC0-8 in
139
these subpopulations as compared to Caucasians. No definitive conclusions regarding
140
gender differences could be made because of the small number of females (12%); however,
141
no differences between males and females were observed.
142
Pediatrics
143
Ganciclovir pharmacokinetics were studied in 27 neonates, aged 2 to 49 days. At an
144
intravenous dose of 4 mg/kg (n=14) or 6 mg/kg (n=13), the pharmacokinetic parameters
145
were, respectively, Cmax of 5.5 ± 1.6 and 7.0 ± 1.6 µg/mL, systemic clearance of
146
3.14 ± 1.75 and 3.56 ± 1.27 mL/min/kg, and t½ of 2.4 hours (harmonic mean) for both.
147
Ganciclovir pharmacokinetics were also studied in 10 pediatric patients, aged 9 months to
148
12 years. The pharmacokinetic characteristics of ganciclovir were the same after single and
149
multiple (q12h) intravenous doses (5 mg/kg). The steady-state volume of distribution was
150
0.64 ± 0.22 L/kg, Cmax was 7.9 ± 3.9 µg/mL, systemic clearance was 4.7 ± 2.2 mL/min/kg,
151
and t½ was 2.4 ± 0.7 hours. The pharmacokinetics of intravenous ganciclovir in pediatric
152
patients are similar to those observed in adults.
153
Elderly
154
No studies have been conducted in adults older than 65 years of age.
155
INDICATIONS AND USAGE
156
CYTOVENE-IV is indicated for the treatment of CMV retinitis in immunocompromised
157
patients, including patients with acquired immunodeficiency syndrome (AIDS).
158
CYTOVENE-IV is also indicated for the prevention of CMV disease in transplant
159
recipients at risk for CMV disease (see CLINICAL TRIALS).
160
SAFETY AND EFFICACY OF CYTOVENE-IV HAS NOT BEEN ESTABLISHED FOR
161
CONGENITAL OR NEONATAL CMV DISEASE; NOR FOR THE TREATMENT OF
162
ESTABLISHED CMV DISEASE OTHER THAN RETINITIS; NOR FOR USE IN NON-
163
IMMUNOCOMPROMISED INDIVIDUALS.
164
CLINICAL TRIALS
165
1. Treatment of CMV Retinitis
166
The diagnosis of CMV retinitis should be made by indirect ophthalmoscopy. Other
167
conditions in the differential diagnosis of CMV retinitis include candidiasis, toxoplasmosis,
168
histoplasmosis, retinal scars and cotton wool spots, any of which may produce a retinal
169
appearance similar to CMV. For this reason it is essential that the diagnosis of CMV be
170
established by an ophthalmologist familiar with the retinal presentation of these conditions.
171
The diagnosis of CMV retinitis may be supported by culture of CMV from urine, blood,
172
throat or other sites, but a negative CMV culture does not rule out CMV retinitis.
173
6
Studies With CYTOVENE-IV
174
In a retrospective, non-randomized, single-center analysis of 41 patients with AIDS and
175
CMV retinitis diagnosed by ophthalmologic examination between August 1983 and April
176
1988, treatment with CYTOVENE-IV solution resulted in a significant delay in mean
177
(median) time to first retinitis progression compared to untreated controls [105 (71) days
178
from diagnosis vs 35 (29) days from diagnosis]. Patients in this series received induction
179
treatment of CYTOVENE-IV 5 mg/kg bid for 14 to 21 days followed by maintenance
180
treatment with either 5 mg/kg once daily, 7 days per week or 6 mg/kg once daily, 5 days per
181
week (see DOSAGE AND ADMINISTRATION).
182
In a controlled, randomized study conducted between February 1989 and December 1990,1
183
immediate treatment with CYTOVENE-IV was compared to delayed treatment in 42
184
patients with AIDS and peripheral CMV retinitis; 35 of 42 patients (13 in the immediate-
185
treatment group and 22 in the delayed-treatment group) were included in the analysis of
186
time to retinitis progression. Based on masked assessment of fundus photographs, the mean
187
[95% CI] and median [95% CI] times to progression of retinitis were 66 days [39, 94] and
188
50 days [40, 84], respectively, in the immediate-treatment group compared to 19 days [11,
189
27] and 13.5 days [8, 18], respectively, in the delayed-treatment group.
190
Studies Comparing Ganciclovir Capsules to CYTOVENE-IV
191
Table 3
Population Characteristics in Studies ICM 1653, ICM 1774
192
and AVI 034
193
ICM 1653
(n=121)
ICM 1774
(n=225)
AVI 034
(n=159)
Median age (years)
Range
38
24-62
37
22-56
39
23-62
Sex
Males
116 (96%)
222 (99%)
148 (93%)
Females
5 (4%)
3 (1%)
10 (6%)
Asian
3 (3%)
5 (2%)
7 (4%)
Ethnicity
Black
11 (9%)
9 (4%)
3 (2%)
Caucasian
98 (81%)
186 (83%)
140 (88%)
Other
9 (7%)
25 (11%)
8 (5%)
Median CD4 Count
Range
9.5
0-141
7.0
0-80
10.0
0-320
Mean (SD)
Observation Time (days)
107.9 (43.0)
97.6 (42.5)
80.9 (47.0)
194
ICM 1653: In this randomized, open-label, parallel group trial, conducted between March
195
1991 and November 1992, patients with AIDS and newly diagnosed CMV retinitis
196
received a 3-week induction course of CYTOVENE-IV solution, 5 mg/kg bid for 14 days
197
followed by 5 mg/kg once daily for 1 additional week.2 Following the 21-day intravenous
198
induction course, patients with stable CMV retinitis were randomized to receive 20 weeks
199
of maintenance treatment with either CYTOVENE-IV solution, 5 mg/kg once daily, or
200
ganciclovir capsules, 500 mg 6 times daily (3000 mg/day). The study showed that the
201
mean [95% CI] and median [95% CI] times to progression of CMV retinitis, as assessed
202
7
by masked reading of fundus photographs, were 57 days [44, 70] and 29 days [28, 43],
203
respectively, for patients on oral therapy compared to 62 days [50, 73] and 49 days [29,
204
61], respectively, for patients on intravenous therapy. The difference [95% CI] in the
205
mean time to progression between the oral and intravenous therapies (oral - IV) was -5
206
days [-22, 12]. See Figure 1 for comparison of the proportion of patients remaining free
207
of progression over time.
208
ICM 1774: In this three-arm, randomized, open-label, parallel group trial, conducted
209
between June 1991 and August 1993, patients with AIDS and stable CMV retinitis
210
following from 4 weeks to 4 months of treatment with CYTOVENE-IV solution were
211
randomized to receive maintenance treatment with CYTOVENE-IV solution, 5 mg/kg
212
once daily, ganciclovir capsules, 500 mg 6 times daily, or ganciclovir capsules, 1000 mg
213
tid for 20 weeks. The study showed that the mean [95% CI] and median [95% CI] times
214
to progression of CMV retinitis, as assessed by masked reading of fundus photographs,
215
were 54 days [48, 60] and 42 days [31, 54], respectively, for patients on oral therapy
216
compared to 66 days [56, 76] and 54 days [41, 69], respectively, for patients on
217
intravenous therapy. The difference [95% CI] in the mean time to progression between
218
the oral and intravenous therapies (oral - IV) was -12 days [-24, 0]. See Figure 2 for
219
comparison of the proportion of patients remaining free of progression over time.
220
AVI 034: In this randomized, open-label, parallel group trial, conducted between June
221
1991 and February 1993, patients with AIDS and newly diagnosed (81%) or previously
222
treated (19%) CMV retinitis who had tolerated 10 to 21 days of induction treatment with
223
CYTOVENE-IV, 5 mg/kg twice daily, were randomized to receive 20 weeks of
224
maintenance treatment with either ganciclovir capsules, 500 mg 6 times daily or
225
CYTOVENE-IV solution, 5 mg/kg/day.3 The mean [95% CI] and median [95% CI] times
226
to progression of CMV retinitis, as assessed by masked reading of fundus photographs,
227
were 51 days [44, 57] and 41 days [31, 45], respectively, for patients on oral therapy
228
compared to 62 days [52, 72] and 60 days [42, 83], respectively, for patients on
229
intravenous therapy. The difference [95% CI] in the mean time to progression between
230
the oral and intravenous therapies (oral - IV) was -11 days [-24, 1]. See Figure 3 for
231
comparison of the proportion of patients remaining free of progression over time.
232
Comparison of other CMV retinitis outcomes between oral and IV formulations
233
(development of bilateral retinitis, progression into Zone 1, and deterioration of visual
234
acuity), while not definitive, showed no marked differences between treatment groups in
235
these studies. Because of low event rates among these endpoints, these studies are
236
underpowered to rule out significant differences in these endpoints.
237
8
Figure 1
ICM 1653
238
239
Figure 2
ICM 1774
240
241
Figure 3
AVI 034
242
243
244
9
2. Prevention of CMV Disease in Transplant Recipients
245
CYTOVENE-IV was evaluated in three randomized, controlled trials of prevention of
246
CMV disease in organ transplant recipients.
247
ICM 1496: In a randomized, double-blind, placebo-controlled study of 149 heart transplant
248
recipients4 at risk for CMV infection (CMV seropositive or a seronegative recipient of an
249
organ from a CMV seropositive donor), there was a statistically significant reduction in the
250
overall incidence of CMV disease in patients treated with CYTOVENE-IV. Immediately
251
posttransplant, patients received CYTOVENE-IV solution 5 mg/kg bid for 14 days
252
followed by 6 mg/kg qd for 5 days/week for an additional 14 days. Twelve of the 76 (16%)
253
patients treated with CYTOVENE-IV vs 31 of the 73 (43%) placebo-treated patients
254
developed CMV disease during the 120-day posttransplant observation period. No
255
significant differences in hematologic toxicities were seen between the two treatment
256
groups (refer to Table 6 in ADVERSE EVENTS).
257
ICM 1689: In a randomized, double-blind, placebo-controlled study of 72 bone marrow
258
transplant recipients5 with asymptomatic CMV infection (CMV positive culture of urine,
259
throat or blood) there was a statistically significant reduction in the incidence of CMV
260
disease in patients treated with CYTOVENE-IV following successful hematopoietic
261
engraftment. Patients with virologic evidence of CMV infection received CYTOVENE-
262
IV solution 5 mg/kg bid for 7 days followed by 5 mg/kg qd through day 100
263
posttransplant. One of the 37 (3%) patients treated with CYTOVENE-IV vs 15 of the 35
264
(43%) placebo-treated patients developed CMV disease during the study. At 6 months
265
posttransplant, there continued to be a statistically significant reduction in the incidence
266
of CMV disease in patients treated with CYTOVENE-IV. Six of 37 (16%) patients treated
267
with CYTOVENE-IV vs 15 of the 35 (43%) placebo-treated patients developed disease
268
through 6 months posttransplant. The overall rate of survival was statistically
269
significantly higher in the group treated with CYTOVENE-IV, both at day 100 and day
270
180 posttransplant. Although the differences in hematologic toxicities were not
271
statistically significant, the incidence of neutropenia was higher in the group treated with
272
CYTOVENE-IV (refer to Table 6 in ADVERSE EVENTS).
273
ICM 1570: A second, randomized, unblinded study evaluated 40 allogeneic bone marrow
274
transplant recipients at risk for CMV disease.6 Patients underwent bronchoscopy and
275
bronchoalveolar lavage (BAL) on day 35 posttransplant. Patients with histologic,
276
immunologic or virologic evidence of CMV infection in the lung were then randomized to
277
observation or treatment with CYTOVENE-IV solution (5 mg/kg bid for 14 days followed
278
by 5 mg/kg qd 5 days/week until day 120). Four of 20 (20%) patients treated with
279
CYTOVENE-IV and 14 of 20 (70%) control patients developed interstitial pneumonia. The
280
incidence of CMV disease was significantly lower in the group treated with CYTOVENE-
281
IV, consistent with the results observed in ICM 1689.
282
CONTRAINDICATIONS
283
CYTOVENE-IV is contraindicated in patients with hypersensitivity to ganciclovir or
284
acyclovir.
285
10
WARNINGS
286
Hematologic
287
CYTOVENE-IV should not be administered if the absolute neutrophil count is less
288
than 500 cells/µL or the platelet count is less than 25,000 cells/µL. Granulocytopenia
289
(neutropenia), anemia and thrombocytopenia have been observed in patients treated with
290
CYTOVENE-IV. The frequency and severity of these events vary widely in different
291
patient populations (see ADVERSE EVENTS).
292
CYTOVENE-IV should, therefore, be used with caution in patients with pre-existing
293
cytopenias or with a history of cytopenic reactions to other drugs, chemicals or irradiation.
294
Granulocytopenia usually occurs during the first or second week of treatment but may
295
occur at any time during treatment. Cell counts usually begin to recover within 3 to 7 days
296
of discontinuing drug. Colony-stimulating factors have been shown to increase neutrophil
297
and white blood cell counts in patients receiving CYTOVENE-IV solution for treatment of
298
CMV retinitis.
299
Impairment of Fertility
300
Animal data indicate that administration of ganciclovir causes inhibition of
301
spermatogenesis and subsequent infertility. These effects were reversible at lower doses
302
and
irreversible
at
higher
doses
(see
PRECAUTIONS:
Carcinogenesis,
303
Mutagenesis‡ and Impairment of Fertility‡). Although data in humans have not been
304
obtained regarding this effect, it is considered probable that ganciclovir at the
305
recommended doses causes temporary or permanent inhibition of spermatogenesis. Animal
306
data also indicate that suppression of fertility in females may occur.
307
Teratogenesis
308
Because of the mutagenic and teratogenic potential of ganciclovir, women of childbearing
309
potential should be advised to use effective contraception during treatment. Similarly, men
310
should be advised to practice barrier contraception during and for at least 90 days following
311
treatment with CYTOVENE-IV (see PRECAUTIONS: Pregnancy‡: Category C).
312
PRECAUTIONS
313
General
314
In clinical studies with CYTOVENE-IV, the maximum single dose administered was 6
315
mg/kg by intravenous infusion over 1 hour. Larger doses have resulted in increased
316
toxicity. It is likely that more rapid infusions would also result in increased toxicity (see
317
OVERDOSAGE). Administration of CYTOVENE-IV solution should be accompanied by
318
adequate hydration.
319
Initially reconstituted solutions of CYTOVENE-IV have a high pH (pH 11). Despite further
320
dilution in intravenous fluids, phlebitis and/or pain may occur at the site of intravenous
321
infusion. Care must be taken to infuse solutions containing CYTOVENE-IV only into veins
322
with adequate blood flow to permit rapid dilution and distribution (see DOSAGE AND
323
ADMINISTRATION).
324
11
Since ganciclovir is excreted by the kidneys, normal clearance depends on adequate renal
325
function. IF RENAL FUNCTION IS IMPAIRED, DOSAGE ADJUSTMENTS ARE
326
REQUIRED FOR CYTOVENE-IV. Such adjustments should be based on measured or
327
estimated creatinine clearance values (see DOSAGE AND ADMINISTRATION).
328
Information for Patients
329
All patients should be informed that the major toxicities of ganciclovir are
330
granulocytopenia (neutropenia), anemia and thrombocytopenia and that dose modifications
331
may be required, including discontinuation. The importance of close monitoring of blood
332
counts while on therapy should be emphasized. Patients should be informed that
333
ganciclovir has been associated with elevations in serum creatinine.
334
Patients should be advised that ganciclovir has caused decreased sperm production in
335
animals and may cause infertility in humans. Women of childbearing potential should be
336
advised that ganciclovir causes birth defects in animals and should not be used during
337
pregnancy. Women of childbearing potential should be advised to use effective
338
contraception during treatment with CYTOVENE-IV. Similarly, men should be advised to
339
practice barrier contraception during and for at least 90 days following treatment with
340
CYTOVENE-IV.
341
Patients should be advised that ganciclovir causes tumors in animals. Although there is no
342
information from human studies, ganciclovir should be considered a potential carcinogen.
343
All HIV+ Patients
344
These patients may be receiving zidovudine. Patients should be counseled that treatment
345
with both ganciclovir and zidovudine simultaneously may not be tolerated by some patients
346
and may result in severe granulocytopenia (neutropenia). Patients with AIDS may be
347
receiving didanosine. Patients should be counseled that concomitant treatment with both
348
ganciclovir and didanosine can cause didanosine serum concentrations to be significantly
349
increased.
350
HIV+ Patients With CMV Retinitis
351
Ganciclovir is not a cure for CMV retinitis, and immunocompromised patients may
352
continue to experience progression of retinitis during or following treatment. Patients
353
should be advised to have ophthalmologic follow-up examinations at a minimum of every
354
4 to 6 weeks while being treated with CYTOVENE-IV. Some patients will require more
355
frequent follow-up.
356
Transplant Recipients
357
Transplant recipients should be counseled regarding the high frequency of impaired renal
358
function in transplant recipients who received CYTOVENE-IV solution in controlled
359
clinical trials, particularly in patients receiving concomitant administration of nephrotoxic
360
agents such as cyclosporine and amphotericin B. Although the specific mechanism of this
361
toxicity, which in most cases was reversible, has not been determined, the higher rate of
362
renal impairment in patients receiving CYTOVENE-IV solution compared with those who
363
12
received placebo in the same trials may indicate that CYTOVENE-IV played a significant
364
role.
365
Laboratory Testing
366
Due to the frequency of neutropenia, anemia and thrombocytopenia in patients receiving
367
CYTOVENE-IV (see ADVERSE EVENTS), it is recommended that complete blood
368
counts and platelet counts be performed frequently, especially in patients in whom
369
ganciclovir or other nucleoside analogues have previously resulted in leukopenia, or in
370
whom neutrophil counts are less than 1000 cells/µL at the beginning of treatment.
371
Increased serum creatinine levels have been observed in trials evaluating both
372
CYTOVENE-IV. Patients should have serum creatinine or creatinine clearance values
373
monitored carefully to allow for dosage adjustments in renally impaired patients (see
374
DOSAGE AND ADMINISTRATION).
375
Drug Interactions
376
Didanosine
377
When the standard intravenous ganciclovir induction dose (5 mg/kg infused over 1 hour
378
every 12 hours) was coadministered with didanosine at a dose of 200 mg orally every 12
379
hours, the steady-state didanosine AUC0-12 increased 70 ± 40% (range: 3% to 121%, n=11)
380
and Cmax increased 49 ± 48% (range: -28% to 125%). In a separate study, when the
381
standard intravenous ganciclovir maintenance dose (5 mg/kg infused over 1 hour every 24
382
hours) was coadministered with didanosine at a dose of 200 mg orally every 12 hours,
383
didanosine AUC0-12 increased 50 ± 26% (range: 22% to 110%, n=11) and Cmax increased 36
384
± 36% (range: -27% to 94%) over the first didanosine dosing interval. Didanosine plasma
385
concentrations (AUC12-24) were unchanged during the dosing intervals when ganciclovir
386
was not coadministered. Ganciclovir pharmacokinetics were not affected by didanosine. In
387
neither study were there significant changes in the renal clearance of either drug.
388
Zidovudine
389
At an oral dose of 1000 mg of ganciclovir every 8 hours, mean steady-state ganciclovir
390
AUC0-8 decreased 17 ± 25% (range: -52% to 23%) in the presence of zidovudine, 100 mg
391
every 4 hours (n=12). Steady-state zidovudine AUC0-4 increased 19 ± 27% (range: -11% to
392
74%) in the presence of ganciclovir. No drug-drug interaction studies have been conducted
393
with IV ganciclovir and zidovudine.
394
Since both zidovudine and ganciclovir have the potential to cause neutropenia and anemia,
395
some patients may not tolerate concomitant therapy with these drugs at full dosage.
396
Probenecid
397
At an oral dose of 1000 mg of ganciclovir every 8 hours (n=10), ganciclovir AUC0-8
398
increased 53 ± 91% (range: -14% to 299%) in the presence of probenecid, 500 mg every 6
399
hours. Renal clearance of ganciclovir decreased 22 ± 20% (range: -54% to -4%), which is
400
consistent with an interaction involving competition for renal tubular secretion. No drug-
401
drug interaction studies have been conducted with IV ganciclovir and probenecid.
402
13
Imipenem-cilastatin
403
Generalized seizures have been reported in patients who received ganciclovir and
404
imipenem-cilastatin. These drugs should not be used concomitantly unless the potential
405
benefits outweigh the risks.
406
Other Medications
407
It is possible that drugs that inhibit replication of rapidly dividing cell populations such as
408
bone marrow, spermatogonia and germinal layers of skin and gastrointestinal mucosa may
409
have additive toxicity when administered concomitantly with ganciclovir. Therefore, drugs
410
such as dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin,
411
amphotericin B, trimethoprim/sulfamethoxazole combinations or other nucleoside
412
analogues, should be considered for concomitant use with ganciclovir only if the potential
413
benefits are judged to outweigh the risks.
414
No formal drug interaction studies of CYTOVENE-IV and drugs commonly used in
415
transplant recipients have been conducted. Increases in serum creatinine were observed in
416
patients treated with CYTOVENE-IV plus either cyclosporine or amphotericin B, drugs
417
with known potential for nephrotoxicity (see ADVERSE EVENTS). In a retrospective
418
analysis of 93 liver allograft recipients receiving ganciclovir (5 mg/kg infused over 1 hour
419
every 12 hours) and oral cyclosporine (at therapeutic doses), there was no evidence of an
420
effect on cyclosporine whole blood concentrations.
421
Carcinogenesis, Mutagenesis‡
422
Ganciclovir was carcinogenic in the mouse at oral doses of 20 and 1000 mg/kg/day
423
(approximately 0.1x and 1.4x, respectively, the mean drug exposure in humans following
424
the recommended intravenous dose of 5 mg/kg, based on area under the plasma
425
concentration curve [AUC] comparisons). At the dose of 1000 mg/kg/day there was a
426
significant increase in the incidence of tumors of the preputial gland in males, forestomach
427
(nonglandular mucosa) in males and females, and reproductive tissues (ovaries, uterus,
428
mammary gland, clitoral gland and vagina) and liver in females. At the dose of 20
429
mg/kg/day, a slightly increased incidence of tumors was noted in the preputial and
430
harderian glands in males, forestomach in males and females, and liver in females. No
431
carcinogenic effect was observed in mice administered ganciclovir at 1 mg/kg/day
432
(estimated as 0.01x the human dose based on AUC comparison). Except for histiocytic
433
sarcoma of the liver, ganciclovir-induced tumors were generally of epithelial or vascular
434
origin. Although the preputial and clitoral glands, forestomach and harderian glands of
435
mice do not have human counterparts, ganciclovir should be considered a potential
436
carcinogen in humans.
437
Ganciclovir increased mutations in mouse lymphoma cells and DNA damage in human
438
lymphocytes in vitro at concentrations between 50 to 500 and 250 to 2000 µg/mL,
439
respectively. In the mouse micronucleus assay, ganciclovir was clastogenic at doses of 150
440
and 500 mg/kg (IV) (2.8 to 10x human exposure based on AUC) but not 50 mg/kg
441
(exposure approximately comparable to the human based on AUC). Ganciclovir was not
442
mutagenic in the Ames Salmonella assay at concentrations of 500 to 5000 µg/mL.
443
14
Impairment of Fertility‡
444
Ganciclovir caused decreased mating behavior, decreased fertility, and an increased
445
incidence of embryolethality in female mice following intravenous doses of 90 mg/kg/day
446
(approximately 1.7x the mean drug exposure in humans following the dose of 5 mg/kg,
447
based on AUC comparisons). Ganciclovir caused decreased fertility in male mice and
448
hypospermatogenesis in mice and dogs following daily oral or intravenous administration
449
of doses ranging from 0.2 to 10 mg/kg. Systemic drug exposure (AUC) at the lowest dose
450
showing toxicity in each species ranged from 0.03 to 0.1x the AUC of the recommended
451
human intravenous dose.
452
Pregnancy‡
453
Category C
454
Ganciclovir has been shown to be embryotoxic in rabbits and mice following intravenous
455
administration and teratogenic in rabbits. Fetal resorptions were present in at least 85% of
456
rabbits and mice administered 60 mg/kg/day and 108 mg/kg/day (2x the human exposure
457
based on AUC comparisons), respectively. Effects observed in rabbits included: fetal
458
growth retardation, embryolethality, teratogenicity and/or maternal toxicity. Teratogenic
459
changes included cleft palate, anophthalmia/microphthalmia, aplastic organs (kidney and
460
pancreas), hydrocephaly and brachygnathia. In mice, effects observed were maternal/fetal
461
toxicity and embryolethality.
462
Daily intravenous doses of 90 mg/kg administered to female mice prior to mating, during
463
gestation, and during lactation caused hypoplasia of the testes and seminal vesicles in the
464
month-old male offspring, as well as pathologic changes in the nonglandular region of the
465
stomach (see Carcinogenesis, Mutagenesis‡). The drug exposure in mice as estimated by
466
the AUC was approximately 1.7x the human AUC.
467
Ganciclovir may be teratogenic or embryotoxic at dose levels recommended for human
468
use. There are no adequate and well-controlled studies in pregnant women. CYTOVENE-
469
IV should be used during pregnancy only if the potential benefits justify the potential risk
470
to the fetus.
471
‡Foo tn ot e: All dose comparisons presented in the Carcinogenesis, Mutagenesis‡,
472
Impairment of Fertility‡, and Pregnancy‡ subsections are based on the human AUC
473
following administration of a single 5 mg/kg intravenous infusion of CYTOVENE-IV as
474
used during the maintenance phase of treatment. Compared with the single 5 mg/kg
475
intravenous infusion, human exposure is doubled during the intravenous induction phase (5
476
mg/kg bid). The cross-species dose comparisons should be divided by 2 for intravenous
477
induction treatment with CYTOVENE-IV.
478
Nursing Mothers
479
It is not known whether ganciclovir is excreted in human milk. However, many drugs are
480
excreted in human milk and, because carcinogenic and teratogenic effects occurred in
481
animals treated with ganciclovir, the possibility of serious adverse reactions from
482
ganciclovir in nursing infants is considered likely (see Pregnancy‡: Category C).
483
Mothers should be instructed to discontinue nursing if they are receiving CYTOVENE-IV.
484
15
The minimum interval before nursing can safely be resumed after the last dose of
485
CYTOVENE-IV is unknown.
486
Pediatric Use
487
SAFETY AND EFFICACY OF CYTOVENE-IV IN PEDIATRIC PATIENTS HAVE
488
NOT BEEN ESTABLISHED. THE USE OF CYTOVENE-IV IN THE PEDIATRIC
489
POPULATION WARRANTS EXTREME CAUTION DUE TO THE PROBABILITY
490
OF LONG-TERM CARCINOGENICITY AND REPRODUCTIVE TOXICITY.
491
ADMINISTRATION TO PEDIATRIC PATIENTS SHOULD BE UNDERTAKEN
492
ONLY AFTER CAREFUL EVALUATION AND ONLY IF THE POTENTIAL
493
BENEFITS OF TREATMENT OUTWEIGH THE RISKS.
494
The spectrum of adverse events reported in 120 immunocompromised pediatric clinical
495
trial participants with serious CMV infections receiving CYTOVENE-IV solution were
496
similar to those reported in adults. Granulocytopenia (17%) and thrombocytopenia (10%)
497
were the most common adverse events reported.
498
Sixteen pediatric patients (8 months to 15 years of age) with life- or sight-threatening CMV
499
infections were evaluated in an open-label, CYTOVENE-IV solution, pharmacokinetics
500
study. Adverse events reported for more than one pediatric patient were as follows:
501
hypokalemia (4/16, 25%), abnormal kidney function (3/16, 19%), sepsis (3/16, 19%),
502
thrombocytopenia (3/16, 19%), leukopenia (2/16, 13%), coagulation disorder (2/16, 13%),
503
hypertension (2/16, 13%), pneumonia (2/16, 13%) and immune system disorder (2/16,
504
13%).
505
There has been very limited clinical experience using CYTOVENE-IV for the treatment of
506
CMV retinitis in patients under the age of 12 years. Two pediatric patients (ages 9 and 5
507
years) showed improvement or stabilization of retinitis for 23 and 9 months, respectively.
508
These pediatric patients received induction treatment with 2.5 mg/kg tid followed by
509
maintenance therapy with 6 to 6.5 mg/kg once per day, 5 to 7 days per week. When retinitis
510
progressed during once-daily maintenance therapy, both pediatric patients were treated with
511
the 5 mg/kg bid regimen. Two other pediatric patients (ages 2.5 and 4 years) who received
512
similar induction regimens showed only partial or no response to treatment. Another
513
pediatric patient, a 6-year-old with T-cell dysfunction, showed stabilization of retinitis for 3
514
months while receiving continuous infusions of CYTOVENE-IV at doses of 2 to
515
5 mg/kg/24
hours.
Continuous
infusion
treatment
was
discontinued
due
to
516
granulocytopenia.
517
Eleven of the 72 patients in the placebo-controlled trial in bone marrow transplant
518
recipients were pediatric patients, ranging in age from 3 to 10 years (5 treated with
519
CYTOVENE-IV and 6 with placebo). Five of the pediatric patients treated with
520
CYTOVENE-IV received 5 mg/kg intravenously bid for up to 7 days; 4 patients went on to
521
receive 5 mg/kg qd up to day 100 posttransplant. Results were similar to those observed in
522
adult transplant recipients treated with CYTOVENE-IV. Two of the 6 placebo-treated
523
pediatric patients developed CMV pneumonia vs none of the 5 patients treated with
524
CYTOVENE-IV. The spectrum of adverse events in the pediatric group was similar to that
525
observed in the adult patients.
526
16
Geriatric Use
527
The pharmacokinetic profiles of CYTOVENE-IV in elderly patients have not been
528
established. Since elderly individuals frequently have a reduced glomerular filtration rate,
529
particular attention should be paid to assessing renal function before and during
530
administration of CYTOVENE-IV (see DOSAGE AND ADMINISTRATION).
531
Clinical studies of CYTOVENE-IV did not include sufficient numbers of subjects aged 65
532
and over to determine whether they respond differently from younger subjects. In general,
533
dose selection for an elderly patient should be cautious, reflecting the greater frequency of
534
decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug
535
therapy. CYTOVENE-IV is known to be substantially excreted by the kidney, and the risk
536
of toxic reactions to this drug may be greater in patients with impaired renal function.
537
Because elderly patients are more likely to have decreased renal function, care should be
538
taken in dose selection. In addition, renal function should be monitored and dosage
539
adjustments should be made accordingly (see Use in Patients With Renal Impairment
540
and DOSAGE AND ADMINISTRATION).
541
Use in Patients With Renal Impairment
542
CYTOVENE-IV should be used with caution in patients with impaired renal function
543
because the half-life and plasma/serum concentrations of ganciclovir will be increased due
544
to reduced renal clearance (see DOSAGE AND ADMINISTRATION and ADVERSE
545
EVENTS).
546
Hemodialysis has been shown to reduce plasma levels of ganciclovir by approximately
547
50%.
548
ADVERSE EVENTS
549
Adverse events that occurred during clinical trials of CYTOVENE-IV solution are
550
summarized below, according to the participating study subject population.
551
Subjects With AIDS
552
Three controlled, randomized, phase 3 trials comparing CYTOVENE-IV and ganciclovir
553
capsules for maintenance treatment of CMV retinitis have been completed. During these
554
trials, CYTOVENE-IV or ganciclovir capsules were prematurely discontinued in 9% of
555
subjects because of adverse events. Laboratory data and adverse events reported during the
556
conduct of these controlled trials are summarized below.
557
17
Laboratory Data
558
Table 4
Selected Laboratory Abnormalities in Trials for Treatment of
559
CMV Retinitis
560
CMV Retinitis Treatment*
Treatment
Ganciclovir
Capsules†
3000 mg/day
CYTOVENE-IV‡
5 mg/kg/day
Subjects, number
320
175
Neutropenia:
<500 ANC/µL
500 – <749
750 – <1000
18%
17%
19%
25%
14%
26%
Anemia:
Hemoglobin:
<6.5 g/dL
6.5 – <8.0
8.0 – <9.5
2%
10%
25%
5%
16%
26%
Maximum Serum
Creatinine:
≥2.5 mg/dL
≥1.5 – <2.5
1%
12%
2%
14%
* Pooled data from Treatment Studies, ICM 1653, Study ICM 1774 and Study AVI 034
561
† Mean time on therapy = 91 days, including allowed reinduction treatment periods
562
‡ Mean time on therapy = 103 days, including allowed reinduction treatment periods
563
564
(See CLINICAL TRIALS.)
565
Adverse Events
566
The following table shows selected adverse events reported in 5% or more of the subjects
567
in three controlled clinical trials during treatment with either CYTOVENE-IV solution (5
568
mg/kg/day) or ganciclovir capsules (3000 mg/day), and in one controlled clinical trial in
569
which CYTOVENE capsules (3000 mg/day).
570
18
Table 5
Selected Adverse Events Reported in ≥ 5% of Subjects in
571
Three Randomized Phase 3 Studies Comparing Ganciclovir
572
Capsules to CYTOVENE-IV Solution for Maintenance
573
Treatment of CMV Retinitis
574
Maintenance Treatment
Studies
Body System
Adverse Event
Capsules
(n=326)
IV
(n=179)
Body as a Whole
Fever
38%
48%
Infection
9%
13%
Chills
7%
10%
Sepsis
4%
15%
Digestive System
Diarrhea
41%
44%
Anorexia
15%
14%
Vomiting
13%
13%
Hemic and
Leukopenia
29%
41%
Lymphatic System
Anemia
19%
25%
Thrombocytopenia
6%
6%
Nervous System
Neuropathy
8%
9%
Other
Sweating
11%
12%
Pruritus
6%
5%
Catheter Related*
Total Catheter
Events
6%
22%
Catheter Infection
4%
9%
Catheter Sepsis
1%
8%
*Some of these events also appear under other body systems.
575
The following events were frequently observed in clinical trials but occurred with equal or
576
greater frequency in placebo-treated subjects: abdominal pain, nausea, flatulence,
577
pneumonia, paresthesia, rash.
578
Retinal Detachment
579
Retinal detachment has been observed in subjects with CMV retinitis both before and after
580
initiation of therapy with ganciclovir. Its relationship to therapy with ganciclovir is
581
unknown. Retinal detachment occurred in 11% of patients treated with CYTOVENE-IV
582
solution and in 8% of patients treated with ganciclovir capsules. Patients with CMV
583
retinitis should have frequent ophthalmologic evaluations to monitor the status of their
584
retinitis and to detect any other retinal pathology.
585
Transplant Recipients
586
There have been three controlled clinical trials of CYTOVENE-IV solution for the
587
prevention of CMV disease in transplant recipients. Laboratory data and adverse events
588
reported during these trials are summarized below.
589
19
Laboratory Data
590
The following table shows the frequency of granulocytopenia (neutropenia) and
591
thrombocytopenia observed:
592
Table 6
Controlled Trials – Transplant Recipients
593
CYTOVENE-IV
Heart Allograft*
Bone Marrow Allograft†
CYTOVENE-IV
(n=76)
Placebo
(n=73)
CYTOVENE-IV
(n=57)
Control
(n=55)
Neutropenia
Minimum ANC
<500/µL
Minimum ANC
500-1000/µL
4%
3%
3%
8%
12%
29%
6%
17%
TOTAL ANC
≤1000/µL
7%
11%
41%
23%
Thrombocytopenia
Platelet count
<25,000/µL
Platelet count
25,000-50,000/µL
3%
5%
1%
3%
32%
25%
28%
37%
TOTAL Platelet
≤50,000/µL
8%
4%
57%
65%
* Study ICM 1496. Mean duration of treatment = 28 days
594
† Study ICM 1570 and ICM 1689. Mean duration of treatment = 45 days
595
(See CLINICAL TRIALS.)
596
The following table shows the frequency of elevated serum creatinine values in these
597
controlled clinical trials:
598
Table 7
Controlled Trials - Transplant Recipients
599
CYTOVENE-IV
Heart Allograft
ICM1496
Bone Marrow Allograft
ICM 1570
Bone Marrow Allograft
ICM 1689
Maximum
Serum
Creatinine
Levels
CYTOVENE-IV
(n=76)
Placebo
(n=73)
CYTOVENE-IV
(n=20)
Control
(n=20)
CYTOVENE-IV
(n=37)
Placebo
(n=35)
Serum
Creatinine
≥2.5 mg/dL
18%
4%
20%
0%
0%
0%
Serum
Creatinine
≥1.5 - <2.5
mg/dL
58%
69%
50%
35%
43%
44%
In these three trials, patients receiving CYTOVENE-IV solution had elevated serum
600
creatinine levels when compared to those receiving placebo. Most patients in these
601
studies also received cyclosporine. The mechanism of impairment of renal function is not
602
known. However, careful monitoring of renal function during therapy with CYTOVENE-
603
IV solution is essential, especially for those patients receiving concomitant agents that
604
may cause nephrotoxicity.
605
20
General
606
Other adverse events that were thought to be "probably" or "possibly" related to
607
CYTOVENE-IV solution or ganciclovir capsules in controlled clinical studies in either
608
subjects with AIDS or transplant recipients are listed below. These events all occurred in
609
at least 3 subjects.
610
Body as a Whole: abdomen enlarged, asthenia, chest pain, edema, headache, injection site
611
inflammation, malaise, pain
612
Digestive System: abnormal liver function test, aphthous stomatitis, constipation,
613
dyspepsia, eructation
614
Hemic and Lymphatic System: pancytopenia
615
Respiratory System: cough increased, dyspnea
616
Nervous System: abnormal dreams, anxiety, confusion, depression, dizziness, dry mouth,
617
insomnia, seizures, somnolence, thinking abnormal, tremor
618
Skin and Appendages: alopecia, dry skin
619
Special Senses: abnormal vision, taste perversion, tinnitus, vitreous disorder
620
Metabolic and Nutritional Disorders: creatinine increased, SGOT increased, SGPT
621
increased, weight loss
622
Cardiovascular System: hypertension, phlebitis, vasodilatation
623
Urogenital System: creatinine clearance decreased, kidney failure, kidney function
624
abnormal, urinary frequency
625
Musculoskeletal System: arthralgia, leg cramps, myalgia, myasthenia
626
The following adverse events reported in patients receiving ganciclovir may be
627
potentially fatal: gastrointestinal perforation, multiple organ failure, pancreatitis and
628
sepsis.
629
Adverse Events Reported During Postmarketing Experience With
630
CYTOVENE-IV and Ganciclovir Capsules
631
The following events have been identified during postapproval use of the drug. Because
632
they are reported voluntarily from a population of unknown size, estimates of frequency
633
cannot be made. These events have been chosen for inclusion due to either the
634
seriousness, frequency of reporting, the apparent causal connection or a combination of
635
these factors:
636
acidosis, allergic reaction, anaphylactic reaction, arthritis, bronchospasm, cardiac arrest,
637
cardiac conduction abnormality, cataracts, cholelithiasis, cholestasis, congenital anomaly,
638
dry eyes, dysesthesia, dysphasia, elevated triglyceride levels, encephalopathy, exfoliative
639
dermatitis, extrapyramidal reaction, facial palsy, hallucinations, hemolytic anemia,
640
hemolytic uremic syndrome, hepatic failure, hepatitis, hypercalcemia, hyponatremia,
641
inappropriate serum ADH, infertility, intestinal ulceration, intracranial hypertension,
642
21
irritability, loss of memory, loss of sense of smell, myelopathy, oculomotor nerve
643
paralysis,
peripheral
ischemia,
pulmonary
fibrosis,
renal
tubular
disorder,
644
rhabdomyolysis, Stevens-Johnson syndrome, stroke, testicular hypotrophy, Torsades de
645
Pointes, vasculitis, ventricular tachycardia
646
OVERDOSAGE
647
Overdosage with CYTOVENE-IV has been reported in 17 patients (13 adults and 4
648
children under 2 years of age). Five patients experienced no adverse events following
649
overdosage at the following doses: 7 doses of 11 mg/kg over a 3-day period (adult), single
650
dose of 3500 mg (adult), single dose of 500 mg (72.5 mg/kg) followed by 48 hours of
651
peritoneal dialysis (4-month-old), single dose of approximately 60 mg/kg followed by
652
exchange transfusion (18-month-old), 2 doses of 500 mg instead of 31 mg (21-month-old).
653
Irreversible pancytopenia developed in 1 adult with AIDS and CMV colitis after receiving
654
3000 mg of CYTOVENE-IV solution on each of 2 consecutive days. He experienced
655
worsening GI symptoms and acute renal failure that required short-term dialysis.
656
Pancytopenia developed and persisted until his death from a malignancy several months
657
later. Other adverse events reported following overdosage included: persistent bone marrow
658
suppression (1 adult with neutropenia and thrombocytopenia after a single dose of 6000
659
mg), reversible neutropenia or granulocytopenia (4 adults, overdoses ranging from 8 mg/kg
660
daily for 4 days to a single dose of 25 mg/kg), hepatitis (1 adult receiving 10 mg/kg daily,
661
and one 2 kg infant after a single 40 mg dose), renal toxicity (1 adult with transient
662
worsening of hematuria after a single 500 mg dose, and 1 adult with elevated creatinine
663
(5.2 mg/dL) after a single 5000 to 7000 mg dose), and seizure (1 adult with known seizure
664
disorder after 3 days of 9 mg/kg). In addition, 1 adult received 0.4 mL (instead of 0.1 mL)
665
CYTOVENE-IV solution by intravitreal injection, and experienced temporary loss of
666
vision and central retinal artery occlusion secondary to increased intraocular pressure
667
related to the injected fluid volume.
668
Since ganciclovir is dialyzable, dialysis may be useful in reducing serum concentrations.
669
Adequate hydration should be maintained. The use of hematopoietic growth factors should
670
be considered (see DOSAGE AND ADMINISTRATION: Renal Impairment).
671
DOSAGE AND ADMINISTRATION
672
CAUTION - DO NOT ADMINISTER CYTOVENE-IV SOLUTION BY RAPID OR
673
BOLUS INTRAVENOUS INJECTION. THE TOXICITY OF CYTOVENE-IV MAY BE
674
INCREASED AS A RESULT OF EXCESSIVE PLASMA LEVELS.
675
CAUTION
-
INTRAMUSCULAR
OR
SUBCUTANEOUS
INJECTION
OF
676
RECONSTITUTED CYTOVENE-IV SOLUTION MAY RESULT IN SEVERE TISSUE
677
IRRITATION DUE TO HIGH pH (11).
678
Dosage
679
THE RECOMMENDED DOSE FOR CYTOVENE-IV SOLUTION SHOULD NOT BE
680
EXCEEDED. THE RECOMMENDED INFUSION RATE FOR CYTOVENE-IV
681
SOLUTION SHOULD NOT BE EXCEEDED.
682
22
For Treatment of CMV Retinitis in Patients With Normal Renal Function
683
Induction Treatment
684
The recommended initial dosage for patients with normal renal function is 5 mg/kg (given
685
intravenously at a constant rate over 1 hour) every 12 hours for 14 to 21 days.
686
Maintenance Treatment
687
Following induction treatment, the recommended maintenance dosage of CYTOVENE-IV
688
solution is 5 mg/kg given as a constant-rate intravenous infusion over 1 hour once daily, 7
689
days per week, or 6 mg/kg once daily, 5 days per week.
690
For patients who experience progression of CMV retinitis while receiving maintenance
691
treatment with CYTOVENE-IV, reinduction treatment is recommended.
692
For the Prevention of CMV Disease in Transplant Recipients With Normal
693
Renal Function
694
The recommended initial dosage of CYTOVENE-IV solution for patients with normal
695
renal function is 5 mg/kg (given intravenously at a constant rate over 1 hour) every 12
696
hours for 7 to 14 days, followed by 5 mg/kg once daily, 7 days per week or 6 mg/kg once
697
daily, 5 days per week.
698
The duration of treatment with CYTOVENE-IV solution in transplant recipients is
699
dependent upon the duration and degree of immunosuppression. In controlled clinical trials
700
in bone marrow allograft recipients, treatment with CYTOVENE-IV was continued until
701
day 100 to 120 posttransplantation. CMV disease occurred in several patients who
702
discontinued treatment with CYTOVENE-IV solution prematurely. In heart allograft
703
recipients, the onset of newly diagnosed CMV disease occurred after treatment with
704
CYTOVENE-IV was stopped at day 28 posttransplant, suggesting that continued dosing
705
may be necessary to prevent late occurrence of CMV disease in this patient population (see
706
INDICATIONS AND USAGE section for a more detailed discussion).
707
Renal Impairment
708
For patients with impairment of renal function, refer to Table 8 for recommended doses of
709
CYTOVENE-IV solution and adjust the dosing interval as indicated:
710
Table 8
Dosing for Patients with Renal Impairment
711
Creatinine
Clearance*
(mL/min)
CYTOVENE-IV
Induction
Dose (mg/kg)
Dosing
Interval
(hours)
CYTOVENE-IV
Maintenance
Dose (mg/kg)
Dosing
Interval
(hours)
≥70
5.0
12
5.0
24
50–69
2.5
12
2.5
24
25–49
2.5
24
1.25
24
10–24
1.25
24
0.625
24
<10
1.25
3 times per week,
following hemodialysis
0.625
3 times per week,
following hemodialysis
* Creatinine clearance can be related to serum creatinine by the formulas given below.
712
23
(140 - age[yrs]) (body wt [kg])
713
Creatinine clearance for males = —————————————
714
(72) (serum creatinine [mg/dL])
715
Creatinine clearance for females = 0.85 x male value
716
Dosing for patients undergoing hemodialysis should not exceed 1.25 mg/kg 3 times per
717
week, following each hemodialysis session. CYTOVENE-IV should be given shortly after
718
completion of the hemodialysis session, since hemodialysis has been shown to reduce
719
plasma levels by approximately 50%.
720
Patient Monitoring
721
Due to the frequency of granulocytopenia, anemia and thrombocytopenia in patients
722
receiving ganciclovir (see ADVERSE EVENTS), it is recommended that complete blood
723
counts and platelet counts be performed frequently, especially in patients in whom
724
ganciclovir or other nucleoside analogues have previously resulted in cytopenia, or in
725
whom neutrophil counts are less than 1000 cells/µL at the beginning of treatment. Patients
726
should have serum creatinine or creatinine clearance values followed carefully to allow for
727
dosage
adjustments
in
renally
impaired
patients
(see
DOSAGE
AND
728
ADMINISTRATION).
729
Reduction of Dose
730
Dosage reductions in renally impaired patients are required for CYTOVENE-IV (see
731
Renal Impairment). Dosage reductions should also be considered for those with
732
neutropenia, anemia and/or thrombocytopenia (see ADVERSE EVENTS). Ganciclovir
733
should not be administered in patients with severe neutropenia (ANC less than 500/µL) or
734
severe thrombocytopenia (platelets less than 25,000/µL).
735
Method of Preparation of CYTOVENE-IV Solution
736
Each 10 mL clear glass vial contains ganciclovir sodium equivalent to 500 mg of
737
ganciclovir and 46 mg of sodium. The contents of the vial should be prepared for
738
administration in the following manner:
739
1. Reconstituted Solution:
740
a. Reconstitute lyophilized CYTOVENE-IV by injecting 10 mL of Sterile Water for
741
Injection, USP, into the vial.
742
DO NOT USE BACTERIOSTATIC WATER FOR INJECTION CONTAINING
743
PARABENS. IT IS INCOMPATIBLE WITH CYTOVENE-IV AND MAY CAUSE
744
PRECIPITATION.
745
b. Shake the vial to dissolve the drug.
746
c. Visually inspect the reconstituted solution for particulate matter and discoloration
747
prior to proceeding with infusion solution. Discard the vial if particulate matter or
748
discoloration is observed.
749
24
d. Reconstituted solution in the vial is stable at room temperature for 12 hours. It
750
should not be refrigerated.
751
2. Infusion Solution:
752
Based on patient weight, the appropriate volume of the reconstituted solution
753
(ganciclovir concentration 50 mg/mL) should be removed from the vial and added to an
754
acceptable infusion fluid (typically 100 mL) for delivery over the course of 1 hour.
755
Infusion concentrations greater than 10 mg/mL are not recommended. The following
756
infusion fluids have been determined to be chemically and physically compatible with
757
CYTOVENE-IV solution: 0.9% Sodium Chloride, 5% Dextrose, Ringer's Injection and
758
Lactated Ringer's Injection, USP.
759
CYTOVENE-IV, when reconstituted with sterile water for injection, further diluted with
760
0.9% sodium chloride injection, and stored refrigerated at 5°C in polyvinyl chloride
761
(PVC) bags, remains physically and chemically stable for 14 days.
762
However, because CYTOVENE-IV is reconstituted with nonbacteriostatic sterile water,
763
it is recommended that the infusion solution be used within 24 hours of dilution to
764
reduce the risk of bacterial contamination. The infusion should be refrigerated. Freezing
765
is not recommended.
766
Handling and Disposal
767
Caution should be exercised in the handling and preparation of solutions of CYTOVENE-
768
IV. Solutions of CYTOVENE-IV are alkaline (pH 11). Avoid direct contact of the skin or
769
mucous membranes with CYTOVENE-IV solutions. If such contact occurs, wash
770
thoroughly with soap and water; rinse eyes thoroughly with plain water.
771
Because ganciclovir shares some of the properties of antitumor agents (ie, carcinogenicity
772
and mutagenicity), consideration should be given to handling and disposal according to
773
guidelines issued for antineoplastic drugs. Several guidelines on this subject have been
774
published.7-9
775
There is no general agreement that all of the procedures recommended in the guidelines are
776
necessary or appropriate.
777
HOW SUPPLIED
778
CYTOVENE-IV (ganciclovir sodium for injection) is supplied in 10 mL sterile vials, each
779
containing ganciclovir sodium equivalent to 500 mg of ganciclovir, in cartons of 25 (NDC
780
0004-6940-03).
781
Storage
782
Store vials at temperatures below 40°C (104°F).
783
REFERENCES
784
1. Spector SA, Weingeis T, Pollard R, et al. A randomized, controlled study of
785
intravenous ganciclovir therapy for cytomegalovirus peripheral retinitis in patients with
786
AIDS. J Inf Dis. 1993; 168:557-563. 2. Drew WL, Ives D, Lalezari JP, et al. Oral
787
25
ganciclovir as maintenance treatment for cytomegalovirus retinitis in patients with AIDS.
788
New Engl J Med. 1995; 333:615-620. 3. The Oral Ganciclovir European and Australian
789
Cooperative Study Group. Intravenous vs oral ganciclovir: European/Australian
790
comparative study of efficacy and safety in the prevention of cytomegalovirus retinitis
791
recurrence in patients with AIDS. AIDS. 1995; 9:471-477. 4. Merigan TC, Renlund DG,
792
Keay S, et al. A controlled trial of ganciclovir to prevent cytomegalovirus disease after
793
heart transplantation. New Engl J Med. 1992; 326:1182-1186. 5. Goodrich JM, Mori M,
794
Gleaves CA, et al. Early treatment with ganciclovir to prevent cytomegalovirus disease
795
after allogeneic bone marrow transplantation. New Engl J Med. 1991; 325:1601-1607.
796
6. Schmidt GM, Horak DA, Niland JC, et al. The City of Hope-Stanford-Syntex CMV
797
Study Group. A randomized, controlled trial of prophylactic ganciclovir for
798
cytomegalovirus pulmonary infection in recipients of allogeneic bone marrow
799
transplants. New Engl J Med. 1991; 15:1005-1011. 7. Recommendations for the Safe
800
Handling of Cytotoxic Drugs. US Department of Health and Human Services, National
801
Institutes of Health, Bethesda, MD, September 1992. NIH Publication No. 92-2621.
802
8. American Society of Hospital Pharmacists technical assistance bulletin on handling
803
cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990; 47:1033-1049. 9. Controlling
804
Occupational Exposures to Hazardous Drugs. US Department of Labor. Occupational
805
Health and Safety Administration. OSHA Technical Manual. Section V - Chapter 3.
806
September 22, 1995.
807
808
Distributed by:
809
810
xxxxxxxx
811
xxxxxxxx
812
Revised: Month Year
813
Copyright 1999-xxxx by Roche Laboratories Inc. All rights reserved.
814
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
Jeffrey Murray
1/31/2006 03:04:29 PM
|
custom-source
|
2025-02-12T13:45:40.056537
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/019661s030lbl.pdf', 'application_number': 19661, 'submission_type': 'SUPPL ', 'submission_number': 30}
|
11,614
|
octreotide acetate
INJECTION
Rx only
50 mcg/mL
octreotide acetate INJECTION
50 mcg/mL; Each mL contains:
octreotide (as acetate) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 mcg
Inactive ingredients
lactic acid, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 mg
mannitol, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 mg
sodium bicarbonate, USP . . . . . . . . . . . . . . . . . . . . . . . . qs to pH 4.2 ± 0.3
water for injection, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . qs to 1 mL
See package insert for dosage and administration information.
Storage: Refrigerate at 2°C to 8°C (36°F to 46°F); protect from light.
At room temperature, (20°C to 30°C or 70°F to 86°F), Sandostatin is
stable for 14 days if protected from light.
Instructions for Use
One-point-cut ampul with
cut below colored point
To open, hold as shown
with thumb above point
and snap off backwards
Manufactured by:
Novartis Pharma Stein AG
Schaffhauserstrasse
CH-4332 Stein, Switzerland
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
©Novartis
1256727
NDC 0078-0180-01
Unit Dose Package
NDC 0078-0180-01
Unit Dose Package
NDC 0078-0180-01
Unit Dose Package
For Subcutaneous Injection
10 Ampuls/1 mL size
50 mcg/mL
10 Ampuls/1 mL size
octreotide acetate INJECTION
NDC 0078-0180-01
Unit Dose Package
50 mcg/mL
10 Ampuls/1 mL size
Please open here
Please open here
EXP.
LOT
120 x 105 x 20.5
1256727
US
1256727
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
octreotide acetate
INJECTION
Rx only
100 mcg/mL
octreotide acetate INJECTION
100 mcg/mL; Each mL contains:
octreotide (as acetate) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 mcg
Inactive ingredients
lactic acid, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 mg
mannitol, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 mg
sodium bicarbonate, USP . . . . . . . . . . . . . . . . . . . . . . . . qs to pH 4.2 ± 0.3
water for injection, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . qs to 1 mL
See package insert for dosage and administration information.
Storage: Refrigerate at 2°C to 8°C (36°F to 46°F); protect from light.
At room temperature, (20°C to 30°C or 70°F to 86°F), Sandostatin is
stable for 14 days if protected from light.
Instructions for Use
One-point-cut ampul with
cut below colored point
To open, hold as shown
with thumb above point
and snap off backwards
Manufactured by:
Novartis Pharma Stein AG
Schaffhauserstrasse
CH-4332 Stein, Switzerland
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
©Novartis
1256728
NDC 0078-0181-01
Unit Dose Package
NDC 0078-0181-01
Unit Dose Package
NDC 0078-0181-01
Unit Dose Package
For Subcutaneous Injection
10 Ampuls/1 mL size
100 mcg/mL
10 Ampuls/1 mL size
octreotide acetate INJECTION
NDC 0078-0181-01
Unit Dose Package
100 mcg/mL
10 Ampuls/1 mL size
Please open here
Please open here
EXP.
LOT
120 x 105 x 20.5
1256728
US
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
octreotide acetate
INJECTION
Rx only
500 mcg/mL
octreotide acetate INJECTION
500 mcg/mL; Each mL contains:
octreotide (as acetate) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500 mcg
Inactive ingredients
lactic acid, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 mg
mannitol, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 mg
sodium bicarbonate, USP . . . . . . . . . . . . . . . . . . . . . . . . qs to pH 4.2 ± 0.3
water for injection, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . qs to 1 mL
See package insert for dosage and administration information.
Storage: Refrigerate at 2°C to 8°C (36°F to 46°F); protect from light.
At room temperature, (20°C to 30°C or 70°F to 86°F), Sandostatin is
stable for 14 days if protected from light.
Instructions for Use
One-point-cut ampul with
cut below colored point
To open, hold as shown
with thumb above point
and snap off backwards
Manufactured by:
Novartis Pharma Stein AG
Schaffhauserstrasse
CH-4332 Stein, Switzerland
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
©Novartis
1256731
NDC 0078-0182-01
Unit Dose Package
NDC 0078-0182-01
Unit Dose Package
NDC 0078-0182-01
Unit Dose Package
For Subcutaneous Injection
10 Ampuls/1 mL size
500 mcg/mL
10 Ampuls/1 mL size
octreotide acetate INJECTION
NDC 0078-0182-01
Unit Dose Package
500 mcg/mL
10 Ampuls/1 mL size
Please open here
Please open here
EXP.
LOT
120 x 105 x 20.5
1256731
US
1256731
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Sandostatin
octreotide acetate
INJECTION
1,000 mcg/5 mL (200 mcg/mL)
Total Volume 5 mL Multi-Dose Vial
Each mL of aqueous solution contains: octreotide (as acetate) 200 mcg
FOR SUBCUTANEOUS INJECTION
STORAGE: Refrigerate at 2°C to 8°C (36°F to 46°F); protect from light.
After initial use, d scard w thin 14 days.
Mfd. by Novartis Pharma Stein AG
Rx only
NDC 0078-0183-25
©Novartis
US
Sandostatin
octreotide acetate
INJECTION
1,000 mcg/5 mL (200 mcg/mL)
Total Volume 5 mL Multi-Dose Vial
Each mL of aqueous solution contains: octreotide (as acetate) 200 mcg
FOR SUBCUTANEOUS INJECTION
STORAGE: Refrigerate at 2°C to 8°C (36°F to 46°F); protect from light.
After initial use, d scard w thin 14 days.
Mfd. by Novartis Pharma Stein AG
Rx only
NDC 0078-0183-25
©Novartis
US
Sandostatin
octreotide acetate
INJECTION
1,000 mcg/5 mL (200 mcg/mL)
Total Volume 5 mL Multi-Dose Vial
Each mL of aqueous solution contains: octreotide (as acetate) 200 mcg
FOR SUBCUTANEOUS INJECTION
STORAGE: Refrigerate at 2°C to 8°C (36°F to 46°F); protect from light.
After initial use, d scard w thin 14 days.
Mfd. by Novartis Pharma Stein AG
Rx only
NDC 0078-0183-25
©Novartis
US
1256734B
1256734B
1256734B
EXP./LOT
EXP./LOT
EXP./LOT
1256734A
256734A
256734A
abel may not be the latest approved by
g information, please visit https://www.f
1,000 mcg/5 mL (200 mcg/mL)
1,000 mcg/5 mL (200 mcg/mL)
STORE REFRIGERATED AT 2°C to 8°C
(36°F to 46°F); PROTECT FROM LIGHT.
AFTER INITIAL USE, DISCARD
WITHIN 14 DAYS
FOR SUBCUTANEOUS INJECTION
FOR SUBCUTANEOUS INJECTION
Total Volume 5 mL Multi-Dose Vial
Total Volume 5 mL
Multi-Dose Vial
Please open here
Please open here
Sandostatin®
octreotide acetate INJECTION
Each mL of aqueous solution contains:
octreotide (as acetate) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200 mcg
Inactive ingredients:
lactic acid, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 mg
mannitol, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 mg
phenol, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.0 mg
sodium bicarbonate, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .qs to pH 4.2 ± 0.3
water for injection, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . qs to 1 mL
DOSAGE: See package insert for dosage information.
STORAGE: Refrigerate at 2°C to 8°C (36°F to 46°F); protect from light.
After initial use, discard within 14 days. At room temperature, (20°C to 30°C or
70°F to 86°F), Sandostatin is stable for 14 days if protected from light.
Manufactured by: Novartis Pharma Stein AG
Schaffhauserstrasse, CH-4332 Stein, Switzerland
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
©Novartis
octreotide acetate
INJECTION
octreotide acetate
INJECTION
1,000 mcg/5 mL (200 mcg/mL)
FOR SUBCUTANEOUS INJECTION
Total Volume 5 mL
Multi-Dose Vial
octreotide acetate
INJECTION
Rx only
1256736
1256736
EXP.
LOT
NDC 0078-0183-25
NDC 0078-0183-25
NDC 0078-0183-25
NDC 0078-0183-25
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Sandostatin
octreotide acetate
Rx only
NDC 0078-0184-25
©Novartis
INJECTION
5,000 mcg/5 mL (1,000 mcg/mL)
Total Volume 5 mL Multi-Dose Vial
Each mL of aqueous solution contains: octreotide (as acetate) 1,000 mcg
FOR SUBCUTANEOUS INJECTION
STORAGE: Refrigerate at 2°C to 8°C (36°F to 46°F); protect from light.
After initial use, discard with n 14 days.
Mfd. by Novartis Pharma Stein AG
Sandostatin
octreotide acetate
Rx only
NDC 0078-0184-25
©Novartis
INJECTION
5,000 mcg/5 mL (1,000 mcg/mL)
Total Volume 5 mL Multi-Dose Vial
Each mL of aqueous so ution contains: octreotide (as acetate) 1,000 mcg
FOR SUBCUTANEOUS INJECTION
STORAGE: Refrigerate at 2°C to 8°C (36°F to 46°F); protect from ight.
After nitial use, discard within 14 days.
Mfd. by Novartis Pharma Stein AG
Sandostatin
octreotide acetate
Rx only
NDC 0078-0184-25
©Novartis
INJECTION
5,000 mcg/5 mL (1,000 mcg/mL)
Total Volume 5 mL Multi-Dose Vial
Each mL of aqueous so ution contains: octreotide (as acetate) 1,000 mcg
FOR SUBCUTANEOUS INJECTION
STORAGE: Refrigerate at 2°C to 8°C (36°F to 46°F); protect from ight.
After nitial use, discard within 14 days.
Mfd. by Novartis Pharma Stein AG
1256740A
1256740B 1256740C
US
EXP./LOT
EXP./LOT
EXP./LOT
256740A
1256740B 1256740C
US
256740A
1256740B 1256740C
US
abel may not be the latest approved by
g information, please visit https://www.f
5,000 mcg/5 mL (1,000 mcg/mL)
STORE REFRIGERATED AT 2°C to 8°C
(36°F to 46°F); PROTECT FROM LIGHT.
AFTER INITIAL USE, DISCARD
WITHIN 14 DAYS
FOR SUBCUTANEOUS INJECTION
Total Volume 5 mL Multi-Dose Vial
Total Volume 5 mL
Multi-Dose Vial
Please open here
Please open here
Sandostatin®
octreotide acetate INJECTION
Each mL of aqueous solution contains:
octreotide (as acetate) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1,000 mcg
Inactive ingredients:
lactic acid, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 mg
mannitol, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 mg
phenol, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.0 mg
sodium bicarbonate, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .qs to pH 4.2 ± 0.3
water for injection, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . qs to 1 mL
DOSAGE: See package insert for dosage information.
STORAGE: Refrigerate at 2°C to 8°C (36°F to 46°F); protect from light.
After initial use, discard within 14 days. At room temperature, (20°C to 30°C or
70°F to 86°F), Sandostatin is stable for 14 days if protected from light.
Manufactured by: Novartis Pharma Stein AG
Schaffhauserstrasse, CH-4332 Stein, Switzerland
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
©Novartis
octreotide acetate
INJECTION
octreotide acetate
INJECTION
5,000 mcg/5 mL (1,000 mcg/mL)
FOR SUBCUTANEOUS INJECTION
5,000 mcg/5 mL (1,000 mcg/mL)
FOR SUBCUTANEOUS INJECTION
Total Volume 5 mL
Multi-Dose Vial
octreotide acetate
INJECTION
Rx only
NDC 0078-0184-25
NDC 0078-0184-25
NDC 0078-0184-25
NDC 0078-0184-25
1256743
1256743
1256743
EXP.
LOT
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
XXXX
For Subcutaneous Injection
10 x 1 mL Single-Dose Vials
NDC 0781-3166-95
OCTREOTIDE Acetate Injection
50 mcg/mL
NDC 0781-3166-95
OCTREOTIDE Acetate Injection
50 mcg/mL
For Subcutaneous Injection
10 x 1 mL Single-Dose Vials
Each mL of aqueous solution contains:
Octreotide (as acetate)................... 50 mcg
Inactive ingredients:
Lactic Acid, USP ............................. 3.4 mg
Mannitol, USP .................................. 45 mg
Sodium Bicarbonate,
USP ...........................qs to pH 4.2 ± 0.3
Water for Injection, USP.............qs to 1 mL
Dosage: See package insert for dosage
information.
Store refrigerated between 2ºC to 8ºC
(36ºF to 46ºF). Protect from light.
At room temperature, (20ºC to 30ºC or
70ºF to 86ºF), Octreotide Acetate is stable
for 14 days if protected from light.
KEEP THIS AND ALL DRUGS OUT OF
THE REACH OF CHILDREN.
01-2015M
Manufactured in Canada by
Sandoz Canada Inc. for
Sandoz Inc., Princeton, NJ 08540
NDC 0781-3166-95
OCTREOTIDE
Acetate Injection
50 mcg/mL
XXXXXXX
10 x 1 mL Single-Dose Vials
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
XXXX
For Subcutaneous Injection
10 x 1 mL Single-Dose Vials
NDC 0781-3167-95
OCTREOTIDE Acetate Injection
100 mcg/mL
NDC 0781-3167-95
OCTREOTIDE Acetate Injection
100 mcg/mL
For Subcutaneous Injection
10 x 1 mL Single-Dose Vials
Each mL of aqueous solution contains:
Octreotide (as acetate)................. 100 mcg
Inactive ingredients:
Lactic Acid, USP ............................. 3.4 mg
Mannitol, USP .................................. 45 mg
Sodium Bicarbonate,
USP............................qs to pH 4.2 ± 0.3
Water for Injection, USP.............qs to 1 mL
Dosage: See package insert for dosage
information.
Store refrigerated between 2ºC to 8ºC (36ºF
to 46ºF). Protect from light.
At room temperature, (20ºC to 30ºC or
70ºF to 86ºF), Octreotide Acetate is stable
for 14 days if protected from light.
KEEP THIS AND ALL DRUGS OUT OF THE
REACH OF CHILDREN.
01-2015M
Manufactured in Canada by
Sandoz Canada Inc. for
Sandoz Inc., Princeton, NJ 08540
NDC 0781-3167-95
OCTREOTIDE
Acetate Injection
100 mcg/mL
XXXXXXX
10 x 1 mL Single-Dose Vials
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
XXXX
XXXXXXX
For Subcutaneous Injection
10 x 1 mL Single-Dose Vials
NDC 0781-3168-95
OCTREOTIDE Acetate Injection
500 mcg/mL
NDC 0781-3168-95
OCTREOTIDE Acetate Injection
500 mcg/mL
For Subcutaneous Injection
10 x 1 mL Single-Dose Vials
Each mL of aqueous solution contains:
Octreotide (as acetate)................. 500 mcg
Inactive ingredients:
Lactic Acid, USP ............................. 3.4 mg
Mannitol, USP .................................. 45 mg
Sodium Bicarbonate,
USP............................qs to pH 4.2 ± 0.3
Water for Injection, USP.............qs to 1 mL
Dosage: See package insert for dosage
information.
Store refrigerated between 2ºC to 8ºC (36ºF
to 46ºF). Protect from light.
At room temperature, (20ºC to 30ºC or
70ºF to 86ºF), Octreotide Acetate is stable
for 14 days if protected from light.
KEEP THIS AND ALL DRUGS OUT OF THE
REACH OF CHILDREN.
01-2015M
Manufactured in Canada by
Sandoz Canada Inc. for
Sandoz Inc., Princeton, NJ 08540
10 x 1 mL Single-Dose Vials
NDC 0781-3168-95
OCTREOTIDE
Acetate Injection
500 mcg/mL
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lot:
Exp.:
RSS 10307813165757
NDC 0781-3165-75
OCTREOTIDE
Acetate Injection
For Subcutaneous Injection
1,000 mcg/5 mL
(200 mcg/mL)
Each mL of aqueous solution
contains: Octreotide (as
acetate) 200 mcg
Storage: Refrigerate at 2°C
to 8°C (36°F to 46°F); protect
from light. After initial use,
discard within 14 days.
01-2015M
Manufactured in Canada by
Sandoz Canada Inc. for
Sandoz Inc.
Princeton, NJ 08540
XXXXX
Total Volume 5 mL
Multi-Dose Vial
abel may not be the latest approved by
g information, please visit https://www.
XXXXXXX
Storage: Refrigerate at
2ºC to 8ºC (36ºF to 46ºF);
protect from light. After
initial use, discard within
14 days.
At room temperature,
(20ºC to 30ºC or 70ºF to
86ºF), Octreotide Acetate
is stable for 14 days if
protected from light.
KEEP THIS AND ALL
DRUGS OUT OF THE
REACH OF CHILDREN.
Each mL of aqueous
solution contains:
Octreotide
(as acetate) .........200 mcg
Inactive Ingredients:
Lactic Acid, USP ....... 3.4 mg
Mannitol, USP............ 45 mg
Phenol, USP ..............5.0 mg
Sodium Bicarbonate,
USP ......qs to pH 4.2 ± 0.3
Water for Injection,
USP ..................qs to 1 mL
DOSAGE: See package
insert for dosage
information.
Manufactured in Canada by
Sandoz Canada Inc. for
Sandoz Inc.
Princeton, NJ 08540
01-2015M
NDC 0781-3165-75
OCTREOTIDE
Acetate
Injection
For
Subcutaneous
Injection
1,000 mcg/5 mL
(200 mcg/mL)
NDC 0781-3165-75
OCTREOTIDE
Acetate Injection
1,000 mcg/5 mL
(200 mcg/mL)
Total Volume
5 mL Multi-
Dose Vial
For
Subcutaneous
Injection
Total Volume 5 mL
Multi-Dose Vial
(b) (4)
(b) (4)
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Lot:
Exp.:
RSS 10307813164750
NDC 0781-3164-75
OCTREOTIDE
Acetate Injection
For Subcutaneous Injection
5,000 mcg/5mL
(1,000 mcg/mL)
Each mL of aqueous solution
contains: Octreotide (as
acetate) 1,000 mcg
Storage: Refrigerate at 2°C
to 8°C (36°F to 46°F); protect
from light. After initial use,
discard within 14 days.
01-2015M
Manufactured in Canada by
Sandoz Canada Inc. for
Sandoz Inc.
Princeton, NJ 08540
XXXXX
Total Volume 5 mL
Multi-Dose Vial
abel may not be the latest approved by
g information, please visit https://www
XXXXXXX
Storage: Refrigerate at
2ºC to 8ºC (36ºF to 46ºF);
protect from light. After
initial use, discard within
14 days.
At room temperature,
(20ºC to 30ºC or 70ºF to
86ºF), Octreotide Acetate
is stable for 14 days if
protected from light.
KEEP THIS AND ALL
DRUGS OUT OF THE
REACH OF CHILDREN.
Each mL of aqueous
solution contains:
Octreotide
(as acetate) ......1,000 mcg
Inactive Ingredients:
Lactic Acid, USP ....... 3.4 mg
Mannitol, USP............ 45 mg
Phenol, USP ..............5.0 mg
Sodium Bicarbonate,
USP ......qs to pH 4.2 ± 0.3
Water for Injection,
USP ..................qs to 1 mL
DOSAGE: See package
insert for dosage
information.
Manufactured in Canada by
Sandoz Canada Inc. for
Sandoz Inc.
Princeton, NJ 08540
01-2015M
NDC 0781-3164-75
OCTREOTIDE
Acetate Injection
5,000 mcg/5 mL
(1,000 mcg/mL)
Total Volume
5 mL Multi-
Dose Vial
For
Subcutaneous
Injection
NDC 0781-3164-75
OCTREOTIDE
Acetate
Injection
For
Subcutaneous
Injection
5,000 mcg/5 mL
(1,000 mcg/mL)
Total Volume 5 mL
Multi-Dose Vial
(b) (4)
(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
|
2025-02-12T13:45:40.334414
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019667Orig1s062lbl.pdf', 'application_number': 19667, 'submission_type': 'SUPPL ', 'submission_number': 62}
|
11,615
|
PATIENT INFORMATION ABOUT CARDURA®
Generic Name:
doxazosin mesylate
FOR BENIGN PROSTATIC HYPERPLASIA (BPH)
Read this leaflet:
• before you start taking CARDURA®
• each time you get a new prescription.
You and your doctor should discuss this treatment and your BPH symptoms before you start
taking CARDURA and at your regular checkups. This leaflet does NOT take the place of
discussions with your doctor.
CARDURA is used to treat both benign prostatic hyperplasia (BPH) and high blood pressure
(hypertension). This leaflet describes CARDURA as treatment for BPH (although you may be
taking CARDURA for both your BPH and high blood pressure).
What is BPH?
BPH is an enlargement of the prostate gland. This gland surrounds the tube that drains the urine
from the bladder. The symptoms of BPH can be caused by a tensing of the enlarged muscle in
the prostate gland which blocks the passage of urine. This can lead to such symptoms as:
• a weak or start-and-stop stream when urinating
• a feeling that the bladder is not completely emptied after urination
• a delay or difficulty in the beginning of urination
• a need to urinate often during the day and especially at night
• a feeling that you must urinate immediately
1
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Treatment Options for BPH
The four main treatment options for BPH are:
• If you are not bothered by your symptoms, you and your doctor may decide on a program of
“watchful waiting.” It is not an active treatment like taking medication or surgery but
involves having regular checkups to see if your condition is getting worse or causing
problems.
• Treatment with CARDURA or other similar drugs. CARDURA is the medication your
doctor has prescribed for you. See “What CARDURA Does,” below.
• Treatment with the medication class of 5-alpha reductase inhibitors (e.g., Proscar®). It can
cause the prostate to shrink. It may take 6 months or more for the full benefit of finasteride
to be seen.
• Various surgical procedures. Your doctor can describe these procedures to you. The best
procedure for you depends on your BPH symptoms and medical condition.
What CARDURA Does
CARDURA works on a specific type of muscle found in the prostate, causing it to relax. This in
turn decreases the pressure within the prostate, thus improving the flow of urine and your
symptoms.
• CARDURA helps relieve the symptoms of BPH (weak stream, start-and-stop stream, a
feeling that your bladder is not completely empty, delay in beginning of urination, need to
urinate often during the day and especially at night, and feeling that you must urinate
immediately). It does not change the size of the prostate. The prostate may continue to
grow; however, a larger prostate is not necessarily related to more symptoms or to worse
symptoms. CARDURA can decrease your symptoms and improve urinary flow, without
decreasing the size of the prostate.
• If CARDURA is helping you, you should notice an effect within 1 to 2 weeks after you start
your medication. CARDURA has been studied in over 900 patients for up to 2 years and the
drug has been shown to continue to work during long-term treatment. Even though you take
CARDURA and it may help you, CARDURA may not prevent the need for surgery in the
future.
• CARDURA does not affect PSA levels. PSA is the abbreviation for Prostate Specific
Antigen. Your doctor may have done a blood test called PSA. You may want to ask your
doctor more about this if you have had a PSA test done.
2
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Other Important Facts
• You should see an improvement of your symptoms within 1 to 2 weeks. In addition to your
other regular checkups you will need to continue seeing your doctor regularly to check your
progress regarding your BPH and to monitor your blood pressure.
• CARDURA (doxazosin mesylate) is not a treatment for prostate cancer. Your doctor has
prescribed CARDURA for your BPH and not for prostate cancer; however, a man can have
BPH and prostate cancer at the same time. Doctors usually recommend that men be checked
for prostate cancer once a year when they turn 50 (or 40 if a family member has had prostate
cancer). A higher incidence of prostate cancer has been noted in men of African-American
descent. These checks should continue even if you are taking CARDURA.
How To Take CARDURA and What You Should Know
While Taking CARDURA for BPH
CARDURA Can Cause a Sudden Drop in Blood Pressure After the VERY FIRST DOSE.
You may feel dizzy, faint or “light-headed,” especially after you stand up from a lying or sitting
position. This is more likely to occur after you’ve taken the first few doses or if you increase
your dose, but can occur at any time while you are taking the drug. It can also occur if you stop
taking the drug and then restart treatment. If you feel very dizzy, faint or “light-headed” you
should contact your doctor. Your doctor will discuss with you how often you need to visit and
how often your blood pressure should be checked.
Your blood pressure should be checked when you start taking CARDURA even if you do not
have high blood pressure (hypertension). Your doctor will discuss with you the details of how
blood pressure is measured.
Blood Pressure Measurement: Whatever equipment is used, it is usual for your blood pressure to
be measured in the following way: measure your blood pressure after lying quietly on your back
for five minutes. Then, after standing for two minutes measure your blood pressure again. Your
doctor will discuss with you what other times during the day your blood pressure should be
taken, such as two to six hours after a dose, before bedtime or after waking up in the morning.
Note that moderate to high-intensity exercise can, over a period of time, lower your average
blood pressure.
You can take CARDURA either in the morning or at bedtime and it will be equally effective. If
you take CARDURA at bedtime but need to get up from bed to go to the bathroom, get up
slowly and cautiously until you are sure how the medication affects you. It is important to get up
slowly from a chair or bed at any time until you learn how you react to CARDURA. You should
not drive or do any hazardous tasks until you are used to the effects of the medication. If you
begin to feel dizzy, sit or lie down until you feel better.
• You will start with a 1 mg dose of CARDURA once daily. Then the once daily dose will be
increased as your body gets used to the effects of the medication. Follow your doctor’s
instructions about how to take CARDURA. You must take it every day at the dose
3
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
prescribed. Talk with your doctor if you don’t take it for a few days for some reason; you
may then need to restart the medication at a 1 mg dose, increase your dose gradually and
again be cautious about possible dizziness. Do not share CARDURA with anyone else; it
was prescribed only for you.
• Other side effects you could have while taking CARDURA, in addition to lowering of the
blood pressure, include dizziness, fatigue (tiredness), swelling of the feet and shortness of
breath. Most side effects are mild. However, you should discuss any unexpected effects you
notice with your doctor.
• WARNING: Extremely rarely, CARDURA and similar medications have caused painful
erection of the penis, sustained for hours and unrelieved by sexual intercourse or
masturbation. This condition is serious, and if untreated it can be followed by permanent
inability to have an erection. If you have a prolonged abnormal erection, call your doctor or
go to an emergency room as soon as possible.
• Tell your surgeon if you take or have taken CARDURA if you plan to have surgery for
cataracts (clouding of the eye). During cataract surgery, a condition called Intraoperative
Floppy Iris Syndrome (IFIS) can happen if you take or have taken CARDURA.
• If you use CARDURA with an oral erectile dysfunction medicine (phosphodiesterase-5
(PDE-5) inhibitor), it can cause a sudden drop in your blood pressure and you can become
dizzy or faint. Talk with your healthcare provider before using PDE-5 inhibitors.
• Keep CARDURA and all medicines out of the reach of children.
FOR MORE INFORMATION ABOUT CARDURA AND BPH TALK WITH YOUR
DOCTOR, NURSE, PHARMACIST OR OTHER HEALTH CARE PROVIDER. company logo
LAB-0070-3.0
Revised January 2010
4
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:40.352286
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019668s022lbl.pdf', 'application_number': 19668, 'submission_type': 'SUPPL ', 'submission_number': 22}
|
11,610
|
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
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
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
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
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
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
---------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
---------------------------------------------------------------------------------------------------------
/s/
----------------------------------------------------
THERESA M MICHELE
12/18/2015
Reference ID: 3863137
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:40.438700
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019658Orig1s044lbl.pdf', 'application_number': 19658, 'submission_type': 'SUPPL ', 'submission_number': 44}
|
11,617
|
_______________________________________________________________________________________________________________________________________
HIGHLIGHTS OF PRESCRIBING INFORMATION
•
Risk of Intraoperative Floppy Iris Syndrome during cataract surgery.
These highlights do not include all the information needed to use
(5.2)
CARDURA safely and effectively. See full prescribing information for
•
Screen for the presence of prostate cancer prior to treatment for BPH
CARDURA.
and at regular intervals afterwards. (5.3)
CARDURA® (doxazosin mesylate) tablets, for oral use
----------------------------------ADVERSE REACTIONS-----------------------------------
Initial U.S. Approval: 1990
The most commonly reported adverse reactions from clinical trials are
Fatigue, malaise, hypotension, and dizziness. (6.1)
------------------------INDICATIONS AND USAGE-----------------------
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at
CARDURA is an alpha1 adrenergic antagonist indicated for:
1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
• Signs and symptoms of Benign Prostatic Hyperplasia (BPH)
• Treatment of Hypertension
-----------------------------------DRUG INTERACTIONS----------------------------------
•
Strong cytochrome P450 (CYP) 3A inhibitors may increase exposure to
doxazosin and increased risk of hypotension (7.1)
-----------------------DOSAGE AND ADMINISTRATION---------------
•
Concomitant administration of CARDURA with a phosphodiesterase-5
•
For the treatment of BPH: Initiate therapy at 1 mg once daily. Dose
(PDE-5) inhibitor can result in additive blood pressure lowering effects
maybe titrated at 1 to 2 week intervals, up to 8 mg once daily.(2.2)
and symptomatic hypotension. (7.2)
•
For the treatment hypertension: Initiate therapy at 1 mg once daily. Dose
may be titrated as needed, up to 16 mg once daily. (2.3)
-------------------------------USE IN SPECIFIC POPULATIONS----------------------
•
Hepatic Impairment: Monitor for hypotension. (8.6, 12.3)
----------------------------DOSAGE FORMS AND STRENGTHS---------------------
See 17 for PATIENT COUNSELING INFORMATION and
•
Tablets: 1 mg, 2 mg, 4 mg, 8 mg.
FDA-approved patient labeling.
------------------------------------CONTRAINDICATIONS--------------------------------
Revised: [06/2016]
•
Hypersensitivity to doxazosin, other quinazolines, or any other
ingredient in CARDURA. (4)
------------------------------WARNINGS AND PRECAUTIONS----------------
•
Postural hypotension with or without syncope may occur. (5.1)
FULL PRESCRIBING INFORMATION: CONTENTS*
8.2 Lactation
8.4 Pediatric Use
1
INDICATIONS AND USAGE
8.5 Geriatric Use
1.1 Benign Prostatic Hyperplasia (BPH)
8.6 Hepatic Impairment
1.2 Hypertension
10 OVERDOSAGE
2
DOSAGE AND ADMINISTRATION
11
DESCRIPTION
2.1 Dosing Information
12
CLINICAL PHARMACOLOGY
2.2 Benign Prostatic Hyperplasia
12.1 Mechanism of Action
2.3 Hypertension
12.2 Pharmacodynamics
3
DOSAGE FORMS AND STRENGTHS
12.3 Pharmacokinetics
4
CONTRAINDICATIONS
13 NONCLINICAL TOXICOLOGY
5
WARNINGS AND PRECAUTIONS
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
5.1 Postural Hypotension
13.2 Animal Toxicology and Pharmacology
5.2 Cataract Surgery
14 CLINICAL STUDIES
5.3 Prostate Cancer
14.1 Benign Prostatic Hyperplasia (BPH)
5.4 Priapism
14.2 Hypertension
16 HOW SUPPLIED/STORAGE AND HANDLING
6
ADVERSE REACTIONS
17 PATIENT COUNSELING INFORMATION
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7
DRUG INTERACTIONS
7.1 CYP 3A Inhibitors
7.2 Phosphodiesterase-5 (PDE-5) inhibitors
*Sections or subsections omitted from the full prescribing information are not
8
USE IN SPECIFIC POPULATIONS
listed.
8.1 Pregnancy
Reference ID: 3943777
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 Benign Prostatic Hyperplasia (BPH)
CARDURA is indicated for the treatment of the signs and symptoms of BPH.
1.2 Hypertension
CARDURA is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of
fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled
trials of antihypertensive drugs from a wide variety of pharmacologic classes, including this drug.
Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid
control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will
require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published
guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been
shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood
pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The
largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial
infarction and cardiovascular mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at
higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk
reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater
in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and
such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive
drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These
considerations may guide selection of therapy.
CARDURA may be used alone or in combination with other antihypertensives.
2
DOSAGE AND ADMINISTRATION
2.1 Dosing Information
Following the initial dose and with each dose increase of CARDURA, monitor blood pressure for at least 6 hours following
administration. If CARDURA administration is discontinued for several days, therapy should be restarted using the initial dosing
regimen.
2.2 Benign Prostatic Hyperplasia
The recommended initial dosage of CARDURA is 1 mg given once daily either in the morning or evening.
Depending on the individual patient’s urodynamics and BPH symptomatology, the dose may be titrated at 1 to 2 week intervals to
2 mg, and thereafter to 4 mg and 8 mg once daily. The maximum recommended dose for BPH is 8 mg once daily.
Routinely monitor blood pressure in these patients.
2.3 Hypertension
The initial dosage of CARDURA is 1 mg given once daily. Daily dosage may be doubled up 16 mg once daily, as needed, to
achieve the desired reduction in blood pressure.
3
DOSAGE FORMS AND STRENGTHS
Tablets (scored): 1 mg (white), 2 mg (yellow), 4 mg (orange) or 8 mg (green).
Reference ID: 3943777
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
4
CONTRAINDICATIONS
The use of CARDURA is contraindicated in patients with a hypersensitivity to doxazosin, other quinazolines (e.g., prazosin,
terazosin), or any of its components.
5
WARNINGS AND PRECAUTIONS
5.1 Postural Hypotension
Postural hypotension with or without symptoms (e.g., dizziness) may develop within a few hours following administration of
CARDURA. However, infrequently, symptomatic postural hypotension has also been reported later than a few hours after dosing.
As with other alpha-blockers, there is a potential for syncope, especially after the initial dose or after an increase in dosage
strength. Advise patient how to avoid symptoms resulting from postural hypotension and what measures to take should they
develop.
Concomitant administration of CARDURA with a PDE-5 inhibitor can result in additive blood pressure lowering effects and
symptomatic hypotension.
5.2 Cataract Surgery
Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients on or previously treated
with alpha1 blockers. This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in
response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard
mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient’s surgeon should be
prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or
viscoelastic substances. There does not appear to be a benefit of stopping alpha1 blocker therapy prior to cataract surgery.
5.3 Prostate Cancer
Carcinoma of the prostate causes many of the symptoms associated with BPH and the two disorders frequently co-exist.
Carcinoma of the prostate should therefore be ruled out prior to commencing therapy with CARDURA for the treatment of BPH.
5.4 Priapism
Alpha1 antagonists, including doxazosin, have been associated with priapism (painful penile erection, sustained for hours and
unrelieved by sexual intercourse or masturbation). This condition can lead to permanent impotence if not promptly treated.
6
ADVERSE REACTIONS
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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Benign Prostatic Hyperplasia (BPH)
The incidence of adverse events has been ascertained from worldwide clinical trials in 965 BPH patients. The incidence rates
presented below (Table 2) are based on combined data from seven placebo-controlled trials involving once-daily administration
of CARDURA in doses of 1 to 16 mg in hypertensives and 0.5 to 8 mg in normotensives. Adverse reactions occurring more than
1% more frequently in BPH patients treated with CARDURA vs placebo are summarized in Table 1.
Reference ID: 3943777
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Table 1.
Adverse Reactions Occurring more than 1% More Frequently in BPH
Patients Treated with Cardura Versus Placebo
Cardura
Placebo
BODY SYSTEM
N=665
N=300
NERVOUS SYSTEM DISORDERS
Dizziness†
15.6%
9.0%
Somnolence
3.0%
1.0%
CARDIAC DISORDERS
Hypotension
1.7%
0%
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
Dyspnoea
2.6%
0.3%
GASTROINTESTINAL DISORDERS
Dry Mouth
1.4%
0.3%
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Fatigue
8.0%
1.7%
Oedema
2.7%
0.7%
†Includes vertigo
Other adverse reactions occurring less than 1% more frequently in BPH patients treated with CARDURA vs placebo but plausibly
related to CARDURA include: palpitations.
Hypertension
CARDURA has been administered to approximately 4000 hypertensive patients in clinical trials, of whom 1679 were included in
the hypertension clinical development program. In placebo-controlled studies, adverse events occurred in 49% and 40% of
patients in the doxazosin and placebo groups, respectively, and led to discontinuation in 2% of patients in each group.
Adverse reactions occurring more than 1% more frequently in hypertensive patients treated with CARDURA vs placebo are
summarized in Table 1. . Postural effects and edema appeared to be dose-related. The prevalence rates presented below are based
on combined data from placebo-controlled studies involving once-daily administration of doxazosin at doses ranging from 1 to
16 mg.
Table 2.
Adverse Reactions Occurring more than 1% More Frequently in
Hypertensive Patients Treated with Cardura versus Placebo
Cardura
Placebo
BODY SYSTEM
N=339
N=336
NERVOUS SYSTEM DISORDERS
Dizziness
19%
9%
Somnolence
5%
1%
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
Rhinitis
3%
1%
RENAL AND URINARY DISORDERS
Polyuria
2%
0%
REPRODUCTIVE SYSTEM AND BREAST DISORDERS
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Fatigue / Malaise
12%
6%
Other adverse reactions occurring less than 1% more frequently in hypertensive patients treated with CARDURA vs placebo but
plausibly related to CARDURA use include vertigo, hypotension, hot flushes, epistaxis and oedema.
CARDURA has been associated with decreases in white blood cell counts
Laboratory changes observed in clinical studies
Leukopenia/Neutropenia: Decreases in mean white blood cell (WBC) and mean neutrophil count were observed in controlled
clinical trials of hypertensive patients receiving CARDURA. In cases where follow-up was available, WBC and neutrophil
Reference ID: 3943777
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
counts returned to normal after discontinuation of CARDURA. No patients became symptomatic as a result of the low WBC or
neutrophil counts.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of CARDURA. 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.
In post-marketing experience, the following additional adverse reactions have been reported:
Blood and Lymphatic System Disorders: leukopenia, thrombocytopenia;
Immune System Disorders: allergic reaction;
Nervous System Disorders: hypoesthesia;
Eye Disorders: Intraoperative Floppy Iris Syndrome [see Warnings and precautions (5.4)];
Cardiac Disorders: bradycardia;
Respiratory, Thoracic and Mediastinal Disorders: bronchospasm aggravated;
Gastrointestinal Disorders: vomiting;
Hepatobiliary Disorders: cholestasis, hepatitis cholestatic;
Skin and Subcutaneous Tissue Disorders: urticaria;
Musculoskeletal and Connective Tissue Disorders: muscle cramps, muscle weakness;
Renal and Urinary Disorders: hematuria, micturition disorder, micturition frequency, nocturia;
Reproductive System and Breast Disorders: gynecomastia, priapism.
7
DRUG INTERACTIONS
7.1. CYP 3A Inhibitors
In vitro studies suggest that doxazosin is a substrate of CYP 3A4. Strong CYP3A inhibitors may increase exposure to doxazosin.
Monitor blood pressure and for symptoms of hypotension when CARDURA is used concomitantly with strong CYP3A inhibitors
[see Clinical Pharmacology (12.3)].
7.2 Phosphodiesterase-5 (PDE-5) inhibitors
Concomitant administration of CARDURA with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure
lowering effects and symptomatic hypotension. Monitor blood pressure and for symptoms of hypotension [see Warnings and
Precautions (5.1)].
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
The limited available data with CARDURA in pregnant women are not sufficient to inform a drug-associated risk for major birth
defects and miscarriage. However, untreated hypertension during pregnancy can result in increased maternal risks [see Clinical
Considerations]. In animal reproduction studies, no adverse developmental effects were observed when doxazosin was orally
administered to pregnant rabbits and rats during the period of organogenesis at doses of up to 41 and 20 mg/kg, respectively
(exposures in rabbits and rats were 10 and 4 times, respectively, the human AUC exposures with a 12 mg/day therapeutic dose).
A dosage regimen of 82 mg/kg/day in the rabbit was associated with reduced fetal survival [see Data].
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general
population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and
15-20%, respectively.
Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk
Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery
complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine
growth restriction and intrauterine death.
Data
Animal Data
Radioactivity was found to cross the placenta following oral administration of labelled doxazosin to pregnant rats. Studies in
pregnant rabbits and rats at daily oral doses of up to 41 and 20 mg/kg, respectively (plasma drug concentrations of 10 and 4 times,
respectively, the human AUC exposures with a 12 mg/day therapeutic dose), have revealed no evidence of adverse developmental
effects. A dosage regimen of 82 mg/kg/day in the rabbit was associated with reduced fetal survival. In peri- and postnatal studies
in rats, postnatal development at maternal doses of 40 or 50 mg/kg/day of doxazosin (about 8 times human AUC exposure with a
12 mg/day therapeutic dose) was delayed, as evidenced by slower body weight gain and slightly later appearance of anatomical
Reference ID: 3943777
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
features and reflexes.
8.2 Lactation
Risk Summary
There is limited information on the presence of CARDURA in human milk [see Data]. There is no information on the effects of
CARDURA on the breastfeed infant or the effects on milk production.
Data
A single case study reports that CARDURA is present in human milk, which resulted in an infant dose of less than 1% of the
maternal weight-adjusted dosage and a milk/plasma ratio of 0.1. However, these data are insufficient to confirm the presence of
CARDURA in human milk.
8.4 Pediatric Use
The safety and effectiveness of CARDURA have not been established in children.
8.5 Geriatric Use
Benign Prostatic Hyperplasia (BPH)
The safety and effectiveness profile of CARDURA was similar in the elderly (age ≥ 65 years) and younger (age < 65 years)
patients.
Hypertension
Clinical studies of CARDURA 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.
8.6 Hepatic Impairment
CARDURA is extensively metabolized in the liver. Hepatic impairment is expected to increase exposure to doxazosin. Use of
CARDURA in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended. Monitor blood pressure and
for symptoms of hypotension in patients with lesser degrees of hepatic impairment (Child-Pugh Class A and B) [see Clinical
Pharmacology (12.3)].
10 OVERDOSAGE
Experience with CARDURA overdosage is limited. Two adolescents, who each intentionally ingested 40 mg CARDURA with
diclofenac or acetaminophen, were treated with gastric lavage with activated charcoal and made full recoveries. A two-year-old
child who accidently ingested 4 mg CARDURA was treated with gastric lavage and remained normotensive during the five-hour
emergency room observation period. A six-month-old child accidentally received a crushed 1 mg tablet of CARDURA and was
reported to have been drowsy. A 32-year-old female with chronic renal failure, epilepsy, and depression intentionally ingested
60 mg CARDURA (blood level = 0.9 mcg/mL; normal values in hypertensives = 0.02 mcg/mL); death was attributed to a grand
mal seizure resulting from hypotension. A 39-year-old female who ingested 70 mg CARDURA, alcohol, and Dalmane®
(flurazepam) developed hypotension which responded to fluid therapy.
The oral LD50 of doxazosin is greater than 1000 mg/kg in mice and rats. The most likely manifestation of overdosage would be
hypotension, for which the usual treatment would be intravenous infusion of fluid. As doxazosin is highly protein bound, dialysis
would not be indicated.
Reference ID: 3943777
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
11 DESCRIPTION
CARDURA® (doxazosin mesylate) is a quinazoline compound that is a selective inhibitor of the alpha1 subtype of alpha
adrenergic receptors. The chemical name of doxazosin mesylate is 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4
benzodioxan-2-ylcarbonyl) piperazine methanesulfonate. The empirical formula for doxazosin mesylate is C23H25N5O5 • CH4O3S
and the molecular weight is 547.6. It has the following structure:
st
ru
ct
ur
al
f
ormul
a
CARDURA (doxazosin mesylate) is freely soluble in dimethylsulfoxide, soluble in dimethylformamide, slightly soluble in
methanol, ethanol, and water (0.8% at 25°C), and very slightly soluble in acetone and methylene chloride. CARDURA is
available as colored tablets for oral use and contains 1 mg (white), 2 mg (yellow), 4 mg (orange) and 8 mg (green) of doxazosin
as the free base.
The inactive ingredients for all tablets are: microcrystalline cellulose, lactose, sodium starch glycolate, magnesium stearate and
sodium lauryl sulfate. The 2 mg tablet contains D & C yellow 10 and FD & C yellow 6; the 4 mg tablet contains FD & C yellow
6; the 8 mg tablet contains FD & C blue 2 and D & C yellow 10.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Benign Prostatic Hyperplasia (BPH)
The symptoms associated with benign prostatic hyperplasia (BPH), such as urinary frequency, nocturia, weak stream, hesitancy,
and incomplete emptying are related to two components, anatomical (static) and functional (dynamic). The static component is
related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma. However,
the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate. The
dynamic component of BPH is associated with an increase in smooth muscle tone in the prostate and bladder neck. The degree of
tone in this area is mediated by the alpha1 adrenoceptor, which is present in high density in the prostatic stroma, prostatic capsule
and bladder neck. Blockade of the alpha1 receptor decreases urethral resistance and may relieve the obstruction and BPH
symptoms and improve urine flow.
Hypertension
The mechanism of action of CARDURA is selective blockade of the alpha1 (postjunctional) subtype of adrenergic receptors.
Studies in normal human subjects have shown that doxazosin competitively antagonized the pressor effects of phenylephrine (an
alpha1 agonist) and the systolic pressor effect of norepinephrine. Doxazosin and prazosin have similar abilities to antagonize
phenylephrine. The antihypertensive effect of CARDURA results from a decrease in systemic vascular resistance. The parent
compound doxazosin is primarily responsible for the antihypertensive activity. The low plasma concentrations of known active
and inactive metabolites of doxazosin (2-piperazinyl, 6'- and 7'-hydroxy and 6- and 7-O-desmethyl compounds) compared to
parent drug indicate that the contribution of even the most potent compound (6'-hydroxy) to the antihypertensive effect of
doxazosin in man is probably small. The 6'- and 7'-hydroxy metabolites have demonstrated antioxidant properties at
concentrations of 5 µM, in vitro.
12.2 Pharmacodynamics
Benign Prostatic Hyperplasia (BPH)
Administration of CARDURA to patients with symptomatic BPH resulted in a statistically significant improvement in maximum
urinary flow rate [see Clinical Studies (14.1)].
Reference ID: 3943777
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Effect on Normotensive Patients with Benign Prostatic Hyperplasia (BPH)
Although blockade of alpha1 adrenoceptors also lowers blood pressure in hypertensive patients with increased peripheral vascular
resistance, CARDURA treatment of normotensive men with BPH did not result in a clinically significant blood pressure lowering
effect (Table 4). The proportion of normotensive patients with a sitting systolic blood pressure less than 90 mmHg and/or
diastolic blood pressure less than 60 mmHg at any time during treatment with CARDURA 1–8 mg once daily was 6.7% with
doxazosin and not significantly different (statistically) from that with placebo (5%).
Hypertension
Administration of CARDURA results in a reduction in systemic vascular resistance. In patients with hypertension, there is little
change in cardiac output. Maximum reductions in blood pressure usually occur 2–6 hours after dosing and are associated with a
small increase in standing heart rate. Like other alpha1-adrenergic blocking agents, doxazosin has a greater effect on blood
pressure and heart rate in the standing position.
12.3 Pharmacokinetics
Absorption
After oral administration of therapeutic doses, peak plasma levels of CARDURA occur at about 2–3 hours. Bioavailability is
approximately 65%, reflecting first-pass metabolism of doxazosin by the liver. The effect of food on the pharmacokinetics of
CARDURA was examined in a crossover study with twelve hypertensive subjects. Reductions of 18% in mean maximum plasma
concentration (Cmax) and 12% in the area under the concentration-time curve (AUC) occurred when CARDURA was administered
with food. Neither of these differences is clinically significant.
In a crossover study in 24 normotensive subjects, the pharmacokinetics and safety of doxazosin were shown to be similar with
morning and evening dosing regimens. The AUC after morning dosing was, however, 11% less than that after evening dosing and
the time to peak concentration after evening dosing occurred significantly later than that after morning dosing (5.6 vs. 3.5 hours).
Distribution
At the plasma concentrations achieved by therapeutic doses, approximately 98% of the circulating drug is bound to plasma
proteins.
Metabolism
CARDURA is extensively metabolized in the liver, mainly by O-demethylation of the quinazoline nucleus or hydroxylation of the
benzodioxan moiety. In vitro studies suggest that the primary pathway for elimination is via CYP 3A4; however, CYP 2D6 and
CYP 2C9 metabolic pathways are also involved to a lesser extent. Although several active metabolites of doxazosin have been
identified, the pharmacokinetics of these metabolites have not been characterized.
Excretion
Plasma elimination of doxazosin is biphasic, with a terminal elimination half-life of about 22 hours. Steady-state studies in
hypertensive patients given doxazosin doses of 2 to 16 mg once daily showed linear kinetics and dose proportionality. In two
studies, following the administration of 2 mg orally once daily, the mean accumulation ratios (steady-state AUC vs. first-dose
AUC) were 1.2 and 1.7. Enterohepatic recycling is suggested by secondary peaking of plasma doxazosin concentrations.
In a study of two subjects administered radiolabelled doxazosin 2 mg orally and 1 mg intravenously on two separate occasions,
approximately 63% of the dose was eliminated in the feces and 9% of the dose was found in the urine. On average only 4.8% of
the dose was excreted as unchanged drug in the feces and only a trace of the total radioactivity in the urine was attributed to
unchanged drug.
Specific Populations
Geriatric
The pharmacokinetics of CARDURA in young (<65 years) and elderly (≥65 years) subjects were similar for plasma half-life
values and oral clearance.
Renal Impairment
Pharmacokinetic studies in elderly patients and patients with renal impairment have shown no significant alterations compared to
younger patients with normal renal function.
Hepatic Impairment
Administration of a single 2 mg dose to patients with cirrhosis (Child-Pugh Class A) showed a 40% increase in exposure to
doxazosin. The impact of moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment on the
pharmacokinetics of doxazosin is not known [see Use in Specific Populations (8.6)].
Drug Interactions
There are only limited data on the effects of drugs known to influence the hepatic metabolism of doxazosin (e.g., cimetidine).
Reference ID: 3943777
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Cimetidine: In healthy volunteers, the administration of a single 1 mg dose of doxazosin on day 1 of a four-day regimen of oral
cimetidine (400 mg twice daily) resulted in a 10% increase in mean AUC of doxazosin, and a slight but not significant increase in
mean Cmax and mean half-life of doxazosin.
In vitro data in human plasma indicate that CARDURA has no effect on protein binding of digoxin, warfarin, phenytoin, or
indomethacin.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis and Mutagenesis: Chronic dietary administration (up to 24 months) of doxazosin mesylate at maximally tolerated
doses of 40 mg/kg/day in rats and 120 mg/kg/day in mice revealed no evidence of carcinogenic potential. The highest doses
evaluated in the rat and mouse studies are associated with AUCs (a measure of systemic exposure) that are 8 times and 4 times,
respectively, the human AUC at a dose of 16 mg/day.
Mutagenicity studies revealed no drug- or metabolite-related effects at either chromosomal or subchromosomal levels.
Fertility in Males: Studies in rats showed reduced fertility in males treated with doxazosin at oral doses of 20 (but not 5 or 10)
mg/kg/day, about 4 times the AUC exposures obtained with a 12 mg/day human dose. This effect was reversible within two
weeks of drug withdrawal. There have been no reports of any effects of doxazosin on male fertility in humans.
13.2 Animal Toxicology and Pharmacology
An increased incidence of myocardial necrosis or fibrosis was observed in long-term (6-12 months) studies in rats and mice
(exposure 8 times human AUC exposure in rats and somewhat equivalent to human Cmax exposure in mice). Findings were not
seen at lower doses. In dogs no cardiotoxicity was observed following 12 months of oral dosing at doses that resulted in
maximum plasma concentrations (Cmax) 14 times the Cmax exposure in humans receiving a 12 mg/day therapeutic dose or in Wistar
rats at Cmax exposures 15 times human Cmax exposure. There is no evidence that similar lesions occur in humans.
14 CLINICAL STUDIES
14.1 Benign Prostatic Hyperplasia (BPH)
The efficacy of CARDURA was evaluated extensively in over 900 patients with BPH in double-blind, placebo-controlled trials.
CARDURA treatment was superior to placebo in improving patient symptoms and urinary flow rate. Significant relief with
CARDURA was seen as early as one week into the treatment regimen, with CARDURA-treated patients (N=173) showing a
significant (p<0.01) increase in maximum flow rate of 0.8 mL/sec compared to a decrease of 0.5 mL/sec in the placebo group
(N=41). In long-term studies, improvement was maintained for up to 2 years of treatment. In 66–71% of patients, improvements
above baseline were seen in both symptoms and maximum urinary flow rate.
In three placebo-controlled studies of 14–16 weeks’ duration, obstructive symptoms (hesitation, intermittency, dribbling, weak
urinary stream, incomplete emptying of the bladder) and irritative symptoms (nocturia, daytime frequency, urgency, burning) of
BPH were evaluated at each visit by patient-assessed symptom questionnaires. The bothersomeness of symptoms was measured
with a modified Boyarsky questionnaire. Symptom severity/frequency was assessed using a modified Boyarsky questionnaire or
an AUA-based questionnaire. Uroflowmetric evaluations were performed at times of peak (2–6 hours post-dose) and/or trough
(24 hours post-dose) plasma concentrations of CARDURA.
Reference ID: 3943777
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
The results from the three placebo-controlled studies (N=609) showing significant efficacy with 4 mg and 8 mg doxazosin are
summarized in Table 3. In all three studies, CARDURA resulted in statistically significant relief of obstructive and irritative
symptoms compared to placebo. Statistically significant improvements of 2.3–3.3 mL/sec in maximum flow rate were seen with
CARDURA in Studies 1 and 2, compared to 0.1–0.7 mL/sec with placebo.
Table 3 graph
In one fixed-dose study (Study 2), CARDURA therapy (4 to 8 mg, once daily) resulted in a significant and sustained improvement
in maximum urinary flow rate of 2.3–3.3 mL/sec (Table 3) compared to placebo (0.1 mL/sec). In this study, the only study in
which weekly evaluations were made, significant improvement with CARDURA vs. placebo was seen after one week. The
proportion of patients who responded with a maximum flow rate improvement of ≥3 mL/sec was significantly larger with
CARDURA (34–42%) than placebo (13–17%). A significantly greater improvement was also seen in average flow rate with
CARDURA (1.6 mL/sec) than with placebo (0.2 mL/sec). The onset and time course of symptom relief and increased urinary
flow from Study 1 are illustrated in Figure 1.
Reference ID: 3943777
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Figure 1 – Study 1 graph
14.2 Hypertension
In a pooled analysis of placebo-controlled hypertension studies with about 300 hypertensive patients per treatment group,
doxazosin, at doses of 1 to 16 mg given once daily, lowered blood pressure at 24 hours by about 10/8 mmHg compared to placebo
in the standing position and about 9/5 mmHg in the supine position. Peak blood pressure effects (1–6 hours) were larger by about
50–75% (i.e., trough values were about 55–70% of peak effect), with the larger peak-trough differences seen in systolic pressures.
There was no apparent difference in the blood pressure response of Caucasians and blacks or of patients above and below age 65.
In the same patient population, patients receiving CARDURA gained a mean of 0.6 kg compared to a mean loss of 0.1 kg for
placebo patients.
TABLE 4
Mean Changes in Blood Pressure from Baseline to the Mean of the Final Efficacy Phase in Normotensives (Diastolic BP <90
mmHg) in Two Double-blind, Placebo-controlled U.S. Studies with CARDURA 1 to 8 mg once daily.
PLACEBO (N=85)
CARDURA (N=183)
Sitting BP (mmHg)
Baseline
Change
Baseline
Change
Systolic
128.4
–1.4
128.8
–4.9*
Diastolic
79.2
–1.2
79.6
–2.4*
Standing BP (mmHg)
Baseline
Change
Baseline
Change
Systolic
128.5
–0.6
128.5
–5.3*
Diastolic
80.5
–0.7
80.4
–2.6*
*p ≤0.05 compared to placebo
16 HOW SUPPLIED/STORAGE AND HANDLING
CARDURA (doxazosin mesylate) is available as scored tablets for oral administration. Each tablet contains doxazosin mesylate
equivalent to 1 mg (white), 2 mg (yellow), 4 mg (orange) or 8 mg (green) of the active constituent, doxazosin.
Bottle of 100:
1 mg
NDC 0049-2750-66
2 mg
NDC 0049-2760-66
4 mg
NDC 0049-2770-66
8 mg
NDC 0049-2780-66
Unit Dose Package of 100:
1 mg
NDC 0049-2750-41
2 mg
NDC 0049-2760-41
4 mg
NDC 0049-2770-41
8 mg
NDC 0049-2780-41
Recommended Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room
Temperature].
Reference ID: 3943777
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Postural Hypotension
Advise patients of the possibility of syncopal and orthostatic symptoms, especially at the initiation of therapy, and urged to avoid
driving or hazardous tasks for 24 hours after the first dose, after a dosage increase, and after interruption of therapy when treatment
is resumed. Advise patients to report symptoms to their healthcare provider.
Priapism
Advise patients of the possibility of priapism and to seek immediate medical attention if symptoms occur.
This product’s label may have been updated. For full prescribing information, please visit www.pfizer.com. company logo
LAB-0071-6.x
Reference ID: 3943777
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
PATIENT INFORMATION
CARDURA®(kar-DUR-a)
(doxazosin mesylate tablets)
What is CARDURA?
CARDURA is a prescription medicine that contains doxazosin mesylate and is called an “alpha-blocker”. CARDURA is
used to treat:
• the symptoms of benign prostatic hyperplasia (BPH)
• high blood pressure (hypertension)
It is not known if CARDURA is safe and effective in children.
Who should not take CARDURA?
Do not take CARDURA if you:
• are allergic to doxazosin, other quinazolines, or any of the ingredients in CARDURA. See the end of this Patient
Information leaflet for a complete list of ingredients in CARDURA.
What should I tell my healthcare provider before taking CARDURA?
Before taking CARDURA, tell your healthcare provider about all of your medical conditions, including if you:
• have had low blood pressure, especially after taking other medicine. Signs of low blood pressure include fainting,
dizziness, and lightheadedness.
• have any planned eye surgery
• have prostate cancer or a history of prostate cancer. Your healthcare provider may have you checked for prostate
cancer before you start taking and while you take CARDURA.
• have liver problems
• are pregnant or plan to become pregnant. It is not known if CARDURA will harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if CARDURA passes into your breastmilk. Talk to your
healthcare provider about the best way to feed your baby if you take CARDURA.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines,
vitamins, and herbal supplements. CARDURA may affect the way other medicines work, and other medicines may affect
the way CARDURA works causing side effects.
Especially tell your healthcare provider if you take:
• other medicine for high blood pressuremedicine to treat erectile dysfunction (ED) called a phosphodiesterase type 5
(PDE-5) inhibitor. The use of CARDURA with PDE-5 inhibitors can lead to a drop in blood pressure or to fainting.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new
medicine.
How should I take CARDURA?
• Take CARDURA exactly as your healthcare provider tells you to take it.
• Your healthcare provider will tell you how much CARDURA to take and when to take it.
• Your healthcare provider may need to change your dose of CARDURA until it is the right dose for you.
What should I avoid while taking CARDURA?
Do not drive or perform any hazardous task until at least 24 hours after you have taken CARDURA if you are taking:
• your first dose of CARDURA
• CARDURA for the first time after your healthcare provider has increased your dose of CARDURA
• CARDURA for the first time after any breaks (interruptions) in your treatment with CARDURA
What are the possible side effects of CARDURA?
CARDURA may cause serious side effects, including:
• A sudden drop in blood pressure, especially when you first start treatment or when there is an increase in your dose
of CARDURA, is common but can also be serious. This may cause you to faint, or to feel dizzy or lightheaded. Your
risk of having this problem may be increased if you take CARDURA with certain other medicines that lower blood
pressure including PDE-5 inhibitors. Your healthcare provider may monitor your blood pressure while you take
CARDURA. See “W hat should I avoid while taking CARDURA?”
• Eye problems during cataract surgery. A condition called Intraoperative Floppy Iris Syndrome (IFIS) can happen
during cataract surgery if you take or have taken alpha-blockers such as CARDURA. If you need to have cataract
surgery, be sure to tell your healthcare provider if you take or have taken CARDURA.
• A painful erection that will not go away. CARDURA can cause a painful erection (priapism), which cannot be
relieved by having sex. If this happens, get medical help right away. If priapism is not treated, you may not be able to
get an erection in the future.
The most common side effects of CARDURA are:
• weakness or lack of energy (asthenia)
•
dizziness
Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the
possible side effects of CARDURA. 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.
General information about the safe and effective use of CARDURA.
Reference ID: 3943777
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use
CARDURA for a condition for which it was not prescribed. Do not give CARDURA to other people, even if they have the
same symptoms you have. It may harm them.
This Patient Information leaflet summarizes the most important information about CARDURA. For more information, ask
your healthcare provider. You can ask your healthcare provider or pharmacist for information that is written for healthcare
professionals.
What are the ingredients in CARDURA?
Active ingredient: doxazosin mesylate
Inactive ingredients: microcrystalline cellulose, lactose, sodium starch glycolate, magnesium stearate and sodium lauryl
sulfate.
Any trademark information should appear here
For more information, go to www.Pfizer.com or call 1-800-438-1985.
This Patient Information has been approved by the U.S. Food and Drug Administration
Revised: 06/2016
Reference ID: 3943777
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:40.788627
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019668s028lbl.pdf', 'application_number': 19668, 'submission_type': 'SUPPL ', 'submission_number': 28}
|
11,618
|
© 2002 Distributed by Schering-Plough HealthCare Products, Inc.
Memphis, TN 38151 USA. All rights reserved. XXXXX-XX
10 EXTENDED RELEASE TABLETS
0
8
41100 80208
The graphics on the front panel of this carton constitute
trademarks of Schering Corporation.
00000000
00000000
Pseudoephedrine Sulfate 120 mg/Nasal Decongestant
NDC 11523-7162-1
Actual Size
EXTENDED
RELEASE TABLETS
10
EXTENDED
RELEASE TABLETS
10
*When taken as directed.
See Drug Facts Panel.
*When taken as directed.
See Drug Facts Panel.
Loratadine 5 mg/Antihistamine
™
EXTENDED
RELEASE TABLETS
10
Non-Drowsy*
Allergy & Congestion
Relief of:
Nasal and Sinus Congestion
Due to Colds or Allergies;
Sneezing; Runny Nose; Itchy, Watery Eyes
Itchy Throat or Nose Due to Allergies
Drug Facts
Active ingredients (in each tablet)
Purpose
Loratadine 5 mg........................................................... Antihistamine
Pseudoephedrine sulfate 120 mg......................... Nasal decongestant
Uses
I temporarily relieves these symptoms due to hay fever or other upper
respiratory allergies:
I sneezing
I itchy, watery eyes
I runny nose
I itching of the nose or throat
I temporarily relieves nasal congestion due to the common cold, hay
fever or other upper respiratory allergies
I reduces swelling of nasal passages
I temporarily relieves sinus congestion and pressure
I temporarily restores freer breathing through the nose
Warnings
Do not use
I if you have ever had an allergic reaction to this product or any of
its ingredients
I 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 heart disease
I thyroid disease
I high blood pressure
I diabetes
I trouble urinating due to an enlarged prostate gland
I liver or kidney disease. Your doctor should determine if you need
a different dose.
Drug Facts (continued)
When using this product do not take more than directed.
Taking more than directed may cause drowsiness.
Stop use and ask a doctor if
I an allergic reaction to this product occurs. Seek medical help right away.
I symptoms do not improve within 7 days or are accompanied by a fever
I nervousness, dizziness or sleeplessness occurs
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 do not divide, crush, chew or dissolve the tablet
adults and children 12 years
1 tablet every 12 hours; not more
and over
than 2 tablets in 24 hours
children under 12 years of age ask a doctor
consumers with liver or
ask a doctor
kidney disease
Other information
I safety sealed: do not use if the individual blister unit imprinted with
Claritin-D
® 12 Hr. is open or torn
I store between 15° to 25° C (59° to 77° F)
I keep in a dry place
Inactive ingredients
acacia, butylparaben, calcium sulfate, carnauba wax, corn starch, lactose,
magnesium stearate, microcrystalline cellulose, neutral soap, oleic acid,
pharmaceutical ink, povidone, rosin, sugar, talc, titanium dioxide, white
wax, zein
Questions or comments?
1-800-CLARITIN (1-800-252-7484) or www
www.claritin.com
SEE NEW USE
ANDERSON DIE
Glue
No Varnish
No Varnish
No Varnish
Code Area
No Varnish
No Ink
STANDARD FORMAT
Helvetica Condensed
Variable horizontal scale adheres to 39 characters
per inch
Drug Facts - 9 pt Helvetica Cnd. Bold Italic
Drug Facts (continued)
Drug Facts - 8 pt Helvetica Cnd. Bold Italic
(continued) - 8 pt Helvetica Cnd.
Headings - 8 pt Helvetica Cnd. Bold Italic
Sub Heads -6 pt Helvetica Cnd. Bold
Text - 6 pt Helvetica Cnd, minimum leading 6.5
Square Bullets - 3.5 pt Zaph Dingbats no compression
Border - 1 pt rule, 3/64" gap all around
Barline - 1 pt rule
Hairline - .5 pt rule
Certified by: ___________________
___________________
___________________
ATTACH LEGEND ON ALL
DIGITAL MECHANICALS
SJ
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Pseudoephedrine Sulfate 240 mg/Nasal Decongestant
Loratadine 10 mg/Antihistamine
Non-Drowsy*
NDC 11523-7161-2
EXTENDED
RELEASE TABLETS
EXTENDED
RELEASE TABLETS
*When taken as directed.
See Drug Facts Panel.
*When taken as directed.
See Drug Facts Panel.
Actual Size
™
10 DAYS OF RELIEF
EXTENDED
RELEASE TABLETS
10
10 EXTENDED RELEASE TABLETS
© 2002 Distributed by Schering-Plough HealthCare Products, Inc.
Memphis, TN 38151 USA. All rights reserved. XXXXX-XX/XXXXXXXX
U.S. Patent No. 5,314,697
The graphics on the front panel of this carton constitute
trademarks of Schering Corporation.
10 EXTENDED
RELEASE TABLETS
10 EXTENDED
RELEASE TABLETS
10
10
XXXXXXXX
XXXXXXXX
Drug Facts (continued)
Stop use and ask a doctor if
I an allergic reaction to this product occurs. Seek medical help right away.
I symptoms do not improve within 7 days or are accompanied by a fever
I nervousness, dizziness or sleeplessness occurs
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 do not divide, crush, chew or dissolve the tablet
adults and children 12 years
1 tablet daily with a full glass of water;
and over
not more than 1 tablet in 24 hours
children under 12 years of age ask a doctor
consumers with liver or
ask a doctor
kidney disease
Other information
I safety sealed: do not use if the individual blister unit imprinted with
Claritin-D
® 24 hour is open or torn
I store between 20° C to 25° C (68° F to 77° F)
I protect from light and store in a dry place
Inactive ingredients
carnauba wax, dibasic calcium phosphate, ethylcellulose,
hydroxypropyl cellulose, hypromellose, magnesium stearate,
pharmaceutical ink, polyethylene glycol, povidone, silicon dioxide,
sugar, titanium dioxide, white wax
Questions or comments?
1-800-CLARITIN (1-800-252-7484) or www
www.claritin.com
Drug Facts
Active ingredients (in each tablet)
Purpose
Loratadine 10 mg.........................................................Antihistamine
Pseudoephedrine sulfate 240 mg.........................Nasal decongestant
Uses
I temporarily relieves these symptoms due to hay fever or other upper
respiratory allergies:
I sneezing
I itchy, watery eyes
I runny nose
I itching of the nose or throat
I temporarily relieves nasal congestion due to the common cold, hay
fever or other upper respiratory allergies
I reduces swelling of nasal passages
I temporarily relieves sinus congestion and pressure
I temporarily restores freer breathing through the nose
Warnings
Do not use
I if you have ever had an allergic reaction to this product or any of
its ingredients
I 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 heart disease
I thyroid disease
I high blood pressure
I diabetes
I trouble urinating due to an enlarged prostate gland
I liver or kidney disease. Your doctor should determine if you need
a different dose.
When using this product do not take more than directed.
Taking more than directed may cause drowsiness.
0
1
41100 08043
Relief of:
Nasal and Sinus Congestion
Due to Colds or Allergies;
Sneezing; Runny Nose; Itchy, Watery Eyes
Itchy Throat or Nose Due to Allergies
Allergy & Congestion
SEE NEW USE
CODE AREA
CODE AREA
Glue
NO VARNISH
NO INK - NO VARNISH
NO INK - NO VARNISH
STANDARD FORMAT
Helvetica Condensed
Variable horizontal scale adheres to 39 characters
per inch
Drug Facts - 9 pt Helvetica Cnd. Bold Italic
Drug Facts (continued)
Drug Facts - 8 pt Helvetica Cnd. Bold Italic
(continued) - 8 pt Helvetica Cnd.
Headings - 8 pt Helvetica Cnd. Bold Italic
Sub Heads -6 pt Helvetica Cnd. Bold
Text - 6 pt Helvetica Cnd, minimum leading 6.5
Square Bullets - 3.5 pt Zaph Dingbats no compression
Border - 1 pt rule, 3/64" gap all around
Barline - 1 pt rule
Hairline - .5 pt rule
Certified by: ___________________
___________________
___________________
ATTACH LEGEND ON ALL
DIGITAL MECHANICALS
sj
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:40.846219
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/19670s019,20470s022lbl.pdf', 'application_number': 19670, 'submission_type': 'SUPPL ', 'submission_number': 19}
|
11,616
|
CARDURA®
(doxazosin mesylate)
Tablets
DESCRIPTION
CARDURA® (doxazosin mesylate) is a quinazoline compound that is a selective inhibitor of
the alpha1 subtype of alpha-adrenergic receptors. The chemical name of doxazosin mesylate is
1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4-benzodioxan-2-ylcarbonyl) piperazine
methanesulfonate. The empirical formula for doxazosin mesylate is C23H25N5O5 • CH4O3S and
the molecular weight is 547.6. It has the following structure:
O
H3CO
O
N
N
N
C
O
CH SO H
3
3
N
H3CO
NH2
CARDURA (doxazosin mesylate) is freely soluble in dimethylsulfoxide, soluble in
dimethylformamide, slightly soluble in methanol, ethanol, and water (0.8% at 25°C), and very
slightly soluble in acetone and methylene chloride. CARDURA is available as colored tablets
for oral use and contains 1 mg (white), 2 mg (yellow), 4 mg (orange) and 8 mg (green) of
doxazosin as the free base.
The inactive ingredients for all tablets are: microcrystalline cellulose, lactose, sodium starch
glycolate, magnesium stearate and sodium lauryl sulfate. The 2 mg tablet contains D & C
yellow 10 and FD & C yellow 6; the 4 mg tablet contains FD & C yellow 6; the 8 mg tablet
contains FD & C blue 10 and D & C yellow 10.
1
Reference ID: 3402675
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CLINICAL PHARMACOLOGY
Pharmacodynamics
A. Benign Prostatic Hyperplasia (BPH)
Benign prostatic hyperplasia (BPH) is a common cause of urinary outflow obstruction in aging
males. Severe BPH may lead to urinary retention and renal damage. A static and a dynamic
component contribute to the symptoms and reduced urinary flow rate associated with BPH.
The static component is related to an increase in prostate size caused, in part, by a proliferation
of smooth muscle cells in the prostatic stroma. However, the severity of BPH symptoms and
the degree of urethral obstruction do not correlate well with the size of the prostate. The
dynamic component of BPH is associated with an increase in smooth muscle tone in the
prostate and bladder neck. The degree of tone in this area is mediated by the alpha1
adrenoceptor, which is present in high density in the prostatic stroma, prostatic capsule and
bladder neck. Blockade of the alpha1 receptor decreases urethral resistance and may relieve the
obstruction and BPH symptoms. In the human prostate, CARDURA antagonizes phenylephrine
(alpha1 agonist)-induced contractions, in vitro, and binds with high affinity to the alpha1c
adrenoceptor. The receptor subtype is thought to be the predominant functional type in the
prostate. CARDURA acts within 1–2 weeks to decrease the severity of BPH symptoms and
improve urinary flow rate. Since alpha1 adrenoceptors are of low density in the urinary bladder
(apart from the bladder neck), CARDURA should maintain bladder contractility.
The efficacy of CARDURA was evaluated extensively in over 900 patients with BPH in
double-blind, placebo-controlled trials. CARDURA treatment was superior to placebo in
improving patient symptoms and urinary flow rate. Significant relief with CARDURA was
seen as early as one week into the treatment regimen, with CARDURA-treated patients
(N=173) showing a significant (p<0.01) increase in maximum flow rate of 0.8 mL/sec
compared to a decrease of 0.5 mL/sec in the placebo group (N=41). In long-term studies,
improvement was maintained for up to 2 years of treatment. In 66–71% of patients,
improvements above baseline were seen in both symptoms and maximum urinary flow rate.
In three placebo-controlled studies of 14–16 weeks’ duration, obstructive symptoms (hesitation,
intermittency, dribbling, weak urinary stream, incomplete emptying of the bladder) and
irritative symptoms (nocturia, daytime frequency, urgency, burning) of BPH were evaluated at
each visit by patient-assessed symptom questionnaires. The bothersomeness of symptoms was
measured with a modified Boyarsky questionnaire. Symptom severity/frequency was assessed
using a modified Boyarsky questionnaire or an AUA-based questionnaire. Uroflowmetric
evaluations were performed at times of peak (2–6 hours post-dose) and/or trough (24 hours
post-dose) plasma concentrations of CARDURA.
The results from the three placebo-controlled studies (N=609) showing significant efficacy
with 4 mg and 8 mg doxazosin are summarized in Table 1. In all three studies, CARDURA
resulted in statistically significant relief of obstructive and irritative symptoms compared to
placebo. Statistically significant improvements of 2.3–3.3 mL/sec in maximum flow rate were
seen with CARDURA in Studies 1 and 2, compared to 0.1–0.7 mL/sec with placebo.
2
Reference ID: 3402675
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
In one fixed-dose study (Study 2), CARDURA therapy (4–8 mg, once daily) resulted in a
significant and sustained improvement in maximum urinary flow rate of 2.3–3.3 mL/sec (Table
1) compared to placebo (0.1 mL/sec). In this study, the only study in which weekly evaluations
were made, significant improvement with CARDURA vs. placebo was seen after one week.
The proportion of patients who responded with a maximum flow rate improvement of
≥3 mL/sec was significantly larger with CARDURA (34–42%) than placebo (13–17%). A
significantly greater improvement was also seen in average flow rate with CARDURA
(1.6 mL/sec) than with placebo (0.2 mL/sec). The onset and time course of symptom relief and
increased urinary flow from Study 1 are illustrated in Figure 1.
3
Reference ID: 3402675
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Figure 1 – Study 1
In BPH patients (N=450) treated for up to 2 years in open-label studies, CARDURA therapy
resulted in significant improvement above baseline in urinary flow rates and BPH symptoms.
The significant effects of CARDURA were maintained over the entire treatment period.
Although blockade of alpha1 adrenoceptors also lowers blood pressure in hypertensive patients
with increased peripheral vascular resistance, CARDURA treatment of normotensive men with
BPH did not result in a clinically significant blood pressure lowering effect (Table 2). The
proportion of normotensive patients with a sitting systolic blood pressure less than 90 mmHg
and/or diastolic blood pressure less than 60 mmHg at any time during treatment with
CARDURA 1–8 mg once daily was 6.7% with doxazosin and not significantly different
(statistically) from that with placebo (5%).
TABLE 2
Mean Changes in Blood Pressure from Baseline to the Mean of the Final Efficacy Phase in
Normotensives (Diastolic BP <90 mmHg) in Two Double-blind, Placebo-controlled U.S.
Studies with CARDURA 1–8 mg once daily.
PLACEBO (N=85)
CARDURA (N=183)
Sitting BP (mmHg)
Baseline
Change
Baseline
Change
Systolic
128.4
–1.4
128.8
–4.9*
Diastolic
79.2
–1.2
79.6
–2.4*
Standing BP (mmHg)
Baseline
Change
Baseline
Change
Systolic
128.5
–0.6
128.5
–5.3*
Diastolic
80.5
–0.7
80.4
–2.6*
*p ≤0.05 compared to placebo
4
Reference ID: 3402675
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
B. Hypertension
The mechanism of action of CARDURA is selective blockade of the alpha1 (postjunctional)
subtype of adrenergic receptors. Studies in normal human subjects have shown that doxazosin
competitively antagonized the pressor effects of phenylephrine (an alpha1 agonist) and the
systolic pressor effect of norepinephrine. Doxazosin and prazosin have similar abilities to
antagonize phenylephrine. The antihypertensive effect of CARDURA results from a decrease in
systemic vascular resistance. The parent compound doxazosin is primarily responsible for the
antihypertensive activity. The low plasma concentrations of known active and inactive
metabolites of doxazosin (2-piperazinyl, 6'- and 7'-hydroxy and 6- and 7-O-desmethyl
compounds) compared to parent drug indicate that the contribution of even the most potent
compound (6'-hydroxy) to the antihypertensive effect of doxazosin in man is probably small.
The 6'- and 7'-hydroxy metabolites have demonstrated antioxidant properties at concentrations
of 5 µM, in vitro.
Administration of CARDURA results in a reduction in systemic vascular resistance. In patients
with hypertension, there is little change in cardiac output. Maximum reductions in blood
pressure usually occur 2–6 hours after dosing and are associated with a small increase in
standing heart rate. Like other alpha1-adrenergic blocking agents, doxazosin has a greater
effect on blood pressure and heart rate in the standing position.
In a pooled analysis of placebo-controlled hypertension studies with about 300 hypertensive
patients per treatment group, doxazosin, at doses of 1–16 mg given once daily, lowered blood
pressure at 24 hours by about 10/8 mmHg compared to placebo in the standing position and
about 9/5 mmHg in the supine position. Peak blood pressure effects (1–6 hours) were larger by
about 50–75% (i.e., trough values were about 55–70% of peak effect), with the larger
peak-trough differences seen in systolic pressures. There was no apparent difference in the
blood pressure response of Caucasians and blacks or of patients above and below age 65. In
these predominantly normocholesterolemic patients, doxazosin produced small reductions in
total serum cholesterol (2–3%), LDL cholesterol (4%), and a similarly small increase in
HDL/total cholesterol ratio (4%). The clinical significance of these findings is uncertain. In the
same patient population, patients receiving CARDURA gained a mean of 0.6 kg compared to a
mean loss of 0.1 kg for placebo patients.
Pharmacokinetics
After oral administration of therapeutic doses, peak plasma levels of CARDURA occur at
about 2–3 hours. Bioavailability is approximately 65%, reflecting first-pass metabolism of
doxazosin by the liver. The effect of food on the pharmacokinetics of CARDURA was
examined in a crossover study with twelve hypertensive subjects. Reductions of 18% in mean
maximum plasma concentration and 12% in the area under the concentration-time curve
occurred when CARDURA was administered with food. Neither of these differences was
statistically or clinically significant.
CARDURA is extensively metabolized in the liver, mainly by O-demethylation of the
quinazoline nucleus or hydroxylation of the benzodioxan moiety. Although several active
5
Reference ID: 3402675
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
metabolites of doxazosin have been identified, the pharmacokinetics of these metabolites have
not been characterized. In a study of two subjects administered radiolabelled doxazosin 2 mg
orally and 1 mg intravenously on two separate occasions, approximately 63% of the dose was
eliminated in the feces and 9% of the dose was found in the urine. On average only 4.8% of
the dose was excreted as unchanged drug in the feces and only a trace of the total radioactivity
in the urine was attributed to unchanged drug. At the plasma concentrations achieved by
therapeutic doses, approximately 98% of the circulating drug is bound to plasma proteins.
Plasma elimination of doxazosin is biphasic, with a terminal elimination half-life of about
22 hours. Steady-state studies in hypertensive patients given doxazosin doses of 2–16 mg once
daily showed linear kinetics and dose proportionality. In two studies, following the
administration of 2 mg orally once daily, the mean accumulation ratios (steady-state AUC vs.
first-dose AUC) were 1.2 and 1.7. Enterohepatic recycling is suggested by secondary peaking
of plasma doxazosin concentrations.
In a crossover study in 24 normotensive subjects, the pharmacokinetics and safety of doxazosin
were shown to be similar with morning and evening dosing regimens. The area under the curve
after morning dosing was, however, 11% less than that after evening dosing and the time to
peak concentration after evening dosing occurred significantly later than that after morning
dosing (5.6 hr vs. 3.5 hr).
The pharmacokinetics of CARDURA in young (<65 years) and elderly (≥65 years) subjects
were similar for plasma half-life values and oral clearance. Pharmacokinetic studies in elderly
patients and patients with renal impairment have shown no significant alterations compared to
younger patients with normal renal function. Administration of a single 2 mg dose to patients
with cirrhosis (Child-Pugh Class A) showed a 40% increase in exposure to doxazosin. There
are only limited data on the effects of drugs known to influence the hepatic metabolism of
doxazosin [e.g., cimetidine (see PRECAUTIONS, Drug Interactions)]. As with any drug
wholly metabolized by the liver, use of CARDURA in patients with altered liver function
should be undertaken with caution.
In two placebo-controlled studies of normotensive and hypertensive BPH patients, in which
doxazosin was administered in the morning and the titration interval was two weeks and one
week, respectively, trough plasma concentrations of CARDURA were similar in the two
populations. Linear kinetics and dose proportionality were observed.
INDICATIONS AND USAGE
A. Benign Prostatic Hyperplasia (BPH). CARDURA is indicated for the treatment of both the
urinary outflow obstruction and obstructive and irritative symptoms associated with BPH:
obstructive symptoms (hesitation, intermittency, dribbling, weak urinary stream, incomplete
emptying of the bladder) and irritative symptoms (nocturia, daytime frequency, urgency,
burning). CARDURA may be used in all BPH patients whether hypertensive or normotensive.
In patients with hypertension and BPH, both conditions were effectively treated with
6
Reference ID: 3402675
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CARDURA monotherapy. CARDURA provides rapid improvement in symptoms and urinary
flow rate in 66–71% of patients. Sustained improvements with CARDURA were seen in
patients treated for up to 14 weeks in double-blind studies and up to 2 years in open-label
studies.
B. Hypertension. CARDURA is indicated for the treatment of hypertension, to lower blood
pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events,
primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials
of antihypertensive drugs from a wide variety of pharmacologic classes, including this drug.
Control of high blood pressure should be part of comprehensive cardiovascular risk
management, including, as appropriate, lipid control, diabetes management, antithrombotic
therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require
more than one drug to achieve blood pressure goals. For specific advice on goals and
management, see published guidelines, such as those of the National High Blood Pressure
Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different
mechanisms of action, have been shown in randomized controlled trials to reduce
cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure
reduction, and not some other pharmacologic property of the drugs, that is largely responsible
for those benefits. The largest and most consistent cardiovascular outcome benefit has been a
reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular
mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute
risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of
severe hypertension can provide substantial benefit. Relative risk reduction from blood
pressure reduction is similar across populations with varying absolute risk, so the absolute
benefit is greater in patients who are at higher risk independent of their hypertension (for
example, patients with diabetes or hyperlipidemia), and such patients would be expected to
benefit from more aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black
patients, and many antihypertensive drugs have additional approved indications and effects
(e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide
selection of therapy.
CARDURA may be used alone or in combination with diuretics, beta-adrenergic blocking
agents, calcium channel blockers, or angiotensin-converting enzyme inhibitors.
7
Reference ID: 3402675
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
CONTRAINDICATIONS
CARDURA is contraindicated in patients with a known sensitivity to quinazolines (e.g.,
prazosin, terazosin), doxazosin, or any of the inert ingredients.
WARNINGS
Syncope and “First-dose” Effect: Doxazosin, like other alpha-adrenergic blocking agents,
can cause marked hypotension, especially in the upright position, with syncope and other
postural symptoms such as dizziness. Marked orthostatic effects are most common with
the first dose but can also occur when there is a dosage increase, or if therapy is
interrupted for more than a few days. To decrease the likelihood of excessive hypotension
and syncope, it is essential that treatment be initiated with the 1 mg dose. The 2, 4, and
8 mg tablets are not for initial therapy. Dosage should then be adjusted slowly (see
DOSAGE AND ADMINISTRATION), with evaluations and increases in dose every two
weeks to the recommended dose. Additional antihypertensive agents should be added with
caution.
Patients being titrated with doxazosin should be cautioned to avoid situations where
injury could result should syncope occur, during both the day and night.
In an early investigational study of the safety and tolerance of increasing daily doses of
doxazosin in normotensives beginning at 1 mg/day, only 2 of 6 subjects could tolerate more
than 2 mg/day without experiencing symptomatic postural hypotension. In another study of
24 healthy normotensive male subjects receiving initial doses of 2 mg/day of doxazosin, seven
(29%) of the subjects experienced symptomatic postural hypotension between 0.5 and 6 hours
after the first dose, necessitating termination of the study. In this study, 2 of the normotensive
subjects experienced syncope. Subsequent trials in hypertensive patients always began
doxazosin dosing at 1 mg/day, resulting in a 4% incidence of postural side effects at 1 mg/day
with no cases of syncope.
In multiple-dose clinical trials in hypertension involving over 1500 hypertensive patients with
dose titration every one to two weeks, syncope was reported in 0.7% of patients. None of
these events occurred at the starting dose of 1 mg, and 1.2% (8/664) occurred at 16 mg/day.
In placebo-controlled clinical trials in BPH, 3 out of 665 patients (0.5%) taking doxazosin
reported syncope. Two of the patients were taking 1 mg doxazosin, while one patient was
taking 2 mg doxazosin when syncope occurred. In the open-label, long-term extension
follow-up of approximately 450 BPH patients, there were 3 reports of syncope (0.7%). One
patient was taking 2 mg, one patient was taking 8 mg, and one patient was taking 12 mg when
syncope occurred. In a clinical pharmacology study, one subject receiving 2 mg experienced
syncope.
8
Reference ID: 3402675
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
If syncope occurs, the patient should be placed in a recumbent position and treated
supportively as necessary.
Priapism: Rarely (probably less frequently than once in every several thousand patients),
alpha1 antagonists, including doxazosin, have been associated with priapism (painful penile
erection, sustained for hours and unrelieved by sexual intercourse or masturbation). Because
this condition can lead to permanent impotence if not promptly treated, patients must be
advised about the seriousness of the condition (see PRECAUTIONS, Information for Patients).
PRECAUTIONS
General:
Prostate Cancer: Carcinoma of the prostate causes many of the symptoms associated with
BPH and the two disorders frequently co-exist. Carcinoma of the prostate should therefore be
ruled out prior to commencing therapy with CARDURA.
Cataract Surgery: Intraoperative Floppy Iris Syndrome (IFIS) has been observed during
cataract surgery in some patients on or previously treated with alpha1 blockers. This variant of
small pupil syndrome is characterized by the combination of a flaccid iris that billows in
response to intraoperative irrigation currents, progressive intraoperative miosis despite
preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the
phacoemulsification incisions. The patient’s surgeon should be prepared for possible
modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or
viscoelastic substances. There does not appear to be a benefit of stopping alpha1 blocker therapy
prior to cataract surgery.
Orthostatic Hypotension: While syncope is the most severe orthostatic effect of CARDURA,
other symptoms of lowered blood pressure, such as dizziness, lightheadedness, or vertigo can
occur, especially at initiation of therapy or at the time of dose increases.
a) Hypertension
These symptoms were common in clinical trials in hypertension, occurring in up to 23% of all
patients treated and causing discontinuation of therapy in about 2%.
In placebo-controlled titration trials in hypertension, orthostatic effects were minimized by
beginning therapy at 1 mg per day and titrating every two weeks to 2, 4, or 8 mg per day.
There was an increased frequency of orthostatic effects in patients given 8 mg or more, 10%,
compared to 5% at 1–4 mg and 3% in the placebo group.
b) Benign Prostatic Hyperplasia
In placebo-controlled trials in BPH, the incidence of orthostatic hypotension with doxazosin
was 0.3% and did not increase with increasing dosage (to 8 mg/day). The incidence of
discontinuations due to hypotensive or orthostatic symptoms was 3.3% with doxazosin and 1%
with placebo. The titration interval in these studies was one to two weeks.
9
Reference ID: 3402675
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Patients in occupations in which orthostatic hypotension could be dangerous should be treated
with particular caution. As alpha1 antagonists can cause orthostatic effects, it is important to
evaluate standing blood pressure two minutes after standing, and patients should be advised to
exercise care when arising from a supine or sitting position.
If hypotension occurs, the patient should be placed in the supine position and, if this measure is
inadequate, volume expansion with intravenous fluids or vasopressor therapy may be used. A
transient hypotensive response is not a contraindication to further doses of CARDURA.
Information for Patients (See patient package insert): Patients should be made aware of the
possibility of syncopal and orthostatic symptoms, especially at the initiation of therapy, and
urged to avoid driving or hazardous tasks for 24 hours after the first dose, after a dosage
increase, and after interruption of therapy when treatment is resumed. They should be
cautioned to avoid situations where injury could result should syncope occur during initiation
of doxazosin therapy. They should also be advised of the need to sit or lie down when
symptoms of lowered blood pressure occur, although these symptoms are not always
orthostatic, and to be careful when rising from a sitting or lying position. If dizziness,
lightheadedness, or palpitations are bothersome, they should be reported to the physician, so
that dose adjustment can be considered. Patients should also be told that drowsiness or
somnolence can occur with CARDURA or any selective alpha1 adrenoceptor antagonist,
requiring caution in people who must drive or operate heavy machinery.
Patients should be advised about the possibility of priapism as a result of treatment with alpha1
antagonists. Patients should know that this adverse event is very rare. If they experience
priapism, it should be brought to immediate medical attention, for, if not treated promptly, it
can lead to permanent erectile dysfunction (impotence).
Drug/Laboratory Test Interactions: CARDURA does not affect the plasma concentration of
prostate-specific antigen in patients treated for up to 3 years. Both doxazosin, an alpha1
inhibitor, and finasteride, a 5-alpha reductase inhibitor, are highly protein-bound and
hepatically metabolized. There is no definitive controlled clinical experience on the
concomitant use of alpha1 inhibitors and 5-alpha reductase inhibitors at this time.
Impaired Liver Function: CARDURA should be administered with caution to patients with
evidence of impaired hepatic function, or to patients receiving drugs known to influence
hepatic metabolism (see CLINICAL PHARMACOLOGY, Pharmacokinetics).
Leukopenia/Neutropenia: Analysis of hematologic data from hypertensive patients receiving
CARDURA in controlled hypertension clinical trials showed that the mean WBC (N=474) and
mean neutrophil counts (N=419) were decreased by 2.4% and 1.0%, respectively, compared
to placebo, a phenomenon seen with other alpha-blocking drugs. In BPH patients, the
incidence of clinically significant WBC abnormalities was 0.4% (2/459) with CARDURA and
0% (0/147) with placebo, with no statistically significant difference between the two treatment
groups. A search through a data base of 2400 hypertensive patients and 665 BPH patients
10
Reference ID: 3402675
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
revealed 4 hypertensives in which drug-related neutropenia could not be ruled out and one
BPH patient in which drug-related leukopenia could not be ruled out. Two hypertensives had a
single low value on the last day of treatment. Two hypertensives had stable, non-progressive
neutrophil counts in the 1000/mm3 range over periods of 20 and 40 weeks. One BPH patient had
a decrease from a WBC count of 4800/mm3 to 2700/mm3 at the end of the study; there was no
evidence of clinical impairment. In cases where follow-up was available, the WBCs and
neutrophil counts returned to normal after discontinuation of CARDURA. No patients became
symptomatic as a result of the low WBC or neutrophil counts.
Drug Interactions: Most (98%) of plasma doxazosin is protein bound. In vitro data in human
plasma indicate that CARDURA has no effect on protein binding of digoxin, warfarin,
phenytoin, or indomethacin. There is no information on the effect of other highly plasma
protein- bound drugs on doxazosin binding. CARDURA has been administered without any
evidence of an adverse drug interaction to patients receiving thiazide diuretics, beta-blocking
agents, and nonsteroidal anti-inflammatory drugs. In a placebo-controlled trial in normal
volunteers, the administration of a single 1 mg dose of doxazosin on day 1 of a four-day
regimen of oral cimetidine (400 mg twice daily) resulted in a 10% increase in mean AUC of
doxazosin (p=0.006), and a slight but not statistically significant increase in mean Cmax and
mean half-life of doxazosin. The clinical significance of this increase in doxazosin AUC is
unknown.
In clinical trials, CARDURA tablets have been administered to patients on a variety of
concomitant medications; while no formal interaction studies have been conducted, no
interactions were observed. CARDURA tablets have been used with the following drugs or
drug classes: 1) analgesic/anti-inflammatory (e.g., acetaminophen, aspirin, codeine and
codeine combinations, ibuprofen, indomethacin); 2) antibiotics (e.g., erythromycin,
trimethoprim and sulfamethoxazole, amoxicillin); 3) antihistamines (e.g., chlorpheniramine);
4) cardiovascular agents (e.g., atenolol, hydrochlorothiazide, propranolol); 5) corticosteroids;
6) gastrointestinal agents (e.g., antacids); 7) hypoglycemics and endocrine drugs; 8) sedatives
and tranquilizers (e.g., diazepam); 9) cold and flu remedies.
Concomitant administration of CARDURA with a phosphodiesterase-5 (PDE-5) inhibitor can
result in additive blood pressure lowering effects and symptomatic hypotension (see DOSAGE
AND ADMINISTRATION).
Cardiac Toxicity in Animals: An increased incidence of myocardial necrosis or fibrosis was
displayed by Sprague-Dawley rats after 6 months of dietary administration at concentrations
calculated to provide 80 mg doxazosin/kg/day, and after 12 months of dietary administration at
concentrations calculated to provide 40 mg doxazosin/kg/day (AUC exposure in rats 8 times
the human AUC exposure with a 12 mg/day therapeutic dose). Myocardial fibrosis was
observed in both rats and mice treated in the same manner with 40 mg doxazosin/kg/day for
18 months (exposure 8 times human AUC exposure in rats and somewhat equivalent to human
Cmax exposure in mice). No cardiotoxicity was observed at lower doses (up to 10 or
20 mg/kg/day, depending on the study) in either species. These lesions were not observed after
12 months of oral dosing in dogs at maximum doses of 20 mg/kg/day [maximum plasma
11
Reference ID: 3402675
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
concentrations (Cmax) in dogs 14 times the Cmax exposure in humans receiving a 12 mg/day
therapeutic dose] and in Wistar rats at doses of 100 mg/kg/day (Cmax exposures 15 times human
Cmax exposure with a 12 mg/day therapeutic dose). There is no evidence that similar lesions
occur in humans.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Chronic dietary administration (up to
24 months) of doxazosin mesylate at maximally tolerated doses of 40 mg/kg/day in rats and
120 mg/kg/day in mice revealed no evidence of carcinogenic potential. The highest doses
evaluated in the rat and mouse studies are associated with AUCs (a measure of systemic
exposure) that are 8 times and 4 times, respectively, the human AUC at a dose of 16 mg/day.
Mutagenicity studies revealed no drug- or metabolite-related effects at either chromosomal or
subchromosomal levels.
Studies in rats showed reduced fertility in males treated with doxazosin at oral doses of 20 (but
not 5 or 10) mg/kg/day, about 4 times the AUC exposures obtained with a 12 mg/day human
dose. This effect was reversible within two weeks of drug withdrawal. There have been no
reports of any effects of doxazosin on male fertility in humans.
Pregnancy: Teratogenic Effects, Pregnancy Category C. Studies in pregnant rabbits and rats
at daily oral doses of up to 41 and 20 mg/kg, respectively (plasma drug concentrations 10 and
4 times human Cmax and AUC exposures with a 12 mg/day therapeutic dose), have revealed no
evidence of harm to the fetus. A dosage regimen of 82 mg/kg/day in the rabbit was associated
with reduced fetal survival. There are no adequate and well-controlled studies in pregnant
women. Because animal reproduction studies are not always predictive of human response,
CARDURA should be used during pregnancy only if clearly needed.
Radioactivity was found to cross the placenta following oral administration of labelled
doxazosin to pregnant rats.
Nonteratogenic Effects: In peri-postnatal studies in rats, postnatal development at maternal
doses of 40 or 50 mg/kg/day of doxazosin (8 times human AUC exposure with a 12 mg/day
therapeutic dose) was delayed, as evidenced by slower body weight gain and slightly later
appearance of anatomical features and reflexes.
Nursing Mothers: Studies in lactating rats given a single oral dose of 1 mg/kg of
[2-14C]-CARDURA indicate that doxazosin accumulates in rat breast milk with a maximum
concentration about 20 times greater than the maternal plasma concentration. 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 CARDURA is administered to a nursing mother.
Pediatric Use: The safety and effectiveness of CARDURA as an antihypertensive agent have
not been established in children.
12
Reference ID: 3402675
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Geriatric Use: The safety and effectiveness profile of CARDURA in BPH was similar in the
elderly (age ≥ 65 years) and younger (age < 65 years) patients.
For hypertension: Clinical studies of CARDURA 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
A. Benign Prostatic Hyperplasia (BPH)
The incidence of adverse events has been ascertained from worldwide clinical trials in
965 BPH patients. The incidence rates presented below (Table 3) are based on combined data
from seven placebo-controlled trials involving once-daily administration of CARDURA in
doses of 1–16 mg in hypertensives and 0.5–8 mg in normotensives. The adverse events when
the incidence in the CARDURA group was at least 1% are summarized in Table 3. No
significant difference in the incidence of adverse events compared to placebo was seen except
for dizziness, fatigue, hypotension, edema, and dyspnea. Dizziness and dyspnea appeared to be
dose-related.
13
Reference ID: 3402675
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
TABLE 3
ADVERSE REACTIONS DURING PLACEBO-CONTROLLED
STUDIES
BENIGN PROSTATIC HYPERPLASIA
CARDURA
PLACEBO
Body System
(N=665)
(N=300)
BODY AS A WHOLE
Back Pain
1.8%
2.0%
Chest Pain
1.2%
0.7%
Fatigue
8.0%*
1.7%
Headache
9.9%
9.0%
Influenza-like Symptoms
1.1%
1.0%
Pain
2.0%
1.0%
CARDIOVASCULAR SYSTEM
Hypotension
1.7%*
0.0%
Palpitation
1.2%
0.3%
DIGESTIVE SYSTEM
Abdominal Pain
2.4%
2.0%
Diarrhea
2.3%
2.0%
Dyspepsia
1.7%
1.7%
Nausea
1.5%
0.7%
METABOLIC AND NUTRITIONAL
DISORDERS
Edema
2.7%*
0.7%
NERVOUS SYSTEM
Dizziness†
15.6%*
9.0%
Mouth Dry
1.4%
0.3%
Somnolence
3.0%
1.0%
RESPIRATORY SYSTEM
Dyspnea
2.6%*
0.3%
Respiratory Disorder
1.1%
0.7%
SPECIAL SENSES
Vision Abnormal
1.4%
0.7%
UROGENITAL SYSTEM
Impotence
1.1%
1.0%
Urinary Tract Infection
1.4%
2.3%
SKIN & APPENDAGES
Sweating Increased
1.1%
1.0%
PSYCHIATRIC DISORDERS
Anxiety
1.1%
0.3%
Insomnia
1.2%
0.3%
*p ≤0.05 for treatment differences
†Includes vertigo
In these placebo-controlled studies of 665 CARDURA patients treated for a mean of 85 days,
additional adverse reactions have been reported. These are less than 1% and not distinguishable
from those that occurred in the placebo group. Adverse reactions with an incidence of less than
1% but of clinical interest are (CARDURA vs. placebo): Cardiovascular System: angina
pectoris (0.6% vs. 0.7%), postural hypotension (0.3% vs. 0.3%), syncope (0.5% vs. 0.0%),
14
Reference ID: 3402675
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
tachycardia (0.9% vs. 0.0%); Urogenital System: dysuria (0.5% vs. 1.3%); and Psychiatric
Disorders: libido decreased (0.8% vs. 0.3%). The safety profile in patients treated for up to
three years was similar to that in the placebo-controlled studies.
The majority of adverse experiences with CARDURA were mild.
B. Hypertension
CARDURA has been administered to approximately 4000 hypertensive patients, of whom 1679
were included in the hypertension clinical development program. In that program, minor
adverse effects were frequent, but led to discontinuation of treatment in only 7% of patients. In
placebo-controlled studies, adverse effects occurred in 49% and 40% of patients in the
doxazosin and placebo groups, respectively, and led to discontinuation in 2% of patients in
each group. The major reasons for discontinuation were postural effects (2%), edema,
malaise/fatigue, and some heart rate disturbance, each about 0.7%.
In controlled hypertension clinical trials directly comparing CARDURA to placebo, there was
no significant difference in the incidence of side effects, except for dizziness (including
postural), weight gain, somnolence, and fatigue/malaise. Postural effects and edema appeared
to be dose-related. The prevalence rates presented below are based on combined data from
placebo-controlled studies involving once-daily administration of doxazosin at doses ranging
from 1–16 mg. Table 4 summarizes those adverse experiences (possibly/probably related)
reported for patients in these hypertension studies where the prevalence rate in the doxazosin
group was at least 0.5% or where the reaction is of particular interest.
15
Reference ID: 3402675
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
TABLE 4
ADVERSE REACTIONS DURING PLACEBO-CONTROLLED STUDIES
HYPERTENSION
DOXAZOSIN
PLACEBO
(N=339)
(N=336)
CARDIOVASCULAR SYSTEM
Dizziness
19%
9%
Vertigo
2%
1%
Postural Hypotension
0.3%
0%
Edema
4%
3%
Palpitation
2%
3%
Arrhythmia
1%
0%
Hypotension
1%
0%
Tachycardia
0.3%
1%
Peripheral Ischemia
0.3%
0%
SKIN & APPENDAGES
Rash
1%
1%
Pruritus
1%
1%
MUSCULOSKELETAL SYSTEM
Arthralgia/Arthritis
1%
0%
Muscle Weakness
1%
0%
Myalgia
1%
0%
CENTRAL & PERIPHERAL N.S.
Headache
14%
16%
Paresthesia
1%
1%
Kinetic Disorders
1%
0%
Ataxia
1%
0%
Hypertonia
1%
0%
Muscle Cramps
1%
0%
AUTONOMIC
Mouth Dry
2%
2%
Flushing
1%
0%
SPECIAL SENSES
Vision Abnormal
2%
1%
Conjunctivitis/Eye Pain
1%
1%
Tinnitus
1%
0.3%
PSYCHIATRIC
Somnolence
5%
1%
Nervousness
2%
2%
Depression
1%
1%
Insomnia
1%
1%
Sexual Dysfunction
2%
1%
GASTROINTESTINAL
Nausea Diarrhea
3%
4%
Constipation
2%
3%
Dyspepsia
1%
1%
Flatulence
1%
1%
Abdominal Pain
1%
1%
0%
2%
Vomiting
0%
1%
16
Reference ID: 3402675
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
TABLE 4
ADVERSE REACTIONS DURING PLACEBO-CONTROLLED STUDIES
HYPERTENSION
DOXAZOSIN
PLACEBO
(N=339)
(N=336)
RESPIRATORY
Rhinitis
3%
1%
Dyspnea
1%
1%
Epistaxis
1%
0%
URINARY
Polyuria
2%
0%
Urinary Incontinence
1%
0%
Micturition Frequency
0%
2%
GENERAL
Fatigue/Malaise
12%
6%
Chest Pain
2%
2%
Asthenia
1%
1%
Face Edema
1%
0%
Pain
2%
2%
Additional adverse reactions have been reported, but these are, in general, not distinguishable
from symptoms that might have occurred in the absence of exposure to doxazosin. The
following adverse reactions occurred with a frequency of between 0.5% and 1%: syncope,
hypoesthesia, increased sweating, agitation, increased weight. The following additional adverse
reactions were reported by <0.5% of 3960 patients who received doxazosin in controlled or
open, short- or long-term clinical studies, including international studies. Cardiovascular
System: angina pectoris, myocardial infarction, cerebrovascular accident; Autonomic Nervous
System: pallor; Metabolic: thirst, gout, hypokalemia; Hematopoietic: lymphadenopathy,
purpura; Reproductive System: breast pain; Skin Disorders: alopecia, dry skin, eczema;
Central Nervous System: paresis, tremor, twitching, confusion, migraine, impaired
concentration; Psychiatric: paroniria, amnesia, emotional lability, abnormal thinking,
depersonalization; Special Senses: parosmia, earache, taste perversion, photophobia, abnormal
lacrimation; Gastrointestinal System: increased appetite, anorexia, fecal incontinence,
gastroenteritis; Respiratory System: bronchospasm, sinusitis, coughing, pharyngitis; Urinary
System: renal calculus; General Body System: hot flushes, back pain, infection, fever/rigors,
decreased weight, influenza-like symptoms.
CARDURA has not been associated with any clinically significant changes in routine
biochemical tests. No clinically relevant adverse effects were noted on serum potassium, serum
glucose, uric acid, blood urea nitrogen, creatinine or liver function tests. CARDURA has been
associated with decreases in white blood cell counts (see PRECAUTIONS,
Leukopenia/Neutropenia).
In post-marketing experience, the following additional adverse reactions have been reported:
Autonomic Nervous System: priapism; Central Nervous System: hypoesthesia; Endocrine
System: gynecomastia; Gastrointestinal System: vomiting; General Body System: allergic
reaction; Heart Rate/Rhythm: bradycardia; Hematopoietic: leukopenia, thrombocytopenia;
17
Reference ID: 3402675
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Liver/Biliary System: hepatitis, hepatitis cholestatic; Respiratory System: bronchospasm
aggravated; Skin Disorders: urticaria; Special Senses: Intraoperative Floppy Iris Syndrome (see
PRECAUTIONS, Cataract Surgery); Urinary System: hematuria, micturition disorder,
micturition frequency, nocturia.
OVERDOSAGE
Experience with CARDURA overdosage is limited. Two adolescents, who each intentionally
ingested 40 mg CARDURA with diclofenac or acetaminophen, were treated with gastric lavage
with activated charcoal and made full recoveries. A two-year-old child who accidently ingested
4 mg CARDURA was treated with gastric lavage and remained normotensive during the
five-hour emergency room observation period. A six-month-old child accidentally received a
crushed 1 mg tablet of CARDURA and was reported to have been drowsy. A 32-year-old
female with chronic renal failure, epilepsy, and depression intentionally ingested 60 mg
CARDURA (blood level = 0.9 µg/mL; normal values in hypertensives = 0.02 µg/mL); death
was attributed to a grand mal seizure resulting from hypotension. A 39-year-old female who
ingested 70 mg CARDURA, alcohol, and Dalmane® (flurazepam) developed hypotension
which responded to fluid therapy.
The oral LD50 of doxazosin is greater than 1000 mg/kg in mice and rats. The most likely
manifestation of overdosage would be hypotension, for which the usual treatment would be
intravenous infusion of fluid. As doxazosin is highly protein bound, dialysis would not be
indicated.
DOSAGE AND ADMINISTRATION
DOSAGE MUST BE INDIVIDUALIZED. The initial dosage of CARDURA in patients with
hypertension and/or BPH is 1 mg given once daily in the a.m. or p.m. This starting dose is
intended to minimize the frequency of postural hypotension and first-dose syncope associated
with CARDURA. Postural effects are most likely to occur between 2 and 6 hours after a dose.
Therefore, blood pressure measurements should be taken during this time period after the first
dose and with each increase in dose. If CARDURA administration is discontinued for several
days, therapy should be restarted using the initial dosing regimen.
18
Reference ID: 3402675
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
Concomitant administration of CARDURA with a PDE-5 inhibitor can result in additive blood
pressure lowering effects and symptomatic hypotension; therefore, PDE-5 inhibitor therapy
should be initiated at the lowest dose in patients taking CARDURA.
A. BENIGN PROSTATIC HYPERPLASIA 1–8 mg once daily. The initial dosage of
CARDURA is 1 mg, given once daily in the a.m. or p.m. Depending on the individual
patient’s urodynamics and BPH symptomatology, dosage may then be increased to 2 mg and
thereafter to 4 mg and 8 mg once daily, the maximum recommended dose for BPH. The
recommended titration interval is 1–2 weeks. Blood pressure should be evaluated routinely in
these patients.
B. HYPERTENSION 1–16 mg once daily. The initial dosage of CARDURA is 1 mg given
once daily. Depending on the individual patient’s standing blood pressure response (based on
measurements taken at 2–6 hours post-dose and 24 hours post-dose), dosage may then be
increased to 2 mg and thereafter if necessary to 4 mg, 8 mg and 16 mg to achieve the desired
reduction in blood pressure. Increases in dose beyond 4 mg increase the likelihood of
excessive postural effects, including syncope, postural dizziness/vertigo and postural
hypotension. At a titrated dose of 16 mg once daily, the frequency of postural effects is
about 12% compared to 3% for placebo.
HOW SUPPLIED
CARDURA (doxazosin mesylate) is available as colored tablets for oral administration. Each
scored tablet contains doxazosin mesylate equivalent to 1 mg (white), 2 mg (yellow), 4 mg
(orange) or 8 mg (green) of the active constituent, doxazosin.
Bottle of 100:
1 mg (NDC 0049-2750-66)
2 mg (NDC 0049-2760-66)
4 mg (NDC 0049-2770-66)
8 mg (NDC 0049-2780-66)
Unit Dose Package of 100:
1 mg (NDC 0049-2750-41)
2 mg (NDC 0049-2760-41)
4 mg (NDC 0049-2770-41)
8 mg (NDC 0049-2780-41)
Recommended Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)
[see USP Controlled Room Temperature].
Rx only
19
Reference ID: 3402675
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
LAB-0071-4.x
Revised November 2013
20
Reference ID: 3402675
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:40.946894
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019668s026lbl.pdf', 'application_number': 19668, 'submission_type': 'SUPPL ', 'submission_number': 26}
|
11,621
|
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
This label may not be the latest approved by FDA.
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
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
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
©2009, GlaxoSmithKline. All rights reserved.
(Date of issue)
ZNT:4PI
15
This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
|
custom-source
|
2025-02-12T13:45:41.101934
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018703s067,019675s034,020251s018lbl.pdf', 'application_number': 19675, 'submission_type': 'SUPPL ', 'submission_number': 34}
|
11,622
|
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
|
custom-source
|
2025-02-12T13:45:41.221074
|
{'url': 'http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/018703s068,019675s035,020251s019lbl.pdf', 'application_number': 19675, 'submission_type': 'SUPPL ', 'submission_number': 35}
|
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.